Mayo Clinic: Gastroenterology and Hepatology Board

MAYO CLINIC
Gastroenterology and
Hepatology Board Review
Stephen C . Hauser Seth ft, Sweetser
EDITOR - IN - CHIEF
Michael D. Leise
Karthik Ravi
David H. Bruining
A 5 5 0CIATE EDITOR S
'
Mayo Clinic Gastroenterology and Hepatology Board Review
Sixth Edition
MAYO CLINIC SCIENTIFIC PRESS
Mayo Clinic Atlas of Regional Anesthesia and Mayo Clinic Critical and Neurocritical Care
Ultrasound-Guided Nerve Blockade Board Review
Edited by James R. Hebl, MD, and Edited by Eelco F. M. Wijdicks, MD, PhD, James Y.
Robert L. Lennon, DO Findlay, MB, ChB, William D. Freeman, MD, and
Ayan Sen, MD
Mayo Clinic Preventive Medicine and Public Health
Board Review Mayo Clinic Internal Medicine Board Review,
Edited by Prathibha Varkey, MBBS, MPH, MHPE Twelfth Edition
Edited by Christopher M. Wittich, MD, PharmD,
Mayo Clinic Infectious Diseases Board Review
Thomas J. Beckman, MD, Sara L. Bonnes, MD,
Edited by Zelalem Temesgen, MD
Nerissa M. Collins, MD, Nina M. Schwenk, MD,
Just Enough Physiology Christopher R. Stephenson, MD, and Jason H.
By James R. Munis, MD, PhD Szostek, MD
Mayo Clinic Electrophysiology Manual Mayo Clinic Strategies for Reducing Burnout and
Edited by Samuel J. Asirvatham, MD Promoting Engagement
Mayo Clinic Gastrointestinal Imaging Review, By Stephen J. Swensen, MD, and
Second Edition Tait D. Shanafelt, MD
By C. Daniel Johnson, MD Mayo Clinic General Surgery
Arrhythmias in Women: Diagnosis and Management By Jad M. Abdelsattar, MBBS, Moustafa M. El Khatib,
Edited by Yong-Mei Cha, MD, Margaret A. Lloyd, MD, MB, BCh, T. K. Pandian, MD, Samuel J. Allen, and
and Ulrika M. Birgersdotter-Green, MD David R. Farley, MD
Mayo Clinic Body MRI Case Review Mayo Clinic Neurology Board Review, Second Edition
By Christine U. Lee, MD, PhD, and Edited by Kelly D. Flemming, MD
James F. Glockner, MD, PhD Mayo Clinic Illustrated Textbook of
Mayo Clinic Gastroenterology and Hepatology Board Neurogastroenterology
Review, Fifth Edition By Michael Camilleri, MD
Edited by Stephen C. Hauser, MD Mayo Clinic Cases in Neuroimmunology
Mayo Clinic Guide to Cardiac Magnetic Resonance Edited by Andrew McKeon, MB, BCh, MD,
Imaging, Second Edition B. Mark Keegan, MD, and W. Oliver Tobin, MB, BCh,
Edited by Kiaran P. McGee, PhD, Eric E. Williamson, BAO, PhD
MD, and Matthew W. Martinez, MD Mayo Clinic Infectious Diseases Case Review
Mayo Clinic Critical Care Case Review Edited by Larry M. Baddour, MD, John C. O’Horo,
Edited by Rahul Kashyap, MBBS, J. Christopher MD, MPH, Mark J. Enzler, MD, and Rahul
Farmer, MD, and John C. O’Horo, MD Kashyap, MBBS
Mayo Clinic Medical Neurosciences, Sixth Edition Mayo Clinic Cardiology: Concise Textbook,
Edited by Eduardo E. Benarroch, MD, Jeremy K. Fifth Edition
Cutsforth-Gregory, MD, and Kelly D. Flemming, MD Edited by Joseph G. Murphy, MD, Nandan S.
Anavekar, MB, BCh, Barry Boilson, MD,
Mayo Clinic Principles of Shoulder Surgery Margaret A. Lloyd, MD, Rekha Mankad, MD, and
By Joaquin Sanchez-Sotelo, MD Raymond C. Shields, MD
Mayo Clinic Essential Neurology, Second Edition Mayo Clinic Case Review for Pulmonary and Critical
By Andrea C. Adams, MD Care Boards
Mayo Clinic Antimicrobial Handbook: Quick Guide, Edited by Alice Gallo De Moraes, MD, Diana J. Kelm,
Third Edition MD, and Kannan M. Ramar, MBBS
Edited by John W. Wilson, MD, and
Lynn L. Estes, PharmD
Mayo Clinic Gastroenterology
and Hepatology Board Review
SIXTH EDITION
Editor-in-Chief
Stephen C. Hauser, MD
Emeritus Member, Division of Gastroenterology and Hepatology,
Mayo Clinic, Rochester, Minnesota; Emeritus Professor of Medicine,
Mayo Clinic College of Medicine and Science
Associate Editors
Seth R. Sweetser, MD
Consultant, Division of Gastroenterology and Hepatology, Mayo
Clinic, Rochester, Minnesota; Associate Professor of Medicine, Mayo
Clinic College of Medicine and Science
Michael D. Leise, MD
Karthik Ravi, MD
David H. Bruining, MD
MAYO CLINIC SCIENTIFIC PRESS

The triple-shield Mayo logo and the words MAYO, MAYO CLINIC, and MAYO CLINIC SCIENTIFIC PRESS
are marks of Mayo Foundation for Medical Education and Research.
Oxford University Press is a department of the University of Oxford. It furthers

the University’s objective of excellence in research, scholarship, and education
by publishing worldwide. Oxford is a registered trade mark of Oxford University
Press in the UK and certain other countries.
Published in the United States of America by Oxford University Press
198 Madison Avenue, New York, NY 10016, United States of America.
© Mayo Foundation for Medical Education and Research 2024
All rights reserved. No part of this publication may be reproduced, stored in
a retrieval system, or transmitted, in any form or by any means, electronic,
mechanical, photocopying, recording, or otherwise, without the prior permission
of Mayo Foundation for Medical Education and Research. Inquiries should be
addressed to Scientific Publications, Plummer 10, Mayo Clinic,
200 First St SW, Rochester, MN 55905
You must not circulate this work in any other form
and you must impose this same condition on any acquirer.
Library of Congress Cataloging-in-Publication Data
Names: Hauser, Stephen C., editor. | Sweetser, Seth R., editor. |
Leise, Michael D., editor. | Ravi, Karthik, editor. | Bruining, David H.,
editor. | Mayo Foundation for Medical Education and Research,
issuing body.
Title: Mayo Clinic gastroenterology and hepatology board review /
Stephen C. Hauser, editor-in-chief ; Seth R. Sweetser, Michael D. Leise,
Karthik Ravi, David H. Bruining, associate editors.
Other titles: Gastroenterology and hepatology board review
Description: Sixth edition. | New York, N.Y. : Oxford University Press ;
[Rochester, Minn.?] : Mayo Foundation for Medical Education and
Research, [2024] | Includes bibliographical references and index.
Identifiers: LCCN 2023034282 (print) | LCCN 2023034283 (ebook) |
ISBN 9780197679753 (paperback) | ISBN 9780197679777 (epub) |
ISBN 9780197679784
Subjects: MESH: Gastrointestinal Diseases | Liver Diseases |
Examination Questions
Classification: LCC RC801 (print) | LCC RC801 (ebook) | NLM WI 18.2 |
DDC 616.3/3—dc23/eng/20231004
LC record available at https://lccn.loc.gov/2023034282
LC ebook record available at https://lccn.loc.gov/2023034283
DOI: 10.1093/med/9780197679753.001.0001
Mayo Foundation does not endorse any particular products or services, and the reference to any products or
services in this book is for informational purposes only and should not be taken as an endorsement by the
authors or Mayo Foundation. Care has been taken to confirm the accuracy of the information presented and
to describe generally accepted practices. However, the authors, editors, and publisher are not responsible for
errors or omissions or for any consequences from application of the information in this book and make no
warranty, express or implied, with respect to the contents of the publication. This book should not be relied
on apart from the advice of a qualified health care provider.
The authors, editors, and publisher have exerted efforts to ensure that drug selection and dosage set forth in
this text are in accordance with current recommendations and practice at the time of publication. However,
in view of ongoing research, changes in government regulations, and the constant flow of information
relating to drug therapy and drug reactions, readers are urged to check the package insert for each drug
for any change in indications and dosage and for added wordings and precautions. This is particularly
important when the recommended agent is a new or infrequently employed drug.
Some drugs and medical devices presented in this publication have US Food and Drug Administration
(FDA) clearance for limited use in restricted research settings. It is the responsibility of the health care
providers to ascertain the FDA status of each drug or device planned for use in their clinical practice.
Printed by Integrated Books International, United States of America
To the many persons who have taught, encouraged, and inspired us so that we can provide
the best care for our patients and help educate our colleagues to do the same.
Preface
Gastroenterology and hepatology encompass a vast anatomical The book is organized by subspecialty topics, including esoph-
assortment of organs that have diverse structure and function and ageal disorders, gastroduodenal disorders, small-bowel disease
potentially are afflicted by a multiplicity of disease processes. We and nutrition, colonic disorders, pancreaticobiliary disease, liver
have designed the Mayo Clinic Gastroenterology and Hepatology disease, and miscellaneous disorders. Numerous color and black-
Board Review course and the revised sixth edition of this book and-white figures support the text. Each subspecialty section
to assist both physicians-in-training who are preparing for the concludes with a chapter containing board examination–type,
gastroenterology board examination and the increasing number single-
best-answer multiple- choice questions with annotated
of gastroenterologists awaiting recertification. Mayo Clinic answers. (The content of the questions and answers is not in-
Gastroenterology and Hepatology Board Review is not intended cluded in the index.) The faculty responsible for the book (at the
to replace the many more encyclopedic textbooks of gastroenter- time it was produced) all are Mayo Clinic gastroenterologists
ology, hepatology, pathology, endoscopy, nutrition, and radiology and hepatologists who spend the majority of their time caring
now available. Nor is this book intended to serve as an “update” to for patients but have a commitment to teaching medical students,
physicians looking for the newest advances in the science and art house officers, fellows, nurses, and physicians. Most of the fac-
of gastroenterology and hepatology. Instead, this book provides a ulty have particular interests in subspecialty areas of clinical gas-
core of essential knowledge in gastroenterology, hepatology, and troenterology and hepatology, which provides broad expertise.
integral related areas of pathology, endoscopy, nutrition, and ra- We want to thank the staffs of Scientific Publications and Media
diology. Clinical knowledge related to diagnostic and therapeutic Support Services at Mayo Clinic and the Mayo Clinic School of
approaches to patient management is emphasized. Case- based Continuous Professional Development for their contributions.
presentations and short board examination–type, single-best-answer The support of Mayo Clinic Scientific Press and our publisher,
multiple-choice questions with annotated answers are featured. The Oxford University Press, are also greatly appreciated. We want
text is also intended to be used by medical students and residents to give special thanks to Barb Hinrichs and to Darrell S. Pardi,
during their clerkships in internal medicine and gastroenterology MD, for his ongoing enthusiasm and support for our faculty and
and by gastroenterology fellows in training. Physicians in practice teaching mission.
should find this book to be a practical review for consolidating their Stephen C. Hauser, MD
knowledge in gastroenterology. Editor
vii
Table of Contents
List of Contributors xi Questions and Answers 123

Edited by Stephen C. Hauser, MD
Section I Esophagus
Section IV Miscellaneous Disorders
1 Gastroesophageal Reflux Disease 3
Amrit K. Kamboj, MD, and Joseph A. Murray, MD 10 Nonvariceal Gastrointestinal Tract Bleeding 127
David H. Bruining, MD, and Jeffrey A. Alexander, MD
2 Barrett Esophagus and Esophageal Cancer 23
Prasad G. Iyer, MD, and Kornpong Vantanasiri, MD 11 Vascular Disorders of the Gastrointestinal Tract 133
Seth R. Sweetser, MD
3 Esophageal Motility 35
Chamil C. Codipilly, MD, and Karthik Ravi, MD 12 Gastrointestinal Manifestations of Systemic
Disease 143
Questions and Answers 45 Seth R. Sweetser, MD
Edited by Karthik Ravi, MD
13 Complications After Roux-en-Y Surgery 159
Section II Stomach Khushboo S. Gala, MBBS, and Andres J. Acosta, MD, PhD
4 Peptic Ulcer Disease 51 14 Endoscopy for the Gastroenterology Board

Stephanie L. Hansel, MD, MS Examination 167
Tarek Sawas, MD, David H. Bruining, MD, and
Andrew C. Storm, MD
5 Gastritis and Gastropathy 57
Stephanie L. Hansel, MD, MS
Questions and Answers 175
Edited by Seth R. Sweetser, MD
6 Gastric Neoplasms and Gastroenteric and Pancreatic
Neuroendocrine Tumors 65
Seth R. Sweetser, MD Section V Colon
7 Gastrointestinal Motility Disorders 83 15 Inflammatory Bowel Disease: Clinical Aspects 185

Xiao Jing (Iris) Wang, MD Victor G. Chedid, MD, MS, and
Nayantara Coelho-Prabhu, MBBS
Edited by Seth R. Sweetser, MD 16 Inflammatory Bowel Disease: Therapy 191
Darrell S. Pardi, MD, and Victor G. Chedid, MD, MS
Section III Small Bowel and Nutrition
17 Inflammatory Bowel Disease: Extraintestinal
Manifestations and Colorectal Cancer 199
8 Clinical Features of Malabsorptive Disorders,
Kevin P. Quinn, MD, and Laura E. Raffals, MD
Small-Bowel Diseases, and Bacterial Overgrowth
Syndromes 105
Amy S. Oxentenko, MD 18 Intestinal Infections 207
Sahil Khanna, MBBS, MS
9 Nutritional Disorders: Vitamins and Minerals 119
Amindra S. Arora, MB, BChir 19 Colorectal Neoplasms 221
Derek W. Ebner, MD, and John B. Kisiel, MD
ix
x Table of Contents
20 Irritable Bowel Syndrome 231 31 Cholestatic Liver Disease 357

Priya Vijayvargiya, MD, and John E. Eaton, MD
David O. Prichard, MB, BCh, PhD
32 Drug-Induced Liver Injury 363
21 Constipation and Fecal Incontinence 237 Omar Y. Mousa, MBBS, MD, and Michael D. Leise, MD
Adil E. Bharucha, MBBS, MD
33 Autoimmune Hepatitis 375
22 Gastrointestinal Disease and Pregnancy 251 John E. Eaton, MD
Sunanda V. Kane, MD
34 Nonalcoholic Fatty Liver Disease 381
Questions and Answers 269 Gopanandan Parthasarathy, MBBS, and
Edited by David H. Bruining, MD Harmeet Malhi, MBBS
Section VI Liver 35 Liver Disease in Pregnancy 391

Prowpanga Udompap, MD, and Alina M. Allen, MD
23 Approach to the Patient With Abnormal Liver Test
Results and Acute Liver Failure 279 36 Liver Transplantation 401
John J. Poterucha, MD Omar Y. Mousa, MBBS, MD, and Sumera I. Ilyas, MBBS
24 Viral Hepatitis 287 Questions and Answers 407

Michael D. Leise, MD Edited by Michael D. Leise, MD, and Stephen C. Hauser, MD
25 Clinical Approach to Liver Mass Lesions 297 Section VII Pancreas and Biliary Tree
Lewis R. Roberts, MB, ChB, PhD
37 Acute Pancreatitis 427
26 Alcohol-Related Liver Disease 315 Daniel B. Maselli, MD, and Vinay Chandrasekhara, MD
Robert C. Huebert, MD, and Vijay H. Shah, MD
38 Chronic Pancreatitis 437
27 Vascular Diseases of the Liver 325 Laurens P. Janssens, MD, and Shounak Majumder, MD
Tasha B. Kulai, MD, and William Sanchez, MD
39 Pancreatic Neoplasms 443
28 Portal Hypertension–Related Bleeding 331 Jaime De La Fuente, MD, and Shounak Majumder, MD
Moira Hilscher, MD, and Douglas A. Simonetto, MD
40 Gallstones 455
29 Ascites, Hepatorenal Syndrome, and Eric J. Vargas Valls, MD, MS
Encephalopathy 335
Tasha B. Kulai, MD, and Douglas A. Simonetto, MD Questions and Answers 467
Edited by Seth R. Sweetser, MD
30 Metabolic Liver Diseases 345
Angela C. Cheung, MD, and William Sanchez, MD
Index 471
Contributors
Andres J. Acosta, MD, PhD Nayantara Coelho-Prabhu, MBBS

Consultant, Division of Gastroenterology and Hepatology, Mayo Consultant, Division of Gastroenterology and Hepatology, Mayo
Clinic, Rochester, Minnesota; Associate Professor of Medicine, Clinic, Rochester, Minnesota; Associate Professor of Medicine,
Mayo Clinic College of Medicine and Science Mayo Clinic College of Medicine and Science
Jeffrey A. Alexander, MD Jaime De La Fuente, MD
Consultant, Division of Gastroenterology and Hepatology, Mayo Fellow in Gastroenterology and Hepatology, Mayo Clinic School of
Clinic, Rochester, Minnesota; Professor of Medicine, Mayo Clinic Graduate Medical Education, Mayo Clinic College of Medicine and
College of Medicine and Science Science, Rochester, Minnesota; now with Eagan Endoscopy Center
& Clinic, Eagan, Minnesota
Alina M. Allen, MD
Consultant, Division of Gastroenterology and Hepatology, Mayo John E. Eaton, MD
Clinic, Rochester, Minnesota; Associate Professor of Medicine, Consultant, Division of Gastroenterology and Hepatology, Mayo
Mayo Clinic College of Medicine and Science Clinic, Rochester, Minnesota; Associate Professor of Medicine,
Amindra S. Arora, MB, BChir
Consultant, Division of Gastroenterology and Hepatology, Mayo Derek W. Ebner, MD
Clinic, Rochester, Minnesota; Professor of Medicine, Mayo Clinic Senior Associate Consultant, Division of Gastroenterology
College of Medicine and Science and Hepatology, Mayo Clinic, Rochester, Minnesota; Assistant
Professor of Medicine, Mayo Clinic College of Medicine and
Adil E. Bharucha, MBBS, MD Science
Clinic, Rochester, Minnesota; Professor of Medicine, Mayo Clinic Khushboo S. Gala, MBBS
College of Medicine and Science Fellow in Gastroenterology, Mayo Clinic School of Graduate
Medical Education, Mayo Clinic College of Medicine and Science,
David H. Bruining, MD Rochester, Minnesota
Clinic, Rochester, Minnesota; Associate Professor of Medicine, Stephanie L. Hansel, MD, MS
Mayo Clinic College of Medicine and Science Consultant, Division of Gastroenterology and Hepatology, Mayo
Clinic, Rochester, Minnesota; Associate Professor of Medicine,
Vinay Chandrasekhara, MD Mayo Clinic College of Medicine and Science
Clinic, Rochester, Minnesota; Associate Professor of Medicine, Moira Hilscher, MD
Mayo Clinic College of Medicine and Science Fellow in Gastroenterology and Hepatology, Mayo Clinic School
of Graduate Medical Education, Mayo Clinic College of Medicine
Victor G. Chedid, MD, MS and Science, Rochester, Minnesota; now with Perelman Center
Consultant, Division of Gastroenterology and Hepatology, Mayo for Advanced Medicine, University of Pennsylvania, Philadelphia,
Clinic, Rochester, Minnesota; Assistant Professor of Medicine, Pennsylvania
Robert C. Huebert, MD
Angela C. Cheung, MD Consultant, Division of Gastroenterology and Hepatology, Mayo
Fellow in Gastroenterology and Hepatology, Mayo Clinic School of Clinic, Rochester, Minnesota; Associate Professor of Medicine and
Graduate Medical Education, Mayo Clinic College of Medicine and of Regenerative Medicine, Mayo Clinic College of Medicine and
Science, Rochester, Minnesota; now with the University of Ottawa Science
Department of Medicine, Ottawa, Ontario, Canada
Sumera I. Ilyas, MBBS
Chamil C. Codipilly, MD Consultant, Division of Gastroenterology and Hepatology, Mayo
Senior Associate Consultant, Division of Gastroenterology Clinic, Rochester, Minnesota; Associate of Medicine and Assistant
and Hepatology, Mayo Clinic, Rochester, Minnesota; Assistant Professor of Immunology, Mayo Clinic College of Medicine and
Professor of Medicine, Mayo Clinic College of Medicine and Science
Science
xi
xii Contributors
Prasad G. Iyer, MD Amy S. Oxentenko, MD

Clinic, Rochester, Minnesota; Professor of Medicine, Mayo Clinic Clinic, Rochester, Minnesota; Professor of Medicine, Mayo Clinic
College of Medicine and Science College of Medicine and Science
Laurens P. Janssens, MD Darrell S. Pardi, MD
Fellow in Gastroenterology, Mayo Clinic School of Graduate Chair, Division of Gastroenterology and Hepatology, Mayo Clinic,
Medical Education, Mayo Clinic College of Medicine and Science, Rochester, Minnesota; Professor of Medicine, Mayo Clinic College
Rochester, Minnesota of Medicine and Science
Amrit K. Kamboj, MD Gopanandan Parthasarathy, MBBS
Fellow in Gastrointestinal and Esophageal Disease, Mayo Clinic Associate Consultant, Division of Gastroenterology and
College of Graduate Medical Education and Instructor in Medicine, Hepatology, Mayo Clinic, Rochester, Minnesota
Mayo Clinic College of Medicine and Science, Rochester,
Minnesota; now with Cedars-Sinai Hospital, Los Angeles, John J. Poterucha, MD
California Supplemental Consultant, Division of Gastroenterology and
Hepatology, Mayo Clinic, Rochester, Minnesota; Emeritus Professor
Sunanda V. Kane, MD of Medicine, Mayo Clinic College of Medicine and Science
Clinic, Rochester, Minnesota; Professor of Medicine, Mayo Clinic David O. Prichard, MB, BCh, PhD
College of Medicine and Science Research Collaborator in Gastroenterology and Hepatology, Mayo
Clinic School of Graduate Medical Education, Mayo Clinic College
Sahil Khanna, MBBS, MS of Medicine and Science, Rochester, Minnesota
Clinic, Rochester, Minnesota; Professor of Medicine, Mayo Clinic Kevin P. Quinn, MD
College of Medicine and Science Research Collaborator in Gastroenterology, Mayo Clinic School of
Graduate Medical Education, Mayo Clinic College of Medicine and
John B. Kisiel, MD Science, Rochester, Minnesota; now with Park Nicollet Clinic, St.
Consultant, Division of Gastroenterology and Hepatology, Mayo Louis Park, Minnesota
Clinic, Rochester, Minnesota; Professor of Medicine, Mayo Clinic
College of Medicine and Science Laura E. Raffals, MD
Tasha B. Kulai, MD Clinic, Rochester, Minnesota; Professor of Medicine, Mayo Clinic
Fellow in Transplant Hepatology, Mayo Clinic School of Graduate College of Medicine and Science
Medical Education, Mayo Clinic College of Medicine and Science,
Rochester, Minnesota; now with Dalhousie University Department Karthik Ravi, MD
of Medicine, Halifax, Nova Scotia, Canada Consultant, Division of Gastroenterology and Hepatology, Mayo
Michael D. Leise, MD Mayo Clinic College of Medicine and Science
Clinic, Rochester, Minnesota; Associate Professor of Medicine, Lewis R. Roberts, MB, ChB, PhD
Clinic, Rochester, Minnesota; Professor of Medicine, Mayo Clinic
Shounak Majumder, MD College of Medicine and Science
Clinic, Rochester, Minnesota; Associate Professor of Medicine, William Sanchez, MD
Harmeet Malhi, MBBS Mayo Clinic College of Medicine and Science
Clinic, Rochester, Minnesota; Professor of Medicine and of Tarek Sawas, MD
Physiology, Mayo Clinic College of Medicine and Science Fellow in Gastroenterology, Mayo Clinic School of Graduate Medical
Education, Mayo Clinic College of Medicine and Science, Rochester,
Daniel B. Maselli, MD Minnesota; now with UT Southwestern Medical Center, Dallas, Texas
Fellow in Gastroenterology and Hepatology, Mayo Clinic School
of Graduate Medical Education, Mayo Clinic College of Medicine Vijay H. Shah, MD
and Science, Rochester, Minnesota; now with Vanderbilt Health, Chair, Department of Internal Medicine, Mayo Clinic, Rochester,
Nashville, Tennessee Minnesota; Professor of Medicine and of Physiology, Mayo Clinic
College of Medicine and Science
Omar Y. Mousa, MBBS, MD
Chair for Gastroenterology, Mayo Clinic Health System – Douglas A. Simonetto, MD
Southwest Minnesota region, Mankato, Minnesota; Assistant Consultant, Division of Gastroenterology and Hepatology, Mayo
Professor of Medicine Mayo Clinic College of Medicine and Clinic, Rochester, Minnesota; Associate Professor of Medicine,
Science, Rochester, Minnesota Mayo Clinic College of Medicine and Science
Joseph A. Murray, MD Andrew C. Storm, MD

Clinic, Rochester, Minnesota; Professor of Medicine, Mayo Clinic Clinic, Rochester, Minnesota; Associate Professor of Medicine,
College of Medicine and Science Mayo Clinic College of Medicine and Science
Contributors xiii
Seth R. Sweetser, MD Eric J. Vargas Valls, MD, MS

Consultant, Division of Gastroenterology and Hepatology, Mayo Senior Associate Consultant, Division of Gastroenterology and
Clinic, Rochester, Minnesota; Associate Professor of Medicine, Hepatology, Mayo Clinic, Rochester, Minnesota; Assistant Professor
Mayo Clinic College of Medicine and Science of Medicine, Mayo Clinic College of Medicine and Science
Prowpanga Udompap, MD Priya Vijayvargiya, MD
Resident in Gastroenterology, Mayo Clinic School of Graduate Fellow in Gastroenterology, Mayo Clinic School of Graduate
Medical Education, Mayo Clinic College of Medicine and Science, Medical Education, Mayo Clinic College of Medicine and Science,
Rochester, Minnesota Rochester, Minnesota; now with Erlanger Gastroenterology,
Chattanooga, Tennessee
Kornpong Vantanasiri, MD
Resident in Gastroenterology, Mayo Clinic School of Graduate Xiao Jing (Iris) Wang, MD
Medical Education, Mayo Clinic College of Medicine and Science, Consultant, Division of Gastroenterology and Hepatology, Mayo
Rochester, Minnesota Clinic, Rochester, Minnesota; Assistant Professor of Medicine,
I
Esophagus
1
Gastroesophageal Reflux Diseasea

AMRIT K. KAMBOJ, MD
JOSEPH A. MURRAY, MD
Gastroesophageal reflux is the reflux of gastric contents other acid production, delayed gastric emptying, and obstructive sleep
than air into or through the esophagus. Gastroesophageal re- apnea (Figure 1.1). The relative contribution of these varies from
flux disease (GERD) refers to reflux that produces frequent patient to patient.
symptoms or results in damage or dysfunction to the esopha-
geal mucosa or contiguous organs of the upper aerodigestive
system.
Box 1.1. Etiologic Factors of Gastroesophageal Reflux
✓ Gastroesophageal reflux disease—reflux that produces frequent Disease
symptoms or results in damage or dysfunction to the esophagus Motility disorders
and occasionally the respiratory tract
Transient lower esophageal relaxationsa
Weak lower esophageal sphinctera
Weak esophageal peristalsis
Etiology
Scleroderma and CREST syndrome
Gastroesophageal reflux results from several factors that lead to Delayed gastric emptying
symptoms or injury of the esophageal mucosa by reflux of corro-
Damaging factors
sive material from the stomach (Box 1.1). These factors include a
weak or defective sphincter, transient lower esophageal sphincter Increased gastric acid production
(LES) relaxation (TLESR), hiatal hernia, poor acid clearance Bile and pancreatic juice
from the esophagus, impaired esophageal peristalsis, diminished Resistance factors
salivary flow, decreased mucosal resistance to injury, increased Reduced production of saliva and bicarbonate
Diminished mucosal blood flow
Growth factors, protective mucus
Others
a
Portions of this chapter were adapted from Szarka LA, DeVault KR,
Murray JA. Diagnosing gastroesophageal reflux disease. Mayo Clin Obesitya
Proc. 2001 Jan; 76(1):97-101; used with permission. Hiatal herniaa
Abbreviations: CMV, cytomegalovirus; CREST, calcinosis cutis, Obstructive sleep apnea
Raynaud phenomenon, esophageal dysfunction, sclerodactyly, and tel-
angiectasia; EGD, esophagogastroduodenoscopy; EoE, eosinophilic Abbreviation: CREST, calcinosis cutis, Raynaud phenomenon, esoph-
esophagitis; GERD, gastroesophageal reflux disease; H2, histamine; ageal dysfunction, sclerodactyly, and telangiectasia.
HSV, herpes simplex virus; LA, Los Angeles; LES, lower esophageal
sphincter; PPI, proton pump inhibitor; SAP, system association proba-
a
Major or common factor.
bility; TLESR, transient lower esophageal sphincter relaxation
3
4 Section I. Esophagus
dysfunction, sclerodactyly, and telangiectasia (CREST). Drugs

and Sjögren syndrome can decrease salivary flow. Normally, sal-
ivary flow is decreased at night; thus, if reflux occurs during the
night when the person is supine, acid will not be cleared by either
gravity or saliva. Consequently, episodes of reflux at night are
long-lasting and have a greater chance of causing severe injury
to the mucosa.
Intrinsic Mucosal Factors

The mucosa of the esophagus has intrinsic factors that protect
the esophageal lining against acid damage. These include the
stratified squamous mucosa, intercellular tight junctions, growth
factors, buffering blood flow, and production of mucin, bicarbo-
nate, and epidermal growth factors. When these factors are over-
come, GERD causes reflux esophagitis (Figure 1.2).
Gastric Factors
Delayed gastric emptying or increased gastric production
of acid is a less frequent part of GERD. Reflux esophagitis
is rarely a manifestation of Zollinger-Ellison syndrome. The
availability of corrosive gastric contents in the cardia of the sto-
mach is necessary for reflux to occur during TLESRs or when
a defective LES is overcome during recumbency or abdominal
Figure 1.1. Causes of Increased Exposure of the Esophagus to

Gastric Refluxate. (Adapted from AstraZeneca Pharmaceuticals LP
[Internet]. Wilmington [DE]. From: http://www.astrazeneca.com; used
with permission.)
Factors Contributing to GERD

Barrier Function of the LES
The LES and its attached structures form a barrier to reflux of
material across the esophagogastric junction and are the central
protection against pathologic reflux of gastric contents into the
esophagus. This barrier has several components, including the
smooth muscle LES, the gastric sling fibers, and the striated
muscle crural diaphragm. The LES maintains tone at rest and
relaxes with swallowing and gastric distention as a venting re-
flex, constituting a TLESR. In persons with mild reflux disease,
acid liquid contents (instead of only air) are vented, resulting
in many episodes of acid reflux. In patients with severe reflux,
the resting pressure of the LES is often diminished and easily
overcome.
The presence of hiatal hernia is important in defective bar-
rier function both by removing the augmentation that the crural
diaphragm provides the LES and by lowering the threshold for
TLESR to occur. Figure 1.2. Mechanism of Action of Refluxate in Gastroesophageal
Reflux Disease. The sequence of events hypothesized to lead to
symptoms and tissue damage in gastroesophageal reflux disease is as
Acid Clearance follows: A and B, Acid-peptic attack weakens cell junctions. C, The cell
The clearance of acid from the esophagus is a combination of gaps widen, thus allowing acid penetration. Exposure to gastric acid
mechanical volume clearance (gravity and peristalsis) and chem- and pepsin can cause microscopic damage to the esophageal mucosa;
ical neutralization of the lumen contents (saliva and mucosal even though the damage may not be visible endoscopically, it may still
result in heartburn. D, Penetration of acid and pepsin into the mucosa
buffering). This may be delayed in patients with GERD because
allows contact of acid with epithelial nerve endings (which may result
of either impaired esophageal peristalsis or reduced buffering in heartburn). E, Additional influx of acid and pepsin into the mucosa
effects of swallowed saliva. The defective peristalsis can be a triggers a cascade of events, ultimately leading to cell rupture and mu-
primary idiopathic motor disorder or, occasionally, it can result cosal inflammation. (Adapted from AstraZeneca Pharmaceuticals LP
from a connective tissue disorder such as limited scleroderma as- [Internet]. Wilmington [DE]. From: http://www.astrazeneca.com; used
sociated with calcinosis cutis, Raynaud phenomenon, esophageal with permission.)
1. Gastroesophageal Reflux Disease 5
straining. The cardia is often submerged under liquid gastric

contents when a person is recumbent, especially in the right
lateral decubitus position. It has been suggested that what
differentiates patients with GERD from healthy patients is not
the number of actual reflux events but the reflux of acidic gas-
tric contents instead of the release of air alone. The timing of
reflux is also important. Because gastric acid is buffered by
food during the first hour after eating, normal physiologic re-
flux that may occur during maximal gastric distention is not as
harmful as the reflux that occurs later after the stomach pH has
again decreased. Any obstruction of the outflow from the sto-
mach increases the propensity to reflux, although this is often
associated with nausea and vomiting. Pure bile reflux may
occur in patients who have had gastric surgery. More common
is pathologic reflux associated with a restrictive bariatric pro-
cedure such as vertical banded gastroplasty. If too much acid-
producing mucosa is present above the restriction, pathologic
Figure 1.3. Efficacy of Proton Pump Inhibitor Therapy. The effi-
reflux may occur. cacy may be greater in patients with gastroesophageal reflux disease who
are positive for Helicobacter pylori (H pylori +) than in those negative
Obesity and Obstructive Sleep Apnea for H pylori (H pylori –).
Obesity has been established as a risk factor for GERD. An

increased body mass index is also associated with Barrett esoph- Mechanism for Extraesophageal Symptoms
agus and reflux esophagitis. In addition, obesity is associated
The mechanism for extraesophageal manifestations of GERD,
with an increased risk of adenocarcinoma of the distal esophagus.
such as wheeze or cough, may not always be direct aspiration or
Moreover, a strong correlation exists between obstructive sleep
damage of mucosa in the respiratory tract but a vagally mediated
apnea and GERD. One proposed mechanism is that obstructive
reflex triggered by acidification of the distal esophageal mucosa.
sleep apnea generates negative intrathoracic pressure, which
However, establishing a causative relationship is challenging,
leads to more episodes of acid reflux.
and in many cases GERD may instead coexist with suspected
extraesophageal symptoms. Subglottic stenosis and granuloma of
Helicobacter pylori and GERD the vocal cords are serious consequences of reflux caused by di-
Whether chronic Helicobacter pylori infection protects against rect contact injury of the delicate mucosa of the airway, resulting
GERD is controversial. Duodenal ulcers and distal gastric cancer in stridor, cough, or dysphonia (Figure 1.5).
(both caused by H pylori infection) are becoming rare in high-
✓ Gastroesophageal reflux can result from several factors, including
income countries, and adenocarcinoma of the proximal sto- the following:
mach and esophagus is becoming more common as the carriage • A weak or defective sphincter
rates of H pylori decrease. Patients with GERD symptoms may • TLESRs
be less likely to carry H pylori than patients without GERD • Hiatal hernia
symptoms. Reports that symptoms of GERD developed after • Poor acid clearance from the esophagus
the eradication of H pylori have led to a reexamination of those • Impaired esophageal peristalsis
treatment trials of duodenal ulcers, which included H pylori • Diminished salivary flow
eradication, for the new development of GERD symptoms. The • Reduced mucosal resistance to injury
evidence is conflicting as to whether the symptoms of GERD • Increased acid production
• Delayed gastric emptying
are more common in those in whom H pylori eradication has
• Obesity and obstructive sleep apnea
been successful or in those with persistent infection. In some ✓ Causes of extraesophageal symptoms (ie, cough) due to GERD:
persons, H pylori infection may cause chronic atrophic gastritis • Direct aspiration and mucosal damage in the respiratory tract
that affects the corpus of the stomach, resulting in diminished • A vagally mediated reflex due to acidification of the distal
acid secretion. It is this relative hypochlorhydria that is thought esophagus
to protect against GERD. Indeed, it has been suggested that
acid suppression heals reflux esophagitis faster in patients with
H pylori infection (Figure 1.3).
Epidemiology of GERD
GERD can be defined as the abnormal reflux of gastric contents
Connective Tissue Disease
causing troublesome symptoms (typically heartburn or acid re-
Scleroderma, CREST syndrome, and mixed connective tissue gurgitation) with or without esophageal damage. GERD is one
diseases are rare causes of reflux, but these should be considered of the most prevalent diseases of the gastrointestinal tract in the
in young women who have Raynaud phenomenon or subtle cuta- US, and its prevalence has increased over the past 3 to 4 decades.
neous features of scleroderma in the hands or face. Occasionally, Symptoms suggestive of GERD are common: In the US, up to
GERD may be the first manifestation of these disorders. 40% of adults report that they have heartburn and regurgitation
Esophageal manometry characteristically demonstrates a low- on a regular basis (Figure 1.6), 18% report that it occurs weekly,
pressure LES and decreased amplitude of contractions in the and GERD accounts for approximately 4.7 million health care
esophagus (Figure 1.4). visits annually in the US. GERD becomes more common as
Figure 1.4. Esophageal Manometric Tracing. The tracing illustrates the complete absence of peristalsis and the hypotonicity of lower esophageal
sphincter (LES) pressure consistent with esophageal involvement in scleroderma.
people age (Figure 1.7). Previously, GERD and its complications percentage have esophageal adenocarcinoma. Complications of
were rare in China, Japan, and other Asian countries, but this is GERD may be more common in persons who are male, White, or
changing rapidly with the adoption of a Western diet worldwide. older. Whether reflux is becoming more common is not clear, but
A protective role of H pylori–induced hypochlorhydria has been it certainly is diagnosed more frequently than in the past. Also,
suggested as a protective influence in countries with high carriage because of direct-to-consumer advertising and public education
rates of infection. campaigns, the public is more aware of GERD.
Esophageal damage from GERD is observed less frequently, For patients with GERD, the quality of life may be impaired
however, and less than 50% of patients who present for medical even more than for those with congestive heart failure or angina
attention for reflux symptoms have esophagitis. Among patients pectoris (Figure 1.8). GERD is associated with considerable
who undergo endoscopy for GERD, 10% have benign strictures, health care costs related to its widespread prevalence, its effect
3% to 4% have Barrett esophagus, and an extremely small on patients’ quality of life, and the frequent need for long-term
therapy, such as with proton pump inhibitors (PPIs).
Figure 1.6. Three-Month Prevalence of Gastroesophageal Reflux

Disease Worldwide. The prevalence varies markedly from country to
Figure 1.5. Endoscopic View of Laryngeal Stenosis. (Courtesy of country, largely because of differences in physicians’ awareness and
Dana M. Thompson, MD, Department of Otorhinolaryngology, Mayo understanding of the condition. Nordic countries include Denmark,
Clinic, Rochester, Minnesota; used with permission.) Finland, Norway, and Sweden.
Esophageal Symptoms
The cardinal symptoms of GERD are heartburn (defined as ret-
rosternal burning ascending toward the neck) and acid regurgi-
tation (the unpleasant return of sour or bitter gastric contents to
the pharynx). These should be differentiated from the nonacid
(bland) regurgitation of retained esophageal contents in an
obstructed esophagus, as occurs in achalasia, or the effortless re-
gurgitation of recently swallowed food that is remasticated and
swallowed, typifying rumination. Patient symptoms of GERD,
reflux, and heartburn should be differentiated from the burning
epigastric sensation of dyspepsia.
Patients may report relief of symptoms with antacids or milk.
The symptoms of heartburn and acid regurgitation are suggestive
for GERD and can warrant empirical medical therapy. Objective
Figure 1.7. Annual Incidence of Gastroesophageal Reflux Disease confirmation, however, is required before consideration is given
With Age. The incidence increases markedly after age 40 years. to endoscopic or surgical management of GERD.
(Adapted from Brunnen PL, Karmody AM, Needham CD. Severe peptic Although regurgitation of acid is a specific symptom highly
oesophagitis. Gut. 1969 Oct;10[10]:831-7; used with permission.) suggestive of GERD, heartburn may have many different
meanings for patients, and, indeed, patients may use different
and imprecise terms to describe their symptoms, such as indiges-
Symptoms tion, upset stomach, or sour stomach. Less common symptoms
suggestive of GERD, but not diagnostic of GERD, include water
The classic symptoms of GERD, that is, heartburn and acid re- brash (hypersalivation associated with an episode of esophageal
gurgitation, are common in the general population and usually acid exposure), dysphagia (difficulty swallowing), odynophagia
readily recognized. GERD may be manifested in a wide array of (painful swallowing), and chest discomfort not identified as heart-
esophageal and extraesophageal symptoms (Box 1.2), and it may burn. Given the broad differential diagnosis for causes of dys-
contribute to many clinical syndromes, either as a common factor phagia, odynophagia, and chest discomfort, if these symptoms
or as a rare culprit. are present, additional evaluation may be required before medical
therapy is empirically started.
✓ Heartburn—retrosternal burning that ascends toward the neck
Reflux is more common after eating. Although reflux
✓ Acid regurgitation—the unpleasant return of gastric contents to
the pharynx

symptoms can occur at any time, they tend to occur most fre-
quently 1 to 3 hours after eating, when acid production overcomes
Figure 1.8. Gastroesophageal Reflux Disease (GERD) and Quality of Life. GERD has a greater effect on quality of life than other common
diseases. Quality of life, assessed by the Psychological General Well-being Index (PGWBI), was compared between patients with untreated GERD
and those with other disorders. For example, the mean PGWBI score for patients with untreated erosive esophagitis is similar to that for patients with
untreated duodenal ulcer and lower (ie, worse) than that for patients with angina pectoris or mild heart failure. Normal scores are 101 for women and
103 for men, but they vary slightly from country to country. (Data from Dimenas E. Methodological aspects of evaluation of quality of life in upper
gastrointestinal diseases. Scand J Gastroenterol Suppl. 1993;199:18-21.)
Because cardiac-related pain may be fatal, a patient who has

Box 1.2. Symptoms of Gastroesophageal Reflux Disease chest pain from an unclear cause must have a cardiac investi-
Esophageal symptoms gation before an esophageal investigation. Frequently, patients
who have both cardiac and esophageal diseases cannot distin-
Heartburn
guish between reflux-associated pain and real angina. GERD
Acid regurgitation may decrease the threshold for coronary ischemia, further con-
Odynophagia fusing the clinical picture. Therefore, it is especially important
Dysphagia to first investigate the heart and then, when appropriate, other
Anginalike chest pain vital structures.
Water brash (hypersalivation)
Airway symptoms Extraesophageal Symptoms
Cough GERD may contribute to symptoms originating in other areas
Wheezing of the upper aerodigestive system. These symptoms, which can
Hoarseness occur without the classic symptoms of heartburn and acid regurgi-
tation, include cough, wheeze, hoarseness, sore throat, repetitive
Throat clearing
throat clearing, postnasal drip, neck or throat pain, globus, apnea,
Globus and otalgia. They are not specific for GERD. Indeed, GERD is
Tracheal stenosis only 1 of many causes of most of these symptoms. Cough and
Aspiration pneumonia wheezing are very common and likely to coexist with GERD by
Pulmonary fibrosis chance alone. Whether these symptoms are due to GERD needs
Apnea in infants
to be confirmed by investigation (if typical esophageal symptoms
are absent) or by the response to an empirical trial of potent
acid-blocking therapy (if typical esophageal symptoms are con-
comitantly present). Ideally, the demonstration of a pathologic
the buffering effects of food (Figure 1.9). It has been reported degree of GERD and a response of the atypical symptoms to an
that a layer of acid may remain unbuffered on the surface of the adequate antireflux regimen are needed to conclude that GERD
gastric meal contents. Reflux may occur also at night or when a is the cause. GERD may produce extraesophageal symptoms in
person with a weak LES is supine or, especially, in the right lat- 1 of 2 ways: 1) by direct irritation or inflammation of the deli-
eral decubitus position. cate mucosa of the larynx, trachea, or bronchi or 2) by reflex-
mediated changes in function. Both mechanisms may operate in
some patients.
Esophageal Chest Pain
GERD is the most common esophageal cause of noncardiac
Establishing a Diagnosis
chest pain. The pain may be referred to any point on the chest,
anteriorly or posteriorly, with radiation to the neck, arms, or A proposed algorithm for the diagnosis of GERD when typical
back. It may be indistinguishable from cardiac-related pain. symptoms are present is shown in Figure 1.10.
Figure 1.9. Temporal Distribution of Symptoms of Gastroesophageal Reflux Disease. Distribution of the mean number of episodes of reflux
symptoms over 24 hours is shown for 105 patients who ate their main meals at the same time of day. Food intake was associated with a marked in-
crease in the number of episodes, and relatively few episodes occurred during the night. (Adapted from Johnsson L, Adlouni W, Johnsson F, Joelsson
B. Timing of reflux symptoms and esophageal acid exposure. Gullet. 1992;2:58-62; used with permission.)
Figure 1.10. A Proposed Algorithm for the Diagnosis of Gastroesophageal Reflux Disease (GERD) When Typical Symptoms Are
Present. EGD indicates esophagogastroduodenoscopy; LA, Los Angeles; PPI, proton pump inhibitor; QOL, quality of life. (Adapted from Katz PO,
Dunbar KB, Schnoll-Sussman FH, Greer KB, Yadlapati R, Spechler SJ. ACG clinical guideline for the diagnosis and management of gastroesophageal
reflux disease. Am J Gastroenterol. 2022 Jan 1;117[1]‌:27-56; used with permission.)
Typical Symptoms of GERD ✓ If patients have typical symptoms of GERD (heartburn or acid
Patients who present with typical symptoms of GERD without regurgitation or both) and no alarm symptoms, an 8-week trial of
alarm symptoms should be given acid-suppressive therapy, typ- acid suppression therapy is appropriate
✓ If symptoms resolve completely with acid suppression but return
ically for 8 weeks. Complete resolution of the symptoms with
when treatment is discontinued, the patient may have GERD but prob-
treatment and relapse when treatment is discontinued confirms ably requires esophagogastroduodenoscopy for further evaluation of
the diagnosis and suggests the need for a long-term manage- recurrent symptoms when PPI therapy has been held for 2 to 4 weeks
ment strategy. However, even in these patients, the specificity of ✓ If the patient has little or no response to acid suppression, further
a response to potent acid suppression is not specific for GERD investigation is needed
because other acid peptic disorders respond to acid-suppressive
therapy. If symptomatic improvement is limited, either an in-
crease in dose or additional diagnostic testing is needed. If the Atypical Symptoms of GERD
patient has little or no symptomatic improvement with acid- GERD may cause or contribute to many different clinical
suppressive therapy, further investigation is indicated. syndromes. The more common or dangerous causes of these
syndromes should be evaluated first. For example, patients with

chest pain should be evaluated for coronary artery disease; patients Box 1.3. Uses of Diagnostic Tests for GERD
with chronic cough, for asthma; and patients with hoarseness, for Endoscopy
laryngeal neoplasm. If GERD is considered a possible cause,
Differentiate reflux esophagitis from other causes of
options include trying a therapeutic trial of acid suppression or esophagitis (eg, eosinophilic or infectious)
performing additional testing. A trial of acid suppression is a rea-
Biopsy for Barrett esophagus or adenocarcinoma
sonable next step if patients have symptoms that are both typical
and atypical. However, if the patient has only atypical symptoms, Dilate strictures
additional testing (eg, a pH monitoring study while medication is Provide endoscopic therapy (if desired)
held) would be the best next test. Contrast radiography (not recommended for GERD
The acid-suppression test uses a potent regimen of acid diagnosis)
suppression, such as PPIs (eg, omeprazole, 20 mg in the morning Identify hiatal hernia
and 20 mg in the evening). If the symptoms resolve, the patient
Identify strictures
should receive long-term treatment, with an attempt at dose re-
duction or cessation. Atypical symptoms may have had alternative Reproduce reflux of barium (not sensitive)
causes that resolved spontaneously. However, if reversible factors Ambulatory 24-h pH studies
are altered and if GERD is the major cause, the symptoms will Quantify acid reflux in the absence of esophagitis
probably recur when therapy is discontinued. If the symptoms do Determine temporal correlation between
not resolve completely, further evaluation with upper endoscopy gastroesophageal reflux and atypical symptoms
or 24-hour ambulatory esophageal pH monitoring with symptom-
reflux correlation (or both) is indicated. Ideally, the test should Abbreviation: GERD, gastroesophageal reflux disease.
be conducted when the patient is not taking a PPI, so that acid
regurgitation can be assessed.
If GERD is confirmed, long-term acid-suppressive therapy
is indicated. If symptoms persist, ambulatory esophageal pH distal esophagus. These usually start at the esophagogastric
monitoring may be repeated to document that the esophagus is junction and extend proximally for various distances. By their
no longer exposed to acid. appearance alone, these erosions usually are readily differentiated
from rarer infectious, allergic (eosinophilic), or corrosive causes
of inflammation. If the diagnosis is in question, biopsy specimens
Diagnostic Tests for GERD should be obtained, not primarily to confirm reflux but to iden-
Diagnostic tests are unnecessary for most persons with GERD. tify alternative pathologic conditions, such as eosinophilic esoph-
Investigations should be conducted if patients have alarm agitis (EoE). Given that the presence of these findings may be
symptoms (ie, dysphagia, odynophagia, hematemesis, vomiting, influenced by PPI intake, endoscopy should be done when the
or unintentional weight loss), equivocal results on a treatment patient has not received PPI therapy for 2 to 4 weeks if this is
trial, recurrent symptoms after completion of a treatment trial, or feasible and if therapy can be held safely without dramatically
atypical symptoms of sufficient importance to warrant confirma- worsening the patient’s symptoms.
tion of GERD. Investigations should also be conducted if patients Several grading schemes, generally based on the extent of
are undergoing surgical or endoscopic therapy for GERD. For involvement, have been used for reflux esophagitis. The Los
most patients, the endoscopic demonstration of severe esoph- Angeles (LA) classification system, the one most commonly used
agitis is sufficient proof of GERD, and further investigation is worldwide, grades esophagitis on a scale from A (least severe) to
unnecessary. However, up to 70% of patients with symptoms typ- D (most severe) (Figure 1.11). It is generally accepted that the
ical of GERD have normal endoscopic findings, with so-called presence of LA grade C or D esophagitis establishes a diagnosis
nonerosive reflux disease, and additional tests are required to of GERD. With the considerable interobserver variability for a di-
identify increased esophageal exposure to acid. This is typically agnosis of LA grade A esophagitis, this finding by itself is not
done with ambulatory pH monitoring (Box 1.3). considered diagnostic of GERD. However, the finding of LA grade
B esophagitis in a patient with typical symptoms and a response
✓ Diagnostic testing for GERD is not necessary if patients have typ- to PPI therapy does confirm a diagnosis of GERD. Severe esopha-
ical symptoms (heartburn or regurgitation or both) of short dura- gitis (ie, LA grade C or D) may occasionally be unrelated to reflux
tion and no alarm symptoms (eg, patients with bulimia who have severe, repeated episodes of
✓ Diagnostic testing for GERD should be performed if patients have vomiting or, rarely, patients who have pill esophagitis). Erythema
any of the following: and increased vascularity are nonspecific features, and a break in
• Alarm symptoms the mucosa is required to make the diagnosis of reflux esophagitis.
• Long-standing symptoms (>5 years)
Careful scrutiny of the esophagogastric junction with adequate air
• An equivocal or poor response to an acid-suppression trial
• Recurrence of symptoms after completion of a PPI trial
insufflation is needed to examine the mucosa in its entirety.
• Atypical symptoms that warrant confirmation of GERD Endoscopy is also used to identify the potential esophageal
• A need for endoscopic or surgical management of GERD complications of GERD, including esophageal ulceration and
peptic stricture, Barrett esophagus, and esophageal adenocarci-
noma. Alarm symptoms that suggest these complications include
long duration (>5 years) of typical symptoms, dysphagia, hema-
Endoscopic Examination
temesis or melena, and weight loss. The presence of these alarm
Endoscopic examination with esophagogastroduodenoscopy symptoms is a strong indication for diagnostic testing, especially
(EGD) allows direct visualization of the esophageal mucosa. endoscopy. Male sex, middle age, and nocturnal heartburn may be
Reflux esophagitis is characterized by mucosal erosions in the associated with a higher risk of esophagitis and its complications.
Figure 1.11. Summary of Los Angeles (LA) Classification for Erosive Esophagitis. LA grade A indicates 1 or more mucosal breaks with maximal
length 5 mm or less; LA grade B, 1 or more mucosal breaks with maximal length more than 5 mm but not continuous between the tops of 2 mucosal
folds; LA grade C, mucosal breaks that are continuous between the tops of 2 or more mucosal folds but involve less than 75% of the esophageal cir-
cumference; LA grade D, mucosal breaks that involve at least 75% of the esophageal circumference. (Adapted from AstraZeneca Pharmaceuticals LP
[Internet]. Wilmington [DE]. From: http://www.astrazeneca.com; used with permission.)
✓ Los Angeles classification system—commonly used to grade ero- inflammation, which requires a double-contrast study. The sen-
sive esophagitis as follows: sitivity for GERD is only 20%. With the addition of provocative
• Grade A: 1 or more mucosal breaks, less than 5 mm long and not maneuvers, the sensitivity increases but the specificity decreases
continuous between the tops of 2 mucosal folds greatly. A barium contrast study may also be useful for the deline-
• Grade B: 1 or more mucosal breaks, 5 mm or longer and not
ation of postoperative anatomical relationships and for evaluation
continuous between the tops of 2 mucosal folds
• Grade C: mucosal breaks that are continuous between the tops
of whether an antireflux repair is intact.
of 2 mucosal folds and involve less than 75% of the esophageal
✓ Although a barium contrast study (esophagram) should not be
circumference
used for the diagnosis of GERD, it can be helpful for evaluation
• Grade D: mucosal breaks that involve at least 75% of the esoph-
of large hiatal hernias and strictures
ageal circumference
✓ LA grade C or D esophagitis is consistent with severe esophagitis,

Prolonged Ambulatory Esophageal pH
confirms a diagnosis of GERD, and warrants treatment with a PPI
twice daily for 6 to 8 weeks with follow-up EGD to assess for
Monitoring Studies
healing of esophagitis and to rule out the presence of underlying Ambulatory pH monitoring of the esophageal lumen, a well-
Barrett esophagus established test, was introduced in the early 1970s. It provides
✓ Long-term acid suppression is typically indicated for patients objective evidence of the degree of GERD and its timing. This
with LA grade C or D esophagitis, usually at the lowest effective test is not needed for most patients with typical symptoms of
dose to control symptoms, given the high risk for recurrence of
GERD and for whom the diagnosis is not in doubt (ie, presence of
symptoms and associated complications without medical therapy
✓ When severe erosive esophagitis (LA grade C or D) or long-
severe erosive esophagitis or Barrett esophagus on endoscopy).
segment Barrett esophagus is seen on endoscopy, the diagnosis of The indications for ambulatory esophageal pH monitoring are
GERD is established and pH monitoring should not be performed listed in Box 1.4.
to determine whether GERD is present
Box 1.4. Indications for Ambulatory Esophageal pH

Barium Upper Gastrointestinal Tract Series Monitoring
Although the barium contrast study is a readily available test, it Atypical symptoms affecting the respiratory tract, ear,
is of limited usefulness in the evaluation of patients with GERD nose, or throat
and is no longer recommended for the diagnosis of GERD. Its Frequent atypical chest pain
major utility in GERD is for identifying strictures and large hi-
Refractory symptoms in well-established GERDa
atal hernias. It is insensitive for detecting erosions or superfi-
cial mucosal changes. The ability to reflux barium while at rest Preoperative confirmation of GERD
or in response to a provocative maneuver or postural change is
Abbreviation: GERD, gastroesophageal reflux disease.
not a sensitive test for GERD because in most patients the LES
pressure is normal. The contrast study has limited value for the a
Esophageal pH monitoring is done during acid blockade.
detection of mucosal changes other than the most pronounced
The test is performed with a probe that has a pH sensor at esophagitis. This may reflect day-to-day variability in reflux, or
its tip. The tip is placed 5 cm above the proximal border of patients may have limited their diet or activities that would lead to
the LES. Accurate location of this sphincter is critical because reflux. Even simultaneous recording of pH from adjacent sensors
normal values for acid exposure apply only if the distance be- may give different results in 20% of patients. Some patients have
tween the pH probe and the sphincter is 5 cm. The position of a physiologic degree of acid reflux but have a strong correlation
the LES usually is determined manometrically with a standard between the short-lived reflux events and symptoms. This may be
esophageal manometry study or with a single-pressure transducer due to a hypersensitive esophagus. Patients who frequently have
in combination with the pH probe, which can locate accurately symptoms of heartburn without corresponding reflux may have
the proximal border of the sphincter. Endoscopic measurement functional heartburn.
and pH step-up on withdrawal are not sufficiently accurate for the Generally, pH monitoring is performed when the patient is not
placement of the nasoesophageal probe. The pH is recorded by a taking any acid-suppressive medication. However, occasionally
small portable recorder, and study duration is 24 hours. and for specific indications, pH monitoring may be performed
Alternatively, wireless pH monitoring uses a wireless pH cap- when a patient is taking these medications. These indications
sule that is pinned to the distal esophagus 6 cm above the endo- include frequent typical reflux symptoms that are refractory to
scopically determined squamocolumnar junction. It transmits the what should be adequate acid-suppressive therapy with usual
pH measurements to a recorder worn on the chest. Its advantages doses of PPIs. Another indication is persistent extraesophageal
are that it can record for prolonged periods and patients may eat symptoms despite high-dose PPI therapy in patients with con-
without the discomfort of the nasal tube. Patients should maintain firmed reflux disease. If pH monitoring is performed while the
their usual diet, activity, and habits during the study to allow the patient is receiving treatment, a usual prerequisite is that the di-
assessment of findings in relation to their normal lifestyle. The agnosis of GERD is fairly certain, and the intent is to verify that
recorders have a patient-activated event button (or buttons) to in- the suppression of acid reflux is complete.
dicate meals, changes in posture, and symptom events. A typical A secondary aim of the study may be to establish a temporal
wireless pH study is 48 hours in duration and can be extended up correlation between symptoms and acid reflux events. However,
to 96 hours to potentially increase diagnostic yield. heartburn and regurgitation may occur in the absence of acid re-
Ambulatory reflux studies are analyzed initially by visual influx. This may be due to nonacid reflux, gastric dyspepsia, rumi-
spection of the graphs and then by computer-assisted quantitative nation, or an unrelated process. Often, gastric pH is measured
analysis of the number and duration of reflux episodes and the simultaneously to assess the degree of gastric acid suppression.
relation to any symptoms the patient may have recorded. Reflux Approximately one-third of patients receiving regular doses of
of acid is defined as a sudden decrease in intraesophageal pH PPIs have marked production of acid in the stomach at night,
to less than 4.0 that lasts longer than 5 seconds. Acid exposure but this breakthrough acid production does not always produce
time is the percentage of time that the esophageal pH is less than symptoms or actual esophageal acid reflux.
4.0 during the ambulatory reflux study. An acid exposure time
less than 4% is considered definitively normal (GERD is absent); ✓ Acid exposure time—percentage of time that the esophageal pH is
acid exposure time greater than 6% is considered definitively ab- less than 4.0 during the pH monitoring study
normal (GERD is present); and values in between are considered ✓ Symptom index—percentage of symptom events that occur imme-
indeterminate or inconclusive. Another important strength of diately after an acid reflux event (>50% is considered meaningful)
ambulatory reflux monitoring is that it allows determination of ✓ Symptom sensitivity index—percentage of reflux events associated
with symptoms (>5% is considered meaningful)
whether a temporal relation exists between the patient’s recorded
symptoms and acid reflux. This determination is made initially by
examining the tracing on which the symptom events have been ✓ Acid exposure time less than 4%—normal (ie, GERD most likely
marked and then performing a semiquantitative analysis. absent)
Several measures have been used to calculate the correla- ✓ Acid exposure time greater than 6%—abnormal (ie, GERD most
tion between symptoms and reflux, including the symptom index likely present)
(ie, the percentage of symptom events that are associated with ✓ For diagnosis or confirmation of GERD, pH monitoring should
a gastroesophageal reflux event). A symptom index greater be performed when the patient has not been receiving acid-
suppressive medication (PPI therapy should be stopped for
than 50% is considered positive. The symptom sensitivity index
≥7 days before the study)
is the percentage of reflux events associated with symptoms. ✓ In certain clinical scenarios, pH monitoring with or without im-
A symptom sensitivity index greater than 5% usually is regarded pedance may be performed while the patient is receiving acid-
as indicating an association between symptoms and acid reflux. suppressive medications (eg, when the diagnosis of GERD is
The symptom association probability (SAP) is the likelihood that fairly certain, and testing is used to verify that acid reflux has
symptoms occurring in association with gastroesophageal re- been completely suppressed with medication)
flux are true associations and not the result of chance. The SAP
uses a 2×2 Fisher exact test that compares time periods with and
without symptoms and with and without reflux events. A pos- Detection of Nonacid Reflux
itive SAP is greater than 0.95. Ultimately, however, the ability The main limitation of standard esophageal pH monitoring is
to determine whether a temporal association exists is dependent the detection of weakly acidic reflux, which may also contribute
on patients recording their symptoms diligently and accurately to symptoms. This limitation is addressed with technology that
during the study. uses a single probe to provide multilumen impedance sensor
The 24-hour ambulatory esophageal pH monitoring test has measurements and pH measurements (Figure 1.12). It is useful
limitations. Absolute values for sensitivity and specificity have especially for explaining persistent or recurrent symptoms in
been estimated because no standards exist for comparison with patients who are already receiving potent acid blockade therapy.
prolonged ambulatory pH monitoring. Also, pH monitoring may Intraluminal impedance uses an array of electrodes spaced along the
give false-negative results in 17% of patients with proven erosive length of a catheter positioned transnasally across the esophagus.
Figure 1.12. Typical Traces From Multichannel Intraluminal Impedance and pH Measurements. A, Acid reflux event. B, Nonacid reflux or
weakly acidic reflux event. (Adapted from Wise JL, Murray JA. Utilising multichannel intraluminal impedance for diagnosing GERD: a review. Dis
Esophagus. 2007; 20[2]‌:83-8; used with permission.)
Intraluminal movement of esophageal contents is detected by the actual change in pH; this relates to the volume of clearance of
decreased or increased impedance moving antegrade or retrograde the refluxate from the esophagus. So-called volumetric clearance
within the esophagus according to the conductivity of the esoph- occurs much faster, whereas the change in pH tends to be slower
ageal contents. In the event of gastroesophageal reflux, the highly because actual buffering is required. The most robust measure
conductive liquid gastric contents result in a retrograde decrease of abnormality of nonacid reflux is based on the frequency of
in esophageal impedance, illustrating a gastroesophageal reflux the events, but the system has limitations. For example, meals
event. Impedance relies on the differences in the impedance to the must be excluded. If patients already have esophagitis or Barrett
flow of electrical current in a medium according to its conductivity. esophagus or retained secretions, the baseline impedance in the
Although this technology has been used for several years, esophagus may be abnormally low, which may preclude the de-
its sensitivity for true reflux is probably about 90% with the use tection of further decreases. Placement of the probe is especially
of computer-based algorithms for detection of reflux. It has not crucial since intermittent movement of the catheter into a hiatal
been validated as well as the 24-hour pH test. The reflux events hernia may result in spurious reflux. In addition, patients who are
detected with impedance tend to be much shorter in duration than not receiving acid blockade therapy may have a normal number
of events, but the probe may not detect the delayed clearance at to endoscopists. It is rare to find severe disease in patients who
night when patients have nocturnal or supine reflux. have been treated with PPIs. This practice poses a problem when
The major strength of this technology and its greatest utility symptoms do not resolve as expected or when they improve only
are in looking with high fidelity at symptom-reflux correlations. partially. Even if the diagnosis of GERD was suggested at the
The most common symptom association is regurgitation. Scoring time of presentation and initiation of PPI therapy, the disease
systems have not yet evolved as they have with 24-hour pH cannot be confirmed by the usual method without stopping the
monitoring; rather, determining the number of reflux events and medications for a substantial time, and this may not be acceptable
the correlation with actual symptoms is the most appropriate use to patients in whom PPIs have healed the esophagitis. A careful
of this technology. It is also necessary to manually review the reexamination of the pretreatment symptoms may show that what
tracing to ensure that events identified as reflux by the monitoring the patient thought was GERD may have been something else,
system are true reflux events. Otherwise, chaotic tracings that such as dyspepsia.
occur after swallowing, for example, may be spuriously identified Acid-suppressive therapy is the cornerstone of GERD treat
as reflux. A further limitation is the lack of a reliable diagnostic ment. It provides excellent healing and relief of symptoms in
threshold for GERD; most experts suggest a threshold of 80 patients with esophagitis or classic heartburn. The relief appears
impedance-detected reflux events when a patient is receiving to be related directly to the degree of acid suppression achieved.
PPI therapy. However, impedance- detected reflux events are If symptoms resolve after an 8- week course of PPIs, an
considered a supportive diagnostic tool and should not be used in attempt should be made to discontinue PPI therapy. However,
isolation to diagnose GERD in clinical practice. before therapy is discontinued, lifestyle modifications should
be emphasized to the patient and the patient should implement
them. Lifestyle modifications alone may produce remission in
Other Tests
25% of patients with symptoms, but only a few patients are com-
Gastroesophageal scintigraphy is used rarely to demonstrate pliant with the restrictions. Consequently, long-term maintenance
gastroesophageal reflux or aspiration. The technique involves therapy is needed for most patients since symptoms often recur
feeding the patient a technetium Tc 99m sulfur colloid–labeled when PPI therapy is discontinued. The same principles that apply
meal and obtaining postprandial images with a gamma camera. to short-term therapy apply also to long-term therapy: Less acid
Delayed images obtained the following morning may show scin- equals less recurrence.
tigraphic activity within the lung fields, demonstrating aspiration
(usually only gross aspiration is apparent). The Bernstein test is
largely of historical interest. Proton Pump Inhibitors
PPIs are absorbed rapidly and taken up and concentrated pref-
Treatment erentially in parietal cells. They irreversibly complex with the
hydrogen-potassium-ATPase pump, which is the final step in acid
Patient-or physician-initiated empirical therapy for presumed production. To produce acid, parietal cells must form new pumps,
GERD has become commonplace. Indeed, guidelines for pri- a process that takes many hours. PPIs are more potent than his-
mary care have supported this approach for patients who have tamine (H2) blockers as suppressors of acid reflux. The healing
typical symptoms without alarm symptoms. Treatment options of esophagitis and the relief of chronic symptoms occur more
for GERD are summarized in Table 1.1. In general, an 8-week rapidly with PPIs than with H2 blockers. With PPI therapy, esoph-
trial of PPIs is recommended. Potent acid suppression with PPIs agitis heals within 4 weeks in more than 80% of patients and in
is effective and heals reflux esophagitis after only a few weeks virtually 100% by 8 weeks. However, the rate of complete relief
of therapy. This has resulted in a shift in the disease as it appears from symptoms is less than the rate of healing. Patients must un-
derstand that PPIs should be taken 30 to 60 minutes before meals
and not with food or at bedtime.
Table 1.1. Summary of Treatment Options for Gastroesophageal In general, if GERD is causing bothersome symptoms, the in-
Reflux Disease itial step in treatment often involves use of PPIs to maximize the
degree of acid suppression. It is well established that sometimes
Healing therapy can be gradually decreased successfully after treatment
Treatment Options rate, % with a PPI or switched to on-demand therapy, but this is rarely
Lifestyle modifications Elevate the head of the bed 20-30 suitable for patients with substantial complications of GERD.
Avoid eating within 3 h before Although routine doses of PPIs (eg, esomeprazole 40 mg daily,
going to bed lansoprazole 30 mg daily, omeprazole 20 mg daily, pantoprazole
Eat meals of moderate size and 40 mg daily, and rabeprazole 20 mg daily) are adequate for most
fat content patients with GERD, some patients may require higher or more
Lose excess weight frequent dosing to suppress GERD completely. If patients do not
Decrease intake of caffeine and
have a response to a PPI, switching to another PPI may be rea-
chocolate
Stop smoking
sonable. Data have demonstrated that standard PPI dosing may
Acid neutralization Antacids 20-30 be limited by nocturnal breakthrough of gastric acid suppression.
Chewing gum In patients with resultant nocturnal GERD symptoms, escalation
Alginate preparations of the PPI dose to twice daily or addition of a nighttime dose of
Acid suppression Histamine blockers 50 an H2 blocker can be considered.
Proton pump inhibitors ≥80 Inadequate response to PPI therapy may be the result of
Prokinetics Metoclopramide (not useful) 30-40 differences in metabolism by cytochrome P450 2C19 isozyme
Mechanical prevention Laparoscopic surgery ≥80
or bioavailability. Optimal timing of PPI administration is also
of reflux Endoscopic therapies ≥50
an important consideration because PPIs such as omeprazole are
Figure 1.13. Effectiveness of Proton Pump Inhibitors (PPIs). PPIs are the most effective drugs for maintenance therapy of gastroesophageal
reflux disease (GERD). Although the remission rate was slightly higher with PPI in combination with prokinetic therapy than with PPI alone, the
difference was not significant. H2RA indicates histamine-receptor antagonist. (Data from Vigneri S, Termini R, Leandro G, Badalamenti S, Pantalena
M, Savarino V, et al. A comparison of five maintenance therapies for reflux esophagitis. N Engl J Med. 1995 Oct;333[17]:1106-10.)
most effective if the stomach parietal cells are stimulated. This benefit when given in moderate doses (eg, cimetidine 400 mg
is achieved by having patients eat within an hour after taking the twice daily, famotidine 20 mg twice daily, nizatidine 150 mg
medication. Variable-release PPIs that are now available can alter twice daily, or ranitidine 150 mg twice daily) and heal esopha-
the pattern of release. They may be useful if stable preprandial gitis in 50% of patients. Higher doses suppress acid more rap-
dosing is not practical for a patient. idly. Lower doses are less effective, and nighttime-only dosing
With maintenance PPI therapy, the rate of relapse of esopha- misses all the daytime reflux that predominates. A particular role
gitis is 20% or less, which is lower than with H2 blockers (Figure for H2 blockers may be to augment PPIs when given at night to
1.13). Also, maintenance PPI therapy is more effective than H2 block nocturnal acid breakthrough; however, tachyphylaxis may
blockers in decreasing the need for redilatation in patients with develop if H2 blockade is used daily for more than 4 weeks.
reflux-associated benign strictures.
PPI therapy causes a clinically insignificant increase in the serum
level of gastrin. However, no risk of carcinoid has been realized. Prokinetics
The increase in serum levels of gastrin and parietal cell mass may The idea that a motility disorder is the genesis of GERD made
lead to rebound acid secretion after the therapy is stopped. a prokinetic approach intellectually enticing. Drugs such as
metoclopramide and, formerly, cisapride, which increase the
Potential Adverse Effects of PPIs tone of the LES and esophageal clearance and accelerate gastric
emptying, have been used to treat reflux. However, the healing
It is well accepted that the benefits of PPIs, when medically indi- rate and safety of these drugs have been questioned. Cisapride has
cated, outweigh their potential adverse effects. The most common been effectively withdrawn from use in the US, and the long-term
adverse effects of PPIs include headache, abdominal pain, use of metoclopramide is associated with a risk of irreversible
nausea, diarrhea, and constipation. Epidemiologic studies have tardive dyskinesia, limiting its use in clinical practice. Further,
raised the possibility of an association between PPI therapy and evidence of the efficacy of prokinetics in the management of
multiple potential adverse events, including osteoporosis, pneu- GERD is lacking. Drugs that target the TLESRs also have been
monia, dementia, and chronic kidney insufficiency. However, by used, including baclofen, which has been shown to reduce the
virtue of their retrospective design and use of large databases, total number of gastroesophageal reflux events, but its use in clin-
these studies are limited by confounders that are amplified by sta- ical practice is limited by its lack of tolerability.
tistically weak associations identified. Further, they are hampered
by protopathic bias, the concept that the identified association is ✓ PPIs produce more acid suppression than H2 blockers because
the result of the PPI being given in the context of the presumed they irreversibly complex with the hydrogen-potassium-ATPase
adverse event and not precipitating it. For these reasons, current pump rather than block histamine-induced stimulation of parietal
guidelines recommend long-term PPI use when clinically indi- cells alone
cated without the need for routine monitoring. ✓ Long-term use (>4 weeks) of daily H2 blockers can result in tach-
yphylaxis or diminished effectiveness with successive dosing of
the medication
H2-Receptor Blockers ✓ Unless they are indicated otherwise (eg, for gastroparesis),
prokinetics should generally not be used in the treatment of
H2-receptor blockers act by blocking the histamine-induced stim- GERD because of their adverse effect profile and limited efficacy
ulation of gastric parietal cells. H2 blockers provide moderate
Refractory Reflux Disease rumination or gastroparesis) or functional conditions (eg, func-

tional heartburn).
Refractory reflux disease can be defined as symptoms of GERD
that are refractory to treatment with regular dosages of PPIs. The ✓ Refractory reflux disease—GERD symptoms that are refractory
many common causes of refractory reflux symptoms are listed to treatment with PPIs

in Box 1.5. In patients with refractory reflux, PPI dosing and ad-
ministration should first be optimized (taken ≥30 minutes before
meals), and patient adherence to therapy should be assessed. If
patients have negative results on a pH monitoring study while
Functional Chest Pain
PPIs are being held, GERD is unlikely, and PPI therapy should be Many patients who describe having severe reflux often have
discontinued. In refractory cases when patients have persistent, very little reflux on 24-hour pH monitoring and have no endo-
bothersome symptoms despite having an initial evaluation, addi- scopic features of reflux. This condition has been termed func-
tional testing may be indicated, such as esophageal manometry tional heartburn. As with other functional gastrointestinal tract
to exclude a motility disorder (eg, achalasia) and EGD with bi- problems, female patients are overrepresented. Features of anx-
opsy (while PPIs are held) to exclude EoE. Other considerations iety, panic, hyperventilation, and somatization may be clues to the
for refractory reflux include nonesophageal conditions (eg, diagnosis. Antacid therapies may help decrease the frequency of
the symptoms, but they rarely relieve them completely. Therapies
aimed at decreasing visceral hypersensitivity may be helpful (eg,
Box 1.5. Causes of Refractory Reflux Symptoms in a low dose of an antidepressant).
Patients Receiving Proton Pump Inhibitor Therapy
✓ Functional heartburn—a sensation of heartburn that has no corre-
Incorrect initial diagnosis
lation with esophageal acid exposure

Nonreflux esophagitis—pill injury, skin diseases,
eosinophilic esophagitis, infection
Heart disease
Surgical and Endoscopic Antireflux Procedures
Chest wall pain
Gastric pain
What is the role of laparoscopic and endoscopic methods of
therapy? Medical therapy has been reduced to acid neutralization
Additional diagnoses or suppression of acid production. Surgeons and endoscopists
Dyspepsia have focused on the role of the mechanical or functional failure
Delayed gastric emptying of the antireflux barrier, and this has become the prime target of
Gastritis various approaches for preventing the reflux of gastric contents
Peptic ulcer disease
into the esophagus. However, most surgical and endoscopic
antireflux procedures are considered irreversible, so patients must
Nonulcer dyspepsia
be selected carefully to maximize chances of long-term success
Inadequate acid suppression without adverse outcomes.
Noncompliance For many years, antireflux surgery was performed through
Rapid metabolizers of proton pump inhibitors a transabdominal or transthoracic approach, but morbidity was
Dose timing
considerable. Surgical treatment was reserved for intractable re-
flux that the available medical therapy could not cure.
Insufficient dose
With the advent of PPIs, even severe degrees of reflux could
Zollinger-Ellison syndrome be well controlled, although the therapy can be expensive. With
Nonacid reflux the advent of minimally invasive surgery, surgical treatment has
Adenocarcinoma in Barrett esophagus had a renaissance. The laparoscopic antireflux procedure, namely
Postoperative reflux
Nissen fundoplication, has become a staple of the community
surgeon, and outcomes are similar to those of the open approach.
Partial gastrectomy
With well-chosen patients and experienced surgeons, a success
Vertical-banded gastroplasty rate of 80% to 90% is expected. The success rate decreases re-
Esophageal dysmotility markably if patients have symptoms refractory to PPI therapy,
Spasm patients have atypical symptoms other than heartburn or acid re-
Achalasia
gurgitation, there is poor documentation of objective evidence
of reflux disease, or the procedure is performed by less experi-
Nutcracker esophagus
enced surgeons. A substantial number of these patients resume
Functional chest pain taking acid-blocking medications after surgery, often for unclear
Hypersensitive esophagus reasons.
Somatic features of depression Preoperatively, it is important to verify that the patient’s
Functional heartburn
symptoms are indeed due to reflux. This is accomplished by
documenting severe reflux esophagitis (LA grade C or D) and a
Free regurgitation response to PPI therapy or by confirming the pathologic degree
Absence of lower esophageal sphincter tone of reflux with a 24-hour pH assessment while the patient is not
Large hiatal hernia receiving therapy. Patients who belch frequently should be in-
Achalasia formed that belching may not be possible after the operation and
Rumination
that gas bloat may result. Preoperative esophageal manometry
should also be performed to rule out achalasia or an important
motility disorder. It can identify a severe motility disturbance motility disorder are not considered good candidates. The Stretta
such as achalasia or connective tissue disease, and some surgeons procedure requires upper endoscopy with radiofrequency en-
want confirmation of a weak LES (if present). ergy delivered to the LES. This technique may be considered for
Postoperatively, 20% of patients have some dysphagia, but this patients who have chronic heartburn or regurgitation (or both),
persists in only 5%. Gas bloat, diarrhea, and dyspepsia may occur have a partial or complete response to acid-suppressive therapy,
or become more evident postoperatively and may be troubling and have decided against surgical management. Patients who
to patients. As many as one-third of patients may still require have large hiatal hernias, LES pressure that is very low, or poor
PPI therapy postoperatively for persistent reflux or dyspepsia. response to acid suppression therapy are not good candidates
Patients who have respiratory symptoms, free regurgitation, or for this procedure. Although early studies of these endoscopic
simple but severe heartburn without gastric symptoms seem to procedures for management of GERD show promising results
have the best response to antireflux surgery. Female sex, lack of with good safety profiles, additional studies are necessary to un-
objective evidence of pathologic reflux, and failure to respond to derstand the long-term clinical course after these procedures.
PPI therapy all predict a poor response to surgery. Patient selec-
tion and operator experience appear to be the main determinants
of a favorable surgical outcome. Reflux surgery is superior to Eosinophilic Esophagitis
long-term treatment with H2 blockers to maintain the healing of The most common cause of esophagitis has been acid reflux di-
GERD; however, follow-up for more than 10 years has shown an sease; however, since the late 1990s, a truly emerging disorder,
unexplained increase in mortality, predominantly due to cardio- EoE, has come to the fore. This typically occurs in adults with
vascular disease, in the surgical group. dysphagia and a history of food impaction. It occurs in young
Newer surgical techniques, such as the use of a band consisting adults and children and more frequently in men than in women.
of multiple permanent magnets, have been developed and shown In children, typical symptoms are vomiting and regurgitation
to have potential benefit. Magnetic sphincter augmentation helps in addition to dysphagia. Most patients with this disorder have
to augment the LES with magnets. Implantation of the mag- a history of atopy or a family history of atopy. Many have
netic sphincter can be performed with laparoscopic or robotic other atopic illnesses, including allergic rhinitis and asthma.
techniques, but patients must be selected carefully to identify Many patients have identified reactions to foods, although this
those that are most likely to benefit from the surgery. This proce- is documented better in children than in adults. In addition to
dure should be avoided in those with large hiatal hernias, severe the classic history of episodic dysphagia or food impaction,
esophagitis, Barrett esophagus, obesity (body mass index >35), adults who present with EoE may or may not have symptoms
and esophageal dysmotility. suggestive of reflux disease.
In patients with both obesity and GERD who desire surgical
management, Roux-en-Y gastric bypass can be helpful for both
conditions. During this surgery, the creation of a small gastric Diagnosis
pouch results in considerably less acid exposure to the esoph- The diagnosis can be suspected endoscopically by finding con-
agus. In patients with obesity, Nissen fundoplication alone risks centric rings, linear fissures or furrows, edema, strictures, or
poor outcomes, such as fundoplication disruption or hernia- white plaque in the esophagus (Figure 1.14). These may occur
tion, due to continued elevated intra-abdominal pressure after in the proximal, middle, or distal esophagus. Occasionally, ab-
surgery. rupt fissuring or cracking of the esophageal mucosa is reported
during endoscopy. Although this can be alarming, it rarely is as-
Patients Who Are Not Surgical Candidates sociated with true esophageal perforation. Rare cases have been
reported of Boerhaave syndrome (ie, spontaneous esophageal
If a patient has symptoms that are refractory to PPIs, the wisdom rupture) or dilatation-induced perforation. An esophagus with a
of recommending surgical therapy should be reconsidered care- normal appearance, however, does not rule out the possibility of
fully. A hypersensitive esophagus or gastric dysmotility may be EoE. Radiographic findings also can include concentric rings or
worse after fundoplication. Also, symptoms of irritable bowel so-called feline esophagus or tapered narrowing. The diagnosis
syndrome may worsen postoperatively. is confirmed by examination of 6 to 8 biopsy samples from the
esophagus. An increased number of eosinophils (>15 per high-
Endoscopic Methods of Therapy power field) in the esophagus is required for diagnosis.
It has become apparent that eosinophilia of the esophagus,
Several endoscopic methods have been tried or are in develop-
a more encompassing term than EoE, does not solely repre-
ment for the treatment of GERD. Endoscopic methods to alter
sent EoE; rather, this is a clinicopathologic condition that also
the shape or to tighten the esophagogastric junction are in var-
requires symptoms of esophageal dysfunction for the diagnosis.
ious stages of development. These consist of inserting sutures or
In addition, patients with gastroesophageal reflux can also have
other devices into the gastric wall to create a mechanical barrier
esophageal mucosal eosinophilia that responds to vigorous acid
to reflux (the barrier acts like a speed bump). Some endoscopic
blockade. In these patients, reflux is the primary cause of the eo-
procedures are an attempt to replicate the mechanical barrier pro-
sinophilia and likely symptoms, and often the recommendation is
vided by fundoplication. Although some of these methods have
to treat patients who have acid suppression and then retest them
been in clinical use, evidence for long-term efficacy is lacking.
after 12 weeks of therapy. However, the diagnosis of EoE does
Transoral incisionless fundoplication also requires upper en-
not require an unsuccessful PPI treatment trial.
doscopy and creates a full-thickness, serosa-to-serosa plication
and partial fundoplication with fastener fixations that extend
longitudinally 3 cm and circumferentially 200° to 300°. For this ✓ Eosinophilic esophagitis—a common cause of dysphagia; diag-
nosis requires the finding of more than 15 eosinophils per high-
procedure, patients should be selected carefully, and those with
power field on esophageal biopsies
a large hiatal hernia, severe esophagitis, Barrett esophagus, or
Figure 1.14. Endoscopic Features of Eosinophilic Esophagitis Showing Spectrum of Severity. A, Fixed rings. Top row, Mild case shows subtle
circumferential ridges with esophageal distention. Middle row, Moderate-severity case shows distinct rings that do not occlude passage of a diagnostic
endoscope. Bottom row, Severe case shows distinct rings that do not permit passage of a diagnostic endoscope. B, Exudates. Upper row, Mild case has
white lesions occupying less than 10% of the esophageal surface area. Lower row, Severe case has white lesions occupying 10% or more of the esoph-
ageal surface area. C, Furrows. Upper row, In this mild case, the vertical lines do not have visible depth. Lower row, In this severe case, the vertical
lines are clearly indented into the mucosa. D, Edema. Top row, Normal findings include distinct vasculature. Middle row, Mild case shows decreased
vascular clarity. Bottom row, In this severe case, the vessels cannot be appreciated. E, Transient rings. Two examples (upper row and lower row) show
the esophagus without insufflation (images on left) and with insufflation (images on right). F, Crepe paper esophagus. (Adapted from Hirano I, Moy N,
Heckman MG, Thomas CS, Gonsalves N, Achem SR. Endoscopic assessment of the oesophageal features of eosinophilic oesophagitis: validation of a
novel classification and grading system. Gut. 2013 Apr;62[4]‌:489-95; used with permission.)
✓ EoE can be accompanied by various endoscopic findings, in-

also be documented. The various treatment options include
cluding rings, furrows, exudates, stricture, and edema; however, pharmacologic and nonpharmacologic therapies. PPIs, top-
an esophagus with a normal appearance does not exclude the pos- ical corticosteroids, and dupilumab are considered to be first-
sibility of EoE line pharmacologic therapies. Although all 3 therapies may be
effective, PPIs are often used initially given their generally fa-
vorable side-effect profile and long track record. However, top-
Treatment ical corticosteroids are generally also considered safe and are not
accompanied by the adverse effects of systemic corticosteroids.
Although treatment of EoE is often focused on symptomatic
Dupilumab, a monoclonal antibody that inhibits interleukin-4
improvement, endoscopic and histologic remission should
and interleukin-13 signaling, has been shown to be effective and
safe and is the first medication approved by the US Food and ✓ Mainstay of treatment of EoE—PPIs, topical corticosteroids, and
Drug Administration for EoE. However, where dupilumab fits in dietary therapy (6-food elimination diet); clinicians and patients
the treatment algorithm for EoE still needs to be fully established. should discuss these options and determine the best initial therapy
The mainstay of nonpharmacologic therapy is the 6-food elim- ✓ Six-food elimination diet
ination diet, whereby patients initially eliminate dairy products, • Initial elimination of 6 food groups (dairy foods, wheat, eggs,
wheat, eggs, soy, seafood, and nuts from their diet. More re- soy, seafood, and nuts) for 6 to 8 weeks
cently, 2-food and 4-food elimination diets have been proposed, • After initial elimination period, reevaluation with upper endos-
which also show a favorable response rate, albeit lower than copy and biopsies
that observed with the 6-food elimination diet. In general, with • If eosinophil count has improved, food allergens are introduced
individually
elimination diets, the food items are eliminated for 6 to 8 weeks,
• Subsequent upper endoscopy with biopsies is used to identify
and then the patient is evaluated with endoscopy and biopsies the culprit food allergen
to monitor for histologic remission. If the eosinophil count has
improved, the food items are slowly introduced 1 at a time (over
4-6 weeks), and follow-up endoscopy with biopsies is performed
with the goal of identifying the food allergen(s). Infectious Esophagitis
The use of intermittent dilatation has also been supported, par- Infections are the third leading cause of esophagitis, behind re-
ticularly in adults, although many physicians restrict the use of flux esophagitis and EoE. Patients with infectious esophagitis
dilatation to dominant strictures that have resisted or have not classically present with odynophagia. The most common causes
responded to treatment with topical corticosteroids. Other agents, include Candida, herpes simplex virus (HSV), and cytomegalo-
including experimental biologic therapies, have been tried with virus (CMV) (Figure 1.16). Infection with Candida is the most
the hope of decreasing the infiltration of eosinophils, and several common cause of infectious esophagitis. The characteristic
clinical trials are underway to identify other novel therapies. finding on endoscopy is thick, white plaques in the esophagus.
The potential overlap between EoE and reflux esophagitis is Topical antifungals (eg, nystatin) are acceptable treatment of oro-
considerable. Reflux esophagitis can be associated with occa- pharyngeal candidiasis, but the mainstay of therapy for esoph-
sional infiltration of eosinophils in the esophagus. In contrast, ageal candidiasis is systemic antifungal therapy, typically with
EoE is associated with at least 15 eosinophils per high-power oral fluconazole.
field. Sampling variation may also be a consideration because in While esophageal candidiasis and HSV esophagitis may
some patients, eosinophilic infiltration sometimes involves only be present in immunocompetent and immunocompromised
specific locations. In general, biopsies should be taken from both patients, esophagitis secondary to CMV is generally present
the distal and the proximal or middle esophagus for evaluation only in immunocompromised patients. The classic endoscopic
of EoE. and histologic appearance of HSV esophagitis is multiple,
Clinicians should be able to recognize the typical clinical sce- small lesions with a punched- out, volcano- like appearance
nario. For example, a young male patient who has a history of and multinucleated giant cells with nuclear molding and nu-
food impaction has concentric rings or fissuring in the esophagus clear chromatin. In contrast, the characteristic endoscopic
in a radiographic or endoscopic image. The diagnosis is made by and histologic findings of CMV esophagitis are linear, deeper
finding a substantial number of eosinophils (>15 per high-power ulcerations with nuclear and cytoplasmic inclusions known
field) in esophageal biopsy specimens (Figure 1.15). as owl’s eyes. The mainstay of therapy is acyclovir for HSV
esophagitis and ganciclovir for CMV esophagitis. Consultation
with an ophthalmologist is also recommended to rule out CMV
retinitis in these patients.
✓ Common causes of infectious esophagitis— Candida, HSV,

and CMV
✓ Endoscopic and histologic findings in infectious esophagitis
• Esophageal candidiasis—thick, white plaques
• HSV esophagitis—multiple, small, punched-out ulcers with a
volcano-like appearance; multinucleated giant cells
• CMV esophagitis—linear, deeper ulcerations; owl’s eyes cyto-
plasmic inclusions
✓ Treatment of infectious esophagitis
• Esophageal candidiasis—systemic (not topical) antifungals
• HSV esophagitis—acyclovir
• CMV esophagitis—ganciclovir or valganciclovir
Pill-Induced Esophagitis
Figure 1.15. Hyperplastic Squamous Esophageal Epithelium. Pill-induced esophagitis is a common cause of odynophagia
Many intraepithelial eosinophils are present (arrows). The superfi- and dysphagia. Although many medications have been
cial distribution is characteristic of eosinophilic esophagitis. Inset, implicated with pill-induced esophagitis, commonly implicated
A collection of eosinophils (arrows) is close to the surface (hematoxylin- medications include oral bisphosphonates, nonsteroidal anti-
eosin). (Courtesy of Thomas C. Smyrk, MD, Department of Laboratory inflammatory drugs, potassium, iron, quinidine, and antibiotics
Medicine and Pathology, Mayo Clinic, Rochester, Minnesota; used with
such as tetracycline and clindamycin. The most common site
permission.)
of injury is the middle esophagus, which may be affected
Suggested Reading
Chang KJ, Bell R. Transoral incisionless fundoplication. Gastrointest
Endosc Clin N Am. 2020 Apr;30(2):267–89.
Dent J. Patterns of lower esophageal sphincter function associated with
gastroesophageal reflux. Am J Med. 1997 Nov 24;103(5A):29S-32S.
DeVault KR, Castell DO; The Practice Parameters Committee of the
American College of Gastroenterology. Updated guidelines for the
diagnosis and treatment of gastroesophageal reflux disease. Am J
Gastroenterol. 1999 Jun;94(6):1434–42.
Elliott EJ, Thomas D, Markowitz JE. Non-surgical interventions for
eosinophilic esophagitis. Cochrane Database Syst Rev. 2010 Mar
17;(3):CD004065.
El-Serag HB, Sweet S, Winchester CC, Dent J. Update on the epidemi-
ology of gastro-oesophageal reflux disease: a systematic review. Gut.
2014 Jun;63(6):871–80.
Fass R, Cahn F, Scotti DJ, Gregory DA. Systematic review and meta-
analysis of controlled and prospective cohort efficacy studies of en-
doscopic radiofrequency for treatment of gastroesophageal reflux
disease. Surg Endosc. 2017 Dec;31(12):4865–82.
Fletcher J, Wirz A, Young J, Vallance R, McColl KE. Unbuffered highly
acidic gastric juice exists at the gastroesophageal junction after a
meal. Gastroenterology. 2001 Oct;121(4):775–83.
Furuta GT, Katzka DA. Eosinophilic esophagitis. N Engl J Med. 2015
Oct 22;373(17):1640–8.
Furuta T, Ohashi K, Kosuge K, Zhao XJ, Takashima M, Kimura M, et al.
CYP2C19 genotype status and effect of omeprazole on intragastric
pH in humans. Clin Pharmacol Ther. 1999 May;65(5):552–61.
Ganz RA, Edmundowicz SA, Taiganides PA, Lipham JC, Smith CD,
DeVault KR, et al. Long-term outcomes of patients receiving a mag-
netic sphincter augmentation device for gastroesophageal reflux. Clin
Gastroenterol Hepatol. 2016 May;14(5):671–7.
Ganz RA, Peters JH, Horgan S, Bemelman WA, Dunst CM, Edmundowicz
SA, et al. Esophageal sphincter device for gastroesophageal reflux di-
sease. N Engl J Med. 2013 Feb 21;368(8):719–27.
Genval Workshop Report. An evidence-based appraisal of reflux disease
management. Gut. 1999 Apr;44 Suppl 2:S1–16.
Gillen D, Wirz AA, Ardill JE, McColl KE. Rebound hypersecretion after
omeprazole and its relation to on- treatment acid suppression and
Helicobacter pylori status. Gastroenterology. 1999 Feb;116(2):239–47.
Figure 1.16. Infectious Esophagitis. Characteristic pathologic Gonsalves N. Dietary therapy for eosinophilic esophagitis. Gastroenterol
findings are shown for esophagitis caused by Candida, herpes simplex Hepatol (N Y). 2015 Apr;11(4):267–76.
virus (HSV), and cytomegalovirus (CMV). Top, Grocott methenamine- Gyawali CP, Kahrilas PJ, Savarino E, Zerbib F, Mion F, Smout AJPM,
silver stain shows numerous yeast forms, including pseudohyphae (arrows) et al. Modern diagnosis of GERD: the Lyon Consensus. Gut. 2018
consistent with Candida species. Middle, HSV immunohistochemical Jul;67(7):1351–62.
stain shows nuclear and granular cytoplasmic positivity in infected cells. Hirano I, Dellon ES, Hamilton JD, Collins MH, Peterson K, Chehade
Bottom, CMV immunohistochemical stain shows intranuclear and cyto- M, et al. Efficacy of dupilumab in a phase 2 randomized trial of
plasmic positivity (arrows) in infected cells. (Adapted from Hoversten P, adults with active eosinophilic esophagitis. Gastroenterology. 2020
Kamboj AK, Katzka DA. Infections of the esophagus: an update on risk Jan;158(1):111–22.
factors, diagnosis, and management. Dis Esophagus. 2018 Dec 1;31[12]; Hirano I, Moy N, Heckman MG, Thomas CS, Gonsalves N, Achem SR.
used with permission.) Endoscopic assessment of the oesophageal features of eosinophilic
oesophagitis: validation of a novel classification and grading system.
Gut. 2013 Apr;62(4):489–95.
by extrinsic compression from the aortic arch or left atrium, Hogan WJ, Shaker R. Supraesophageal complications of gastroesophageal
resulting in mild luminal narrowing and allowing for medica- reflux. Dis Mon. Mar 2000;46(3):193–232.
tion to lodge in this area. Most cases resolve within a few days Holtmann G, Cain C, Malfertheiner P. Gastric Helicobacter pylori in-
with discontinued use of the medication. Rarely, strictures de- fection accelerates healing of reflux esophagitis during treatment
velop. When possible, use of culprit medications should be dis- with the proton pump inhibitor pantoprazole. Gastroenterology. 1999
continued; otherwise, they should be taken with precautions. In Jul;117(1):11–6.
general, potentially offending medications should be taken with Hoversten P, Kamboj AK, Katzka DA. Infections of the esophagus: an
update on risk factors, diagnosis, and management. Dis Esophagus.
at least 250 mL (about 8 oz) of water, and patients should sit in
2018 Dec 1;31(12).
the upright position for a minimum of 30 minutes after taking Kahrilas PJ, Shi G, Manka M, Joehl RJ. Increased frequency of tran-
the medication. While the diagnosis is primarily based clini- sient lower esophageal sphincter relaxation induced by gastric
cally on the history and presence of a culprit medication, EGD distention in reflux patients with hiatal hernia. Gastroenterology.
may be considered if patients have severe or alarm symptoms or 2000 Apr;118(4):688–95.
symptoms that last beyond 1 week after use of the medication Katz PO, Dunbar KB, Schnoll- Sussman FH, Greer KB, Yadlapati
was discontinued. R, Spechler SJ. ACG clinical guideline for the diagnosis and
management of gastroesophageal reflux disease. Am J Gastroenterol. Shaheen NJ, Falk GW, Iyer PG, Souza RF, Yadlapati RH, Sauer BG, et al.
2022 Jan 1;117(1):27–56. Diagnosis and management of Barrett’s esophagus: an updated ACG
Katz PO, Gerson LB, Vela MF. Guidelines for the diagnosis and manage- guideline. Am J Gastroenterol. 2022 Apr 1;117(4):559–87.
ment of gastroesophageal reflux disease. Am J Gastroenterol. 2013 Shay S, Tutuian R, Sifrim D, Vela M, Wise J, Balaji N, et al. Twenty-
Mar;108(3):308–28. four hour ambulatory simultaneous impedance and pH monitoring: a
Katzka DA. Eosinophilic esophagitis. Curr Opin Gastroenterol. 2006 multicenter report of normal values from 60 healthy volunteers. Am J
Jul;22(4):429–32. Gastroenterol. 2004 Jun;99(6):1037–43.
Katzka DA, Paoletti V, Leite L, Castell DO. Prolonged ambulatory pH Stanghellini V. Three- month prevalence rates of gastrointestinal
monitoring in patients with persistent gastroesophageal reflux disease symptoms and the influence of demographic factors: results from
symptoms: testing while on therapy identifies the need for more aggressive the Domestic/ International Gastroenterology Surveillance Study
anti-reflux therapy. Am J Gastroenterol. 1996 Oct;91(10):2110–3. (DIGEST). Scand J Gastroenterol Suppl. 1999;231:20–8.
Klauser AG, Schindlbeck NE, Muller-Lissner SA. Symptoms in gastro- Tobey NA. How does the esophageal epithelium maintain its integrity?
oesophageal reflux disease. Lancet. 1990 Jan 27;335(8683):205–8. Digestion. 1995;56 Suppl 1:45–50.
Klinkenberg-Knol EC, Nelis F, Dent J, Snel P, Mitchell B, Prichard P, Tobey NA. Systemic factors in esophageal mucosal protection. Digestion.
et al. Long-term omeprazole treatment in resistant gastroesophageal 1995;56 Suppl 1:38–44.
reflux disease: efficacy, safety, and influence on gastric mucosa. Trad KS, Fox MA, Simoni G, Shughoury AB, Mavrelis PG, Raza M,
Gastroenterology. 2000 Apr;118(4):661–9. et al. Transoral fundoplication offers durable symptom control for
Labenz J, Jaspersen D, Kulig M, Leodolter A, Lind T, Meyer-Sabellek chronic GERD: 3-year report from the TEMPO randomized trial with
W, et al. Risk factors for erosive esophagitis: a multivariate analysis a crossover arm. Surg Endosc. 2017 Jun;31(6):2498–508.
based on the ProGERD study initiative. Am J Gastroenterol. 2004 Triadafilopoulos G. Stretta: a valuable endoscopic treatment modality
Sep;99(9):1652–6. for gastroesophageal reflux disease. World J Gastroenterol. 2014 Jun
Locke GR, 3rd, Talley NJ, Fett SL, Zinsmeister AR, Melton LJ, 28;20(24):7730–8.
3rd. Prevalence and clinical spectrum of gastroesophageal re- Vakil N, Kahrilas P, Magner D, Skammer W, Levine J. Does baseline Hp
flux: a population- based study in Olmsted County, Minnesota. status impact erosive esophagitis (EE) healing rates? [Abstract]. Am
Gastroenterology. May 1997;112(5):1448–56. J Gastroenterol. 2000;95(9):2438–9.
Orlando RC. Why is the high grade inhibition of gastric acid secretion Vigneri S, Termini R, Leandro G, Badalamenti S, Pantalena M, Savarino
afforded by proton pump inhibitors often required for healing of re- V, et al. A comparison of five maintenance therapies for reflux esoph-
flux esophagitis? An epithelial perspective. Am J Gastroenterol. Sep agitis. N Engl J Med. 1995 Oct 26;333(17):1106–10.
1996;91(9):1692–6. Wise JL, Murray JA. Utilising multichannel intraluminal impedance for
Peery AF, Crockett SD, Murphy CC, Jensen ET, Kim HP, Egberg MD, diagnosing GERD: a review. Dis Esophagus. 2007;20(2):83–8.
et al. Burden and cost of gastrointestinal, liver, and pancreatic Wu ZH, Yang XP, Niu X, Xiao XY, Chen X. The relationship between
diseases in the United States: update 2021. Gastroenterology. 2022 obstructive sleep apnea hypopnea syndrome and gastroesophageal re-
Feb;162(2):621–44. flux disease: a meta-analysis. Sleep Breath. 2019 Jun;23(2):389–97.
Richter JE, Rubenstein JH. Presentation and epidemiology of gastroeso Zografos GN, Georgiadou D, Thomas D, Kaltsas G, Digalakis M. Drug-
phageal reflux disease. Gastroenterology. 2018 Jan;154(2):267–76. induced esophagitis. Dis Esophagus. 2009;22(8):633–7.
2
Barrett Esophagus and Esophageal Cancer

PRASAD G. IYER, MD
KORNPONG VANTANASIRI, MD
Barrett Esophagus The pathologic criterion is the presence of intestinal meta-

plasia with goblet cells (ie, specialized intestinal metaplasia) in
Definitions
the endoscopic biopsy specimens (Figure 2.2). This criterion is
Barrett esophagus (BE) is an acquired condition characterized by based on evidence that columnar metaplasia with goblet cells in
the replacement of the squamous epithelium lining the esophagus the esophagus is associated with an increased risk of progression
by partially intestinalized columnar epithelium. It is thought to to esophageal adenocarcinoma.
be a complication of gastroesophageal reflux and may reflect an BE has been classified into long-segment BE (length of visible
adaptive response to reflux of gastric contents into the esophagus. columnar mucosa in the esophagus ≥3 cm) and short-segment
It is the strongest known risk factor for esophageal adenocarci- BE (length of visible columnar mucosa in the esophagus <3 cm).
noma (EAC) and increases the risk of EAC by 30-to 50-fold. Intestinal metaplasia of the cardia or intestinal metaplasia of the
Endoscopic and pathologic criteria must be met to make the di- EGJ refers to the histologic finding of intestinal metaplasia with
agnosis of BE. goblet cells at a squamocolumnar junction in the normal location
The endoscopic criterion is the presence of columnar-appearing and with a normal appearance (Figure 2.3). Given this distinc-
mucosa in the tubular esophagus (Figure 2.1), extending at least tion, a normal-appearing and normally located squamocolumnar
1 cm above the proximal extent of the gastric folds, which is the junction should not be biopsied.
anatomical landmark for the esophagogastric junction (EGJ).
A population- based study from Olmsted County, Minnesota, ✓ Diagnosis of BE—endoscopic evidence of at least 1 cm of columnar
published in 2011, showed that patients with specialized intes- mucosa in the tubular esophagus and histopathologic evidence of
tinal metaplasia of the EGJ have a significantly lower risk for intestinal metaplasia with goblet cells on biopsy specimens
EAC compared with patients who have BE. The most commonly
used endoscopic grading system for BE, the Prague C & M
criteria, was developed to help promote the use of standardized Pathophysiology
reporting systems to uniformly determine the endoscopic length
BE is thought to be a reparative response to the epithelial
and appearance of BE with good interobserver agreement.
damage caused by chronic reflux of gastric contents into the
distal esophagus. In the US, approximately 10% of patients with
chronic gastroesophageal reflux symptoms have evidence of BE
Abbreviations: BE, Barrett esophagus; BMI, body mass index; CT,
on endoscopy. Patients who have BE have longer durations of
computed tomography; EAC, esophageal adenocarcinoma; EGJ,
esophagogastric junction; EMR, endoscopic mucosal resection; ESD,
esophageal acid exposure, larger hiatal hernias, decreased lower
endoscopic submucosal dissection; GERD, gastroesophageal reflux di- esophageal sphincter pressures, evidence of decreased esopha-
sease; HGD, high- grade dysplasia; LGD, low-
grade dysplasia; PET, geal motility, and decreased esophageal sensitivity to acid re-
positron emission tomography; RFA, radiofrequency ablation; SCC, flux compared with patients who do not have gastroesophageal
squamous cell carcinoma reflux and those who have gastroesophageal reflux but without
23
Epidemiology
An autopsy study from Olmsted County, Minnesota, published
in 1990 documented that the prevalence of long-segment BE in
Olmsted County was 376 cases per 100,000 population. This
study also highlighted that the prevalence of long-segment BE
when assessed by autopsy was almost 20-fold the prevalence
when assessed by clinically indicated endoscopy (22 cases per
100,000 population), indicating that most cases of BE in the com-
munity are not diagnosed.
Data from 2 population-based studies from Europe have shed
additional light on the population prevalence of BE. In a Swedish
study, 1,000 participants living in 2 counties underwent endos-
copy; 16 of the participants (prevalence, 1.6%) were identified
as having BE (with endoscopic evidence of columnar mucosa
in the esophagus and histologic confirmation of intestinal meta-
plasia). The prevalence of BE in those with symptomatic reflux
(2.3%) and those without (1.8%) was not statistically different.
In a second study, performed in Italy, 1,033 participants with and
without reflux symptoms had endoscopy and 1.3% were found
to have BE. The generalizability of these study estimates to the
US is not clear. In both studies the prevalence of BE may have
been underestimated because of the low rate of confirmation of
intestinal metaplasia in patients with endoscopically suspected
BE; this may have been due to differences in the number and size
of biopsy specimens. In addition, the threshold of the length of
suspected BE for biopsy acquisition was not specified. Compared
with the US population, the population studied was younger and
had a higher prevalence of Helicobacter pylori infection (37%)
and a lower prevalence of obesity (only 16% had a body mass
index [BMI] >30 [calculated as weight in kilograms divided by
height in meters squared]).
A recent systematic review and meta-analysis reported that the
prevalence of BE was 0.8% in low-risk populations overall and
slightly higher (1.1%) in Western populations. The prevalence
increases with the increasing number of additional risk factors,
such as age older than 50 years, male sex, gastroesophageal re-
flux disease (GERD), family history of BE or EAC, and obesity.
Different studies have reported that the incidence of the di-
agnosis of BE is increasing in conjunction with the increasing
incidence of EAC both in older patients and in younger patients
(<50 years old). A recent study showed that the incidence of
young- onset EAC has been rapidly increasing, and patients
have been presenting with more advanced stages. A study from
Olmsted County, Minnesota, showed a parallel increase in the
number of endoscopic examinations performed (Figure 2.4).
However, a study from Europe showed that the increase in the
incidence of BE persisted even after adjustment for the number
Figure 2.1. Endoscopic Appearance of Barrett Esophagus. A, of endoscopic examinations.
Columnar mucosa in the distal esophagus is shown with white light im-
aging. B, This corresponding image was obtained with narrow band im-
aging (tongues and islands of pink mucosa are present amid pale white Risk Factors
squamous mucosa). Age
BE is an acquired disorder. The prevalence of long-segment BE
BE. Control of acid reflux (when documented with ambulatory increases with age, particularly after the fifth decade. The mean
pH studies) in patients with BE is more difficult than in patients age at the time of clinical diagnosis was 63 years in 1 population-
without BE. Resolution of acid reflux symptoms correlates based study. Long-segment BE is rare in children.
poorly with control of acid reflux in patients with BE. Persistent
acid reflux (documented with 24-hour pH studies) occurs in
26% to 40% of patients with BE who are asymptomatic while Male Sex
receiving proton pump inhibitor therapy. Predictors of persistent BE is more prevalent among male patients. In a Mayo Clinic
acid reflux despite symptom control in patients with BE are not study of patients who had endoscopy between 1976 and 1989,
well described. long-segment BE was twice as common in male patients as in
2. Barrett Esophagus and Esophageal Cancer 25
were more likely to have BE of any length than Black (1.6%, P=
.004) or Hispanic persons (1.7%, P <.001).
Reflux Symptoms
BE has been described in 2% to 20% of patients with symptoms of
gastroesophageal reflux (higher estimates are from referral center
studies and lower estimates are from population-based studies).
The duration of reflux symptoms (>5-10 years, compared with
shorter durations) appears to predict the presence of BE better
than the severity or frequency of symptoms. Short-segment BE
is twice as prevalent as long-segment BE in patients with reflux
symptoms. However, it is important to note that a substantial pro-
portion of patients with BE (as many as 40%-50%) do not have
frequent symptoms of gastroesophageal reflux. Recent studies
have reported that the association of reflux symptoms with BE
is strong for long-segment BE and weak for short-segment BE.
Figure 2.2. Intestinal Metaplasia With Goblet Cells. (Hematoxylin-
eosin, original magnification ×400.) Obesity
The association of BMI with BE has been investigated by mul-
female patients. This finding has been corroborated in other tiple authors, but the results have been conflicting (some studies
studies as well. In a large multicenter Italian study (patients were have shown an association with increased BMI and others have
enrolled from 1987-1989), BE was 2.6 times more common not). A systematic review clarified this: BMI was not significantly
in male patients than in female patients. In the 2005 Swedish different between patients with BE and controls with GERD, but
population-based study, the male to female ratio of biopsy- it was higher for patients with BE than for healthy controls. This
proven BE was 1.5:1. led the authors to conclude that increased BMI may contribute to
an increased risk of BE by causing increased gastroesophageal
reflux, but it may not increase the risk of BE in patients with
Geography and Ethnicity GERD. In addition, the strong male and White predominance
BE has been described frequently in countries in North America, of BE and esophageal carcinoma is not explained by increasing
Europe, and Australia, but it appears to be less common in other obesity (as measured by BMI), which afflicts both sexes and all
countries, such as Japan. However, recent reports from China, ethnic groups.
Singapore, and other Asian countries have appeared. In a recent Visceral adiposity (in contrast to BMI as a measure of overall
single-center US retrospective cross-sectional cohort study of adiposity) may provide a better explanation for the male and
2,100 people (11.8% Black, 22.2% Hispanic, and 37.7% White) White predilection of BE. The distribution of body fat is more
who had endoscopy from 2005 to 2006, White persons (6.1%) visceral than truncal in groups at high-risk for BE (male and
Figure 2.3. Barrett Esophagus (BE) Compared With Intestinal Metaplasia of the Cardia. Patients with long-segment or short-segment BE have
columnar mucosa extending into the tubular esophagus. Biopsy specimens show intestinal metaplasia with goblet cells. If intestinal metaplasia with
goblet cells is found at a normally located Z line, the patient has intestinal metaplasia of the cardia, which confers a lower cancer risk. Asterisk indicates
end of tubular esophagus and beginning of stomach.
Figure 2.4. Incidence of Diagnosed Barrett Esophagus (BE) and Number of Upper Endoscopic Examinations Performed Annually in
Residents of Olmsted County, Minnesota, From 1965 to 1995. (Adapted from Conio M, Cameron AJ, Romero Y, Branch CD, Schleck CD, Burgart
LJ, et al. Secular trends in the epidemiology and outcome of Barrett’s oesophagus in Olmsted County, Minnesota. Gut. 2001 Mar;48[3]‌:304-9; used
with permission.)
White) compared to others (female and Black). Also, abdom- symptoms in relatives of probands with BE or esophageal adeno-
inal diameter (independent of BMI) is associated with symptoms carcinoma has been reported, although data are not definitive for
of gastroesophageal reflux in White persons but not in Black or an increased risk of BE in relatives of probands with BE. BE is
Asian persons. Several authors have reported an association be- probably a complex genetic disease influenced by environmental
tween visceral adiposity (measured as waist circumference) and factors. Research into identifying gene loci that may influence the
BE. A population-based case-control study found an associa- risk of BE is continuing.
tion between increased waist circumference and the diagnosis
of BE, independent of BMI (odds ratio, 2.24), when compared
Cigarette Smoking
with population controls. This study reported an increased risk
for persons with a waist circumference greater than 80 cm. The Several studies have shown that cigarette smoking is a strong
study did not find an association between BMI and BE. Another risk factor for BE and significantly increases the risk of pro-
clinic-based case-control study reported that an increased waist gression of BE to EAC. A study analyzing data from the
to hip ratio, a measure of central adiposity, was associated with Barrett’s and Esophageal Adenocarcinoma Consortium showed
the diagnosis of BE (odds ratio, 2.8). The association between that cigarette smoking is a risk factor for BE, and the associ-
BMI and BE was attenuated when both waist to hip ratio and ation strengthened with increased smoking exposure. Another
BMI were modeled together. This association is strengthened population-based study (from Northern Ireland) showed that to-
further by studies that found that abdominal obesity (measured bacco smoking doubled the risk of progression of BE to high-
by waist circumference) is associated with increased postpran- grade dysplasia (HGD) or EAC, compared to patients with BE
dial intragastric pressure, disruption of the EGJ (leading to the who were nonsmokers.
formation of hiatal hernia), and increased transient lower esoph-
ageal sphincter relaxations in the postprandial state. A reflux-
Intestinal Metaplasia of the Cardia or EGJ
independent systemic effect of abdominal fat on esophageal
inflammation and neoplasia has been postulated, mediated by In various studies, the prevalence of intestinal metaplasia of the
proinflammatory factors, adipokines produced by visceral fat, EGJ has been reported to range from 6% to 15%. Compared
and insulin or insulin growth factors. with patients who have BE, patients with intestinal meta-
plasia appear to have a lower prevalence of reflux symptoms,
no evidence of male predominance, and a higher prevalence
Family History of H pylori infection. Also, the prevalence of dysplasia among
Familial aggregation of BE and esophageal adenocarcinoma patients with intestinal metaplasia of the EGJ has been reported
has been reported in multiple studies. Studies have reported to be lower than that among patients with BE. The natural his-
the presence of confirmed BE or esophageal adenocarcinoma tory of intestinal metaplasia of the EGJ was described in 2
in first-or second-degree relatives in 7% of probands with BE studies, which found substantially lower rates of prevalent or
or esophageal adenocarcinoma. Increased prevalence of reflux incident dysplasia among patients who had intestinal metaplasia
of the EGJ compared with patients who had BE. However, be- polyurethane foam spheres and inflatable balloons) in combination
cause intestinal metaplasia is more common than BE, it is likely with biomarkers (trefoil factor 3 or methylated DNA markers).
that the rate of progression to adenocarcinoma would be much A recent randomized trial demonstrated substantially higher rates
lower than for patients with BE. of BE detection with the use of a swallowable cell collection de-
vice in combination with a protein biomarker. Analysis of exhaled
volatile organic compounds may have a potential role in BE
Cancer Risk
screening.
Among patients with BE, the rate of progression to esopha-
geal adenocarcinoma in the absence of prevalent dysplasia was ✓ Endoscopic screening for BE should be considered for patients
estimated to be 5 to 6 per 1,000 patient-years of follow-up. More who have chronic reflux symptoms and at least 3 risk factors (age
recent European studies have reported a lower risk of progression, >50 years, male sex, White race, central obesity, current or past
and a recent meta-analysis reported that the risk of progression in history of smoking, and family history of BE or EAC)
patients with nondysplastic BE was 3.3 per 1,000 patient-years ✓ Endoscopic screening after only 1 negative endoscopic evaluation
is not recommended
of follow-up. The risk of progression in patients with low-grade
✓ Patients with erosive esophagitis (Los Angeles grade B, C, or D)
dysplasia (LGD) is debated, with estimates ranging from 0.6% should have another endoscopic evaluation after 8 to 12 weeks of
to 1.2% per year. A recent meta-analysis reported that the rate of proton pump inhibitor therapy to assess for underlying BE and
progression to esophageal adenocarcinoma in persons with LGD healing of esophagitis
was 16.98 per 1,000 person-years compared with 5.98 per 1,000
person-years for persons with no dysplasia, although there was
considerable heterogeneity between the studies. The estimated Surveillance
rate of progression among patients with HGD is the highest: 65.8
Surveillance of patients with known BE is endorsed by all major
per 1,000 patient-years of follow-up.
gastrointestinal societies. The goal of surveillance is the early de-
tection of dysplasia or carcinoma so that therapeutic intervention
Screening may be applied to improve patient outcomes. Surveillance has
Screening for BE in patients with symptomatic gastroesophageal several limitations, including the following:
reflux or in the general population is a matter of controversy. 1. Poor interobserver agreement between pathologists on the grade of
However, there is growing evidence and support from major dysplasia (particularly LGD)
gastrointestinal societies to consider BE screening in high-risk 2. Variable natural predictive value of dysplasia, with variable pro-
patients with multiple risk factors. Endoscopic evaluation of gression rates reported for different cohorts for the same grade of
patients thought to be at high risk for BE may be considered on an dysplasia
individual basis after discussing the pros and cons with patients. 3. Patchy and subtle distribution of advanced dysplasia, so that sam-
pling error is likely during surveillance
Arguments in favor of screening include the large number of un-
diagnosed cases of BE in the community and the progression of Despite these limitations, the grade of dysplasia (no dysplasia,
BE from gastroesophageal reflux to metaplasia, dysplasia, and LGD, or HGD) is the primary clinical risk-stratification tool
adenocarcinoma (which can be detected at an early stage with a (Figure 2.5). Patients with long-segment BE and patients with
screening and surveillance program). Furthermore, retrospective short-segment BE should undergo similar surveillance because
studies have found that adenocarcinomas diagnosed in surveil- the primary predictor of progression is the grade of dysplasia.
lance programs were earlier-stage adenocarcinomas and were as- Surveillance should be offered to patients with reasonable life
sociated with improved survival compared with adenocarcinomas expectancy so that therapy for progression (if detected) would
diagnosed after the onset of symptoms. However, arguments be tolerated and would benefit the patient. Optimization of the
against screening include the following: The presence of symp- acid-suppressive regimen titrated to control symptoms and to
tomatic gastroesophageal reflux has poor accuracy for predicting heal esophagitis should be undertaken to minimize confounding
or excluding the absence of BE on endoscopy, surveillance poses the interpretation of dysplasia grade by reactive atypia (which
challenges, and there is a lack of strong prospective evidence that can occur from inflammation caused by uncontrolled reflux).
screening and surveillance may improve survival of patients who Diagnoses of LGD and HGD should be confirmed by expert
have esophageal adenocarcinoma. gastrointestinal pathologists because community pathologists
Current American College of Gastroenterology guidelines may tend to overcall LGD (and report false-positive results).
suggest that BE screening should be considered for patients who There is some evidence that the risk of progression in patients
have chronic GERD (>5 years) or frequent gastroesophageal re- with LGD confirmed by expert gastrointestinal pathologists
flux symptoms (at least weekly) and at least 3 risk factors (male may be higher.
sex, White race, age >50 years, central obesity, current or past Surveillance biopsies should be performed after careful in-
history of cigarette smoking, and confirmed history of BE or spection of the segment of BE with high-resolution endoscopy
EAC in a first-degree relative). For female patients, the yield from to identify any visible lesions that may indicate a higher grade
BE screening may be low because they have a significantly lower of dysplasia. The use of narrow band imaging (Figure 2.1B)
risk of EAC, but screening can be considered, after a discussion or other imaging techniques that enhance superficial mucosal
of the risks and benefits, if they have multiple risk factors. and vascular patterns may improve detection rates of focal
Conventional high- definition upper endoscopy is the gold abnormalities (such as nodules and ulcers) and advanced dys-
standard for screening and diagnosis of BE. However, the use of plasia. These areas should be biopsied separately and sent for
novel minimally invasive screening methods may make screening histopathologic study in specifically labeled bottles. The re-
high-risk populations more accessible and cost-effective. Several maining BE mucosa should be biopsied in a 4-quadrant manner
options are available, such as unsedated transnasal endoscopy every 2 cm, with tissue being submitted in separate bottles at
and swallowable esophageal cell collection devices (encapsulated each 2-cm level. For patients with HGD, surveillance should be
Figure 2.5. Algorithm for Management of Nondysplastic and Dysplastic Barrett Esophagus (BE). EMR indicates endoscopic mucosal resection; ESD, endoscopic submucosal dissection; HGD,
high-grade dysplasia; LGD, low-grade dysplasia.
performed every 1 cm in a 4-quadrant fashion to exclude prev- variable and is characterized, in most cases, by reversion to no
alent carcinoma. dysplasia or stability at LGD.
No Dysplasia and LGD High-Grade Dysplasia

Patients with no dysplasia should undergo endoscopic surveil- If HGD is detected (Figure 2.7), it should be confirmed by an
lance every 3 to 5 years to exclude prevalent dysplasia. Patients expert gastrointestinal pathologist because therapeutic decisions
with LGD (Figure 2.6) should have the diagnosis of LGD con- may need to be made on the basis of the confirmation. In a
firmed by a pathologist who has expertise in BE pathology. If multicenter randomized study for photodynamic therapy, the di-
LGD is confirmed, endoscopic ablation should be considered agnosis of HGD made by a community pathologist was overruled
as a first-line treatment option. In a multicenter randomized by an expert pathologist in two-thirds of cases.
control trial from Europe, endoscopic ablation significantly Diagnosis should be followed by careful endoscopic eval-
decreased the rate of neoplastic progression to HGD or EAC uation, with the use of high- resolution or high- definition
over a 3- year follow-up period. However, endoscopic sur- endoscopes (with dye-based or virtual chromoendoscopy and
veillance every 6 to 12 months is also an acceptable strategy, the use of techniques such as narrow band imaging), to assess
particularly for patients who have poor performance status or for the presence of any visual abnormality. Also, endoscopic
life-limiting comorbidities. If no dysplasia is detected in 2 ultrasonography may be performed to exclude the presence of
successive years, the surveillance frequency can be changed a coexisting invasive neoplasm (which may be present in 10%-
to every 3 to 5 years. The natural history of LGD is somewhat 12% of patients treated with esophagectomy). Any visible lesion
should be removed by endoscopic resection. Endoscopic resec-
tion techniques include cap-assisted endoscopic mucosal resec-
tion (EMR) and endoscopic submucosal dissection (ESD).
In EMR, a submucosal injection is used to lift a mucosal
lesion that is then resected by use of either a plastic cap with a
snare or band ligation with subsequent snare excision. The tech-
nique allows precise staging of the depth of invasion into the
mucosa or submucosa (with better interobserver agreement be-
tween pathologists in grading dysplasia than with biopsies) and
the assessment of margins, and it may be therapeutic if lateral
and deep margins are clear (Figure 2.8). Studies have shown that
EMR of visible lesions may show that the grade of dysplasia is
higher in as many as 30% of patients with HGD.
In ESD, specialized endoscopic knives are used to dissect the
lesion in the submucosal plane after being lifted with submucosal
injection. ESD is recommended for larger lesions (>15 mm), for
lesions that may be invading the submucosa, and for lesions with
fibrosis. ESD has been shown to achieve a substantially higher
rate of en bloc and histologic resection compared to EMR, but
ESD requires a steep learning curve and carries a higher compli-
cation rate.
Options for the management of HGD can be divided into 2
approaches:
1. Endoscopic eradication therapy includes EMR or ESD to remove
any visible lesions with subsequent ablation of the remaining
segment of BE. Ablation is based on the concept that destruction of
the metaplastic mucosa, with subsequent control of reflux, leads to
regrowth of squamous epithelium. Several published studies have
shown comparable outcomes for patients treated endoscopically or
surgically. Treatment options for ablation include radiofrequency
ablation (RFA), which involves the use of thermal energy delivered
with balloon-based and over-the-scope catheters to destroy BE mu-
cosa. It is the most commonly used ablation modality for treatment
of dysplastic BE. In a randomized controlled trial, RFA was found
to be superior to sham procedure in eliminating dysplasia and met-
aplasia at 1 year and in decreasing the risk of progression to EAC.
Multiple studies have reported variable rates of recurrent intestinal
Figure 2.6. Low-Grade Dysplasia in Barrett Esophagus. A, Nuclei metaplasia after successful ablation. Other techniques such as cry-
show evidence of stratification; they are longer, darker, and more crowded otherapy, which involves the use of cryogens (liquid nitrogen and
than when dysplasia is absent (Figure 2.2) (hematoxylin-eosin, original carbon dioxide) to damage the metaplastic mucosa, are being studied
magnification ×200). B, Nuclei retain polarity toward the basement mem- as alternatives, with preliminary observational reports showing effi-
brane and are not pleomorphic (hematoxylin-eosin, original magnifica- cacy comparable to that of RFA.
tion ×400). (Courtesy of Jason T. Lewis, MD, Department of Laboratory 2. Endoscopic surveillance involves careful endoscopic evalua-
Medicine and Pathology, Mayo Clinic, Rochester, Minnesota; used with tion every 3 months, with surveillance biopsy samples taken at
permission.) every centimeter along the segment of BE. If a focal abnormality
is visualized, the patient undergoes additional EMR or ESD. This

option is reserved for patients with limited life expectancy.
✓ Patients with reasonable life expectancy who have dysplastic BE

(confirmed by an expert gastrointestinal pathologist) should un-
dergo endoscopic resection (with EMR or ESD) of all visible lesions
and subsequent endoscopic ablation of residual flat BE mucosa
✓ Goal of endoscopic eradication therapy—complete eradication of
all intestinal metaplasia
Risk Stratification of BE
The histologic finding of dysplasia (LGD or HGD) is the best clin-
ical tool for identifying patients at risk for progression to EAC.
However, it is challenging to predict the trajectory of neoplastic
progression on the basis of the histologic grade of dysplasia alone
in a real-world practice setting, given that in some patients HGD
does not progress to EAC. To help bridge this gap, risk stratifica-
tion tools have been developed on the basis of clinical parameters
(eg, male sex, cigarette smoking, older age, and length of BE
segment). Moreover, the use of clinical biomarkers to determine
the risk of progression to EAC in patients with BE has been studied
and has shown potential to improve risk stratification of patients
with BE. One of the most studied biomarkers for BE is p53 onco-
protein. Aberrant expression of p53 oncoprotein is associated with
increased risk of neoplastic progression in patients with BE.
Esophageal Cancer
Epidemiology
Squamous cell carcinoma (SCC) (Figure 2.9A) and adenocarci-
noma (Figure 2.9B) are the most common types of esophageal
cancer. Esophageal carcinoma is the seventh leading cause of
death in the world. SCC accounts for most cases of esophageal
cancer throughout the world and is more common in Asia and
resource-limited countries; esophageal adenocarcinoma is more
common in industrialized countries.
In the US, approximately 18,000 cases of esophageal carci-
noma are diagnosed annually, with the proportion of esophageal
adenocarcinoma increasing to more than 50% since 2000. The
incidence of esophageal adenocarcinoma in the US has been
increasing exponentially since the 1970s (from 1.0 new cases
per 100,000 persons per year in the 1970s to 5.69 new cases per
100,000 persons per year in 2004 for White men, and from 0.17
new cases per 100,000 persons per year in the 1970s to 0.70 new
cases per 100,000 persons per year in 2004 for White women).
However, the incidence of SCC in the US has decreased from 3.8
new cases per 100,000 persons per year in the 1970s to 1.90 new
cases per 100,000 persons per year in 2004 for White men, with a
similar trend for White women. In contrast, in certain regions of
China, India, and Iran, SCC is exceedingly common, occurring in
132 new cases per 100,000 persons per year.
Overall, neoplasms of the esophagus carry a poor prognosis,
particularly if they are diagnosed after the patient has symptoms.
In the US, the number of deaths from esophageal carcinoma
closely approximates the number of new cases per year, and the
overall 5-year survival rate is less than 20%.
Figure 2.7. High-Grade Dysplasia in Barrett Esophagus. A, Nuclei
are rounded and oriented haphazardly (not perpendicular to basement
membrane), unlike in low-grade dysplasia (Figure 2.6). B, Nuclei are pleo Risk Factors for SCC
morphic (ie, with different shapes and sizes) (hematoxylin-eosin, original
magnification ×400). (Courtesy of Jason T. Lewis, MD, Department of Several types of factors increase the risk for SCC: geographic,
Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota; dietary, preexisting diseases, and smoking and alcohol consump-
used with permission.) tion. In the US, the incidence rates for SCC are higher in urban
areas and in low-income areas. The higher incidence rates in

parts of Asia (China, India, and Iran) may be influenced by die-
tary and environmental issues. Dietary risk factors include foods
with N-nitroso compounds (which can cause DNA damage);
betel nuts (when chewed); selenium, zinc, vitamin C, and fo-
late deficiencies; and intake of hot liquids. Preexisting esopha-
geal diseases that are recognized risk factors include lye-induced
strictures and achalasia; systemic diseases include tylosis. The
risk of SCC increases with increasing use of tobacco and alcohol.
Risk Factors for Adenocarcinoma

The risk factors for esophageal adenocarcinoma mirror the risk
factors for BE, and BE is the strongest risk factor for esopha-
geal adenocarcinoma. Other established risk factors for esoph-
ageal adenocarcinoma are older age, male sex, chronic reflux of
gastric contents, White race, obesity (particularly central or male
pattern obesity), and smoking. Heartburn and acid regurgitation,
Figure 2.8. Endoscopic Mucosal Resection Specimen. This technique
especially if present for more than 12 years, are also risk factors.
enables visualization of the mucosa, lamina propria, muscularis mucosa, and
submucosa, thus allowing an accurate determination of the depth of invasion As many as 40% to 50% of patients who have esophageal adeno-
of malignant lesions (hematoxylin-eosin, original magnification ×12.5). carcinoma do not have symptoms of frequent gastroesophageal
reflux. Debate continues on the role of H pylori infection in
the increasing incidence of esophageal adenocarcinoma. Some
reports suggest that an inverse correlation exists (with atrophic
gastritis from H pylori infection decreasing gastric acid output
and, hence, decreasing reflux of gastric contents and protecting
against esophageal adenocarcinoma), but other studies do not.
Signs and Symptoms

The symptoms of esophageal cancer include progressive solid
food dysphagia that progresses to dysphagia with soft solids
and then with liquids. Unintentional weight loss is commonly
reported with late-stage disease. Other than the skin changes of
tylosis or lichen planus in patients with SCC, there are no spe-
cific signs of esophageal cancer. In most patients, the physical
examination findings are normal. With late-stage disease or di-
sease of the proximal esophagus, supraclavicular lymphadenop-
athy or hepatomegaly can be palpated, indicating the possibility
of metastatic disease.
Diagnosis and Staging

Diagnosis of esophageal carcinoma requires endoscopy with bi-
opsy. Although the diagnosis may be suspected from the results
of a barium study or other imaging tests, tissue to confirm a diag-
nosis is obtained best from endoscopy. After histologic confirma-
tion of the diagnosis, attention should be directed toward staging.
The goal of staging is to classify the tumor as early or localized
to the esophagus, locally advanced, or metastatic. Tools available
for staging include positron emission tomography (PET), which
is best suited and most sensitive for detecting distant metastatic
disease. It has greater sensitivity than computed tomography
(CT) and can be used to detect unsuspected metastatic disease
in 10% to 15% of patients who have no evidence of disease on
CT. The use of PET has been shown to lead to a change in man-
agement in 10% to 20% of patients. However, PET is expensive
and may not be widely available. Usually CT is performed first to
Figure 2.9. Histologic Features of Esophageal Carcinoma. A,
exclude metastatic disease before PET (if available) is performed
Squamous cell carcinoma. Irregular nests of malignant squamous cells show
abnormal production of keratin (hematoxylin-eosin, original magnification to exclude any metastatic lesions missed with CT. Endoscopic
×200). B, Adenocarcinoma. Infiltrative adenocarcinoma glands have complex ultrasonography is used to perform locoregional staging for
architecture (hematoxylin-eosin, original magnification ×100). (Courtesy assessing the T (tumor) stage (invasion into the esophageal wall)
of Tsung-Teh Wu, MD, PhD, Department of Laboratory Medicine and and the N (node) stage. Endoscopic ultrasonography is most
Pathology, Mayo Clinic, Rochester, Minnesota; used with permission.) sensitive for staging locally advanced disease (T2 or T3), with
Table 2.1. TNM Staging System for Esophageal Suggested Reading

Adenocarcinoma Abrams JA, Fields S, Lightdale CJ, Neugut AI. Racial and ethnic
Stage Description disparities in the prevalence of Barrett’s esophagus among patients
who undergo upper endoscopy. Clin Gastroenterol Hepatol. 2008
Primary tumor (T) Jan;6(1):30–4.
T1 Tumor invades lamina propria, muscularis mucosae, or Codipilly DC, Sawas T, Dhaliwal L, Johnson ML, Lansing R, Wang KK,
submucosa et al. Epidemiology and outcomes of young-onset esophageal ade-
T1a Tumor invades lamina propria or muscularis mucosae nocarcinoma: an analysis from a population-based database. Cancer
T1b Tumor invades submucosa
Epidemiol Biomarkers Prev. 2021 Jan;30(1):142–9.
T2 Tumor invades muscularis propria
Coleman HG, Bhat S, Johnston BT, McManus D, Gavin AT, Murray
T3 Tumor invades adventitia
T4 Tumor invades adjacent structures LJ. Tobacco smoking increases the risk of high-grade dysplasia and
T4a Resectable tumor is invading pleura, pericardium, diaphragm cancer among patients with Barrett’s esophagus. Gastroenterology.
T4b Unresectable tumor is invading aorta, vertebral body, trachea 2012 Feb;142(2):233–40.
Conio M, Cameron AJ, Romero Y, Branch CD, Schleck CD, Burgart
Regional lymph nodes (N)a
LJ, et al. Secular trends in the epidemiology and outcome of
N0 No regional lymph node metastasis
Barrett’s oesophagus in Olmsted County, Minnesota. Gut. 2001
N1 Metastasis in 1 or 2 regional lymph nodes
N2 Metastasis in 3-6 regional lymph nodes Mar;48(3):304–9.
N3 Metastasis in ≥7 regional lymph nodes Cook MB, Shaheen NJ, Anderson LA, Giffen C, Chow WH, Vaughan
TL, et al. Cigarette smoking increases risk of Barrett’s esoph-
Distant metastasis (M)
agus: an analysis of the Barrett’s and Esophageal Adenocarcinoma
M0 No distant metastasis
Consortium. Gastroenterology. 2012 Apr;142(4):744–53.
M1 Distant metastasis present
Desai TK, Krishnan K, Samala N, Singh J, Cluley J, Perla S, et al. The
a
The 2010 edition of the staging recommendations eliminated emphasis on incidence of oesophageal adenocarcinoma in non-dysplastic Barrett’s
the location of lymph nodes and replaced it with the number of lymph nodes oesophagus: a meta-analysis. Gut. 2012 Jul;61(7):970–6.
involved (because the number of lymph nodes has been shown to be more El-
Serag H. Role of obesity in GORD- related disorders. Gut. 2008
prognostic of survival). Mar;57(3):281–4.
Adapted from Edge SB, Byrd DR, Compton CC, Fritz AG, Greene FL, Trotti
Fitzgerald RC, di Pietro M, O’Donovan M, Maroni R, Muldrew B,
A 3rd, eds; American Joint Committee on Cancer. AJCC cancer staging manual. Debiram-Beecham I, et al. Cytosponge-trefoil factor 3 versus usual
7th ed. New York (NY): Springer; 2010:109; used with permission. care to identify Barrett’s oesophagus in a primary care setting: a
multicentre, pragmatic, randomised controlled trial. Lancet. 2020 Aug
1;396(10247):333–44.
modest accuracy for staging early disease (mucosal or submu- Iyer PG, Taylor WR, Johnson ML, Lansing RL, Maixner KA, Hemminger
cosal), and for establishing the N stage (particularly with the use LL, et al. Accurate nonendoscopic detection of Barrett’s esophagus
of fine-needle aspiration of enlarged lymph nodes). Metastatic by methylated DNA markers: a multisite case control study. Am J
involvement of celiac lymph nodes is detected best with endo- Gastroenterol. 2020 Aug;115(8):1201–9.
Jung KW, Talley NJ, Romero Y, Katzka DA, Schleck CD, Zinsmeister
scopic ultrasonography. The current TNM staging criteria for
AR, et al. Epidemiology and natural history of intestinal meta-
esophageal adenocarcinoma are listed in Table 2.1. plasia of the gastroesophageal junction and Barrett’s esophagus:
In early-stage disease (T1N0M0), endoscopic mucosal resec- a population-based study. Am J Gastroenterol. 2011 Aug;106(8):
tion is an accurate tool to distinguish between mucosally con- 1447–55.
fined disease (T1a) and submucosally invasive disease (T1b). Lagergren J, Bergstrom R, Lindgren A, Nyren O. Symptomatic
This distinction is important because endoscopic therapy may gastroesophageal reflux as a risk factor for esophageal adenocarci-
be considered for T1a disease, given the low risk of metastatic noma. N Engl J Med. 1999 Mar 18;340(11):825–31.
lymphadenopathy (2%) compared with submucosal disease, for Peters Y, Schrauwen RWM, Tan AC, Bogers SK, de Jong B, Siersema
which the risk of metastatic lymphadenopathy is 20% to 30%, PD. Detection of Barrett’s oesophagus through exhaled breath using
and the therapy of choice is esophagectomy (which allows lymph an electronic nose device. Gut. 2020 Jul;69(7):1169–72.
Prasad GA, Wang KK, Buttar NS, Wongkeesong LM, Krishnadath KK,
node dissection and removal) in operative candidates.
Nichols FC 3rd, et al. Long-term survival following endoscopic and
Treatment options depend on the stage of the disease. surgical treatment of high-grade dysplasia in Barrett’s esophagus.
Endoscopic therapy (with endoscopic mucosal resection and ad- Gastroenterology. 2007 Apr;132(4):1226–33.
ditional ablative techniques) may be considered for T1a disease; Prasad GA, Wu TT, Wigle DA, Buttar NS, Wongkeesong LM, Dunagan
recent reports have documented excellent overall 5-year survival KT, et al. Endoscopic and surgical treatment of mucosal (T1a) esoph-
outcomes in comparison with outcomes after surgery. More in- ageal adenocarcinoma in Barrett’s esophagus. Gastroenterology.
vasive disease is treated by esophagectomy with lymph node 2009 Sep;137(3):815–23.
dissection (T2 or N0 disease) or neoadjuvant chemoradiotherapy, Qumseya BJ, Bukannan A, Gendy S, Ahemd Y, Sultan S, Bain P,
with subsequent restaging and esophagectomy (for T3 or et al. Systematic review and meta- analysis of prevalence and
N1 disease). This treatment strategy is based on limited data risk factors for Barrett’s esophagus. Gastrointest Endosc. 2019
Nov;90(5):707–17.
from studies that reported a modest survival advantage with
Reid BJ, Li X, Galipeau PC, Vaughan TL. Barrett’s oesophagus and
neoadjuvant chemoradiotherapy when results from neoadjuvant oesophageal adenocarcinoma: time for a new synthesis. Nat Rev
chemoradiotherapy and subsequent surgery were compared with Cancer. 2010 Feb;10(2):87–101.
results from surgery alone. Metastatic disease can be managed Sharma P, Dent J, Armstrong D, Bergman JJ, Gossner L, Hoshihara Y,
with a combination of palliative chemoradiotherapy, esophageal et al. The development and validation of an endoscopic grading system
stent placement, and nutritional support (administered orally with for Barrett’s esophagus: the Prague C & M criteria. Gastroenterology.
supplements or with percutaneously placed enteric tubes). 2006 Nov;131(5):1392–9.
Sharma P, McQuaid K, Dent J, Fennerty MB, Sampliner R, Spechler van Soest EM, Dieleman JP, Siersema PD, Sturkenboom MC, Kuipers
S, et al; AGA Chicago Workshop. A critical review of the diagnosis EJ. Increasing incidence of Barrett’s oesophagus in the general popu-
and management of Barrett’s esophagus. Gastroenterology. 2004 lation. Gut. 2005 Aug;54(8):1062–6.
Jul;127(1):310–30. Wang KK, Sampliner RE; Practice Parameters Committee of the
Spechler SJ, Fitzgerald RC, Prasad GA, Wang KK. History, molec- American College of Gastroenterology. Updated guidelines 2008 for
ular mechanisms, and endoscopic treatment of Barrett’s esophagus. the diagnosis, surveillance and therapy of Barrett’s esophagus. Am J
Gastroenterology. 2010 Mar;138(3):854–69. Gastroenterol. 2008 Mar;103(3):788–97.
Vakil N, van Zanten SV, Kahrilas P, Dent J, Jones R; Global Wani S, Puli SR, Shaheen NJ, Westhoff B, Slehria S, Bansal A, et al.
Consensus Group. The Montreal definition and classification of Esophageal adenocarcinoma in Barrett’s esophagus after endoscopic
gastroesophageal reflux disease: a global evidence-based consensus. ablative therapy: a meta- analysis and systematic review. Am J
Am J Gastroenterol. 2006 Aug;101(8):1900–20. Gastroenterol. 2009 Feb;104(2):502–13.
3
Esophageal Motility
CHAMIL C. CODIPILLY, MD
KARTHIK RAVI, MD
The esophagus is the conduit for oral contents to pass from the (LES), which is also tonically contracted at rest, prohibits the re-
oropharynx into the stomach. An intricate network of neuro- flux of gastric contents into the esophagus.
muscular processes allows for the propulsion of food into the Each of the distinct layers of the esophagus is vital to proper
stomach while avoiding the passage of boluses into the respi- functioning of the organ (Figure 3.1). The innermost layer, the
ratory system and inhibiting the reflux of gastric contents into mucosa, is normally composed of squamous epithelium and
the esophagus. Esophageal dysmotility manifests mainly as dys- provides a measure of protection from oral contents. The submu-
phagia or gastroesophageal reflux disease (GERD), although in cosa provides nourishment to the mucosa and contains mucus-
rare instances it may also result in chest pain and discomfort. secreting glands; mucus eases the passage of food boluses. The
This chapter reviews the normal physiology of swallowing and muscularis propria consists of 2 layers: The inner layer contains
discusses the pathophysiology, diagnostic evaluation, and man- muscle arranged circularly around the esophagus, and the outer
agement of esophageal motility disorders. layer includes longitudinal muscle running the length of the
esophagus. Coordinated contraction of the 2 layers allows for
peristalsis of contents down the esophagus. The outermost layer
Anatomy
of the esophagus, the adventitia, provides connective tissue and
The esophagus is a tubular structure that passes through the pos- structure to the organ.
terior mediastinum. The proximal esophagus acts as a funnel, In the upper third of the esophagus, the muscular layer (the
shuttling oral contents from the pharynx, with passage controlled muscularis propria) is made of striated skeletal muscle; the lower
by the upper esophageal sphincter (UES), which at rest is typ- two-thirds is made of smooth muscle. A transition zone near the
ically contracted to prevent the reflux of esophageal or gas- level of the aortic arch marks the change in muscle type, although
tric contents into the mouth and airways. The distal esophagus this landmark cannot typically be identified on endoscopy.
attaches to the proximal stomach; the lower esophageal sphincter The proximal striated muscle innervation is carried by cranial
nerves IX (glossopharyngeal nerve) and X (vagus nerve), while
the smooth muscle is innervated mainly by input from cranial
nerve X.
Abbreviations: CDP, contraction deceleration point; DCI, distal contrac-
tile integral; DES, distal esophageal spasm; DI, distensibility index; DL,
distal latency; EGD, esophagogastroduodenoscopy; EGJ, esophagogastric Normal Physiology
junction; EGJOO, esophagogastric junction outflow obstruction; FLIP,
The initiation of swallowing is a voluntary process that, once
functional lumen imaging probe; GERD, gastroesophageal reflux disease;
HRM, high- resolution manometry; IRP, integrated relaxation pressure; started, cannot be halted under normal circumstances. Swallowing
LES, lower esophageal sphincter; LHM, laparoscopic Heller myotomy; begins with movement of the tongue cephalad to the hard palate,
PD, pneumatic dilation; POEM, peroral endoscopic myotomy; PPI, proton which pushes the food bolus into the pharynx. This triggers the
pump inhibitor; RYGB, Roux-en-Y gastric bypass; UES, upper esophageal involuntary swallowing reflex, in which the tongue and soft palate
sphincter; VFSS, videofluoroscopic swallow study seal off the nasopharynx and oral cavity, while the epiglottis
35
Figure 3.1. Layers Within the Wall of the Esophagus.
everts to prevent food from entering the laryngeal (and by ex- hoarseness, and regurgitation (particularly through the nose if the
tension, pulmonary) spaces. Shortening of the pharynx removes seal between the tongue and soft palate is ineffective).
the recesses formed by the valleculae and piriform sinuses, and Structural or mechanical abnormalities may also cause oro-
peristalsis of the pharyngeal muscles pushes the bolus posteri- pharyngeal dysphagia. Causes include malignancy, thyromegaly,
orly to the UES, which mainly consists of the cricopharyngeus prominent cricopharyngeal bar (Figure 3.2), tonsillar enlarge-
muscle. The UES relaxes, allowing the bolus to enter the prox- ment, and cervical osteophytes. Erosion or migration of anterior
imal esophagus, but quickly contracts again after the bolus has cervical spine hardware may also result in oropharyngeal dys-
passed. Peristalsis of the esophageal body then propels the food phagia. Zenker diverticulum (Figure 3.2) can form in the Killian
toward the stomach. Relaxation of the LES allows passage of the triangle, an area of relative pharyngeal weakness due to high
bolus into the stomach; with contraction of the LES afterward, a pressure from the cricopharyngeus muscle, and result in dys-
reflux barrier is formed. phagia and retention with resultant regurgitation of food. Patients
This process is mediated by the competing effects of nitric with proximal esophageal body obstruction may also have oro-
oxide and acetylcholine. Excitatory input, resulting in peristalsis, pharyngeal symptoms.
is mediated by acetylcholine, while relaxation of the sphincters is Physical examination findings may include weakness
mediated by the inhibitory effect of nitric oxide. involving cranial nerves. Patients may not be able to retain oral
contents in the mouth without drooling. Coughing may occur
with swallowing. Patients may need to swallow 2 or 3 times to
Oropharyngeal Dysphagia
clear small boluses (such as a sip of water). Halitosis may be
Symptoms of oropharyngeal dysphagia, which may be dis- present in patients with a Zenker diverticulum.
tinct from those of esophageal body dysphagia, may include A videofluoroscopic swallow study (VFSS), done in conjunc-
difficulties with formation of food boluses, transfer of food tion with a speech and swallowing pathologist, is the best test
boluses, coughing, and choking. Patients may localize symptoms to evaluate oropharyngeal dysphagia. Functions assessed include
to the neck superior to the sternal notch. the following:
Patients frequently have a history of neuromuscular or sys-
temic diseases, or mechanical obstruction. Causes of oropha- • Tongue coordination—an uncoordinated tongue impairs transmis-
ryngeal dysphagia are shown in Table 3.1. Neurologic deficits sion of the bolus
• Soft palate elevation—dysfunction of the soft palate can lead to
may affect other functions that are controlled by the same nerves
nasopharyngeal regurgitation
involved in the initial steps of swallowing, and concurrent • Laryngeal closure— failure of laryngeal closure can lead to
difficulties with speaking, tongue movement, oral bolus reten- aspiration
tion, and laryngeal protection may be elicited from the history • Pharyngeal peristalsis— poor pharyngeal peristalsis results in
or physical examination. Expectedly, patients with oropharyn- residue in the valleculae or piriform sinuses, requiring multiple
geal dysphagia may present with recurrent aspiration pneumonia, swallows and often leading to aspiration
3. Esophageal Motility 37
Table 3.1. Causes and Treatment of Oropharyngeal maneuvers, such as the chin tuck, can improve swallowing me-
Dysphagia chanics and help the patient avoid aspiration, and the maneuvers
can be tailored on the basis of the VFSS findings. Swallowing
Cause Therapy
rehabilitation may improve oropharyngeal dysphagia even in
Neuromuscular patients with structural abnormalities. However, in patients with
Cerebrovascular accident Swallowing rehabilitation structural abnormalities, endoscopic or surgical intervention
Trauma (or both) may improve symptoms. Dysphagia due to a prox-
Peripheral neuropathy
Amyotrophic lateral sclerosis
imal cricopharyngeal bar or hypertensive UES may respond to
Muscular dystrophy bougienage or myotomy, particularly if radiographic evidence
Poliomyelitis confirms obstruction at the level of the cricopharyngeus muscle.
Multiple sclerosis Treatment of underlying medical As previously mentioned, many patients with oropharyngeal
Myasthenia gravis condition; swallowing rehabilitation dysphagia have underlying neuromuscular disease processes that
Parkinson disease if needed result in symptoms. Therefore, in appropriate patients, evalua-
Polymyositis, dermatomyositis tion may include laboratory assessment (creatine kinase and an-
Guillain-Barré syndrome tinuclear antibody) and imaging (magnetic resonance imaging
Hypothyroidism
Lymphadenopathy
of the brain). These patients should be evaluated and treated
Tardive dyskinesia in a multidisciplinary manner with input from neurologists,
Obstructive
otorhinolaryngologists, rheumatologists, and gastroenterologists.
Zenker diverticulum Bougienage, dilation; cricomyotomy Targeted pharmacologic therapies should be administered in
Prominent cricopharyngeus muscle appropriate patients (eg, carbidopa- levodopa in patients with
Proximal esophageal strictures, Bougienage, dilation; assessment for Parkinson disease), but in these patients dysphagia is frequently
webs iron deficiency anemia and treatment progressive. Swallowing rehabilitation may delay the need for
Thyromegaly Treatment of underlying medical enteral or parenteral feeding.
Malignancy (head, neck, or condition
esophageal cancer) ✓ Videofluoroscopic swallow study—diagnostic test of choice when
Migration of anterior cervical Conservative measures and patients present with symptoms of oropharyngeal dysphagia
hardware reassurance; if severe, possibly ✓ Oropharyngeal dysphagia may be a manifestation of an underlying
Tonsillar enlargement surgery neuromuscular condition; a multidisciplinary approach for evalu-
Cervical osteophytes ation should be considered
Multifaceted therapeutic approaches are used in the manage- Esophageal Dysphagia

ment of oropharyngeal dysphagia. Patients should be counseled In contrast to oropharyngeal dysphagia (characterized by patients
to carefully focus on eating and to chew food well to avoid aspi- choking, coughing, or aspirating with swallowing), esophageal
ration events. Soft or pureed foods may be recommended. Certain dysphagia is characterized by the sense that swallowed boluses
get “stuck” or “hung up” after the swallow is initiated, and
symptoms can be localized anywhere from the neck to the lower
chest. Patients may have pain or discomfort when the bolus is
delayed in the esophagus. They may report having symptoms at a
level that differs from the actual site of obstruction.
Obstruction is the major cause of esophageal dysphagia,
and the usual evaluation includes a barium esophagram and
esophagogastroduodenoscopy (EGD). Solid food dysphagia
alone typically implies an obstructive process, although a rap-
idly growing lesion will eventually cause dysphagia with both
solids and liquids. However, the onset of both solid and liquid
dysphagia may indicate a motility disorder.
It can be helpful to have the esophagram done before the EGD
so that therapies, such as dilation of a subtle esophageal stricture,
can be planned and performed during the endoscopy. In appro-
priate patients who do not have clear structural abnormalities,
random esophageal biopsies (from the proximal and distal esoph-
agus) should be performed to rule out eosinophilic esophagitis.
Rapidly progressive symptoms accompanied by weight loss
are concerning for esophageal cancer, although patients with
secondary causes of achalasia (which may also include malig-
nancy) can present similarly. Evaluation of these patients should
be expedited to establish the diagnosis. Notably, the sense of dys-
phagia from a cancer typically implies that it is deeper than a T2
Figure 3.2. Obstructive Causes of Oropharyngeal Dysphagia. lesion (invading at least into the muscularis propria).
Barium esophagram shows a prominent cricopharyngeal bar (A) that is If obstruction and inflammatory disorders of the esophagus
obstructing the esophageal lumen by more than 75% and a concomitant are ruled out, esophageal high-resolution manometry (HRM) is
Zenker diverticulum (B). usually the best next step in the evaluation of dysphagia.
Esophageal HRM Assessment of HRM With the Chicago

Classification Version 4.0
During esophageal HRM, a thin, flexible catheter is inserted
through the nares and traverses the entire length of the esoph- Currently in its fourth iteration, the Chicago Classification was
agus into the stomach. Solid-state pressure transducers are developed to standardize the interpretation of HRM tracings.
positioned every centimeter along the catheter length to Although it is a valuable tool for gastroenterologists, this classifi-
allow for simultaneous assessment of the entire esophagus cation system is not all-encompassing, and clinicians need to care-
during swallowing and at rest. Further, this allows creation of fully consider HRM findings in the appropriate clinical context.
a color-coded pressure topographic image, a Clouse plot, in The Chicago Classification uses 3 metrics to interpret an
which high pressures are represented by red and orange, while HRM study. The integrated relaxation pressure (IRP), which is
low pressures are displayed in blue and green. The Clouse a marker of deglutitive LES relaxation, is the lowest mean LES
plot eases study interpretation and has been shown to im- pressure for 4 noncontiguous seconds in the first 10 seconds
prove interobserver agreement compared to conventional line after a swallow. The reference range for median IRP is less
tracings. The length of the esophagus is shown along the y- than 15 mm Hg as measured from 10 swallows in the supine
axis, while time is along the x-axis. After a baseline landmark position. A second metric is distal latency (DL), a measure
phase is captured, the patient is instructed to drink 10 swallows of esophageal inhibitory input. Normal esophageal peristalsis
of water (5 mL water in each swallow) typically in the su- is defined by graded inhibitory and excitatory input such that
pine position and another 5 swallows in the upright position. there is relatively more inhibitory input in the distal esophagus
Standard esophageal HRM can be supplemented with adjunc- than in the proximal esophagus. The contraction deceleration
tive tests such as the multiple rapid swallow sequence, during point (CDP) is the point at which the velocity of the peristaltic
which a patient is instructed to swallow water every 2 seconds wave slows, marking the end of the stripping peristaltic segment
for 5 swallows to assess inhibitory input and peristaltic reserve, of esophageal body emptying. The DL is simply the time from
and a rapid drink challenge to assess functional obstruction at when a swallow begins (ie, the opening of the UES) until the
the esophagogastric junction (EGJ). CDP. A short CDP indicates that distal esophageal contrac-
During a normal swallow (Figure 3.3), relaxation of the UES tion occurred earlier than expected, reflecting loss of inhibitory
can be seen as a decrease in the tonic contraction of the UES input, and is used to define a spastic contraction. The reference
with a subsequent peristaltic wave traveling distally to the LES, range is greater than 4.5 seconds. A third metric is the distal
which is represented as a change in color that indicates increased contractile integral (DCI), which is the product of the ampli-
esophageal pressure propagating from the proximal esophagus tude, length, and time of the peristaltic wave and is a measure
to the distal esophagus. When the UES opens, the LES pressure of peristaltic vigor.
also decreases, as indicated by a change in color that represents The current version of the Chicago Classification can be used
the deglutitive window. to broadly categorize esophageal motility disorders as either
disorders of EGJ outflow or disorders of peristalsis (Figure 3.4).
The first step in the classification process is to assess the IRP.
If the median IRP is abnormally high (≥15 mm Hg in the su-
pine position), the interpretation follows the pathway for disorders
of EGJ outflow. If peristalsis is absent in 100% of swallows, the
manometric diagnosis of achalasia is made. If peristalsis is pre-
sent in any swallows, LES relaxation is then assessed in another
position with at least 5 swallows. If the median IRP is consist-
ently high (≥12 mm Hg in the upright position) and results are
abnormal from a timed barium esophagram or functional lumen
imaging probe planimetry (or from both) in the appropriate clin-
ical context, the manometric diagnosis is EGJ outflow obstruc-
tion (EGJOO).
If the median IRP is normal, the interpretation follows the
pathway for disorders of peristalsis in a hierarchal fashion.
Absent contractility is diagnosed from 100% failed peristalsis.
Distal esophageal spasm is the diagnosis when 20% or more
of the swallows have premature contraction (ie, DL <4.5 s).
Hypercontractile esophagus is diagnosed when 20% or more of
the swallows show hypercontractility (DCI >8,000 mm Hg·cm·s).
Figure 3.3. Normal Swallow on High- Resolution Esophageal Ineffective esophageal motility is characterized by more than
Manometry. At the initiation of the swallow (white arrow), the upper 70% ineffective swallows (DCI <450 mm Hg·cm·s or transi-
esophageal sphincter (upper arrowhead) relaxes, and the waveform
tion zone defect >5 cm) or more than 50% failed swallows (DCI
moves toward the lower esophageal sphincter (LES) (lower arrowhead)
in a peristaltic fashion. The distal latency (DL) (double arrow) is normal
<100 mm Hg·cm·s). If none of these criteria are met, the swallow
(ie, >4.5 s); a short DL would indicate spasm. The oval shows where is considered normal. Table 3.2 provides diagnostic criteria for
the distal contractile integral, a measure of peristaltic vigor (normally select motility disorders.
450-8,000 mm Hg·cm·s), is assessed. The 2 boxes indicate measure-
ment of the integrated relaxation pressure (IRP), which is a composite
Functional Lumen Imaging Probe Planimetry
of the lowest 4 seconds of pressure (not necessarily contiguous seconds)
in the first 10 seconds after initiation of the swallow. An increased IRP The functional lumen imaging probe (FLIP) is a recent addition
indicates nonrelaxation of the LES during swallowing. to the armamentarium of esophageal motility testing. FLIP
Figure 3.4. Chicago Classification Version 4.0. EGJ indicates esophagogastric junction; EGJOO, esophagogastric junction outflow obstruction;
FLIP, functional lumen imaging probe; IBP, intrabolus pressurization; IRP, integrated relaxation pressure; LES, lower esophageal sphincter; MRS,
multiple rapid swallow; PEP, panesophageal pressurization; RDC, rapid drink challenge; TBE, timed barium esophagram. (Adapted from Yadlapati
R, Kahrilas PJ, Fox MR, Bredenoord AJ, Prakash Gyawali C, Roman S, et al. Esophageal motility disorders on high-resolution manometry: Chicago
classification version 4.0(c). Neurogastroenterol Motil. 2021 Jan;33[1]‌:e14058; used with permission.)
planimetry uses impedance planimetry to measure pressure and FLIP planimetry, performed immediately after the patient
esophageal luminal cross-sectional area. In addition, real-time has undergone endoscopy with sedation, involves placement of
FLIP planimetry allows for the assessment of esophageal con- a transoral catheter with impedance electrodes along its length
tractility through dynamic changes in esophageal diameter. surrounded by an infinitely compliant balloon, which is positioned
Table 3.2. Diagnostic Criteria and Therapeutic Options for Select Esophageal Motility Disorders
Disorder Manometric diagnostic criteria Treatment
Achalasia (IRP ≥15 mm Hg)
Type I Absent peristalsis (100% of swallows) Definitive treatment, types I and II:
Type II Panesophageal pressurization in ≥20% of POEM is equivalent to HM with fundoplication
swallows (pressure >30 mm Hg with isobaric HM with fundoplication is equivalent to PD, but PD is associated with higher
contour tool) and 100% failed swallows perforation rate (2%)
Type III ≥20% spastic swallows (DL <4.5 s) without Recommendation: HM with fundoplication or POEM according to clinical
evidence of peristalsis scenario
Definitive treatment, type III:
POEM is preferred to HM with fundoplication, so myotomy length can be
tailored to length of spastic component on manometry
Temporary treatment for poor surgical candidates:
Botulinum toxin injection into LES
Distal esophageal DL <4.5 s and DCI ≥450 mm Hg·cm·s with PPI therapy
spasm normal IRP Botulinum toxin injection into LES
Long myotomy tailored to spastic component (in refractory cases)
Hypercontractile DCI >8,000 mm Hg·cm·s in ≥20% of swallows PPI therapy
esophagus with normal IRP CCBs or nitrates (poor-quality evidence)
Botulinum toxin injection into LES
Ineffective esophageal Normal IRP, but ≥70% weak swallows (DCI Assess and treat underlying medical condition (connective tissue diseases)
motility 100-450 mm Hg·cm·s) or ≥50% failed PPI therapy
swallows (DCI <100 mm Hg·cm·s) Lifestyle modifications if considerable reflux burden
Abbreviations: CCB, calcium channel blocker; DCI, distal contractile integral; DL, distal latency; HM, Heller myotomy; IRP, integrated relaxation pressure; LES, lower
esophageal sphincter; PD, pneumatic dilation; POEM, peroral endoscopic myotomy; PPI, proton pump inhibitor.
in the Medicare population. The diagnosis tends to be more

common among older patients; although achalasia can occur at
any age, onset of symptoms before the age of 20 years is un-
common. No sex or racial predilection is apparent.
Achalasia can be categorized as primary (idiopathic) or sec-
ondary (pseudoachalasia). Secondary achalasia is most com-
monly caused by malignant compression or infiltration of the
distal esophagus, and this must be considered, particularly during
assessment of older patients who present with rapid onset of
symptoms and marked weight loss (>10 kg) within a short time
(<6 months). Less commonly, secondary achalasia may indicate
a paraneoplastic phenomenon typically associated with lung
cancer. Nonmalignant causes of secondary achalasia include
amyloid deposition, benign tumors, peripheral neuropathy, and
central nervous system disorders. Iatrogenic causes of secondary
achalasia include tight fundoplications, lap band surgery, and
antireflux rings. In endemic regions (Central and South America),
Chagas disease, due to infection with Trypanosoma cruzi, can re-
sult in achalasia and can be accompanied by megacolon, cardio
megaly, and neurologic dysfunction.
Pathophysiology
The underlying pathogenesis of achalasia is loss of esophageal

peristaltic activity coupled with a lack of LES relaxation,
which impedes bolus transit through the esophagus and results
Figure 3.5. Functional Luminal Imaging Probe (FLIP). An infi-
in dysphagia. Histologic analysis shows degeneration of my-
nitely compliant balloon is used to assess distensibility and secondary
enteric plexus ganglion cells associated with lymphocytic in-
contractions. A, Repetitive anterograde contractions are present in a pa-
filtration. The possibility of an autoimmune or inflammatory
tient with normal motility. B, FLIP in a patient with achalasia shows the
reaction to infection or another trigger naturally arises from
lack of peristalsis and the poorly distensible esophagogastric junction
this finding, but no clear link has been established.
marked by the red band.
with the distal 2 to 3 cm in the stomach. The balloon is sequen- Diagnosis

tially filled with a liquid of known conductivity, and, with use of
Patients universally complain of dysphagia, often to both solids
the Ohm law, the cross-sectional area at each impedance electrode
and liquids and may describe a stacking phenomenon, in which
can be determined along with pressure within the balloon itself.
food can accumulate in the chest during a meal. Patients may also
If the ratio of the cross-sectional area at the EGJ and the pressure
have chest pain and discomfort. Regurgitation may be associated
within the balloon have been determined, the distensibility index
with relief of symptoms, and some patients may find regurgitated
(DI) can be calculated. The DI can be predictive of disordered LES
contents on their pillow upon awakening. Patients with achalasia
relaxation. In addition, real-time diameter changes from distention-
may describe themselves as slow eaters, and they often use adap-
induced secondary peristalsis are plotted topographically and allow
tive behaviors such as extending the torso and “power drinking”
for assessment of esophageal contractility. A low DI and smaller
liquids. Consequently, primary achalasia has an average diag-
diameter at the EGJ in addition to disordered or absent contrac-
nostic delay of 2 years from symptom onset and is typically asso-
tility are predictive and can confirm achalasia (Figure 3.5). Overall,
ciated with minimal weight loss. The Eckardt score (Table 3.3) is
FLIP planimetry is safe and well tolerated.
a validated assessment tool that incorporates patient symptoms.
✓ A motility disorder of the esophagus should be considered after The diagnostic evaluation for achalasia involves a single-contrast
an obstructive or mechanical cause of dysphagia is ruled out with esophagram with barium, which may show the characteristic bird-
esophagogastroduodenoscopy and possibly a barium esophagram beak sign with a smooth tapering of the dilated distal esophagus
✓ Chicago classification—an algorithmic approach to interpreting as it approaches the tonically contracted LES (Figure 3.6). If the
high-
resolution manometry by first assessing esophagogastric esophagram is timed, a distinct retained column may be present at 1
junction relaxation (integrated relaxation pressure) and potential and 5 minutes after the swallow.
achalasia and subsequently assessing potential abnormalities of
esophageal body peristalsis in a hierarchal manner
Table 3.3. Eckardt Score for Assessment of Achalasia
Weight
Achalasia Scorea Dysphagia Regurgitation Retrosternal pain loss, kg
Achalasia (from the Greek prefix a- denoting absence and the 0 None None None 0
Greek word for relaxation, chalasis) is defined by failure of 1 Occasional Occasional Occasional <5
2 Daily Daily Daily 5-10
LES relaxation along with the absence of esophageal peristalsis. 3 With every meal With every meal Several times daily >10
Although achalasia was thought to be rare, recent publications
have highlighted an incidence rate of more than 25 per 100,000 a
Scores of 4 or more typically indicate more severe symptoms.
further into 3 subtypes (Figure 3.8). As outlined above, FLIP pla-

nimetry can be confirmatory in select cases.
Therapy
There are currently no medications or procedures that specifi-
cally address the lack of peristalsis in achalasia. As a result, all
therapies involve some disruption (either physically or pharma-
cologically) of the LES. Although multiple oral medications have
been used for achalasia (eg, nitrates, calcium channel blockers,
and nitric oxide donors), none have demonstrated efficacy.
Furthermore, the use of these medications is limited by their ad-
verse effects. Consequently, medical therapies are not typically
used in achalasia management.
Botulinum toxin injection into the LES is another effective
therapeutic option in achalasia. The therapeutic effect lasts for an
average of 3 to 6 months. The injection must be administered into
the muscle, not the submucosa, at approximately 1 to 2 cm above
the endoscopic EGJ. Repeated botulinum toxin injections can
make future surgical or endoscopic myotomy more complicated
because of fibrosis, and the injections may lose efficacy over
time. Consequently, this therapy is typically reserved for patients
who have serious comorbidities and thus are not candidates for
Figure 3.6. Esophagram From Patient With Achalasia. The bird- more invasive treatment.
beak sign is apparent where the esophagus tapers distally as it approaches For all other patients with achalasia, 3 durable therapeutic
the esophagogastric junction. options can be used: pneumatic dilation (PD) with a balloon, lapa-
roscopic Heller myotomy (LHM) with partial fundoplication, and
peroral endoscopic myotomy (POEM). Randomized controlled
Findings on EGD include a dilated esophagus (frequently trials have shown equivalence in therapeutic efficacy between PD
filled with food), a puckered EJG (Figure 3.7), and resistance to and LHM and between LHM and POEM.
passage of the scope through the EJG. However, the absence of PD involves the use of the Rigiflex balloon dilator (Boston
these findings does not rule out achalasia. Endoscopic evalua- Scientific Corp), which is available in various sizes (30-mm, 35-
tion is required for ruling out secondary causes of achalasia as mm, and 40-mm diameters) and uses pneumatic pressure rather
outlined above. However, patients with particularly concerning than hydrostatic pressure. Under fluoroscopic guidance, the
clinical histories may require further evaluation with computed balloon is typically positioned across the EGJ and inflated until
tomography of the chest or endoscopic ultrasonography before the waist (ie, a narrowing at the muscular ring of the LES) is
malignancy can be ruled out. obliterated, which signals disruption of the muscle at the LES.
HRM can be considered the gold standard for diagnostic testing. The main risk of this procedure is perforation, which is reported
According to the Chicago Classification version 4.0 criteria, acha- to occur in up to 2% of patients. Therefore, patients who undergo
lasia is diagnosed when the median IRP is high (≥15 mm Hg) and PD should be candidates for major surgery in case a perforation
peristalsis is 100% absent or has failed. Achalasia can be stratified occurs, and the procedure should not be considered for patients
who are not appropriate candidates. Although a 30-mm balloon is
typically used first, durable success may require sequential dila-
tion with a 35-mm and a 40-mm balloon.
LHM typically involves an anterior myotomy, which is usu-
ally extended 2 cm into the gastric cardia. Given that the ensuing
patulous EGJ affords no protection from gastroesophageal reflux,
LHM is performed in combination with either an anterior (Dor)
or a posterior (Toupet) partial fundoplication, which improves
control of gastroesophageal reflux without adversely affecting
the improvement in dysphagia. However, approximately 10% of
patients may still have reflux symptoms.
POEM is an endoscopic procedure in which a submucosal
tunnel is created to access the muscular layer of the esoph-
agus and then carefully dissected with electrosurgical knives.
The approach can be either anterior or posterior. Advantages
of POEM include its minimally invasive nature and the ability
to complete a long myotomy, which is limited by vascular
structures with LHM. However, because POEM does not in-
volve an antireflux procedure, up to 50% to 60% of patients who
undergo POEM have reflux symptoms, positive results on acid
Figure 3.7. Endoscopic Image From a Patient With Achalasia. reflux testing, or erosive esophagitis at 3 to 6 months, although
The esophagogastric junction has a puckered appearance. most patients have good results with proton pump inhibitor
Figure 3.8. Manometry Tracings of Subtypes of Achalasia. In all 3 subtypes, the integrated relaxation pressure (IRP) is increased (IRP ≥15 mm
Hg). Left, In type I achalasia, peristalsis is absent. The large dashed rectangle indicates a distal contractile integral (DCI) of 0 mm Hg·s·cm; the small
dashed square, an integrated relaxation pressure (IRP) of 21.2 mm Hg. Center, Type II achalasia shows panesophageal pressurization. The DCI (large
dashed square) is not applicable (NA); the IRP (small dashed square) is 35.3 mm Hg. Right, Type III achalasia has a spastic wave (distal latency <4.5
seconds). The DCI (large dashed square) is 4,561 mm Hg·s·cm; the IRP (small dashed square) is 40.9 mm Hg; and the distal latency (DL) (small dashed
rectangle) is 3.9 seconds. (Adapted from Yadlapati R, Kahrilas PJ, Fox MR, Bredenoord AJ, Prakash Gyawali C, Roman S, et al. Esophageal motility
disorders on high-resolution manometry: Chicago classification version 4.0(c). Neurogastroenterol Motil. 2021 Jan;33[1]‌:e14058; used with permission
of University of California San Diego Center for Esophageal Diseases.)
(PPI) therapy. PD, LHM, and POEM are largely considered

equivalent therapeutic options for type I or II achalasia, with
type II achalasia representing an early form of achalasia with
a greater therapeutic response rate than the other achalasia
subtypes. POEM is considered superior for type III achalasia
because it allows for a longer myotomy in patients who have
spastic esophageal body contraction.
✓ Secondary achalasia related to malignancy should be suspected in

an older patient with rapidly progressive dysphagia and marked
weight loss
✓ Three subtypes of achalasia—type II has the best response to
treatment, and type III is preferentially treated with peroral en-
doscopic myotomy
EGJ Outflow Obstruction

Patients with EGJOO have an increased median IRP (≥15 mm
Hg supine and ≥12 mm Hg upright), but peristalsis is preserved
(unlike in patients with achalasia) (Figure 3.9). Patients may pre-
sent with regurgitation, dysphagia, chest discomfort, or reflux or
a combination of these symptoms, but the high IRP may also be
an incidental manometric finding. Consequently, the latest itera-
tion of the Chicago Classification (version 4.0) mandates further
testing to make this diagnosis (in contrast to earlier versions). The
recommendation is that swallows be assessed in an alternate posi- Figure 3.9. Esophagogastric Junction Outflow Obstruction. This
tion (supine and upright), with the median IRP remaining high in manometry tracing shows preserved peristalsis but lack of relaxation of
both positions. Further, a clinically relevant diagnosis of EGJOO the lower esophageal sphincter (arrowhead). This patient presented with
requires symptoms of dysphagia or chest pain (or both) along dysphagia after placement of an antireflux ring.
with findings on timed barium esophagram or FLIP (or both) that precipitated by the ingestion of contents that are extremely cold
support obstruction. or hot. Although esophageal spasm is a frequently proposed diag-
Before EGJOO is diagnosed, mechanical causes must be ruled nosis for noncardiac chest pain, results from only 1% of all ma-
out (eg, a tight fundoplication, benign obstruction or stricture, nometry studies support this finding. The esophagram may show
esophageal antireflux ring device, or laparoscopic gastric band). a corkscrew appearance (which may also be seen on endoscopy),
If patients present with the possibility of coexistent malignancy, but frequently the appearance is normal.
they may need to undergo cross-sectional imaging or endoscopic The pathophysiology of spasm is also unclear but may be
ultrasonography. However, that imaging is not indicated other- a reflex for clearing esophageal contents in persons with acid
wise because the diagnostic yield is low. Finally, chronic opioid reflux. Confirmed DES is rare, so evidence-based treatment
use can have important effects on esophageal motility, including options are lacking. However, case reports have described
increased contractile vigor and impaired LES relaxation; the pos- the use of smooth muscle relaxants, such as calcium channel
sibility of this condition, opioid-induced esophageal dysfunction, blockers and nitrates, and endoscopic and surgical options such
must be considered. as POEM or LHM.
Hypercontractile Esophagus Absent Contractility

Hypercontractile esophagus is defined by a normal IRP Patients with absent contractility may present with dysphagia, re-
but increased peristaltic vigor reflected by a DCI of at least gurgitation, and classic heartburn symptoms. Absent contractility
8,000 mm Hg·cm·s (Figure 3.10). Symptoms may be nonspecific, is confirmed by the absence of peristasis on all swallows but with
but patients may complain of intermittent chest pain or dysphagia preserved LES relaxation. Absent contractility may be present in
(or both). However, the clinical significance of this finding is un- patients with connective tissue diseases, and the diagnostic evalu-
clear, and in many patients the finding does not reliably corre- ation may include assessment of autoantibody profiles to exclude
spond with symptoms and may be an incidental finding. As noted diseases such as limited scleroderma.
above, chronic opioid use can be associated with hypercontractile Management is not well determined. Patients with connective
esophagus and should be considered. Further, in some patients tissue disease such as scleroderma may have a patulous EGJ,
hypercontractile esophagus may be associated with GERD, and so PPI therapy is recommended to prevent the formation of
PPI therapy can be considered. However, for most patients, con- strictures, Barrett esophagus, and other complications that can
servative treatment is often considered (eg, use of peppermint oil arise from long-term exposure to acid reflux. Diagnostic eval-
or neuromodulators). uation of new-onset dysphagia mandates an EGD to assess for
treatable GERD-related complications, such as erosive esoph-
agitis, peptic stricture, and esophageal malignancy. If patients
Distal Esophageal Spasm
have dysphagia without complications, conservative measures
Distal esophageal spasm (DES) is defined by a shortened DL are instituted to decrease symptom burden. These measures in-
(<4.5 s) with a normally relaxing LES (median IRP <15 mm Hg) clude adequate fluid intake, elevation of the head of the bed,
and a DCI greater than 450 mm Hg·cm·s. Clinically, patients with remaining upright for 3 to 4 hours after eating, and slow, careful
DES have intermittent onset of chest pain and dysphagia, often eating.
Postfundoplication Motor Disorders

Patients with postfundoplication motor disorders may present
with dysphagia, and the usual cause is a fundoplication that is too
tight, although a slipped or herniated fundoplication should also
be ruled out. An esophagram with a 13-mm barium tablet may
illustrate these issues, particularly if the tablet becomes lodged at
the level of the fundoplication. Results from manometry may be
nonspecific, but the findings could be consistent with achalasia or
EGJOO, with increased LES pressure or increased IRP (or both).
Dilation, potentially with a pneumatic balloon, may be required
to relieve symptoms, but in severe cases fundoplication may need
to be redone.
Post–Obesity Surgery
Esophageal Dysfunction
Post–obesity surgery esophageal dysfunction is an uncommon
but increasingly recognized cause of dysphagia in patients who
have had bariatric surgery, such as Roux-en-Y gastric bypass
(RYGB) or sleeve gastrectomy. The underlying pathology most
Figure 3.10. Hypercontractile Esophagus. Multiple peaks are likely stems from the high pressures of the gastric pouch in an
shown (white arrowheads) with a distal contractile integral greater RYGB or low compliance of the stomach after sleeve gastrec-
than 8,000 mm Hg·cm·s, which is consistent with jackhammer esoph- tomy. Stenosis at the gastrojejunal anastomosis after RYGB
agus (a subset of hypercontractile esophagus) according to the Chicago may also result in compatible symptoms. The diagnosis can
Classification version 4.0. be suspected from findings on a barium esophagram. Potential
therapeutic options are dilation, myotomy, botulinum toxin injec- Suggested Reading
tion, and surgical revision.
Ahuja NK, Clarke JO. Scleroderma and the esophagus. Gastroenterol
Clin North Am. 2021 Dec;50(4):905–18.
Opioid-Induced Esophageal Dysmotility Balko RA, Codipilly DC, Ravi K. Minor esophageal functional
disorders: are they relevant? Curr Treat Options Gastroenterol. 2020
Long-term opiate use can result in dysphagia with nonspecific Jan 17. [Epub ahead of print]
abnormalities on esophageal manometry. Common findings in- Jansson-Knodell CL, Codipilly DC, Leggett CL. Making dysphagia
clude increased IRP, shortened DL, and absent (or weak) peri- easier to swallow: a review for the practicing clinician. Mayo Clin
stalsis. FLIP planimetry has also been used to identify aberrations Proc. 2017 Jun;92(6):965–72.
in secondary peristalsis. If patients have dysphagia and chronic Kahrilas PJ, Bredenoord AJ, Fox M, Gyawali CP, Roman S, Smout AJPM,
opiate use, the use of opiates should be discontinued. et al; International Working Group for Disorders of Gastrointestinal
Motility and Function. Expert consensus document: Advances in the
✓ Esophagogastric junction outflow obstruction—clinically relevant management of oesophageal motility disorders in the era of high-
diagnosis requires fulfillment of manometric criteria, symptoms resolution manometry: a focus on achalasia syndromes. Nat Rev
of dysphagia or chest pain (or both), and findings supportive of Gastroenterol Hepatol. 2017 Nov;14(11):677–88.
obstruction with timed barium esophagram or functional lumen Miller AT, Matar R, Abu Dayyeh BK, Beran A, Vela MF, Lacy BE,
imaging probe (or both) et al. Postobesity surgery esophageal dysfunction: a combined
✓ Absent contractility can be a manifestation of connective tissue cross-sectional prevalence study and retrospective analysis. Am J
disease (specifically, limited scleroderma) Gastroenterol. 2020 Oct;115(10):1669–80.
✓ Long- term opioid use can cause esophageal manometric Ponds FA, van Raath MI, Mohamed SMM, Smout A, Bredenoord AJ.
abnormalities Diagnostic features of malignancy- associated pseudoachalasia.
Aliment Pharmacol Ther. 2017 Jun;45(11):1449–58.
Vaezi MF, Pandolfino JE, Yadlapati RH, Greer KB, Kavitt RT. ACG
clinical guidelines: diagnosis and management of achalasia. Am J
Summary Gastroenterol. 2020 Sep;115(9):1393–411.
Yadlapati R, Kahrilas PJ, Fox MR, Bredenoord AJ, Prakash Gyawali C,
The differential diagnosis of dysphagia is broad. Clinicians must first Roman S, et al. Esophageal motility disorders on high-resolution ma-
differentiate between oropharyngeal dysphagia and esophageal dys- nometry: Chicago classification version 4.0(c). Neurogastroenterol
phagia from the history and physical examination. If obstruction is Motil. 2021 Jan;33(1):e14058.
ruled out, esophageal HRM may be used to elucidate the underlying Yazaki E, Sifrim D. Anatomy and physiology of the esophageal body.
motility disorder and allow for appropriate therapeutic management. Dis Esophagus. 2012 May;25(4):292–8.
Questions and Answers
Questions I.2. A 65-year-old man presents with a 10-year history of heart-

burn. He has symptoms multiple times per week, and the
Abbreviations used: symptoms are worse at night. He has had some relief by man-
BE, Barrett esophagus aging the heartburn with over-the-counter antacids as needed.
CT, computed tomography He has never taken a PPI or a histamine blocker. Over the past
EAC, esophageal adenocarcinoma 6 months, he has also had occasional dysphagia and nausea.
EGD, esophagogastroduodenoscopy He has not had any weight loss. His comorbidities include
EGJ, esophagogastric junction obesity, type 2 diabetes, and hypertension. His medications in-
EMR, endoscopic mucosal resection clude metformin, amlodipine, and lisinopril. He describes oc-
EoE, eosinophilic esophagitis casional use of alcohol and tobacco. What is the best next step
EUS, endoscopic ultrasonography in management?
FLIP, functional lumen imaging probe
GERD, gastroesophageal reflux disease a. EGD
HGD, high-grade dysplasia b. A pH monitoring study
LES, lower esophageal sphincter c. A 2-week trial of oral omeprazole twice daily
LGD, low-grade dysplasia d. Referral to a thoracic surgeon for Nissen fundoplication
POEM, peroral endoscopic myotomy I.3. A 25- year-old man with a history of asthma and eczema
PPI, proton pump inhibitor presents for evaluation of intermittent solid food dysphagia
RFA, radiofrequency ablation over the past year. He has solid food dysphagia approximately
TLESR, transient lower esophageal sphincter relaxation once every 2 weeks and, rarely, he has a mild food impac-
tion that clears in 1 to 2 minutes. He cannot recall any food
triggers, and he does not have difficulty swallowing liquids. He
Multiple Choice (choose the best answer) has not had to visit an emergency department for food impac-
tion. On EGD, his esophagus appears normal; esophageal bi-
I.1. A 42-year-old woman presents with cough and frequent throat
opsy specimens have 35 eosinophils per high-power field. What
clearing without any heartburn, regurgitation, dysphagia,
is the best next step in management?
or vomiting. She took omeprazole 20 mg twice daily, but her
symptoms did not improve. Both her parents were told that they a. Dietary modifications with small, frequent meals consisting
had GERD, although their primary symptom was heartburn. primarily of liquids
The patient is convinced that her symptoms are secondary to b. Begin therapy with infliximab 5 mg/kg every 8 weeks
GERD, so she came to the gastroenterology clinic for further c. Begin therapy with omeprazole 20 mg twice daily
evaluation. What is the best next test in her management? d. Begin a prednisone taper starting at 40 mg daily and decreasing
by 5 mg every week
a. EGD
b. A pH monitoring study when omeprazole therapy has been held I.4. A 68-year-
old man presents with a 3- month history of
c. A pH monitoring study during omeprazole therapy odynophagia. The symptoms are worse with solid foods, but
d. CT of the neck they occur intermittently with liquids. He does not report any
45
nausea, vomiting, or weight loss. His comorbidities include in- I.9. A 72-year-old man presents with a 3-month history of solid
termittent asthma, which is treated with albuterol as needed; food and liquid dysphagia. He reports food sticking in his
heartburn, which is treated with once-daily omeprazole; and midchest and describes a stacking phenomenon that occurs
osteoarthritis that requires frequent use of acetaminophen and during meals. In the past 3 months, he has lost approximately
ibuprofen several times weekly. Examination of his oral cavity 20 kg. His medical comorbidities include high blood pressure
shows mild thrush. EGD shows 2 superficial ulcerations located and type 2 diabetes, and he is a current smoker with a his-
opposite one another in the middle esophagus. Otherwise, the tory of more than 50 pack-years. On upper endoscopy, the
esophagus does not have rings, furrows, exudates, strictures, esophageal lumen is dilated and there is moderate resistance
or inflammation. What is the most likely cause of the patient’s to passage of the endoscope through the EGJ, but the findings
odynophagia? are normal otherwise. An esophagram shows distal tapering
of the esophagus as it approaches the EGJ and poor opening
a. Medication-induced esophagitis
of the junction itself. High-resolution esophageal manometry
b. Infectious esophagitis
results confirm the diagnosis of type II achalasia. Which of the
c. Erosive esophagitis due to GERD
following is the best next step?
d. EoE
a. No further evaluation is required, but he should be advised to
I.5. A 55-year-old man with a history of tobacco use presented for
chew his food carefully and to eat slowly
further evaluation of long-standing heartburn that had con-
b. No further evaluation is required, but arrangements should be
tinued for more than 7 years. He underwent upper endoscopy,
made for enteral nutrition access
which showed a 3-cm segment of circumferential, salmon-
c. He should be referred for either Heller myotomy with
colored mucosa proximal to the EGJ and a 1-cm nonulcerated,
fundoplication or POEM
raised lesion within the area of columnar metaplasia. The rest
d. He should undergo CT of the chest
of the esophagus looked normal. Which of the following would
e. He should receive an injection of botulinum toxin into
be the most appropriate next step?
the LES
a. Perform RFA
I.10. A 53-year-old woman presents with a 10-year history of
b. Perform EUS
heartburn symptoms, and in the past 2 to 3 years progres-
c. Perform targeted biopsies or EMR of the visible lesion
sive solid food dysphagia has developed. Her heartburn
d. Start PPI therapy and have the patient return for endoscopic
had been well controlled with once-daily omeprazole, but
follow-up in 3 years
in the past 6 months she has had difficulty controlling the
I.6. Which of the following patients should undergo endoscopic symptoms even though she has increased the PPI dosage.
screening for BE? Upper endoscopy shows grade C esophagitis and a patu-
lous EGJ. Esophageal biopsy findings are unremarkable.
a. A 45-year-old White woman with a history of tobacco use who
An esophagram shows mild dysmotility without other
has had GERD symptoms for more than 7 years
abnormalities. The results of high-resolution esophageal
b. A 55-year-old White man with a history of alcohol use disorder
manometry are shown below:
and Helicobacter pylori–associated peptic ulcer disease
c. A 70-year-old Hispanic man with a family history of BE in a
first-degree relative who is being treated with a daily PPI for
functional dyspepsia
d. A 65-year-old Asian man with a history of tobacco use who has
weekly GERD symptoms
I.7. A 60-year-old White man with obesity and chronic GERD
symptoms underwent upper endoscopy and was found to have
a 6-cm segment of salmon-colored mucosa proximal to the
EGJ without any focal lesions seen on a good-quality endo-
scopic evaluation. Biopsies were consistent with BE with HGD.
Which of the following is the most appropriate next step?
a. Repeat the upper endoscopy with biopsies in 6 months
b. Repeat the upper endoscopy with biopsies in 12 months
c. Start twice-daily PPI therapy and continue indefinitely
d. Perform RFA in 1 to 2 months
e. Consult a thoracic surgeon about the possibility for antireflux
surgery
I.8. A 52- year-
old man with long- standing GERD underwent
upper endoscopy for BE screening at his community hospital
and was found to have a 2-cm columnar-lined segment in the
distal tubular esophagus. Biopsies showed intestinal meta-
plasia with LGD. Which of the following is the most appro-
priate next step? Which of the following is the best next step?
a. Repeat the upper endoscopy with biopsies in 6 months a. Proceed with FLIP planimetry
b. Confirm the dysplasia with a gastrointestinal pathologist who b. Discontinue PPI therapy and initiate twice-daily histamine-
has expertise in BE pathology receptor antagonist therapy
c. Start twice-daily PPI therapy and repeat the upper endoscopy c. Test for anticentromere and anti–Scl-70 antibodies
with biopsies in 1 year d. Arrange for botulinum toxin injection into the LES
d. Perform EUS e. Perform 24-hour pH-impedance testing when she is not re-
e. Repeat the upper endoscopy with biopsies in 3 to 5 years ceiving PPI therapy
I.11. Which of the following may result in excess gastric acid expo- to rule out a structural cause for his symptoms before the admin-
sure in the esophagus? istration of empirical medical therapy with a PPI. EGD would
a. Increased number of TLESRs allow for assessment of complications due to long- standing
b. Diminished activity of nitric oxide on esophageal sphincter GERD such as erosive esophagitis, peptic stricture, Barrett
receptors esophagus, and esophageal adenocarcinoma. The patient has a
c. Diminished visceral body fat typical symptom of GERD and a positive response to antacids,
d. Rapid gastric emptying which is suggestive of GERD; therefore, pH monitoring should
e. Increased rate of secondary contractions in the esophagus not be the next test. A referral for surgery without an appropriate
I.12. A 65-year-old man presents with a 5-year history of slowly pro- evaluation would not be recommended.
gressive dysphagia. He reports that food, particularly meats
and dry breads, hang at the top of his chest. He describes noc- I.3. Answer c.
turnal regurgitation of food that he had eaten earlier in the This young man with a history of atopic conditions (asthma and
day. His wife remarks that he has always been a slow eater. eczema) presents with dysphagia, and this scenario is character-
He has hypertension that is controlled well with once-daily istic of a patient with EoE. The diagnosis is confirmed with the
hydrochlorothiazide. A representative swallow from high- esophageal biopsies showing more than 15 eosinophils per high-
resolution esophageal manometry is shown below:
power field. Notably, sometimes the esophagus does appear
normal in EoE. First-line treatment of EoE includes PPIs, topical
(not systemic) corticosteroids, and a food-elimination diet. Dietary
modifications with small, frequent meals of primarily liquids are
not a good long-term option and may be more appropriate for a
patient with gastroparesis. Infliximab is not a good initial choice,
but it may be considered rarely for patients with truly refractory di-
sease. Oral corticosteroids may be effective but are associated with
adverse effects and are not a good long-term option for this young
patient. The use of topical corticosteroids would be reasonable and
would avoid the adverse effects of systemic corticosteroids.
I.4. Answer a.
The most common causes of odynophagia include medication-
induced esophagitis and infectious esophagitis. This patient takes
The integrated relaxation pressure is 28.3 mm Hg, and distal ibuprofen, which is associated with medication-induced esopha-
latency is 2.3 seconds. Which of the following would be the de- gitis. Additionally, the EGD shows kissing ulcers in the middle
finitive therapeutic option for this patient? esophagus, which is also suggestive of this condition. The aortic
a. Calcium channel blockers arch is near the middle esophagus, and medications often become
b. Botulinum toxin injection into the LES lodged in this area when patients do not take pills with water
c. Heller myotomy with fundoplication or take them in the supine position. This can result in ulceration
d. Pneumatic dilation on opposite walls of the esophagus. In patients with medication-
e. POEM induced esophagitis, commonly implicated medications include
oral bisphosphonates, nonsteroidal anti-inflammatory drugs, po-
tassium, iron, and antibiotics such as tetracycline. Endoscopic
Answers findings from this patient did not show thick, white exudates
that are characteristic of esophageal candidiasis. The presence of
I.1. Answer b. thrush in the oral cavity does not necessarily indicate the presence
The patient presents with atypical, extraesophageal symptoms of esophageal candidiasis. Patients with erosive esophagitis from
that can sometimes be associated with GERD. However, she has GERD most commonly present with erosions, inflammation, or
had no response to acid-suppressive therapy, so GERD is less ulcerations in the distal esophagus instead of involvement of only
likely. To determine whether she has GERD, she should undergo the middle esophagus. EoE would not be likely because patients
a pH monitoring study when omeprazole therapy has been held. usually have dysphagia, and this patient did not have the typical
She does not have any alarm symptoms such as nausea, vomiting, endoscopic features of this condition (ie, rings, furrows, exudates,
dysphagia, odynophagia, hematemesis, or unintentional weight strictures, or edema).
loss, so EGD would not be the best next test. A pH monitoring
study should be performed during therapy with a PPI when the I.5. Answer c.
diagnosis of GERD is certain, but the patient has not had a re- EMR should be performed in patients who have visible mucosal
sponse to acid-suppressive therapy. CT of the neck is used to abnormalities within the underlying Barrett mucosa to rule out
evaluate for structural causes of oropharyngeal symptoms and invasive adenocarcinoma and obtain a precise histologic diag-
may be considered after an evaluation has been completed for nosis. EMR provides larger specimens, decreases interobserver
GERD, which is the patient’s primary concern. variability among pathologists, and leads to upstaging of the
histologic diagnosis (compared to biopsies) in 30% to 40% of
I.2. Answer a. cases. In the absence of EMR expertise, targeted biopsies from
The patient presents with long-standing symptoms typical of the lesion (placed in a separate appropriately labeled jar) may be
GERD. However, recently he has had alarm symptoms, including acceptable. If histologic examination from the EMR shows dys-
dysphagia and nausea. Therefore, additional evaluation is needed plasia or intramucosal carcinoma with negative deep and lateral
margins, the remaining flat BE mucosa should be treated with because the dysphagia may improve with treatment of the pri-
ablative therapy to eradicate the residual Barrett mucosa given mary issue. Temporary therapy with a botulinum toxin injection
the risk of metachronous dysplasia within the remaining Barrett would not be appropriate because evaluation of the cause of sec-
segment. EUS would not be indicated in the absence of confirmed ondary achalasia has not been initiated. CT of the chest is the best
invasive adenocarcinoma. next step because of the patient’s smoking history. An underlying
pulmonary malignancy should be ruled out as a cause of his sec-
I.6. Answer d. ondary achalasia.
Current American College of Gastroenterology guidelines
suggest that BE screening should be considered for patients who I.10. Answer c.
have chronic GERD (>5 years) or frequent gastroesophageal re- This patient has gastroesophageal reflux and dysphagia, and en-
flux symptoms (at least weekly) and have at least 3 risk factors doscopic findings include a patulous EGJ. Results from manom-
(male sex, White race, age >50 years, central obesity, current or etry show essentially an absence of peristalsis and weak LES
past history of cigarette smoking, and confirmed history of BE or pressures. The overall clinical picture is consistent with connective
EAC in a first-degree relative). tissue disease, and testing should proceed for anticentromere and
anti–Scl-70 antibodies to assess for scleroderma. FLIP planim-
I.7. Answer d. etry will not provide further information. Given the patulous EGJ
If HGD is detected in patients without limited life expectancy, en- seen on endoscopy, the distensibility index of the EGJ is prob-
doscopic eradication therapy should be performed. This includes ably high, but management would not be changed. PPIs are more
endoscopic resection to remove any visible lesions with subse- effective than histamine- receptor antagonists, so PPI therapy
quent endoscopic ablation of the remaining BE segment. For should not be discontinued. Botulinum toxin injection will not
nonnodular BE, endoscopic ablative therapy such as RFA should improve dysphagia and would probably worsen this patient’s
be performed to ensure complete eradication of Barrett mucosa reflux because her LES is already weak. The presence of grade
and to prevent further progression to EAC. Antireflux surgery C esophagitis confirms the presence of reflux disease, and pH-
is not indicated if HGD has been confirmed by an expert gas- impedance testing may be helpful to assess the degree of gastric
trointestinal pathologist and medical therapy has controlled the acid suppression when the patient is receiving PPI therapy, but
gastroesophageal reflux (symptomatically with confirmation by if this testing were performed when she was not receiving PPI
the absence of esophagitis or stricturing). Confirmed HGD is un- therapy, the results would not be clinically useful.
likely to reverse by optimizing antireflux therapy and is an ac-
tionable diagnosis. I.11 Answer a.
TLESRs allow for the release of increased pressure within the
I.8. Answer b. stomach. While this can allow for air to escape, TLESRs may
The presence of LGD or HGD should be confirmed by a gastro- allow for acid to reflux into the esophagus, and a higher number
intestinal pathologist before the treatment strategy is finalized. of TLESRs has been hypothesized to be a cause of reflux disease
Studies have shown that most cases of LGD reported in the com- and excess acid exposure. Nitric oxide mediates sphincter relax-
munity are downgraded to “no dysplasia” after they are reviewed ation; therefore, diminished activity may result in less acid reflux
by academic or expert pathologists. This is most likely due to the owing to fewer sphincter relaxations. Excess visceral body fat
lack of experience in the diagnosis of BE dysplasia in the com- can increase pressure on the stomach, resulting in heightened re-
munity and the overcalling (ie, providing false-positive results) flux events, and may explain why obesity is a risk factor for reflux
of inflammation-related reactive atypia as dysplasia (particularly and reflux-related complications. However, diminished visceral
LGD). Given that current recommendations are to consider en- body fat would not be expected to increase esophageal acid expo-
doscopic ablation in patients with LGD (on the basis of evidence sure. Similarly, gastroparesis can result in excess acid exposure
from randomized controlled trials), it is critically important that because of increased gastric pressures, but rapid emptying would
all diagnoses of dysplasia (LGD and HGD) be confirmed by an not be expected to cause excess gastric acid exposure. Secondary
expert gastrointestinal pathologist. After LGD is confirmed, ab- contractions in the esophagus would allow for clearance of
lative therapy can be discussed with the patient, and both sur- refluxate, so increased numbers of contractions should decrease
veillance (at 6 months, 12 months, and annually thereafter) and esophageal acid exposure.
endoscopic ablative therapy are reasonable options. Additionally,
evaluation at an expert BE center (after optimization of the PPI I.12. Answer e.
dose) leads to upstaging to HGD or carcinoma in almost 25% of This patient has classic symptoms of achalasia. Results of ma-
these patients. In the absence of EAC, EUS is not indicated and nometry are consistent with a diagnosis of type III achalasia.
surveillance in 3 to 5 years is recommended for patients without Lack of relaxation of the LES and a spastic component (distal
dysplasia. latency <4.5 seconds) are hallmarks of this diagnosis. Calcium
channel blockers are poorly effective in management of acha-
I.9. Answer d. lasia. Botulinum toxin injection would probably provide some
This patient presents with typical symptoms of achalasia. symptomatic improvement, but the effects would not last long,
However, his symptom onset was quite rapid. Secondary acha- and symptoms would probably return in 3 to 6 months. For
lasia must be ruled out given his age and comorbidities (smoking patients with type III achalasia, POEM is preferred because the
history) and the considerable weight loss over a short time. length of the myotomy can be tailored to that of the spastic com-
Therefore, further evaluation is required. Definitive therapy for ponent as identified on manometry. Therefore, POEM would be
achalasia (with Heller myotomy or POEM) would not be the preferred for definitive management over Heller myotomy with
best next step before secondary causes of achalasia are ruled out fundoplication or pneumatic dilation.
II
Stomach
4
Peptic Ulcer Disease

STEPHANIE L. HANSEL, MD, MS
A peptic ulcer is a persistent break in the gastrointestinal mu- the infection rate is lower in the non-Hispanic White population
cosa of the stomach or duodenum that is at least 5 mm and and higher in other racial and ethnic groups.
penetrates through the muscularis mucosa. At endoscopy, an
ulcer with perceivable depth should be readily apparent. Smaller,
Pathophysiology
shallower mucosal breaks are erosions. Most peptic ulcers are
due to Helicobacter pylori infection or the administration of Peptic ulcers result from an imbalance between processes that
nonsteroidal anti-inflammatory drugs (NSAIDs). The term peptic damage the gastrointestinal mucosa and mechanisms that protect
ulcer disease (PUD) refers to ulceration that depends in part on it. Acid secretion occurs through gastric proton pumps located
the acid and peptic (ie, with pepsins) activity of gastric juice. in parietal cells. These are hydrogen-potassium-ATPase pumps,
Most peptic ulcers occur in the stomach or duodenal bulb. which use adenosine triphosphate to transport hydrogen across
the cell membrane into the gastric lumen and to transport potas-
✓ Peptic ulcer—a persistent break in the gastrointestinal mucosa sium in the opposite direction. At rest, these pumps are located
of the stomach or duodenum that is at least 5 mm and penetrates intracellularly. Stimulation of parietal cells by a combination of
through the muscularis mucosa acetylcholine (vagus nerve), gastrin (antral G cells), and hista-
✓ Helicobacter pylori—a gram-negative, urease-producing bacte- mine (enterochromaffin-like [ECL] cells) translocates the proton
rium that lives in the mucous layer of the gastric epithelium; the
pumps to the apical secretory canalicular (luminal) membrane,
major infectious cause of peptic ulcer disease

where they become functional (Figure 4.1). During the ce-
phalic phase of meal-stimulated acid secretion, vagal activity
stimulates ECL cells, G cells, and parietal cells. During the gas-
Epidemiology tric phase, distention of the stomach augments vagal output, and
PUD is a common condition worldwide and occurs in persons of short peptides, amino acids, calcium, and alkaline pH stimulate
all ages. In resource-limited countries, most children are infected gastrin release by G cells. Gastrin release is inhibited by a gastric
with H pylori before they are 10 years old, and they may carry pH less than 3. Acid pH also stimulates somatostatin-producing
a chronic infection into adulthood. Children living in resource- D cells in the antrum and body of the stomach, with somatostatin
rich countries are unlikely to be infected with H pylori. The inhibiting gastrin release from G cells and acid secretion from
overall prevalence in the US is approximately 30%. In the US, parietal cells.
The normal mucosal defense mechanisms against gastric acid
include the surface mucous layer; the secretion of bicarbonate,
Abbreviations: COX-2, cyclooxygenase 2; ECL, enterochromaffin-like; mucus, and phospholipid by gastroduodenal epithelial surface
EGD, esophagogastroduodenoscopy; GERD, gastroesophageal reflux di- mucous cells; the epithelial barrier; mucosal blood flow; epithe-
sease; H2, histamine; NSAID, nonsteroidal anti-inflammatory drug; PPI, lial cell restitution; and epithelial cell renewal (Figure 4.2). Many
proton pump inhibitor; PUD, peptic ulcer disease of these defense mechanisms are prostaglandin dependent.
51
52 Section II. Stomach
Etiology
As stated above, the most common causes of PUD are H pylori
infection and use of NSAIDs, including low- dose aspirin.
Less common causes of PUD include hypersecretory states,
viral infections (cytomegalovirus and herpes simplex virus 1
infections), drug exposure (cocaine), ischemia, radiotherapy,
and infiltrative disorders (malignancy, sarcoidosis, and Crohn di-
sease). Cirrhosis, chronic obstructive pulmonary disease, kidney
failure, and organ transplant are associated with PUD, but the
pathophysiologic mechanisms are unclear. When stress-related
ulcerations of the stomach occur in critically ill patients, ischemia
is the most likely mechanism.
H pylori Infection
Worldwide, H pylori infection is the main cause of both gastric
Figure 4.1. Physiology of the Parietal Cell. ECL indicates ulcers (60%) and duodenal ulcers (up to 90%). More than half of
enterochromaffin-like. all persons in the world are infected with H pylori, but ulcers de-
velop in only 10% of them. In resource-limited countries, many
children (>70%) are infected with H pylori before the age of
10 years, and more than 90% of adults are infected by the age of
50 years. In the US, H pylori infection is uncommon in persons
born after 1945—improved sanitation and the increased use of
antibiotics during childhood may be largely responsible. Persons
born before 1945 are more likely to have been infected with H
pylori (60% of them were infected by age 60 years). Having a
lower socioeconomic status, residing in a crowded household,
and living with someone infected with H pylori are known risk
factors for H pylori infection. In the US, people of Hispanic or
East Asian ethnicity have the highest rates of H pylori infection.
The infection rates are similar between men and women. The
mode of transmission is believed to be from person to person
through oral-oral and fecal-oral routes.
H pylori is a gram-negative, spiral-shaped microaerophilic
bacterium with multiple flagella. The organisms exist as dor-
mant coccoid forms in culture and survive only on gastric-type
mucosa in the stomach or metaplastic gastric-type epithelium in
the duodenum or small bowel (Meckel diverticulum). In the sto-
mach, H pylori lives within the mucous layer, surviving the acidic
pH of the stomach in part by its urease activity, which converts
urea (ubiquitous) to ammonia, and by its motility, its ability to
adhere to epithelial cells, its microaerophilic properties, and its
proteases, which may digest mucus (Figure 4.3). Often H pylori
does not survive in an alkaline environment in the stomach (eg,
after gastroenterostomy).
Gastric-type mucosa is damaged by H pylori through its pro-
duction of ammonia, proteases, lipases, phospholipases, and
mucinases and by its induction of a local immune response (che-
motactic factors for neutrophils and monocytes and a host T-cell
response). Virulence factors specific for H pylori and associated
with ulcer disease include a cag pathogenicity island, whose
product (CagA) enters host epithelial cells, and certain vacA loci
Figure 4.2. Cascade of Mucosal Defense and Repair Mechanisms. that encode a bacterial toxin (VacA). In many persons infected
Damaging effects on epithelial cells of exogenous and endogenous with H pylori, gastrin levels are higher than normal because of
factors are amplified by peptic acid activity. If the 3 lines of defense antral-predominant, active chronic gastritis that decreases the
fail, epithelial cell injury occurs. Repair is by restitution and cell rep- number of antral D cells and the level of somatostatin; the re-
lication. If these repair mechanisms fail, an acute wound forms. Ulcers
sult is an increased rate of gastric acid secretion and a greater
form only with the failure of acute wound healing mechanisms. NSAID
indicates nonsteroidal anti-inflammatory drug. (Adapted from Soll AH. likelihood of the development of a duodenal ulcer. Abnormally
Peptic ulcer and its complications. In: Feldman M, Sleisenger MH, high levels of gastric acid secretion may damage the duodenum
Scharschmidt BF, editors. Sleisenger & Fordtran’s gastrointestinal and and result in gastric metaplasia, allowing H pylori to colonize the
liver disease: pathophysiology, diagnosis, management. Vol 1. 6th ed. duodenum. This pattern of duodenal ulcers appears to be more
Philadelphia [PA]: WB Saunders Company; c1998. p. 620-78; used with common in persons who are infected with H pylori later in life.
permission.) In contrast, persons infected with H pylori early in life have a
4. Peptic Ulcer Disease 53
The risk of injury to the gastroduodenal mucosa by aspirin

is dose-related and can occur even with administration of low-
dose aspirin. Because of the antiplatelet effects of aspirin and
other NSAIDs, complications such as ulceration with bleeding
or perforation can occur throughout the gastrointestinal tract.
Cyclooxygenase 2 (COX-2) selective inhibitors have been asso-
ciated with a decreased risk of clinically apparent PUD, including
complications, but as with nonselective NSAIDs, cardiovascular
risks are a concern. PUD may develop in up to 5% of patients
who take COX-2 inhibitors, and ulceration may heal slowly in
persons who continue to ingest COX-2 inhibitors. COX-2 activity
appears to be important for ulcer healing. Persons who take both
low-dose aspirin and a COX-2 inhibitor have an increased risk
for PUD and its complications compared with those who take
either drug alone. Antiplatelet agents such as clopidogrel have
been linked to a high rate of complications, such as gastrointes-
tinal tract bleeding, particularly in patients who previously have
had gastrointestinal tract complications, whether the antiplatelet
agents were taken alone or with NSAIDs. Platelet activity, like
COX-2 activity, appears to be important for ulcer healing.
✓ Most common causes of PUD—NSAIDs and H pylori infection

✓ PUD may develop in up to 15% of long-term users of NSAIDs; up
to 4% of those patients may have a complication such as bleeding
or perforation
H pylori Infection and NSAIDs

The relationship between NSAID use and H pylori infection is
complex and controversial. Patients who are infected with H pylori
and have increased levels of gastric acid secretion and patients
who have active or subclinical PUD are most likely to be at
increased risk for PUD and its complications after initiation of
NSAID therapy. These risks are decreased if H pylori infection
Figure 4.3. Section of Stomach Showing Helicobacter pylori. The
is eradicated before treatment with NSAIDs. In contrast, persons
bacteria are the black rods (Wenger-Angritt stain). (Adapted from Emory
TS, Carpenter HA, Gostout CJ, Sobin LH. Atlas of gastrointestinal who take NSAIDs long-term and who have a history of compli-
endoscopy & endoscopic biopsies. Washington [DC]: Armed Forces cated PUD and are infected with H pylori are not protected from
Institute of Pathology, American Registry of Pathology; c2000.) additional PUD complications after eradication of H pylori in-
fection. Ongoing ingestion of NSAIDs perpetuates the increased
risk of additional complications.
multifocal and pan-gastric gastritis. These patients have parietal
cell damage, decreased production of acid, and a greater risk for
Hypersecretion of Gastric Acid
gastric ulcer.
Eradication of H pylori eliminates gastric and duodenal ulcers Mild hypersecretion of gastric acid occurs in many but not all
and prevents recurrence. In the US, the recurrence rate of infec- patients who have PUD and are infected with H pylori, especially
tion with H pylori is less than 3% per year. in those who have duodenal ulcers. Zollinger-Ellison syndrome
is a rare cause of hypersecretion of gastric acid. In most patients
who have the syndrome, upper gastrointestinal tract ulceration
Nonsteroidal Anti-inflammatory Drugs
occurs, often involving the esophagus, stomach, and duodenum
NSAIDs constitute approximately 5% of all prescribed medi and including ulceration of the duodenum beyond the duodenal
cations worldwide. PUD has been estimated to develop in up bulb. Gastric acid hypersecretion with PUD occurs in about one-
to 15% of long-term NSAID users, and a complication such as third of patients who have systemic mastocytosis because of the
bleeding or perforation may develop in up to 4% of them. When increased release of histamine by mast cells. Increased release
ingested orally, NSAIDs cause damage to the gastric epithelium of histamine, acid hypersecretion, and PUD have been identified
topically and cause systemic damage by inhibiting the produc- also in patients who have basophilic leukemia and chronic
tion of prostaglandins by gastroduodenal epithelial cells. Risk myelogenous leukemia with basophilia. Uncommonly, antral
factors for NSAID-related gastrointestinal tract ulceration and its G-cell hyperplasia has been found in patients who do not have
complications include age older than 60 years; previous history Zollinger-Ellison syndrome (according to negative secretin test
of PUD (especially if complicated); the first 30 to 90 days of results) but do have PUD with gastric acid hypersecretion due to
NSAID therapy; use of high-dose NSAIDs or simultaneous use hypergastrinemia. Many of these patients also have H pylori in-
of multiple NSAIDs; concomitant use of corticosteroids, use of fection, and their PUD and gastric acid hypersecretion resolve
other antiplatelet drugs, alendronate, or anticoagulants; history of when H pylori is eradicated. Gastric outlet or duodenal ob-
comorbid conditions; and H pylori infection. struction due to various causes can produce gastric distention,
ulcers present with epigastric burning or a hunger sensation, es-

pecially 1 to 3 hours after a meal or during the night. The pain
improves after the ingestion of food, antacids, or antisecretory
agents. Thus, these patients tend to gain weight. In contrast, per-
sons with gastric ulcers are more likely to feel discomfort after
eating and may have weight loss. Patients who have nonulcer
dyspepsia can have the same symptoms as those with PUD,
and many persons with PUD have atypical symptoms. Also, the
overlap of symptoms between patients with gastroesophageal re-
flux disease (GERD) and those with PUD is considerable. The
differential diagnosis for PUD includes functional dyspepsia,
GERD, biliary pain, gastric or duodenal malignancy, medication
adverse effect, pancreatitis, and ischemia.
Diagnosis
Diagnosis of PUD is difficult from the history and physical exami-
Figure 4.4. Retained Antrum After Billroth II Operation. (Adapted
nation alone given the wide variation in presentation. The definitive
from Tringali A, Loperfido S, Costamagna G, Familiari P. Endoscopic diagnosis can be established with esophagogastroduodenoscopy
retrograde cholangiopancreatography (ERCP) after Billroth II recon- (EGD). It is sensitive for detecting small ulcerations and is the
struction [Internet]. In: Howell DA, editor. UpToDate: Waltham [MA]. best method for determining the location and severity of the ul-
c2020. [updated 2020 Dec 18; cited 2022 Sep 8]. Available from: http:// ceration. In addition, biopsies can be obtained to assess for the
www.uptodate.com/; used with permission.) cause of PUD, or endoscopic therapy can be applied if the ulcer
is bleeding.
hypergastrinemia, hypersecretion of acid, and ulceration prox-

imal to the obstruction. Severe PUD, hypersecretion of gastric Diagnosis of H pylori Infection
acid, and hypergastrinemia are common in the few patients in Many tests are available for diagnosing H pylori infection (Table
whom retained gastric antrum syndrome occurs after a Billroth 4.1). However, testing should be ordered only if the patient will
II operation, when a small cuff of gastric antrum is left as part be offered treatment if the results are positive. No single test is
of the afferent limb (Figure 4.4). In patients who undergo sub- considered the criterion standard for the diagnosis of H pylori.
stantial small-bowel resection, postoperative complications can Two categories of test are available: noninvasive and invasive
include hypergastrinemia, hypersecretion of gastric acid, and se- (or endoscopic). The decision as to which test to order should be
vere PUD because of the sudden loss of inhibitors of gastrin and based on the clinical circumstances, the pretest probability, and
acid secretion. the cost and availability of the test. In patients who have PUD
without an obvious cause, a second test for H pylori should be
Miscellaneous Conditions conducted because false-negative results are possible. Many tests
(culture, histology, breath and stool antigen tests, and urease
Ulceration of the gastroduodenal area rarely occurs with testing) depend on the number of organisms, and false-negative
infections other than those caused by H pylori. In immunocom- results are frequent if the patient has been exposed recently to
promised patients, cytomegalovirus infection may cause ulcer- antibiotics, bismuth, or a proton pump inhibitor (PPI). Before
ation, often producing large, deep, and multiple ulcers that are testing, patients should not receive treatment with antibiotics or
frequently complicated by bleeding, perforation, or obstruction. bismuth for 4 to 6 weeks or with PPIs for 2 weeks before testing
Rarely, ulceration can occur from infections such as syphilis or (histamine [H2]-receptor blockers can be taken).
tuberculosis (often antral), after radiotherapy, and from sarcoid-
osis, Crohn disease, vasculitis, and ischemia. Gastric ulceration Serologic Tests
can be due to malignancy, including adenocarcinoma, lym-
phoma, sarcoma, gastrointestinal stromal tumors, and metastatic Serologic testing for H pylori should be avoided because it has
malignancies. low accuracy in low-prevalence populations (such as in the US)
Among persons who smoke cigarettes, compared with
nonsmokers, PUD is more common and is more likely to be Table 4.1. Diagnostic Tests for Helicobacter pylori
complicated, to require surgery, to be slow to heal, and to recur.
Although alcohol can directly damage the gastroduodenal mu- Test Sensitivity, % Specificity, %
cosa and stimulate acid secretion, there is no evidence that al- Nonendoscopic tests
cohol is a risk factor for PUD. Similarly, there is no clear link In-office antibody test 88-94 74-88
between either diet or psychologic factors and ulcer disease. ELISA on serum 85 79
Stool antigen test 94 97
Urea breath test 88-95 95-100
Clinical Features Endoscopic tests
The presentation of patients with PUD varies. Many patients pre- Biopsy urease test 90 95
Histology 95 98
sent with dyspeptic symptoms, but some are asymptomatic, and Culture 80-98 100
others present with perforation. Ulcerlike dyspepsia is one of the
most common symptoms. Classically, patients with duodenal Abbreviation: ELISA, enzyme-linked immunosorbent assay.
4. Peptic Ulcer Disease 55
and would result in inappropriate treatment of many patients. If ✓ Serologic testing for H pylori should be avoided because it has
serologic testing is performed, it should be confirmed with addi- poor accuracy where the prevalence is low, such as in the US
tional testing for H pylori, such as the stool antigen test or urea
breath test.
Treatment
Stool Antigen Test
With improved understanding of the pathogenesis of PUD, ap-
The H pylori stool antigen test is rapid, highly sensitive, and
propriate treatment has been developed. PPIs are a mainstay of
highly specific. In contrast to serologic testing, it can be used
therapy and are critical to ulcer healing independently of the
to evaluate both active infection and response to therapy; thus,
cause. PPI therapy is superior to antacids, H2-receptor antagonists,
it is cost-effective. This test is affected by recent use of bismuth
sucralfate, and prostaglandins. Additional treatment depends on
compounds, antibiotics, and PPIs.
the cause of the ulcer.
Urea Breath Test

Treatment of H pylori Infection
Because H pylori is practically the only infectious organism in the
upper gastrointestinal tract capable of producing urea via urease, Patients who test positive for H pylori should be given therapy
urea labeled with carbon 13 or carbon 14 can be administered as to eradicate it because H pylori is classified as a carcinogen.
a breath test. The urea breath test is rapid, highly sensitive, and Therapy is also indicated for patients who have H pylori infec-
highly specific. Like stool antigen testing, it is a highly reliable tion and extranodal marginal zone B-cell lymphoma or gastric
method for confirming eradication of H pylori after treatment. adenocarcinoma. In addition, first-degree relatives of patients
who have H pylori infection and gastric adenocarcinoma should
receive treatment.
Rapid Urease Tests
The optimal therapeutic regimen for H pylori infection has not
Biopsy specimens obtained during endoscopy can be tested for been defined, but the guidelines for first-line therapy for eradica-
urease with rapid urease testing. These tests are rapid, highly sen- tion of H pylori require 14 days of therapy. If a patient with an
sitive, and highly specific. False-positive results can occur with active infection has been exposed to macrolides or the local rates
small intestinal bacterial overgrowth (from urease- producing for clarithromycin resistance exceed 15%, bismuth-based quad-
Proteus) and from Helicobacter species other than H pylori. ruple therapy should be prescribed. Quadruple therapy includes a
Gastrointestinal tract bleeding can cause false-negative results. PPI, bismuth, metronidazole, and tetracycline.
Patients may be offered triple therapy if they have not been
Histologic Examination exposed to macrolides and if the local clarithromycin resistance
rates are low. Triple therapy includes a PPI in combination with
Histologic examination is highly sensitive and highly specific but clarithromycin and amoxicillin (metronidazole is used instead of
expensive. Biopsy specimens (5 or 6) should be taken from the amoxicillin for patients allergic to penicillin) (Table 4.2).
antrum, fundus, and incisura. Silver staining is recommended to Although metronidazole resistance may occur, the use of met-
facilitate the detection of H pylori. ronidazole in combination with other agents (PPI, bismuth, or
tetracycline) besides clarithromycin and the use of a higher dose
Culture (500 mg twice daily) can diminish the rate of treatment failure.
Culture for H pylori after endoscopic biopsy is not widely avail- Resistance to amoxicillin, tetracycline, or bismuth is rare.
able, is not rapid, and is less sensitive than noninvasive tests and If a patient has a persistent H pylori infection, the choice of
histologic examination. Culture may be used best to determine therapy should be guided by the prior treatment regimen. For ex-
antimicrobial sensitivity for patients who have resistant H pylori ample, if triple therapy was given, quadruple therapy should be
infections. prescribed. If quadruple therapy was given, a levofloxacin-based
Table 4.2. American College of Gastroenterology First-Line Regimens for Helicobacter pylori Eradication
Patients Regimen
Patients who are not allergic to penicillin and have not Bismuth subsalicylate 300 mg orally 4 times daily, metronidazole
previously received a macrolide 250-500 mg orally 4 times daily, tetracycline 500 mg orally 4
times daily, and standard-dose PPI twice daily for 10-14 d
Patients who are not allergic to penicillin and have Bismuth subsalicylate 300 mg orally 4 times daily, metronidazole
Patients who are allergic to penicillin and have not Standard-dose PPI twice daily, clarithromycin 500 mg twice daily,
previously received a macrolide or cannot tolerate and metronidazole 500 mg twice daily for 10-14 d
bismuth quadruple therapy
Patients who are allergic to penicillin and have Bismuth subsalicylate 300 mg orally 4 times daily, metronidazole
Abbreviation: PPI, proton pump inhibitor.
Data from Chey WD, Leontiadis GI, Howden CW, Moss SF. ACG clinical guideline: Treatment of Helicobacter pylori infection. Am J
Gastroenterol. 2017 Feb;112(2):212-39.
regimen could be offered. In discussions with the patient, the cli- decision to perform follow-up endoscopy for gastric ulcers to ex-
nician should assess for medication nonadherence and reinforce clude malignancy is made on a case-by-case basis depending on
the importance of completing the regimen. Eradication of H the level of concern. However, about 95% of gastric cancers as-
pylori should be confirmed after treatment. sociated with gastric ulceration can be diagnosed at initial endos-
copy when an adequate number of biopsy specimens are obtained
from the edge of the ulcer (≥4) and from the base (≥1). Patients
Treatment of NSAID Ulcers
at high risk for gastric cancer or gastric ulcers with worrisome
If possible, a patient who has active ulceration should stop taking features at endoscopy should undergo follow-up endoscopy to
all NSAIDs, especially if the patient is losing blood. If NSAID document complete healing of the ulcer. Patients with gastric or
therapy cannot be discontinued, the use of a decreased NSAID duodenal ulcers without an obvious cause (ie, idiopathic ulcers)
dose should be considered. In addition, PPI therapy should be should receive maintenance PPI therapy to prevent ulcer relapse.
started and the patient should be monitored.
Prevention of PUD
Antacids
Persons about to be prescribed aspirin or NSAIDs for long-term
Antacids can heal ulcers by binding bile, inhibiting pepsin, and therapy should be tested for H pylori and treated if infected. If they
promoting angiogenesis. However, ulcer healing requires high are at high risk for PUD, prophylactic therapy with misoprostol
doses of antacids, which often cause adverse effects. Thus, antacids or a PPI should be considered. H2-receptor blockers have not
are rarely used to treat PUD. been useful for these patients. Patients at highest risk are those
who have a previous history of ulcer disease; the elderly; patients
H2-Receptor Antagonists who are also receiving treatment with warfarin, corticosteroids,
or other antiplatelet agents; and those who have clinically impor-
Three H2-receptor antagonists (cimetidine, nizatidine, and famoti tant comorbid conditions.
dine) are available. All 3 are highly effective for the treatment of
PUD. Cimetidine is rarely prescribed because it has a short half-
life, several drug-drug interactions, and adverse effects. Cimetidine PUD in Pregnancy
binds to cytochrome P450 and may affect the metabolism of cer- The occurrence of PUD in pregnant patients is uncommon.
tain drugs, such as warfarin, lidocaine, theophylline, and phen- The focus of treatment during pregnancy is acid suppression.
ytoin. It also has dose- dependent adverse effects that include Medications that are considered safe include sucralfate and
gynecomastia, breast tenderness, and impotence. Nizatidine and antacids, particularly the magnesium- containing antacids in
famotidine are longer acting, and famotidine has the longest du- the second and early third trimesters and aluminum-containing
ration of action. (Ranitidine was recalled from the US market in antacids in the second and third trimesters. H2-receptor
April 2020.) Healing of ulceration can be accomplished with an antagonists can be given because they are considered relatively
8-week regimen of single dosing at bedtime with any H2-receptor safe, and PPI therapy is also considered to be low risk in preg-
blocker. H2-receptor blockers do not have activity against H pylori. nancy. Misoprostol is contraindicated and should be avoided be-
cause it increases the risk of major birth defects. If patients have
Proton Pump Inhibitors severe symptoms or have symptoms refractory to treatment, EGD
examination can be considered for confirmation of the diagnosis.
PPIs are the most potent antisecretory agents available. They are Clear communication is necessary between the obstetrician, gas-
enteric coated or combined with sodium bicarbonate to protect troenterologist, and patient about the benefits and risks of the pro-
them from acid inactivation. After being absorbed in the upper cedure. If H pylori is present, treatment is typically delayed until
small bowel, PPIs are taken up by parietal cells and secreted into after delivery.
the canalicular (luminal) space, where they are converted to a me-
tabolite that binds covalently with proton pumps and irreversibly
inactivates them. These proton pumps must be active, and the pari- Suggested Reading
etal cells must be stimulated for the PPI–proton pump interaction to Bindu S, Mazumder S, Bandyopadhyay U. Non- steroidal anti-
occur. Thus, PPIs should be taken 15 to 30 minutes before a meal. inflammatory drugs (NSAIDs) and organ damage: A current perspec-
They are not as effective if administered while acid secretion is tive. Biochem Pharmacol. 2020 Oct;180:114147.
being inhibited by H2-receptor blockers. Several PPIs are available, Chey WD, Leontiadis GI, Howden CW, Moss SF. ACG clinical guide-
including omeprazole, lansoprazole, pantoprazole, rabeprazole, line: Treatment of Helicobacter pylori infection. Am J Gastroenterol.
esomeprazole, and dexlansoprazole. All PPIs are capable of healing 2017 Feb;112(2):212–39.
Kamboj AK, Cotter TG, Oxentenko AS. Helicobacter pylori: The
duodenal ulcers in 4 weeks. Gastric ulcers, depending on size, may
past, present, and future in management. Mayo Clin Proc. 2017
require a considerably longer duration of treatment. Apr;92(4):599–604.
Kavitt RT, Lipowska AM, Anyane-Yeboa A, Gralnek IM. Diagnosis and
✓ First-line therapy for H pylori infection—quadruple therapy with treatment of peptic ulcer disease. Am J Med. 2019 Apr;132(4):447–56.
a PPI, bismuth, metronidazole, and tetracycline Lanas A, Chan FKL. Peptic ulcer disease. Lancet. 2017 Aug;390(10094):
613–24.
Sonnenberg A, Turner KO, Genta RM. Low prevalence of Helicobacter
Follow-up and Maintenance Therapy pylori-positive peptic ulcers in private outpatient endoscopy
centers in the United States. Am J Gastroenterol. 2020 Feb;115(2):
Patients who have uncomplicated duodenal ulcers without 244–50.
H pylori infection do not require follow- up endoscopy after Waskito LA, Salama NR, Yamaoka Y. Pathogenesis of Helicobacter
therapy if they do not have recurrent or persistent symptoms. The pylori infection. Helicobacter. 2018 Sep;23 Suppl 1:e12516.
5
Gastritis and Gastropathy

STEPHANIE L. HANSEL, MD, MS
Inflammation of the stomach can manifest itself as gastritis or Gastritis

gastropathy. Gastritis is a histologic diagnosis referring to in-
Acute Gastritis
flammatory processes of the stomach. Patients with gastritis
may or may not have identifiable endoscopic findings or clinical Acute gastritis is an acute inflammatory process that involves the
symptoms. Gastropathy refers to epithelial damage with little or stomach with a predominantly neutrophilic infiltration. It may
no inflammation. or may not have features of intramucosal hemorrhage, superfi-
There are several classifications of gastritis and gastropathy. cial mucosal sloughing, or erosion. Most often, acute gastritis is
Most of them distinguish between acute and chronic disease related to use of aspirin or other nonsteroidal anti-inflammatory
and the predominant inflammatory infiltrate seen in biopsy drugs (NSAIDs), excess alcohol intake, uremic toxins, heavy
specimens. The etiology of the gastritis or gastropathy is also an use of tobacco, therapy with cancer chemotherapeutic drugs, is-
important factor in the classification, as is the topography or spe- chemia, or infection.
cific areas of involvement in the stomach. The updated Sydney Acute gastritis due to Helicobacter pylori infection is rarely
System (Table 5.1) often is used to classify gastritis. To ensure identified. Abdominal pain, nausea, or vomiting may develop.
proper mucosal sampling, the diagnosis and classification of gas- Endoscopic findings such as erythema or erosion are absent or
tritis require a total of 6 biopsy specimens: 2 from the antrum, 2 nonspecific. Biopsy specimens show mucosal neutrophilic infil-
from the body, and 2 from the incisura (Figure 5.1). Sometimes tration in the antrum, with or without desquamation and erosions.
duodenal biopsies may assist in the overall diagnosis of a disease, In most persons acutely infected with H pylori, an active chronic
such as celiac disease in patients with lymphocytic gastritis, gastritis develops.
Crohn disease in patients with granulomatous gastritis, and eo- Aspirin and other NSAIDs can cause acute injury to the
sinophilic gastroenteritis in patients with eosinophilic infiltration gastric mucosa. With gastritis, endoscopic findings range from
of the antrum. minimally visible changes to erythema, petechial hemorrhages,
or erosions. Histologically, there can be evidence of superficial
✓ Gastritis—histologic diagnosis of acute or chronic inflammation lamina propria hemorrhage, mucosal sloughing, neutrophilic in-
of the stomach filtration, and mucosal necrosis. The changes are limited to the
✓ Gastropathy—epithelial damage to the stomach with little or no mucosa and do not extend into the muscularis mucosa. Clinical
inflammation

symptoms such as abdominal pain, nausea, vomiting, or gas-
trointestinal tract bleeding may or may not be present as well.
Similar findings occur after the ingestion of large amounts of al-
cohol and other toxic substances and after ischemia (Figure 5.2).
All these insults impair mucosal barrier function by affecting
Abbreviations: CMV, cytomegalovirus; HLA, human leukocyte antigen; prostaglandin synthesis (NSAIDs) or mucosal blood flow (al-
NSAID, nonsteroidal anti-inflammatory drug cohol or ischemia) or by direct injury to the surface mucosal cells
57
Table 5.1. Sydney System for Classification of Gastritis

Type of gastritis Etiologic factors Synonyms
Nonatrophic Helicobacter pylori Superficial
Diffuse antral
Chronic antral
Interstitial follicular
Type B
Atrophic-autoimmune Autoimmunity Type A
H pylori Diffuse corporeal
Pernicious anemia
Atrophic-multifocal H pylori Type B
Environmental
Metaplastic
Atrophic pangastritis
Progressive intestinalizing
pangastritis
Chemical/radiation Bile Reactive
NSAIDs Reflux
Alcohol or other Radiation
agents (possibly)
Radiation
Lymphocytic Idiopathic Varioliform
Autoimmune Celiac disease–associated
Gluten Figure 5.2. Acute Hemorrhagic Gastritis. (Adapted from Emory
H pylori TS, Carpenter HA, Gostout CJ, Sobin LH. Atlas of gastrointestinal en-
Granulomatous Crohn disease Isolated granulomatous doscopy & endoscopic biopsies. Washington, DC: Armed Forces Institute
Sarcoidosis of Pathology, American Registry of Pathology; c2000. p. 101.)
Granulomatosis with
polyangiitis (NSAIDs, other drugs, or infection). Treatment of acute gastritis
Infectious includes management of the underlying condition, withdrawal of
Eosinophilic Food sensitivities Allergic
any offending drug or toxin, and acid-suppression therapy with a
Allergies
proton pump inhibitor.
Idiopathic
Infectious Bacteria Phlegmonous
Viruses Cytomegalovirus Chronic Gastritis
Fungi Anisakiasis
Parasites Chronic gastritis is classified as nonatrophic, atrophic, or special
forms. Mucosal injury occurs in all forms of chronic gastritis.
Abbreviation: NSAID, nonsteroidal anti-inflammatory drug. The atrophic forms of chronic gastritis can be autoimmune or
Adapted from Dixon MF, Genta RM, Yardley JH, Correa P. Classification multifocal, and, subsequently, metaplasia, dysplasia, and carci-
and grading of gastritis: The updated Sydney System. International Workshop noma may develop.
on the Histopathology of Gastritis, Houston 1994. Am J Surg Pathol. 1996
Oct;20(10):1161-81; used with permission.
Nonatrophic Chronic Gastritis
Nonatrophic chronic gastritis is typical in persons who have
H pylori infections with acute gastritis and who do not clear the
infection (Figure 5.3). Endoscopic findings include gastric mu-
cosal erythema, erosions, granularity, and nodularity. Nonatrophic
chronic gastritis usually is most evident in the antrum. Histologic
findings include a marked lymphoplasmacytic and neutrophilic
infiltrate. Lymphoid aggregates or germinal centers may be seen.
Gastric atrophy, metaplasia, and dysplasia are not seen. However,
this type of active chronic gastritis due to H pylori infection does
increase the risk of duodenal ulcer disease.
Atrophic Chronic Gastritis

Multifocal Atrophic Gastritis. Multifocal atrophic gastritis
may develop in persons infected with H pylori. This type of active
chronic gastritis includes the loss of glands and metaplastic change
principally involving the body and antrum of the stomach (Figure
5.4). Inflammation consists of both acute and chronic inflamma-
tory cells. Affected persons have an increased risk of gastric ulcer
disease and gastric adenocarcinoma with this type of gastritis.
Figure 5.1. Gastric Biopsy Protocol to Diagnose Gastritis. Biopsy ✓ Aspirin and NSAIDs—common causes of gastropathy
specimens (circles) should be obtained from the greater and lesser ✓ H pylori can cause acute or chronic gastritis
curvatures of the body and the antrum and from the incisura (dotted line).
5. Gastritis and Gastropathy 59
Figure 5.4. Multifocal Atrophic Gastritis. (Adapted from Emory

TS, Carpenter HA, Gostout CJ, Sobin LH. Atlas of gastrointestinal en-
doscopy & endoscopic biopsies. Washington, DC: Armed Forces Institute
of Pathology, American Registry of Pathology; c2000. p. 93.)
gastric adenocarcinoma (<3%). Patients or their relatives may

have other autoimmune disorders, including Hashimoto thyroid-
itis, Graves disease, Addison disease, diabetes, and vitiligo. There
is also an association with human leukocyte antigen (HLA)-B8
and HLA-DR3.
Figure 5.3. Active (Nonatrophic) Chronic Gastritis of the Antrum
of the Stomach. Stain is hematoxylin-eosin. (Adapted from Emory TS, Special Forms of Gastritis
Carpenter HA, Gostout CJ, Sobin LH. Atlas of gastrointestinal endos- Infectious Gastritis. Bacterial gastritis is most often caused
copy & endoscopic biopsies. Washington, DC: Armed Forces Institute of
by H pylori (see Chapter 4, “Peptic Ulcer Disease”). However,
Pathology, American Registry of Pathology; c2000. p. 90.)
other species of bacteria may be found in the stomach after an-
trectomy or in association with achlorhydria. Organisms such
as Streptococcus, Staphylococcus, Lactobacillus, Bacteroides,
✓ H pylori—the most common cause of chronic gastritis Klebsiella, and Escherichia coli have all been cultured from gastric
✓ Persons with antral gastritis due to H pylori are more prone to du-
juice but rarely have clinical significance. These organisms likely
odenal ulcers, whereas persons with multifocal atrophic gastritis
due to H pylori are more prone to gastric ulceration represent oral flora that has been swallowed. In circumstances of
ischemia or immunosuppression, these organisms may produce
marked morbidity.
Autoimmune Atrophic Gastritis. Patients with autoimmune Mycobacterium tuberculosis is an important cause of bacte-
atrophic gastritis can present with abdominal discomfort or pain, rial gastritis in resource-limited countries. Patients present with
weight loss, and pernicious anemia. This type of gastritis is an weight loss, anorexia, night sweats, and fevers and can have
autosomal dominant condition and is responsible for less than symptoms of gastric outlet obstruction. Biopsies from ulcerated
5% of all cases of chronic gastritis (Figure 5.5). It involves the or nodular areas with stains for acid-fast bacilli and cultures for
body and fundus of the stomach, sparing the antrum. Endoscopic M tuberculosis are necessary for diagnosis. Secondary or tertiary
findings include a loss of gastric folds and prominence of the sub- syphilis can also involve the stomach, especially the antrum.
mucosal vasculature. Laboratory findings include autoantibodies Phlegmonous gastritis is a rare, life-threatening condition as-
to parietal cells and intrinsic factor, elevated serum gastrin level, sociated with full-thickness purulent necrosis of the gastric wall.
and low vitamin B12 level. Hypochlorhydria, achlorhydria, iron Multiple bacteria are responsible, and it usually occurs in immu-
deficiency, or pernicious anemia may develop in some patients. nocompromised patients, including alcoholics and patients with
Histologically, the abnormal findings are limited to the body and diabetes. Invasive procedures may trigger the onset; fever, chills,
fundic mucosa. A typical finding is the loss of oxyntic glands abdominal pain, and hypotension are common. If gas-forming
(chief and parietal cells) and a prominent lamina propria lym- organisms are involved, emphysematous changes may be apparent
phocytic and plasma cell infiltration directed at the fundic glands. on imaging studies. The mortality rate is high, and surgery may be
Patients do have a small risk of gastric carcinoids (<10%) and required to remove the necrotic portion of the stomach.
Figure 5.5. Chronic Autoimmune Atrophic Gastritis. A, Gross Figure 5.6. Cytomegalovirus (CMV) Infection of the Stomach. A,
appearance. B, Section through the body of the stomach (hematoxylin- Gross appearance of CMV ulcers. B, CMV gastropathy (hematoxylin-
eosin stain). (Adapted from Emory TS, Carpenter HA, Gostout CJ, eosin stain). (Adapted from Emory TS, Carpenter HA, Gostout CJ,
Sobin LH. Atlas of gastrointestinal endoscopy & endoscopic biopsies. Sobin LH. Atlas of gastrointestinal endoscopy & endoscopic biopsies.
Washington, DC: Armed Forces Institute of Pathology, American Washington, DC: Armed Forces Institute of Pathology, American
Registry of Pathology; c2000. p. 94.) Registry of Pathology; c2000. p. 123.)
Cytomegalovirus (CMV) infection is the most recognized or mucormycosis. Ingestion of raw fish can result in anisakiasis.
viral infection of the stomach (Figure 5.6). This infection may Cryptosporidium and Strongyloides infections can rarely in-
or may not have endoscopic findings that include edema, ery- volve the stomach in immunosuppressed patients.
thema, erosions, or ulcers. Patients with CMV infection of the
stomach may or may not have symptoms, such as fever, ab- Noninfectious Granulomatous Gastritis. In the absence
dominal pain, nausea, vomiting, or bleeding, and they usually of infection, granulomatous gastritis (Figure 5.7) occurs most
are immunosuppressed. Biopsy specimens from macroscopi- commonly with Crohn disease (52%). The differential diagnosis
cally involved and apparently normal areas may show typical includes isolated granulomatous gastritis (25%), foreign body
CMV cells and inclusions. When ulceration is present, biopsy granuloma (10%; eg, suture, food), tumor-associated granuloma,
specimens from the center of the ulcer are more likely to be di- sarcoidosis, infection (H pylori infection, tuberculosis, histo-
agnostic than specimens from the edge because of vascular en- plasmosis, syphilis), and vasculitis-associated granulomas. Most
dothelial involvement of this virus. If the diagnosis is in doubt, often, an antral inflammatory infiltration is found. Many patients
immunohistochemistry enhances the diagnostic yield. with granulomatous gastritis are asymptomatic. In a few patients,
Fungal and parasitic infections of the stomach are un- particularly those with Crohn disease or sarcoidosis, symptoms
common. In immunosuppressed patients, gastric infections may of gastric outlet obstruction due to ulceration and scarring of the
be caused by Histoplasma, Candida, Aspergillus, Cryptococcus, antrum and pylorus can develop. Nonspecific treatment, such as
Figure 5.8. Lymphocytic Gastritis. Intraepithelial lymphocytes

can be seen without any destruction of surrounding epithelial cells
(hematoxylin-eosin stain). (Adapted from Owen DA. Gastritis and car-
ditis. Mod Pathol. 2003 Apr;16[4]‌:325-41; used with permission.)
acid-reduction therapy, or therapy directed toward the underlying

disorder usually is indicated.
Lymphocytic Gastritis. Lymphocytic gastritis is uncommon
and often is asymptomatic. If symptoms do occur, dyspepsia is
most common. On endoscopy, mucosal nodules, erosions, and
enlarged gastric folds may be seen. Histologic findings include
active chronic pangastritis with epithelial infiltration by mature
lymphocytes, which are usually T lymphocytes (Figure 5.8). The
lamina propria is expanded by the lymphocytes and plasma cells.
Most often, when found in patients with celiac disease, lympho-
cytic gastritis is antral predominant. However, when lymphocytic
gastritis occurs in patients with H pylori infection, it tends to be
gastric body predominant and often has polymorphonuclear cells.
Staining for H pylori should be performed in every case of lym-
phocytic gastritis. Patients with microscopic colitis or Ménétrier
disease may also have lymphocytic gastritis. Therapy is directed
toward the underlying condition.
Eosinophilic Gastritis. Various disorders are associated with
eosinophilic infiltration of the stomach, including parasitic in-
festation, hypereosinophilic syndrome, gastric Crohn disease,
gastric carcinoma, lymphoma, connective tissue disorder, peptic
ulcer disease, mast cell disease, and Churg-Strauss vasculitis.
Eosinophilic gastritis is a rare inflammatory condition. Patients
generally have a history of allergy, asthma, food intolerance, ec-
zema, drug sensitivities, or peripheral eosinophilia and increased
serum levels of immunoglobulin E. On endoscopy, the gastric
mucosa ranges from normal to erosions and erythema. In the most
common mucosa-predominant form, biopsy specimens typically
show patchy but dense eosinophilic infiltration (Figure 5.9). The
antrum is typically involved. Less commonly, full-thickness or
open biopsy may be necessary for diagnosis if only the muscle or
serosa layers are affected. Corticosteroids are used for treatment.
✓ Autoimmune atrophic gastritis is characterized by hypochlorhydria

and hypergastrinemia with autoantibodies to parietal cells and in-
Figure 5.7. Granulomatous Gastritis. A, Gross appearance.
trinsic factor
B, Histologic appearance of granuloma (hematoxylin-eosin stain).
✓ Pernicious anemia due to autoimmune atrophic gastritis is the
(Adapted from Emory TS, Carpenter HA, Gostout CJ, Sobin LH. Atlas
most common cause of vitamin B12 deficiency
of gastrointestinal endoscopy & endoscopic biopsies. Washington,
✓ H pylori infection and celiac disease—the 2 main causes of lym-
DC: Armed Forces Institute of Pathology, American Registry of
phocytic gastritis
Pathology; c2000. p. 98, 99.)
or other NSAIDs, bile reflux, and alcohol. Endoscopic findings

include edema, erythema, erosions, and visible bile in the sto-
mach. Most involvement is in the antrum, and biopsy specimens
show foveolar hyperplasia, loss of mucin, proliferation of lamina
propria smooth muscle, and vascular congestion in the lamina
propria. Bile reflux gastropathy usually follows surgical inter-
vention, such as gastroenterostomy, vagotomy, or pyloroplasty,
but can occur in persons with gastric emptying disorders or in
stomachs that have not had a surgical procedure. Symptoms such
as epigastric discomfort, nausea, and vomiting do not correlate
well with endoscopic or histologic findings. Treatment of chem-
ical gastropathy includes discontinued use of the offending agent
if possible and use of acid-reducing medication and ursodiol if
bile acid is the most likely cause. Cholestyramine, sucralfate,
and aluminum-containing antacids have been prescribed for bile
acid gastropathy but have mostly been unsuccessful. Ursodiol has
been shown to decrease symptoms without improving histologic
findings. A surgical Roux-en-Y revision to divert bile from the
stomach in patients with previous gastroenterostomy and sympto-
matic bile reflux gastropathy has been found to reduce symptoms
in 50% to 90% of patients.
Vascular Gastropathies
Vascular gastropathies are defined as abnormalities of the gas-
tric vasculature affecting mucosal blood vessels, with little or no
inflammation. Typical examples include congestive gastropathy
from congestive heart failure, portal hypertensive gastropathy,
and gastric vascular ectasia (ie, watermelon stomach).
In patients with portal hypertension, dilatation and sclerosis
of small mucosal and submucosal venules and capillaries can
produce an endoscopically recognizable mucosal mosaic pattern,
usually most prominent in the fundus and body of the stomach
(Figure 5.10). Nodularity and punctate erythema also may be
seen. Clinically, patients may have iron deficiency anemia or
melena. Treatment involves attempts to decrease portal pressure;
endoscopic therapy is not effective (see Chapter 27, “Vascular
Diseases of the Liver”).
Patients with gastric vascular ectasia develop dilated mucosal
capillaries with fibrin thrombi and fibromuscular hyperplasia of
the lamina propria with minimal or no inflammation. Endoscopic
findings typically include linear or nodular erythematous streaks
without a mosaic pattern, usually involving the antrum but some-
times extending into the gastric body (Figure 5.11). Gastric
vascular ectasia tends to occur in patients who have an array of
underlying conditions, including pernicious anemia, collagen vas-
cular disease, cirrhosis, kidney failure, bone marrow transplant,
and antral mucosal trauma (as in pyloric prolapse). Like patients
with portal hypertensive gastropathy, patients may have iron defi-
Figure 5.9. Eosinophilic Gastritis. Note the marked eosinophilic ciency anemia or melena. Endoscopic therapy with argon plasma
infiltration. A, High-power view. B, Low-power view. (Adapted from coagulation can diminish blood loss in patients with anemia (see
Emory TS, Carpenter HA, Gostout CJ, Sobin LH. Atlas of gastrointes- Chapter 10, “Nonvariceal Gastrointestinal Tract Bleeding”). Liver
tinal endoscopy & endoscopic biopsies. Washington, DC: Armed Forces transplant can benefit patients with gastric vascular ectasia who
Institute of Pathology, American Registry of Pathology; c2000. p. 97.) have cirrhosis, but transjugular intrahepatic portosystemic shunts
are not helpful (see Chapter 27, “Vascular Diseases of the Liver”).
Gastropathy
Hypertrophic Gastropathy
Chemical Gastropathy
Hypertrophic gastropathy refers to a group of conditions with giant
Long-term exposure to substances that can damage the gastric mu- enlargement of the rugal folds. This group includes some cases of
cosa can result in chronic gastropathy. Other common names for chronic gastritis from H pylori infection or lymphocytic gastritis,
this condition include reactive gastritis, reactive gastropathy, and Zollinger-
Ellison syndrome, infiltrative disorders (sarcoidosis
bile reflux gastritis or gastropathy. The etiology includes aspirin and malignancy), and Ménétrier disease. Patients with Ménétrier
Figure 5.11. Watermelon Stomach (Antrum). A, Gross specimen.

B, Histologic section shows thick-walled, ectatic vessels (hematoxylin-
eosin stain). (Adapted from Emory TS, Carpenter HA, Gostout CJ,
Sobin LH. Atlas of gastrointestinal endoscopy & endoscopic biopsies.
Washington, DC: Armed Forces Institute of Pathology, American
Registry of Pathology; c2000. p. 118.)
disease often have such symptoms as epigastric pain, nausea,

vomiting, diarrhea, edema, and weight loss. Many patients have
evidence of a protein-losing gastropathy manifested by low serum
level of albumin and increased stool clearance of α1-antitrypsin.
Endoscopically, giant gastric rugal folds and a cobblestone pattern
are present but may spare the antrum. A full-thickness gastric bi-
opsy specimen or endoscopic snare biopsy specimen from an
enlarged fold usually is necessary to make the diagnosis. Histologic
examination shows extreme surface mucous cell hyperplasia with
deeper glandular atrophy. Often, gastric hypochlorhydria or achlor-
hydria is present together with excessive secretion of mucus. The
driver of the histologic changes is increased levels of transforming
Figure 5.10. Portal Hypertensive Gastropathy. A and B, Gross
specimens show mosaic mucosal pattern. C, Histologic section show
growth factor-α signaling through epidermal growth factor receptor
dilated, tortuous blood vessels (hematoxylin-eosin stain). (Adapted from on surface mucous cells. Treatment with agents to counteract the
Emory TS, Carpenter HA, Gostout CJ, Sobin LH. Atlas of gastrointes- effects of transforming growth factor-α, such as cetuximab, has
tinal endoscopy & endoscopic biopsies. Washington, DC: Armed Forces been successful. Patients with Ménétrier disease most likely have
Institute of Pathology, American Registry of Pathology; c2000. p. 116.) an increased risk for gastric adenocarcinoma.
Bhattacharya B. Non-neoplastic disorders of the stomach. In: Iacobuzio-

✓ Gastric vascular ectasia often manifests as iron deficiency anemia
Donahue CA, Montgomery E, eds. Gastrointestinal and liver pa-
✓ Ménétrier disease— a rare hypertrophic, protein- losing
thology. 2nd ed. Elsevier/Saunders; 2012. p. 65–141
gastropathy due to increased mucosal levels of transforming
Chen PH, Anderson L, Zhang K, Weiss GA. Eosinophilic gastritis/gas-
growth factor-α
troenteritis. Curr Gastroenterol Rep. 2021 Jul;23(8):13.
Dixon MF, Genta RM, Yardley JH, Correa P. Classification and grading
of gastritis: The updated Sydney System. International Workshop on
the Histopathology of Gastritis, Houston 1994. Am J Surg Pathol.
Suggested Reading 1996 Oct;20(10):1161–81.
Annibale B, Esposito G, Lahner E. A current clinical overview of atrophic Gala K, Luckett RT, Shah N. Gastric sarcoidosis presenting as dyspepsia.
gastritis. Expert Rev Gastroenterol Hepatol. 2020 Feb;14(2):93–102. Cureus. 2020 Feb;12(2):e7139.
Bacha D, Walha M, Ben Slama S, Ben Romdhane H, Bouraoui S, Shah SC, Piazuelo MB, Kuipers EJ, Li D. AGA clinical practice update
Bellil K, et al. Chronic gastritis classifications. Tunis Med. 2018 on the diagnosis and management of atrophic gastritis: expert review.
Jul;96(7):405–10. Gastroenterology. 2021 Oct;161(4):1325–32.
Yee EU, Kuo E, Goldsmith JD. Pathologic features of infectious gastritis.
Adv Anat Pathol. 2018 Jul;25(4):238–53.
6
Gastric Neoplasms and Gastroenteric and

Pancreatic Neuroendocrine Tumorsa
SETH SWEETSER, MD
Gastric neoplasms are an important contributor to cancer-related The incidence of gastric cancer varies by geographic loca-
mortality. Of the various neoplasms that can affect the stomach, tion, with 60% of gastric cancers occurring in resource-limited
adenocarcinoma is the most common and accounts for up to 85% countries. The highest incidence rates are in Japan, China, Chile,
of gastric neoplasms, with 15% due to lymphomas, gastrointes- and Ireland. Incidence rates are lower in industrialized nations.
tinal stromal tumors (GISTs), neuroendocrine tumors (NETs), Regardless of region, gastric cancer is more common in men than
and metastatic disease involving the stomach (Table 6.1). This in women.
chapter considers the epidemiology, pathogenesis, clinical mani- In the US, gastric cancer is diagnosed in approximately 28,000
festation, diagnostic evaluation, treatment, and prognosis of these patients annually, and over 10,000 are expected to die of gastric
neoplastic diseases. cancer each year. Although gastric cancer is relatively infrequent
in North America, its contribution to the burden of cancer deaths
is substantial: It is the third most common gastrointestinal tract
Gastric Adenocarcinoma
malignancy, after colorectal and pancreatic cancer, and the third
Epidemiology most lethal neoplasm overall.
Gastric adenocarcinoma is the third most frequent cause of The worldwide incidence of gastric cancer has decreased
cancer-related death worldwide. Gastric cancer is rare in persons since the middle of the 20th century. Part of the decrease in gas-
younger than 40 years, but its incidence increases steadily there- tric cancer in the US may be due to the recognition and alteration
after, peaking in the seventh decade of life. of certain risk factors, such as the identification and treatment of
Helicobacter pylori infection and changes in dietary trends. The
increasingly widespread use of refrigerators was likely the initial
a
Portions of this chapter were adapted from Ravi K, Sweetser turning point for the decrease in the incidence of gastric cancer.
S. Persistent nausea and vomiting in pregnancy. Gastroenterology. 2014 Refrigeration decreased bacterial and fungal contamination of
Jan;146(1):33, 323; used with permission.
Abbreviations: CgA, chromogranin A; CHOP, cyclophosphamide, doxo-
rubicin, vincristine, and prednisone; CT, computed tomography; DLBCL, Table 6.1. Frequency of Different Types of Gastric Neoplasms
diffuse large B-cell lymphoma; EGJ, esophagogastric junction; ENMZL,
extranodal marginal zone B-cell lymphoma; EUS, endoscopic ultraso- Percentage
nography; 5-HIAA, 5-hydroxyindoleacetic acid; GIM, gastric intestinal of gastric
metaplasia; GIST, gastrointestinal stromal tumor; GNET, gastroenteric Tumor type neoplasms
neuroendocrine tumor; HDGC, hereditary diffuse gastric cancer; MALT,
Adenocarcinoma 85
mucosa-associated lymphoid tissue; MEN, multiple endocrine neoplasia; Lymphomas (diffuse large B cell and extranodal 15
MRI, magnetic resonance imaging; NET, neuroendocrine tumor; PET, marginal zone B cell), gastroenteric and pancreatic
positron emission tomography; PNET, pancreatic neuroendocrine tumor; neuroendocrine tumors, gastrointestinal stromal
SEER, Surveillance, Epidemiology, and End Results; SRS, somatostatin tumors, and metastatic disease to the stomach
receptor scintigraphy; VIP, vasoactive intestinal polypeptide
65
food, increased the availability of fresh fruits and vegetables cells are precancerous and undergo increasing degrees of nuclear
(which provide protective antioxidants), and lessened the need atypia and cellular disorganization, evolving from low-grade to
for salt-based preservation—all of which may have reduced some high-grade dysplasia, which increases the risk of an invasive,
of the most important risk factors for gastric cancer. Although intestinal-type adenocarcinoma.
the incidence of gastric cancer overall is decreasing, the absolute Intestinal-
type gastric adenocarcinoma does not develop
number of new cases annually is increasing because the world de novo. Whether the cause is autoimmune or from environ-
population is increasing and aging. Consequently, gastric cancer mental factors or H pylori infection, gastritis is usually the first
will continue to be an important cause of cancer and cancer- step in cancer induction. A sequence of pathologic changes
related death for the foreseeable future. occurs: Inflammation is followed by intestinal metaplasia and
then dysplasia, as genetic variations occur in rapidly dividing
cells, and, finally, intestinal-type cancer. This model of gastric
Pathogenesis
carcinogenesis is commonly referred to as the Correa cascade
Much effort has been made to understand the etiology of gastric (Figure 6.1), named after the gastrointestinal pathologist who
adenocarcinoma. It is widely held that there is no single cause first described this sequence of tissue changes leading to cancer.
but rather multiple causative factors, including diet, exogenous Gastric intestinal metaplasia (GIM) is a premalignant condi-
substances, infectious agents, and genetic factors. tion and an intermediate step in the progression to intestinal-type
Gastric adenocarcinomas are subdivided into 2 pathologically adenocarcinoma. Patients with GIM have up to a 9-fold risk for
defined categories: 1) an intestinal type, which is characterized gastric cancer irrespective of race. For progression, high-risk
by cohesive neoplastic cells that form glandular structures, and groups include patients who have a family history of gastric
2) a diffuse type in which cellular cohesion is absent, so that indi- cancer or who are members of ethnic populations at high risk,
vidual cells infiltrate the stomach wall without forming a discrete patients who smoke tobacco, patients who have extensive and
mass. In addition, these 2 types of gastric adenocarcinoma have multifocal GIM, and patients who have dysplasia on biopsies.
distinct molecular genetic profiles and appear to have separate The finding of GIM confers a risk such that approximately 1 in
pathogenetic pathways. A key difference is the presence or ab- 40 patients would be expected to have gastric adenocarcinoma
sence of intercellular adhesion molecules produced when there is develop within 20 years after index endoscopy. Therefore, if ex-
expression of the cell adhesion protein E-cadherin encoded by the tensive or multifocal GIM is identified, a reasonable approach
CDH1 gene (OMIM 192090). would be to monitor with endoscopic surveillance every 3 years
In the diffuse type of gastric adenocarcinoma, an initial car- to detect the development of dysplasia or gastric cancer.
cinogenic event is the loss of expression of CDH1, the tumor
suppressor gene encoding for the protein E-cadherin that is crit- ✓ The 2 histologic types of gastric adenocarcinoma differ in
ical for establishing intercellular connections and maintaining pathogenesis
the organization of epithelial tissues. Without this protein, in- • Intestinal type has cohesive neoplastic cells that form glandular
dividual tumor cells tend to invade surrounding tissues without structures
• Diffuse type lacks cellular cohesion; individual cells infiltrate
forming typical epithelial glands. The diffuse type of gastric
the stomach wall without forming a discrete mass
cancer tends to invade and then broadly extend along the gastric ✓ Correa cascade—multistep process leading to intestinal-type gas-
wall. Occasionally, the stomach is infiltrated extensively, giving tric adenocarcinoma
it a rigid, fixed appearance, a condition known as linitis plastica.
Diffuse-type tumors are highly metastatic and are characterized
by rapid disease progression and generally a poor prognosis.
In contrast, intercellular adhesion molecules are well pre- Risk Factors
served in intestinal-type gastric adenocarcinomas, and the tumor
cells tend to occur in tubular or glandular formations, similar in Diet
appearance to adenocarcinomas in the colorectum and small in- Epidemiologic studies have documented an association between
testine. The pathogenesis appears to follow a multistep progres- diet and gastric cancer. Although dietary factors have been
sion that usually results from H pylori infection. The first stage shown to influence the development of gastric cancer, specific
is chronic gastritis, when there are fluctuating periods of greater substances have not been isolated. The most consistent associa-
or lesser inflammatory infiltrates. In some patients, this process tion is the ingestion of nitroso compounds. Nitroso compounds
results in atrophic gastritis, sometimes referred to as gastric at- are formed from nitrates, which are found naturally in foods such
rophy, which is the multifocal disappearance of gastric glands as vegetables and potatoes but are also used as preservatives for
within the epithelium. When multifocal atrophy is present, glands meats, cheeses, and pickled foods. These preservatives were
that mimic intestinal epithelial glands may appear. This represents common in foods before the era of refrigerators. The inci-
intestinal metaplasia. As atrophy and metaplasia become more ex- dence of gastric cancer is higher in regions where nitrate-based
tensive, the chance of dysplasia developing increases. Dysplastic fertilizers are used.
Figure 6.1. Correa Cascade of Gastric Adenocarcinoma Carcinogenesis.

6. Gastric Neoplasms and Gastroenteric and Pancreatic Neuroendocrine Tumors 67
Diets high in salt also have been linked with an increased inci-
dence of gastric cancer. In animal models, high salt intake has been Box 6.1. Genetic Testing Criteria for Hereditary
associated with atrophic gastritis. Diets low in uncooked fruits Diffuse Gastric Cancer Syndromea,b
(particularly citrus fruits) and vegetables and high in processed DGC when younger than 50 y
meat, fried food, and alcohol are associated with an increased risk DGC at any age with a personal or family history of
of gastric cancer. The protective effect from fruits and vegetables is cleft lip or cleft palate
thought to be from their vitamin C content, which may decrease the
History of DGC and LBC when younger than 70 y
formation of nitroso compounds inside the stomach.
Bilateral LBC or LCIS when younger than 70 y
Gastric biopsy with in situ SRCs or pagetoid spread
Tobacco Use of SRCs when younger than 50 y
Smoking increases the risk of gastric cancer, especially in men, ≥2 Cases of gastric cancer in family (at any age),
at least 1.5-fold. This risk decreases after 10 years of smoking with ≥1 confirmed case of DGCc
cessation. Socioeconomic status also affects the risk of gastric ≥2 Cases of LBC in family members when younger
cancer. Distal cancer is 2-fold higher among patients of low so- than 50 yc
cioeconomic status, and proximal gastric cancer is more likely ≥1 Case of DGC any age and ≥1 case of LBC when
among those of higher socioeconomic status. younger than 70 y in different family membersc
Gastric Surgery Abbreviations: DGC, diffuse gastric cancer; LBC, lobular breast cancer;
LCIS, lobular carcinoma in situ; SRC, signet ring cell.
Patients who have had gastric surgery have a higher risk of gas- a
Germline testing for CDH1 mutations is recommended when 1 of the
tric cancer. This risk is greatest 15 to 20 years after the operation.
criteria listed below has been met.
Billroth II surgery carries a higher risk than Billroth I surgery,
most likely because a Billroth II operation increases the reflux b
All diagnoses of DGC and LBC must be confirmed with histology.
of bile and pancreatic juices into the stomach, which is thought c
Family members must be first-or second-degree blood relatives of
to be instrumental in the development of gastric cancer. Because each other.
this risk is low, patients who have had a partial gastric resection
Adapted from Blair VR, McLeod M, Carneiro F, Coit DG, D’Addario
do not warrant endoscopic screening. JL, van Dieren JM, et al. Hereditary diffuse gastric cancer: updated
clinical practice guidelines. Lancet Oncol. 2020 Aug;21(8):e386-e97;
Infection used with permission.
The most important risk factor for the development of gastric

adenocarcinoma is H pylori infection of the stomach. Although
several viral infections cause cancer, H pylori infection was the cadherin 1 tumor suppressor gene (CDH1) causes an auto-
the first bacterial infection linked to a human cancer. In 1994, somal dominantly inherited form of the diffuse type of gastric
the World Health Organization classified H pylori as a group 1 adenocarcinoma, hereditary diffuse gastric cancer (HDGC),
human carcinogen for gastric adenocarcinoma. H pylori is also a which is characterized by high penetrance and young age at
key factor in the development of gastric extranodal marginal zone onset. Female carriers of this mutation are also at greater risk
lymphoma of the mucosa-associated type. As reviewed above, H for development of lobular breast cancer. Established diagnostic
pylori infection causes inflammation that results in atrophy and criteria for cadherin 1 (CDH1) genetic testing for HDGC are
may progress to intestinal metaplasia, dysplasia, and cancer. outlined in Box 6.1.
Although gastric cancer develops in a minority of individuals It is recommended that identification of a germline pathogenic
with H pylori infection (<1%), 90% of those with gastric cancer variant in the cadherin 1 gene (CDH1) should prompt prophy-
have evidence of H pylori infection. lactic total gastrectomy by age 20 years. Annual endoscopic sur-
The precise mechanism by which H pylori infection leads veillance incorporating multiple, nontargeted gastric biopsies is
to gastric cancer is not understood clearly. It is well established an alternative for surveillance for those who decline risk reduc-
that H pylori infection leads to chronic gastritis. The inflammation surgery. However, endoscopy is associated with low sensi-
tion associated with chronic gastritis reduces the mucous layer tivity for occult cancer detection.
overlying mucosal cells and exposes these cells to mutagenic Although the principal familial gastric cancer syndrome is
compounds (eg, nitroso compounds and free radicals). Chronic HDGC caused by germline pathogenic variants in CDH1, sev-
infection with H pylori can result in the destruction of the gas- eral other hereditary cancer syndromes have been associated with
tric mucosa, leading to atrophic gastritis. H pylori infection has gastric cancer (Table 6.2). These syndromes include Lynch syn-
been associated most strongly with cancers in the distal portion drome, familial adenomatous polyposis, Li-Fraumeni syndrome,
of the stomach and does not seem to be associated with cancers and hamartomatous polyposis syndromes (juvenile polyposis
involving the gastroesophageal junction and cardia regions. First- and Peutz-Jeghers syndrome). In addition, gastric adenocarci-
degree relatives of persons with gastric cancer should be tested noma and proximal polyposis of the stomach is caused by point
for H pylori infection and treated if infected. mutations in the APC gene (OMIM 619182) promoter 1B and
carries an overall high lifetime risk for gastric adenocarcinoma of
approximately 15%.
Genetics Persons with blood group A have a higher incidence of gastric
Genetic predisposition to the development of gastric cancer has cancer, which may be related to differences in mucous secretion
been identified. An inactivating germline sequence variation in that lead to altered mucosal protection from carcinogens.
Table 6.2. Hereditary Cancer Syndromes Associated With Gastric Cancer

Lifetime gastric
Syndrome Gene(s) cancer risk, % Surveillance
Lynch Mismatch repair 5 Upper endoscopy every 3-5 y
FAP and MUTYH-associated APC and MYH 5 Upper endoscopy according to
polyposis Spigelman classification
Li-Fraumeni TP53 5 Upper endoscopy every 2-5 y
Peutz-Jeghers STK11 30 Upper endoscopy every 2-3 y
Juvenile polyposis SMAD4 and BMPR1A 20 Upper endoscopy every 1-3 y
GAPPS APC promoter 1B 15 No guidelines
Abbreviations: FAP, familial adenomatous polyposis; GAPPS, gastric adenocarcinoma and proximal polyposis of the stomach.
Gastric Disorders the symptoms are so vague that the diagnosis is delayed. Patients
Persons with atrophic gastritis have an increased risk for gastric may complain of early satiety, abdominal bloating, meal-induced
cancer. Gastric polyps also may increase the risk of gastric cancer dyspepsia, nausea, or anorexia. Abdominal pain in the epigastric
depending on histologic type. The most common type of gastric area may be mild and intermittent initially but more severe and
polyp is the cystic fundic gland polyp, which does not have neo- constant as the disease progresses. Patients with cancer involving
plastic potential unless it occurs with familial adenomatous pol- the distal antrum or pylorus may have persistent vomiting due to
yposis. Hyperplastic gastric polyps are common and should be gastric outlet obstruction. Occult or overt bleeding may occur in
removed because they have a small risk of malignant transforma- early-or late-stage cancers. Dysphagia is a prominent symptom
tion when they are relatively large (>1 cm). Adenomatous gastric in lesions of the gastric cardia or gastroesophageal junction.
polyps are less common but may give rise to or coexist with gas- Patients who have a diffuse cancer called linitis plastica,
tric adenocarcinoma. Adenomatous polyps usually occur in areas which is characterized by poor distensibility of the stomach,
of chronic atrophic gastritis. Because they have malignant poten- may present with nausea and early satiety. Occult gastrointes-
tial, all gastric adenomas should be completely excised. tinal tract bleeding with or without iron deficiency anemia is
Hypertrophic gastropathy (Ménétrier disease) is a rare, id- not uncommon, while overt bleeding (eg, hematemesis) is seen
iopathic condition characterized by rugal fold enlargement and infrequently.
protein-losing gastropathy. Gastric cancer reportedly occurs in up A pseudoachalasia syndrome may occur as the result of
to 10% of patients with this disease. The major risk factors for tumor involvement of the gastric cardia and gastroesophageal
gastric cancer are listed in Box 6.2. junction area. For this reason, gastric malignancy must always be
considered when older patients present with symptoms suggestive
✓ H pylori infection—the most important risk factor for gastric of achalasia.
adenocarcinoma Gastric cancer spreads by direct extension through the sto-
✓ HDGC is the principal familial gastric cancer syndrome and is mach wall to perigastric tissue, and it invades adjacent structures,
caused by pathogenic germline mutations in the CDH1 gene including the pancreas, colon, spleen, kidney, and liver.
Lymphatic metastases occur early, and local and regional nodes
are the first to be involved. The disease then spreads to more
Clinical Features distant intra-abdominal lymph nodes and to the supraclavicular
region (Virchow node), periumbilical area (Sister Mary Joseph
Weight loss and persistent midepigastric pain are the most nodule), left axilla (Irish node), or peritoneal cul-de-sac (Blumer
common symptoms at initial presentation, but for many patients shelf palpable on rectal or vaginal examination), or it may result
in peritoneal carcinomatosis with malignant ascites. The liver is
the most common site of hematogenous spread; other sites are the
lungs, bones, and brain.
Box 6.2. Risk Factors for Gastric Adenocarcinoma Patients with gastric cancer occasionally present with
Helicobacter pylori infection paraneoplastic syndromes such as acanthosis nigricans, the sign
Chronic atrophic gastritis of Leser-Trélat (sudden onset of diffuse seborrheic keratoses on
the trunk), migratory thrombophlebitis, and microangiopathic he-
Intestinal metaplasia
molytic anemia.
Dysplasia
Adenomatous gastric polyps
Tumor Features
Cigarette smoking
History of gastric surgery (especially Billroth II Location
operation) Endoscopically, gastric adenocarcinoma may appear as an
Genetic factors exophytic, polypoid mass or as an irregular, infiltrating lesion
Ménétrier disease with surface nodularity or ulceration. The location of the primary
tumor in the stomach has etiologic and prognostic significance.
Data from Zali H, Rezaei-Tavirani M, Azodi M. Gastric cancer: pre- Proximal lesions are biologically more aggressive and carry a
vention, risk factors and treatment. Gastroenterol Hepatol Bed Bench. worse prognosis, stage for stage, than distal cancers—a finding
2011 Fall;4(4):175-85. that suggests that the pathogenesis differs from that of cancers
arising in other parts of the stomach. Distal cancers may be re-

lated closely to chronic H pylori infection, whereas cardia and
gastroesophageal junction cancers may have a different cause,
such as chronic gastroesophageal reflux. A contributing factor to
the persistently high mortality rate among persons with gastric
cancer may be that since the 1980s the distribution of cancers
has changed from the body and antrum to the proximal sto-
mach. The incidence of cancers involving the proximal stomach
and gastroesophageal junction has increased steadily at a rate
exceeding that of any other cancer except melanoma and lung
cancer. The reasons for this are unclear. Distal cancers (in the
gastric body or antrum) are more common in populations with a
high incidence of gastric cancer, whereas cardia cancers are more
prevalent in populations with a low incidence of gastric cancer.
Infiltration
Linitis plastica, the diffusely infiltrating form of gastric adeno-
carcinoma, occurs in 5% of gastric adenocarcinomas. The tumor Figure 6.2. Diffuse Type of Gastric Adenocarcinoma With Mucus-
Producing Signet Ring Cells. (Stain is hematoxylin-eosin.) (Courtesy of
may extend over a broad region of the gastric wall, resulting in a
Thomas C. Smyrk, MD, Anatomic Pathology, Mayo Clinic; used with
rigid, thickened stomach. The presence of this lesion at the time permission.)
of diagnosis is usually associated with locally advanced or meta-
static disease and portends a worse prognosis.
epicenter no more than 2 cm into the proximal stomach are staged
Histology as esophageal cancers rather than gastric cancers. In contrast,
The most widely used histologic classification of gastric ade- EGJ tumors with their epicenter located more than 2 cm into the
nocarcinoma divides these tumors into 2 types: intestinal and proximal stomach are staged as gastric cancers.
diffuse. Intestinal-type gastric adenocarcinoma has epithelial Preoperative staging for patients with gastric cancer begins
cells that form discrete glands, microscopically resembling co- with physical examination. Next, computed tomography (CT)
lonic adenocarcinoma. Typically, the intestinal type is better of the chest (for proximal lesions), abdomen, and pelvis is usu-
circumscribed than the diffuse type, and it may be polypoid or ally the initial imaging test. CT is widely available and is suit-
ulcerated or both. The intestinal type is the more frequent va- able for evaluating widely metastatic disease, especially hepatic
riety in populations with a high incidence of gastric adenocar- involvement, and for assessing ascites or distant nodal spread.
cinoma. It often arises within an area of intestinal metaplasia. Patients who have CT-defined visceral metastatic disease (biopsy
This pathologic variant generally carries a better prognosis than proven) can often avoid unnecessary surgery. However, perito-
the diffuse type. neal metastases are frequently missed with CT.
Diffuse-type gastric adenocarcinoma is characterized by
sheets of epithelial cells. Glandular structure is rarely present.
The diffuse type extends widely, with no distinct margins. Table 6.3. The TNM Staging System for Gastric Adenocarcinoma
Mucus-producing signet ring cells are often present (Figure
6.2). The diffuse type occurs more commonly in younger per- Stage Description
sons, is less likely to be associated with intestinal metaplasia, Tumor (T)
tends to be infiltrating and poorly differentiated, and is less TX Primary tumor cannot be assessed
likely to be associated with H pylori infection; generally, the T0 No evidence of primary tumor
Tis Carcinoma in situ (intraepithelial tumor without invasion
prognosis is poor.
of the lamina propria; high-grade dysplasia)
T1 Tumor invades lamina propria or submucosa
✓ Mucus-secreting signet ring cells—the hallmark histologic feature
T2 Tumor invades muscularis propria or subserosa
of diffuse gastric cancer
T3 Tumor penetrates serosa without invasion to adjacent
structures
T4 Tumor invades adjacent structures
Staging Nodal (N)
NX Regional nodes cannot be assessed
Most patients with gastric cancer who are symptomatic already N0 No regional node metastasis
have advanced, incurable disease at the time of their initial N1 Metastasis in 1 or 2 regional lymph nodes
presentation. The most important aspect of staging is determi- N2 Metastasis in 3-6 regional lymph nodes
N3 Metastasis in ≥7 regional lymph nodes
nation of whether the cancer is resectable. Clinical stage is de-
Metastasis (M)
termined preoperatively, whereas pathologic staging is based MX Presence of distant metastasis cannot be assessed
on findings during surgical exploration and examination of the M0 No distant metastasis
pathology specimen. The TNM staging system of the American M1 Distant metastasis or positive peritoneal cytology
Joint Committee on Cancer, updated in 2017, is used most fre-
Adapted from Ajani J, In H, Sano T, Gaspar L, Erasmus J, Tang L, et al. Stomach.
quently (Table 6.3). The 2017 update changes the definition of In: Amin MB, Edge SB, American Joint Committee on Cancer, eds. AJCC cancer
the boundary between esophageal and gastric cancers. Tumors staging manual. Eighth ed. American Joint Committee on Cancer; 2017:203-20;
that involve the esophagogastric junction (EGJ) with the tumor used with permission.
Another limitation of CT is determination of the depth of symptoms (fever and night sweats) are present in only about
tumor invasion, particularly with small tumors. CT is accurate 12% of patients.
for assessment of the T stage of the primary tumor in about 50%
to 70% of cases. Endoscopic ultrasonography (EUS) is the best
Diagnostic Evaluation
nonsurgical method for estimating accurately the depth of in-
vasion, particularly for early (T1 or T2) lesions. Although the Endoscopically, gastric lymphoma has a broad range of
accuracy of EUS for nodal staging is only slightly better than appearances—from large, firm rugal folds to eroded nodules to
with CT, EUS-guided fine-needle aspiration of suspicious nodes exophytic ulcerated masses. Enlarged folds, if present, are due to
and regional areas adds to the accuracy of EUS nodal staging; the subepithelial infiltrative growth pattern of lymphomas.
however, this added feature is operator dependent. Positron When the disease is suspected, standard endoscopic biopsy
emission tomography (PET) or combined PET/CT is more sen- specimens may not be adequate or the histologic findings may
sitive than CT alone for the detection of distant metastases, but be equivocal, especially when the involvement is primarily sub-
its sensitivity for detecting peritoneal carcinomatosis appears to mucosal without affecting the mucosa. Deeper biopsy or snare
be limited. biopsy specimens from a polypoid mass or large rugal fold may
be needed to make the diagnosis.
CT of the abdomen and chest is useful for identifying in-
Treatment and Prognosis
volvement of regional lymph nodes, extension of the tumor into
Surgery is the mainstay of therapy for gastric cancer. Complete surrounding structures, and distant metastases. If there is no evi-
surgical removal of a gastric tumor, with resection of the adja- dence of metastatic disease, EUS is accurate for determining the
cent lymph nodes, offers the only chance for cure. However, extent of gastric wall infiltration and can provide useful informa-
two-thirds of patients present with advanced disease, which is tion for treatment planning.
incurable by surgery alone. This problem is complicated further
by a recurrence rate of 50% among patients who had resection
Tumor Features
with curative intent.
For patients with potentially resectable noncardia gastric The vast majority of gastric lymphomas are of B-cell origin.
cancer, there are data to support several approaches, including ad- More than 90% of gastric lymphomas are approximately equally
juvant chemoradiotherapy, perioperative chemotherapy, and adju- divided into 2 histologic subtypes: low-grade extranodal mar-
vant chemotherapy, over surgery alone. Most experts recommend ginal zone B-cell lymphoma (ENMZL) of mucosa (gut)-associ-
a combined modality therapy over surgery alone for patients with ated lymphoid tissue (MALT) and diffuse large B-cell lymphoma
stage T2 or higher gastric cancer. An optimal therapeutic approach (DLBCL).
of multimodality therapy has not been established. In addition,
the best approach to patients with locally advanced, unresectable
Extranodal Marginal Zone B-Cell Lymphoma
but nonmetastatic disease is unclear. A common approach is to
attempt downstaging with chemotherapy or chemoradiotherapy ENMZLs of the MALT type, formerly known as MALT lym-
with subsequent restaging. phoma, constitute a group of low-grade neoplasms that have sim-
ilar clinical, pathologic, immunologic, and molecular features
✓ Surgery is the mainstay of therapy for localized gastric cancer
and arise in the context of preexisting prolonged lymphoid pro-
liferation in mucosal sites. ENMZLs occur most often in the gas-
trointestinal tract but have been described in various extranodal
Gastric Lymphoma sites, including the ocular adnexa, salivary glands, thyroid, lungs,
thymus, and breast.
Epidemiology Like gastric adenocarcinoma, infection with H pylori increases
The stomach is the most frequent site of extranodal lymphoma. the risk for gastric lymphoma in general and ENMZLs in partic-
Primary gastric lymphoma is uncommon and accounts for 2% ular. Gastric ENMZLs are associated with H pylori infection in
of all lymphomas and up to 15% of gastric neoplasms. Although as many as 90% of cases. In health, the stomach does not have
these are rare tumors, the incidence of primary gastric lymphoma much lymphoid tissue. H pylori–induced gastritis leads to an ag-
has increased in frequency during the past 35 years. gregation of CD4+ lymphocytes and B cells in the gastric lamina
propria. Antigen presentation occurs, followed by T-cell activa-
tion, B-cell proliferation, and lymphoid follicle formation. As
Risk Factors these follicles become prominent, they develop B-cell monoclonal
There are several risk factors for the development of gastric lym- populations that appear to be sustained by stimuli that come from
phoma. They include H pylori–associated chronic gastritis, au- H pylori–sensitized T cells. As the monoclonal B-cell populations
toimmune diseases, immunodeficiency syndromes, long- term proliferate, they begin to spill into the gastric epithelium and in-
immunosuppressive therapy, and celiac disease. vade gastric glands, forming lymphoepithelial lesions that are
characteristic of ENMZLs (Figure 6.3).
The best evidence supporting the role of H pylori in ENMZL in
Clinical Features the stomach is remission of the tumor after eradication of H pylori
The clinical features of gastric lymphoma are nonspecific infection with antibiotic therapy. Several clinical studies have
and frequently include abdominal discomfort, anorexia, early documented complete remission in approximately 50% of patients
satiety, and weight loss as well as gastric outlet complaints with ENMZL and in 80% if the tumor is in an early clinical stage.
due to obstruction or impairment of gastric motility and A lack of response to antimicrobial treatment has been linked to
also anemia due to blood loss from ulceration. Systemic B a specific chromosomal abnormality, the translocation t(11;18).
may be indicated when stage I disease is suspected. For stage II,

III, or IV disease, the primary therapy is systemic chemotherapy.
Radiotherapy generally is used to reduce the size of large lesions
and to control localized disease.
Rituximab (a chimeric monoclonal antibody targeting the
CD20 epitope present on virtually all B cells) is effective therapy
for patients with various lymphomas, including ENMZL and
DLBCL. It is commonly used in combination with cyclophos-
phamide, doxorubicin, vincristine, and prednisone (CHOP).
Prognosis
The 5-year survival rate for all patients with gastric lymphoma is
50%. Patients with stage I or II tumors less than 5 cm in diameter
have a 10-year survival rate greater than 80%.
✓ Stomach—the most frequent extranodal site for lymphoma

✓ Like gastric adenocarcinoma, H pylori infection increases the risk
for gastric lymphoma
Figure 6.3. Lymphoepithelial Lesion of Mucosa- Associated ✓ The 2 most common types of primary gastric lymphoma are
Lymphoid Tissue Lymphoma With Neoplastic Lymphocytes ENMZL and DLBCL
Infiltrating Gastric Gland. (Stain is hematoxylin-eosin.) ✓ Eradication treatment with antibiotics for H pylori infection is the
first-line therapy for ENMZL
Diffuse Large B-Cell Lymphoma

DLBCL describes a heterogenous group of non-Hodgkin lym- Gastrointestinal Stromal Tumors
phoma. DLBCL may occur de novo, but it also may occur as Stromal or mesenchymal neoplasms affecting the gastrointes-
a high-grade transformation from a low-grade B-cell lymphoma tinal tract include GISTs, lipomas, hemangiomas, schwannomas,
such as an ENMZL. Transformation from indolent ENMZL to leiomyomas, and leiomyosarcomas. The most common of these
DLBCL has been described repeatedly in the course of the dis tumors is the GIST.
ease, and some investigators believe that all DLBCLs of the sto-
mach are due to transformation of an ENMZL.
Epidemiology
GISTs are the most common mesenchymal tumor involving the
Staging
gastrointestinal tract. The true incidence and prevalence of GISTs
The staging systems for primary gastric lymphoma are compli- are unknown because most of them are found incidentally.
cated (a variant of the standard staging by lymph node involve- Surveillance, Epidemiology, and End Results (SEER) analysis
ment). Generally, stage I disease is limited to the stomach, and of histologically confirmed GISTs showed an incidence of 0.68
stage II disease implies localized involvement of the lymph nodes per 100,000. In autopsy series of patients with gastric cancer, the
within the abdomen. In stage III disease, lymph nodes are in- frequency of incidental subcentimeter GISTs is much higher,
volved on both the thoracic and the abdominal sides of the dia- which suggests that only a few microscopic tumors grow to a
phragm. Stage IV disease is disseminated disease. clinically relevant size.
Treatment Pathogenesis
First-line therapy for gastric ENMZL in patients infected with The cellular origins of GISTs are the interstitial cells of Cajal,
H pylori is antibiotics to eradicate H pylori. Only patients with the gastrointestinal pacemaker cells, which form an interface
localized, mucosal, or submucosal flat lesions and without meta- between the autonomic innervation of the bowel wall and the
static disease, lymphadenopathy, or frank DLBCL are candidates smooth muscle. GISTs almost universally express the CD117 an-
for antimicrobial therapy alone. For patients who do not meet these tigen, which allows differentiation from leiomyomas and other
criteria, therapy for H pylori eradication should be administered in subepithelial tumors of the gastrointestinal tract.
conjunction with conventional therapy. The CD117 molecule is part of the c-kit receptor, a membrane
When treatment of H pylori infection has been administered, tyrosine kinase that is a product of the c-kit or KIT proto-oncogene
eradication of the organism must be proved. Histologic regression (OMIM 164920). In 80% of cases, c-kit activation is the result of
requires several months after the infection has been cured with an activating KIT variant. The majority (>90%) of mesenchymal
antibiotics, and patients require endoscopic follow-up at frequent tumors arising within the gastrointestinal tract are GISTs.
intervals. If the response to antibiotics is incomplete or the disease
recurs, standard therapies for lymphoma, such as systemic chemo-
therapy, radiotherapy, or surgery, should be administered. Patients
Clinical Features
who do not initially have a response to anti–H pylori therapy or Patients with GISTs are often asymptomatic, and the tumors are
who have disease relapse after therapy still have a high cure rate. found incidentally at endoscopy or at surgery. Patients with large
Conventional therapy for DLBCL depends primarily on the GISTs may present with vague symptoms, as with all cancers
tumor stage. Exploratory laparotomy and partial gastrectomy of the upper gastrointestinal tract, or with gastrointestinal tract
bleeding. Cases have been reported of patients with GISTs who Treatment
present with hypoglycemia due to paraneoplastic production of
Surgical resection is the treatment of choice for potentially re-
insulinlike growth factor 2 by the tumor.
sectable tumors, and the recommendation is to resect all GISTs
that are 2 cm or larger. The management of smaller GISTs is
Tumor Features controversial because their natural history is unknown. Imatinib
GISTs can arise anywhere in the gastrointestinal tract, but they mesylate (Gleevec), a potent inhibitor of KIT signaling, is often
are most common in the stomach and proximal small bowel. The used in neoadjuvant and adjuvant therapy.
biologic behavior of GISTs is variable, and all GISTs have the
potential for malignant behavior. Tumor site, size, and mitotic Prognosis
rate are used for stratifying lesions for risk of recurrence and
Prognosis is influenced by tumor site (small intestine is worse
metastasis. Small intestinal primary site, tumor size larger than
than stomach), tumor size (if larger, the prognosis is worse),
5 cm, and mitotic rate greater than 5 per 50 high-power fields
the ability to resect the tumor completely, and the response to
are poor prognostic factors that indicate an increased risk of ma-
imatinib in advanced disease.
lignant behavior. When GISTs metastasize, metastasis is usually
hematogenous to the liver and peritoneum. Lymphatic spread of ✓ GISTs
GISTs, like other sarcomas, is unusual. • Most common mesenchymal tumor of the gastrointestinal tract
• Originate from the interstitial cells of Cajal and most frequently
Staging occur in the stomach
✓ CD117 antigen is the immunostain marker for GISTs
Staging of GISTs involves primarily endoscopy and imaging ✓ Risk factors for malignant behavior of GISTs include larger size,
studies. Many GISTs occur in the upper gastrointestinal tract and greater number of mitotic figures, and location other than stomach
are discovered incidentally. A common manifestation is gastroin-
testinal tract bleeding secondary to tumor ulceration (Figure 6.4).
Endoscopic biopsy specimens obtained with standard techniques Gastroenteropancreatic NETs
typically are not sufficient for definite diagnosis. Although EUS-
guided biopsy may not yield sufficient tissue, specific sonographic Neuroendocrine cells occur throughout the body; for example,
features may distinguish GIST from other submucosal lesions. they cluster together in small groups called islets throughout the
The characteristic EUS feature of a GIST is a hypoechoic lesion pancreas. NETs can be classified by their site of origin: Those
arising from the muscularis propria. CT is the imaging method that develop from pancreatic endocrine cells are referred to as
of choice to characterize large GISTs and to identify metastatic pancreatic neuroendocrine tumors (PNETs), and those that orig-
disease. On CT, a GIST appears as a solid mass that enhances inate in the stomach or gut, as gastroenteric neuroendocrine
brightly with an intravenous contrast agent. tumors (GNETs).
If noninvasive methods are unsuccessful for correctly defining Further classification of NETs is complex since they arise
a GIST when it is suspected, preoperative biopsy may not be nec- from many locations, their histologic features are quite varied,
essary if the tumor appears to be resectable and the patient is oth- and they have a wide range of clinical behaviors. In general, they
erwise a surgical candidate. GISTs frequently metastasize to liver are separated into 2 major categories:
and peritoneum and rarely to regional lymph nodes. However, if 1. Poorly differentiated neuroendocrine carcinomas are high-
metastatic disease is present, surgical biopsy may be necessary to grade carcinomas that resemble small cell or large cell neu-
confirm the diagnosis if chemotherapy is a consideration. roendocrine carcinoma of the lung. They are associated with a
rapidly progressing downhill clinical course and, in general, a
poor prognosis.
2. Well-differentiated NETs of the digestive tract traditionally in-
clude both gastrointestinal tumors and PNETs.
Although both tumor types have similar histologic characteris-
tics, morphology alone does not allow prediction of the clinical
course associated with these tumors. They are not a clinically ho-
mogeneous group, and while most are slow growing and have a
relatively indolent course, they display a wide spectrum of bio-
logic and clinical behavior. Up to 40% of patients with GNETs
present with liver metastases at the time of diagnosis, but many
patients survive for many years even with advanced-stage dis
ease; overall 5-year survival is about 67%.
Epidemiology
Both GNETs and PNETs are relatively rare; however, the in-
cidence of both has been increasing in the US and elsewhere;
data from the SEER program showed a 5-fold increase since the
1980s. The reasons are not clear, but the increase may largely re-
Figure 6.4. Endoscopic Image of an Ulcerated Gastrointestinal sult from increased detection on cross-sectional imaging, such as
Stromal Tumor in the Proximal Portion of the Stomach. CT or magnetic resonance imaging (MRI), and during endoscopy.
Pathogenesis Carcinoid syndrome, which is the primary clinical manifestation,

occurs in a subset of patients with NETs (10% of patients). When
Most NETs occur sporadically, although some may appear as part
the syndrome is present, it is associated most commonly with
of an autosomal dominant inherited multiple endocrine neoplasia
tumors in the small bowel; these are the most common and fre-
(MEN) syndrome. All NETs can be associated with MEN-1,
quently metastasize.
which is characterized by pituitary, parathyroid, and pancreatic
Carcinoid syndrome is due to peptides released by the
hyperplasia or tumors. In addition, PNETs can occur as part of
tumor into the systemic circulation. As many as 40 secretory
3 other inherited disorders: von Hippel-Lindau disease, neuro-
products have been identified; the common ones are histamine,
fibromatosis 1 (von Recklinghausen disease), and the tuberous
kallikrein, prostaglandins, serotonin, and tachykinins. The
sclerosis complex.
liver is capable of inactivating these peptides, which is why
carcinoid syndrome primarily occurs in association with liver
Clinical Features metastases: The bioactive products are secreted directly into
NETs are usually diagnosed in the sixth or seventh decade of the hepatic veins.
life. Because they develop from neuroendocrine cells, they may The most common symptoms of carcinoid syndrome are di-
secrete various peptides and hormones simultaneously. Secretion arrhea and facial flushing; others are cramping abdominal pain,
of some of these will not result in clinical symptoms, whereas skin telangiectasia, peripheral edema, and wheezing. The most
others, if produced in large enough quantities, will result in the common physical finding is hepatomegaly. Intermittent facial
appearance of a clinical syndrome. flushing occurs in up to 85% of patients. The flush usually starts
suddenly and can last from 30 seconds to 30 minutes. The typ-
ical flush is red or violaceous and appears on the face, neck, and
NETs and Carcinoid Syndrome upper chest. Flushes can be associated with hypotension and
NETs (previously termed carcinoid tumors) most commonly tachycardia. Several inciting factors are known for the flushing
occur in the gastrointestinal tract (about two- thirds), while associated with carcinoid syndrome: eating, alcohol ingestion,
about one-fourth arise in the bronchopulmonary system. They the Valsalva maneuver, increased emotional states, trauma or
can occur anywhere in the alimentary tract, with the ileum and pressure on the liver (including on physical examination), and
rectum being the most common sites. The clinical manifestation anesthesia. Anesthesia can provoke long episodes of flushing that
varies from an asymptomatic incidental finding to symptomatic can result in life-threatening hypotension known as carcinoid
tumors from local invasion, metastases, or production of bioac- crisis. Carcinoid crisis can be prevented by the administration of
tive amines causing the classic carcinoid syndrome. octreotide before anesthesia.
Diarrhea occurs in 80% of patients with carcinoid syndrome
and can be quite severe. It is a secretory diarrhea, and patients
Clinical and Tumor Features
may pass as many as 30 stools per day. Although the diarrhea
Most NETs are found incidentally; thus, at the time of diagnosis, usually is unrelated to the flushing episodes, the associated dehy-
most patients are asymptomatic. If symptoms are present, they dration can contribute to the hypotension from flushing.
often are nonspecific and associated with the location and ex- Wheezing is a common component of carcinoid syndrome
tent of the tumor. Symptoms due to the direct effects of a tumor and is due to bronchospasm and right- sided valvular heart
in the gastrointestinal tract may be abdominal pain, intestinal disease. Unlike diarrhea, wheezing and dyspnea are worse
obstruction, nausea, weight loss, or intestinal bleeding. Many during flushing episodes. Of importance, wheezing associated
patients have vague or mild symptoms for years and are some- with carcinoid syndrome should not be treated like bronchial
times thought to have irritable bowel syndrome or other func- asthma: Treatment with β-agonists can incite prolonged vasodi-
tional disorders of the gastrointestinal tract for years before the lation and severe hypotension. Hypertension usually is not pres
correct diagnosis is made. ent in carcinoid syndrome but, as stated above, the syndrome
Most NETs do not produce noticeable symptoms since the can cause paroxysmal and clinically important hypotension.
metabolic products are efficiently metabolized by the liver. Aside from carcinoid syndrome, the clinical presentation,
However, when secreting tumors metastasize to the liver (the tumor features, treatment recommendations, and prognosis related
most common site of metastasis), substances are released directly to NETs vary by the location of the primary tumor. Characteristics
into the systemic circulation, circumventing hepatic metabolism. of NETs based on location are outlined in Table 6.4.
Table 6.4. Characteristics of Neuroendocrine Tumors Based on Location

Location Secretory products Carcinoid syndrome Clinical characteristics
Foregut
Stomach, duodenum, Serotonin, histamine Atypical (with type 3) Indolent except for type 3
pancreas, bronchus
Midgut
Jejunum, ileum, appendix, Serotonin, prostaglandins, Classic, but present in Often multiple; usually in
ascending colon polypeptides only 10% of cases ileum
Hindgut
Transverse, descending, and None Rare Usually indolent
sigmoid colon and rectum
Stomach 3. They are the most aggressive of the gastric NETs, and 65% of
patients have local or liver metastases when the tumor is discov-
Gastric NETs tend to occur in the body of the stomach. They may
ered. Type 3 is the only type of gastric NET that is associated with
be single or multiple, and, to endoscopists, they may appear to
an atypical carcinoid syndrome; these tumors can produce hista-
be an ordinary ulcer, polyp, or tumor mass. They are often round
mine that results in flushing. Because sporadic gastric carcinoids
and gray or yellow.
(type 3) are more aggressive, they usually are treated with partial
Gastric NETs occur most frequently in patients with hyper
or total gastrectomy with local lymph node resection.
gastrinemia caused by atrophic gastritis and achlorhydria. They
also occur in patients with MEN-1–associated Zollinger-Ellison
syndrome. Any condition in which serum levels of gastrin are Small Intestinal NETs
increased for a prolonged period should alert clinicians to the Clinically, small intestinal NETs are the most important NETs
possible presence of gastric NETs. because patients are more likely to present with intestinal
Gastric NETs are classified into 3 types, each of which has a symptoms and carcinoid syndrome, which occurs in up to 10%
different behavior and prognosis (Table 6.5). of these patients. Abdominal pain or bowel obstruction can be
caused by the direct mechanical effect of the tumor and an as-
Type 1 sociated fibroblastic reaction, intussusception, or mesenteric is-
Up to 80% of all gastric NETs are type 1. They are associated chemia due to tumor-associated fibrosis or angiopathy.
with pernicious anemia or chronic atrophic gastritis. The tumors Most small intestinal NETS occur in the ileum near the
are derived from enterochromaffin- like cells and are thought ileocecal valve. Small intestinal NETs may be multicentric in 30%
to develop from long-standing stimulation by increased serum of individuals and have a higher likelihood than NETs of arising
levels of gastrin. Type 1 NETs usually are diagnosed in patients from other portions of the gastrointestinal tract and metastasizing
aged 60 to 70 years. As with chronic atrophic gastritis and per- to regional lymph nodes and the liver. Because small intestinal
nicious anemia, type 1 NETs are more common in women than NETs have the potential to metastasize, regardless of size, they
in men. These tumors are usually small and multiple. Metastatic should be removed surgically along with local lymph node re-
disease is rare and occurs in less than 10% of tumors 2 cm or section. Patients with these tumors are most at risk for synchro-
smaller but in as many as 20% of larger tumors. These tumors nous lesions (present in 30% of cases), so at surgery, the surgeon
generally are indolent and often are considered benign. should thoroughly inspect the remaining small bowel. Resection
may be required for palliation, even in patients with metastatic
disease. The prognosis for patients with small intestinal NETs
Type 2 varies with the stage of disease. The 5-year survival rate ranges
NETs of the stomach due to hypergastrinemia from MEN-1– from 35% to 80%.
associated gastrinomas are classified as type 2 NETs. They are
rare (5% of gastric carcinoids) and, like type 1 NETs, they are Appendix
typically small, multiple, slow growing, and indolent and have
little malignant potential. Up to one-half of intestinal NETs are appendiceal tumors, and
For gastric NET types 1 and 2 smaller than 1 cm, the treatment NETs are the most common neoplasms of the appendix. Patients
of choice is endoscopic resection, if possible. Because the patients are almost always asymptomatic, and typically these tumors are
often have sustained hypergastrinemia, endoscopic surveillance discovered incidentally at appendectomy. Incidental NETs are
every 12 months has been recommended, but progression to ma- found in 0.5% of appendectomy specimens. Appendiceal NETs
lignant disease and death is unusual. are often smaller than 1 cm and usually are solitary and benign.
For patients with multiple tumors or advanced disease that Although local invasion by appendiceal NETs is common, meta-
is not appropriate for resection, antrectomy or medical therapy static disease is rare.
aimed at decreasing the serum levels of gastrin has been If symptoms are present, they usually are associated with
advocated. Antrectomy decreases hypergastrinemia by removing large tumors, tumors located at the base of the appendix, and
much of the gastrin-producing cell mass in the stomach. tumors with associated metastatic disease. Approximately 10%
of patients with appendiceal carcinoids have tumors at the base
of the appendix, where the tumor can cause obstruction that may
Type 3 result in appendicitis. Patients with appendiceal NETs may pre-
Type 3 gastric NETs are sporadic and do not appear to be asso- sent with carcinoid syndrome, but this occurs almost always with
ciated with hypergastrinemia. Of all gastric NETs, 15% are type liver metastases.
Table 6.5. Three Types of Gastric Neuroendocrine Tumors

Characteristic Type 1 Type 2 Type 3
Tumor frequency, % 80 5 15
Tumor frequency by sex Women more than men Women same as men Women less than men
Tumor features <1 cm; multiple 1-2 cm; multiple >2 cm; single
Gastric mucosa Atrophic Hyperplastic Normal
Associated conditions Gastric atrophy MEN-1, ZES None
Gastric pH High Low Normal
Fasting serum gastrin High High Normal
Treatment <1 cm, EndoR; >2 cm, surgery <1 cm, EndoR; >2 cm, surgery Surgery
Abbreviations: EndoR, endoscopic resection; MEN, multiple endocrine neoplasia; ZES, Zollinger-Ellison syndrome.
The prognosis for patients with appendiceal NETs is deter-

mined by the size of the tumor. Tumors smaller than 2 cm (most
tumors) are unlikely to have metastasized when diagnosed.
Tumors larger than 2 cm are uncommon, but when they are
present, up to 30% have metastasized at the time of diagnosis.
Appendiceal tumors smaller than 2 cm can be treated with simple
appendectomy. However, for larger tumors, right hemicolectomy
should be performed.
The overall 5-year survival rate for patients with appendiceal
NETs is 70% to 100%, but for patients with metastatic disease at
the time of presentation, it ranges from 10% to 30%.
Colon
NET of the colon is rare. When it occurs, it is often located on
the right side of the colon. Unlike patients with NETs in other
locations, those with a NET of the colon may present with
symptoms, and when they do, they often have locally advanced Figure 6.5. Small-Bowel Carcinoid. Computed tomographic image,
coronal view, shows classic spoke wheel sign in mesentery.
disease. Local resection of the tumor has been reported to be
effective in the early stages of disease, but many patients require
radical colectomy because of advanced disease at the time of di-
agnosis. Patients with colonic NETs rarely have carcinoid syn- CgA is a more sensitive indicator of a NET than chromogranin
drome. The overall 5-year survival rate for patients with colonic B or C. Levels of CgA vary daily in healthy persons and in those
NETs is 30% to 75%. with NETs. False-positive increases in CgA can be present in
various other conditions, including inflammatory conditions and
endocrine, gastrointestinal, and cardiovascular diseases, and as a
Rectum result of medications, such as histamine-receptor antagonists and
Patients with rectal NETs are nearly always asymptomatic, and proton pump inhibitors. Because of its low specificity, measure-
the tumors are found incidentally during screening colonos- ment of CgA alone is not recommended as a screening test for the
copy. They are not associated with carcinoid syndrome. Tumors diagnosis of a NET or carcinoid syndrome. However, for patients
smaller than 1 cm can be treated with local excision. Radical with an established diagnosis, CgA can be used as an appropriate
excision is more appropriate for tumors larger than 2 cm or for tumor marker to assess disease progression or response to therapy
smaller tumors that have invaded the muscularis propria. The or after surgical resection.
overall 5-year survival rate for patients with rectal NETs ranges
✓ Gastroenteric NETs
from 75% to 100%.
• Most patients are asymptomatic
• Most patients have vague abdominal symptoms for years that
mimic irritable bowel syndrome
Diagnosis of NETs and Carcinoid Syndrome
✓ Carcinoid syndrome
Most NETs are found incidentally on endoscopy or cross- • To develop from gastroenteric NET, liver metastases must be
sectional imaging, such as CT performed for other indications. If present
symptoms of carcinoid syndrome are strongly suspected, the best • Most common symptoms—diarrhea and facial flushing
initial evaluation is to measure urinary 5-hydroxyindoleacetic ✓ Small intestinal NETs
• Propensity to metastasize even when small
acid (5-HIAA), which is the end product of serotonin metabo-
• Multicentric in 30% of cases
lism. This test has a sensitivity of more than 90% and a spec- ✓ Appendiceal NETs
ificity of 90% for carcinoid syndrome. Sensitivity is less for • Tumor size dictates management
patients who have NETs without symptoms of carcinoid syn- • Appendectomy if smaller than 2 cm
drome. Measurement of urinary excretion of 5-HIAA is gener- ✓ Rectal NETs
ally most useful in patients with primary tumors of the midgut • Most often found incidentally at colonoscopy
(small bowel and right colon), which tend to produce the highest • Local excision—usual treatment if smaller than 1 cm
levels of serotonin. The normal rate of excretion of 5-HIAA ✓ Dotatate PET/CT—imaging test of choice to identify an occult
over 24 hours is 2 to 8 mg daily. The rate of excretion may be primary NET
up to 30 mg daily in patients with malabsorption syndromes,
such as celiac disease and Whipple disease, as well as after NETs are highly vascular, and those that originate in the
the ingestion of large amounts of tryptophan-or serotonin-rich small intestine often produce mesenteric masses with dense
foods. Patients should avoid the ingestion of tryptophan-and desmoplastic fibrosis. These features are usually well seen on CT
serotonin-rich foods, such as bananas, tomatoes, avocados, and or MRI scans of the abdomen and pelvis with the classic finding
certain nuts at least 24 hours before and during the 24-hour of the spoke wheel sign from mesenteric retraction (Figure 6.5).
urine collection. Both imaging modalities can show liver metastases, although
Chromogranins are proteins that are stored and released MRI is probably more sensitive than contrast-enhanced CT. Most
with peptides and amines in various neuroendocrine tissues NETs express high levels of somatostatin receptors and can be
and are designated as chromogranin A (CgA), B, and C. Well- detected with functional imaging assessing somatostatin receptor
differentiated NETs are associated with high blood concentrations expression. Traditionally this imaging was done with somato-
of chromogranins, which increase with a larger tumor burden. statin receptor scintigraphy (SRS) and a radiolabeled form of the
Table 6.6. WHO Histopathologic Classification of NETs Gastrinoma

Classification and grade Mitotic count a
Ki-67 index, %b
Gastrinomas produce the classic triad of symptoms called
NET G1 <2 <3
Zollinger-Ellison syndrome. This syndrome consists of peptic
NET G2 2-20 3-20 ulcer disease, gastric acid hypersecretion, and a gastrin-producing
NET G3 >20 >20 tumor. Gastrinomas are rare and occur in less than 1% of patients
NEC (G3), poorly differentiated, >20 >20 who have peptic ulcer disease. Gastrinomas are associated fre-
small or large cell quently with MEN-1 syndrome.
Abbreviations: G, grade; NEC, neuroendocrine carcinoma; NET, neuroendocrine
tumor; WHO, World Health Organization.
Etiology and Pathogenesis
a
Mitotic count is determined from evaluation of mitoses in 50 high-power fields
The majority of gastrinomas occur in an anatomical area called
and indicated as number of mitoses per 2 mm2.
the gastrinoma triangle (Figure 6.6) with 60% occurring in the
b
Ki-67 proliferation index is determined from more than 500 cells in the area of duodenal wall; the pancreas is the second most common site.
highest labeling (hot spot).
Gastrinomas are slow growing, and it can be difficult to dis-
Data from Rindi G, Arnold R, Bosman FT, Capella C, Klimstra D, Kloppel tinguish benign tumors from malignant ones. Approximately
G, et al. Nomenclature and classification of neuroendocrine neoplasms of the two-thirds of gastrinomas are malignant. The best indicator of
digestive system. In: Bosman FT, Carneiro F, Hruban RH, Theise ND, eds. WHO
malignancy is the presence of metastases, which most often affect
classification of tumours of the digestive system. 4th ed. International Agency for
Research on Cancer; 2010:13. the regional lymph nodes or the liver. It is important to determine
whether liver metastases are present. If they are, the patient is not
a candidate for surgical treatment.
somatostatin analogue octreotide (Octreoscan). However, PET
with newer somatostatin-receptor–targeting radiotracers, such as
gallium Ga 68 dotatate, is more sensitive than SRS, particularly Clinical Features
for small tumors. Because of the greater sensitivity, gallium Ga 68 Peptic ulcer disease is the most common endoscopic sign of
dotatate PET/CT is the imaging test of choice to identify an occult gastrinoma and occurs in more than 90% of patients. Traditionally,
primary tumor. The World Health Organization histopathologic the ulcer disease associated with gastrinomas has been characterized
classification of NETs defines a grading system based on both mi- by multiple duodenal ulcers (including postbulbar ulcers) and
totic index and Ki-67 index determined by immunohistochemistry esophagitis refractory to medical treatment. However, the most
(Table 6.6). This grading system along with staging is effective at common type of ulcer associated with gastrinoma is an ordinary
defining risk groups of well-differentiated NETs across the entire duodenal bulb ulcer. Gastric folds in Zollinger-Ellison syndrome
gastroenteropancreatic spectrum. are characteristically enlarged from gastrin-stimulated hyperplasia
of parietal cells (Figure 6.7).
Pancreatic Neuroendocrine Tumors As many as 70% of patients with a gastrinoma have
symptoms or endoscopic findings of severe gastroesophageal
The most common pancreatic malignancy is adenocarcinoma, reflux, which likely is caused by hypersecretion of gastric acid.
which arises from pancreatic exocrine cells. PNETs are less than Also, 50% of the patients have diarrhea due to the effect of acid
4% of all diagnosed pancreatic cancers. These malignancies may hypersecretion on the small bowel. Increased acid exposure to
progress, and the tumor cells may spread to other sites such as the small bowel causes morphologic and inflammatory changes
lymph nodes, liver, lung, or bone. Advanced PNETs may be func- that can result in malabsorption. In addition, the low pH may
tional or nonfunctional. Functional PNETs produce hormones inactivate pancreatic lipase and cause precipitation of bile
such as gastrin, insulin, and glucagon, which are released into the salts, resulting in malabsorption of fat and steatorrhea, which is
blood and cause symptoms. Nonfunctional PNETs are more diffi- the most common mechanism of diarrhea in Zollinger-Ellison
cult to diagnose, since they produce substances that often do not syndrome.
cause overt symptoms until the tumor has spread and continued If a patient has a duodenal ulcer that is not caused by either
to grow. PNETs include the following: gastrinoma, insulinoma, H pylori infection or nonsteroidal anti-inflammatory drugs, or if
VIPoma, glucagonoma, and somatostatinoma. The functional a patient has duodenal ulcer disease and diarrhea, the concurrent
NET syndromes are summarized in Table 6.7. presence of gastrinoma should be considered.
Table 6.7. Functional Neuroendocrine Tumor Syndromes

Location in MEN-1
Tumor (syndrome) Presentation pancreas, % Malignant, % associated, %
Gastrinoma (ZES) Abdominal pain, diarrhea 30 70 25
Insulinoma Hypoglycemic symptoms 100 10 10
VIPoma Severe watery diarrhea, hypokalemia 90 80 5
Glucagonoma 4 D’sa 100 60 5
Somatostatinoma 3 S’sb 60 60 5
Abbreviations: MEN-1, multiple endocrine neoplasia type 1; ZES, Zollinger-Ellison syndrome.

a
4 D’s is a mnemonic for dermatitis, diabetes, deep vein thrombosis, and diarrhea.
b
3 S’s is a mnemonic for sugar (diabetes), stones (gallstones), and steatorrhea.
A gastric pH probe can be used to determine whether acid

hypersecretion is present. For a patient who has not been re-
ceiving proton pump inhibitor therapy for at least 7 days, gastric
pH less than 2 is consistent with a hypersecretory condition, and
this, in combination with a markedly increased gastrin level, is
nearly diagnostic of Zollinger-Ellison syndrome.
A secretin stimulation test is warranted for only a few clin-
ical situations (Figure 6.8). If a patient has hypergastrinemia and
acid hypersecretion, an intravenous secretin test is indicated.
In patients with Zollinger-Ellison syndrome, the serum level of
gastrin increases at least 120 pg/mL over the basal gastrin level.
Patients with other causes of hypergastrinemic hyperchlorhydria
have only a slight or no increase in the serum level of gastrin.
After there is biochemical evidence of gastrinoma, the
Figure 6.6. The Gastrinoma Triangle. Most gastrinomas (90%)
tumor should be localized. Most gastrinomas have somatostatin
occur inside this triangle. receptors, and the test of choice for localizing these tumors is gal-
lium Ga 68 dotatate PET/CT. Because most gastrinomas occur in
the gastrinoma triangle, EUS is very sensitive for localizing the
Diagnostic Tests primary tumor but is less helpful for evaluating metastatic dis
ease. CT of the abdomen detects approximately half the tumors
For patients with the clinical manifestations of gastrinoma, the
and may be useful for directing biopsy of liver metastases, if
first screening test is measurement of the serum level of gastrin.
present.
This should be done after proton pump inhibitor therapy has been
withheld for at least 7 days. A serum gastrin level of more than
1,000 pg/mL is suggestive of the presence of a gastrinoma but Treatment
is not diagnostic. A level less than 1,000 pg/mL but more than Surgical resection is the treatment of choice for patients with re-
110 pg/mL may be consistent with several conditions that cause sectable disease (ie, not metastatic or locally advanced). Patients
hypergastrinemia. The most common cause of hypergastrinemia with liver metastases or MEN-1 syndrome (with multifocal dis
generally is achlorhydria. The most common cause of achlor- ease) may not be candidates for surgical treatment because they
hydria, in turn, is atrophic gastritis. It is important to note that may have multiple tumors.
most patients with a gastrinoma have a serum gastrin level of If resection is not possible, the objective in treating Zollinger-
approximately 600 pg/mL, and atrophic gastritis can cause serum Ellison syndrome is to control gastric acid hypersecretion.
gastrin levels greater than 1,000 pg/mL; therefore, no level of Medical treatment to decrease gastric acid hypersecretion usually
hypergastrinemia is diagnostic of Zollinger-Ellison syndrome. consists of high doses of proton pump inhibitors; often the dose
Other causes of hypergastrinemia associated with achlorhydria can be gradually decreased. The administration of octreotide,
include gastric ulcer, gastric carcinoma, vagotomy, and current which inhibits the secretion of gastrin, often produces an unpre-
proton pump inhibitor therapy. Also, some disorders cause dictable clinical response and generally is not considered first-
hypergastrinemia with normal or increased acid secretion; these line therapy.
are gastric outlet obstruction and retained gastric antrum in
patients with previous gastric surgery. ✓ Most common type of ulcer in Zollinger-Ellison syndrome—
ordinary duodenal bulb ulcer
✓ Diagnostic threshold for a secretin stimulation test for gastrinoma
is an increase in serum gastrin of at least 120 pg/mL
✓ Imaging modality of choice to localize a gastrinoma—gallium Ga
68 dotatate PET/CT
Insulinoma
Insulinomas are insulin-secreting islet cell tumors that originate
in the pancreas and cause symptoms of hypoglycemia. They are
usually solitary but, rarely, may be multiple.
Clinical Features
Most patients present with clinical manifestations of hypogly-
cemia: altered or loss of consciousness, confusion, dizziness,
and visual disturbances. Symptoms may result also from cate-
cholamine release caused by hypoglycemia. These symptoms are
anxiety, weakness, fatigue, headache, palpitations, tremor, and
sweating. Typically, symptoms occur with fasting, when a meal
is delayed or missed, or during exercise. Patients may learn to
Figure 6.7. Zollinger-Ellison Syndrome. Endoscopic image shows avoid symptoms by eating frequently; as a result, 40% of patients
enlarged gastric folds. have a history of weight gain from increased eating.
Figure 6.8. Diagnostic Evaluation of Gastrinoma and Zollinger-Ellison Syndrome (ZES). FSG indicates fasting serum gastrin; PPI, proton
pump inhibitor.
Diagnosis Treatment
The presence of an insulinoma is determined by the combi- As for any GNET, definitive treatment is surgical removal
nation of a low fasting blood glucose level and an inappro- of the tumor, and this is indicated for any patient in whom
priately increased plasma level of insulin. This combination metastatic disease has not been identified. According to most
is identified in 65% of patients with insulinoma. For a de- reports, 70% to 95% of all patients are cured with surgical
finitive diagnosis, a 72-hour fast is required, with the serum treatment.
levels of glucose and insulin determined at regular intervals For patients with metastatic disease and those with insulinomas
and when the patient becomes symptomatic. With this fasting that have not been removed by partial pancreatectomy, the disease
test, symptoms develop in 75% of patients with an insulinoma can be managed with hyperglycemic agents such as diazoxide
within 24 hours, in 95% by 48 hours, and in virtually 100% and octreotide. Also, patients with metastatic insulinoma may
within 72 hours. receive chemotherapy. The most effective combination chemo-
When there is biochemical evidence of an insulinoma, locali- therapy is streptozocin and doxorubicin.
zation of the tumor can be difficult since most tumors are small.
Because it is less common for insulinomas than for gastrinomas ✓ Most insulinomas are small and located in the pancreas
to have somatostatin receptors, functional imaging with somato- ✓ EUS—imaging modality of choice for detection of insulinomas

statin analogues can localize only 50% of the tumors. Also, CT
of the abdomen shows only 50% of insulinomas because of their
small size. These tumors are almost exclusively in the pancreas,
and EUS, the imaging modality of choice, allows detection of
VIPoma
nearly 90% of pancreatic insulinomas. Metastatic insulinoma is VIPoma is caused by a NET that produces vasoactive intestinal
evaluated best with MRI. polypeptide (VIP). VIP induces intestinal water and chloride
secretion and inhibits gastric acid secretion. This syndrome fluorouracil, which achieves partial remission in up to 90% of
is characterized by severe watery diarrhea, hypokalemia, and patients.
achlorhydria and is known as the WDHA (watery diarrhea, hy-
pokalemia, and achlorhydria) syndrome, Verner-Morrison syn- ✓ Large-volume secretory diarrhea with hypokalemia is the hall-
drome, or pancreatic cholera. mark clinical presentation of VIPoma
✓ VIPomas are usually large pancreatic masses at presentation, and
most are malignant
Pathogenesis
Approximately 90% of VIPomas are in the pancreas. Although
other tumors, including intestinal carcinoids, pheochromocytomas, Glucagonoma
and bronchogenic carcinomas, may produce VIP, they rarely
Glucagonomas produce a rare syndrome of dermatitis, glucose
cause VIPoma syndrome. VIPomas are usually solitary tumors,
intolerance, weight loss, and anemia.
and more than 75% of them occur in the body or tail of the pan-
creas. Although these tumors are slow growing, they frequently
become large before diagnosis; 75% of VIPomas are malignant, Pathogenesis
and 50% have metastasized at the time of diagnosis. VIPomas Glucagonomas usually are solitary, large tumors with an average
cannot be distinguished from other pancreatic endocrine tumors size of 5 to 6 cm at the time of diagnosis; 65% are located in the
with conventional histologic or electron microscopic examina- head of the pancreas, and the other 35% occur equally in the body
tion. However, the demonstration of immunoreactive VIP in the and tail. Most tumors are metastatic at the time of diagnosis.
tumor and plasma establishes the diagnosis.
Clinical Features
Clinical Features
Glucagonomas occur in persons 45 to 70 years old. Typically, the
As stated above, VIPomas cause secretory diarrhea, which results patient presents with a distinct dermatitis called necrolytic migra-
in hypokalemia and dehydration. Stool volume may exceed 3 tory erythema, which usually develops a mean of 7 years before
L daily. The watery diarrhea resembles that of cholera, hence the onset of other symptoms. This rash starts as an erythematous
the term pancreatic cholera is sometimes used. Erythematous area, typically in an intertriginous area such as the groin, buttocks,
flushing of the head and trunk occurs in some patients. Also, thighs, or perineum, or it may start in periorificial areas. The er-
hyperglycemia develops in some patients because of VIP-and ythematous lesions spread laterally and then become raised, with
hypokalemia-induced glycogenolysis in the liver. superficial central blistering or bullous formation. When the
bullae rupture, crusting occurs and the lesions begin to heal in
Diagnosis the center. Healing is associated with hyperpigmentation. The en-
tire sequence usually takes 1 to 2 weeks and consists of a mixed
VIPoma should be suspected if patients present with high-volume pattern of erythema, bullous formation, epidermal separation,
watery diarrhea that persists despite fasting and is associated with crusting, and hyperpigmentation, which wax and wane. Glossitis,
hypokalemia and dehydration. The diagnosis is confirmed by the angular stomatitis, dystrophic nails, and hair thinning are other
finding of an increased plasma concentration of VIP. Because clinical findings. The majority of patients with glucagonoma also
these tumors are large, frequently malignant, and metastatic, have hypoaminoacidemia, which may be responsible for the rash.
the abdomen should be scanned with CT to localize and deter- The rash improves with treatment with amino acids and nutrition.
mine the extent of tumor involvement. MRI is also effective for Glucagon stimulates glycogenolysis, gluconeogenesis, lipol-
localizing the tumor and identifying metastatic disease. Other im- ysis, ketogenesis, and insulin secretion and inhibits pancreatic
aging studies may not be necessary. and gastric secretion and intestinal motility. Most patients have
glucose intolerance, and some may have frank type 2 diabetes.
Treatment Most patients with glucagonoma also have noticeable weight
loss, even if the tumor is found incidentally and is small. It is
The first priority of treatment is to correct the dehydration and believed that glucagon exerts a catabolic effect. Some patients
electrolyte abnormalities. Patients may require at least 5 L of also may have anorexia.
fluid daily with aggressive potassium replacement. Long-acting
octreotide controls diarrhea in most patients with VIPoma,
and this agent is considered the initial treatment of choice. For Diagnosis
patients who do not have a response to somatostatin analogues, If the clinical features of glucagonoma are present, the diagnosis
concomitant administration of glucocorticoids may be tried be- can be confirmed by the finding of an increased plasma glucagon
cause the combination has had some success. level of more than 1,000 pg/mL. Because glucagonomas occur
After imaging studies have been used to localize the tumor in the pancreas and tend to be large and metastatic at the time
and determine the extent of tumor involvement, surgery should of clinical presentation, CT of the abdomen usually localizes
be considered for all patients who do not have evidence of meta- the tumor.
static disease. Surgical resection of a pancreatic VIPoma relieves
all symptoms and is curative in approximately 30% of patients.
Surgery also may be indicated to relieve local effects produced by Treatment
the large size of the tumor. The initial treatment objectives are to control the symptoms and
For patients with metastatic disease, the best treatment hyperglycemia and to restore the nutritional status. The surgical
option is chemotherapy. The most effective chemotherapy reg- risk for these patients usually is increased because of the catabolic
imen is streptozocin in combination with either doxorubicin or effects of glucagon, glucose intolerance, and hypoaminoacidemia.
Patients should receive nutritional support, and the hypergly- Surgical excision is the treatment of choice, but most patients
cemia should be corrected. The rash may improve with correction present with metastatic disease. Cytotoxic chemotherapy is
of the hypoaminoacidemia. If anemia is pronounced, transfusion offered to patients who have evidence of metastatic disease, but
may be needed. Octreotide is useful for controlling symptoms, there is no clear evidence that this treatment is effective.
and it improves the dermatitis, weight loss, diarrhea, and abdom-
inal pain but not type 2 diabetes. Surgery is offered to all patients
Management Principles for GNETs and PNETs
who are acceptable surgical risks and who do not have evidence
of metastatic spread of the tumor, but it is curative in only 20% In general, the treatment of GNETs and PNETs is based on the
of them. following: localization of the tumor and identification of meta-
For patients with metastatic disease, it is important to remember static disease if present, resection of the primary tumor if appro-
that the tumors are slow growing and survival is good even for priate, and control of symptoms, such as those associated with
those who do not receive chemotherapy. There is no clear evidence carcinoid syndrome.
that chemotherapy has any important effect on these tumors. The The liver is the predominant site of metastatic disease.
most commonly used chemotherapeutic agents are streptozocin in Liver resection is indicated for the treatment of meta-
combination with either doxorubicin or fluorouracil. static liver disease in the absence of diffuse bilobar involve-
ment, compromised liver function, or extensive extrahepatic
✓ Necrolytic migratory erythema— the characteristic rash of metastases. Although surgery is not curative in the majority
glucagonoma of cases, symptoms of hormone hypersecretion are effectively
✓ Plasma glucagon level greater than 1,000 pg/mL is diagnostic of palliated and prolonged survival is often possible because these
glucagonoma tumors are slow growing.
Other therapies can be directed at specific components of the
syndrome. Patients who have carcinoid syndrome with flushing
Somatostatinoma should avoid ingesting substances, such as alcohol, that can in-
duce flushing. Also, physical therapy that could involve pressure
Somatostatinomas are the least common of the GNETs. They or trauma to the right upper quadrant should be avoided. Certain
produce a distinct syndrome of type 2 diabetes, gallbladder dis drugs, such as codeine and cholestyramine, can help control
ease, and steatorrhea. flushing and diarrhea. Severe symptoms often require a somato-
statin analogue such as octreotide.
Pathogenesis Flushing and diarrhea can be ameliorated in up to 80% of
patients treated with octreotide. The depot form of octreotide
Somatostatinomas are NETs that occur in the pancreas and in-
(Sandostatin LAR) allows for administration monthly, rather
testine. Tumors that arise in the pancreas tend to have higher
than 3 times daily. Typically, patients start a brief trial of the
levels of somatostatin and are more likely to produce symptoms.
short-acting form of octreotide (to assess for symptomatic
Somatostatinomas are usually solitary and large, and the majority
response and tolerance) and then start receiving a monthly
have metastasized at the time of diagnosis. Somatostatin inhibits
dose of 20 mg intramuscularly, with a gradual increase in the
insulin release, gallbladder motility, and secretion of pancreatic
dose as needed for control of symptoms. Patients also can be
enzymes and bicarbonate. Somatostatinomas are associated with
given short-acting, subcutaneous octreotide for breakthrough
neurofibromatosis type 1.
symptoms.
In addition to improving symptoms, octreotide may retard
Clinical Features tumor growth. Because octreotide is not cytotoxic, the disease
Type 2 diabetes occurs in half the patients with somatostatinoma. rarely regresses.
Gallbladder disease occurs in 65% of the patients and usually is Patients who have progressive metastatic carcinoid tumors
manifested as cholelithiasis, acalculous cholecystitis, or obstruc- have few therapeutic options, and the best systemic therapy has
tive jaundice from local tumor invasion. Steatorrhea occurs in not been defined. Several cytotoxic drugs (streptozocin in combi-
one-third of the patients. nation with either doxorubicin or fluorouracil) have been tried in
various combinations and generally have had minimal effect on
these tumors. The lack of effectiveness of any 1 agent or combi-
Diagnosis nation of agents has led to debate about whether chemotherapy is
Most somatostatinomas are found incidentally when laparotomy appropriate for these patients.
is performed for gallbladder disease. The diagnosis is established
by the finding of somatostatin-containing D cells in the resected Metastatic Disease to the Stomach
tumor and an increased plasma concentration of somatostatin-
like immunoreactive material. Tumors are localized with CT, When a patient presents with upper gastrointestinal tract
EUS, or ultrasonography of the abdomen. symptoms and a history of a primary extragastric neoplasm, met-
astatic involvement of the stomach should be considered as a pos-
sible explanation of the symptoms.
Treatment Malignant melanoma is one of the most frequently encountered
Diabetes usually is mild and responds to oral hypoglycemic metastatic lesions to the stomach. At endoscopy, it usually
agents or low doses of insulin. No specific medical treatment appears as a slightly elevated black nodule or as a lesion with
exists for treating somatostatinomas. Octreotide may be helpful the appearance of a volcano (Figure 6.9). Cancer of the breast,
in treatment. However, somatostatinomas are rare, and more lung, ovary, testis, liver, or colon or sarcoma can all involve the
reports are needed to determine the efficacy of octreotide. stomach.
Suggested Reading
Basuroy R, Srirajaskanthan R, Ramage JK. Neuroendocrine tumors.
Gastroenterol Clin North Am. 2016 Sep;45(3):487–507.
Blair VR, McLeod M, Carneiro F, Coit DG, D’Addario JL, van Dieren
JM, et al. Hereditary diffuse gastric cancer: updated clinical practice
guidelines. Lancet Oncol. 2020 Aug;21(8):e386-e97.
Cives M, Strosberg J. Treatment strategies for metastatic neuroendocrine
tumors of the gastrointestinal tract. Curr Treat Options Oncol. 2017
Mar;18(3):14.
Ito T, Jensen RT. Molecular imaging in neuroendocrine tumors: recent
advances, controversies, unresolved issues, and roles in management.
Curr Opin Endocrinol Diabetes Obes. 2017 Feb;24(1):15–24.
Singh S, Moody L, Chan DL, Metz DC, Strosberg J, Asmis T, et al. Follow-
up recommendations for completely resected gastroenteropancreatic
neuroendocrine tumors. JAMA Oncol. 2018 Nov 1;4(11):1597–604.
Trieu JA, Bilal M, Saraireh H, Wang AY. Update on the diagnosis and
management of gastric intestinal metaplasia in the USA. Dig Dis Sci.
2019 May;64(5):1079–88.
Van Cutsem E, Sagaert X, Topal B, Haustermans K, Prenen H. Gastric
Figure 6.9. Endoscopic Image of Metastatic Melanoma in Stomach.
cancer. Lancet. 2016 Nov 26;388(10060):2654–64.
Lesion resembles a volcano.
7
Gastrointestinal Motility Disordersa,b

XIAO JING (IRIS) WANG, MD
Motility disorders result from impaired control of the neuromus- dysfunction (eg, urinary bladder). For many people, the rela-
cular apparatus of the gut. Symptoms vary according to which tion between motility and the generation of symptoms is unclear.
portion of the gastrointestinal tract is affected. Motility disorders Patients who have similar symptoms without structural or mo-
specifically affecting the esophagus and colon are addressed tility abnormalities are thought to have a disorder of gut-brain
in other chapters of this book and can lead to symptoms such interaction (previously termed functional gastrointestinal dis-
as dysphagia (ineffective esophageal peristalsis, achalasia) or order), specifically functional dyspepsia, which is discussed in
constipation (slow transit constipation). Gastroparesis, which this chapter.
affects the stomach, and intestinal pseudo-obstruction, which
affects the small intestine and colon, are motility disorders that
Gastrointestinal Neuromuscular Function
can cause symptoms of recurrent or chronic nausea, vomiting,
bloating and abdominal discomfort, constipation, or diarrhea, all Neuromuscular Control of the Gastrointestinal
of which occur in the absence of a structural lesion. Occasionally, System
gastroparesis and intestinal pseudo- obstruction are associated Motor function of the gastrointestinal tract depends on the con-
with generalized disease and systemic or extraintestinal organ traction of smooth muscle cells, which is under the control of
a complex neuronal network consisting of enteric and extrinsic
nerves (via the central and autonomic nervous systems) and on
a
Portions of this chapter were adapted from Camilleri M. Disorders of the interstitial cells of Cajal, which serve as pacemaker cells in
gastrointestinal motility. In: Goldman L, Schafer AI, editors. Goldman’s the wall of the gut. The central nervous system, autonomic nerves,
Cecil Medicine, 24th ed. Philadelphia (PA): WB Saunders; 2012. p. 862-8; and enteric nervous system all serve as neurogenic modulators
used with permission. Camilleri M, Andresen V. Motility disorders. In: of gastrointestinal motility. Extrinsic neural control of gastroin-
Waldman SA, Terzic A, eds. Pharmacology and therapeutics: Principles testinal motor function consists of the cranial and sacral para-
to practice. Saunders/ Elsevier; 2009:475- 86; used with permission.
sympathetic outflow (excitatory to non-sphincteric muscle) and
Locke GR, 3rd. Nonulcer dyspepsia: What it is and what it is not. Mayo
Clin Proc. 1999 Oct;74(10):1011-4; used with permission. Ouyang A,
the thoracolumbar sympathetic supply (excitatory to sphincters
Locke GR, 3rd. Overview of neurogastroenterology-gastrointestinal mo- and inhibitory to non-sphincteric muscle). The cranial outflow
tility and functional GI disorders: Classification, prevalence, and epide- is predominantly through the vagus nerve, which innervates the
miology. Gastroenterol Clin North Am. 2007 Sep;36(3):485-98; used gastrointestinal tract from the stomach to the right colon and
with permission. consists of preganglionic cholinergic fibers that synapse with
b
G. Richard Locke III, MD, Lawrence A. Szarka, MD, and Michael the enteric nervous system. The supply of sympathetic fibers to
Camilleri, MD, are gratefully acknowledged as authors of this chapter in the stomach and small bowel arises from levels T5 to T10 of the
previous editions (parts of which appear in this edition). intermediolateral column of the spinal cord. The prevertebral
Abbreviations: FDA, US Food and Drug Administration; 5-HT, sero- ganglia are important in the integration of afferent impulses be-
tonin; G-POEM, gastric peroral endoscopic myotomy; QTc, corrected tween the gut and the central nervous system and reflex control
QT interval; TPN, total parenteral nutrition of abdominal viscera.
83
The enteric nervous system is an independent nervous system phenomenon called the interdigestive migrating motor complex.
consisting of approximately 100 million neurons organized In healthy persons, 1 cycle of the interdigestive migrating motor
into ganglionated plexuses. The larger myenteric (or Auerbach) complex is completed every 60 to 90 minutes, although it may
plexus is situated between the longitudinal and circular muscle occur much less frequently. The 3 phases of the interdigestive
layers of the muscularis externa and contains neurons respon- migrating motor complex are a period of quiescence (phase I), a
sible for gastrointestinal motility. The submucosal (or Meissner) period of intermittent pressure activity (phase II), and an activity
plexus controls absorption, secretion, and mucosal blood flow. front (phase III), during which the stomach and small intestine
The enteric nervous system is also important in visceral afferent contract at a frequency that is maximal for each site: 3 per mi-
function. nute in the stomach and 12 per minute in the upper small intes-
The enteric nervous system develops in utero by migration tine. The phase III activity front migrates for a variable distance
of neural crest cells to the developing alimentary canal. This through the small intestine; there is a gradient in the frequency of
migration and the sequence of innervation of different levels of contractions from approximately 12 per minute in the duodenum
the gut are regulated by specific signaling molecules, which in- to approximately 8 per minute in the ileum. Another character-
clude transcription factors (eg, Mash1), neurotrophic factors (eg, istic interdigestive motor pattern in the distal small intestine is the
glial-derived neurotrophic factor), and the neuregulin signaling giant migrating complex, or power contraction, which empties
system. These facilitate the growth, differentiation, and persist- residue from the ileum into the colon in bolus transfers.
ence of the migrating nerve cells after they arrive in the gut. The In the postprandial period, the interdigestive migrating motor
receptors for neuregulin proteins are tyrosine kinases, which are complex is replaced by an irregular pressure response pattern of
important in cell signaling. variable amplitude and frequency, which enables mixing and ab-
Myogenic factors regulate the electrical activity generated sorption. This pattern is observed in the regions in contact with
by gastrointestinal smooth muscle cells. The interstitial cells of food. The maximal frequency of contractions is lower than that
Cajal, located at the interface of the circular and longitudinal noted during phase III of the interdigestive migrating motor
smooth muscle layers of the small intestine, form a nonneural complex. The duration of the postprandial motor activity is pro-
pacemaker system and function as intermediaries between the portional to the number of calories consumed during the meal: ap-
neurogenic (enteric nervous system) and myogenic control sys- proximately 1 hour for every 200 kcal ingested. Segments of the
tems. Electrical control activity generated by the interstitial cells small intestine that are not in contact with food continue to dis-
of Cajal spreads through the contiguous segments of the gut play interdigestive motor patterns.
through neurochemical activation by excitatory (eg, acetylcho- In the stomach, the response to stimuli indicating impending
line and substance P) and inhibitory (eg, nitric oxide, somato- oral intake leads to gastric accommodation: a decrease in prox-
statin, and vasoactive intestinal peptide) transmitters. imal stomach tone, which facilitates the ingestion of food without
an increase in pressure. This reflex is mediated by the vagus nerve
and involves an intrinsic neuronal network that inhibits contrac-
Gastric and Small-Bowel Motility tions (eg, nitrergic neurons). The accommodation response, in
The motor functions of the stomach and small intestine are conjunction with gastric emptying, allows for controlled transfer
characterized by distinct manometric patterns of activity in of gastric contents from the stomach to the small intestine.
the fasting and postprandial periods (Figure 7.1). The fasting Solids and liquids have different gastric emptying charac-
(or interdigestive) period is characterized by a cyclic motor teristics. Liquids empty from the stomach in an exponential
Figure 7.1. Fasting and Postprandial Gastroduodenal Manometric Recordings From a Healthy Volunteer. The volunteer ingested a 535-kcal
meal during the study. The recordings show the cyclic interdigestive migrating motor complex (MMC) (left) and the sustained, high-amplitude but ir-
regular pressure activity after the meal (right). Desc. indicates descending. (Adapted from Coulie B, Camilleri M. Intestinal pseudo-obstruction. Annu
Rev Med. 1999;50:37-55; used with permission.)
7. Gastrointestinal Motility Disorders 85
Table 7.1. Classification of Gastroparesis and Pseudo-obstruction

Type Neuropathic Myopathic
Infiltrative Progressive systemic Progressive systemic
sclerosis sclerosis
Amyloidosis Amyloidosis
Systemic lupus
erythematosus
Ehlers-Danlos syndrome
Dermatomyositis
Familial Familial visceral Familial visceral
neuropathies myopathies
Metabolic myopathies
Idiopathic Idiopathic intestinal Sporadic hollow visceral
pseudo-obstruction myopathy
Neurologic Porphyria Myotonia
Heavy-metal poisoning Other dystrophies
Figure 7.2. Schematic Representation of Typical Gastric Emptying Brainstem tumor
and Colonic Filling Curves. Liquids are emptied at an exponential rate; Parkinson disease
solids are retained initially (lag phase) but then are emptied at a generally Multiple sclerosis
linear postlag rate. The colonic filling curve is characterized by intermit- Spinal cord transection
tent bolus transfers. Infectious Chagas disease
Cytomegalovirus
Norwalk virus
manner (Figure 7.2). The gastric emptying half-time for non- Epstein-Barr virus
nutrient liquids in healthy persons is usually less than 20 minutes. Drug-induced Tricyclic antidepressants
Solids are retained selectively in the stomach until particles Narcotic agents
have been triturated to less than 2 mm in diameter. Therefore, Anticholinergic agents
Antihypertensive agents
gastric emptying of solids is characterized by an initial lag pe-
Antipsychotics
riod and then a linear postlag emptying phase. The small in- Vincristine
testine transports solids and liquids at approximately the same Laxatives
rate. However, owing to the lag phase for the transport of solids Paraneoplastic Small cell lung carcinoma
from the stomach, liquids typically arrive in the colon before Carcinoid syndrome
solids. Chyme moves from the ileum to the colon intermittently Postoperative Postvagotomy with or
in boluses (Figure 7.2). The movement of gas in the intestines without pyloroplasty or
results from fluctuations in intestinal tone and capacitance that gastric resection
Endocrine Type 2 diabetes
produce pressure gradients.
Hypothyroidism or
hyperthyroidism
✓ Gastric accommodation, a vagally mediated response to food Hyperparathyroidism
stimulus, leads to a decrease in proximal stomach tone
✓ Liquids empty from the stomach at an exponential rate, whereas Adapted from Camilleri M. Disorders of gastrointestinal motility. In: Goldman
solids empty in a sigmoidal fashion at a rate that has an initial lag L, Schafer AI, eds. Goldman’s Cecil medicine. 24th ed. Elsevier Saunders;
phase and then a linear postlag phase 2012:862-8; used with permission.
Gastroparesis and Intestinal Pathogenesis

Pseudo-obstruction Gastrointestinal motility disturbances (Table 7.1) can result
Definitions from disturbances at the level of the extrinsic nervous system,
enteric nervous system, interstitial cells of Cajal (or intestinal
Gastroparesis is a syndrome of objectively delayed gastric pacemakers), or smooth muscle. In addition, some disorders
emptying of solids in the absence of mechanical obstruction; key affect both nerves and muscles (eg, systemic sclerosis, amy-
symptoms are nausea, vomiting, postprandial fullness (early sa- loidosis, and mitochondrial cytopathy) and can appear initially
tiety), belching, bloating, and upper abdominal pain. Intestinal with neuropathic patterns that progress to myopathic characteris-
pseudo-obstruction is characterized by signs and symptoms of tics during advanced disease. These disorders can be congenital
mechanical obstruction involving the small or large bowel in the (eg, disruption of the development of the motility apparatus) or
absence of an anatomical lesion that obstructs the flow of contents. acquired.
✓ Gastroparesis—a syndrome of objectively delayed gastric

emptying of solids in the absence of mechanical obstruction; key Congenital Disorders
symptoms are nausea, vomiting, postprandial fullness (early sa- Disruptions in the development of gut neuromuscular apparatus
tiety), belching, bloating, and upper abdominal pain result from genetic defects in migration, differentiation, and sur-
✓ Intestinal pseudo-obstruction—characterized by signs and
vival of enteric neurons that have been identified in several causes
symptoms of mechanical obstruction involving the small or large
bowel in the absence of an anatomical lesion that obstructs the flow
of gut dysmotility. These genetic defects include abnormalities
of contents of cRET (OMIM 601496) (the gene that encodes for the tyro-
sine kinase receptor); the endothelin B system (which tends to
retard development of neural elements, thereby facilitating col- incontinence. All these manifestations may be caused by auto-
onization of the entire gut from the neural crest as primitive nomic dysfunction (Table 7.2), although evidence points to the
neural elements enter through the proximal and distal segments importance of reversible changes in persons with acute hyper-
of the developing gut and migrate in oral and anal directions, re- glycemia (blood glucose >250 mg/dL) and, more importantly,
spectively, and innervate the entire gut); Sox10 (a transcription chronic persistent changes in the structure and function of the
factor that enhances the maturation of neural precursors); and enteric nervous system or the interstitial cells of Cajal in persons
c-kit (a marker for the interstitial cells of Cajal). Disturbances in with chronic hyperglycemia.
these mechanisms result in syndromic motility disorders such as From a population perspective, constipation is the most im-
Hirschsprung disease, Waardenburg-Shah syndrome (pigmentary portant gastrointestinal symptom in patients with type 2 diabetes
defects, piebaldism, neural deafness, and megacolon), and idio- because it is the most prevalent symptom. In a large group that had
pathic hypertrophic pyloric stenosis. screening tests for autonomic neuropathy, the prevalence of consti-
pation was 22% among patients who had diabetes and neuropathy
but only 9.2% among those without neuropathy, which was not
Extrinsic Neuropathic Disorders
significantly different from the percentage among persons in the
Extrinsic neuropathic processes that disrupt autonomic or central healthy control group. In a questionnaire-based study of patients
nervous system input include vagotomy, type 2 diabetes, trauma, with diabetes in the community, constipation was more prevalent
Parkinson disease, amyloidosis, and a paraneoplastic syndrome among patients who had type 1 diabetes than in patients who had
usually associated with small cell carcinoma of the lung. Another type 2 diabetes and was associated with symptoms of dysautonomia
common “neuropathic” problem encountered in clinical prac- and the use of constipating drugs (eg, calcium channel blockers).
tice results from the effects of medications such as α2-adrenergic Gastroparesis frequently is encountered as a complication of di-
agonists and anticholinergic agents on neural control. abetes in hospitalized patients. Apart from the added attention
Damage to the autonomic nerves from trauma, infection, needed for metabolic control, management follows that of other
neuropathy, or neurodegeneration may lead to motor, secretory, causes of gastroparesis and pseudo-obstruction. Patients with di-
and sensory disturbances, most frequently resulting in constipa- abetic gastroparesis (ie, symptoms and objective delay in gastric
tion rather than upper gastrointestinal tract motility disorders. emptying) require more hospitalizations and physician visits and
Parkinson disease and multiple sclerosis are 2 neurologic diseases have higher morbidity and mortality than controls.
involving the extrinsic nervous system that frequently are associ-
ated with constipation. A feature of Parkinson disease is a decrease ✓ Diabetes is associated with a wide spectrum of gastrointestinal mo-
in the number of dopamine-containing neurons and the presence tility disorders, including gastroparesis, pylorospasm, intestinal
of Lewy bodies in myenteric plexus neurons. Also, failure of the pseudo-obstruction, diarrhea, constipation, and fecal incontinence
striated muscles of the pelvic floor to relax may be an extrapy- ✓ Diabetes-associated gastrointestinal motility disorders can be re-
versible if induced by acute hyperglycemia or irreversible if they
ramidal manifestation of Parkinson disease that aggravates the
result from chronic hyperglycemia-induced neuropathy
disturbance of colonic emptying and contributes to the common
symptom of constipation, which often precedes other neurologic
changes. Multiple sclerosis is associated with slow colonic transit
and absence of the postprandial motor contractile response in the Enteric or Intrinsic Neuropathic Disorders
colon. Gastroparesis and pseudo-obstruction can occur but are Enteric or intrinsic neuropathic disorders include disruptions to
less frequent than constipation in these diseases. the enteric nervous system or to the interstitial cells of Cajal.
A broad spectrum of gastrointestinal motility disorders may Disorders of the enteric nervous system usually result from a
be related to type 2 diabetes: gastroparesis, pylorospasm, in- degenerative, immune, or inflammatory process. Only rarely
testinal pseudo- obstruction, diarrhea, constipation, and fecal can the cause be ascertained in these disturbances. Infection
may be an important predisposing factor, as suggested by vi-
Table 7.2. Gastrointestinal Manifestations of Type 2 Diabetes rally induced gastroparesis (eg, Rotavirus, Norwalk virus, cyto-
megalovirus, or Epstein-Barr virus) and pseudo-obstruction as
Associated well as degenerative disorders associated with infiltration of the
Manifestation disease Clinical presentation
myenteric plexus by inflammatory cells. In idiopathic chronic
Decreased gallbladder motility Gallstones intestinal pseudo-obstruction, there is no disturbance of extrinsic
Antral hypomotility Gastric stasis neural control and no identified cause for abnormality of the en-
Pylorospasm Bezoars teric nervous system.
Decreased α2-adrenergic tone Diarrhea, steatorrhea
A full-thickness biopsy specimen from the intestine may be
in enterocytes
SB dysmotility SB bacterial Gastric or SB stasis or
required to evaluate the myenteric plexus and interstitial cells
overgrowth rapid SB transit of Cajal. The decision to perform a biopsy needs to be weighed
Colonic dysmotility Bile acid Constipation or carefully against the risk of complications, including the subse-
malabsorption diarrhea quent formation of adhesions and, possibly, mechanical obstruc-
Anorectal dysfunction Diarrhea or fecal tion superimposed on episodes of pseudo-obstruction.
incontinence
Sensory neuropathy
IAS-sympathetic neuropathy Smooth Muscle Disorders
EAS-pudendal neuropathy
Disturbances of smooth muscle may result in major disorders
Abbreviations: EAS, external anal sphincter; IAS, internal anal sphincter; SB, of gastric emptying and small-bowel and colonic transit. These
small-bowel. disturbances include systemic sclerosis and amyloidosis.
Adapted from Camilleri M. Gastrointestinal problems in diabetes. Endocrinol Dermatomyositis, myotonic dystrophy, and metabolic muscle
Metab Clin North Am. 1996 Jun;25(2):361-78; used with permission. disorders such as mitochondrial cytopathy are seen infrequently.
Abnormal facial and external ocular muscle functions may be clearly in the degree of nutritional and electrolyte depletion.
useful clinical signs of these diseases. In rare instances, there is a Disturbances of bowel movements, such as diarrhea and consti-
positive family history (eg, hollow visceral myopathy may occur pation, indicate that the motility disorder is more extensive than
either sporadically or in families). Patients with more subtle mo- gastroparesis. Severe vomiting may be complicated by aspiration
tility disturbances often present with constipation from metabolic pneumonia or Mallory-Weiss tears that may result in gastrointes-
disorders such as hypothyroidism or hyperparathyroidism. tinal tract hemorrhage. When patients have a more generalized
Scleroderma is a multisystemic disorder characterized by vas- motility disorder, they also may have symptoms referable to ab-
cular dysfunction and progressive fibrosis with nearly 90% of normal swallowing or delayed colonic transit.
patients showing some degree of gastrointestinal tract involve-
ment, most frequently in the esophagus. Scleroderma in the gas-
History and Risk Factors
trointestinal system initially presents with neuronal dysfunction
and eventually progresses to muscle dysfunction and fibrosis. In A family history and medication history are essential for
the stomach and small bowel, it may result in focal or general dil- identifying underlying etiologic factors such as diabetes. Review
atation, diverticula (often wide-mouthed, especially in the colon), of systems may be helpful to diagnose an underlying collagen
and delayed transit at the levels affected. The amplitude of con- vascular disease (eg, scleroderma) or disturbances of extrinsic
tractions is decreased (average <30 mm Hg in the distal esoph- neural control that also may be affecting the abdominal viscera.
agus, <40 mm Hg in the antrum, and <10 mm Hg in the small Such symptoms include orthostatic dizziness, difficulties with
bowel) compared with that of controls, indicative of smooth erection or ejaculation, recurrent urinary tract infections, diffi-
muscle dysfunction. Bacterial overgrowth is common and may culty with visual accommodation, absence of sweating, and dry
result in steatorrhea, and it is more likely to occur in myopathic mouth, eyes, or vagina.
disorders, often with concomitant dilation or diverticula of the
small intestine. Physical Examination
A mitochondrial disorder that affects the gut is mitochondrial
neurogastrointestinal encephalomyopathy. It is referred to also Physical examination findings are limited for diagnoses of a mo-
as oculogastrointestinal muscular dystrophy or familial visceral tility disorder but are helpful for evaluation of potential systemic
myopathy type II and is an example of a spectrum of diseases causes. A succussion splash detected on physical examination
that affect oxidative phosphorylation. It is an autosomal reces- usually indicates a region of stasis within the gastrointestinal
sive condition with gastrointestinal and liver manifestations tract, typically the stomach. The hands and mouth may show
that may occur at any age, typically with hepatomegaly or liver signs of Raynaud phenomenon or scleroderma. Testing pupillary
failure in the neonate, seizures or diarrhea in infants, and liver responses to light and accommodation, testing external ocular
failure or chronic intestinal pseudo-obstruction in children and movement, measuring blood pressure in the supine and standing
adults. positions, and noting the general features of peripheral neurop-
Mitochondrial neurogastrointestinal encephalomyopathy is athy can be used to identify patients who have a neurologic dis-
characterized also by external ophthalmoplegia, ptosis, periph- turbance or oculogastrointestinal dystrophy associated typically
eral neuropathy, and leukoencephalopathy. The small intestine with mitochondrial cytopathy.
is dilated or has multiple diverticula, and the amplitude of con- A motility disorder of the stomach or small bowel should be
tractions is low, typical of a myopathic disorder. Some patients suspected whenever large volumes are aspirated from the sto-
have a combination of intestinal dysmotility or transfer dys- mach, particularly after an overnight fast or when undigested
phagia due to abnormal coordination and propagation of the solid food or large volumes of liquids are observed during
swallow through the pharynx and the skeletal muscle portion esophagogastroduodenoscopy.
of the esophagus. This becomes even more devastating when
the smooth muscle portion of the esophagus is also affected by Differential Diagnosis
the cytopathy.
In the evaluation of a suspected motility disorder, exclusion of
mechanical obstruction (eg, from peptic stricture, obstructing
Presentation and Diagnosis of Gastroparesis masses in the stomach or intestines, or Crohn disease of the sto-
and Intestinal Pseudo-obstruction mach or small bowel) is key as treatments to speed up bowel mo-
Evaluation of motility disorders should be considered in 4 tility in pseudo-obstruction would be relatively contraindicated
categories: in patients with mechanical obstruction. Other considerations for
patients who present with abdominal pain, nausea, and vomiting
1. Timing and chronicity: Are the symptoms acute or chronic?
include disorders of gut-brain interaction such as functional dys-
2. Etiology: Is the disease due to neuropathy or myopathy? Is there an
underlying systemic disorder? pepsia, eating disorders such as anorexia nervosa, and rumina-
3. Location: What regions of the digestive tract are affected? tion syndrome. The degree of impairment of gastric emptying in
4. Severity: What is the status of hydration and nutrition? eating disorders is relatively minor compared with that of dia-
betic or postvagotomy gastric stasis.
Clinical Features
Diagnostic Evaluation
The clinical features of gastroparesis and chronic intestinal
pseudo-obstruction are similar and include nausea, vomiting, The recommended sequence for diagnostic evaluation is as
early satiety, abdominal discomfort, distention, bloating, and an- follows:
orexia. Patients with severe stasis and vomiting may have consid- 1. Rule out mechanical obstruction. The initial step in evaluation
erable weight loss and depletion of mineral and vitamin stores. should be to exclude mechanical obstruction. This can be done with
The severity of the motility problem often manifests itself most upper endoscopic and radiologic studies with an oral contrast agent,
including upper gastrointestinal series with small- bowel follow- distention as well as the distensibility of the pylorus to assess for
through or computed tomographic enterography. Imaging findings hypertonicity at this junction.
that support pseudo-obstruction show dilated small- bowel loops 3. Identify the pathogenesis. Causes of gastroparesis and intestinal
with associated air-fluid levels but no transition points. Gross dil- pseudo-obstruction are outlined in Table 7.1. In the absence of a
atation of the intestines, dilution of barium, and retained solid food cause for a neuropathic pattern of motor activity in the small in-
within the stomach also provide support for a motility disorder but testine, it is necessary to pursue additional investigations, in-
are rarely seen. Therefore, these studies are undertaken largely for cluding testing for autonomic dysfunction, antineuronal nuclear
exclusion of mechanical obstruction as opposed to positive diag- autoantibodies type 1 associated with paraneoplastic syndromes,
nosis of a motility disorder. An exception is small-bowel systemic and magnetic resonance imaging of the brain to exclude a brainstem
sclerosis, which is characterized by megaduodenum and packed lesion in patients with vomiting (Figure 7.4). Autonomic testing
valvulae conniventes in the small intestine resulting in the hide- may include evaluation for orthostatic hypotension, assessment of
bound radiographic sign. supine and standing serum norepinephrine levels, measurement of
2. Diagnose dysmotility. For definitive assessment of a motility dis- the heart rate interval changes during deep breathing, and plasma
order, bowel transit studies should be performed to assess gastric pancreatic polypeptide response to modified sham feeding. This
and small-bowel function. For evaluating efficiency in the emptying testing can identify sympathetic adrenergic or vagal neuropathy.
of solids, scintigraphy offers the most sensitive measurement of The identification of a myopathic disorder on initial testing should
upper gastrointestinal tract transit. Scans typically are performed at lead to a search for amyloidosis (immunoglobulin electrophoresis,
0, 1, 2, 4, and 6 hours after ingestion of a radiolabeled meal and fat aspirate, or rectal biopsy), systemic sclerosis (Scl-70), and a
should be done after all medications that affect gastric emptying family history of gastrointestinal motility disorders.
have been withheld for at least 48 hours. Delayed gastric emptying Laboratory studies to consider include assessment of thy-
is defined as gastric retention of more than 10% at 4 hours or more roid function and levels of antinuclear antibody, lactate, creatine
than 60% at 2 hours (or both) after a standard low-fat, scrambled egg phosphokinase, aldolase, and porphyrins and serologic study for
meal, although the 4-hour residual has higher sensitivity for diag- Chagas disease. In certain cases, a laparoscopically obtained full-
nosis of delayed gastric emptying. Alternatives to measuring transit thickness biopsy specimen from the small intestine may be required.
include use of the stable isotope breath test and the wireless motility Special staining techniques may be needed to identify metabolic
capsule, but these tests are not as well validated as scintigraphic gas- muscle disorders, including mitochondrial myopathy, for which ge-
tric emptying. netic testing may be available.
If the cause of the motility disturbance is obvious, such as 4. Identify complications of the motility disorder. Morbidity in
gastroparesis in a patient with long-standing type 2 diabetes, fur- motility disorders is often due to complications that should be
ther diagnostic testing usually is not needed. If the cause is unclear, addressed to make the primary dysmotility more manageable.
gastroduodenal manometry, with the use of a multilumen tube with These complications include bacterial overgrowth, dehydration,
sensors in the distal stomach and proximal small intestine, can be and malnutrition. In patients with diarrhea, it is important to assess
used to distinguish between neuropathic and myopathic processes nutritional status (including essential mineral and vitamin levels)
(Figure 7.3). Neuropathies are characterized by contractions with and to exclude bacterial overgrowth by culturing small- bowel
normal amplitude but with abnormal patterns of contractility. In con- aspirates or performing hydrogen breath testing. Bacterial over-
trast, the predominant disturbance in myopathic disorders is the low growth is relatively uncommon in neuropathic disorders but is
average amplitude of contractions in the segments affected (<40 mm more common in myopathic conditions, such as scleroderma, that
Hg in the antrum; <10 mm Hg in the small intestine) (Figure 7.3). are associated more often with bowel dilatation, low-amplitude
Endoflip (Medtronic) is an endoscopically deployed device that contractions, or small- bowel diverticula that allow for bacte-
has been used to measure the pyloric dimensions at rest and with rial proliferation. Bacterial overgrowth should be suspected in
Figure 7.3. Gastroduodenal Manometric Profiles. Postprandial manometric profiles in small-bowel dysmotility due to neuropathy (left; type 2
diabetes) and myopathy (right; systemic sclerosis). In myopathy the profiles show simultaneous, prolonged contractions of low amplitude. Although
the contraction amplitudes are normal in neuropathy, contractile activity is uncoordinated and contractile frequency is decreased. Desc. indicates de-
scending. (Adapted from Coulie B, Camilleri M. Intestinal pseudo-obstruction. Annu Rev Med. 1999;50:37-55; used with permission.)
Figure 7.4. Flow Diagram of Steps in Diagnosis of Gastroparesis and Intestinal Pseudo-obstruction. ANA indicates antinuclear antibodies;
ANNA-1, antineuronal nuclear antibodies type 1; CPK, creatine phosphokinase; GI, gastrointestinal. (Adapted from Camilleri M, Prather CM. Gastric
motor physiology and motor disorders. In: Feldman M, Sleisenger MH, Scharschmidt BF, editors. Sleisenger & Fordtran’s gastrointestinal and liver
disease: pathophysiology, diagnosis, management. 6th ed. Philadelphia [PA]: Saunders; c1998. p. 572-86; used with permission.)
patients with an increased folate level but a deficiency of vitamin than 3 months, usually the best approach is to provide feedings
B12. Bacterial overgrowth may be difficult to detect with culture of through a jejunostomy tube. Gastrostomy tubes should be
small-bowel aspirates; however, breath hydrogen after a glucose or avoided in gastroparesis for delivery of nutrition, but combined
lactulose load is a nonspecific test that should be interpreted with gastrojejunal tubes can be considered so that gastric ports may be
caution and in conjunction with small-bowel transit time because
used for venting purposes. Many patients who require long-term
the early breath hydrogen peak may be due to bacterial metabolism
of the substrate in the colon resulting from fast small-bowel transit.
parenteral nutrition continue to tolerate some oral feeding, which
Often, an empirical trial of antibiotic therapy is used as a surrogate should be encouraged.
for formal testing.
Management of Bacterial Overgrowth in the

Treatment of Gastroparesis and Intestinal Small Intestine
Pseudo-obstruction
Antibiotic therapy is indicated for patients who have docu
Treatment of gastroparesis and intestinal pseudo-obstruction mented symptomatic bacterial overgrowth (typically manifested
should be tailored for each patient depending on complications as diarrhea and steatorrhea with bloating). Owing to persistent
present and the specific effects of the underlying motility dis- underlying motility disorder, patients with intestinal pseudo-
order. In patients with a systemic disorder driving gastroin- obstruction typically have frequent recurrence of bacterial
testinal motility, control of these disorders can occasionally overgrowth and require cycling of various antibiotics for long-
improve motility but are of greater importance in preventing term suppression. Although formal clinical trials have not been
progression. conducted, common practice is to use different antibiotics for
7 to 10 days each month to avoid development of resistance.
Management of Complications Common antibiotics include doxycycline (100 mg twice daily),
metronidazole (500 mg 3 times daily), ciprofloxacin (500 mg
Correction of Hydration and Nutritional Deficiencies twice daily), double-strength trimethoprim-sulfamethoxazole
Rehydration, electrolyte repletion, and nutritional supplemen- (2 tablets twice daily), and rifaximin (550 mg 3 times daily).
tation are particularly important during acute exacerbations Antibiotic therapy for patients with diarrhea and fat malabsorp-
of gastroparesis and chronic intestinal pseudo- obstruction. tion due to bacterial overgrowth produces considerable symp-
Restoration of nutrition can be achieved orally, enterally, or par- tomatic relief.
enterally, depending on the severity of the clinical syndrome.
✓ Bacterial overgrowth in the small intestine
Oral intake should be low in fiber and fat, both of which delay
• High likelihood of recurrence if a patient has a motility
gastrointestinal transit, with the addition of iron, folate, cal- disturbance
cium, and vitamins D, K, and B12. Patients with more severe • Cycling of various antibiotics is often needed for long-term
symptoms may require enteral or parenteral supplementation of suppression
nutrition. If enteral supplementation may be required for more
Management of Underlying Motility a selective 5-HT4 receptor agonist, has been shown in trials to sig-
Disturbance nificantly decrease gastric emptying half-time compared to pla-
cebo and improve gastroparesis symptoms, but prucalopride has
Medications
not received FDA approval for use in gastroparesis. Velusetrag,
Medications may be used to treat neuromuscular motility felcisetrag (TAK 954), and naronapride are other selective 5-HT4
disorders. However, there is little evidence that they are effective agonists with positive evidence in clinical trials for improving
in primary myopathic disturbances, except for the rare case of gastroparesis in various clinical settings with minimal cardiac ad-
myotonic dystrophy affecting the stomach and for small-bowel verse effects.
systemic sclerosis. Neostigmine and pyridostigmine are acetylcholinesterase
Erythromycin, a macrolide antibiotic that stimulates motilin inhibitors that improve gastric and duodenal contractility and
receptors at higher doses (eg, 250-500 mg) and cholinergic mecha have been shown in trials to increase gastric and small bowel
nisms at lower doses (eg, 40-80 mg), results in the dumping of solids emptying. Neostigmine is limited to parenteral administration and
from the stomach. It has been shown to accelerate gastric emptying must be administered under cardiac monitoring because of the
in gastroparesis; it also increases the amplitude of antral contractions potential for bradycardia and excess vagal tone. Pyridostigmine
and improves antroduodenal coordination. Erythromycin is most is available in enteral formulation as a liquid or a tablet and has
effective when it is given intravenously during acute exacerbations been shown to improve chronic intestinal pseudo-obstruction,
of gastroparesis or intestinal pseudo-obstruction. The usual dose of delayed small-bowel transit with gastroparesis, and chronic con-
intravenous erythromycin lactobionate is 3 mg/kg infused over 45 stipation in pediatric patients in open-label trials with dosing of
minutes every 8 hours. The efficacy of oral erythromycin appears 0.25 to 2.0 mg/kg daily. Neither medication has FDA approval for
to be restricted by tolerance and gastrointestinal adverse effects, the indication of improving gastrointestinal motility.
which often prevent treatment for longer than 1 month; sometimes Octreotide, a cyclized analogue of somatostatin, has been
a low dosage of liquid erythromycin (eg, 40-80 mg 3 times daily shown to induce activity fronts in the small intestine that mimic
before meals) can be tolerated. The elixir formulation may im- phase III activity of the interdigestive migrating motor complex.
prove absorption if the patient has dysmotility. Although studies The clinical effects of octreotide include an initial acceleration
demonstrated that 2 weeks of treatment was effective for patients of gastric emptying, a decrease in postprandial gastric motility,
with diabetic gastroparesis, there is little evidence that continued and inhibition of small-bowel transit. The therapeutic efficacy of
therapy produces long-term improvement in gastric emptying or octreotide in intestinal dysmotility associated with gastroparesis
associated symptoms. Similar benefit has been seen with other and pseudo-obstruction has not been demonstrated in clinical
macrolides, including azithromycin and clarithromycin, but the trials. Currently, octreotide administered before meals appears to
use of these agents is similarly limited by concerns for tachyphy- be more useful in the treatment of dumping syndromes associated
laxis, cardiac risks from potential drug interactions, and antibiotic with accelerated transit. However, it may be useful just before
resistance. bedtime to induce activity of the migrating motor complex and
Metoclopramide is a dopamine antagonist that has both to propel residue toward the colon with the goal of avoiding bac-
prokinetic and antiemetic properties. Antiemetic effects are due terial overgrowth. If required during the daytime, octreotide is
partly to its antiserotoninergic3 antagonist actions. Long-term use often given in combination with oral erythromycin to normalize
of metoclopramide is limited by the adverse effects of tremor and the gastric emptying rate.
Parkinson-like symptoms, a consequence of antidopaminergic Antiemetics, including diphenhydramine, prochlorperazine,
activity in the central nervous system. Occasionally, tardive scopolamine, and metoclopramide, are important in the manage-
dyskinesia occurs. This led to a recommendation to limit use of ment of nausea and vomiting in patients with gastroparesis and in-
metoclopramide to less than 3 months (the US Food and Drug testinal pseudo-obstruction. The more expensive 5-HT3 antagonists
Administration [FDA] ordered a boxed warning). It is available (eg, ondansetron) have not provided greater benefit than the less
in tablet or elixir form and typically is taken 30 minutes before expensive alternatives. Ondansetron causes prolongation of the
meals and at bedtime. Usual dosages range from 5 to 20 mg 4 QTc and should be used with caution, particularly if patients are
times daily, but the drug is safest when the total daily dose is re- taking other medications that affect the QTc. Granisetron is a
stricted to a maximum of 30 mg. sustained-release transdermal patch that has shown improvement
Domperidone, a dopamine D2 receptor antagonist that is not in gastroparesis symptoms in open-label trials.
available in the US, has been made available for prescription Newer medications include neurokinin-1 antagonists such as
through the FDA’s Expanded Access to Investigational Drugs aprepitant. Aprepitant, available parenterally and enterally, has
program. The efficacy of domperidone is generally like that of FDA approval for the prevention of chemotherapy-induced or
metoclopramide, but domperidone has fewer adverse effects on postoperative nausea and vomiting and has been shown in trials
the central nervous system. The recommended starting dose of to improve overall symptoms, although it does not improve gas-
domperidone is 10 mg 3 times daily with the option to titrate the tric emptying.
dose to 20 mg 4 times daily (before meals and at bedtime). Use of Several medications are currently undergoing investigation
domperidone should be avoided in patients with a corrected QT for the treatment of gastroparesis, including cannabidiol, a low-
interval (QTc) that is prolonged (>470 ms in men; >450 ms in tetrahydrocannabinol extract from Cannabis sativa; tradipitant, a
women) because of the risk of cardiac dysrhythmias. neurokinin-1 antagonist; relamorelin, a ghrelin receptor agonist;
Serotonin (5-HT) receptor agonists may prove to be bene- and trazpiroben, a dopamine D2/D3–receptor antagonist with
ficial in the treatment of gastroparesis and intestinal pseudo- limited effects on the central nervous system.
obstruction. The combined 5-HT4 agonist and 5-HT3 antagonist,
cisapride, was previously the only medication for which there
was evidence for medium-and long-term efficacy; however, the Decompression
medication is no longer available for prescription because of the Decompression is rarely necessary in patients with gastroparesis
risks of cardiac dysrhythmias (torsades de pointes). Prucalopride, or chronic pseudo-obstruction. However, venting enterostomy
(gastrostomy or jejunostomy) is effective in relieving abdominal the future, Endoflip may be used for guidance for the efficacy of
distention and bloating. It has been shown to decrease the fre- G-POEM and as a predictor of response.
quency of nasogastric intubations and hospitalizations for acute
exacerbations of severe intestinal pseudo-obstruction in patients Small-Bowel Transplant. Small-bowel transplant is limited to
requiring central parenteral nutrition. Access to the small intes- patients with intestinal failure who have reversible total parenteral
tine by enterostomy also provides a way to deliver nutrients en- nutrition (TPN)-induced liver disease or life-threatening or recur-
terally and should be considered for patients with intermittent rent catheter-related sepsis. Combined small-bowel and liver trans-
symptoms. The currently available enteral tubes allow for gastric plant is performed in patients with irreversible TPN-induced liver
aspiration and feeding by a single apparatus. However, because disease. Complications after small-bowel transplant include infec-
venting can lead to displacement, some patients need a feeding tion, rejection, and lymphoproliferative disorders due to long-term
tube in the jejunum and a venting tube in the stomach. immunosuppression and Epstein-Barr virus infection. Studies have
suggested that small-bowel transplant may improve quality of life
and may be more cost-effective than long-term TPN. Improvements
Surgical and Endoscopic Interventions in immunosuppressive regimens, earlier detection of rejection, and
Surgical treatment has a limited role in patients with gastroparesis treatment of cytomegalovirus infection have enhanced outcomes of
and intestinal pseudo-obstruction. For patients who have had small-bowel transplant for short bowel syndrome or severe pseudo-
multiple abdominal operations, it becomes difficult to discern obstruction uncontrolled by TPN. In the meantime, parenteral nu-
whether exacerbations of symptoms reflect an underlying disease trition is the treatment of choice for most patients.
or adhesions and mechanical obstruction. Recent advancements
have focused more on therapy directed to the pylorus to address Functional Dyspepsia
the pyloric dysfunction seen in a subset of patients who have
gastroparesis with prolonged, intense tonic pyloric contractions Functional dyspepsia is in the group of disorders now termed
(ie, pylorospasm). disorders of gut-brain interaction. The pathophysiology is not
well understood, but some experts consider that functional dys-
Surgical Resection. Surgical treatment should be considered pepsia exists along a continuum with gastroparesis because of the
whenever the motility disorder is localized to a resectable portion overlap of symptoms.
of the gut. Three instances in which to consider this approach Symptoms of dyspepsia are encountered commonly in clin-
are 1) duodenojejunostomy or duodenoplasty for patients with ical practice. These include epigastric pain or discomfort, nausea,
megaduodenum or duodenal atresia in children; 2) near-total gas- vomiting, early satiation, postprandial fullness, and upper ab-
trectomy with Roux-en-Y reconstruction or completion gastrec- dominal bloating. The roles of gastroesophageal reflux, peptic
tomy for patients with postgastric surgical stasis syndrome; and 3) ulcer disease, gastritis, and cancer in causing these symptoms are
colectomy with ileorectostomy for intractable constipation asso- reviewed in other chapters in this book.
ciated with chronic colonic pseudo-obstruction. Several mechanisms have been postulated for functional
dyspepsia (Table 7.3). Similarly, many different therapies have
Gastric Electrical Stimulation. Open-
label treatment with
been tried. This multitude of diagnostic and therapeutic options
externally provided gastric pacing improved gastric emptying
underscores the fact that the cause of functional dyspepsia is not
and symptoms in patients with severe gastroparesis. Gastric
uniform; hence, treatment must be tailored to the identified dis-
pacing has not successfully entrained gastric slow waves to nor-
order of function.
malize gastric dysrhythmias or to accelerate gastric emptying,
and placement of the device is associated with complications, in-
cluding local infection and lead migration. Gastric electrical stim- Definition
ulation is an approved treatment (under the FDA’s Humanitarian Dyspepsia is not a condition: It is a symptom complex. Dyspepsia
Device Exemption Program), but data on efficacy are inconclu- can be defined as persistent or recurrent abdominal pain or ab-
sive, and current guidelines do not provide consensus for which dominal discomfort centered in the upper abdomen. The term
patients would benefit from this device. discomfort includes symptoms of nausea, vomiting, early satiety,
Pylorus-Directed Interventions. Botulinum toxin injected into postprandial fullness, and upper abdominal bloating. The Rome
the pylorus has been shown to have short-term, dose-dependent IV criteria (Box 7.1) define functional dyspepsia as 1 or more of
efficacy for symptom improvement in a subset of patients with the following: bothersome postprandial fullness, bothersome early
gastroparesis. Repeated injections, however, may induce pyloric satiation, bothersome epigastric pain, and bothersome epigastric
fibrosis. burning in the absence of structural disease likely to explain the
Surgical pyloroplasty that uses a longitudinal incision across symptoms. The criteria must be fulfilled for the past 3 months
the pylorus through the longitudinal and circular muscle layers with symptom onset at least 6 months before the diagnosis.
(ie, Heineke- Mikulicz pyloroplasty) has improved gastric Functional dyspepsia is further categorized into postprandial
emptying and symptoms. Complication rates were high, however, distress syndrome and epigastric pain syndrome. Postprandial
and 10% of patients required subsequent surgical intervention.
Gastric peroral endoscopic myotomy (G-POEM) was devel- Table 7.3. Proposed Causes of Functional Dyspepsia
oped to replicate the positive effects of surgical pyloroplasty in
a minimally invasive manner to decrease morbidity. G-POEM Acid or Helicobacter pylori Motility or sensitivity
is performed endoscopically and involves tunneling through the H pylori infection Gastroparesis
submucosa from the luminal stomach with the goal of severing Gastritis, duodenitis Abnormal relaxation
the circular muscle layer without disrupting the longitudinal Missed peptic ulcer disease Visceral hypersensitivity
Acid sensitivity Brain-gut disorder
muscle layer. Early trial data are promising, but long-term results
Occult gastroesophageal reflux disease Psychologic disorder
and large randomized trials to validate efficacy are necessary. In
distress syndrome necessitates bothersome postprandial fullness heartburn in the definition of dyspepsia and report a prevalence
or bothersome early satiation (or both). Epigastric pain syndrome rate of 40%. Other surveys exclude persons with symptoms of
in contrast must include bothersome epigastric pain or bother- heartburn or irritable bowel syndrome and report prevalence rates
some epigastric burning (or both). These 2 conditions may co- of less than 5%. Nonetheless, it is reasonable to state that 15% of
exist, but 1 generally is determined to be predominant. the adult population (about 1 in 7) has dyspepsia. Not all these
Other symptoms that are often present in both disorders in- people with dyspepsia have functional dyspepsia. In 1 study, when
clude epigastric bloating, excessive belching, and nausea. While a random sample of the population with dyspepsia underwent en-
the symptoms of heartburn and acid regurgitation frequently co- doscopy, only 53% had normal endoscopic findings. The remark-
exist, they are not considered dyspeptic symptoms and should able findings were esophagitis, peptic ulcer disease, duodenitis,
prompt evaluation for gastroesophageal reflux disease. Patients and duodenogastric reflux. Furthermore, in this study only 66% of
with symptoms or signs typical for biliary tract or pancreatic the asymptomatic controls had normal endoscopic findings. Peptic
disease should not be considered to have functional dyspepsia. ulcer disease and duodenitis were more common in the persons
Thus, right upper quadrant pain or epigastric pain that radiates with dyspepsia than in the controls. Other findings such as gastritis
to the back should not be included in the definition of dyspepsia. were found in a similar number of cases and controls.
Presence of vomiting suggests another disorder. Guidelines of the American Gastroenterological Association
Functional dyspepsia is diagnosed if the above symptom recommend that in the absence of visible lesions on endoscopy,
criteria are met for more than 3 months without an anatom- esophageal and duodenal biopsies are not indicated. However,
ical or biochemical abnormality. Typically, this means negative biopsies of the stomach can be performed to look for H pylori if
findings on blood tests and on evaluation of the upper gastroin- the status of H pylori is unknown.
testinal tract with endoscopy or barium radiography. However,
describing endoscopic findings as negative for functional dys-
Pathophysiology
pepsia can be difficult. Does this include biopsy study of the
esophagus for esophagitis or biopsy study of the stomach for The most frequently mentioned etiologic possibilities for func-
gastritis or H pylori infection? Are erythema, erosions, and his- tional dyspepsia are listed in Table 7.3. The possible causes have
tologic inflammation meaningful findings? These issues are been divided into 2 categories: acid or H pylori vs motility or
somewhat controversial. sensitivity.
Surveys have evaluated how many people in the community Whether H pylori infection causes symptoms in the absence of
have symptoms of dyspepsia. The rates vary in large part because an ulcer is still debated. The prevalence of H pylori infection and
of the definitions used. Some surveys include the symptom of gastritis is only slightly more common in patients with dyspepsia.
Still, physicians, investigators, and patients have been interested
in the idea that the histologic inflammation produces symptoms.
In multicenter, placebo-controlled clinical trials, the effect of the
Box 7.1. Rome IV Criteria for Selected Gastroduodenal eradication of H pylori on functional dyspepsia has been small.
Disorders Patients commonly take antacids for relief of dyspepsia, but
gastric acid secretion is normal in patients with functional dys-
B1. Functional dyspepsia
pepsia. One hypothesis is that patients with functional dyspepsia
≥1 of the following:
may have visceral hypersensitivity and be more sensitive to acid.
1. Bothersome postprandial fullness Placebo-controlled trials have shown that acid suppression is
2. Bothersome early satiation modestly more effective than placebo in functional dyspepsia. The
3. Bothersome epigastric pain question has been whether this is due to occult gastroesophageal
4. Bothersome epigastric burning reflux that manifests as dyspepsia.
and
Although clinicians often focus on epigastric pain as the car-
dinal symptom of functional dyspepsia, most investigators include
No evidence of structural disease (including at
other symptoms, such as nausea, fullness, and early satiety. These
upper endoscopy) that is likely to explain the
symptoms
symptoms suggest that motor abnormalities (delayed or paradoxi-
cally accelerated emptying or impaired accommodation) may be a
B1a. Postprandial distress syndrome factor in causing this condition. Of the patients with functional dys-
≥1 of the following ≥3 d/wk:
pepsia who are evaluated in gastrointestinal clinics of referral centers,
1. Bothersome postprandial fullness (ie, severe one-third to one- half have delayed gastric emptying. Multiple
enough to affect usual activities) studies, primarily in Europe, have evaluated the role of prokinetics in
2. Bothersome early satiation (ie, severe enough to functional dyspepsia. Generally, prokinetics are 30% more effective
prevent finishing a regular-size meal) than placebo, although the rates varied considerably among studies.
B1b. Epigastric pain syndrome Most of these studies were with cisapride or domperidone, neither of
≥1 of the following symptoms ≥1 d/wk: which is currently available in the US. They may be helpful in part
1. Bothersome epigastric pain (ie, severe enough because of their antiemetic effects. Treatment with metoclopramide
to affect usual activities) for more than 3 months should be avoided because of the risk of tar-
2. Bothersome epigastric burning (ie, severe dive dyskinesia and other adverse effects.
enough to affect usual activities) More recently, attention has shifted from gastric emptying to
gastric accommodation and gastric sensitivity. Like the heart, the
Adapted from Stanghellini V, Chan FKL, Hasler WL, Malagelada JR, stomach has both systolic and diastolic functions. Recent studies
Suzuki H, Tack J, et al. Gastroduodenal disorders. Gastroenterology. have shown that gastric accommodation (ie, the relaxation of the
2016 150(6):1380-92; used with permission. stomach in response to a meal) is abnormal in patients with func-
tional dyspepsia. Medications such as the anxiolytic buspirone (a
5-HT1A receptor agonist) and the experimental anticholinesterase Recommendations for Evaluation and Therapy
inhibitor acotiamide appear effective in clinical trials with
A test-and-treat approach for this H pylori infection is indicated
patients who have functional dyspepsia.
and may be effective in relieving functional dyspepsia. Yet, many
The disorders of gut-brain interaction form a continuum
patients still have symptoms after testing and eradication of H
of illnesses characterized by gastrointestinal symptoms and
pylori, and a trial of acid inhibition, usually with a proton pump
nondiagnostic findings on evaluations. The disorders have con-
inhibitor, is the next recommended treatment option. Because
siderable overlap. Specifically, at least one-third of patients with
of the controversy from conflicting studies and inadequate data,
functional dyspepsia also have symptoms of irritable bowel syn-
practice guidelines recommend either a trial of acid inhibition
drome. Patients with irritable bowel syndrome have been shown
or testing for H pylori infection before any diagnostic investiga-
to have a lower threshold for rectal distention. A similar phe-
tion for dyspepsia in the absence of alarm or high-risk symptoms
nomenon has been noted in functional dyspepsia for distention
(Figure 7.5). These include clinically significant weight loss
of the stomach. More recently, imaging of the central nervous
(>5% body weight over 6-12 months), progressive dysphagia
system has highlighted the activation of different parts of the
or odynophagia, unexplained iron deficiency anemia or covert
brain in persons with functional gastrointestinal disorders.
gastrointestinal bleeding, persistent vomiting, family history of
Thus, the concept of visceral hypersensitivity remains a strong
upper gastrointestinal cancer, palpable abdominal or epigastric
consideration in all the functional gastrointestinal disorders,
mass or lymphadenopathy, and the patient being 60 years or older
including functional dyspepsia. Currently, however, no spe-
with new-onset symptoms. If 1 or more of these alarm symptoms
cific medication is available for visceral hypersensitivity, al-
is present, or if patients have no benefit from empirical dyspepsia
though new agents are being investigated. Clinically, low-dose
treatment (Figure 7.5A), upper gastrointestinal endoscopy should
antidepressants are being prescribed, but formal clinical trial
be performed to exclude peptic ulcer disease, esophagitis, and
data are not available.
Figure 7.5. Diagnostic and Treatment Algorithms for Undiagnosed Dyspepsia and Functional Dyspepsia. A, Undiagnosed dyspepsia. Alarm
symptoms are 1) clinically significant weight loss with progressive dysphagia or odynophagia; 2) unexplained iron deficiency anemia or overt gas-
trointestinal bleeding; 3) persistent vomiting; 4) family history of upper gastrointestinal cancer; 5) palpable abdominal or epigastric mass or lym-
phadenopathy; and 6) age older than 60 years with new-onset symptoms. B, Functional dyspepsia. EPS indicates epigastric pain syndrome; H pylori,
Helicobacter pylori; PDS, postprandial distress syndrome; PPI, proton pump inhibitor; TCA, tricyclic antidepressant. (Adapted from Moayyedi P,
Lacy BE, Andrews CN, Enns RA, Howden CW, Vakil N. ACG and CAG clinical guideline: management of dyspepsia. Am J Gastroenterol. 2017
Jul;112(7):988-1013; used with permission.)
Figure 7.5. Continued
malignancy. After the diagnosis of functional dyspepsia has been delay of gastric emptying of liquids. In epigastric pain syndrome,
made, the first step is to provide reassurance. Some patients with and in patients with postprandial distress who do not respond
functional dyspepsia want only to be assured that they do not to buspirone, a tricyclic antidepressant can be tried. Tricyclic
have cancer. They find their symptoms tolerable and require no antidepressants are preferred over selective serotonin reuptake
further intervention. The more difficult decision is whether to inhibitors and serotonin and norepinephrine reuptake inhibitors,
perform additional diagnostic testing. The alternative is to pro- although mirtazapine may be considered for patients with unin-
ceed directly with empirical trials (Figure 7.5B). Often, the di- tentional weight loss attributed to functional dyspepsia.
agnostic tests can be interfaced with therapies that have shown The use of prokinetic agents, including a short course of
benefit in functional dyspepsia, including H pylori eradication metoclopramide, can be considered at 5 to 10 mg 3 times daily if
(if H pylori is present), proton pump inhibitors, intermittent use patients have not had a therapeutic response with a proton pump in-
of prokinetics, buspirone for postprandial distress syndrome, or hibitor, H pylori eradication, or a trial of an antidepressant. A second
low-dose tricyclic antidepressants for epigastric pain syndrome. trial can be administered for recurrent symptoms. Psychological
An 8-week trial of a proton pump inhibitor should be started at therapy with cognitive behavioral therapy, hypnotherapy, or psy-
once-daily dosing and discontinued if ineffective. If the therapy chotherapy can decrease visceral hypersensitivity and resulting
is effective, discontinuation of the therapy should be attempted symptoms and should be considered if patients have not had a re-
every 6 to 12 months. Histamine blockers have modest effect, but sponse to medical therapies. Complementary medicines with data
antacids, bismuth, and sucralfate have not shown efficacy. for functional dyspepsia include peppermint oil and caraway oil,
In postprandial distress syndrome, 4 weeks of buspirone which have been coformulated in various commercial products. In
administered at 10 mg 3 times daily has been shown to im- small trials, these products have been shown to improve symptoms
prove postprandial fullness, early satiation, and upper abdom- in patients with functional dyspepsia, but current guidelines recom-
inal bloating with improvement in gastric accommodation and mend against their routine use because of the low-quality evidence.
Summary Camilleri M, Iturrino J, Bharucha AE, Burton D, Shin A, Jeong ID, et al.
Performance characteristics of scintigraphic measurement of gastric
Disorders of gastric and small-bowel motility may result in ei- emptying of solids in healthy participants. Neurogastroenterol Motil.
ther stasis or accelerated transit. Functional dyspepsia most likely 2012 Dec;24(12):1076–e562.
resides on a continuum with disturbances in gastric sensation Camilleri M, Parkman HP, Shafi MA, Abell TL, Gerson L; American
or function that are yet to be clinically defined. Understanding College of Gastroenterology. Clinical guideline: management of
the mechanisms that control motility and the pathophysiologic gastroparesis. Am J Gastroenterol. 2013 Jan;108(1):18–37.
mechanisms is the key to optimal management. Simple, quantita- Camilleri M, Sanders KM. Gastroparesis. Gastroenterology. 2022
tive measures of transit and an algorithmic approach to identifying Jan;162(1):68–87.
Camilleri M, Stanghellini V. Current management strategies and
the underlying cause may lead to correction of abnormal function.
emerging treatments for functional dyspepsia. Nat Rev Gastroenterol
Correcting dehydration and nutritional abnormalities and pro- Hepatol. 2013 Mar;10(3):187–94.
viding symptomatic relief are important steps in the management Moayyedi P, Lacy BE, Andrews CN, Enns RA, Howden CW, Vakil N.
of these disorders. More medications and interventions are in de- ACG and CAG clinical guideline: management of dyspepsia. Am J
velopment to target the underlying neuromuscular disturbances Gastroenterol. 2017 Jul;112(7):988–1013.
in gastroparesis. Patient education is essential to avoid aggrava- Moayyedi P, Soo S, Deeks J, Delaney B, Harris A, Innes M, et al.
tion of symptoms caused by dietary indiscretions. Eradication of helicobacter pylori for non-ulcer dyspepsia. Cochrane
Database Syst Rev. 2006 Apr 19;(2):CD002096.
Parkman HP, Jones MP. Tests of gastric neuromuscular function.
Suggested Reading Gastroenterology. 2009 May;136(5):1526–43.
Camilleri M. Enteric nervous system disorders: genetic and molecular Tack J, Talley NJ, Camilleri M, Holtmann G, Hu P, Malagelada JR,
insights for the neurogastroenterologist. Neurogastroenterol Motil. et al. Functional gastroduodenal disorders. Gastroenterology. 2006
2001 Aug;13(4):277–95. Apr;130(5):1466–79.
Questions diarrhea. He says that he takes omeprazole 40 mg orally

twice daily, but his symptoms have not improved. What is
Abbreviations used: the most likely diagnosis?
CMV, cytomegalovirus
CT, computed tomography a. Gastrinoma
EGD, esophagogastroduodenoscopy b. Crohn disease
FDA, US Food and Drug Administration c. Cryptogenic multifocal ulcerous stenosing enteritis
FSG, fasting serum gastrin d. Retained antrum syndrome
GIST, gastrointestinal stromal tumor II.3. A 62-year-old woman presents with iron deficiency anemia.
HDGC, hereditary diffuse gastric cancer Results of a colonoscopy with terminal ileal examination
NSAID, nonsteroidal anti-inflammatory drug were normal 1 month ago. She does not take aspirin or other
PET, positron emission tomography NSAIDs. Her bowel movements have been normal. For the
PPI, proton pump inhibitor past 6 months, she has had mild epigastric discomfort and oc-
ZES, Zollinger-Ellison syndrome casional reflux. What is the best next step in management?
a. Stool test for Helicobacter pylori
Multiple Choice (choose the best answer) b. EGD with gastric biopsy
II.1. Peptic ulcers result from an imbalance between processes c. Occult stool test
that damage the mucosa of the gastrointestinal tract and d. Follow-up colonoscopy
mechanisms that protect it. Which of the following is not a II.4. A 35-year-old man with HIV presents with epigastric pain and
normal defense mechanism against gastric acid? melena. He does not take aspirin or other NSAIDs. Recently
a. Surface mucous layer he declined antiretroviral therapy. EGD shows multiple ulcers
b. Inhibition of prostaglandin synthesis in the antrum and lesser curvature of the stomach. Biopsy
c. Secretion of bicarbonate findings are negative for Helicobacter pylori. What is the most
d. Epithelial cell restitution likely diagnosis?
II.2. A 75-year-old man is referred to your office for recurrent a. Epstein-Barr virus infection
abdominal pain and bleeding from anastomotic and je- b. HIV ulcers
junal ulcers. He reports that he had surgery many years c. CMV infection
ago for peptic ulcer disease, but he is unsure about the d. Gastric adenocarcinoma
type of surgery performed. Recent testing was nega- II.5. A 45-year-old woman is referred to the gastroenterology clinic
tive for Helicobacter pylori. He does not take aspirin or for epigastric pain, unintentional weight loss, and macroscopic
other NSAIDs. He does not smoke, and he does not have anemia. Upper endoscopy shows decreased folds in the body
97
and fundus of the stomach. Biopsy samples were collected, but

results are not yet available. What laboratory findings would
support the suspected diagnosis?
a. Autoantibodies to parietal cells and intrinsic factor, increased
serum gastrin level, and low vitamin B12 level
b. Autoantibodies to parietal cells and intrinsic factor, decreased
c. Autoantibodies to chief cells and intrinsic factor, increased
d. Autoantibodies to G cells and D cells, decreased serum gastrin
level, and low vitamin B12 level
II.6. A 60-year-old man underwent upper endoscopy for dyspepsia.
The antrum appeared erythematous and was biopsied. Biopsy
results were consistent with gastric intestinal metaplasia and
Helicobacter pylori infection. What is the most important
action to decrease his risk for gastric cancer?
a. Perform another upper endoscopy with gastric mapping biopsies
b. Recommend the use of proton pump inhibitor medication
indefinitely
c. Treat the H pylori infection Adapted from Ravi K, Sweetser S. Gastroenterology. 2014;146(1):33;
d. Treat the H pylori infection and test for eradication used with permission.
II.7. A 56-year-old woman presents with frank hematemesis with Which gene most likely has a sequence variation?
subsequent coffee-ground emesis. She was recently given a di-
agnosis of diffuse large B-cell lymphoma. She is hospitalized a. APC
on the gastroenterology service and found to have a large gas- b. CDH1
tric ulcer in the cardia of her stomach. Biopsy samples are c. MSH6
obtained from the edge and center of the gastric ulceration. d. STK11
She does not use aspirin or other NSAIDs. The ulceration does II.10. A 33-year-old woman who has a history of gastroesophageal reflux
not appear to be malignant. What is the most likely infectious disease treated with omeprazole presents with persistent substernal
cause of her gastric ulceration? burning discomfort for 3 months. She appears well and physical
a. Mycobacterium tuberculosis examination findings are unremarkable. Upper endoscopy shows
b. Herpes simplex virus mild erosive esophagitis and a single superficial duodenal bulb
c. CMV ulcer without stigmata of recent hemorrhage. Laboratory study
d. Mucormycosis results are normal for a complete blood cell count and chemistry
panel. The FSG level is 600 pg/mL (upper limit of the reference
II.8. A 40-year-old woman presents for upper endoscopy because range, 100 pg/mL). What is the best next step?
she has symptoms of nausea, vomiting, and heartburn that
have progressively worsened over the past 3 months. Her pri- a. Perform a secretin stimulation test
mary care physician prescribed omeprazole 40 mg daily, but b. Perform a gallium Ga 68 PET/CT scan
her symptoms have not improved. Upper endoscopy shows c. Perform endoscopic ultrasonography
nodularity and erosions in the distal gastric body and antrum. d. Recheck the FSG when she has not received PPI therapy for
You obtain biopsy samples to assess for Helicobacter pylori. 1 week
The pathologist reports that staining for H pylori is nega-
II.11. A 56-year-old man presents with dyspepsia. He appears well,
tive. The biopsy samples show noncaseating granulomatous
and abdominal examination findings are unremarkable. Upper
lesions with multinucleated giant cells. A subsequent chest ra-
endoscopy shows a 2-cm ulcerated lesion in the gastric body,
diograph shows bilateral hilar adenopathy. What is the most
which on biopsy shows monotonous sheets of small round cells
likely diagnosis?
with uniform nuclei consistent with a neuroendocrine tumor.
a. NSAID-induced gastropathy The Ki-67 index is 10%. In addition, results from biopsies of the
b. Sarcoidosis surrounding gastric mucosa are normal. Laboratory study results
c. Isolated granulomatous gastritis include a normal complete blood cell count and serum gastrin
d. Vasculitis-associated granulomas level. A gallium Ga 68 PET/CT scan shows no metastatic disease.
Endoscopic ultrasonography shows that the lesion is confined to
II.9. A 24-year-old woman presents with postprandial nausea,
the submucosa. What is the best next step in management?
vomiting, abdominal pain, and weight loss of 9.1 kg (20 lb).
Symptoms have been present for 3 months and are progres- a. Surgical resection
sive. Her father died of gastric cancer at age 39 years. On b. Endoscopic submucosal resection
examination, she appears comfortable. Physical examination c. Ablation with argon plasma coagulation
findings are remarkable for a nondistended abdomen with d. Octreotide
mild epigastric discomfort on palpation. Laboratory assessment
shows a microcytic anemia with hemoglobin level of 7 g/dL. I.12. A 25-year-old woman with no past medical history presents
Upper endoscopy shows gastric luminal narrowing and poor with a 1-week history of exertional dyspnea, melena, and ab-
distention of the stomach with air insufflation. The gastric mu- dominal discomfort. On physical examination she is a pale
cosa appears normal. Gastric biopsy was performed, and the woman with a heart rate of 119 beats/min, respiratory rate
findings are shown below: of 26 breaths/min, and blood pressure of 87/51 mm Hg with
orthostatic hypotension. Results of laboratory studies in- epigastrium that worsens 10 to 40 minutes after eating. She is
clude hemoglobin, 5.6 g/dL; serum urea nitrogen, 35 mg/dL; eating only 50% of her previous meal sizes before feeling full.
and creatinine, 1.0 mg/dL. She receives volume resuscitation, Eating more causes nausea, and rarely she has an episode of em-
transfused blood products, and a PPI. Upper endoscopy shows esis. She has not had weight loss, dysphagia, blood in her em-
a gastric submucosal mass with central ulceration and visible esis, or changes in her bowel habits. What is the best next step in
vessel, as in the image below: management?
a. Perform upper endoscopy with small-bowel aspirates
b. Test for Helicobacter pylori stool antigen
c. Perform a gastric emptying study
d. Begin empirical treatment with omeprazole twice daily
I.14. A 67-year-old man presents with nausea, vomiting, epigastric
abdominal pain, postprandial fullness, and decreased appetite.
His past medical history is notable for hypertension, hyper-
lipidemia, and type 2 diabetes. His most recent hemoglobin
A1c was 10%, and he recently received a diagnosis of periph-
eral neuropathy. EGD findings are unremarkable, and gastric
biopsies do not show evidence of Helicobacter pylori infection.
What is the best next step in diagnosis?
a. Gastric emptying study with radiolabeled high-fat liquid sup-
plement for 4 hours
b. Gastric emptying study with radiolabeled oatmeal for 2 hours
c. Gastric emptying study with radiolabeled eggs and toast for 2
hours
d. Gastric emptying study with radiolabeled eggs and toast for 4
hours
Subsequent CT imaging of the abdomen and pelvis with II.15. A 43-year-old woman with a history of systemic sclerosis for
an intravenous contrast agent shows a 4.5-cm heterogeneously the past 20 years presents for evaluation of abdominal discom-
enhancing mass arising from the gastric fundus without adja- fort, bloating, and diarrhea that started 3 months earlier and
cent lymphadenopathy, as shown in the image below: has been increasing in severity. She reports having increased
abdominal distention about an hour after eating and mild
fatigue. She has not had dysphagia or odynophagia, but she
thinks her weight has decreased about 3 kg (6.6 lb) over the
past 2 months. Her vital signs are unremarkable. Laboratory
tests show the following: hemoglobin, 11.0 g/dL; MCV, 101
fL; iron studies, unremarkable; vitamin B12, less than the
lower limit of the reference range; and folate levels, greater
than the upper limit of the reference range. What is the best
next step in diagnosis?
a. Upper endoscopy with small-bowel aspirates
b. Abdominal fat pad aspirate
c. Esophageal manometry
d. Four-hour gastric emptying study
II.16. Which of the following patients is most likely to have ad-
verse neurologic or extrapyramidal effects from use of
metoclopramide for gastroparesis?
a. A 65-year-old man with idiopathic gastroparesis who has taken
10 mg metoclopramide 3 times daily for the past month
b. A 20-year-old man with diabetic gastroparesis who has taken
10 mg metoclopramide 4 times daily for the past 4 months
c. A 45-year-old woman with postviral gastroparesis who has
taken 5 mg metoclopramide 3 times daily for the past 2 months
d. A 70-year-old woman with postsurgical gastroparesis who has
taken 5 mg metoclopramide up to once daily as needed for the
past 3 months
What is the most likely diagnosis?
a. GIST
Answers
b. Lymphoma
c. Adenocarcinoma II.1. Answer b.
d. Carcinoid Several defense mechanisms protect against gastric acid, and
II.13. A 38-year-old woman presents with a 12- month history of many of these defense mechanisms are prostaglandin dependent.
early satiation and postprandial pain occurring at least 5 times Therefore, inhibition of prostaglandin synthesis would lead to
per week. She describes the pain as a vague sensation in the mucosal damage of the gastrointestinal tract.
II.2. Answer d. II.9. Answer b.

The patient has a history of surgery for peptic ulcer disease. He This patient has diffuse gastric cancer, and gastric biopsy shows
most likely had a Billroth II operation, which is a partial gastrec- signet ring cell carcinoma. Given her young age, HDGC should
tomy. If removal of the distal antrum is inadequate, continued be considered. HDGC is an autosomal dominant, inherited gas-
exposure to the alkaline fluid from the duodenum will cause it tric cancer syndrome characterized by germline variation of the
to secrete excessive acid and promote ulcer development. A se- CDH1 gene, which encodes for the cell-to-cell adhesion protein
cretin provocation test may help to differentiate retained antrum E-cadherin. HDGC is a relatively rare cancer syndrome but may
from a gastrinoma because the serum gastrin concentration will account for approximately 1% of all cases of gastric carcinoma
increase (>120 pg/mL) in Zollinger-Ellison syndrome and remain in populations with a low incidence of gastric cancer, such as in
the same in retained antrum syndrome. the US, Canada, and the UK. Diffuse-type gastric adenocarci-
noma with signet ring cells is the most common cancer in carriers
II.3. Answer b. of germline CDH1 variations. Genetic testing for CDH1 variants
Iron deficiency anemia is an alarm sign for Helicobacter pylori is widely available. However, only 50% of families meeting di-
infection. The patient also has had a new onset of dyspeptic agnostic criteria carry a predisposing CDH1 variant. Established
symptoms at an age older than 60 years. An EGD with gastric bi- diagnostic criteria for CDH1 variant testing include any 1 of the
opsy is warranted to assess for H pylori and the cause of the iron following: 1) 2 persons with gastric cancer in a family, regardless
deficiency anemia. of their ages, with at least 1 having a confirmed diffuse gastric
II.4. Answer c. cancer; 2) diffuse gastric cancer in a person younger than 40 years;
CMV infection is the most likely diagnosis since the biopsy and 3) personal or family history (first-or second-degree relative)
findings were negative for Helicobacter pylori, and the patient is of diffuse gastric cancer and lobular breast cancer, 1 of which was
immunocompromised. CMV can infect various sites, including diagnosed when the patient was younger than 50 years. The other
the gastrointestinal tract, lungs, liver, and central nervous system. malignancy that occurs with an increased frequency in families
Biopsy samples should be obtained from the center of the ulcers with HDGC is lobular breast carcinoma. There is a high lifetime
to increase the diagnostic yield. risk for advanced gastric cancer with HDGC (approximately 70%)
by 80 years of age. The risk for advanced gastric cancer is age re-
II.5. Answer a. lated and estimated to be less than 1% at 20 years and increasing
This patient most likely has autoimmune atrophic gastritis (ie, to 4% at 30 years. Because most patients have advanced-stage
pernicious anemia), which is the most common cause of vitamin gastric carcinoma at diagnosis, prophylactic gastrectomy is
B12 deficiency. Autoantibodies to the parietal cells and intrinsic recommended in asymptomatic patients who carry the CDH1 var-
factor are characteristic of autoimmune atrophic gastritis. The iant and are older than 20 years to prevent the development of
loss of parietal cells leads to an inability to secrete hydrochloric this lethal cancer. If the patient declines prophylactic gastrectomy,
acid and a high gastric pH, which permits uninhibited gastrin re- intensive gastroscopic surveillance should be performed and the
lease. Chief cells secrete pepsin and gastric lipase, G cells secrete patient informed of the limitations with endoscopic detection of
gastrin, and D cells secrete somatostatin. early lesions in HDGC. The APC gene (variants are involved in
familial adenomatous polyposis), the MSH6 gene (variants are
II.6. Answer d. involved in Lynch syndrome), and the STK11 gene (variants are
Helicobacter pylori is a gastric carcinogen and accounts for involved in Peutz-Jeghers syndrome) can all predispose a patient
almost 90% of noncardia gastric cancers in the world. It is to gastric cancer; however, a diffuse signet ring cell carcinoma at
recommended that patients with gastric intestinal metaplasia be a young age would be highly unusual with these gene variants.
tested and treated for H pylori. Routine endoscopy surveillance is
not recommended. Use of proton pump inhibitors alone without II.10. Answer d.
eradication of H pylori infection is not a recommended strategy. This patient presents with acid peptic disease complications (ero-
II.7.Answer c. sive esophagitis and duodenal ulcer) while taking a PPI. The high
CMV is the agent for the most recognized viral infection of the FSG level increases concern for ZES. However, the use of a PPI
stomach. CMV gastrointestinal disease can occur in up to 5% of can increase the FSG level. Therefore, the next step is to recheck
patients with advanced immunosuppression. The patient’s new di- the FSG when she has not received PPI therapy for 1 week. If that
agnosis of lymphoma has resulted in her being immunocompro- result is still high, the next step would be to measure a fasting gastric
mised. Biopsy samples from the center of the ulceration aid in the pH. If the gastric pH is greater than 2, ZES is unlikely. In contrast, if
diagnosis of CMV infection; samples from the edge of the ulcera- gastric pH is 2 or less, ZES is possible and a secretin stimulation test
tion aid in making the diagnosis of herpes simplex virus infection. should be performed. Localization studies such as endoscopic ultra-
sonography or gallium Ga 68 PET/CT scan should be performed
II.8. Answer b. only after a gastrinoma has been confirmed biochemically.
Sarcoidosis is a multisystemic disease characterized by the his-
tologic presence of noncaseating granulomas. It most commonly II.11. Answer a.
affects the lungs. Gastrointestinal sarcoidosis is rare and usually This patient has a type 3 gastric carcinoid. Type 3 gastric carcinoids
asymptomatic. The most involved gastrointestinal organ is the are more common in men and are typically 2 to 5 cm. With type 3
stomach. The mainstay of treatment is glucocorticoids. NSAIDs gastric carcinoids, the surrounding gastric mucosa is normal in con-
are unlikely to cause noncaseating granulomatous inflammation, trast to type 1 gastric carcinoids (atrophic mucosa) and type 2 gastric
and isolated granulomatous gastritis and vasculitis are less likely carcinoids (hyperplastic mucosa). In addition, the fasting serum gas-
causes of this clinical scenario given the radiographic finding of bi- trin level in patients with type 3 gastric carcinoid is normal, whereas
lateral hilar adenopathy, which is highly suggestive of sarcoidosis. it is high in patients with types 1 or 2. The recommended treatment
of type 3 gastric carcinoid without evidence of distant metastases is II.15. Answer a.

surgical resection with removal of regional lymph nodes. Systemic sclerosis can be complicated by a motility disturbance
leading to intestinal pseudo-obstruction. While this is generally
II.12. Answer a. neuropathic in early disease, progressive systemic sclerosis will
The morphologic features of the tumor and presentation with lead to myopathic disease, which increases rates of small intes-
marked bleeding make GIST the most likely diagnosis. GISTs are tinal bacterial overgrowth. The best diagnostic step is to per-
the most common mesenchymal tumor of the gastrointestinal tract, form upper endoscopy and obtain duodenal aspirates to assess
with 60% of them occurring in the stomach. Patients with a GIST for the complication of small intestinal bacterial overgrowth.
may present with gastrointestinal tract bleeding, abdominal pain While amyloidosis can also cause myopathic motility distur-
or discomfort, and, rarely, signs of obstruction. More than 90% of bance and may be detected with an abdominal fat pad aspirate,
patients with GISTs have sequence variants of the c-KIT proto- this patient is known to have systemic sclerosis, which is prob-
oncogene. Surgical resection would be the treatment of choice for ably a contributing risk factor for bacterial overgrowth in this
this patient. A patient with gastric lymphoma would most likely case. Patients who have systemic sclerosis can have esophageal
present with adjacent lymphadenopathy and without a well- peristalsis disturbance and decreased lower esophageal sphincter
circumscribed lesion. In addition, adenocarcinoma is unlikely to tone. However, this patient does not have symptoms of esopha-
occur as a well-circumscribed, submucosal lesion. Carcinoids arise geal dysfunction that would require esophageal manometric eval-
in the submucosa but would not have this endoscopic appearance. uation at this time. Gastroparesis can also be a complication of
II.13. Answer b. systemic sclerosis and can lead to symptoms such as bloating and
The Rome IV criteria define functional dyspepsia as 1 or more abdominal discomfort. The patient may have gastroparesis; how-
of the following symptoms: postprandial fullness, early satiation, ever, pursuing a gastric emptying study would be lower yield as
epigastric pain, or epigastric burning over the past 3 months with small intestinal bacterial overgrowth is more likely the diagnosis
onset of symptoms occurring at least 6 months before the diag- because the patient has diarrhea, a low level of vitamin B12, and
nosis. Helicobacter pylori testing, either with stool antigen or urea a high level of folate.
breath testing, should be completed in the initial diagnostic evalu-
II.16. Answer b.
ation for patients presenting with dyspepsia. Upper endoscopy is
The FDA has given metoclopramide a boxed warning for the de-
recommended for patients older than 60 years or those with alarm
velopment of tardive dyskinesia with a high dose or long-term
features, including dysphagia, weight loss, and treatment-resistant
use. The risk of tardive dyskinesia is directly related to duration
dyspepsia. A gastric emptying study is not recommended as part
of therapy, and the FDA recommendation is that the drug be used
of the initial evaluation for dyspepsia but can be considered if
only if the duration is no longer than 12 weeks. In addition, tar-
symptoms of gastroparesis are present. An empirical trial with a
dive dyskinesia and other extrapyramidal signs are most likely
PPI is reasonable after H pylori is ruled out but should be initiated
to develop in pediatric patients, patients with diabetes, and eld-
at a standard daily dosage (not twice daily).
erly patients (especially women). When metoclopramide is used,
II.14. Answer d. the daily dose should not exceed 40 mg, and treatment duration
Gastroparesis, a known complication of poorly controlled dia- should not exceed 3 months without an interruption in admin-
betes, should be a strong consideration if a patient has consistent istration. A decreased dose should be considered for elderly
symptoms, concomitant neuropathic complications, and normal patients and for patients with decreased kidney function. Answer
findings on endoscopic evaluation. The gastric emptying study choice b is correct because of the patient’s young age, the cause
should use a solid meal because it is the most sensitive means of of the gastroparesis, the high daily dose, and the long duration of
detecting a delay in gastric emptying. Oatmeal-based meals are drug use. The patients described in the other answer choices have
semiliquid and not validated to the same extent as meals of egg and lower risk because of 1 or more of the following: shorter duration
toast, and gastric emptying should be measured for a full 4 hours. of use, lower dose, and less frequent administration.
III
Small Bowel and Nutrition

8
Clinical Features of Malabsorptive Disorders,

Small-Bowel Diseases, and Bacterial
Overgrowth Syndromes
AMY S. OXENTENKO, MD
Malabsorptive Disorders and Diarrhea sodium–glucose-linked transporter 1 (SGLT-1); oral rehydration

solutions are effective because of the inclusion of both sodium
Both malabsorption (a defect in the mucosal absorption of
and glucose in concentrations that maximize use of this transport
nutrients) and maldigestion (a defect in the hydrolysis of nutrients)
system (see below).
imply disordered physiologic mechanisms in the gastrointestinal
Carbohydrate malabsorption can be caused by either a decrease
system. Malabsorption and maldigestion of nutritional substrates
in mucosal surface area (absolute or relative) or a decrease in
can occur in multiple phases: 1) the luminal phase, in which there
disaccharidases or transport proteins. Unabsorbed carbohydrates
is contact between ingested food and various digestive enzymes;
increase the osmolality within the intestinal lumen, resulting in
2) the mucosal phase, in which substances are assimilated and
more fluid being drawn into the lumen to maintain an isosmotic
absorbed in the required constituent form; and 3) the delivery
state, which can lead to diarrhea. Colonic bacterial fermentation
phase, in which nutrients are taken up into the cytoplasm and
of these malabsorbed substances increases intestinal gas. The
transported to the lymphatics or portal venous system (Table 8.1).
most common clinical syndrome of carbohydrate malabsorption
is from lactase deficiency. Congenital lactase deficiency is pre-
Carbohydrate Malabsorption sent at birth and is rare. Primary lactase deficiency has a delayed
onset, with the highest prevalence among American Indians and
Starch, sucrose, and lactose account for nearly 85% of ingested
people from sub-Saharan Africa and Asia. A secondary, or late-
carbohydrates, with starches alone comprising 50%. For starches
onset, acquired lactase deficiency may occur after intestinal re-
to be absorbed, they first are digested by salivary α-amylase and
section, mucosal disease, or a postinfectious syndrome. Because
pancreatic α-amylase—mainly the latter—into disaccharides
lactase is present on the microvillous surface, it is often the first
and oligosaccharides of maltose, maltotriose, and α-dextrins,
disaccharidase affected by small-bowel mucosal diseases. Less
which are then hydrolyzed by brush border enzymes to form
common conditions associated with disaccharidase deficiencies
the monosaccharide glucose. Sucrose is hydrolyzed by sucrase
include sucrase-isomaltase deficiency (an inherited condition)
to form glucose and fructose, whereas lactose is hydrolyzed
and trehalase deficiency (trehalose is a sugar found in various
by lactase to form glucose and galactose. After being cleaved
mushrooms).
by the brush border disaccharidases, these monosaccharides
The clinical features of carbohydrate malabsorption in-
can be absorbed into the cytoplasm. Fructose is transported by
clude flatus, bloating, and osmotic diarrhea. Weight loss should
facilitated diffusion, but glucose and galactose are transported by
not occur with isolated carbohydrate malabsorption; if weight
loss has occurred, possible contributing conditions should be
Abbreviations: DGP, deamidated gliadin peptide; EATL, enteropathy- considered. A detailed dietary history can suggest the type of car-
associated T-cell lymphoma; EMA, endomysial antibody; Ig, immuno- bohydrate malabsorption that may be occurring. The diagnosis
globulin; PAS, periodic acid–Schiff; PCR, polymerase chain reaction; may be supported by the findings of an increased stool osmotic
SGLT-1, sodium–glucose-linked transporter 1; SIBO, small intestinal gap (>100 mOsm/kg) and stool pH less than 6 (the pH reflects the
bacterial overgrowth; tTG, tissue transglutaminase release of hydrogen and short-chain fatty acids from carbohydrate
105
106 Section III. Small Bowel and Nutrition
Table 8.1. Mechanisms of Malabsorption and Maldigestion

Defect Cause Examples
Luminal phase
Defective fat hydrolysis Decreased lipase Pancreatic insufficiency
Decreased duodenal pH Zollinger-Ellison syndrome
Impaired mixing Postgastrectomy
Defective protein Decreased proteases Pancreatic insufficiency
hydrolysis Absence of enterokinase Congenital deficiency
Impaired solubilization Decreased micelle formation Liver disease
Biliary obstruction
Ileal resection or disease
Drugs (cholestyramine)
Deconjugation of bile salts Bacterial overgrowth
Mucosal phase
Diffuse mucosal damage Diminished surface area, altered Celiac disease, tropical sprue, Crohn
absorption or secretion disease, Whipple disease, amyloidosis
Decreased brush border Congenital or acquired deficiency Lactase, trehalase, or sucrose deficiency
enzymes Small-bowel damage Postinfectious lactase deficiency
Transporter defects Single enzyme defects Hartnup disease, cystinuria
Delivery phase
Lymphatic derangement Ectasia of lymphatics Lymphangiectasis
Increased lymphatic pressure Congestive heart failure, pericardial
constriction, lymphoma, fibrosis
Data from Riley SA, Marsh MN. Maldigestion and malabsorption. In: Feldman M, Scharschmidt BF, Sleisenger MH, editors.
Sleisenger & Fordtran’s gastrointestinal and liver disease: pathophysiology, diagnosis, management. 6th ed. Vol 2. Philadelphia
(PA): Saunders; c1998. p. 1501-22.
fermentation in the colon). The mucosal enzyme activity of the reesterified, synthesized into chylomicrons, and distributed sys-
various disaccharidases can be quantified (rarely done for adult temically through the lymphatics. Although pancreatic function
patients), but this practice is invasive and not widely available. is required for fat digestion, a person may lose nearly 90% of
Hydrogen breath tests have largely replaced oral tolerance tests; lipase output from the pancreas before the efficiency of fat diges-
an increase in breath hydrogen of at least 20 ppm above baseline tion and absorption is affected. Unlike long-chain triglycerides,
during the 3-hour study is indicative of colonic fermentation of which require bile salts and micelle production for absorption,
the nonabsorbed carbohydrate by bacteria. False-positive results medium-chain triglycerides do not require micelle formation for
(small intestinal bacterial overgrowth [SIBO] or inadequate die- absorption and can be absorbed directly into the portal blood.
tary instructions) and false-negative results (recent treatment with This mechanism can be used to provide triglycerides in the diet
antibiotics or nonhydrogen producers) can occur with breath without worsening fat malabsorption in patients with bile salt
testing. Tolerance to lactose-containing products can be improved deficiency, such as patients who have had more than 100 cm of
if they are ingested with other foods, especially in amounts less distal small bowel resected.
than 15 g (equivalent to about 300 mL of milk). The clinical features of fat malabsorption include diarrhea,
weight loss, and complications from deficiencies of fat-soluble
✓ Carbohydrates need to be broken down to monosaccharides to vitamins (vitamins A, D, E, and K). Although the amount of fat
allow for absorption in the stool can be assessed qualitatively with Sudan staining,
✓ Lactase deficiency— the most common cause of carbohydrate this test has relatively low sensitivity and specificity. The test
malabsorption for fecal elastase is an indirect method for evaluation of pan-
creatic function; sensitivity increases according to the severity
of the pancreatic insufficiency, and the specificity exceeds 90%.
Quantification of fecal fat excretion is considered the gold
Fat Malabsorption standard for establishing the presence of fat malabsorption. The
Fat malabsorption is a complex process that requires adequate normal value for fecal fat excretion is less than 7 g daily, and
function of the pancreas, liver and biliary system, small-bowel levels of 7 to 14 g may be present when patients have chronic di-
mucosa, and lymphatic system. Triglycerides constitute the ma- arrhea without true fat malabsorption. A 72-hour stool collection
jority of dietary fat. Initial lipolytic activity begins in the stomach is optimal; the patient should receive a diet containing 100 g
through the action of gastric lipase, although this contributes of fat daily for several days before stool collection commences
little to digestion in most people, whereas pancreatic lipase has and continue to receive the high-fat diet throughout the stool
a much larger role in hydrolyzing dietary triglycerides. Because collection process. The patient should be instructed to avoid
the optimal activity of pancreatic lipase occurs at a pH of 8, it antidiarrheal agents or pancreatic enzyme replacement imme-
is inactivated in acid overproduction states (eg, Zollinger-Ellison diately before and during the stool collection so that the stool
syndrome and mastocytosis). Pancreatic lipase hydrolyzes die- volume and fat will be accurately reflected.
tary triglycerides into free fatty acids and β-monoglycerol. These Once fat malabsorption has been confirmed, the cause should
constituents then combine with conjugated bile salts from the be determined. In some cases, the cause may be apparent clini-
liver to form water-soluble micelles, which allow passage into cally. The most common clinical conditions result from small-
enterocytes. At the level of the enterocyte, triglycerides are bowel diseases or pancreatic insufficiency. Evaluation for
8. Malabsorptive Disorders, Small-Bowel Diseases, and Bacterial Overgrowth 107
small-bowel abnormalities that can lead to fat malabsorption

could include small-bowel biopsies (eg, celiac disease or am- Box 8.1. Causes of Protein-Losing Enteropathies
yloid), small-bowel cultures (eg, SIBO), and small-bowel im- Nonerosive disease
aging (eg, Crohn disease or radiation enteritis). To evaluate for
Ménétrier disease
pancreatic causes of fat malabsorption, imaging (computed to-
mography, magnetic resonance cholangiopancreatography, or en- Helicobacter pylori gastritis
doscopic ultrasonography) can be used to examine for changes Eosinophilic gastroenteritis
from chronic pancreatitis. Pancreatic calcifications seen on plain Celiac disease
films can be helpful, but they are present infrequently. Tests Small intestinal bacterial overgrowth
of pancreatic function, which are not widely available, can be Whipple disease
performed with secretin (to measure bicarbonate) and cholecys-
Vasculitides
tokinin (to measure lipase or trypsin). Alternatively, an empirical
trial of pancreatic enzymes can be recommended, with fecal fat Erosive disease
quantification before and after the trial to assess objectively for Amyloidosis
improvement. Inflammatory bowel disease
Graft-vs-host disease
✓ Up to 90% of lipase output from the pancreas (from resection or
insufficiency) may be lost before fat digestion and absorption is Clostridioides difficile colitis
affected Ischemia
✓ Pancreatic lipase function is inhibited by acid hyperproduction
Increased lymphatic pressure
states
✓ Long-chain triglycerides require bile salts and micelles for ab- Congestive heart failure
sorption; medium-chain triglycerides do not require micelles, so Constrictive pericarditis
patients with bile salt deficiency can receive dietary triglycerides Lymphangiectasia (primary vs acquired)
without worsening fat malabsorption
Lymphatic obstruction (lymphoma)
Mesenteric venous thrombosis
Protein Malabsorption Retroperitoneal fibrosis
Protein digestion and absorption require adequate pancreatic

function as well as integrity of the intestinal mucosa. Ingested Adapted from Greenwald DA. Protein-losing gastroenteropathy. In:
Feldman M, Friedman LS, Brandt LJ, editors. Sleisenger & Fordtran’s
proteins are cleaved initially by pepsin (an endopeptidase), which gastrointestinal and liver disease: pathophysiology, diagnosis, manage-
is produced from the precursor pepsinogen in response to a gas- ment. 9th ed. Vol 1. Philadelphia (PA): Saunders/Elsevier; c2010.
tric pH of 1 to 3, with inactivation at a pH greater than 5. When p. 437-43; used with permission.
gastric chyme reaches the small intestine, enterokinase from
duodenal enterocytes activates trypsin. Trypsin then converts
pancreatic proteases from inactive to active forms in a cascade
fashion, subsequently cleaving proteins into various amino a protein- losing enteropathy, an α1- antitrypsin clearance test
acids and small peptides. Additional mucosal brush border should be performed. α1-Antitrypsin is unique in that it is nei-
oligopeptidases further cleave small peptides, with free amino ther absorbed nor secreted from the intestinal mucosa, and unlike
acids and oligopeptides crossing into the cytoplasm either freely other proteins, it is resistant to proteolysis (with the exception
or through carrier-mediated channels, some of which are sodium- of pepsin). Therefore, its clearance reflects a true protein-losing
mediated channels. state. If a protein-losing gastropathy is suspected (eg, Ménétrier
In addition to disorders that affect protein digestion and ab- disease), the patient should receive acid-suppressive therapy be-
sorption, considerable amounts of protein can be lost from the fore an α1-antitrypsin clearance test is performed. This sequence
intestinal tract; these conditions are referred to as protein-losing avoids degradation of α1-antitrypsin by pepsin, since the elevated
enteropathies. Although the liver can respond to protein loss by pH from acid suppression will inactivate pepsin and hence allow
increasing the production of various proteins such as albumin, a adequate assessment of gastric loss.
protein-losing state develops when net loss exceeds net produc- ✓ Protein malabsorption rarely occurs in isolation
tion. Three major categories of gastrointestinal-related disorders ✓ The α1-antitrypsin clearance test is used to assess for protein-losing
are associated with excess protein loss: 1) diseases with increased enteropathy
mucosal permeability without erosions, 2) diseases with mucosal
erosions, and 3) diseases with increased lymphatic pressure.
Examples of clinical conditions in each of these categories are
listed in Box 8.1. Diarrhea
The clinical features of a protein- losing enteropathy may The mechanism for diarrhea is often from a combination of
include diarrhea, edema, or ascites. Because isolated pro- decreased absorption (a villous function) and increased secretion
tein malabsorption or loss is infrequent, features of concomi- (a crypt function). Diarrhea can be categorized as inflammatory
tant carbohydrate and fat malabsorption may also be apparent. or noninflammatory or as secretory or osmotic.
Laboratory studies may show a low serum level of protein, al- The clinical features of inflammatory diarrhea may include ab-
bumin, and immunoglobulins, except for immunoglobulin dominal pain, fever, and tenesmus. Stools may be mucoid, bloody,
(Ig) E, which has a short half-life and rapid synthesis. If the smaller volume, and more frequent, unless the small bowel also
protein-losing state is from lymphangiectasia (primary or ac- is affected. Microscopically, the stools can contain blood and
quired), patients may also have lymphocytopenia. To diagnose leukocytes. However, if the inflammation is microscopic, these
clinical and stool features may be absent (eg, microscopic co- Table 8.2. Comparison of Osmotic and Secretory Diarrhea
litis). Common causes of inflammatory diarrhea include invasive
Osmotic diarrhea Secretory diarrhea
infections, inflammatory bowel disease, radiation enteropathy,
and ischemia. Characteristics
Noninflammatory causes of diarrhea tend to produce watery Daily stool volume <1 L Daily stool volume >1 L
Stops with fasting Continues with fasting
diarrhea, without fever or gross blood, and the stool appears
Stool osmotic gap >100 mOsm/kg Stool osmotic gap <50 mOsm/kg
normal on microscopy. There are many causes, but infections,
particularly by toxin-producing organisms, are a common cause Common causes
Disaccharidase deficiency Infections and toxins
of acute, self-limited diarrhea. Lactase Cholera
Distinguishing whether diarrhea is osmotic or secretory can Trehalase Bile acids
be useful clinically in order to narrow the differential diagnosis. Sucrase-isomaltase Microscopic colitis
Osmotic diarrhea is due to the ingestion of poorly absorbed Iatrogenic Neuroendocrine tumors
cations, anions, sugars, or sugar alcohols (such as sorbitol or Polyethylene glycol solution Medullary carcinoma of thyroid
xylitol). These ingested ions obligate retention of water in the Lactulose (calcitonin)
Magnesium antacids or VIPoma
intestinal lumen to maintain osmolality equal to that of other supplementation Gastrin (not pure secretory)
body fluids (290 mOsm/kg); this subsequently causes diarrhea. Sweeteners and elixirs Carcinoid syndrome
Osmotic diarrhea can occur also from maldigestion or malab- Sorbitol Laxatives (nonosmotic)
sorption (pancreatic insufficiency or disaccharidase deficiency). Xylitol Diabetic diarrhea
The stool osmotic gap is calculated by adding the stool sodium Fructose Transporter defects or deficiencies
and potassium concentrations, multiplying by 2, and subtracting Chloridorrhea
Idiopathic
this amount from 290 mOsm/kg. A gap greater than 100 mOsm/
kg strongly supports an osmotic cause for the diarrhea, whereas Testing strategies
a gap less than 50 mOsm/kg supports a secretory cause. Stool Dietary review Stool cultures
Carbohydrate malabsorption Structural or mucosal evaluation
osmolality does not necessarily need to be measured because Breath testing Neuroendocrine hormone levels
the value should be the same as that of the serum (290 mOsm/ Stool pH <6 Bile acid sequestrant trial
kg), with lower values indicating urine or water contamination Avoidance
and higher values indicating that the specimen was not processed Stool magnesium
readily. The utility of checking stool osmolality therefore lies in
determining whether the stool specimen was processed properly.
Stool volumes tend to be less with osmotic diarrhea than with Intestinal Resections and Shortened Bowel
secretory diarrhea, and diarrhea due to an osmotic cause tends to
Diarrhea and malabsorption can result from any process that
abate with fasting.
shortens the length of the functioning small bowel, whether from
When secretory diarrhea occurs, the primary bowel function
surgery or from relative shortening due to underlying disease.
converts from net absorption to net secretion. Normally, up to
Whether diarrhea and malabsorption occur with a shortened
9 to 10 L of intestinal fluid crosses the ligament of Treitz each
small bowel depends on several factors: the length of the resected
day, and all but 1.5 L crosses the ileocecal valve, demonstrating
bowel, the location of the resected bowel, the integrity of the re-
the tremendous absorptive capacity of the small bowel. The
maining bowel, and the presence of the colon.
colon then absorbs all but 100 to 200 mL of the fluid, which is
The length and location of the resected small bowel affect the
evacuated as stool. In secretory diarrhea, net absorption converts
enterohepatic circulation of bile. Typically, bile salts are reabsorbed
to net secretion, and the small bowel loses its normal capacity
from the terminal ileum. If less than 100 cm of distal ileum is
to absorb the large volume of fluid; thus, liters of fluid pass into
resected, the liver can compensate for the loss of absorptive ca-
the colon daily. Although the colon can adapt and absorb nearly
pacity by producing an increased amount of bile salts, which enter
4 L of liquid from the stool each day, larger fluid loads cannot
the colon and cause a bile-irritant secretory diarrhea. This diarrhea
be absorbed, and this results in diarrhea (often liters per day).
is treated with a bile acid sequestrant, such as cholestyramine,
Secretory diarrhea does not abate with fasting. Dehydration
which binds the excess bile salts and improves diarrhea. If more
can occur easily, and replacement fluids need to contain ade-
than 100 cm of distal small bowel is resected, including the terminal
quate concentrations of both sodium and glucose, as in oral re-
ileum, the liver can no longer compensate for the loss of absorp-
hydration solutions, to maximize small- bowel absorption of
tive capacity. The resulting bile salt deficiency leads to steatorrhea
sodium and water. Consuming beverages that have low sodium
since micelle production is negatively affected and long-chain
concentrations (water, some sports drinks, or juices) may worsen
triglycerides cannot be effectively handled. This can be managed
the volume status of the patient because sodium will be secreted
by prescribing a diet that consists of medium-chain triglycerides,
into the bowel lumen to maintain an isosmotic state, and the
which do not require bile salts or micelle formation for absorption
volume of water eliminated will increase because of the stool so-
because they are absorbed directly into the portal blood.
dium loss. Sodium and glucose absorption from the small bowel
The location of the small-bowel resection is also important.
occurs through the transporter SGLT-1. Characteristics, common
The terminal ileum has the specialized function of absorbing and
causes, and testing strategies for secretory and osmotic diarrhea
recirculating bile salts and binding the cobalamin-intrinsic factor
are listed in Table 8.2.
complex. When the jejunum is resected, the ileum assumes all
the functions of the jejunum. However, the opposite is not true;
✓ Osmotic diarrhea—volume is usually smaller, stops with fasting,
the jejunum cannot compensate for the loss of the specialized
and leads to a stool osmotic gap greater than 100 mOsm/kg
✓ Secretory diarrhea— volume is usually larger, continues with
functions of the ileum.
fasting, and leads to a stool osmotic gap less than 50 mOsm/kg Outcomes of ileal resection include diarrhea (from either an
excess of bile salts or a deficiency of bile salts, depending on the
length resected), vitamin B12 deficiency, SIBO (from resection The diagnosis of celiac disease can be facilitated with the
of the ileocecal valve), gallstones (from disruption of the cho- following: 1) the presence of a clinical feature or features com-
lesterol pool), and calcium oxalate kidney stones. Normally, in patible with the disease, although they are not always present;
the small bowel, calcium binds to oxalate, with this calcium ox- 2) supportive, highly sensitive and specific serology; 3) charac-
alate complex passing into the colon and being excreted in stool. teristic small-bowel biopsy findings; and 4) a clinical response to
If the small bowel has been shortened and the colon is absent, a gluten-free diet. The diagnosis no longer requires rechallenging
calcium preferentially binds to fatty acids in the stool, leaving the patient with gluten to invoke symptoms because of the risk
oxalate unbound. Unbound oxalate is incorporated into the stool for highly sensitive patients. Before patients are tested for ce-
and excreted through the ostomy. In the case of a shortened small liac disease, they need to be eating a gluten-containing diet.
bowel and intact colon, calcium again binds to the fatty acids, and While diagnostic changes may be seen as early as 2 weeks after
the free or unbound oxalate is absorbed from the colon, leading reintroducing gluten as part of a gluten challenge, a 6-to 8-week
to the formation of calcium oxalate kidney stones. Although the challenge, with the consumption of 3 to 5 g of gluten daily, may
absolute length of resected small bowel is important, the integ- lead to definitive results. Patients with classic celiac disease have
rity of the remaining bowel is crucial because diffuse pathologic features of malabsorption, whereas those with nonclassical ce-
processes such as Crohn disease or radiation enteritis can result liac disease tend to have extraintestinal manifestations. These
in a functionally shortened bowel without surgical resection. nonclassical (previously referred to as “atypical”) forms of celiac
Whether a patient has an intact colon is of considerable impor- disease are now the most common clinical presentations of the
tance if there has been prior small-bowel resection. The colon can disease. The gastrointestinal and extraintestinal manifestations of
adapt by increasing water and sodium absorption, by acting as an celiac disease are outlined in Table 8.3. The many diseases asso-
intestinal “brake” to slow motility, and by salvaging nonabsorbed ciated with celiac disease are listed in Table 8.4.
carbohydrates to provide additional calories for patients with The available serologic tests for celiac disease measure levels
short bowel syndrome. Patients who still have an intact colon of 1) antigliadin antibodies, 2) endomysial antibodies (EMAs),
may not need parenteral nutrition if they have 50 to 100 cm of 3) tissue transglutaminase (tTG) antibodies, and 4) deamidated
small bowel remaining. However, patients who no longer have a gliadin peptides (DGPs). The IgA-based tTG antibody test is
colon may need parenteral nutrition when the length of the small considered the single best screening test for celiac disease in
bowel is less than 150 to 180 cm. patients older than 2 years and has a sensitivity of about 95%
In short bowel syndrome, multiple mechanisms contribute to and a specificity greater than 95%. The original antigliadin anti-
malabsorption. In the early postoperative stage, hypersecretion body test had less sensitivity and specificity than other serologic
of gastric acid inactivates pancreatic enzymes, leading to diar- markers and should be avoided in practice. EMA testing may be
rhea and steatorrhea. Until the remaining small bowel has time more expensive and subjective than tTG antibody testing. A serum
to adapt, intestinal transit is rapid because of the loss of surface IgA level is often determined with the initial IgA tTG antibody
area. As mentioned above, patients may be at risk for SIBO, testing because IgA deficiency affects 2% to 3% of patients with
and because of the disruption of the enterohepatic circulation celiac disease. If patients are found to have or are known to have
of bile, bile acid excess (shorter resection) or deficiency asso- IgA deficiency, an IgG-based test (IgG tTG antibody or IgG DGP
ciated with steatorrhea (longer resection) may develop. Early antibody) should be performed. In children younger than 2 years,
management of short bowel syndrome includes aggressive EMA and tTG antibody testing may be less sensitive, so a com-
treatment with antidiarrheal agents, total parenteral nutrition, bination of both tTG and DGP antibody testing is recommended
and gastric acid suppression. Later management includes the in this age group. Panel testing (ie, checking >1 serology in adult
introduction of a low-fat enteral diet, with progressive increase patients) is not recommended to screen for celiac disease because
in carbohydrates, medium-chain triglyceride supplementation it will increase the sensitivity but decrease the specificity.
as needed, lactose restriction, and treatment of SIBO if present Serologic tests for celiac disease should be considered for
or suspected. 1) patients with classic gastrointestinal manifestations of the di-
sease, 2) patients with well-described nonclassic manifestations,
✓ Small- bowel resection shorter than 100 cm tends to lead to 3) at-risk groups, and 4) patients who are being followed for their
bile acid–induced diarrhea, which can improve with a bile acid response to a gluten-free diet. For symptomatic patients, however,
sequestrant biopsies of the small bowel are needed regardless of the results
✓ Small-bowel resection longer than 100 cm leads to bile acid defi-
of serologic testing. Also, any positive serologic results need
ciency and steatorrhea, which can improve with an emphasis on
the use of a medium-chain triglyceride diet to be confirmed with small-bowel biopsies. Recent guidelines
support that the diagnosis of celiac disease can be made in chil-
dren without small-bowel biopsies if the children have permissive
celiac haplotyping and a tTG antibody level 10 times the upper
Small-Bowel Diseases limit of normal (confirmed with EMA testing); however, it is still
recommended that all adults have histologic assessment to ensure
Celiac Disease baseline confirmation of the disease.
Celiac disease may occur in genetically susceptible persons Endoscopic findings in celiac disease include loss of mu-
(those with HLA-DQ2 or HLA-DQ8 positivity) as an immune re- cosal folds, a mosaic pattern, scalloping, and nodularity. The
sponse to gliadins in the diet. The prevalence is highest among sensitivity of these endoscopic markers is quite poor; however,
persons of European descent, and the disease is being diagnosed if the markers are seen, small-bowel biopsy specimens should
with greater frequency in North America as clinicians become be obtained regardless of the indication for upper endoscopy
more familiar with the many manifestations of the disease. In the because of the high likelihood of demonstrating an enteropathy
general population, the prevalence of celiac disease is nearing 1 from celiac disease or a similar process. Small-bowel biopsies
in 100 (0.7%-1.0%). Celiac disease occurs in patients of all ages, are required for the diagnosis of celiac disease and should be
but as many as 20% are older than 60 years at diagnosis. performed in all patients before treatment is initiated. The classic
Table 8.3. Manifestations of Celiac Disease

Manifestation Clinical features Details
Gastrointestinal Diarrhea, steatorrhea
Flatulence, distention
Weight loss, anorexia
Abdominal pain
Nausea, vomiting
Constipation
Aphthous stomatitis
Angular cheilosis
Extraintestinal
Laboratory findings Anemia Deficiencies of iron, vitamin B12, folate (may be normocytic,
dimorphic with >1 deficiency)
Vitamin and mineral deficiencies Examples: vitamin D, vitamin B12, iron, zinc, copper
Abnormal liver biochemistry values Evaluate for AIH, PBC, PSC
Skin Dermatitis herpetiformis Pruritic, papulovesicular, on extensor surfaces
Hematologic Splenic atrophy Functional, predisposed to encapsulated organisms
Musculoskeletal Osteopenia, osteoporosis Calcium or vitamin D loss or lactose avoidance
Osteomalacia Vitamin D deficiency, increased bone alkaline phosphatase level
Enamel defects Similar to Sjögren syndrome
Arthropathy Nonerosive, polyarticular, symmetrical, large joint
Muscle cramps, tetany From low levels of calcium, vitamin D, or magnesium
Neurologic Peripheral neuropathy Symmetrical, distal, small-fiber most common
Ataxia Cerebellar
Epilepsy Bilateral parieto-occipital calcifications
Reproductive Infertility Female or male
Recurrent miscarriage
Psychiatric Depression, anxiety One-third of celiac patients
Abbreviations: AIH, autoimmune hepatitis; PBC, primary biliary cholangitis; PSC, primary sclerosing cholangitis.
Data from Farrell RJ, Kelly CP. Diagnosis of celiac sprue. Am J Gastroenterol. 2001 Dec;96(12):3237-46.
histologic findings include villous atrophy (total or partial), crypt late Marsh lesions. An increase in the number of intraepithelial
hyperplasia, intraepithelial lymphocytosis (≥25 intraepithelial lymphocytes is the minimal histologic lesion needed for the di-
lymphocytes per 100 surface enterocytes), and chronic inflamma- agnosis of celiac disease; villous atrophy alone is not sufficient
tory cell infiltrate in the lamina propria (Figure 8.1). The spectrum for diagnosis because it is a nonspecific finding. Other conditions
of histologic findings in celiac disease is indicated by the modi- that may show either isolated intraepithelial lymphocytosis or
fied Marsh (Oberhuber) classification (Figure 8.2). Early Marsh villous flattening in small-bowel biopsy specimens are listed in
lesions are more likely to produce fewer or no symptoms than Box 8.2. These should be considered, especially if the results of
serologic studies are negative.
Approximately 95% of patients with celiac disease are posi-
tive for HLA-DQ2, and the other 5% are positive for HLA-DQ8.
Table 8.4. Disorders Associated With Celiac Disease However, 30% to 40% of the general population is also posi-
Type of disorder Disorder tive for HLA-DQ2 or HLA-DQ8. Therefore, the presence of 1 of
these permissive genes is necessary but not sufficient for the di-
Endocrine Type 1 diabetes agnosis of celiac disease. HLA testing is not necessary for most
Autoimmune thyroiditis
patients being evaluated for celiac disease; however, the nega-
Adrenal insufficiency
Connective tissue disorders Sjögren syndrome
tive predictive value of nearly 100% can be useful in evaluating
Rheumatoid arthritis 1) patients who have early Marsh lesions, 2) patients who have
Systemic lupus erythematosus negative serologic results but typical small- bowel histology,
Immunologic IgA deficiency 3) patients who already have been prescribed a gluten-free diet
Inflammatory conditions Inflammatory bowel disease and are unwilling to reintroduce gluten in the diet, or 4) at-risk
Microscopic colitis patients (eg, patients with Down syndrome) for whom reporting
Hepatic AIH, PSC, PBC symptoms may be difficult.
Neurologic Epilepsy
Kidney IgA mesangial nephropathy
The only therapy for celiac disease is a lifelong gluten-free
Cardiopulmonary Carditis diet, which includes the avoidance of wheat, barley, and rye.
Fibrosing alveolitis Food items that contain oats can be tolerated by most patients
Pulmonary hemosiderosis with the disease, but cross- contamination or hypersensitivity
Other Down syndrome, Turner syndrome may limit oat tolerability. Oats are generally avoided for the first
year after diagnosis in severely symptomatic patients and then
Abbreviations: AIH, autoimmune hepatitis; Ig, immunoglobulin; PBC, primary
biliary cholangitis; PSC, primary sclerosing cholangitis. reintroduced if the patient is doing well clinically. Consultation
with a skilled dietician is imperative for patients with celiac di-
Data from Farrell RJ, Kelly CP. Diagnosis of celiac sprue. Am J Gastroenterol. sease. Determining baseline vitamin and mineral levels and
2001 Dec;96(12):3237-46.
providing replacement therapy when needed is recommended.
In adults, consideration should be given for bone densitometry.

Since patients are at risk for functional asplenia, vaccinations
against the encapsulated organisms should be considered. First-
degree relatives should be advised to be screened for celiac di-
sease, often with an IgA tTG antibody test.
Dermatitis herpetiformis is an intensely pruritic papulo
vesicular rash, typically on the extensor surfaces, that represents
an intestinal sensitivity to gliadins in the diet. Biopsy specimens
from the skin adjacent to the affected area may show granular
IgA deposits in the papillary dermis; these deposits are pathog-
nomonic for dermatitis herpetiformis (Figure 8.3). Therapy
for dermatitis herpetiformis, as for celiac disease, is a lifelong
gluten-free diet. Dapsone may help with healing the skin, but it
does not heal the intestinal abnormality.
For patients with celiac disease in whom initial therapy fails
or symptoms recur after early clinical improvement, several
questions should be answered. First, was the initial diagnosis
of celiac disease correct? Results of the original small-bowel
biopsies and serologic studies should be reviewed. Second, has
there been inadvertent or surreptitious ingestion of gluten? The
ingestion of gluten is the most likely cause of ongoing or recur-
ring symptoms in a patient with celiac disease; thus, the patient’s
diet and medications should be reviewed. Also, patients with ce-
liac disease are at risk for other conditions that can cause diar-
rhea, and these should be considered: microscopic colitis, SIBO,
pancreatic insufficiency, lactase deficiency, fructose malabsorp-
tion, inflammatory bowel disease, and irritable bowel syndrome.
Celiac-specific complications also need to be considered, in-
cluding ulcerative jejunitis, refractory sprue, and malignancy.
Patients with refractory celiac disease type 1 (without clonality)
or type 2 (with clonality) can be initially treated with open-
capsule budesonide with good clinical and histologic responses.
Patients with celiac disease are at increased risk for a rare
enteropathy-associated T-cell lymphoma (EATL), which may be
manifested as a recurrence of symptoms. EATL is associated with
poor survival. Compliance with a gluten-free diet can decrease
the risk of EATL considerably. Patients with celiac disease are at
increased risk for other malignancies, including other forms of
non-Hodgkin lymphoma, small-bowel adenocarcinoma, and oro-
pharyngeal and esophageal cancers.
✓ Iron deficiency anemia—the most common nonclassical feature

of celiac disease
✓ Immunoglobulin A tissue transglutaminase antibody test—the
serology of choice to screen for celiac disease
✓ The presence of either HLA-DQ2 or HLA-DQ8 is necessary for
the diagnosis of celiac disease; their absence has nearly 100%
negative predictive value in ruling out the disease
✓ Most common cause of nonresponsive celiac disease—gluten
ingestion
✓ Several entities can mimic celiac disease, including medications
such as olmesartan
Whipple Disease
Whipple disease is a multisystem disorder caused by the gram-
positive bacillus Tropheryma whipplei. This disease usually occurs
in White men in the fourth or fifth decade of life. The clinical
features include diarrhea, weight loss, adenopathy, arthralgias,
Figure 8.1. Small-Bowel Histopathologic Findings in Celiac Disease.A,
fevers, carditis, hyperpigmentation, pleural effusions, and ocular
Normal findings (hematoxylin-eosin). B, Intraepithelial lymphocytes alone and neurologic symptoms. The diagnosis can be established with
as seen in an early Marsh lesion of celiac disease (hematoxylin-eosin). C, a combination of small-bowel biopsy studies and the polymerase
Classic histologic findings of celiac disease, with marked villous atrophy, chain reaction (PCR). Small-bowel biopsy specimens typically con-
crypt hyperplasia, and intraepithelial lymphocytosis, with a chronic inflam- tain periodic acid– Schiff (PAS)-positive macrophages (Figure
matory cell infiltrate in the lamina propria (hematoxylin-eosin). 8.4). T whipplei needs to be differentiated from Mycobacterium
Figure 8.2. Marsh Classification of the Spectrum of Histologic Findings in Celiac Disease. IEL indicates intraepithelial lymphocyte. (Adapted
from Rostom A, Murray JA, Kagnoff MF. American Gastroenterological Association [AGA] Institute technical review on the diagnosis and manage-
ment of celiac disease. Gastroenterology. 2006 Dec;131[6]‌:1981-2002; used with permission.)
avium-intracellulare complex, which, in addition to being PAS- ✓ Whipple disease is a multisystem disorder that typically occurs
positive, is also acid- fast–
positive. Electron microscopy can in White men in the fourth or fifth decade of life and can be
be used to show sickle-shaped T whipplei bacteria with their diagnosed through polymerase chain reaction testing
trilaminar cell wall. If the biopsy specimens are PAS-positive and ✓ Treatment of Whipple disease includes intravenous antibiotics in-
PCR is positive, the diagnosis is established. A testing algorithm itially and then prolonged use of oral antibiotics
is provided in Figure 8.5.
Treatment of Whipple disease includes long-term adminis-
tration of antibiotics that penetrate the blood-brain barrier. In
a randomized controlled study, 14 days of intravenous therapy Tropical Sprue
with either ceftriaxone or meropenem, followed by 1 year of oral Features of tropical sprue may be indistinguishable from those
trimethoprim-sulfamethoxazole, was curative. Therapies that have of classic celiac disease: diarrhea, weight loss, anorexia, and
had variable success include doxycycline, hydroxychloroquine, lactose intolerance. Tropical sprue needs to be considered if the
and interferon-based regimens. patient has traveled to certain geographic areas, such as Asia,
India, the Caribbean, and Central or South America. In patients
with acute tropical sprue, the onset of clinical features is rapid
Box 8.2. Causes of Small-Bowel Biopsy Findings That
and is independent of the length of stay in a tropical area.
May Mimic Celiac Disease
By comparison, in patients with chronic tropical sprue, clin-
Small intestinal bacterial overgrowth ical features occur gradually after several years of residence
Nonsteroidal anti-inflammatory drugs in a tropical area. Physical examination may show evidence
Helicobacter pylori infection of weight loss or cachexia, glossitis, and hyperactive bowel
Giardiasis sounds. Laboratory features can indicate megaloblastic anemia
Crohn disease with vitamin B12 and folate deficiencies and a protein-losing
state. No specific test helps establish the diagnosis, and other
Viral gastroenteritis
infectious disorders need to be ruled out. Small-bowel biopsy
Autoimmune enteropathy specimens may show villous atrophy similar to what is found in
Eosinophilic gastroenteritis celiac disease; therefore, for all patients with newly diagnosed
Combined variable immunodeficiency celiac disease, the travel history must be documented, espe-
Tropical sprue cially if the serologic test results are negative. Treatment with
folate, 5 mg daily, and vitamin B12 replacement produces rapid
Lymphoma
improvement in the anemia, glossitis, and weight loss in many
Zollinger-Ellison syndrome patients with tropical sprue. In addition, antibiotic therapy with
Hypersensitivity to nongluten protein tetracycline, 250 mg 4 times daily, may be needed in combina-
Medications (olmesartan) tion with folate for 3 to 6 months, especially to treat the chronic
form of the disease.
Figure 8.3. Dermatitis Herpetiformis. A, Pruritic papulovesicular Figure 8.4. Histopathologic Features of Whipple Disease. A, The
rash on the extensor surface of the skin. (Adapted from Bennett ML, villi are widened (hematoxylin-eosin). B, The villi are filled with foamy
Jorizzo JL, Sherertz EF. Skin lesions associated with gastrointestinal macrophages that are periodic acid-Schiff–positive.
and liver diseases. In: Yamada T, editor. Textbook of gastroenterology.
4th ed. Vol 1. Philadelphia [PA]: Lippincott Williams & Wilkins; c2003.
p. 992-1009; used with permission.)
serum eosinophil count in patients with serosal disease. However,
B, Immunofluorescence of biopsy specimen showing the characteristic a normal serum eosinophil count does not exclude eosinophilic
immunoglobulin A deposits in the papillary dermis. (Courtesy of Dr
gastroenteritis. With the mucosal form of the disease, the diag-
Kristin M. Leiferman, Immunodermatology Laboratory, University of
Utah; used with permission.) nosis is established with intestinal biopsy specimens that show
more than 20 to 25 eosinophils per high-power field. With mus-
cular or serosal involvement, full-thickness biopsy may be re-
quired. Eosinophilia found on ascitic fluid analysis also can be
✓ Tropical sprue may be indistinguishable from celiac disease clin-
suggestive. Parasitic infections need to be ruled out before eo-
ically and histologically, but patients with tropical sprue are sero-
logically negative
sinophilic gastroenteritis is diagnosed. Also, eosinophilic gas-
✓ Treatment of tropical sprue includes folate, vitamin B12, and pro- troenteritis needs to be differentiated from hypereosinophilic
longed use of antibiotics syndrome, which is characterized by a serum eosinophil count
greater than 1.5×109/L for more than 6 months and multiorgan
involvement.
An elimination diet may be incorporated in the treatment
Eosinophilic Gastroenteritis program for eosinophilic gastroenteritis, although it has a lim-
Eosinophilic gastroenteritis has various clinical manifestations ited role. Prednisone, 20 to 40 mg orally daily, often produces
depending on the location of bowel involvement. With mucosal a prompt clinical response, regardless of the layer of bowel
disease, patients often have diarrhea, malabsorption, and evidence involved. Treatment with mast cell stabilizers, such as so-
of a protein-losing enteropathy. Involvement of the muscularis dium cromoglycate, and leukotriene receptor antagonists,
layer may lead to features of bowel obstruction, whereas serosal such as montelukast, has had variable success. Open-capsule
involvement may lead to ascites and peritonitis. budesonide can be given in place of prednisone to patients who
Laboratory studies typically show an increased serum level require ongoing maintenance therapy. The monoclonal antibody
of IgE and peripheral eosinophilia, with a greater increase in the omalizumab has also been used.
Figure 8.5 Strategy for Diagnosing Whipple Disease With Use of Periodic Acid-Schiff (PAS) Staining and Polymerase Chain Reaction
(PCR) Assay. (Adapted from Fenollar F, Puechal X, Raoult D. Whipple’s disease. N Engl J Med. 2007 Jan 4;356[1]‌:55-66; used with permission.)
✓ Eosinophilic gastroenteritis—clinical manifestations vary depending

Patients present with pronounced edema, diarrhea, nausea, and
on whether involvement is mucosal, muscular, or serosal vomiting; also, chylothorax and chylous ascites may be present.
✓ Eosinophilic gastroenteritis—parasitic infection must be ruled out
Steatorrhea may be concurrent with a protein-losing enterop-
athy. Laboratory findings include a decrease in the plasma level
of proteins and lymphocytopenia, which may affect cellular im-
munity. Endoscopically, punctate white dots may be seen on the
Intestinal Lymphangiectasia
bowel mucosa; histologic examination shows marked dilatation
Intestinal lymphangiectasia occurs as either a primary form or a of the lacteals (Figure 8.6). Abnormalities of the lymphatics may
secondary form. Primary lymphangiectasia is characterized by also be assessed with contrast lymphangiography or nuclear scin-
diffuse or localized ectasia of the enteric lymphatic system and tigraphy after a high-fat load. The protein-losing state can be
often is diagnosed at a young age. Secondary lymphangiectasia verified with an α1-antitrypsin clearance test (described above).
occurs with conditions that produce impaired lymphatic flow; Treatment of the primary form includes a low-fat, high-protein
the causes are cardiac (congestive heart failure or constriction), diet and supplementation with medium-chain triglycerides as
neoplastic (lymphoma), or structural (retroperitoneal fibrosis). needed. If the disease is localized, resection could be considered.
may also have small-bowel diverticulosis, another risk factor for

SIBO. Also, chronic intestinal pseudo- obstruction may occur
with systemic scleroderma. In addition, diarrhea may occur from
decreased mucosal blood flow due to vasospasm, or diarrhea
may result from lactose malabsorption. Treatment of diarrhea
in patients with scleroderma includes antibiotics for SIBO and
a lactose-restricted diet, as indicated. Treatment with low-dose
octreotide, 50 µg at bedtime, could be considered because it can
help stimulate intestinal motility and improve symptoms; how-
ever, octreotide can be prohibitively expensive.
Diabetes
Patients with diabetes may present with diarrhea or malabsorp-
tion (or both) for various reasons: 1) Several oral hypoglycemic
agents, such as metformin and acarbose, are associated with di-
arrhea; the relation between the initiation of treatment with these
medications and the onset of diarrhea needs to be determined.
Figure 8.6. Lymphangiectasia. Dilated lacteals are in several contig- 2) Delayed intestinal transit in patients with diabetes puts them
uous villi (hematoxylin-eosin). at risk for SIBO. 3) Because of the increased prevalence of ce-
liac disease among patients with type 1 diabetes, celiac disease
Treatment of the secondary form should be directed at the under- needs to be considered. 4) Pancreatic insufficiency needs to be
lying disease process. considered because it may explain not only the diarrhea but also
the hyperglycemia. 5) Patients with diabetes may ingest a con-
siderable amount of sugar-free substances for better glycemic
Amyloidosis control; these substances often contain sorbitol, xylitol, or other
Amyloidosis is a multisystem disease that frequently involves the sugar alcohols that may induce osmotic diarrhea. 6) In patients
gastrointestinal tract. Amyloid deposits can be found at various who have diabetes with end-organ involvement, an autonomic
levels of the bowel wall, although they usually are detected in the neuropathy may develop that will affect the gastrointestinal tract
submucosa. Amyloid also can be deposited in neuromuscular or and lead to “diabetic diarrhea,” for which clonidine therapy may
perivascular sites. Patients with amyloidosis may have diarrhea be helpful if the patient does not have orthostatism.
for many reasons. Delayed transit related to autonomic neurop-
athy may lead to SIBO; accelerated transit related to autonomic Hospitalized Patients
neuropathy may lead to bile acid malabsorption. Also, the amy- New diarrhea or malabsorption in hospitalized patients has a
loid deposits may act as a barrier that prevents proper absorption; broad differential diagnosis that includes the following causes:
patients can have a combination of fat, protein, or carbohydrate antibiotics, Clostridium difficile infection, tube feedings (based
malabsorption. They commonly have lactose malabsorption. on the location of the tube in the bowel, concentration of the for-
Endoscopic findings in amyloidosis include granularity, friability, mula, and bolus effect of the nutrition), elixir medications (that
and erosions, but they are often normal. The yield of detecting contain sorbitol), magnesium (as in antacids and magnesium re-
amyloidosis involvement of the gastrointestinal tract depends placement or supplementation), intestinal ischemia (especially in
on the site from which biopsy samples are obtained: esophagus, critically ill patients), and fecal impaction with secondary over-
70%; stomach, 75% to 95%; small intestine, 85% to 100%; and flow. Also, use of any new medication that was started during the
colorectum, 75% to 95%. A fat aspirate can be obtained for di- hospitalization should be scrutinized as a cause of new-onset di-
agnostic purposes, but this may have a lower yield than intes- arrhea. Diarrhea that is long-standing or was present before hos-
tinal biopsies if there is clinical suggestion of involvement of the pitalization requires diagnostic evaluation for chronic diarrhea
gastrointestinal tract. Congo red staining can show apple-green (which can be done in the outpatient setting).
birefringence, which is seen best in the walls of the vasculature if
the biopsy specimens contain lamina propria. Treatment of amy-
loidosis involvement of the gastrointestinal tract includes treating Miscellaneous
the underlying disease, but treatment of SIBO and lactose avoid- Many other conditions are associated with diarrhea, malabsorption,
ance should be considered. and mucosal disease of the small bowel but cannot be considered
in detail here. Conditions to review include immunodeficiencies
✓ If a patient is suspected to have bowel involvement with amy- (IgA deficiency, combined variable immunodeficiency, and
loid, the greatest yields are from biopsies from the small bowel or graft-
vs-
host disease), autoimmune enteropathy, collagen vas-
colorectum cular diseases and vasculitides, radiation enteritis, ischemia,
mastocytosis, abetalipoproteinemia, and endocrinopathies (thy-
roid and adrenal).
Other Conditions
Scleroderma Bacterial Overgrowth Syndromes
Patients with systemic scleroderma may have diarrhea and mal- Normally, the small- bowel flora contains a relatively small
absorption from gastrointestinal disease. The diarrhea may be number of bacteria (<103 organisms/mL), with a predominance
due to ineffectual motility, which may lead to SIBO. Patients of gram-positive organisms. In contrast, the colonic flora has a
Table 8.5. Risk Factors for Small Intestinal Bacterial above laboratory findings, serum levels of iron, protein, albumin,
Overgrowth and fat-soluble vitamins may be low, depending on the degree of
malabsorption.
Category Risk factor
The reference standard for making the diagnosis of SIBO is
Structural Small-bowel diverticula small-bowel cultures from direct aspiration of the jejunum, with
Intestinal strictures (Crohn disease, radiation, NSAIDs) more than 105 organisms/mL of aerobes and anaerobes being di-
Enterocolonic fistula agnostic. Limitations of small-bowel cultures include availability,
Surgical Blind loops, afferent limbs
Ileocecal valve resection
Dysmotility Chronic intestinal pseudo-obstruction
Scleroderma
Gastroparesis
Diabetic autonomic neuropathy
Diminished acid Achlorhydria, gastric atrophy
Gastric resection
Acid suppression (PPI therapy)
Others Cirrhosis
Pancreatitis
Immunodeficiencies
Celiac disease
Advanced age
Idiopathic
Abbreviations: NSAID, nonsteroidal anti-inflammatory drug; PPI, proton pump

inhibitor.
Adapted from Dukowicz AC, Lacy BE, Levine GM. Small intestinal bacterial
overgrowth: a comprehensive review. Gastroenterol Hepatol (NY). 2007
Feb;3(2):112-22; used with permission.
significantly higher concentration of bacteria, which are largely

gram-negative and anaerobic organisms. When there is stasis, al-
tered motility, or loss of protective defenses in the proximal in-
testinal tract, bacteria that are more representative of colonic flora
can overgrow in the small bowel and result in SIBO, a syndrome
of diarrhea and nutritional deficiencies.
The many risk factors for SIBO are listed in Table 8.5; the
principal causes are associated with stasis of small- bowel
contents or loss of protective gastric acid. Structural or surgical
changes in the bowel that produce relative stasis or reflux of co-
lonic flora into the small bowel can be obtained from the his-
tory and radiographic imaging of the small bowel. Any motility
disorder that affects the small bowel (scleroderma, diabetes, or
pseudo-obstruction) can lead to stasis and overgrowth. Gastric
acid is thought to be a protective barrier that keeps pathogenic
bacteria out of the small intestine; when there is loss of gastric
acid, SIBO may ensue. Advanced age alone may be a factor. In
many patients, no discrete risk factor is identified.
Symptoms of SIBO include abdominal pain, bloating, flatu-
lence, diarrhea, and weight loss. Malabsorption of fat, protein,
or carbohydrates (or a combination of these) can occur with
secondary diarrhea. Fat malabsorption results from bacterial
deconjugation of bile salts and leads to steatorrhea. Carbohydrate
malabsorption can occur because of early sugar breakdown
and fermentation from bacteria as well as from decreased
disaccharidase activity caused by mucosal damage and bacterial
by-products. Mucosal damage is thought to have a role in protein
malabsorption because of the effect on oligopeptidase levels.
A classic pattern of laboratory findings in SIBO includes
Figure 8.7. Breath Testing Patterns for Small Intestinal Bacterial
a low serum level of vitamin B12 and an increased serum level
Overgrowth. A, Lactulose breath test without bacterial overgrowth. B,
of folate. The low level of vitamin B12 is the result of bacteria Lactulose breath test with bacterial overgrowth. C, Lactulose breath test
cleaving vitamin B12 prematurely from intrinsic factor and from showing double-peak pattern. (Adapted from Dukowicz AC, Lacy BE,
the competitive binding and consumption of vitamin B12 by an- Levine GM. Small intestinal bacterial overgrowth: a comprehensive
aerobic bacteria. The increased serum level of folate is the result review. Gastroenterol Hepatol [NY]. 2007 Feb;3[2]‌:112-22; used with
of folate synthesis by the intestinal bacteria. In addition to the permission.)
lack of excess intestinal secretions for aspiration, recent antibi- as amoxicillin-clavulanate, fluoroquinolones, rifaximin, tetracy-
otic therapy, and decreased or no reimbursement for the test. cline derivatives, and metronidazole. Initial treatment may consist
Breath testing can also be used to diagnose SIBO. The test of 10 to 14 days of an antibiotic, with repeated shorter courses
involves giving an oral load of substrate (lactulose hydrogen, when symptoms recur. Some patients may need monthly rotation
glucose hydrogen, or 14C-xylose) and then measuring the breath of antibiotic therapy, while others may not require retreatment for
hydrogen concentration every 15 to 30 minutes for 2 to 4 hours. many months. Also, modified lactose intake should be considered
Either glucose or lactulose hydrogen breath testing can be safely in those with ongoing symptoms after antibiotic therapy, given the
performed in children or pregnant women. A diagnosis of SIBO damaging effects that can be seen on the small-bowel microvilli
is supported by an increase of more than 12 ppm above baseline due to SIBO.
for glucose or 20 ppm above baseline for lactulose during the first
90 minutes. An increase is seen again as these substances reach ✓ Among the many potential risk factors for small intestinal bacte-
the colon, thus producing a double-peak pattern that can also be rial overgrowth (SIBO), the most common are stasis due to ana-
used as a criterion for diagnosis (Figure 8.7). Breath testing for tomical changes or altered motility
✓ SIBO may lead to low vitamin B12 and high serum folate levels
SIBO is not without challenges. False-positive results of breath
✓ Breath testing for SIBO is fraught with the risk of both false-
testing can occur from rapid intestinal transit, in which the car- positive and false-negative results
bohydrate substance rapidly reaches the colon and produces an
early but not double-peaked pattern. False-negative results of
breath testing can occur from recent antibiotic therapy. Also, the
results are falsely negative in 20% of the population who have Suggested Reading
methanogenic colonic bacteria; for those patients, breath methane Bushyhead D, Quigley EM. Small intestinal bacterial overgrowth.
levels rather than hydrogen levels can be checked. Breath testing Gastroenterol Clin North Am. 2021 Jun;50(2):463–74.
results also can be affected by recent laxative use, high carbohy- Camilleri M, Nurko S. Bile acid diarrhea in adults and adolescents.
drate consumption, recent intense physical activity, and smoking. Neurogastroenterol Motil. 2022 Apr;34(4):e14287.
Once SIBO is diagnosed on the basis of cultures or breath testing, Elli L, Topa M, Rimondi A. Protein- losing enteropathy. Curr Opin
evaluating for predisposing conditions could be considered. Also, Gastroenterol. 2020 May;36(3):238–44.
Havlichek D, 3rd, Choung RS, Murray JA. Eosinophilic gastroenter-
an empirical trial of antibiotics could be considered for patients in
itis: using presenting findings to predict disease course. Clin Transl
whom testing for SIBO may not be available or may lead to inac- Gastroenterol. 2021 Oct;12(10):e00394.
curate results. Kamboj AK, Oxentenko AS. Clinical and histologic mimickers of celiac
Treatment of SIBO lies in managing the symptoms and disease. Clin Transl Gastroenterol. 2017 Aug;8(8):e114.
replacing the deficiencies. Although modifying the underlying Marth T, Moos V, Muller C, Biagi F, Schneider T. Tropheryma
risk factor that predisposes to SIBO is feasible in only a small whipplei infection and Whipple’s disease. Lancet Infect Dis. 2016
fraction of patients, it should be considered (tighter glycemic con- Mar;16(3):e13–22.
trol in patients with diabetes, surgery for patients with stricturing Massironi S, Cavalcoli F, Rausa E, Invernizzi P, Braga M, Vecchi M.
disease, and possibly octreotide for patients with scleroderma). Understanding short bowel syndrome: Current status and future
Vitamin and mineral levels should be measured and deficiencies perspectives. Dig Liver Dis. 2020 Mar;52(3):253–61.
Oxentenko AS, Murray JA. Celiac disease: Ten things that every gas-
corrected before irreversible sequelae ensue (eg, as with vitamin
troenterologist should know. Clin Gastroenterol Hepatol. 2015
B12 deficiency). The role of antibiotic therapy is not to sterilize Aug;13(8):1396–404.
the small bowel but rather to decrease and modify the bacterial Sharma P, Baloda V, Gahlot GP, Singh A, Mehta R, Vishnubathla S, et al.
makeup so that it more closely resembles the flora that should be Clinical, endoscopic, and histological differentiation between ce-
present in the small intestine, with therapy targeting gram-negative liac disease and tropical sprue: A systematic review. J Gastroenterol
and anaerobic organisms. Various antibiotics have been used, such Hepatol. 2019 Jan;34(1):74–83.
9
Nutritional Disorders: Vitamins and Mineralsa

AMINDRA S. ARORA, MB, BCHIR
Vitamins and minerals are critical for normal health because they Deficiency of vitamin B12, like folic acid deficiency, results
are essential in a vast assortment of metabolic functions. This in megaloblastic anemia and hyperhomocysteinemia. However,
chapter focuses on selected important vitamins and minerals and in contrast to folic acid deficiency, vitamin B12 deficiency can
their relationships with gastrointestinal tract disorders. cause neuropsychiatric abnormalities, including dementia, and
disorders such as ataxia, paresthesia, chorea, dystonia, subacute
combined degeneration of the posterior columns of the spinal
Water-Soluble Vitamins
cord (ie, loss of lower extremity vibratory and sometimes pro-
Vitamin B12 prioceptive sensation), and loss of taste sensation. Both vitamin
Dietary intake of vitamin B12 (cobalamin) requires the ingestion B12 deficiency and folate deficiency can cause glossitis, anorexia,
of animal products (meat, dairy, fish, and shellfish). As cobal- and diarrhea.
amin is bound to animal proteins, it is released in the stomach by Serum methylmalonic acid levels (which are normal in folic
a combination of gastric contractions, gastric acid, and pepsins. acid deficiency) may be abnormally increased before vitamin B12
Free vitamin B12 then binds to salivary and gastric R proteins (also levels are subnormal. Because large amounts of cobalamin (2.0-
called haptocorrins), a process that is facilitated by the acidic gas- 2.5 mg) are stored in the body, especially in the liver, the lack of
tric pH. The production and secretion of intrinsic factor by gas- adequate dietary vitamin B12 (eg, in a person who is a true vegan
tric parietal cells is critical for the binding of cobalamin from and does not take supplements) may take several years to cause
haptocorrins, which occurs in the duodenum and is facilitated by cobalamin deficiency.
both the neutral pH and the pancreatic proteases. Finally, in the Achlorhydria is a common cause of vitamin B12 deficiency in
terminal ileum, the cobalamin–intrinsic factor complex is bound elderly persons. Pernicious anemia causes vitamin B12 deficiency
to specific receptors and vitamin B12 is absorbed into the circu- from the lack of intrinsic factor and gastric acid. In contrast to
lation, where it binds to transcobalamin II. About half the cir- achlorhydria, hyperacidity (as in Zollinger- Ellison syndrome)
culating vitamin B12 in cobalamin–transcobalamin II is secreted can disrupt the duodenal phase of cobalamin absorption (by acid-
into bile, of which half is recycled and the other half is excreted ification of duodenal contents causing inactivation of pancreatic
in stool. Cobalamin in bile is bound to a biliary haptocorrin, and proteases) and result in cobalamin deficiency. Vitamin B12 defi-
this binding protein is then degraded by pancreatic proteases in ciency rarely occurs with pancreatic insufficiency itself or with
the duodenum, once again liberating vitamin B12 for its binding to long-term treatment with acid-suppressive medications. Bacterial
intrinsic factor. In healthy persons, overall about 70% of ingested overgrowth, infestation with Diphyllobothrium latum, and ileal
cobalamin is absorbed. disease (Crohn disease and radiation enteritis) or resection also
can result in vitamin B12 deficiency. Gastric bypass surgery is
often complicated by subsequent cobalamin deficiency (lack of
intrinsic factor, acid, and gastric grinding). Chronic use of the
a
The author thanks Stephen C. Hauser, MD, who authored previous antidiabetic agents metformin and phenformin can decrease ab-
versions of this chapter. sorption of cobalamin, resulting in vitamin B12 deficiency.
119
Cobalamin deficiency, especially that due to pernicious short half-life, and storage in the body is limited, so deficiencies
anemia, gastrectomy, or ileal disease, generally is treated with can occur quickly when oral intake is decreased.
parenteral cobalamin (1 mg daily for a week, then once weekly
for a few weeks, and then once monthly). The use of high doses
Riboflavin (Vitamin B2)
of oral cobalamin (1-2 mg daily) has a role in patients after co-
balamin stores have been repleted or as initial therapy for persons Riboflavin (vitamin B2) deficiency can cause angular stomatitis,
who have a residual ability to absorb cobalamin and a mild co- cheilosis, glossitis, seborrheic dermatitis, peripheral neuropathy,
balamin deficiency. and impaired vision. Risk factors for deficiency include chronic
alcohol use disorder and malabsorptive disorders. Riboflavin is
found in many foods, including fortified cereals, milk, and eggs.
Folic Acid
Folic acid (vitamin B9) has many dietary sources, including green Niacin (Vitamin B3)
leafy vegetables, grains, orange juice, and organ meats. Pregnant
and lactating patients need higher daily doses than others. Unlike Niacin (vitamin B3) deficiency can occur as a result of malabsorptive
the body stores of vitamin B12, those of folate are small, so de- syndromes, gastric bypass, chronic alcohol use disorder, carci-
ficiency can occur within a few months when intake is poor noid syndrome, or drug therapy (isoniazid, 6- mercaptopurine,
or absent. After brush border membrane hydrolysis of dietary or azathioprine). Persons with a niacin deficiency can have pel-
folylpolyglutamates, active transport of folylmonoglutamates lagra (diarrhea, dermatitis, and dementia occasionally resulting
occurs, principally in the duodenum and upper jejunum. in death), glossitis, cheilosis, dyssebacia, and angular stomatitis.
Folic acid deficiency may lead to megaloblastic anemia, di- Excess niacin therapy for hyperlipidemia treatment (such as crys-
arrhea (macrocytic enterocytes), glossitis, neural tube defects in talline nicotinic acid) can cause flushing, nausea, diarrhea, and
newborns (maternal folic acid deficiency in the first 2 weeks of occasionally hepatocellular injury. Sources of niacin include tryp-
pregnancy), and increased risk of colorectal cancer and cardio- tophan, fortified cereals, legumes, and fish.
vascular disease. The following increase a person’s risk for folic
acid deficiency: dietary deficiency of folic acid (body stores may Pyridoxine (Vitamin B6)
last up to 4 months); gastric bypass surgery; small bowel mal- Pyridoxine (vitamin B6) deficiency is uncommon but can occur
absorption states; use of drugs such as sulfasalazine, phenytoin, in patients receiving isoniazid, cycloserine, hydralazine, oral con
methotrexate, and alcohol; pregnancy; lactation; chronic hemo- traceptives, dopamine, or D-penicillamine, which directly inter-
lytic anemia; and hemodialysis. fere with vitamin B6 metabolism. Malabsorptive syndromes and
Folic acid by mouth, 1 to 5 mg daily, should be given for several chronic alcohol use disorder also are risk factors. Manifestations
weeks to persons with folic acid deficiency. Cobalamin deficiency include cheilosis, angular stomatitis, seborrheic dermatitis, side
needs to be ruled out or treated before folic acid therapy is begun. roblastic anemia, seizures, and peripheral neuropathy. Vitamin
B6 deficiency may be responsible for both the limited increase
Other Water-Soluble Vitamins in aminotransferase values and the increased ratio of aspartate
aminotransferase to alanine aminotransferase in alcoholic hepa-
Vitamin C
titis. Pyridoxine occurs in meat, fish, fortified cereals, and noncitrus
Vitamin C deficiency results in scurvy due to decreased col- fruit. Massive doses may cause sensory neuropathy.
lagen synthesis. Clinical features may include perifollicular
hyperkeratotic papules and petechiae; swollen, red, bleeding Biotin
gums; or anemia. Severe malabsorptive disease and alcohol use
disorder increase the risk of vitamin C deficiency, especially if Although biotin deficiency is rare, it can occur in patients re-
the diet includes few fruits and vegetables. Vitamin C supplemen- ceiving total parenteral nutrition without biotin supplementation.
tation enhances iron absorption and can increase the risk of ad- They may have altered mental status, metabolic acidosis, and
verse cardiac arrhythmias in those with iron overload conditions. seborrheic dermatitis.
Supplementation with more than 250 mg daily of vitamin C also
can produce false-negative results on fecal occult blood tests and Fat-Soluble Vitamins
increase the risk of oxalate kidney stones in persons with chronic
kidney disease. Vitamin A
As with other fat-soluble vitamins, the absorption of vitamin
Thiamine (Vitamin B1) A requires luminal bile salts and pancreatic esterases, assembly
into chylomicrons, and lymphatic transport. Lack of vitamin
Thiamine (vitamin B1) is involved in the decarboxylation of pyru- A can produce night blindness, xerophthalmia, a follicular
vate, which is important in the citric acid cycle. It is found in yeast, hyperkeratotic rash, abnormalities of taste and smell, bone and
cereals from whole grains, brown rice, and pork. Deficiency can muscle pain, and increased risk of infections. Deficiency of vi-
result in wet beriberi with cardiac abnormalities (cardiomyopathy tamin A can occur after bariatric surgery and in persons with
and high-output failure) or dry beriberi with neurologic disorders chronic liver disease. Similar to other fat-soluble vitamins, excess
(peripheral neuropathy, cerebellar dysfunction, gaze pareses, vitamin A can cause toxicity (liver failure, increased cerebrospinal
or Wernicke-Korsakoff syndrome), which may be exacerbated fluid pressure, desquamating rash, alopecia, or hypercalcemia).
by the administration of glucose to patients who are deficient
in thiamine. Chronic alcohol use disorder, overuse of diuretics,
Vitamin D
long-term kidney dialysis, pregnancy, malabsorptive disorders
(including gastric bypass surgery), and chronic malnutrition all Adequate vitamin D levels are achieved mainly through expo-
are risk factors for thiamine deficiency. Thiamine has a relatively sure to sunlight. Few foods contain vitamin D, so they need to be
9. Nutritional Disorders: Vitamins and Minerals 121
fortified. Risk factors for vitamin D deficiency, in addition to lack infection. (Iron overload is discussed in Chapter 30, “Metabolic
of sunlight, are liver disease, kidney disease, and malabsorptive Liver Diseases.”)
conditions. Hypercalcemia from excess vitamin D can result in
anorexia, nausea, vomiting, constipation, confusion, and abdom-
Zinc
inal pain (from hypercalcemia). In addition, polyuria and kidney
stones (from hypercalciuria) can occur. Vitamin D deficiency Zinc is required as a cofactor for many enzymes (eg, alkaline phos-
results in rickets and osteomalacia and may be associated with phatase), and its deficiency impairs growth, development, and
osteoporosis. reproductive and immune functions. Meat and seafood are good
sources. Risk factors for zinc deficiency are chronic diarrhea, short
bowel syndrome, cystic fibrosis, pancreatic insufficiency, cirrhosis,
Vitamin E alcohol use disorder, chronic kidney failure, anorexia nervosa,
Malabsorptive disorders and particularly chronic cholestasis in pregnancy, sickle cell anemia, and use of the drug d-penicillamine.
children are major risk factors for vitamin E deficiency. Mani A scaly red rash involving the face, groin, and hands may occur
festations of vitamin E deficiency include neurologic symptoms with zinc deficiency. Acrodermatitis enteropathica is an auto-
(posterior column disease, peripheral neuropathy, and brainstem somal recessive condition with impaired zinc absorption. Other
and cranial nerve damage), retinal disease, and hemolysis. High manifestations of zinc deficiency include alopecia, dysgeusia,
doses of vitamin E may cause coagulation disorders. growth retardation, poor wound healing, hypogonadism, diarrhea,
and night blindness. Excess zinc intake (eg, supplements such as
those used to treat Wilson disease) can cause copper deficiency.
Vitamin K
Vitamin K is acquired from exogenous dietary sources (green
Copper
leafy vegetables) and endogenous sources (intestinal bacteria).
Malabsorptive syndromes, dietary inadequacy, and antibiotic ad- Copper is present in meat, nuts, and grains. Copper deficiency
ministration are risk factors for vitamin K deficiency. Factor VII can occur after gastrectomy or gastric bypass, celiac disease,
usually is the rate-limiting factor for normal prothrombin time (or and excessive zinc ingestion. Deficiency results in a microcytic
the international normalized ratio). Excessive doses of vitamin E hypochromic anemia, leukopenia, neutropenia, infections, di-
can interfere with vitamin K–dependent metabolism, resulting in arrhea, neurologic disturbances mimicking vitamin B12 defi-
hemorrhage. ciency, hypopigmentation of the skin and hair, and bony changes.
Toxicity from excess administration of oral copper includes acute
hemorrhagic gastritis.
Minerals
Iron
Phosphorus
Loss of endogenous iron from the gastrointestinal tract (usually
Phosphorus deficiency is common in patients with malnutri-
1.0-2.0 mg daily), urinary tract, and skin and menstrual loss in
tion, malabsorptive disorders, and alcohol use disorder and in
women needs to be matched by iron absorption from the duo-
refeeding syndrome. Cardiac failure, hemolytic anemia, rhabdo-
denum and upper jejunum. Iron in the form of heme from meat is
myolysis, acidosis, and encephalopathy may develop with phos-
absorbed more readily (up to 25%) than inorganic ferric iron salts
phorus deficiency.
(3%-10%). Gastric grinding, gastric acid, and vitamin C help
make ferric iron compounds more soluble. Ferric reductase (du-
odenal cytochrome B) on the brush border and ascorbate reduce Miscellaneous Minerals
inorganic iron from the ferric form (Fe3+) to the ferrous form (Fe2+
Deficiencies of selenium (cardiomyopathy and myositis), chromium
). An iron transporter, divalent metal transporter 1, also on the
(hyperglycemia and neurologic symptoms), manganese (very rare,
brush border, facilitates the absorption of ferrous iron. This same
with nonspecific features), or molybdenum (neurologic symptoms)
transporter can also facilitate the absorption of divalent copper,
may develop in patients receiving long-term total parenteral nutri-
zinc, lead, and manganese, each of which can compete with and
tion or tube feeding without proper supplementation. Manganese
inhibit the absorption of divalent iron.
excess may occur in patients who are oversupplemented with par-
Ferroportin 1 along with ferroxidase hephaestin (both located
enteral nutrition; they may present with headache, vomiting, and
on the basolateral membrane) transports iron into the circu-
parkinsonian-like symptoms due to the effects on the basal ganglia.
lation, oxidizes it to the ferric form, and allows it to bind to
apotransferrin, forming transferrin. The liver produces hepcidin,
which regulates iron transport through its interactions with Bariatric Surgery
ferroportin 1, decreasing iron absorption. The basolateral mem- Metabolic complications should be anticipated after bariatric sur-
brane transferrin receptor, regulated by the hemochromatosis gery. Protein malnutrition or zinc deficiency can cause hair loss.
gene HFE, allows intestinal cell reuptake of iron from transferrin. Deficiencies of vitamins D, A, E, and B12 and thiamine, folate,
Normally, with adequate total body iron stores, up to about 10% iron, and copper may occur if supplementation and monitoring
of dietary inorganic iron can be absorbed. With iron deficiency, are deficient.
this may increase to 30%.
Iron deficiency can result in microcytic hypochromic anemia,
altered immune function, angular stomatitis, koilonychia, and Suggested Reading
atrophic lingual papillae. Causes of iron deficiency include lack Buchman AL, Howard LJ, Guenter P, Nishikawa RA, Compher CW,
of dietary iron, increased gastrointestinal loss of iron (bleeding), Tappenden KA. Micronutrients in parenteral nutrition: too little or
poor absorption of iron (celiac disease), surgical procedures that too much? The past, present, and recommendations for the future.
bypass the duodenum, achlorhydria, and Helicobacter pylori Gastroenterology. 2009 Nov;137(5 Suppl):S1–6.
Khambatta S, Nguyen DL, Wittich CM. 38-Year-old woman with O’Donnell K. Severe micronutrient deficiencies in RYGB patients: rare
increasing fatigue and dyspnea. Mayo Clin Proc. 2010 Apr;85(4): but potentially devastating. Pract Gastroenterol. 2011;35(11):13–27.
392–5. Puig A, Mino-Kenudson M, Dighe AS. Case records of the Massachusetts
Koch TR, Finelli FC. Postoperative metabolic and nutritional General Hospital: case 13–2012: a 62-year-old man with paresthesias, weight
complications of bariatric surgery. Gastroenterol Clin North Am. loss, jaundice, and anemia. N Engl J Med. 2012 Apr;366(17):1626–33.
2010 Mar;39(1):109–24. Stabler SP. Clinical practice: vitamin B12 deficiency. N Engl J Med.
Merriman NA, Putt ME, Metz DC, Yang YX. Hip fracture risk in 2013 Jan;368(2):149–60.
patients with a diagnosis of pernicious anemia. Gastroenterology. Thacher TD, Clarke BL. Vitamin D insufficiency. Mayo Clin Proc. 2011
2010 Apr;138(4):1330–7. Jan;86(1):50–60.
Questions job. When the tTG level is checked, it is high. Which of the
following is the most likely?
Abbreviations used:
EATL, enteropathy-associated T-cell lymphoma a. Microscopic colitis
EMA, endomysial antibody b. EATL
Ig, immunoglobulin c. Gluten ingestion
MAC, Mycobacterium avium-intracellulare complex d. Refractory celiac disease
MCV, mean corpuscular volume
III.3. A 72-year-old woman presents for evaluation of chronic diar-
PAS, periodic acid–Schiff
rhea that has been present for 2 years. When she underwent
PCR, polymerase chain reaction
a complete evaluation for diarrhea, results were negative for
tTG, tissue transglutaminase
C-reactive protein and celiac serology, thyroid function results
were normal, and findings were normal from random co-
Multiple Choice (choose the best answer) lonic biopsies. Small- bowel biopsy samples showed features
consistent with celiac disease, but the patient has had no im-
III.1. A 27-year-old woman has a 1-year history of diarrhea and provement while consuming a gluten-free diet. Her past med-
weight loss of 4.5 kg. She has not had fever, abdominal ical history is notable for osteoporosis, hypertension, impaired
pain, or melena, and she has not traveled outside the US. fasting glucose, and mild depression; she has received therapy
She takes no medications. Laboratory results include the for all those. Which is the most likely to cause this presentation?
following: hemoglobin, 11.2 g/dL; MCV, 74 fL; and serum
ferritin, 8 ng/mL. Which of the following antibody tests a. Metformin
should be performed next? b. Alendronate
c. Fluoxetine
a. IgA gliadin d. Olmesartan
b. IgA tTg
c. IgA and IgG deamidated gliadin peptide III.4. A 57-year-old farmer presents for evaluation of diarrhea and
d. IgA anti-EMA cognitive changes. Results for celiac serology are negative, and
findings from colonoscopy with biopsies are unremarkable.
III.2. A 32- year-
old woman with celiac disease presents with Biopsy findings from the small intestine show broad villi with
recurrent diarrhea and weight loss. Celiac disease was patchy atrophy. The biopsy samples stain positive with PAS
diagnosed 4 years earlier when she had similar symptoms. and are acid-fast negative. Which of the following is the most
At that time, testing showed an increased level of tTG, and likely diagnosis?
biopsy findings were compatible with celiac disease. She ini-
tially had a good response to a gluten-free diet, and the tTG a. Whipple disease
and biopsy results were normal. For the past several months, b. Celiac disease
she has had recurrent symptoms. She says that her oral in- c. MAC infection
take has not changed. Recently she moved and started a new d. Tropical sprue
123
III.5. A 45-year-old woman is undergoing an evaluation for fatigue. indicate the presence of gluten in the diet. Microscopic colitis and
Results of a 25-hydroxyvitamin D2 and D3 test were 11 ng/mL. refractory celiac disease can occur in patients with celiac disease,
She is interested in pursuing a “natural” way to supplement but gluten ingestion would be more likely given the high tTG
vitamin D. Which of the following would provide the most results. Although patients with celiac disease are at increased risk
vitamin D?
for EATL, it is rare.
a. Cheese
b. UV-A III.3. Answer d.
c. UV-B Olmesartan, an angiotensin-receptor blocker, has been reported
d. Carrots to cause a small-bowel enteropathy that appears identical to ce-
e. Eggs liac disease. The drug should be considered a possible factor if
III.6. A 32-year-old professional body builder has been taking nat- patients are receiving it and have a serologically negative enter-
ural supplements daily for the past 12 years and presents with opathy. Patients may receive the medication for years before they
hematemesis and headache. He is hypotensive. Test results present with symptoms, but discontinuation of the drug results
were hemoglobin, 7.1 g/dL, and platelet count, 88×109/L. in marked improvement in symptoms and is often all that is
Varices were apparent on endoscopic examination. Which of needed. Other medications that can result in enteropathy include
the following supplements was the patient most likely taking mycophenolate mofetil and checkpoint inhibitors. Metformin can
in excess? cause diarrhea, and selective serotonin reuptake inhibitors (eg,
a. Selenium fluoxetine) have been associated with microscopic colitis, but
b. Protein none of the answer choices besides olmesartan have been known
c. Anabolic steroids to cause an enteropathy.
d. Vitamin A
e. Vitamin D III.4. Answer a.
III.7. A 57-year-old woman is evaluated for confusion that has been Both Tropheryma whipplei and MAC can infect the small bowel
progressively worsening over the past 6 months. Her only and cause macrophages to stain positive with PAS. However,
medication is thyroid replacement for a history of Hashimoto acid-fast staining of biopsy samples will be positive if patients
thyroiditis. On examination, she has vitiligo. On neurologic have MAC infection and negative if patients have Whipple dis
evaluation, her ankle and knee show hyperreflexia. Which of ease. PCR for T whipplei is useful for confirmation of Whipple
the following blood concentrations should be tested? disease, which is rare but most often occurs in men in this age
a. Ferritin group who present with features of multisystem disease.
b. Vitamin A
c. Vitamin D III.5. Answer c.
d. Vitamin B12 Sunshine is 95% UV-A and 5% UV-B. Only UV-B is required
e. Vitamin E for vitamin D synthesis. In commercial tanning salons, UV-A is
the major light source, and the exposure doses are considerably
III.8. A 57-year-old woman presents with general fatigue. She has a
history of atrophic gastritis and receives vitamin B12 supple-
higher than those provided by the sun. Both UV-A and UV-B are
mentation. On physical examination she has some conjunctival implicated in skin damage and carcinogenesis. If a person eats
pallor, but findings are otherwise normal. What is the most normal portions of food sources of vitamin D, it is difficult to
likely cause of her symptoms? achieve the recommended daily allowance. However, vitamin D
supplements are widely available and inexpensive. Vitamin D3 is
a. Insufficient vitamin B12 supplementation
b. Copper deficiency
more potent than vitamin D2.
c. Thiamine deficiency
III.6. Answer d.
d. Iron deficiency
Vitamin A toxicity is often associated with portal hypertension,
rash, and headaches (pseudotumor cerebri).
Answers
III.7. Answer d.
III.1. Answer b. Pernicious anemia is often associated with other autoimmune
The serologic test of choice to screen for celiac disease is IgA conditions (eg, Hashimoto thyroiditis and vitiligo). Deficiencies
tTG antibody. This patient has a high probability of celiac dis of vitamin B12 take several years to develop as stores are
ease given that she has diarrhea, weight loss, and iron deficiency quite high in the liver. In addition to a megaloblastic anemia,
anemia, all of which are characteristic of celiac disease. It would neurologic signs with spasticity and confusion can be present.
be prudent to start with celiac serology, but because the likeli- Vitamin B12 deficiency is easily treated with high doses of oral
hood of disease is so strong for this patient, she would also need supplementation (1,000 µg daily) or subcutaneous injections
to have small-bowel biopsies even if the celiac serology were monthly.
negative.
III.8. Answer d.
III.2. Answer c. To be absorbed, iron must be in the reduced form (Fe2+), which
Ingestion of gluten, which may be inadvertent, is the most requires gastric acid. Patients with atrophic gastritis have achlor-
common reason a patient with celiac disease lacks a response to hydria, and some of them may have iron deficiency. Younger
a gluten-free diet or has a recurrence of symptoms while eating a patients with atrophic gastritis may present with iron deficiency
gluten-free diet. Abnormally high results for celiac serology also before vitamin B12 deficiency.
IV
Miscellaneous Disorders
10
Nonvariceal Gastrointestinal Tract Bleedinga

DAVID H. BRUINING, MD
JEFFREY A. ALEXANDER, MD
Upper Gastrointestinal Tract Bleeding Initial Approach to Patients With UGI Bleeding
Introduction The initial evaluation of a patient with UGI bleeding should
focus on assessment of 1) hemodynamic status and 2) comorbid
Upper gastrointestinal (UGI) tract bleeding (“UGI bleeding”)
conditions.
constitutes 75% to 80% of all cases of acute gastrointestinal
Melena can result when as little as 100 mL of blood is instilled
tract bleeding. Although the incidence has decreased consider-
into the UGI tract, and instillation of 1,000 mL or more initially
ably, the mortality rate from acute UGI bleeding has decreased
leads to hematochezia. Hematochezia from UGI bleeding is a
minimally in the past 50 years, ranging from 2.5% to 10%. This
sign of significant bleeding and, if associated with a red naso-
lack of change in the mortality rate likely is related to the older
gastric aspirate, the mortality rate is nearly 30%. Patients still
age of patients who present with UGI bleeding and the increase
in associated comorbid conditions. Peptic ulcers (Box 10.1)
are the most common source of UGI bleeding, accounting for
about 40% to 50% of patients. Other major causes are gastric Box 10.1. Causes of Upper Gastrointestinal Tract
erosions (5%-25%), bleeding varices (5%-30%), and Mallory- Bleedinga
Weiss tears (5%-15%). The use of aspirin or other nonsteroidal
Peptic ulcer disease (40%-50%)
anti-inflammatory drugs (NSAIDs) is prevalent in 45% to 60%
of all patients with acute bleeding. Moreover, the risk of UGI Varices (5%-30%)
bleeding is increased in patients who take as few as 1 low-dose Mallory-Weiss tear (5%-15%)
aspirin (81 mg) daily. Gastric erosions (5%-25%)
Other
Tumor
Dieulafoy lesion
AVM, angioectasia
a
Portions previously published in Huprich J, Alexander J, Mullan B,
Stanson A. Gastrointestinal Hemorrhage. In: Gore RM, Levine MS, eds. GAVE
Textbook of gastrointestinal radiology. 4th ed. 2015:2271-81:chap 125; Portal hypertensive gastropathy
used with permission.
Abbreviations: CREST, calcinosis cutis, Raynaud phenomenon, esoph-
Abbreviations: AVM, arteriovenous malformation; GAVE, gastric an-
ageal dysfunction, sclerodactyly, and telangiectasia; CT, computed to- tral vascular ectasia.
mography; HHT, hereditary hemorrhagic telangiectasia; H2, histamine;
NSAID, nonsteroidal anti-inflammatory drug; PPI, proton pump inhib- a
Percentages indicate percentage of patients.
itor; UGI, upper gastrointestinal
127
128 Section IV. Miscellaneous Disorders
bleed whole blood; therefore, the hematocrit may not decrease Predictive Models
immediately with acute bleeding. Extravascular fluid will enter Multiple models are available for predicting survival and the need
the vascular space and restore volume for up to 72 hours, thereby for endoscopic intervention. These models cannot unequivocally
leading to a subsequent decrease in the hematocrit. Similarly, predict the need for intervention. However, a patient has a very
the hematocrit may continue to decrease for a few days after small chance (<1%) of requiring intervention if the Blatchford
bleeding has stopped, and a decrease in hematocrit without score is 0 (serum urea nitrogen <18.2 mg/dL; hemoglobin ≥13.0
clinical evidence of blood loss is not diagnostic of recurrent g/dL for men and ≥12.0 g/dL for women; systolic blood pressure
bleeding. Adequate intravenous access should be obtained. ≥110 mm Hg; pulse rate <100/min; and an absence of melena,
Volume resuscitation with stabilization of any comorbid active syncope, cardiac failure, and liver disease).
medical conditions should be achieved before endoscopy.
Most guidelines support a restrictive transfusion threshold (<7
g/dL) in the absence of hemodynamic instability or cardiac Specific Lesions
comorbidities. Rarely, massive bleeding cannot be stabilized Peptic Ulcers
before endoscopy. Intubation for airway protection should be
considered in patients with ongoing hematemesis or those with The approach to a patient who has bled from peptic ulcer dis
suspected active bleeding and decreased consciousness or loss ease is determined at endoscopy. There are many options for
of the gag reflex. Nasogastric tube aspiration should not be used endoscopic therapy. Thermal- coaptive coagulation involves
routinely as it does not adequately differentiate UGI bleeding placement of the coagulating probe directly on the bleeding
from lower gastrointestinal tract bleeding in patients presenting vessel. This is uniformly effective for vessels up to 2 mm in di-
with melena, it does not allow for predicting the presence of ameter with a bipolar hemostasis probe (14-16 W). Injection
high-risk lesions requiring endoscopic therapy, and it has not therapy results in short-term tamponade and vasospasm and
been shown to improve major clinical outcomes. can be induced with the liberal use of epinephrine (1:10,000).
Vasodestruction is long-term and can be induced by sclerosants
or alcohol (total injection volume ≤2 mL). Endoscopic clipping
Prognostic Factors has not been shown to be any more effective than thermal
Clinical therapy. However, it may have appeal for use in patients with
coagulation disorders or when further coaptive coagulation may
Age older than 70 years is a risk factor for death from UGI
not be desirable. Hemostatic powder can be used when other
bleeding. Comorbid conditions that increase mortality include pul-
treatment modalities have failed or are not reasonable options
monary disease (acute respiratory failure, pneumonia, and symp-
for temporizing tumor-related bleeding.
tomatic chronic obstructive pulmonary disease), malignancy, liver
Endoscopic therapy is indicated for patients with active
disorders (cirrhosis and alcoholic hepatitis), neurologic disorders
arterial bleeding and those with a nonbleeding visible vessel
(delirium and recent stroke), sepsis, postoperative state, and pos-
(pigmented protuberance). An adherent clot is a predictor of
sibly cardiac disease (congestive heart failure, ischemic heart
rebleeding and can be managed with endoscopic therapy or
disease, and dysrhythmia) and kidney disorders (acute kidney
high-dose proton pump inhibitor (PPI) therapy (or both). All
failure, creatinine >4 mg/dL, and dialysis). Signs of large-volume
3 endoscopic treatment options have been shown to have a
bleeding may include hematemesis or bright red nasogastric
relatively similar efficacy. However, the use of epinephrine
aspirate and shock, the 2 most predictive risk factors for death
injection with subsequent use of a more permanent form of
from UGI bleeding. Tachycardia (heart rate >100 beats/ min),
treatment (coagulation, vasodestruction, or clipping) has been
orthostasis, and hypotension (systolic blood pressure <100 mm
shown to be more effective than epinephrine therapy alone.
Hg) are predictive of rebleeding. Vomitus that resembles coffee
Patients with a clean ulcer base (rebleeding rates <5%) and a
grounds (“coffee ground emesis”) has no prognostic value.
flat pigmented spot (rebleeding rates, 5%-10%) do not require
A transfusion requirement of 4 units of blood or more per re-
endoscopic therapy and likely could be discharged soon after
suscitative event is predictive of rebleeding and death from UGI
endoscopy. Deep ulcers may expose larger vessels that may
bleeding. Laboratory findings of note include thrombocytopenia,
not be amenable to endoscopic coagulation. Deep ulcers in the
leukocytosis, and abnormal coagulation profile, all of which in-
stomach should not be treated, particularly if the ulcers are in
crease mortality.
the upper part of the body on the lesser curvature (left gas-
tric artery) or posterior duodenal bulb (gastroduodenal artery)
Endoscopic with nonbleeding visible vessels larger than 2 to 3 mm in di-
Only the finding of varices or gastric cancer has been shown ameter. Rebleeding after endoscopic therapy occurs 20% to
clearly to be a predictor of death from UGI bleeding. Active ar- 30% of the time. Re-treatment for recurrent bleeding achieves
terial spurting has been associated inconsistently with increased long- term hemostasis in more than 70% of patients. For
mortality. Endoscopic findings, however, have clear prognostic patients with recurrent bleeding peptic ulcers, over-the-scope
value in assessing rebleeding rates. For reliable prognostica- clips are more effective than standard endoscopic therapy for
tion of rebleeding, endoscopy should be performed within 24 bleeding control.
hours after presentation. Nearly 94% of episodes of rebleeding If endoscopic therapy fails, angiographic embolization of the
occur within 72 hours and 98% within 96 hours. The 3 endo- bleeding vessel is preferable to surgical intervention. No data
scopic observations that are independent predictors of rebleeding support the use of histamine (H2)-blockers or antacids in control-
regardless of the type of lesion are arterial spurting (rebleeding ling peptic ulcer bleeding. High-dose PPI therapy is beneficial
in 70%-90% of cases), visible vessel or pigmented protuberance for patients with peptic ulcer bleeding and high-risk stigmata,
(40%-50%), and adherent clot resistant to washing (10%-35%). both with and without endoscopic therapy. The presumed ben-
Ulcers larger than 2 cm and posterior duodenal bulb ulcers also efit is related to clot stabilization occurring in a nonacid envi-
are predictive of rebleeding. ronment. In vitro studies suggest that a pH greater than 6.0 is
10. Nonvariceal Gastrointestinal Tract Bleeding 129
required for platelet aggregation and fibrin formation, whereas Portal Hypertensive Gastropathy
a pH less than 5.0 is associated with clot lysis. This pH increase Portal hypertensive gastropathy is more frequent in the prox-
is achieved best with PPI therapy administered as a contin- imal portion of the stomach than the distal portion and gives
uous intravenous infusion. Because of its effects on decreasing the gastric mucosa a mosaic or snakeskin appearance, with or
splanchnic blood flow, octreotide can be considered for patients without red spots. Severe portal hypertensive gastropathy has a
who have torrential bleeding and no response to intravenous PPI mosaic pattern and diffuse red spots and can be associated with
and endoscopic therapy. both chronic and acute gastrointestinal tract bleeding. Bleeding
Patients with UGI bleeding and Helicobacter pylori in- usually is not massive, and therapy is directed at decreasing the
fection should be treated, and eradication of the H pylori in- portal pressure. Rebleeding can be decreased with nonselective
fection should be confirmed. Patients taking NSAIDs should β-blocker therapy.
avoid them if possible. Patients without a reversible cause of
peptic ulcer disease should receive long-term ulcer prophy-
laxis with a PPI. Without treatment, recurrent ulcer bleeding Aortoenteric Fistula
will occur in approximately one-third of these patients within Fistulas can occur between any major vascular structure and the
3 to 5 years. This rate can be decreased to less than 10% gastrointestinal tract. Aortoesophageal fistulas are caused by tho-
with full-dose H2- blocker prophylaxis. Ulcer rebleeding is racic aortic aneurysms, esophageal foreign bodies, or neoplasms.
uncommon in patients with proven eradication of H pylori Up to 75% of aortoenteric fistulas communicate with the duo-
infection who avoid the use of NSAIDs. However, ulcer pro- denum, usually in the distal third. These may develop from an
phylaxis may be reasonable for patients in whom H pylori aortic aneurysm but are related more commonly to abdominal
infection has been eradicated but who have a clinically im- aortic (graft) reconstructive surgery. Infection appears to have
portant comorbid condition, especially if they take NSAIDs a major pathogenic role in the development of these fistulas,
continuously or intermittently. which usually develop off the origin of the graft, often with
pseudoaneurysm formation. The classic “herald bleed,” in which
Mucosal Erosive Disease bleeding stops spontaneously hours to months before massive
bleeding, occurs in about half of patients. The diagnostic test of
Endoscopic esophagitis, gastritis, and duodenitis are defined by choice is computed tomography (CT) with an intravenous con-
the endoscopic findings of hemorrhage, erythema, or erosions. trast agent to show loss of the tissue plane between the graft and
These lesions rarely are associated with major UGI bleeding. the bowel or to show air surrounding the graft near the duodenum.
Large hiatal hernias can be associated with chronic blood loss Extended upper endoscopy is often used next to exclude other
related to Cameron lesions, which are linear erosions along causes of UGI bleeding; however, endoscopy has a low sensitivity
the crests of gastric folds at or near the diaphragmatic hiatus. for the diagnosis of an aortoenteric fistula. Explorative surgery is
Gastric erosive disease usually is related to NSAID use, alcohol indicated for a patient with an aortic graft, severe bleeding, and
intake, or stress gastritis. Bleeding generally is minor unless ul- no relevant radiologic and endoscopic findings. The correct diag-
ceration develops. Prophylaxis of NSAID injury with a PPI or nosis of an aortoenteric fistula is established preoperatively in as
treatment with cyclooxygenase-2–specific NSAIDs decreases few as one-third of patients.
the risk of ulcer development. Stress gastritis leads to clini-
cally significant UGI bleeding in more than 3% of patients in
intensive care units. Patients at higher risk are those receiving Hemobilia and Hemosuccus Pancreaticus
mechanical ventilation for more than 48 hours, patients with Hemobilia is manifested classically as UGI bleeding accompanied
coagulopathy, and patients with head injury or extensive burn by biliary colic and jaundice. The diagnosis is suggested when
injuries. Prophylactic therapy should be reserved for these blood is visualized coming from the ampulla at endoscopy. CT
groups. Maintenance of gastric pH greater than 4, with enteral angiography is the diagnostic test of choice. The most common
feedings and use of H2-receptor antagonists or PPIs, is effective cause of hemobilia is trauma, including liver biopsy, to the liver
for preventing stress ulcer bleeding. PPI therapy appears more or biliary tree. Extrahepatic or intrahepatic artery aneurysms
effective than H2- blocker therapy for preventing bleeding. often are caused by trauma and may communicate with the bile
Sucralfate has been shown to be effective for prophylaxis of ducts. Bleeding can be caused also by gallstones, hepatic or bile
stress ulcer bleeding without affecting gastric pH; in some duct tumors, and cholecystitis.
studies, it has been associated with less pneumonia and possibly In hemosuccus pancreaticus, the bleeding is usually from
less mortality than H2 blockers. peripancreatic blood vessels into the pancreatic duct. This com-
monly is due to rupture of true aneurysms or pseudoaneurysms
often associated with necrotizing pancreatitis. CT angiography
Mallory-Weiss Tear
is the diagnostic test of choice; subsequent treatment is with
Mallory-Weiss tears occur at the gastroesophageal junction and transcatheter embolization. Surgery may be required for embo-
often are present with a classic history of recurrent retching, lization failures.
frequently in a patient with alcohol use disorder, before the de-
velopment of hematemesis. Most tears occur on the gastric side
Neoplasms
of the gastroesophageal junction, but 10% to 20% may involve
the esophagus. Bleeding stops spontaneously in 80% to 90% of Bleeding can occur from primary UGI tumors (adenocarcinoma,
patients and rebleeding occurs in 2% to 5%. Endoscopic therapy stromal tumors, lymphomas, or neuroendocrine tumors) and, oc-
with thermal coagulation, injection therapy, or banding is ben- casionally, metastatic UGI tumors (melanoma or breast cancer).
eficial for active bleeding. Angiographic therapy with intra- Gastrointestinal stromal tumors often appear as a submucosal
arterial vasopressin or embolization also can be effective, as can mass with central ulceration and may cause severe UGI bleeding.
oversewing the lesion intraoperatively. Effective therapy generally is surgical.
Vascular Anomalies
Anomalies With Skin Lesions. Vascular lesions can be seen
throughout the gastrointestinal tract in several systemic diseases
and syndromes such as Osler-Weber-Rendu disease (ie, hereditary
hemorrhagic telangiectasia [HHT]), the elastic tissue disorders of
pseudoxanthoma elasticum and Ehlers-Danlos syndrome, CREST
(calcinosis cutis, Raynaud phenomenon, esophageal dysfunction,
sclerodactyly, and telangiectasia) syndrome, and blue rubber bleb
nevus syndrome. Endoscopic coagulation therapy is the treatment
of choice. For patients who have HHT with acutely bleeding gas-
trointestinal telangiectasias, endoscopic coagulation treatment is
indicated. Treatment of nonbleeding HHT-related telangiectasis
is anti-angiogenic therapy with an agent such as bevacizumab.
Endoscopic therapy of nonbleeding lesions is not recommended be-
cause thermal injury may incite further telangiectasia development.
Anomalies Without Skin Lesions. Vascular ectasias can occur
anywhere in the UGI tract but are more common in the duodenum
and stomach, particularly in older patients and those with chronic
kidney failure or previous radiotherapy. These lesions are cherry
red and often fernlike in appearance. Histologically, dilated, Figure 10.1. Dieulafoy Lesion. Endoscopic image shows active
ectatic, or tortuous submucosal blood vessels (or a combination bleeding.
of these) are seen; the pathogenesis of these vessels is not known.
These lesions may be diffuse or localized. Vascular ectasias are Vater; 2) mid—from the ampulla of Vater to the terminal ileum;
treated with endoscopic thermal coagulation. and 3) lower—distal to the terminal ileum. Only 3% to 5% of
Gastric antral vascular ectasia (also called watermelon sto- episodes of gastrointestinal tract bleeding originate from a
mach) is a specific type of localized ectasia often seen in elderly midbowel source.
women who present with iron deficiency anemia and evidence of Depending on the transit time, which in turn is determined
mild UGI tract blood loss. This lesion is associated with several by the volume of bleeding, patients with non-UGI bleeding may
other disease processes, most notably, connective tissue disorders, present with melena, hematochezia, or occult bleeding. An im-
atrophic gastritis, pernicious anemia, and portal hypertension. Red portant point is that bacterial metabolism needs sufficient time for
streaks that traverse the gastric antrum and converge at the pylorus, melena to be generated from fresh blood.
resembling the stripes on a watermelon, are seen with endoscopy. Hematochezia most commonly indicates bleeding from a co-
Histologically, large blood vessels with intravascular fibrin thrombi lonic source. However, the source is more proximal in 5% to 10%
and fibromuscular hyperplasia are seen, but the diagnosis usually is of patients. It would be extremely uncommon for hematochezia to
based on the classic endoscopic appearance. If iron replacement is originate from a source in the proximal portion of the gastrointes-
inadequate to maintain a normal level of hemoglobin, endoscopic tinal tract without hemodynamic evidence of bleeding or clinical
thermal therapy often is helpful. Argon plasma coagulation is the evidence of rapid gastrointestinal transit (eg, hyperperistalsis).
preferred thermal treatment for gastric antral vascular ectasia be- If blood is limited to the toilet paper or the surface of formed
cause of the large area usually requiring treatment. Rarely, antrec- stool, a perianal source (eg, hemorrhoids or fissures) is likely.
tomy is necessary. Tenesmus suggests a rectal origin (eg, proctitis). For all patients,
A Dieulafoy lesion (Figure 10.1) is an abnormally large submu- the possibility of neoplasia must at least be considered and often
cosal artery that can rupture and bleed. The bleeding is arterial and excluded.
is usually moderate to severe. Most of these lesions are within 6 cm
of the esophageal junction, but they can occur in the duodenum and
jejunum as well as in the esophagus, colon, rectum, and biliary tree. Specific Lesions
They can be difficult to diagnose when the bleeding has stopped, Diverticular Bleeding
and endoscopy may need to be repeated several times to identify
the lesion. When the lesion is identified, endoscopic tattooing of Patients with diverticular bleeding typically present with acute
the lesion often is helpful, especially if surgical therapy is planned. blood loss, as manifested by maroon stools or hematochezia.
A Dieulafoy lesion appears as a small protruding vessel surrounded Minor or occult bleeding is not characteristic of diverticular
by normal mucosa or as a minute mucosal defect. These lesions are bleeding or diverticulosis. Diverticular bleeding and diverticu-
amenable to conventional endoscopic therapy, band ligation, and litis are distinct conditions that rarely occur together. Diverticular
endoscopic clipping. Rebleeding rates after endoscopic therapy are bleeding is painless except for the cramping that may occur with
low. A nonbleeding visible vessel should be treated. Angiographic the cathartic effect of blood within the colon.
embolization can be effective in high-risk surgical patients. Diverticular bleeding is thought to originate more commonly
from the right colon, where ostia tend to be wider and the colon
wall thinner. Diverticular bleeding develops in an estimated 3%
Non-UGI Bleeding to 5% of patients with diverticulosis. Bleeding most commonly
occurs during the sixth and seventh decades of life and stops spon-
Introduction
taneously in more than 75% of patients. Generally, rebleeding
Gastrointestinal tract bleeding has been classified according occurs in about 15% to 20% of patients. After a second episode,
to the level of the tract: 1) upper—proximal to the ampulla of the risk of rebleeding is approximately 25% to 50%.
10. Nonvariceal Gastrointestinal Tract Bleeding 131
For ongoing or recurrent bleeding, angiography often is per for ulcerative colitis. Hemodynamically significant hemorrhage
formed with the intention of identifying an actively bleeding is uncommon.
vessel. If the vessel is identified, transcatheter embolization can
be attempted, although in some series colonic infarction has been Benign Rectoanal Disease
as high as 20%. Transcatheter vasopressin can control bleeding in
90% of cases, but rebleeding rates are high. Endoscopic therapy is Patients with benign rectoanal disease often present with
safe and effective, but locating the bleeding lesion is often difficult. hematochezia. Painless hematochezia with blood on the toilet
paper or the surface of formed stool is most suggestive of hem-
orrhoidal bleeding. Painful outlet bleeding is typical of a rectal
Vascular Ectasia fissure.
Vascular ectasias are typically smaller than 5 mm and are found in Stercoral ulcers are associated with constipation and occur
3% to 6% of patients undergoing colonoscopy. Most commonly, most commonly in the rectosigmoid area or, occasionally, in the
they are in the right colon but may occur anywhere in the gastro- more proximal portion of the colon. They often become manifest
intestinal tract. These lesions are usually angiodysplasias, which after disimpaction. Solitary rectal ulcer syndrome often is asso-
are often multiple and believed to be related to the aging process. ciated with excessive straining. The ulcer usually occurs on the
Less than 10% of patients with angiodysplasia eventually have anterior wall, 6 to 10 cm above the anal verge. Both lesions may
bleeding. Not uncommonly, these lesions become apparent become to attention because of considerable bleeding.
cause of a bleeding diathesis, such as anticoagulation or platelet Patients with radiation proctitis may present months to years
dysfunction. The lesions may lead to acute overt as well as occult after receiving radiotherapy to the prostate or pelvic organs.
gastrointestinal tract bleeding. Sigmoidoscopy shows characteristic mucosal telangiectasias.
For many patients, iron repletion therapy alone is sufficient. The bleeding is rarely severe, and endoscopic argon plasma co-
Endoscopic therapy is effective but is associated with a high agulation therapy is the treatment of choice.
rebleeding rate. Angiographic embolization can be used to con-
trol acute bleeding. Octreotide and thalidomide have been of ben- Infection
efit in small trials of patients with obscure gastrointestinal tract
bleeding presumed to be related to vascular ectasias. Infections may be associated with non-UGI bleeding. Clues in-
clude a travel history or evidence of systemic toxicity such as
fevers, rashes, arthralgias, eosinophilia, or diarrhea. In patients
Neoplasm infected with HIV, common causes of non-UGI bleeding are cy-
Patients with neoplasm of the colon and small bowel may pre- tomegalovirus colitis and lymphoma.
sent with either acute or occult non-UGI bleeding. Tumors of
the small intestine may be a relatively common cause of obscure NSAID Enteropathy and Colonopathy
non-UGI bleeding in patients younger than 50 years; two-thirds
of the tumors are malignant. Carcinoids, adenocarcinomas, and Increasingly, NSAID enteropathy and colonopathy are being
gastrointestinal stromal tumors account for most of these lesions. recognized as explanations for non- UGI bleeding. Autopsy
studies have documented small intestinal ulcers in 8% of
patients who had taken NSAIDs within the preceding 6 months.
Colonic Ischemia Diaphragmatic strictures are strongly suggestive of NSAID-
Patients with colonic ischemia often present with mild lower ab- induced inflammation. NSAIDs may cause a flare of inflamma-
dominal pain and bloody diarrhea or hematochezia. Colonic is- tory bowel disease.
chemia most often occurs in persons older than 60 years who
have atherosclerotic cardiovascular risk factors, but it may occur Approach
in patients after abdominal vascular surgery, in patients who have
vasculitis or clotting disorders, or in those who receive estrogen The evaluation and management of patients who present with
therapy. However, usually no etiologic factor is identified. It non-UGI bleeding is determined largely by the clinical presen-
is the result of a low-flow, nonocclusive process in the colonic tation and the differential diagnosis that has been generated. The
microvasculature. A large-vessel disease is rarely found, and an- following points are essential to keep in mind:
giography is not indicated for left-sided ischemic disease. There • Diagnostic colonoscopy is indicated for patients with positive
is no specific therapy, and recovery is usually complete in several findings on fecal occult blood testing. In addition, the presence of
days. Occasionally, however, a colonic stricture may develop. signs or symptoms of UGI tract disease or iron deficiency warrant
upper endoscopy.
• Technetium Tc 99m– tagged red blood cell radionuclide scans
Meckel Diverticulum can detect bleeding rates as low as 0.1 mL/min. The patient may
A Meckel diverticulum, a remnant of the vitelline duct, usually undergo scanning repeatedly over a 12-to 24-hour period in an
occurs 100 cm proximal to the ileocecal valve. Autopsy series attempt to identify intermittent bleeding. Radionuclide scans gen-
erally are not useful for identifying a specific site of bleeding. They
suggest a prevalence rate of 2%. Approximately 50% of these
are more sensitive for bleeding, are less invasive than angiography,
diverticula contain gastric mucosa, and patients, typically a child and often are used to determine the best timing for angiography.
or young adult, may present with bleeding from acid-induced ul- Tagged red blood cell scans are rarely used now with the availa-
ceration of the ileum. bility of CT angiography.
• Mesenteric angiography is more accurate than radionuclide scans
Inflammatory Bowel Disease but requires a faster bleeding rate (>0.5 mL/min). Angiographic
yields are much greater with active gastrointestinal tract bleeding
Patients with inflammatory bowel disease may present with (60%-70%) than when angiography is performed after bleeding has
bloody diarrhea or hematochezia, which is the classic presentation ceased (<20%). Angiographic therapy with transcatheter infusion
of vasopressin or embolization has been effective but carries a risk ASGE Standards of Practice Committee, Fisher L, Lee Krinsky M,
of bowel infarction. Anderson MA, Appalaneni V, Banerjee S, et al. The role of endos-
• Capsule endoscopy is the method of choice for evaluating suspected copy in the management of obscure GI bleeding. Gastrointest Endosc.
small-bowel bleeding. It shows an abnormal finding about 70% of 2010 Sep;72(3):471–9.
the time. Push enteroscopy has been reported to identify probable Barkun AN, Bardou M, Kuipers EJ, Sung J, Hunt RH, Martel M, et al.
bleeding sites in 50% of patients with obscure gastrointestinal tract International consensus recommendations on the management of
bleeding. This can be done with an adult or pediatric colonoscope. patients with nonvariceal upper gastrointestinal bleeding. Ann Intern
Approximately 25% of the diagnoses made with push enteroscopy Med. 2010 Jan;152(2):101–13.
are within the reach of a standard endoscope. Davila RE, Rajan E, Adler DG, Egan J, Hirota WK, Leighton JA, et al.
• Balloon- assisted endoscopy, with a single or double balloon, ASGE Guideline: the role of endoscopy in the patient with lower-GI
can be performed by the peroral or peranal route (or both), with bleeding. Gastrointest Endosc. 2005 Nov;62(5):656–60.
a diagnostic yield greater than 60%. Endoscopic therapy can be Elmunzer BJ, Young SD, Inadomi JM, Schoenfeld P, Laine L. Systematic
administered. Double-balloon endoscopy appears to provide deeper review of the predictors of recurrent hemorrhage after endoscopic he-
small-bowel intubation than single-balloon or spiral endoscopy. mostatic therapy for bleeding peptic ulcers. Am J Gastroenterol. 2008
Complete enteroscopy can be achieved with double-balloon endos- Oct;103(10):2625–32.
copy in over 40% of patients with the combined antegrade and ret- Gerson LB, Fidler JL, Cave DR, Leighton JA. ACG Clinical
rograde approach. Guideline: diagnosis and management of small bowel bleeding. Am J
• Intraoperative enteroscopy has been used to detect abnormalities Gastroenterol. 2015 Sep;110(9):1265–87.
in about 70% of patients. However, recurrent bleeding may occur, Gralnek IM, Barkun AN, Bardou M. Management of acute bleeding from
and only about 40% to 50% of these patients are free of bleeding at a peptic ulcer. N Engl J Med. 2008 Aug;359(9):928–37.
2 years. Furthermore, it is rarely needed with the advent of capsule Holster IL, van Beusekom HM, Kuipers EJ, Leebeek FW, de Maat MP,
endoscopy and deep enteroscopy. Tjwa ET. Effects of a hemostatic powder hemospray on coagulation
• CT enterography and CT angiography are having an increased role and clot formation. Endoscopy. 2015 Jul;47(7):638–45.
in the evaluation and localization of small-bowel blood loss. They Hwang JH, Fisher DA, Ben-Menachem T, Chandrasekhara V, Chathadi
are particularly useful in the evaluation of bleeding related to small- K, Decker GA, et al. The role of endoscopy in the management of
bowel mass lesions. CT angiography is preferred over red blood acute non-variceal upper GI bleeding. Gastrointest Endosc. 2012
cell scintigraphy for hemodynamically unstable patients with lower Jun;75(6):1132–8.
gastrointestinal tract bleeding and allows transarterial embolization Laine L, Barkun AN, Saltzman JR, Martel M, Leontiadis GI. ACG
if CT angiography shows active extravasation. Clinical Guideline: upper gastrointestinal and ulcer bleeding. Am J
Gastroenterol. 2021 May;116(5):899–917.
Lanza FL, Chan FK, Quigley EM, Practice Parameters Committee of
✓ Resuscitation and risk stratification are critical for successful
the American College of Gastroenterology. Guidelines for prevention
management of gastrointestinal tract bleeding
of NSAID-related ulcer complications. Am J Gastroenterol. 2009
✓ Peptic ulcer disease—the most common cause of UGI bleeding
Mar;104(3):728–38.
✓ Capsule endoscopy, CT enterography, or CT angiography (or >1 of
Lau J, Sung JJ. From endoscopic hemostasis to bleeding peptic ulcers:
these procedures) may be useful for suspected small-bowel bleeding
strategies to prevent and treat recurrent bleeding. Gastroenterology.
2010 Apr;138(4):1252–4.
Rondonotti E, Sunada K, Yano T, Paggi S, Yamamoto H. Double-balloon
endoscopy in clinical practice: where are we now? Dig Endosc. 2012
Suggested Reading Jul;24(4):209–19.
Alhazzani W, Alenezi F, Jaeschke RZ, Moayyedi P, Cook DJ. Proton Schmidt A, Golder S, Goetz M, Meining A, Lau J, von Delius S,
pump inhibitors versus histamine 2 receptor antagonists for stress et al. Over-the-scope clips are more effective than standard endo-
ulcer prophylaxis in critically ill patients: a systematic review and scopic therapy for patients with recurrent bleeding of peptic ulcers.
meta-analysis. Crit Care Med. 2013 Mar;41(3):693–705. Gastroenterology. 2018 Sep;155(3):674–86.
11
Vascular Disorders of the Gastrointestinal Tract

SETH R. SWEETSER, MD
Mesenteric Ischemia Mesenteric Vascular Anatomy

Mesenteric ischemia (MI) is a broad term that includes sev- The principal blood supply to the gut is from the celiac, superior
eral clinical conditions that occur when splanchnic blood flow mesenteric, and inferior mesenteric arteries, which arise directly
is inadequate and thus fails to meet the metabolic demands of from the aorta. The celiac artery (CA) has its origin from the an-
the intestines. The condition can result in symptomatic and terior aorta and supplies blood to the stomach, the proximal duo-
life-threatening clinical presentations. The incidence of MI is denum, part of the pancreas, the liver, and the spleen. The superior
increasing because of the aging population, increasing number mesenteric artery (SMA) arises from the anterior aorta at an acute
of critically ill patients, and heightened clinical awareness. MI angle (25°-60°) and supplies blood to the distal duodenum, je-
produces a spectrum of disorders that depend on many factors, junum, ileum, and proximal colon. The inferior mesenteric artery
including the acuity of the event, the vessel involved, and the (IMA) arises just above the aortic bifurcation and supplies the large
length of bowel affected. In general, MI can be divided into 4 intestine from the distal transverse colon to the proximal rectum.
clinical syndromes: acute mesenteric ischemia (AMI), chronic The distal rectum is supplied by branches of the internal iliac artery.
mesenteric ischemia (CMI), colonic ischemia (CI), and focal The 3 major mesenteric vessels share an extensive collateral
segmental ischemia (FSI). These 4 syndromes account for most circulation that allows for redundant flow to mesenteric vascular
manifestations of ischemic injury to the gut (Table 11.1). This territories in the event of arterial occlusion and protects the gut
chapter reviews the epidemiology, pathophysiology, clinical pre- from episodes of arterial hypoperfusion. However, if the episodes
sentation, and management of these conditions and discusses of arterial hypoperfusion are abrupt, complete, or prolonged, the
other vascular syndromes of the gastrointestinal tract. adaptive mechanisms are overwhelmed, and MI or mesenteric in-
farction (or both) occur. The major collateral pathways between
✓ Mesenteric ischemia—a broad term that includes several clinical the CA and SMA are the gastroduodenal and pancreaticoduodenal
conditions that occur when splanchnic blood flow is inadequate arteries and, less commonly, the arc of Barkow (an anastomosis
and thus fails to meet the metabolic demands of the intestines
between the left and right gastroepiploic arteries) and the arc of
Buhler (a persistent communication between embryonic ventral
Abbreviations: AMI, acute mesenteric ischemia; ANCA, antineutrophil

cytoplasmic antibody; CA, celiac artery; CI, colonic ischemia; CMI, Table 11.1. Types and Frequencies of Mesenteric Ischemia
chronic mesenteric ischemia; CTA, computed tomographic angiography;
EDS, Ehlers-Danlos syndrome; FSI, focal segmental ischemia; IMA, in- Type Frequency, %
ferior mesenteric artery; MALS, median arcuate ligament syndrome; MI,
Colonic ischemia 70
mesenteric ischemia; NOMI, nonocclusive mesenteric ischemia; RA,
Acute mesenteric ischemia 25
rheumatoid arthritis; SLE, systemic lupus erythematosus; SMA, superior Chronic mesenteric ischemia <5
mesenteric artery; SMAE, superior mesenteric artery embolus; SMAT, Focal segmental ischemia <5
superior mesenteric artery thrombus; VAA, visceral artery aneurysm
133
segmental arteries). The SMA and IMA collateralize through the cases of AMI. Risk factors include a personal or family history
arc of Riolan (a connection between the middle and left colic of thrombophilia and a history of deep vein thrombosis. Causes
arteries) and the marginal artery of Drummond, which consists of include hypercoagulable states; hyperviscosity syndromes; intra-
branches of the ileocolic and right, left, and middle colic arteries. abdominal infections (pyelophlebitis, diverticulitis, and appendi-
citis) or inflammation (Crohn disease and pancreatitis); malignant
obstruction; portal hypertension; vasculitis; and trauma.
Acute Mesenteric Ischemia
NOMI, which accounts for 20% of cases of AMI, occurs when
Epidemiology and Pathogenesis splanchnic vasoconstriction is precipitated by hypoperfusion in
AMI is a rare condition that accounts for approximately 0.1% the context of decreased cardiac output (myocardial infarction or
of hospital admissions and 25% of patients with MI. AMI is dyskinesia, arrhythmia, shock, sepsis, pancreatitis, burns, multiple
caused by an abrupt decrease in blood flow to the small bowel. organ failure, congestive heart failure, or hemorrhage); vasospasm
Four distinct pathophysiologic processes can result in the clin- (digoxin, α-adrenergic agonists, amphetamines, or cocaine); dial-
ical manifestations of AMI (Table 11.2): acute embolism, arte- ysis; and pre-existing atherosclerotic disease (hypertension, type
rial thrombosis, mesenteric venous thrombosis, and nonocclusive 2 diabetes, hyperlipidemia, or vasculopathy).
mesenteric ischemia (NOMI). Intestinal infarction occurs with
prolonged reduction in blood flow; therefore, AMI is an abdom- Clinical Manifestations of AMI
inal emergency with a high mortality rate.
Early diagnosis of AMI requires a high degree of clinical aware-
Embolic disease most frequently affects the SMA because
ness. Patients most commonly present with abrupt onset of severe,
of its wide caliber and narrow takeoff angle from the abdominal
unrelenting, periumbilical abdominal pain with a subsequent
aorta. SMA embolus (SMAE) is the most common cause of AMI
urge to defecate. The abdominal pain is constant, and the patient
(accounting for 50% of cases). The emboli usually originate from
may subsequently have loose, nonbloody stools. Hematochezia,
a left atrial or ventricular mural thrombus; an aortic origin (ather-
which occurs in a minority of patients with AMI (15%), signifies
omatous cholesterol embolism) is less common. Emboli usually
concomitant ischemia of the right colon. In the early course of
obstruct distally to the origin of the SMA, distal to the origin
AMI, findings from examination of the abdomen may be falsely
of the middle CA, and spare the proximal jejunum and the right
reassuring without peritoneal signs or other abnormalities despite
colon. In contrast, embolic occlusion rarely occurs in the IMA
the patient’s report of severe abdominal pain. This “pain out of
because it has a small caliber, and embolism to the CA is un-
proportion to physical examination findings” should immediately
common because it arises from the aorta at a right angle. Major
increase suspicion for early AMI. However, this classic descriptor
risk factors for SMAE are arrhythmias, cardioversion, cardiac
is present in only 30% to 50% of patients, so its absence should
catheterization, myocardial infarction or dyskinesia, congestive
not exclude the diagnosis. Compared to patients with AMI due
heart failure, valvular heart disease, atheromatous cholesterol
to arterial embolus or thrombus, patients with NOMI have pain
embolism, previous embolism, and age older than 50 years.
less often and more commonly present with nausea, abdom-
SMA thrombus (SMAT) accounts for about 25% of cases of
inal distention, fever, diarrhea, and altered mental status. With
primary mesenteric small- bowel ischemia. Nonlaminar blood
a delayed or late presentation, intestinal ischemia progresses to
flow around vessel branch points makes the ostia of mesenteric
infarction with peritoneal findings on abdominal examination.
vessels a common location for development of atherosclerotic di-
sease; therefore, acute thrombosis often occurs at the origin of
the SMA, which results in occlusion of blood flow at a level that Diagnosis of AMI
is typically more proximal to that in embolic AMI. The result is
In the early course of AMI, before intestinal infarction develops,
a longer section of ischemic bowel and consequently a higher
laboratory and abdominal imaging findings are nonspecific. The
mortality rate. Risk factors for SMAT include old age; low-flow
peripheral leukocyte count is usually high. A serum lactate con-
states (arrhythmia, hypotension, sepsis, dialysis, vasoconstric-
centration within the reference range should not be used to ex-
tive drugs, myocardial infarction, dyskinesia, and congestive
clude the diagnosis.
heart failure); atherosclerosis (acute-on-chronic ischemia, hyper-
Computed tomographic angiography (CTA), the recommended
tension, type 2 diabetes, hyperlipidemia, smoking history, and
method of imaging for diagnosis of AMI, depicts the origins and
vasculopathy); hypercoagulable states; vasculitis; fibromuscular
lengths of vessels and characterizes the occlusion. CTA has a
dysplasia; trauma; and aortic or mesenteric artery aneurysm. Up
95% sensitivity and specificity in the diagnosis of AMI. Given
to one-third of patients with SMAT have a history of CMI (see
the potentially catastrophic consequences of a missed diagnosis
below).
of AMI, laboratory results that indicate a high creatinine value or
Mesenteric venous thrombosis, usually superior mesenteric
kidney insufficiency should not preclude performance of CTA.
vein thrombosis (up to 95% of cases), accounts for about 5% of
Magnetic resonance angiography avoids the risks of radiation and
contrast exposure but takes longer and is less sensitive for distal
and nonocclusive disease. Duplex ultrasonography is an effective,
Table 11.2. Causes and Frequencies of Acute Mesenteric low-cost method to assess the proximal mesenteric vessels, but
Ischemia adequate ultrasonography often cannot be performed in patients
with AMI. The classic angiographic finding in obstructive AMI is
Cause Frequency, %
an embolus or thrombus in the SMA (Figure 11.1). The diagnosis
SMA embolus 50 of NOMI is made by excluding an obstructive mesenteric process
SMA thrombosis 25 with the following angiographic features: 1) narrowing of the
Nonocclusive mesenteric ischemia 20
origins of the SMA branches, 2) irregularities of these branches,
Mesenteric venous thrombosis 5
3) spasm of the mesenteric arcades, and 4) impaired filling of
Abbreviation: SMA, superior mesenteric artery. intramural vessels. The most important factor in improving
11. Vascular Disorders of the Gastrointestinal Tract 135
After aggressive resuscitation and administration of intrave-

nous heparin and broad-spectrum antibiotics, emergent surgery
is indicated if mesenteric infarction is suggested from imaging
findings such as gas within the intestinal wall (pneumatosis
intestinalis) or in the portal vein (Figure 11.2). Otherwise, angi-
ography with selective catheterization of the mesenteric vessels
may be performed, along with endovascular intervention, if
possible.
✓ Acute mesenteric ischemia—an abrupt decrease in blood flow to

the small bowel
✓ Most common cause of acute mesenteric ischemia (AMI)—

emboli to the superior mesenteric artery (SMA)
✓ Major risk factors for SMA embolus include arrhythmias, my-
ocardial infarction, congestive heart failure, and valvular heart
disease
✓ Early diagnosis of AMI requires a high degree of clinical
awareness
✓ In the early course of AMI, findings from examination of the ab-
domen may be falsely reassuring with “pain out of proportion to
physical examination findings”
✓ A serum lactate concentration within the reference range should
not be used to exclude the diagnosis of AMI
✓ Computed tomographic angiography is the recommended method
of imaging for diagnosis of AMI
✓ The 3 R’s for management of AMI: resuscitation, rapid diagnosis,
and revascularization
Figure 11.1. Embolic Occlusion of the Proximal Superior

Mesenteric Artery (SMA). Computed tomographic angiography, sag- Chronic Mesenteric Ischemia
ittal view, shows the narrowed SMA distal to the embolus.
Epidemiology and Pathogenesis
outcome in AMI is timely diagnosis before the occurrence of gut CMI is the least common ischemic gut syndrome (<5% of
infarction. Once mesenteric infarction occurs, the mortality of cases) and involves a gradual decrease in blood flow to the small
patients with AMI exceeds 60% even with surgery. intestine over months to years. It most commonly results from
atherosclerosis involving the proximal segments of the mes-
enteric arteries (95% of cases), but it can also be a manifes-
Management of AMI
tation of nonatherosclerotic disorders such as median arcuate
Management for patients with AMI can be remembered by the ligament syndrome, vasculitic syndromes, isolated dissection of
3 R’s: resuscitation, rapid diagnosis, and revascularization. the visceral arteries, radiation, and fibromuscular dysplasia. It
Figure 11.2. Mesenteric Infarction. Computed tomography of the abdomen, axial view, shows portal venous gas represented by linear branching
lucencies in the liver (A) and pneumatosis intestinalis represented by linear lucencies in the bowel wall (B).
is thought that less than 1 in every 100,000 hospital admissions ✓ Postprandial abdominal pain—the hallmark symptom of chronic
is due to CMI. A common history with atherosclerotic-related mesenteric ischemia (CMI)
CMI includes previous vascular disease, hypertension, type 2 ✓ Diagnosis of CMI requires compatible ischemic symptoms, ex-
diabetes, kidney insufficiency, and smoking. CMI occurs with clusion of alternative causes of postprandial abdominal pain and
severe narrowing of 2 of the 3 adjacent mesenteric vessels (CA, weight loss, and compatible angiographic findings
SMA, and IMA). ✓ Most patients with ischemic symptoms have severe stenosis
(>70%) in at least 2 of 3 mesenteric arteries
✓ Chronic mesenteric ischemia— a gradual decrease in blood ✓ CMI is treated with either percutaneous endovascular stenting or
flow to the small intestine that most commonly results from surgical revascularization
atherosclerosis

Colonic Ischemia
Clinical Manifestations of CMI
Epidemiology and Pathogenesis
Postprandial abdominal pain is the hallmark symptom of CMI.
CI is an acute event that is the most common form of ischemic
Occurrence of abdominal pain 30 to 60 minutes after eating is
bowel disease. The incidence of CI increased from 6 per 100,000
characteristic and is often self- treated with food restriction,
people in 1976-1980 to 23 per 100,000 in 2005-2009. This in-
which results in weight loss and often sitophobia (ie, fear of
crease may have resulted from several factors, such as a longer life
food). This classic symptom triad of postprandial abdominal pain,
expectancy of patients who have many comorbid conditions and
sitophobia, and weight loss is present in only 30% of patients
an increased recognition of CI. Most cases of CI are idiopathic
with CMI, though, and CMI should be suspected in patients who
and result from a nonocclusive low-flow state in microvessels,
have recurrent postprandial abdominal pain. The pain begins ap-
which occurs in the setting of hypovolemia or hypotension. Risk
proximately 20 to 30 minutes after ingestion of food because the
factors for CI include older age (>60 years), female sex, vaso-
fixed narrowing of the mesenteric arteries prevents blood flow
constrictive and antihypertension medications, irritable bowel
from increasing and meeting the increased functional demand of
syndrome, constipation, thrombophilia, and chronic obstructive
the stomach with resultant steal ischemia. If not treated, the con-
pulmonary disease. The degree of ischemic injury is dependent
dition in up to 50% of patients with CMI will progress to life-
on the duration of low-flow perfusion, the existence of collateral
threatening AMI.
circulation, and the extent of the involved area.
Diagnosis and Treatment of CMI ✓ Colonic ischemia—an acute event that most often results from a
nonocclusive low-flow state in microvessels

The diagnosis of CMI requires compatible ischemic symptoms,
exclusion of alternative causes of postprandial abdominal pain and
weight loss, and compatible angiographic findings (Box 11.1).
A critical step is to rule out other intra-abdominal processes that Anatomical Considerations
cause postprandial pain and weight loss, such as peptic ulcer di- The SMA and the IMA supply most of the blood to the colon.
sease, pancreaticobiliary disease, and malignancy. CTA is the Robust collateral vascular pathways (the marginal artery of
standard and preferred imaging modality for CMI. Most patients Drummond and the arc of Riolan) protect the colon from is-
with ischemic symptoms have severe stenosis (>70%) in at least chemic injury. However, the right colon, splenic flexure, and
2 of 3 mesenteric arteries because of the numerous collateral rectosigmoid junction are regions of the colon that are more
pathways that allow for redundant flow to the mesenteric vascular susceptible to ischemia. The right colon has less developed vasa
territories. However, patients may have ischemic symptoms even recta (ie, end-arteries providing blood to the colonic wall), and
with single-vessel stenosis if they have poor collateral circula- the splenic flexure and rectosigmoid junction are watershed
tion, but this is uncommon (<5% of patients). areas. These watershed regions are more susceptible to ischemia
Traditionally, CMI was treated with either percutaneous as they lie at the most distal reaches of the arterial blood supply
endovascular stenting or surgical revascularization. The choice (ie, the border zones between 2 arterial territories).
of therapy depended on operative risk and occlusive lesion char-
acteristics. However, endovascular therapy with balloon expand-
able stents is now the preferred method for revascularization Clinical Manifestations of CI
because of lower periprocedural morbidity and mortality when CI manifests with a wide spectrum of injury that includes both
compared with surgical revascularization. Early diagnosis and reversible and irreversible ischemic disease. Reversible types
treatment of CMI is important to prevent life-threatening acute- of CI include colopathy (subepithelial hemorrhage and edema)
on-chronic MI. and transient ulcerating colitis. Irreversible CI includes chronic
segmental ulcerating colitis, fibrotic stricture, and gangrenous
bowel. The initial presentation of CI is the same for both revers-
ible and irreversible types.
Box 11.1. Criteria for Diagnosis of Chronic Mesenteric Patients with CI most commonly present with an abrupt onset
Ischemia of lower abdominal discomfort that is mild to moderate and
cramping; within 24 hours diarrhea and hematochezia occur.
Consistent symptoms
The onset of bleeding often prompts the patient to seek med-
Exclusion of alternative causes ical attention. On physical examination, a typical finding is mild
Compatible angiographic findings lower abdominal tenderness over the involved bowel segment
without peritoneal signs.
Diagnosis of CI
The diagnosis of CI is made clinically and supported by radio-
graphic imaging and colonoscopic evaluation. Laboratory studies
may show mild increases in the leukocyte count and the serum
urea nitrogen level.
Plain radiographs of the abdomen may show evidence of sub-
mucosal edema and hemorrhage, so-called thumbprinting (Figure
11.3), or the findings may be normal. CT of the abdomen is in-
dicated to assess the severity, phase, and distribution of CI. The
phase of CI can be broadly described as hemorrhagic with marked
thickening on CT or predominantly ischemic with wall thinning. CT
findings in CI are nonspecific and include thickening of the bowel
wall (Figure 11.4) and pericolonic fat stranding (ie, an increase in
density within pericolonic fat secondary to inflammation), often in
the distribution of the watershed areas of the colon (splenic flexure
and rectosigmoid junction). CI is typically a segmental disease that
can involve any region of the colon, but the left side is most affected.
Pancolonic and rectal involvement are rare. Infections with agents
such as the following can mimic CI and must be excluded: cyto-
megalovirus, Clostridioides difficile, and Shiga toxin–producing Figure 11.4. Bowel Wall Thickening in Colonic Ischemia. Computed
Escherichia coli. Colonoscopy with biopsy is the test of choice tomography of the abdomen, axial view, shows segmental thickening of
to confirm the diagnosis of CI. The findings vary in severity and the transverse colon (arrow) in a patient with colonic ischemia.
include erythema, edema, friability, ulcerations, and blue- black
nodules suggestive of gangrenous infarction (Figure 11.5). The co-
lonic single-stripe sign, an erythematous band of ulceration along epithelial necrosis, submucosal hemorrhage and edema, and neu-
the longitudinal axis of the colon, is a highly specific endoscopic trophilic infiltrate (Figure 11.7), but they are helpful in making the
sign of CI and is a predictor of a good outcome (Figure 11.6). diagnosis when considered in clinical context.
Biopsies should be performed unless there is evidence of infarc- Because CI is most often caused by a nonocclusive low-flow
tion. Histopathology findings in CI are often nonspecific, showing state of the microvasculature, dedicated imaging of the mesenteric
arteries is of low yield and generally not indicated. The exception is
right-sided CI, which can be a harbinger of AMI caused by a focal
thrombus or embolus of the SMA. Therefore, patients with right-
sided CI should undergo noninvasive imaging of the mesenteric
vasculature to exclude an occlusive process of the SMA.
Treatment of CI
Most cases of CI are mild and transient, with a rapid spontaneous
resolution. Patients who have more severe disease require hospi-
talization for supportive care with bowel rest, restoration of in-
travascular volume, antimicrobial therapy (in many cases), and
close observation. Patients who have CI and several risk factors
for poor outcome should receive broad- spectrum antibiotics.
As an aid that can help guide antibiotic therapy, the American
College of Gastroenterology has devised a risk stratification
based on features associated with poor outcomes in patients with
CI (Table 11.3). Antibiotics are predicted to improve outcomes
by decreasing bacterial translocation from lack of mucosal integ-
rity. Only a small percentage of patients with CI require opera-
tive intervention for necrotic bowel or irreversible complications,
such as gangrene or fibrotic stricture.
✓ The splenic flexure and rectosigmoid junction are watershed areas

that are more susceptible to ischemia
✓ Patients with CI usually present with an abrupt onset of cramping
and mild to moderate discomfort in the lower abdomen; within 24
hours diarrhea and hematochezia occur
✓ Diagnosis of CI is made clinically and supported by radiographic
and colonoscopic findings
✓ Colonoscopy with biopsy is the test of choice to confirm the diag-
nosis of CI
Figure 11.3. “Thumbprinting” in Colonic Ischemia. Abdominal ✓ Most cases of CI are mild and transient, with rapid spontaneous
radiograph shows thumbprinting (arrowhead), which indicates thick- resolution
ening of haustral folds from severe submucosal hemorrhage and edema.
Figure 11.5. Spectrum of Endoscopic Findings in Colonic Ischemia. The range of findings includes mild edema and erythema (A); erythema,
edema, and erosions (B); extensive ulceration (C); and hemorrhagic blue-black nodules (D).
Focal Segmental Ischemia because the collateral blood flow is usually adequate to prevent
transmural infarction. Among the many causes of FSI, the most
FSI is a condition characterized by vascular insults to short
frequent are atheromatous emboli, strangulated hernias, vascu-
segments of the small intestine without the life-threatening
litis, segmental venous thrombosis, and radiotherapy.
consequences that characterize the other ischemic syndromes
✓ Focal segmental ischemia—an ischemic syndrome characterized
by vascular insults to short segments of the small intestine

FSI has a broad spectrum of clinical features but generally

manifests in 1 of 3 ways: acute enteritis, chronic enteritis, or chronic
small bowel obstruction. The acute enteritis form often mimics ap-
pendicitis with an acute abdomen. Patients with the chronic enteritis
variety may appear to have Crohn disease with fever, intermittent
cramping, abdominal pain, and diarrhea. The most common pre-
sentation of FSI is that of chronic small bowel obstruction from a
stricture with intermittent abdominal pain. Radiologic evaluation
of the acute and chronic enteritis forms usually shows segmental
thickening of the small bowel (Figure 11.8). Imaging of chronic
FSI typically shows a smooth, tapered stricture of variable length.
Treatment of FSI is surgical resection of the involved bowel.
✓ FSI has a broad spectrum of clinical features but generally

manifests in 1 of 3 ways: acute enteritis, chronic enteritis, or
chronic small bowel obstruction
✓ Imaging of chronic FSI typically shows a smooth, tapered stric-
ture of variable length
✓ Treatment of FSI—surgical resection of the involved bowel
Miscellaneous Syndromes
Median Arcuate Ligament Syndrome
Figure 11.6. Colonic Single-Stripe Sign. The single-stripe sign is a
highly specific endoscopic finding for colonic ischemia and indicates a Median arcuate ligament syndrome (MALS), also known as celiac
favorable prognosis. artery compression syndrome, is a rare condition that results from
Figure 11.7. Histologic Findings in Mild Colonic Ischemia. The findings include surface and crypt epithelial necrosis with focal crypt preservation.
extrinsic compression of the celiac axis (celiac artery or celiac necrotizing vasculitis involving small and medium-sized arteries
ganglion or both) by the MAL and diaphragmatic crura. Ischemia and gastrointestinal manifestations due to mesenteric vasculitis
to the gut is unlikely to cause the pain (because only 1 vessel is and can occur in 60% of patients. Many patients have fever,
affected, and collateral blood flow exists). Alternatively, the pain abdominal pain, increased levels of inflammatory markers, hy-
associated with MALS may be neuropathic resulting from com- pertension, and multiple organ involvement. Some have gastroin-
pression and stimulation of the celiac ganglion. MALS most com- testinal tract bleeding or perforation. Most cases of polyarteritis
monly occurs in women aged 30 to 50 years and in individuals nodosa are idiopathic, although hepatitis B virus infection, hep-
who have a thin body habitus. Its hallmark characteristics include atitis C virus infection, and hairy cell leukemia are important in
postprandial abdominal pain, nausea, vomiting, diarrhea, and the pathogenesis of some cases. The characteristic CTA finding
weight loss. MALS is a diagnosis of exclusion; other possible is mesenteric arterial segmental microaneurysms. CTA can be
causes of the symptoms must be excluded. On lateral mesenteric used to detect aneurysms in vessels as small as 3 mm and is the
angiography, a typical concave defect is evident over the superior recommended initial test in suspected cases. However, catheter-
aspect of the celiac artery near its takeoff from the aorta (Figure based angiography has superior spatial resolution and is preferred
11.9) with respiratory variability. Treatment is laparoscopic sur- if suspicion is high despite negative CTA findings.
gical MAL release or celiac ganglionectomy (or both). Immunoglobulin A vasculitis, formerly known as Henoch-
Schönlein purpura, is an immune complex–mediated vasculitis
affecting small blood vessels. Characteristic clinical features in-
Vasculitis
clude palpable purpura, arthritis, kidney, and gastrointestinal tract
Many types of vasculitis can involve the gastrointestinal tract, involvement. A palpable purpuric skin rash occurs in all patients
most commonly by FSI. Polyarteritis nodosa is a systemic and predominates on the lower extremities. Gastrointestinal tract
involvement occurs in 50% of patients; abdominal pain and
Table 11.3. CI Disease Severity and Use of Antibiotics

Disease Features in a patient with typical Antibiotics
severity signs and symptoms of CI recommended?
Mild No risk factors for poor outcomea No
Moderate ≤3 Risk factors for poor outcomea Yes
Severe >3 Risk factors for poor outcomea Yes
or
Peritoneal signs, pneumatosis, portal
venous gas, gangrene on colonic
examination
Abbreviation: CI, colonic ischemia.

a
Risk factors for poor outcome: male gender; hypotension (systolic blood
pressure <90 mm Hg); tachycardia (heart rate >100 beats/min); abdominal pain
without rectal bleeding; colonic mucosal ulceration on colonic examination;
increased serum urea nitrogen (>20 mg/dL), lactate dehydrogenase (>350 U/L),
and white blood cell count (>15×109/L); and decreased hemoglobin (<12 g/dL)
and serum sodium (<136 mmol/L).
Adapted from Brandt LJ, Feuerstadt P, Longstreth GF, Boley SJ, American
College of Gastroenterology. ACG clinical guideline: epidemiology, risk factors, Figure 11.8. Focal Segmental Ischemia. Computed tomography of
patterns of presentation, diagnosis, and management of colon ischemia (CI). Am the abdomen, axial view, shows a region of jejunal thickening in a patient
J Gastroenterol. 2015 Jan;110(1):18-44; used with permission. with immunoglobulin A vasculitis.
Figure 11.10. Lupus Enteritis. Computed tomography of the ab-

domen, coronal view, shows diffuse wall thickening and submucosal
edema involving the entire small bowel and colon in a patient with lupus
enteritis.
Figure 11.9. Median Arcuate Ligament Compression. Computed if gastrointestinal tract manifestations develop, they usually arise
tomographic mesenteric angiogram, sagittal view, shows a concave de- several months after other symptoms of ANCA-associated vascu-
fect in the celiac artery (arrow) related to compression of the median litis. In a small percentage of patients with long-standing or un-
arcuate ligament. controlled rheumatoid arthritis (RA), small-vessel vasculitis may
involve the gastrointestinal tract. Risk factors for development
of RA-associated vasculitis include high titers of rheumatoid
bleeding are frequent manifestations. In a subset of patients, gas- factor, subcutaneous nodules, and long-standing erosive arthritis.
trointestinal tract manifestations precede the onset of palpable Patients with RA-associated mesenteric vasculitis present with
purpura, which may confound the diagnosis. abdominal pain and bleeding that results from ischemic ulcera-
Systemic lupus erythematosus (SLE) is a systemic autoim- tion of the gastrointestinal tract mucosa.
mune disease characterized by immune complex formation. Behçet disease is a multisystem vasculitis characterized by oral
SLE has the potential to affect virtually every organ system, in- and genital ulcers, skin lesions, and recurrent iritis. Gastrointestinal
cluding the gastrointestinal system. Mild gastrointestinal tract in- tract involvement most often affects the ileocecal region with large,
volvement is common and most commonly consists of nausea deep ulcerations resulting in bleeding and perforation. This vascu-
and vomiting, anorexia, and abdominal pain. A subset of SLE litis often mimics Crohn disease in presentation.
patients have mesenteric vasculitis (Figure 11.10), also termed
lupus enteritis, and most commonly present with abdominal
pain. Mesenteric vasculitis is usually associated with active di- Visceral Aneurysms
sease involving other organs, and gastrointestinal tract activity The most common location of visceral artery aneurysms (VAAs)
arising in isolation without additional manifestations of active is the splenic artery (70% of cases). Splenic artery aneurysms
SLE is highly unusual. Mesenteric vasculitis leads to ischemia are more common in women and are associated with medial
and infarctions of the bowel wall and perforation. fibrodysplasia, multiple pregnancies, portal hypertension, and
Antineutrophil cytoplasmic antibody (ANCA)- associated liver transplant. The second most common location of VAAs is the
vasculitis includes 3 diseases: granulomatosis with polyangiitis hepatic artery (20% of cases). They are usually extrahepatic and
(formerly Wegener granulomatosis), eosinophilic granulomatosis occur more frequently in men. Intrahepatic aneurysms typically
with polyangiitis (formerly Churg- Strauss syndrome), and develop from trauma or percutaneous interventions. Hemobilia
microscopic polyangiitis. They are small- vessel necrotizing may occur with hepatic artery aneurysms. Pseudoaneurysms of
vasculitides that uncommonly affect the mesenteric circulation; peripancreatic vessels, the most common being splenic artery,
can complicate necrotizing pancreatitis and present with gastroin- ✓ Vascular EDS— life-
threatening complications can occur (eg,
testinal tract or intraperitoneal hemorrhage. SMA aneurysms are VAA formation and dissection and spontaneous organ rupture)
rare and associated with endocarditis. Symptomatic aneurysms,
sizable aneurysms (hepatic artery aneurysm ≥1 cm or splenic ar-
tery aneurysm ≥2 cm), and splenic artery aneurysms discovered
during pregnancy should be treated, usually with interventional Suggested Reading
radiology. Ahmed M. Ischemic bowel disease in 2021. World J Gastroenterol. 2021
Ehlers-Danlos syndrome (EDS) is a group of clinically and Aug;27(29):4746–62.
genetically heterogeneous, heritable connective tissue disorders Bala M, Kashuk J, Moore EE, Kluger Y, Biffl W, Gomes CA, et al. Acute
affecting skin, bones, and other organs and systems. Life- mesenteric ischemia: guidelines of the World Society of Emergency
threatening complications such as VAA formation and dissection Surgery. World J Emerg Surg. 2017;12:38.
and spontaneous organ rupture (most commonly colon and Brandt LJ, Feuerstadt P, Longstreth GF, Boley SJ, American College of
Gastroenterology. ACG clinical guideline: epidemiology, risk factors,
uterus) are limited to vascular EDS, previously known as EDS
patterns of presentation, diagnosis, and management of colon is-
type 4. Vascular EDS is caused by alterations of the autosomal chemia (CI). Am J Gastroenterol. 2015 Jan;110(1):18–44.
dominant gene COL3A1 leading to defective type III collagen Clair DG, Beach JM. Mesenteric ischemia. N Engl J Med. 2016
in the lungs, skin, intestines, and blood vessels. Vascular EDS Mar;374(10):959–68.
is associated with characteristic facies, thin or translucent skin, Cotter TG, Bledsoe AC, Sweetser S. Colon ischemia: an update for
and easy bruising. clinicians. Mayo Clin Proc. 2016 May;91(5):671–7.
Kim EN, Lamb K, Relles D, Moudgill N, DiMuzio PJ, Eisenberg JA.
✓ Diagnosis of median arcuate ligament syndrome requires exclu- Median arcuate ligament syndrome: review of this rare disease.
sion of other possible causes of abdominal pain, nausea, vomiting, JAMA Surg. 2016 May;151(5):471–7.
diarrhea, and weight loss Koster MJ, Warrington KJ. Vasculitis of the mesenteric circulation. Best
✓ Polyarteritis nodosa and immunoglobulin A vasculitis— Pract Res Clin Gastroenterol. 2017 Feb;31(1):85–96.
systemic vasculitides that commonly have gastrointestinal Luther B, Mamopoulos A, Lehmann C, Klar E. The ongoing challenge of
tract involvement acute mesenteric ischemia. Visc Med. 2018 Jul;34(3):217–23.
✓ Behçet disease— gastrointestinal tract involvement most often Sardar P, White CJ. Chronic mesenteric ischemia: diagnosis and manage-
affects the ileocecal region, where large, deep ulcerations result in ment. Prog Cardiovasc Dis. 2021 Mar-Apr;65:71–5.
bleeding and perforation Singal AK, Kamath PS, Tefferi A. Mesenteric venous thrombosis. Mayo
Clin Proc. 2013 Mar;88(3):285–94.
12
Gastrointestinal Manifestations
of Systemic Diseasea
SETH R. SWEETSER, MD
Many systemic diseases can have gastrointestinal (GI) mani patients with aortic stenosis, the aortic wall shear stress is high. As
festations. Both the gut and the liver may be the main targets a result of high macrovascular shear stress, there is increased con-
of the disease process, or they may be affected indirectly; in ei- sumption of high-molecular-weight multimers of von Willebrand
ther case, the GI symptoms or signs may be the initial reason factor (vWF) from the increased activity of shear- dependent
for seeking medical attention. This chapter is an overview of vWF-cleaving metalloprotease. This leads to a relative deficiency
the more common systemic disorders that have well-recognized of high-molecular-weight multimers of vWF and an acquired
GI and liver manifestations, with an emphasis on disorders not type IIA von Willebrand disease that predisposes the patient to
considered elsewhere in this book. clinically manifest bleeding from angiectatic lesions in the GI
tract. Support for this pathophysiologic mechanism comes from
observations that the severity of GI bleeding from GI angiectasias
Cardiovascular Diseases
decreases after aortic valve replacement, which is associated with
Aortic Stenosis a concomitant increase in the level of circulating high-molecular-
Aortic stenosis is associated with an increased incidence of GI weight vWF multimers. Similarly, hypertrophic obstructive car-
bleeding (Heyde syndrome). The GI bleeding in patients with diomyopathy has been associated with GI angiectasias.
aortic stenosis is typically from small intestinal angiectasias. In
Heart Failure
Impairment of myocardial filling or contraction results in inad-
a
Portions previously published in Sweetser S, Camilleri M. Gastrointestinal
manifestations and management. In: Varga J, Denton CP, Wigley FM, eds. equate perfusion of tissues and a resultant inability to maintain
Scleroderma: from pathogenesis to comprehensive management. Springer; metabolic demands. Heart failure leads to congestion of the mes-
2012:463-9 and Podboy A, Anderson BW, Sweetser S. 61-year-old man enteric venous system, which can manifest with anorexia, nausea,
with chronic diarrhea. Mayo Clin Proc. 2016 Feb;91(2):e23-8; used with bloating, and abdominal pain. In extreme cases, mesenteric ve-
permission nous congestion results in diarrhea, malabsorption, protein-
Abbreviations: ALA, aminolevulinic acid; BD, Behçet disease; BRBNS, losing enteropathy, and the clinical picture of cardiac cachexia.
blue rubber bleb nevus syndrome; CF, cystic fibrosis; CVID, common Hepatic congestion from right- sided heart failure may cause
variable immunodeficiency; DIOS, distal intestinal obstruction syn- hepatomegaly, jaundice, abnormal liver test results, and a high
drome; DM, diabetes mellitus; EPS, encapsulating peritoneal sclerosis; serum-ascites albumin gradient. In cases of prolonged hepatic
GI, gastrointestinal; GVHD, graft-versus-host disease; HHT, hereditary congestion from heart failure, cardiac cirrhosis may develop.
hemorrhagic telangiectasia; HSP, Henoch- Schönlein purpura; KTW,
Klippel-Trénaunay-Weber; PAN, polyarteritis nodosa; PCI, pneumatosis ✓ Aortic stenosis causing acquired von Willebrand disease that is
cystoides intestinalis; RA, rheumatoid arthritis; SCD, sickle cell disease; associated with GI bleeding from small-intestinal angiectasias is
SIBO, small intestinal bacterial overgrowth; SLE, systemic lupus erythe- known as Heyde syndrome
matosus; vWF, von Willebrand factor
143
✓ Heart failure may result in mesenteric venous congestion causing

diarrhea, malabsorption, protein-losing enteropathy, and cardiac
cachexia
Vascular Diseases
Hereditary Hemorrhagic Telangiectasia
Hereditary hemorrhagic telangiectasia (HHT) (Osler- Weber-
Rendu syndrome) is an autosomal dominant disorder with high
penetrance and an estimated prevalence of 1 per 10,000. It is
characterized by the development of telangiectasias and arterio-
venous malformations throughout the body, and it has a propen-
sity to involve the small intestine. Mucocutaneous telangiectasias
typically develop in the second decade of life, leading to recur-
rent, spontaneous epistaxis, which is the most common manifes-
tation of HHT.
Clinical criteria for the diagnosis of HHT are the following:
1. Epistaxis— spontaneous, recurrent nosebleeds, usually present Figure 12.1. Endoscopic Finding of Jejunal Angiectasia in
since adolescence Hereditary Hemorrhagic Telangiectasia.
2. Telangiectasias—multiple lesions at characteristic sites (lips, oral
cavity, fingers, nose)
3. Visceral involvement—pulmonary, liver, central nervous system, on endoscopy, occurring throughout the GI tract (Figure 12.1).
GI tract Endoscopic ablation with argon plasma coagulation is commonly
4. Family history—a first-degree relative with definite HHT used for bleeding telangiectasias; antivascular endothelial growth
factor therapy is the mainstay of treatment.
If 3 of the 4 criteria are present, the clinical diagnosis of HHT is
definite. If 2 criteria are present, the diagnosis of HHT is prob-
able. If only 1 criterion is present, HHT is unlikely. Blue Rubber Bleb Nevus Syndrome
GI hemorrhage occurs in 30% of patients with HHT and does
Blue rubber bleb nevus syndrome (BRBNS) is a rare disorder
not usually start until the fourth or fifth decade of life. HHT is
characterized by the development of venous malformations in
the most common cause of diffuse vascular malformations of
many organs; the skin and GI tract are the organs most involved
the liver in adults. Although hepatic vascular malformations
(Figures 12.2 and 12.3). It is usually sporadic, but it may be
are present in most patients with HHT, symptoms occur in only
inherited in an autosomal dominant fashion. The 2 most common
30%. With the dual blood supply to the liver, 3 types of vas-
manifestations of BRBNS are skin lesions alone or iron defi-
cular shunts may develop, which give rise to 3 distinct clinical
ciency anemia from GI bleeding. Most patients with GI bleeding
presentations: high-output heart failure, portal hypertension, and
from BRBNS are asymptomatic and generally respond to blood
biliary disease (Box 12.1).
transfusion and oral iron supplementation. Capsule endoscopy
After recurrent epistaxis, GI bleeding is the most common
is a noninvasive way to exclude or confirm GI involvement
clinical manifestation of HHT. Telangiectasias are readily visible
(Figure 12.4), but the distribution of lesions is important to know
only if bleeding cannot be controlled by conservative measures.
Caution should be used when attempting endoscopic ablation of
lesions, which may involve the full thickness of the bowel wall,
Box 12.1. Three Distinct Clinical Manifestations so that perforation does not occur. The venous malformations can
of Liver Involvement in Hereditary Hemorrhagic cause numerous extraintestinal complications, including ortho-
Telangiectasia pedic deformities, central nervous system involvement, spinal
1. High-output heart failure results from an arteri cord compression, hemothorax, and hemopericardium.
ovenous shunt involving the hepatic artery and
hepatic veins. This is the most common initial man
ifestation of liver involvement in hereditary hemor Klippel-Trénaunay-Weber Syndrome
rhagic telangiectasia.
Klippel-Trénaunay-Weber (KTW) syndrome is a rare congen-
2. Portal hypertension results from a hepatic artery– ital vascular anomaly characterized by the clinical triad of 1) soft
portal vein fistula and occurs most commonly with tissue and bony hypertrophy of an extremity, 2) varicose veins
ascites.
limited to the affected side, and 3) vascular nevus of the hy-
3. Biliary disease with bile duct abnormalities is similar pertrophied extremity. The cause of this syndrome is unknown.
to sclerosing cholangitis. Bile duct abnormalities KTW can be diagnosed by the presence of any 2 of these 3 clin-
result from ischemia of the biliary tree because
ical features, with 60% of KTW patients having the full triad.
the bile ducts obtain all their blood supply from
the hepatic artery. Hepatic artery– hepatic vein
Visceral hemangiomas in KTW have been described involving
or hepatic artery– portal vein fistulas may cause organs such as the GI tract, liver, spleen, bladder, kidney, lung,
biliary ischemia. Clinical manifestations include and heart. GI hemorrhage is a potentially serious complication
right upper quadrant pain and cholestasis with or resulting from diffuse hemangiomatous involvement of the gut.
without cholangitis. Transfusion- dependent anemia and life- threatening bleeding
may result from extensive cavernous hemangiomas involving the
12. Gastrointestinal Manifestations of Systemic Disease 145
Figure 12.4. Capsule Endoscopic Finding of Characteristic

Venous Lesions of Blue Rubber Bleb Nevus Syndrome in Jejunum.
may be enhanced by consumption coagulopathy (Kasabach-

Merritt syndrome) resulting from intravascular clotting within
the venous sinusoids of the visceral hemangiomas. Endoscopic
therapy has a limited role in the management of colorectal intes-
Figure 12.2. Cutaneous Venous Bleb of Blue Rubber Bleb Nevus tinal hemangiomas in KTW and is best reserved for management
Syndrome. of localized lesions or ablation of postoperative residual disease.
Resection of the involved bowel segment is usually necessary to
adequately control bleeding.
rectum. Although diffuse cavernous hemangiomas of the distal
colon and rectum are the most reported causes of GI bleeding in
KTW, other potential causes of GI hemorrhage related to KTW Degos Disease
include localized rectovaginal varices caused by an obstructed Degos disease (malignant atrophic papulosis) is a vasculopathy
internal iliac system and portal hypertension–related bleeding of unknown cause characterized by a predominantly non-
from a hypoplastic portal venous system. GI bleeding in KTW inflammatory vascular occlusive process, mainly affecting
arterioles. Progressive arteriolar occlusion results in tissue
ischemia and infarction, which are responsible for the clin-
ical manifestations of the disease. Age at onset of the disease
ranges from the first months of life to the seventh decade. In
the GI tract, the submucosal arteries are typically affected,
causing infarction of the bowel. Endoscopic examination
may show infarcts and ulcers throughout the GI tract. The
most common cause of death in Degos disease is microvas-
cular infarctions in the intestines, resulting in perforation
and peritonitis. Cutaneous lesions typically precede visceral
symptoms and have a characteristic appearance described as
porcelain-white, atrophic, umbilicated papules with erythema-
tous or telangiectatic borders. There is no known treatment for
this disease, and it is usually fatal.
✓ HHT is an autosomal dominant disorder characterized by

telangiectasias and arteriovenous malformations involving the
skin, GI tract, and other organs
✓ GI hemorrhage occurs in 30% of patients with HHT and typically
begins in the fourth or fifth decade of life
✓ BRBNS is a rare disorder characterized by venous malformations
Figure 12.3. Colonoscopic Finding of Venous Lesions of Blue involving mainly the skin and GI tract
Rubber Bleb Nevus Syndrome.
✓ The clinical triad of KTW syndrome is soft tissue and bony hyper-
trophy of an extremity, varicose veins limited to the affected side,
and vascular nevus of the hypertrophied extremity
✓ GI bleeding in KTW syndrome is most commonly from a cav-
ernous hemangioma of the distal colon or rectum
Dermatologic Diseases
The skin and the GI tract may be affected concurrently by the same
processes. Although many dermatologic diseases can manifest
with involvement of the GI tract, 3 with notable GI manifestations
are epidermolysis bullosa, lichen planus, and mastocytosis.
(Mastocytosis is discussed in the Hematologic Disorders section
of this chapter.)
Epidermolysis Bullosa
Epidermolysis bullosa is an inherited disorder characterized
by the development of trauma-induced blisters with resultant
scarring. It results from mutations of genes encoding for structural
proteins located at the dermal-epidermal junction. Disruption in
these structural proteins results in mechanical fragility of the skin
and other epithelialized organs. It is important for the gastroente- Figure 12.5. Radiographic Findings in Lichen Planus of the
rologist to be aware of this condition because it may lead to poor Esophagus. Esophagogram shows diffuse esophageal narrowing and
dentition, dysphagia from esophageal strictures, malabsorption, areas of more focal narrowing.
severe constipation, and anal fissures. Minor trauma from food
boluses leads to bullae, ulceration, and scarring of the esophageal
mucosa with formation of strictures, most commonly in the prox- Koebner phenomenon with a predilection for disease to flare in
imal esophagus. Supportive therapy is the mainstay of treatment sites of trauma. Therefore, although esophageal dilation is often a
of epidermolysis bullosa. Minimizing trauma with a soft diet, necessary treatment to relieve dysphagia, unnecessary dilatations
attention to wound care, and adequate nutritional support are actually might cause a disease flare, particularly if done without
paramount. Antireflux measures and antisecretory medication concurrent therapies aimed at controlling the disease.
may help to minimize esophageal injury. It is important to be An increased risk of squamous cell carcinoma has been described
aware of the risk of mucosal trauma from endoscopic procedures. with lichen planus; however, there are no recommendations for
Esophageal strictures from epidermolysis bullosa are usually cancer screening of patients who have esophageal lichen planus,
dilated with balloons rather than bougies to avoid shearing forces although the co-occurrence should be entertained. The diagnosis
associated with bougies. of esophageal lichen planus should be considered for patients with
Lichen Planus
Lichen planus is a mucocutaneous, autoimmune, inflammatory
disease that most frequently involves the skin and oral mucosa.
Because lichen planus is a disease that affects squamous mucosa,
it can also involve the esophagus. Esophageal lichen planus is
predominantly a disease of middle-aged women. Up to 95% of
patients with esophageal lichen planus having preexisting oral
disease. Symptomatic esophageal involvement may be the initial
manifestation of the disease, and solid food dysphagia of vari-
able severity is the predominant symptom of esophageal disease.
There is typically a long delay in diagnosis, often preceded by
multiple endoscopies, dilations, and treatment of reflux.
A proximal esophageal stricture is a common finding, al-
though variations of esophageal disease include distal strictures,
multiple rings, and long esophageal strictures with a small-caliber
esophagus (Figure 12.5) that is radiologically identical to eosin-
ophilic esophagitis. Common endoscopic findings include diffi-
cult passage of the endoscope through the proximal esophagus
on initial esophageal intubation, mucosal thickening with su-
perficial ulceration, mucosal sloughing, and rings (Figure 12.6).
Mucosal sloughing is often evident on initial passage of the en- Figure 12.6. Endoscopic Findings in Esophageal Lichen
doscope or on withdrawal. This shearing off of friable epidermis Planus. Endoscopic examination shows multiple, thin, membranous
from minor endoscopic trauma has been termed an endoscopic webs and luminal narrowing.
refractory strictures, particularly middle-aged white women, with

or without known lichen planus. Box 12.2. Four Major Syndromic Presentations of
Symptomatic Patients With Gastrointestinal Amyloidosis
✓ Epidermolysis bullosa is an inherited blistering skin disease that 1. Gastrointestinal bleeding—secondary to vascular
can be complicated by esophageal strictures fragility, mucosal lesions, or ischemia
✓ The typical profile of a patient with esophageal lichen planus is a
middle-aged White woman with persistent dysphagia 2. Intestinal dysmotility—causing dysphagia, gastro
paresis, chronic intestinal pseudo- obstruction,
constipation, bacterial overgrowth, or bile acid
malabsorption
Hematologic Disorders 3. Malabsorption—due to mucosal infiltration
Amyloidosis 4. Protein-losing gastroenteropathy—should be
considered in patients with hypoalbuminemia
Amyloidosis is characterized by the extracellular deposition of and edema
an abnormal fibrillar protein, which disrupts tissue structure and
function. Amyloidosis can be acquired or hereditary, and sys-
temic or localized to 1 or more organs, such as the liver or the GI
tract. Amyloidosis is classified according to the type of precursor Less common GI manifestations include intestinal obstruction
protein. The 2 major types of amyloidosis with clinically impor- from amyloid masses, called amyloidomas, and cholangitis from
tant GI involvement are primary and secondary amyloidosis. In amyloid deposition around the ampulla of Vater, resulting in bil-
primary (AL) amyloidosis, the protein fibrils are composed of iary obstruction. Liver involvement is common in both AL amy-
fragments of monoclonal light chains; in reactive (secondary, loidosis and AA amyloidosis. Common symptoms with hepatic
AA) amyloidosis, the protein fibrils are composed of fragments amyloidosis include weight loss, fatigue, and abdominal pain.
of the circulating acute-phase reactant serum amyloid A protein. Most patients have hepatomegaly, with an elevated serum alka-
GI disease in amyloidosis results from either mucosal in- line phosphatase level being the most frequent abnormal liver test
filtration or neuromuscular infiltration. Within the GI tract, the result.
most common sites of infiltration are the descending duodenum The diagnosis of GI amyloidosis can be challenging in patients
(100%), the stomach and colorectum (>90%), and the esoph- without an established diagnosis of amyloidosis. It is important to
agus (70%). Mucosal infiltration by amyloid causes polypoid maintain a high degree of awareness when patients have disorders
protrusions, erosions, ulcerations (Figure 12.7), mucosal fria- known to be associated with amyloidosis, such as multiple mye-
bility, and wall thickening. loma and chronic inflammatory disorders. When AL amyloidosis
Characteristic endoscopic findings in AL amyloidosis in- is suspected, testing should be done to assess for the presence
clude submucosal hematomas and hemorrhagic bullous colitis. of serum or monoclonal proteins. However, diagnostic confir-
Neuromuscular infiltration initially affects the intrinsic enteric mation of GI involvement requires tissue biopsy of duodenal or
nervous system, resulting in a neuropathic process characterized colorectal mucosa, which is more sensitive than a subcutaneous
by normal amplitude but uncoordinated contractions. In more ad- fat biopsy. The diagnostic histologic finding is a red appearance
vanced disease, tissue wall infiltration causes a myopathic proof amyloid with Congo red stain under normal light microscopy
cess with low-amplitude contractions. and apple-green birefringence in polarized light (Figure 12.8).
Symptomatic patients with GI amyloidosis have 4 major Treatment of amyloid-related GI complications is directed to-
presentations: GI bleeding, chronic intestinal dysmotility, mal- ward symptom control and the underlying cause of amyloidosis.
absorption, and protein- losing gastroenteropathy (Box 12.2).
Porphyria
Porphyria results from a deficiency in 1 of the enzymes in-
volved in the heme synthetic pathway. The porphyrias are com-
monly classified by clinical features into 2 main groups: acute
porphyrias and cutaneous porphyrias. The acute porphyrias
are characterized by dramatic and potentially life-threatening
neurologic symptoms and usually present with severe abdom-
inal pain, whereas the cutaneous porphyrias have no neurologic
or abdominal symptoms but instead manifest with severe skin
photosensitivity.
The 4 acute porphyrias are acute intermittent porphyria, var-
iegate porphyria, hereditary coproporphyria, and aminolevulinic
acid (ALA) dehydratase deficiency porphyria. Acute intermittent
porphyria is the most common acute porphyria. Patients with any
of the 4 acute porphyrias can present with acute neurovisceral
attacks consisting of severe abdominal pain, nausea and vomiting,
constipation, tachycardia, paresthesias, weakness, dark urine, and
peripheral sensory deficits. The abdominal pain of acute attacks
typically develops gradually over hours and lasts days. Factors
that commonly precipitate an episode of acute porphyria include
Figure 12.7. Amyloid Ulcer. This large amyloid ulcer with certain medications, alcohol ingestion, smoking, fasting or ca-
surrounding polypoid mucosa was in the gastric antrum. loric restriction, infections, and pregnancy.
Figure 12.8. Histologic Appearance of Amyloid in Intestinal Biopsy Specimen. A, Subtle pink staining of thickened blood vessel walls in lamina
propria suggestive of amyloid. B, Congo Red staining of amyloid. C, Characteristic apple-green birefringence of amyloid in blood vessel walls under
polarized light.
Acute intermittent porphyria is inherited in an autosomal Givosiran is a small interfering RNA that neutralizes excess ALA
dominant manner with low penetrance. It is associated with synthase mRNA in hepatocytes, an effect that decreases the pro-
increased levels of ALA and porphobilinogen; there are no duction of ALA and porphobilinogen. Givosiran is approved for
skin findings. Variegate porphyria is characterized by increased treatment of acute intermittent porphyria and has been shown to
levels of urine coproporphyrin and stool protoporphyrin and
coproporphyrin; patients can have skin disease, with or without
an abdominal attack. In hereditary coproporphyria, stool and
urine coproporphyrin levels are increased; skin disease can be
present, usually with an abdominal attack. In the very rare ALA
dehydratase deficiency porphyria, only the ALA level is increased;
there are no skin findings, and the condition is autosomal reces-
sive. Urine ALA and porphobilinogen levels are always increased
during an acute abdominal crisis (ALA accumulates in the ab-
sence of ALA dehydratase). In acute intermittent porphyria, urine
ALA and porphobilinogen values usually are increased between
attacks. The diagnostic test for acute intermittent porphyria is a
spot urine sample for porphobilinogen.
The most common cutaneous porphyria is porphyria cutanea
tarda, which affects only the skin and is associated with high
alcohol intake, iron overload states such as hereditary hemo-
chromatosis, hepatitis C virus infection, and systemic illnesses
including systemic lupus erythematosus (SLE), diabetes mellitus
(DM), and chronic kidney disease. Excess porphyrins, which are
photoreactive, are deposited in the dermis, causing tissue damage
that manifests as vesicles and bullae.
The second most common cutaneous porphyria is erythro-
poietic protoporphyria, with exquisite photosensitivity being its
principal clinical manifestation. In addition, in 10% of patients,
clinically evident liver disease (cirrhosis and liver failure) results
from progressive hepatic accumulation of protoporphyrin (Figure
12.9). In patients with erythropoietic protoporphyria, liver dis
ease typically occurs after age 30 years; the urine is notable in
lacking porphyrin metabolites, which are detected only in the
stool. The diagnosis of acute porphyria should be considered if
patients have recurrent episodes of severe abdominal pain, consti-
pation, dark urine, and neuropsychiatric disturbances, while the
diagnosis of cutaneous porphyria should be considered if patients
have typical dermatologic findings.
Management of an acute porphyric attack consists of
quickly identifying and reversing the precipitating factors.
Acetaminophen, meperidine, and morphine can be used safely
Figure 12.9. Erythropoietic Protoporphyria. A, Liver biopsy spec-
for pain management. Ondansetron is the preferred antiemetic, imen shows distorted lobular architecture with red-brown protoporphyrin
and use of promethazine should be avoided. Intravenous glucose pigment in hepatocytes and lumen of bile canaliculi (hematoxylin-eosin,
is beneficial. The definitive treatment of an acute porphyric attack original magnification ×200). B, Polarizing microscopy shows character-
is intravenous hemin, which replenishes the depleted heme pool istic bright red and centrally located Maltese cross appearance of globular
and ameliorates signs and symptoms of the acute porphyric attack. protoporphyrin deposits (hematoxylin-eosin, original magnification ×200).
substantially decrease the rate of acute attacks. Liver transplant is masses of sickled erythrocytes in the liver. The gallstones in SCD
the final treatment option for acute porphyrias. are typically of the black-pigment type as a result of increased bil-
irubin excretion. They are commonly seen on plain radiographs
because the bilirubin is in the form of a calcium salt. There is
Systemic Mastocytosis
an increased incidence of cholecystitis and choledocholithiasis in
Mastocytosis refers to the infiltration of mast cells in the skin or SCD. Cholecystectomy is the most frequent surgical procedure in
various other organs. Cutaneous mastocytosis is the most common patients with SCD, and some experts advocate early cholecystec-
form; however, the spectrum of disease includes symptoms related tomy in asymptomatic patients.
to the release of mast cell mediators (eg, histamine) and signs Liver abscesses are more common in SCD due to asplenism
resulting from multiorgan mast cell infiltration, including infil- and an impaired reticuloendothelial system. Patients with
tration of the liver and intestines. The characteristic dermatologic SCD have a notable predisposition to liver abscesses due to
lesion is urticaria pigmentosa, which manifests as yellow- tan Yersinia enterocolitica infection because of iron overload and
macules involving the extremities and trunk, with the classic deferoxamine therapy, which are 2 conditions that increase sus-
finding of Darier sign (urticaria after scratching). GI manifestations ceptibility to this organism.
of systemic mastocytosis are varied and include nausea, vomiting, Iron overload may cause chronic liver disease in SCD and is
diarrhea, and abdominal pain. Hyperhistaminemia can result in related to accumulation of transfused iron and continuous hemol-
gastric acid hypersecretion and peptic ulcer disease. Infiltration of ysis. Chronic hepatitis C is more prevalent in patients with SCD
the liver causes hepatomegaly, liver test abnormalities, and portal who received transfusions before blood products were screened
hypertension. Mast cell infiltration of the small intestine and (June 1992).
colon causes mast cell enterocolopathy. Systemic mastocytosis is Nodular regenerative hyperplasia may occur in SCD and is
a clonal disorder of mast cell progenitors and is associated with characterized by nodules of regenerative hepatocytes distributed
activating mutations of the c-kit gene. However, the tyrosine ki- diffusely throughout the liver, with atrophy of the intervening pa-
nase inhibitors, such as imatinib mesylate, are rarely effective renchyma (Figure 12.10). Lack of fibrosis and hepatic dysfunction
in systemic mastocytosis because the most common mutation differentiate it from cirrhosis. Nodular regenerative hyperplasia is
interferes with drug binding. believed to result from an obstructive portal venopathy and can be
seen with hematologic disorders, rheumatologic conditions, and
Sickle Cell Disease adverse effects of certain medications (eg, azathioprine).
GI complications of SCD include abdominal crisis, acute pan-
Sickle cell disease (SCD) is an autosomal recessive abnormality creatitis, peptic ulcer disease, and ischemic bowel. In an acute
of the β-globin chain of hemoglobin that results in poorly de- vasoocclusive crisis, small infarcts occur in the mesentery and
formable, sickled red blood cells that cause microvascular abdominal viscera and cause severe abdominal pain and signs
occlusion and hemolytic anemia. The spleen is nearly always in- of peritoneal irritation with radiographic evidence of ileus. The
volved in SCD, with hyposplenism or asplenism resulting from crisis may mimic other acute abdominal processes but usually
splenic infarction. Patients with splenic infarction present with resolves with supportive care. Acute pancreatitis related to SCD
left upper quadrant pain, nausea and vomiting, a friction rub over may result from microvascular occlusion and ischemic injury.
the splenic area, and leukocytosis. Splenic atrophy predisposes to Peptic ulcer disease is more common in SCD and may be due to
infection with encapsulated bacteria. Liver and GI complications reduced mucosal resistance from ischemia. Ischemic bowel due
are common in SCD. to intravascular sickling, causing microvascular occlusion, is an
Several different acute and chronic processes can involve the uncommon complication of SCD.
liver in SCD. Hepatic injuries due to sickle cell anemia can be
grouped as sickle cell hepatopathy. Acute hepatobiliary compli
cations of SCD include acute hepatic crisis, sickle cell intrahepatic
cholestasis, acute hepatic sequestration, and cholecystitis. Chronic
liver disease in SCD may be due to hemosiderosis, chronic viral
hepatitis, or nodular regenerative hyperplasia.
Patients with 1 of the 4 hepatobiliary complications of SCD
most commonly present with right upper quadrant pain and acute
painful hepatomegaly. High blood viscosity in SCD predisposes
to liver ischemia and infarction despite the dual blood supply of
the liver. Acute sickle hepatic crisis affects 10% of patients with
a painful vasoocclusive crisis and simulates acute cholecystitis
with fever, right upper quadrant pain, leukocytosis, and variable
increases in liver enzymes. The liver is usually enlarged and tender
in acute sickle hepatic crisis. Sickle cell intrahepatic cholestasis
is a rare but potentially fatal complication. It is an unusually se-
vere hepatic crisis caused by widespread sickling in the hepatic
sinusoids, resulting in hepatic ischemia. It is characterized by
profound conjugated hyperbilirubinemia (bilirubin level >50 g/
dL) with renal failure, encephalopathy, and coagulopathy. Sickle
cell intrahepatic cholestasis is treated with exchange transfusion, Figure 12.10. Nodular Regenerative Hyperplasia. Liver biopsy
but affected patients often die of liver failure. Acute hepatic se- specimen shows atrophy of zone 3 hepatocytes (arrowheads) and hy-
questration with jaundice is accompanied by a decrease in he- pertrophy of zone 1 hepatocytes (arrows) without fibrosis (hematoxylin-
moglobin and is due to obstruction of sinusoidal blood flow by eosin, original magnification ×100).
✓ The 2 major types of amyloidosis involving the GI tract are AL

Acute pancreatitis, which develops in 10% of patients with
and AA amyloidosis CF who have preserved pancreatic function, occurs when there
✓ The most common segment of the GI tract to be involved by am- is decreased ductal flow from inspissated secretions leading to
yloid is the duodenum premature activation of trypsinogen and local inflammation.
✓ Submucosal hematomas are the characteristic endoscopic finding Treatment of recurrent acute or chronic pancreatitis in patients
of AL amyloid with CF is like treatment in those without CF. Intravenous fluids
✓ The most common acute porphyria is acute intermittent porphyria are the cornerstone of management; however, use of narcotic
✓ Severe abdominal pain is the usual presentation of acute intermit- analgesics should be minimized because they can precipitate con-
tent porphyria stipation and DIOS (see below).
✓ Laboratory analysis of a spot urine sample for porphobilinogen is
Gastroesophageal reflux disease occurs in approximately 30%
the diagnostic test for acute intermittent porphyria
✓ GI manifestations of systemic mastocytosis are varied but include
of adults with CF. The basic mechanism, transient lower esoph-
peptic ulcer disease and diarrhea ageal sphincter relaxation, is the same in patients with CF as in
✓ The 4 acute hepatobiliary complications of SCD are acute hepatic healthy controls. However, transient lower esophageal sphincter
crisis, sickle cell intrahepatic cholestasis, acute hepatic sequestra- relaxations cause more frequent and more proximal reflux events in
tion, and cholecystitis those with CF. Proton pump inhibitors are the first-line therapy for
gastroesophageal reflux disease in CF. Lung function improves in
patients who CF who have treatment with gastric acid suppression.
Pulmonary Disorders DIOS, a unique feature of CF, is characterized by partial or
complete fecal obstruction of the ileocecal region. It occurs in
Cystic Fibrosis patients with CF of all ages, including adults, and results from
Cystic fibrosis (CF) is an autosomal recessive disorder resulting accumulation of viscous fecal material with adherence to the
from mutations in the CF transmembrane regulator (CFTR) gene. mucosa. Patients with DIOS present with acute or chronic in-
The CFTR gene encodes for a chloride channel protein in the testinal obstruction with abdominal pain and distention. They
apical surface of epithelial membranes. Dysfunction of CFTR may continue to have stool output. On physical examination, a
results in altered electrolyte content in the environment external right lower quadrant mass may be palpable. Radiographic im-
to the surface epithelial membranes, with desiccation and reduced aging typically shows fecal loading in the right lower quadrant as
clearance of secretions from tubular structures lined by affected evidenced by a bubbly-granular fecal mass (Figure 12.11). DIOS
epithelia. The pulmonary manifestations of CF are the most se- can be diagnosed from clinical symptoms, physical findings, and
rious because they lead to respiratory failure. However, the CFTR suggestive radiographic imaging. Management of DIOS includes
protein is found throughout all GI tract epithelia, including the surgical consultation, receiving nothing by mouth, nasogastric
small intestine, pancreas, and hepatobiliary system. Therefore, tube decompression, and intravenous fluids. In cases of complete
CFTR dysfunction can result in many GI complications, in- obstruction, a hyperosmolar contrast enema such as diatrizoate
cluding meconium ileus, pancreatic insufficiency, pancreatitis, should be administered to clear the impacted fecal mass.
gastroesophageal reflux disease, distal intestinal obstruction Hyperosmolar agents cause luminal hydration with resultant mo-
syndrome (DIOS), constipation, small intestinal bacterial over- bilization of the mucus-stool mass and relief of obstruction. With
growth (SIBO), and liver disease. Because more than half of partial bowel obstructions, lavage with oral polyethylene glycol
patients with CF in the US are adults, it is important to be able to
recognize and manage the GI complications of CF.
The GI manifestations of CF begin in infancy. The earliest
manifestation is meconium ileus, a neonatal bowel obstruction.
It is the presenting symptom in 15% of infants with CF, and it
classically manifests with signs of intestinal obstruction within
48 hours of birth. Characteristic radiographic findings show dis-
tended loops of bowel devoid of air-fluid levels. Acetylcysteine
(Mucomyst), a mucolytic, is a safe and effective treatment to
dissolve and dislodge meconium. Meconium-induced obstruc-
tion is also treated with diatrizoate (Gastrografin) enemas.
Complicated meconium ileus requires surgical therapy.
Pancreatic insufficiency is the most common GI complication
of CF. It often develops early in life with the more severe CFTR
gene mutations. Pancreatic insufficiency leads to maldigestion
and malabsorption of nutrients. Long-term sequelae of malnu-
trition include growth retardation, cognitive dysfunction related
to vitamin E deficiency, and more rapid decline in pulmonary
function. Measurement of fecal fat in a 72-hour stool collection
can be done to screen for pancreatic insufficiency. Patients with
pancreatic insufficiency require lifelong pancreatic enzyme re-
placement therapy. Fibrosing colonopathy is a severe intestinal
Figure 12.11. Distal Intestinal Obstruction Syndrome of Cystic
fibrostenotic process that occurred in patients with CF who Fibrosis. Computed tomographic image shows dilated loops of fluid-
ingested large doses of pancreatic enzyme replacement therapy; filled small bowel throughout the abdomen and pelvis with fecalization
because of this complication, the recommended upper limit is of bowel contents and gradual tapering of small-bowel caliber in the
2,500 lipase units per kg per meal. distal ileum.
solutions and oral laxatives can be effective. Surgical intervention tract. Symptomatic liver involvement is infrequent. Most patients
remains the last resort when medical management fails or bowel have only biochemical liver test abnormalities, most commonly
ischemia develops. After recovery from an episode, prevention of an increased alkaline phosphatase level. However, in a small per-
recurrent episodes of DIOS with routine use of osmotic agents centage of patients, progressive liver disease develops, including
such as polyethylene glycol is critical. cholestasis, hepatitis, and nodular regenerative hyperplasia with
Constipation is a frequent symptom in CF and, like DIOS, is resultant portal hypertension. In addition, portal vein thrombosis
related to decreased water secretion caused by the CFTR defect. may occur because of stasis from obliteration of small portal
In contrast to DIOS, which is an obstructive process that starts at veins by granulomatous phlebitis. Budd-Chiari syndrome may
the terminal ileum and extends distally, constipation in CF is an develop from extrinsic compression of hepatic veins by enlarged
obstructive process that begins in the sigmoid colon and extends granulomatous lymph nodes.
proximally. Osmotic laxatives are the first-line treatment of CF- In contrast to sarcoidosis involvement of the liver, sarcoid-
related constipation. osis of the GI tract is rare, with the stomach being the most
SIBO occurs in up to 50% of patients with CF. Thick mucus commonly involved portion of the GI tract. Patients with gas-
secretions, intestinal dysmotility, and the use of acid-suppressing tric sarcoidosis most commonly present with postprandial ep-
medications predispose patients to the development of SIBO. igastric pain related either to peptic ulceration or to gastric
Diagnostic tests, such as culture of duodenal aspirates and luminal narrowing from granulomatous inflammation and fi-
breath hydrogen testing, have limitations. Empirical therapy with brosis of the gastric wall. Patients may initially present with
antibiotics is frequently performed for SIBO. massive GI hemorrhage from ulceration. Endoscopic findings
CF-related liver disease is becoming a more prevalent compli- in gastric sarcoid include ulcerations, thickened gastric folds,
cation. There is a broad spectrum of hepatobiliary disease in CF, mucosal polyps or nodules, and antral deformities. A charac-
which includes microgallbladder, cholelithiasis, hepatic steatosis, teristic finding on upper GI series is a resemblance to linitis
nodular regenerative hyperplasia, and focal biliary cirrhosis with plastica because of granulomatous involvement of the gastric
portal hypertension. Notably, asymptomatic increase in serum wall. Involvement of other portions of the GI tract by sarcoid-
liver enzymes or hepatosplenomegaly may be the only clinical osis is much less common. Patients with esophageal involve-
manifestations of CF-related liver disease. ment may present with dysphagia related to either dysmotility
The treatment of symptomatic liver disease in CF is a challenge or mechanical obstruction. Patients with sarcoidosis of the
and depends on the age of the patient and the extent of the liver dis small intestine may present with abdominal pain, diarrhea,
ease. Cholestatic liver disease is best treated with ursodeoxycholic malabsorption, or protein-losing enteropathy. Colonic involve-
acid (15-20 mg/kg daily), and treatment should be initiated with ment manifests with polypoid lesions, stenosis, and ulceration.
early recognition of CF-related liver disease to improve the bio- Pancreatic sarcoidosis may simulate carcinoma with a mass in
chemical profile, facilitate biliary drainage, and delay progression the head of the pancreas and associated obstructive jaundice
of liver disease. and weight loss. Most patients with pancreatic sarcoidosis have
In addition to CF-related GI and liver complications, several bilateral hilar adenopathy.
GI diseases, including celiac disease and GI malignancies, are The diagnosis of hepatic and luminal GI tract sarcoidosis is
associated with CF. The prevalence of celiac disease is higher in made from the presence of noncaseating granulomas on biopsy,
patients with CF than in the general population. It is important to extra-abdominal organ involvement, and exclusion of granulom-
recognize that tissue transglutaminase IgA can be increased in CF atous infections. The differential diagnosis of GI sarcoidosis
even in the absence of histologic evidence of active celiac disease. includes Crohn disease, foreign body reaction, tuberculosis, his-
Thus, the diagnosis of celiac disease should not be made solely toplasmosis, and syphilis. At times, sarcoidosis coexists with
because of positive IgA tissue transglutaminase serologic results Crohn disease or ulcerative colitis. Treatment of GI sarcoidosis
and requires compatible small intestinal histologic changes and depends on the severity and extent of the disease, with asympto-
response to a gluten-free diet. Compared with the general popula- matic patients requiring no treatment. Corticosteroids and other
tion, patients with CF are at increased risk for esophageal, gastric, immunosuppressive agents are the treatment of choice for symp-
hepatobiliary, gallbladder, small intestinal, and colon cancers. The tomatic patients.
risk for colorectal cancer in these patients is markedly increased;
most cases occur before 50 years of age. Therefore, the Cystic ✓ CF can result in many GI complications, including meconium
Fibrosis Foundation recommends that colorectal cancer screening ileus, pancreatic insufficiency, pancreatitis, gastroesophageal re-
begin at age 40 years in patients with CF and be continued every flux disease, DIOS, constipation, SIBO, and liver disease
✓ Pancreatic insufficiency is the most common GI complica-
5 years. In addition, patients with CF in whom adenomatous polyps
tion of CF
have been found at colonoscopy should have surveillance in 3 years, ✓ DIOS is a unique complication of CF characterized by partial or
unless a shorter interval is indicated by findings. Patients with CF complete fecal obstruction of the ileocecal region
who are older than 30 years and have recovered from solid-organ ✓ The spectrum of hepatobiliary disease in CF includes micro
transplant should begin colorectal cancer screening within 2 years gallbladder, cholelithiasis, hepatic steatosis, nodular regenerative
because of the additional risk for colorectal cancer in association hyperplasia, and focal biliary cirrhosis with portal hypertension
with immunosuppression. Furthermore, the unique physiochemical ✓ Patients with CF are at increased risk of colorectal cancer when
characteristics of the stool and intestinal mucus in CF complicates they are young; screening for this is recommended to begin at age
bowel preparation for colonoscopy; therefore, increased intensity 40 years with continued screening every 5 years
regimens are recommended to allow optimal examination. ✓ Luminal GI tract involvement by sarcoidosis is uncommon; the
stomach is the most commonly involved portion, presenting with
a granulomatous gastritis
Sarcoidosis ✓ A characteristic finding of the stomach on upper GI series in sar-
coidosis is a linitis plastica appearance due to granulomatous in-
Sarcoidosis is a multisystem granulomatous disease that com- volvement of the gastric wall
monly involves the lungs and less frequently the liver and GI
Immunologic Disorders Common Variable Immunodeficiency

Angioedema Common variable immunodeficiency (CVID) is a primary
immunodeficiency disorder characterized by impaired B-
Angioedema affecting the intestinal tract causes severe abdom-
lymphocyte maturation with hypogammaglobulinemia.
inal pain with vomiting due to edematous bowel obstruction.
T-lymphocyte dysfunction occurs variably in CVID. It is
Intestinal angioedema results from hereditary, acquired, or
estimated to affect 1 in 25,000 individuals; age at onset is typ-
drug-induced causes. Hereditary angioedema is an autosomal
ically after puberty and before 30 years. Affected individuals
dominant disorder characterized by quantitative or functional
have recurrent respiratory infections, autoimmune phenomena,
deficiency of C1 inhibitor protein, which inhibits complement
and increased rates of malignancy. GI manifestations of CVID
proteases and coagulation system proteases. C1 inhibitor defi-
occur in up to 50% of individuals and include atrophic gas-
ciency results in unregulated activation of the complement and
tritis, chronic diarrhea, nodular lymphoid hyperplasia, and
coagulation systems and increased levels of bradykinin, which
GI malignancies. Gastric manifestations of CVID include
is responsible for angioedema. Hereditary angioedema is asso-
atrophic gastritis and achlorhydria, and the development of
ciated with localized swelling involving all layers of the skin or
pernicious anemia is common. The risk of gastric carcinoma
walls of hollow organs such as in the respiratory or GI tracts. GI
is markedly increased in patients with CVID, with concomi-
manifestations include nausea, vomiting, abdominal pain, diar-
tant Helicobacter pylori infection further increasing the risk.
rhea, and ascites. Orthostatic symptoms may occur as a result of
The most common GI manifestation of CVID is chronic di-
fluid shifts into the intestinal lumen or peritoneal cavity, which
arrhea, which can be due to several conditions, including GI
decrease the effective circulating volume. Symptoms are at max-
infections, a spruelike disorder, SIBO, inflammatory bowel
imum intensity for approximately 24 hours and can resolve spon-
disease, or small intestinal lymphoma.
taneously. Imaging may show edematous bowel (Figure 12.12)
Giardiasis is the most common GI infection in CVID and can
and ascites.
be challenging to treat. It may cause refractory diarrhea, malab-
Measurement of a serum level of C4 is a cost- effective
sorption, and weight loss. Other GI infections causing diarrhea
screening test to rule out hereditary angioedema because virtu-
in CVID include cytomegalovirus, cryptosporidiosis, and chronic
ally all patients with hereditary angioedema have a persistently
norovirus infection.
low C4 level. Subsequent measurement of quantitative and func-
A spruelike syndrome that occurs in CVID is distinct from
tional levels of C1 inhibitor confirms the diagnosis. On-demand
celiac disease because it does not respond to a gluten-free diet.
treatment for acute attacks of hereditary angioedema includes
The absence of plasma cells in the lamina propria is a specific his-
administration of plasma or recombinant C1 inhibitor, blocking
tologic feature that helps to distinguish CVID from other small
the bradykinin receptor with icatibant or inactivating plasma
intestinal enteropathies. Some patients with spruelike intestinal
kallikrein with ecallantide.
changes benefit from treatment with corticosteroids.
Intestinal angioedema may be acquired, with C1 in-
Liver disease with significant hepatic dysfunction occurs in
hibitor deficiency related to collagen vascular diseases or
approximately 10% of patients with CVID. The most common
lymphoproliferative disorders. Angiotensin- converting enzyme
cause of liver dysfunction is nodular regenerative hyperplasia.
inhibitors can cause angioedema of the intestine, independently of
Initial evaluation of patients with CVID includes measure-
diminished complement or C1 inhibitor levels. Angiotensin II re-
ment of immunoglobulin levels and demonstration of an impaired
ceptor antagonists and renin inhibitors have also been implicated.
response to vaccination. Referral to a clinical immunologist is
Women taking medications containing estrogen may present with
indicated to determine the most appropriate therapies and to help
similar clinical manifestations.
monitor the patient for associated disorders.
Selective IgA Deficiency

Selective IgA deficiency is the most common primary immu-
nodeficiency disorder, occurring in about 1 in 500 persons. It
is characterized by selective loss of secretory and serum IgA.
Individuals are susceptible to respiratory, urogenital, and GI
infections (especially giardiasis). Celiac disease and pernicious
anemia occur with increased frequency in patients with selective
IgA deficiency.
✓ Intestinal angioedema can be hereditary or acquired and com-

monly manifests with abdominal pain and diarrhea
✓ Measurement of serum C4 levels is the screening test of choice to
rule out hereditary angioedema
✓ GI manifestations of CVID are common and include diarrhea and
spruelike disease, and the risk of gastric cancer and lymphoma is
markedly increased in this disorder
✓ Giardiasis is the most common GI infection in CVID
✓ Patients with selective IgA deficiency have an increased fre-
Figure 12.12. Mesenteric Angioedema. Computed tomographic quency of celiac disease
image shows thickened small-bowel loop (arrow).
Renal Diseases and Hemodialysis

Chronic Kidney Disease
Chronic kidney disease can be complicated by dysgeusia, ano-
rexia, nausea, vomiting, esophagitis, gastritis, angiodysplasias
of the GI tract, peptic ulcer disease, duodenitis, duodenal
pseudomelanosis (asymptomatic), abdominal pain, constipation,
pseudo-obstruction, perforated colonic diverticula, small-bowel
and colonic ulceration, intussusception, GI tract bleeding, amy-
loidosis, diarrhea, fecal impaction, and SIBO.
Hemodialysis
In patients undergoing hemodialysis, a refractory exudative as-
cites of unclear pathogenesis can develop; this resolves with renal
transplant. These patients also have a greater risk of colon is-
chemia. Infections and ulcerative complications of the GI tract,
diverticulitis, and perforated colonic diverticula often develop in
patients who have had renal transplant.
Peritoneal Dialysis
Patients undergoing continuous ambulatory peritoneal dial-
ysis are at increased risk of bacterial peritonitis and a rare but Figure 12.13. Computed Tomographic Finding of Multiple Liver
serious complication, encapsulating peritoneal sclerosis (EPS). Cysts in Adult Polycystic Kidney Disease.
EPS is characterized by partial or intermittent bowel obstruction
accompanied by marked sclerotic thickening of the peritoneal
membrane. The bowel loops within the sclerotic membrane be- ✓ Angiodysplastic lesions of the GI tract occur more commonly in
come adherent and encapsulated, leading to bowel obstruction. patients with chronic kidney disease
A typical computed tomographic feature of EPS is an enhancing ✓ Individuals undergoing hemodialysis have a greater risk of colon
thickened peritoneum, which may progress to peritoneal encap- ischemia
sulation of the involved bowel loops and is frequently described ✓ Bowel obstruction from EPS is a rare but serious complication of
as “cocooning.” Tamoxifen has been successful for decreasing peritoneal dialysis
EPS-related fibrosis and improving intestinal function. ✓ Adult polycystic kidney disease has many GI manifestations, in-
cluding hepatic cysts, diverticular disease, pancreatic cysts, and
choledochal cysts
Polycystic Kidney Disease
The adult form (autosomal dominant) of polycystic kidney dis
ease is the most commonly inherited kidney disease; it affects Endocrine Disorders
between 1 in 400 to 1 in 1,000 people in the general popula-
Diabetes Mellitus
tion. It is a systemic disorder that is associated with numerous
extrarenal manifestations, many of which occur in the GI tract. GI symptoms are common in patients with DM. Autonomic
GI manifestations include hepatic cysts, diverticular disease, neuropathy complicating DM can involve the entire GI tract.
hernias, pancreatic cysts, choledochal cysts, common bile duct Dysphagia from esophageal dysmotility occurs as the result of
dilation, and splenic cysts. Liver cysts are common (Figure vagal dysfunction. Esophageal stasis can predispose to Candida
12.13); their frequency increases with age, and they are more infection, and new-onset odynophagia in a patient with diabetes
prevalent in women. Despite large cysts, liver function is pre- should suggest the presence of Candida esophagitis. Gastroparesis
served. Complications of hepatic cysts include infection and is a common complication of poorly controlled DM. Symptoms
biliary obstruction, which requires antibiotic treatment and per- include early satiety, bloating, heartburn, nausea, and intermit-
cutaneous drainage. Colonic diverticulosis is more common in tent vomiting. A succussion splash may be appreciated on phys-
adult polycystic kidney disease with end-stage renal disease. It ical examination. Phase III of the migrating motor complex is
may result from smooth muscle dysfunction leading to suscepti- frequently absent, which predisposes to the formation of gastric
bility for the development of diverticulosis. In addition, affected bezoars. Diarrhea and fecal incontinence are frequent complaints
patients are more prone for the development of complicated di- in DM. The diarrhea is often watery and nocturnal. Intestinal au-
verticulitis. Hernias of the inguinal, incisional, and paraumbilical tonomic neuropathy may be the cause; however, other conditions
types are more common in adults with polycystic kidney disease. to consider include celiac disease (more prevalent in type 1 DM),
Hernias are suspected to be the result of abnormal extracellular pancreatic exocrine insufficiency, and SIBO. Severe constipation
matrix production and increased intra-abdominal pressure from associated with colonic dysmotility occurs in 20% of patients
cystic liver disease. Large bile duct abnormalities occur more fre- with diabetes who have neuropathy. Fecal incontinence is com-
quently in polycystic kidney disease, including Caroli disease, monly due to anal sphincter dysfunction and decreased rectal
which is multifocal cystic dilation of the intrahepatic bile ducts. sensation. Fatty liver disease is frequent.
Thyroid Disease of small hepatic veins and venules due to conditioning therapy
(radiotherapy or chemotherapy), usually occurs 8 to 23 days after
Hyperthyroidism may manifest as hyperphagia, weight loss,
transplant.
mild diarrhea, steatorrhea, abdominal pain, vomiting, concomi-
tant atrophic gastritis, dysphagia, ascites, jaundice, and nonspe- ✓ Mantle cell lymphoma may present as lymphomatous polyposis
cific mild abnormalities on liver function testing. Autoimmune ✓ Small cell lung carcinoma is associated with a paraneoplastic
hepatitis and primary biliary cholangitis also may be associated pseudo-obstruction and positive anti-Hu antibodies
disorders. Hypothyroidism often results in anorexia, weight gain, ✓ The histologic hallmark of intestinal GVHD is crypt apop-
constipation, dysphagia, heartburn, and, less often, intestinal totic bodies
pseudo-obstruction, achlorhydria, and ascites (high concentra-
tion of total protein and high serum-ascites albumin gradient).
Associated GI diseases include pernicious anemia, ulcerative co- Neuromuscular Disorders
litis, primary biliary cholangitis, autoimmune hepatitis, and ce-
liac disease. Many neurologic and muscular disorders affect the GI tract.
Acute head injury with intracranial hypertension, like many other
serious illnesses, can result in stress gastritis. However, deep ul-
Parathyroid Disease ceration, sometimes with perforation, can occur with acute head
Hyperparathyroidism, with hypercalcemia, classically produces injury, apparently as a result of vagal stimulation of gastrin and
anorexia, nausea, vomiting, constipation, and abdominal pain; gastric acid production. Similar ulceration can occur after burns
rarely, peptic ulcer disease and pancreatitis develop. Patients that cover a large surface area of the body. Abdominal pain,
with hypoparathyroidism can present with diarrhea, steatorrhea, nausea, and vomiting rarely are attributed to migraine or tem-
abdominal pain, pseudo-obstruction, protein-losing enteropathy, poral lobe epilepsy (temporal lobe epilepsy often includes central
and lymphangiectasia; also, autoimmune hepatitis may develop. nervous system symptoms). Patients with cyclic vomiting may
present with recurrent attacks of abdominal pain, nausea, and
✓ DM is associated with a spectrum of GI conditions, including vomiting. Some persons with this disorder find relief with hot
gastroparesis, intestinal autonomic neuropathy, and colonic showers or baths and recover with cessation of the use of mari-
dysmotility juana. Cerebrovascular disease and cerebral palsy commonly re-
✓ Severe hypothyroidism can result in a high- protein and high sult in oropharyngeal dysphagia due to dysmotility.
serum-ascites albumin gradient Multiple sclerosis frequently affects the GI tract with oropha-
ryngeal dysphagia, gastroparesis, constipation, or disorders of
defecation or fecal incontinence. Patients with Parkinson disease
Oncologic Disorders often have oropharyngeal dysphagia, gastroesophageal reflux
disease, esophageal dysphagia, constipation, and fecal inconti-
Leukemias and lymphomas commonly involve the GI tract and nence. Both amyotrophic lateral sclerosis and myasthenia gravis
liver. Hodgkin disease can involve the liver, extrahepatic bile can cause oropharyngeal dysphagia.
ducts, or lymph nodes, or it can manifest as intrahepatic cholestasis More diffuse GI tract dysmotility syndromes occur with po-
without hepatobiliary involvement. Unusual tumors affecting the liomyelitis, Huntington chorea, dysautonomia syndromes, Shy-
gut include α chain disease (also called immunoproliferative Drager syndrome, Chagas disease, and spinal cord injuries.
small intestinal disease), which diffusely infiltrates the small in- Patients with dementia may be at risk for aspiration because of
testine and adjacent lymph nodes (B cells and α heavy chains are oropharyngeal dysphagia, and they may have weight loss because
produced in excess); mantle cell lymphomas, which mimic a mul- of decreased intake, poor diet, and pica.
tiple polyposis syndrome; multiple myeloma or amyloidosis, with Muscular dystrophies such as oculopharyngeal muscular
focal plasmacytomas (mass, ulceration, bleeding, or obstruction), dystrophy (third nerve palsy, often in persons who have French-
GI mucosal infiltration with malabsorption, or hyperviscosity Canadian ancestry) and Duchenne muscular dystrophy can
syndrome (ischemia); Waldenström macroglobulinemia, with GI be complicated by oropharyngeal dysphagia. Duchenne mus-
tract and hepatosplenic infiltration and malabsorption; and small cular dystrophy is associated with more widespread GI tract
cell lung carcinoma and other malignancies, with paraneoplastic dysmotility.
pseudo-obstruction (patients may be positive for antineuronal nu-
clear antibody [anti-Hu], type 1 Purkinje cell antibody, or N-type ✓ Multiple sclerosis frequently affects the GI tract from the mouth
calcium channel–binding antibody). to anus
Allogenic bone marrow transplant often is complicated by ✓ Muscular dystrophies can be complicated by oropharyngeal
graft-vs-host disease (GVHD). Usually occurring in the first 20 dysphagia
to 80 days after transplant, acute GVHD is characterized by er-
ythematous maculopapular rashes, small and large intestinal
mucosal involvement (diarrhea, protein-losing enteropathy, mal- Rheumatologic and Collagen
absorption, pain, bleeding, and crypt apoptotic bodies seen in bi- Vascular Diseases
opsy specimens, even in areas that appear normal on endoscopy),
and cholestatic liver disease. Usually occurring 80 to 400 days
Scleroderma
after transplant (and usually in persons with previous acute Scleroderma is a chronic, connective tissue disease characterized
GVHD), chronic GVHD is characterized by cholestatic liver by vascular damage and fibrosis of the skin and internal organs,
disease (vanishing bile ducts), esophageal disease (dysphagia, including those in the GI tract. After skin involvement, the GI
strictures, and webs), small-bowel disease (diarrhea or bacterial tract is the second most commonly involved organ system,
overgrowth), skin disease, and polyserositis. Sinusoidal obstruc- with the esophagus being the most frequent segment in-
tion syndrome of the liver, with bland, nonthrombotic obliteration volved. Involvement of the stomach, small intestine, colon, and
anorectum is less common but may lead to severe complications octreotide stimulates small intestinal motility and is beneficial
and debility. The GI tract involvement is due to smooth muscle in patients with intestinal pseudo-obstruction and bacterial over-
atrophy, fibrosis, small-vessel vasculitis, and neural damage. The growth. Despite these measures, many patients require home par-
esophagus is most frequently involved with smooth muscle at- enteral nutrition.
rophy and fibrosis of the distal two-thirds of the esophagus. Pneumatosis cystoides intestinalis (PCI) is an uncommon con-
Patients complain of dysphagia, heartburn, and regurgitation dition characterized by multiple gas-filled cysts within the wall
due to reflux and dysmotility. Most patients have Raynaud phe- of the intestine. These cysts most commonly occur in the small
nomena. Manometry classically shows an absence of peristaltic bowel. PCI may be identified on plain radiographs or on computed
contractions and decreased lower esophageal sphincter pressure. tomographic scans. PCI is not a disease and can be classified as
Complications include strictures, Barrett esophagus, adenocarci- either primary (idiopathic) or secondary. Scleroderma is a sec-
noma, and Candida esophagitis. ondary cause of PCI. The cysts of PCI may rupture, resulting
Replacement of the smooth muscle layers of the stomach by in benign, chronic pneumoperitoneum. Patients with benign
collagen leads to gastric hypomotility. In addition, a subset of chronic pneumoperitoneum do not have signs of peritonitis, and
scleroderma patients may have autonomic dysfunction affecting no therapy is required for this condition.
gastric emptying. Gastroparesis is reported to occur in up to 50% Lower GI symptoms from anorectal dysfunction are not in-
of patients and can result in significant morbidity and mortality. frequent in scleroderma. Scleroderma patients with impaired an-
An additional gastric abnormality in scleroderma is gastric antral orectal function may complain of various symptoms including
vascular ectasia. constipation, diarrhea, urgency, and fecal incontinence. The 2
The small intestine is frequently involved in scleroderma. Small main complications of anorectal involvement by scleroderma
intestinal complications include intestinal pseudo- obstruction, are fecal incontinence and rectal prolapse. Fecal incontinence
bacterial overgrowth, pneumatosis cystoides intestinalis, and per associated with scleroderma is multifactorial and includes diar-
foration. Characteristic radiographic findings in cases of sclero- rhea, decreased rectal compliance, and weakening of the internal
derma pseudo-obstruction are dilatation of the small intestine and anal sphincter. Deposition of collagen in the rectal wall likely
narrow valvulae conniventes, which remain tightly packed to- contributes to the development of rectal prolapse by weakening
gether despite the bowel dilatation and show the hidebound bowel the rectal submucosa. Rectal prolapse may further exacerbate the
sign (Figure 12.14). This characteristic mucosal fold pattern in already reduced capacity and compliance of the rectum in sclero-
scleroderma is caused by bowel shortening from fibrosis of the derma. Therefore, rectal prolapse should be sought in all sclero-
longitudinal muscle layer, with a relative decrease in the distance derma patients with fecal incontinence, particularly because it is
separating the valvulae conniventes for a given degree of small- a potentially treatable cofactor of anorectal symptoms.
bowel dilatation.
The intestinal stasis from pseudo-obstruction may cause ab-
Rheumatoid Arthritis
dominal distention and pain, with bacterial overgrowth resulting
in diarrhea, steatorrhea, malabsorption, and weight loss. GI manifestations of rheumatoid arthritis (RA) are varied and
Treatment of episodes of pseudo- obstruction complicated by often catastrophic. The spectrum of GI involvement includes oro-
bacterial overgrowth involves cycled antibiotics and octreotide. pharyngeal dysphagia, esophageal dysphagia, mesenteric vascu-
When used at low doses (25-50 μg subcutaneously once nightly), litis, amyloidosis, and Felty syndrome.
Severe sicca manifestations from associated Sjögren syn-
drome may interfere with deglutition and cause oropharyngeal
dysphagia in RA. Abnormal esophageal motility, with low-
amplitude peristaltic contractions and reduced lower esophageal
sphincter pressures, predisposes patients with RA to reflux, dys-
phagia, and esophagitis.
Rheumatoid vasculitis of the GI tract is rare but often cata-
strophic. Presentations vary with involvement of small arterioles
causing ischemic ulcers and perforation, while large-vessel vas-
culitis results in extensive bowel infarction and intraperitoneal
hemorrhage. Patients with rheumatoid mesenteric vasculitis may
present with appendicitis, cholecystitis, or bowel obstruction
from stricture formation.
RA is the most common disease that causes AA amyloidosis.
Long-standing RA with poorly controlled inflammation is the
major risk factor for development of AA amyloidosis. GI tract
involvement is common with AA amyloidosis (see Amyloidosis
subsection above). RA also is associated with liver disease, in-
cluding mild liver function test abnormalities, autoimmune hep-
atitis, and primary biliary cholangitis. RA may be part of Felty
syndrome (splenomegaly and neutropenia) with nodular regener-
ative hyperplasia and portal hypertension (variceal hemorrhage).
Systemic Lupus Erythematosus

Figure 12.14. Small-Bowel Radiographic Finding of “Hidebound” SLE is a multisystem disease that predominantly affects women
Bowel Sign of Scleroderma. and can involve the entire GI tract and liver. Approximately 15%
of patients with SLE have skeletal myopathy that affects the occur in both conditions. In addition, the 2 diseases share
upper one-third of the esophagus and results in hoarseness and extraintestinal manifestations, such as uveitis, skin changes, and
dysphagia from involvement of laryngeal and pharyngeal mus- arthritis. However, a small-vessel vasculitis with deep ulcerations,
cles. Patients with esophageal dysmotility may have heartburn, no cobblestoning, and absence of granulomas characterizes BD.
regurgitation, and dysphagia. Mesenteric vasculitis can involve Large-vessel involvement may cause Budd-Chiari syndrome or
the stomach, small intestine, and colon. The presentation of portal vein thrombosis. BD has an unpredictable course, with im-
patients with intestinal vasculitis ranges from nausea, vomiting, munosuppressive medications being the mainstay of treatment.
and abdominal pain to an acute abdomen. Mesenteric vasculitis
is almost always accompanied by lupus involvement of other
Polyarteritis Nodosa
organ systems. Less common GI complications of SLE that may
be the initial manifestation of lupus include intestinal pseudo- PAN is a necrotizing vasculitis of medium-sized arteries that
obstruction and protein-losing enteropathy. Primary lupus perito- involves many different organ systems. It is associated with hep-
nitis is rare and sometimes occurs without ascites. Patients with atitis B virus infection in about 7% of cases, but PAN develops in
primary lupus peritonitis present with abdominal pain simulating less than 1% of patients with hepatitis B. Patients with PAN have
an acute abdomen, typically during a lupus flare. It responds to a variable clinical presentation; up to 65% of patients have GI
corticosteroids. Hepatic involvement in SLE includes mildly ab- involvement. The small intestine is the most commonly affected
normal liver enzyme levels, fatty liver, nodular regenerative hy- part of the GI tract, followed by the mesentery and colon. The
perplasia, autoimmune hepatitis, and primary biliary cholangitis. most frequent symptom is postprandial abdominal pain from in-
testinal ischemia. Ischemia limited to the intestinal mucosa results
✓ The GI tract is the second most commonly involved organ system in ulceration and GI bleeding. Bowel perforation may occur from
in scleroderma transmural ischemic necrosis. Acalculous ischemic cholecystitis
✓ Esophageal manometry in scleroderma classically shows absence may develop from arteritis involving the wall of the gallbladder.
of peristalsis and decreased lower esophageal sphincter pressure Liver involvement may manifest as liver infarction, acute liver
✓ Small intestinal complications of scleroderma include intestinal
failure, nodular regenerative hyperplasia, and hemobilia from he-
pseudo-obstruction, bacterial overgrowth, pneumatosis cystoides
intestinalis, and perforation patic artery aneurysm rupture. Angiography, the main method of
✓ The characteristic small-bowel radiographic finding in scleroderma diagnosing PAN, typically shows saccular aneurysms. Tissue bi-
is the hidebound bowel sign opsy confirms the diagnosis—a common biopsy site is the sural
✓ The 2 main complications of anorectal scleroderma involvement nerve. Corticosteroids are the mainstay of treatment.
are fecal incontinence and rectal prolapse
✓ GI involvement by RA includes oropharyngeal dysphagia, esoph-
ageal dysphagia, mesenteric vasculitis, amyloidosis, and Felty IgA Vasculitis (Henoch-Schönlein Purpura)
syndrome HSP is a systemic, small- vessel, leukocytoclastic vasculitis
✓ RA is the most common disease that causes AA amyloidosis characterized by the tetrad of palpable purpura, arthralgias, renal
✓ GI complications of SLE include mesenteric vasculitis, intestinal disease, and GI involvement. It is the most common systemic
pseudo-obstruction, protein-losing enteropathy, and lupus peritonitis
vasculitis of children; however, it can occur in adults. The cuta-
neous hallmark of HSP is palpable purpura of dependent areas
such as the legs and arms (Figure 12.15). In palpable purpura,
Vasculitides blood leaks from injured vessels into the tissues. GI involvement
Systemic vasculitides involve the GI tract to a variable degree. in adult-onset HSP is common, with GI symptoms caused by
Symptoms and signs of systemic vasculitis involving the GI tract immune complex deposition in vessel walls, which leads to im-
result from mesenteric ischemia. The vasculitides with well- paired perfusion and ischemia. The most common GI features are
described and frequent GI involvement include Behçet disease abdominal pain and bleeding. The abdominal pain is characteris-
(BD), polyarteritis nodosa (PAN), and IgA vasculitis (ie, Henoch- tically located in the periumbilical area and, as in chronic mesen-
Schönlein purpura [HSP]). teric ischemia, the pain worsens after meals. The small intestine
Behçet Disease
BD is a vasculitis that may involve blood vessels of all sizes and
both arterial and venous circulations. Recurrent oral ulceration
is the sine qua non of BD. It typically affects individuals in the
second through fourth decades of life. Its prevalence is similar in
men and women, with more severe disease in men. GI involve-
ment is variable. The small intestine and colon are the most fre-
quently involved segments of the GI tract. Intestinal involvement
may occur either from small-vessel disease with mucosal ulcer-
ation or from large-vessel disease resulting in ischemia and in-
farction. Intestinal lesions occur most frequently in the ileocecal
region with the characteristic endoscopic finding of deep,
punched-out ulcers. Complications include intestinal perforation
from penetrating ulcers and type AA amyloidosis, with diarrhea
and malabsorption.
BD with GI involvement may be difficult to distinguish from Figure 12.15. IgA Vasculitis (Henoch-Schönlein Purpura). Discrete
Crohn disease since oral and genital ulcers and rectal sparing hemorrhagic papules on the hand of affected patient.
is the most frequently involved site in the GI tract. Computed to- hormone. Type 1 antineuronal nuclear (also known as anti-Hu)
mography characteristically shows small-bowel wall thickening antibodies usually are detectable.
involving mainly the jejunum and ileum. Complications include
intussusception, perforation, and stricture.
The diagnosis is made from the presence of palpable purpura Suggested Reading
along with 1 of the following: abdominal pain, IgA deposition, Bissell DM, Anderson KE, Bonkovsky HL. Porphyria. N Engl J Med.
arthritis, or renal involvement. HSP can be difficult to diagnose, 2017 Aug 31;377(9):862–72.
especially if the GI symptoms develop before the characteristic Brito-Zeron P, Bari K, Baughman RP, Ramos-Casals M. Sarcoidosis
cutaneous lesions, as in 15% of cases. In addition, when the ileum involving the gastrointestinal tract: diagnostic and therapeutic man-
is involved, the presentation and findings mimic Crohn disease. agement. Am J Gastroenterol. 2019 Aug;114(8):1238–47.
GI manifestations of HSP typically resolve without treatment. Busse PJ, Christiansen SC. Hereditary angioedema. N Engl J Med. 2020
Mar 19;382(12):1136–48.
The role of corticosteroids to prevent complications and relapses
Davila M, Bresalier RS. Gastrointestinal complications of oncologic
is controversial. Adults may have malignancies associated with therapy. Nat Clin Pract Gastroenterol Hepatol. 2008 Dec;5(12):682–96.
HSP, with solid tumors being the most common (non– small Ebert EC, Nagar M, Hagspiel KD. Gastrointestinal and hepatic
cell lung carcinoma and prostate cancer). Appropriate cancer complications of sickle cell disease. Clin Gastroenterol Hepatol.
screening and surveillance among adults with a new diagnosis of 2010 Jun;8(6):483–9.
HSP is important. Gelfond D, Borowitz D. Gastrointestinal complications of cystic fibrosis.
Clin Gastroenterol Hepatol. 2013 Apr;11(4):333–42.
✓ Intestinal lesions of BD most frequently occur in the ileocecal Iida T, Yamano H, Nakase H. Systemic amyloidosis with gastrointestinal
region with the characteristic finding of deep, punched-out ulcers involvement: diagnosis from endoscopic and histological views. J
that can mimic Crohn disease Gastroenterol Hepatol. 2018 Mar;33(3):583–90.
✓ PAN is a necrotizing vasculitis associated with hepatitis B virus Jackson SB, Villano NP, Benhammou JN, Lewis M, Pisegna JR, Padua
infection; up to 65% of patients have GI involvement D. Gastrointestinal manifestations of hereditary hemorrhagic telan-
✓ The clinical tetrad of HSP is palpable purpura, arthralgias, renal giectasia (HHT): a systematic review of the literature. Dig Dis Sci.
disease, and GI involvement 2017 Oct;62(10):2623–30.
✓ In HSP, the small intestine is the most frequently involved site in Jacobs JW, Jr, Kukreja K, Camisa C, Richter JE. Demystifying esopha-
the GI tract geal lichen planus: a comprehensive review of a rare disease you will
see in practice. Am J Gastroenterol. 2022 Jan 1;117(1):70–7.
Koster MJ, Warrington KJ. Vasculitis of the mesenteric circulation. Best
Pract Res Clin Gastroenterol. 2017 Feb;31(1):85–96.
Gynecologic Conditions Kroner PT, Tolaymat OA, Bowman AW, Abril A, Lacy BE.
Endometriosis can affect the gut; most frequently, the sigmoid Gastrointestinal manifestations of rheumatological diseases. Am J
colon is involved. It can cause obstruction (adhesions), perfora- Gastroenterol. 2019 Sep;114(9):1441–54.
Loscalzo J. From clinical observation to mechanism: Heyde’s syndrome.
tion, bleeding, diarrhea, and, more often, abdominal pain or con-
N Engl J Med. 2012 Nov 15;367(20):1954–6.
stipation. These GI tract symptoms may or may not be cyclical. Mikolajczyk AE, Te HS, Chapman AB. Gastrointestinal manifestations
Associated gynecologic symptoms, such as pain with intercourse, of autosomal-dominant polycystic kidney disease. Clin Gastroenterol
are common. Estrogen administration after menopause may be Hepatol. 2017 Jan;15(1):17–24.
associated with symptoms. Patients with Meigs syndrome pre- Pikkarainen S, Martelius T, Ristimaki A, Siitonen S, Seppanen MRJ, Farkkila
sent with ascites and, often, pleural effusion in association with M. A high prevalence of gastrointestinal manifestations in common var-
benign ovarian neoplasms. iable immunodeficiency. Am J Gastroenterol. 2019 Apr;114(4):648–55.
Shields HM, Shaffer K, O’Farrell R P, Travers R, Hayward JN, Becker
LS, et al. Gastrointestinal manifestations of dermatologic disorders.
Miscellaneous Conditions Clin Gastroenterol Hepatol. 2007 Sep;5(9):1010–7.
The vascular type (type IV) of Ehlers-Danlos syndrome, usually Shreiner AB, Murray C, Denton C, Khanna D. Gastrointestinal
manifestations of systemic sclerosis. J Scleroderma Relat Disord.
autosomal dominant, is associated often with bowel perforation,
2016 1(3):247–56.
vascular aneurysms, arteriovenous fistulas, and rupture. Stolzel U, Doss MO, Schuppan D. Clinical guide and update on
Paraneoplastic syndromes with diffuse GI tract motor dysfunc- porphyrias. Gastroenterology. 2019 Aug;157(2):365–81.
tion occur most often with small cell lung carcinoma, autonomic Thrash B, Patel M, Shah KR, Boland CR, Menter A. Cutaneous
neuropathy, cerebellar degeneration, peripheral neuropathy, manifestations of gastrointestinal disease: Part II. J Am Acad
seizures, or syndrome of inappropriate secretion of antidiuretic Dermatol. 2013 Feb;68(2):211 e1–33.
13
Complications After Roux-en-Y Surgery

KHUSHBOO S. GALA, MBBS
ANDRES J. ACOSTA, MD, PHD
The incidence of obesity continues to increase at an alarming Anatomy and Physiology of RYGB
rate, the burden of disease having tripled since 1975. In the
To better understand complications associated with RYGB, it
United States, nearly 50% of the population is obese. There has
is necessary to understand the anatomy and physiology behind
also been an associated increase in the incidence of obesity-
the procedure. It entails construction of a small gastric pouch
related conditions, including heart disease, stroke, type 2 dia-
that is divided and separated from the distal aspect of the sto-
betes mellitus, and certain types of cancer. Bariatric surgery is
mach. The gastric pouch is generally 30 to 50 mL in volume,
the only effective treatment for severe obesity, resulting in sus-
is composed primarily of the lesser curvature of the stomach,
tained weight loss, improved obesity-associated comorbidities,
and is anastomosed to a limb of small bowel. The anastomosis
and reduced mortality.
is the gastrojejunal anastomosis. The limb is referred to as the
Roux-en-Y gastric bypass (RYGB) remains one of the most
Roux limb and is typically 75 to 150 cm in length. The other
popular bariatric procedures. It is extremely effective for weight
intestinal limb attached to the gastric remnant is known as the
loss. Maximal weight loss is about 30% of total body weight
biliopancreatic limb; it helps to transport secretions from the gas-
within the 1 to 2 years after the procedure, and long-term data
tric remnant, liver, and pancreas. The anastomosis of both limbs,
show that patients are able to maintain more than 25% of total
known as the jejunojejunal anastomosis, is approximately 75 to
weight loss even over 20 years. It is the bariatric procedure of
150 cm distally from the gastrojejunostomy (Figure 13.1).
choice in patients with insulin resistance (type 2 diabetes mel-
The mechanism of weight loss in RYGB is multifactorial.
litus, nonalcoholic fatty liver disease, metabolic syndrome, and
The small gastric pouch and narrow anastomotic outlet serve
polycystic ovarian syndrome). It is also preferred for patients with
as restrictive elements and limit caloric intake by inducing sa-
Barrett esophagus, severe or complicated gastroesophageal reflux
tiation. There is also a component of nutrients bypassing the
disease, or bile reflux. RYGB has a complication rate of approx-
biliopancreatic intestinal limb, which decreases the length of
imately 15%, and most complications are minor. This chapter
absorptive surface of the small intestine, and results in the food
reviews the RYGB procedure and the related complications and
bolus reaching the distal intestine faster. Neurohormonal changes,
their management.
including suppression of ghrelin and an increase in peptide YY,
glucagon-like peptide-1, and plasma bile acids, contribute to an
increase in satiation and reduction of food intake.
✓ Roux-en-Y gastric bypass—a bariatric surgery that involves crea-

Abbreviations: ASL, anastomotic or staple leak; ASMBS, American tion of a small gastric pouch with anastomosis to a limb of jejunum
Society for Metabolic and Bariatric Surgery; GGF, gastrogastric fistula; that bypasses 75 to 150 cm of small bowel
GI, gastrointestinal; PHH, postprandial hyperinsulinemic hypoglycemia; ✓ Gastric pouch—a small, divided pouch composed of the lesser
RYGB, Roux-en-Y gastric bypass; SBO, small-bowel obstruction; SIBO, curvature of the stomach that is created to restrict food intake
small intestinal bacterial overgrowth
159
Figure 13.1. Anatomy of Roux-en-Y Gastric Bypass. (Used with permission of Mayo Foundation for Medical Education and Research.)
✓ Gastric remnant—the portion of the stomach that is excluded to 12 mm in diameter and should permit passage of the standard
during creation of the pouch; it includes the majority of the sto- adult gastroscope. The Roux limb is typically 100 to 150 cm
mach, including fundus, greater curvature, and pylorus in length; its anastomosis to the biliopancreatic limb forms the
✓ Roux limb (efferent limb)—the jejunal limb that is attached to the jejunojejunal anastomosis and common channel. The gastric
gastric pouch and serves as the primary recipient of food after the
remnant and biliopancreatic limb are not visualized during a
surgery
✓ Biliopancreatic limb (afferent limb)—the intestinal limb that is
routine endoscopy and require double balloon enteroscopy for
connected to the gastric remnant and serves as the recipient for bil- examination.
iary and pancreatic secretions
✓ Common limb or channel—the intestinal limb that is formed after Complications of RYGB
anastomosis of the Roux and biliopancreatic limbs, 75 to 150 cm
distally from the gastrojejunostomy
RYGB is associated with multiple surgical complications in both
the early and the delayed postoperative periods. Complications
in the immediate postoperative period (earlier than 1 month after
the procedure) include anastomotic or staple line leak, postoper-
Endoscopic Anatomy of RYGB ative hemorrhage, and bowel obstruction. Delayed complications
Familiarity with postsurgical RYGB anatomy is important when (1 month or after) include anastomotic stricture, marginal ulcer-
performing endoscopy in patients who have had the procedure. ation, fistula formation, intestinal obstruction, and nutritional
The operative notes should be reviewed before performing an deficiencies.
endoscopy to be aware of limb lengths, because these may vary Different surgical techniques have different rates of complica
by surgeons and centers. A patient with RYGB should have a tions. In general, hand- sewn anastomoses have lower rates of
normal esophagus and gastroesophageal junction. The endo- postoperative bleeding, marginal ulcer, and strictures than stapled
scopically visualized stomach is the gastric pouch, which is typ- anastomoses. Specifically, circular stapling has a higher risk of
ically 3 to 5 cm in length. This is anastomosed to the jejunum postoperative hemorrhage, wound complications, anastomotic
(the Roux limb). The gastrojejunal anastomosis is generally 10 leaks, marginal ulcers, and anastomotic strictures.
13. Complications After Roux-en-Y Surgery 161
Early Complications within 2 to 3 months postoperatively. Risk factors for strictures

include older age, circular stapled gastrojejunostomy, anasto-
Anastomotic or Staple Line Leaks
motic leaks, and marginal ulceration. Strictures can have multiple
Anastomotic or staple line leaks (ASLs) are the most severe compli- causes, including ischemia, tension on the anastomosis, edema,
cation of RYGB and one of the major contributors to death. The fre- or a foreign-body reaction.
quency of ASL has been reported to be 0.5 to 5%; the lower rate is
associated with more experienced surgeons. The frequency of ASL Clinical Presentation and Diagnosis. Clinical manifesta
is higher in revisional RYGB. ASL generally occurs within the first tions of strictures include nausea, vomiting, dysphagia, gastro
week of hospitalization; in rare instances, it may occur up to 30 days esophageal reflux, and eventually an inability to tolerate oral
postoperatively. ASLs occur most frequently at the gastrojejunal intake, including liquids. These generally present when the stric-
anastomosis. Many surgical techniques have been explored to de- ture narrows to less than 10 mm. Anastomotic strictures can be
crease the risk of ASL, including appropriate staple sizing, staple- diagnosed from a thorough history and examination. The diagnosis
line reinforcement, hand-sewn otomy closures, placement of stay can be confirmed with an upper GI series or upper endoscopy.
sutures, intraoperative leak testing, and placement of fibrin sealant. Management. Strictures can be managed either with endo-
Clinical Presentation and Diagnosis. ASL can have varied scopic dilations or surgical revision. Endoscopic balloon dila-
clinical presentations. The more obvious presentations include tion is a safe and effective treatment of anastomotic strictures.
fever, abdominal pain, and purulent drain output. However, be- Strictures should generally be dilated to 12 to 16 mm; over-
cause clinical findings can frequently be subtle in patients with dilation should be avoided because it can reduce the restrictive
severe obesity, ASL can be challenging to diagnose. Sustained effect of RYGB. Many centers schedule follow-up endoscopies
tachycardia (heart rate >120 beats per minute) postoperatively because most patients require serial dilations every 2 to 3 weeks.
can be indicative of ASL. Generally, strictures should not be dilated by more than 3 to 4 mm
The diagnosis of ASL requires a strong clinical suspicion. It at a time to decrease the risk of perforation. There is a small risk
can be confirmed radiographically with barium studies or contrast- of perforation after balloon dilation, reported to be less than 3%.
enhanced computed tomography. Some centers routinely order Rarely, strictures can be refractory to multiple dilations and may
postoperative upper gastrointestinal (GI) series on all patients with require surgical revision of the gastrojejunostomy anastomosis.
RYGB; however, there are no concrete data to support this practice.
Use of intraoperative measures to evaluate for ASL, including meth- Gastrojejunal Anastomosis (Marginal) Ulceration
ylene blue dye instillation with an orogastric tube or insufflation of
Ulceration of any depth at the gastrojejunal junction is termed
air during intraoperative endoscopy, can help detect early leaks. If
marginal ulceration. This is one of the most common complications
a leak is suspected clinically and the patient is unstable, surgical
after RYGB; the reported incidence is 15%. The pathophysiologic
exploration should be prioritized to prevent progression to sepsis.
mechanism of marginal ulceration is multifactorial; the contribu-
Management. Surgical exploration and management of tory factors differ for early and late ulceration. Local factors such
leaks by repairing defects and draining the abdominal cavity are as inflammation and the technical aspects of anastomosis creation
often feasible laparoscopically, especially at experienced centers. contribute to early ulceration, whereas microvascular ischemia has
Minimally invasive endoscopic repair techniques, including use a major role in late ulceration. A prominent risk factor for both
of glue, placement of covered stents, and placement of clips, early and late marginal ulceration is the use of nonsteroidal anti-
can also be an option in clinically stable patients but should be inflammatory drugs. Other purported risk factors include diabetes
considered adjuncts to surgical therapy. mellitus, obstructive sleep apnea, female sex, smoking, and alcohol
dependence. Preoperative Helicobacter pylori infection is associ-
ated with a risk for ulceration even after treatment, likely from
Postoperative Hemorrhage persistent damage to the mucosal barrier that may precipitate mar-
Hemorrhage after RYGB can be early (<30 days postoperatively) ginal ulceration even when the organism has been eradicated. The
or late (≥30 days postoperatively). Early bleeding is likely due to technique used to perform the gastrojejunal anastomosis may also
bleeding from the anastomosis or staple line and is usually cata- affect the rate of marginal ulcer formation.
strophic. Late bleeding is generally caused by significant gastritis,
marginal ulcers at the gastrojejunostomy, and ulcers in the pouch, Clinical Presentation and Diagnosis. Marginal ulcera-
gastric remnant stomach, or duodenum. A study of patients who had tion can present with nausea, abdominal pain, and recurrent GI
RYGB in the Metabolic and Bariatric Surgery Accreditation and bleeding. Chronic marginal ulcers can lead to anastomotic ste-
Quality Improvement Program data set found an early postopera- nosis. Gastrogastric fistulas have been known to develop from
tive hemorrhage rate of 1.5%. Postoperative bleeding leads to worse chronic marginal ulcers. In rare cases, perforation can be caused
outcomes, including longer duration of stay, higher in-hospital mor- by marginal ulceration.
tality rate, higher 30-day mortality rate, discharge to an extended- Marginal ulceration is usually diagnosed with endoscopic
care facility, and higher rates of major complications. Most patients evaluation. It is located at the gastrojejunal anastomotic site, typ-
are managed with reoperation or endoscopy. Endoscopy may be ically on the posterior aspect of the jejunum.
successful in minor bleeds with use of interventions such as clips, Management. Medical management is the first step in the
epinephrine injection, hemostatic powder, and thermal therapy. treatment of marginal ulceration and is successful in most cases.
It includes 6 to 8 weeks of antisecretory therapy with proton
Delayed Complications pump inhibitors alone or in combination with oral luminal coating
agents, such as sucralfate. It is important to have the patient open
Gastrojejunal Anastomotic Stricture the proton- pump- inhibitor capsules to allow better absorption
Anastomotic strictures (or stenosis) are a common complication within the RYGB anatomy. Testing and treating for H pylori in-
of RYGB (approximate incidence is 15%). They generally occur fection are also strongly recommended. Avoidance of nonsteroidal
anti-inflammatory drugs and smoking cessation are extremely im- after RYGB is internal hernias (described in detail above); other
portant for preventing the progression of these ulcers. common causes are incisional hernias, jejunojejunostomy ste-
A minority of patients (<10%) may have persistent symptoms, nosis, and adhesions. Rare causes of SBO include intussuscep-
including intractable pain, despite medical management, and tion (most commonly in the jejunojejunal anastomotic site) and
may have development of recurrent GI hemorrhage or perfora- bezoars. SBO is more common with laparoscopic RYGB (given
tion. In these cases, surgical or endoscopic revision is warranted. the popularity of the procedure and predisposition for internal
Generally, this includes revision of the gastrojejunostomy, hernias, which are the most common cause of SBO); a retrocolic
with or without truncal vagotomy. Endoscopy and overstitch technique of laparoscopic RYGB is also a risk factor for SBO. In
techniques have also been shown to be useful. In cases of perfora- summary, causes for SBO among different types of surgery are
tion, a Graham patch and feeding tube can be placed for unstable as follows:
patients, with formal revision after healing of the perforation. • Open RYGB: adhesive disease
• Laparoscopic RYGB: internal hernias
Internal Hernias • Retrocolic laparoscopic RYGB: internal hernias (mesocolic)
• Anterocolic laparoscopic RYGB: jejunojejunostomy stenosis
Internal hernias are common after laparoscopic RYGB; the in-
cidence varies from 0.5% to 10%. There are several types of in- Clinical Presentation, Diagnosis, and Management. The
ternal hernias, including mesenteric, Petersen, and mesocolic. symptoms of SBO are like those of internal hernias; there is
a wide variety of presentations, from vague, intermittent ab-
• Mesenteric hernia: formed in the space adjacent to the
jejunojejunal anastomosis, which is created by division of the je- dominal pain to severe acute pain. A strong suspicion for and
junal mesentery low threshold for surgical exploration are warranted in cases
• Petersen hernia: formed in the space between the Roux limb and with SBO.
its mesentery anteriorly and the transverse colon and its mesentery
posteriorly Nutritional Deficiencies
• Mesocolic hernia: formed in a defect in the transverse colon mesen-
tery. Only formed with retrocolic Roux limbs Clinical Presentation and Diagnosis. Given the restrictive
and malabsorptive state brought about by RYGB, both macronu-
Risk factors for formation of internal hernias include
trient and micronutrient deficiencies are common after the pro-
nonclosure or incomplete closure of mesenteric defects at the in-
cedure. Also, preoperatively, the prevalence of micronutrient is
itial surgery, major weight loss, and pregnancy.
high. The major macronutrient deficiency that occurs with RYGB
Clinical Presentation and Diagnosis. Internal hernias most is protein deficiency. Patients may have nausea and vomiting
commonly present with intermittent abdominal pain that occurs leading to electrolyte imbalances and thiamine deficiency.
because of transient incarceration that resolves spontaneously. Fat malabsorption leads to deficiency of fat-soluble vitamins
This is more commonly found in antecolic constructions, which (vitamins A, D, E, and K) and zinc. Over time, patients are also at
typically have wide internal defects that allow spontaneous re- risk for vitamin B12, calcium, iron, and copper deficiencies.
duction of the herniated intestines. Occasionally, internal hernias Postoperatively, protein deficiency occurs in patients with
can present as small-bowel obstructions or incarcerations. long Roux limbs (>150 cm), maladaptive eating behaviors,
Diagnosis of internal hernias is challenging because they inadequate protein food sources, and protracted vomiting.
have a heterogeneous clinical presentation and, most commonly, Protein deficiency presents with generalized edema and low al-
present with vague intermittent symptoms. Imaging can confirm bumin level.
the presence of internal hernias; however, imaging findings must Preoperative screening for micronutrient deficiency is an im-
be strongly correlated to symptoms before confirming the di- portant part of optimizing patients for bariatric surgery. Studies
agnosis. The mesenteric swirl sign is the most sensitive radio- show that less than 25% of patients undergo preoperative
graphic sign for diagnosis of internal hernias; it is the swirled screening for micronutrient deficiency. The American Society
appearance of mesenteric vessels or fat at the root of the mesen- for Metabolic and Bariatric Surgery (ASMBS) guidelines for
tery in hernia defects. If there is a clinical concern for internal patients undergoing bariatric surgery suggest screening for
herniation, computed tomographic scans should be carefully most vitamins and minerals before RYGB. These include thi-
reviewed by an experienced radiologist and bariatric surgeon. amine, folate, iron, calcium, zinc, copper, and vitamins A, B12,
and D. Screening recommendations are further summarized in
Management. Management of internal hernias is primarily Table 13.1.
through surgical exploration and repair. A patient who has had
RYGB and presents with acute severe pain, even in the absence Management. All patients undergoing RYGB should have
of characteristic computed tomographic findings, should be micronutrient supplementation postoperatively. In general,
evaluated by a surgical team and exploratory surgery considered. the ASMBS recommends multivitamin tablets daily. Generic
This approach is used because uncorrected bowel obstructions multivitamins can be used after a careful review of the products’
can lead to incarceration and bowel necrosis, which then require micronutrient contents; however, high- potency, bariatric
extensive bowel resection. Recommended measures to decrease surgery–specific multivitamins are also available. Multivitamins
the risk of formation of internal hernia are closure of all mesen- generally do not contain recommended doses of calcium, which
teric defects, use of nonabsorbable running suture, and construc- must be supplemented separately. Detailed dosages are listed in
tion of an antecolic Roux limb. Table 13.1.
In general, there should be a strong suspicion for micronu-
trient deficiencies postoperatively. Clinical signs and symptoms
Small-Bowel Obstruction of various micronutrient deficiencies are listed in Table 13.2.
Small-bowel obstructions (SBOs) are common after RYGB; Periodic screening for micronutrient deficiency can help
the lifetime incidence is 5%. The most common cause of SBO with early detection of these deficiencies. ASMBS guidelines
Table 13.1. Micronutrient Screeninga and Supplementation After Roux-en-Y Gastric Bypass
Standard postoperative supplementation Postoperative monitoring
Micronutrient Screening laboratory test dosage recommendations
Vitamin A Vitamin A 5,000-10,000 IU/d Optional (or based on signs and symptoms)
Vitamin B1 (thiamine) Thiamine 12 mg/d Optional (or based on signs and symptoms)
Vitamin B12 (cobalamin) B12; can also test for MMA Oral or sublingual: 350-500 μg/d 6, 12, 18, 24 mo and annually thereafter
Intranasal: 1,000 μg/wk
Intramuscular: 1,000 μg/mo
Vitamin D Vitamin D Vitamin D3 3,000 IU/d 6, 12, 18, 24 mo and annually thereafter
Iron Iron, TIBC, ferritin 45-60 mg/d 6, 12, 18, 24 mo and annually thereafter
Folate (folic acid) Folate; can also test for RBC, 400-800 μg/d 6, 12, 18, 24 mo and annually thereafter
folate, homocysteine, MMA Women of childbearing age: 800-1,000 μg/d
Calcium Calcium 1,200-1,500 mg/d 6, 12, 18, 24 mo and annually thereafter
Zinc Zinc 8-22 mg/d Optional (or based on signs and symptoms)
Copper Copper and ceruloplasmin 2 mg/d Optional (or based on signs and symptoms)
Abbreviations: MMA, methylmalonic acid; RBC, red blood cell; TIBC, total iron-binding capacity.
a
All patients should be screened for the listed nutrients.
recommend nutrient assessments every 3 to 6 months in the first to 3 hours after meals. The pathogenesis and presentation of these
year after bariatric surgery and annually thereafter with labora- 2 types differ.
tory tests. Early dumping is primarily an osmotic process. Passage of
undigested food into the small intestine triggers rapid fluid shifts
into the intestinal lumen. These shifts result in a decrease in
Dumping Syndrome plasma volume and a consequent sympathetic nervous system
Clinical Presentation and Diagnosis. Dumping syndrome is response. The resulting symptoms occur within a few minutes
a common complication of RYGB. It is classified as early or late, to within an hour of eating and include hypotension and tach-
depending on timing of symptoms after meals. Early dumping ycardia, colicky abdominal pain, diarrhea, and nausea. Early
happens within an hour of eating, whereas late dumping occurs 1 dumping is common, occurring in 10% to 20% of patients after
Table 13.2. Clinical Signs and Symptoms of Micronutrient Deficiencies and Replacement Dosages After Roux-en-Y
Gastric Bypass
Micronutrient Clinical signs and symptoms of deficiency Therapeutic replacement dose
Vitamin A Xerophthalmia, loss of nocturnal vision, decreased Vitamin A deficiency without corneal changes: vitamin A 10,000-25,000 IU
immunity daily orally until clinical improvement is evident (1-2 wk)
Vitamin A deficiency with corneal changes: vitamin A 50,000-100,000 IU
IM for 3 d, followed by 50,000 IU daily IM for 2 wk
Screen for concurrent iron or copper deficiencies because these can impair
resolution of vitamin A deficiency
Thiamine Neurologic symptoms (Wernicke-Korsakoff Oral therapy: 100 mg 2-3 times daily until symptoms resolve
syndrome). Common in patients with rapid IV therapy: 200 mg 3 times daily to 500 mg once or twice daily for 3-5
weight loss and alcohol use d, followed by 250 mg daily for 3-5 d or until symptoms resolve, then
consider treatment with 100 mg daily orally, usually indefinitely or until
risk factors have been resolved
IM therapy: 250 mg once daily for 3-5 d or 100-250 mg monthly
Simultaneous administration of magnesium, potassium, and phosphorus
should be given to patients at risk for refeeding syndrome
Vitamin B12 (cobalamin) Pernicious anemia, tingling in fingers and toes, 1,000 mg daily
depression, dementia
Vitamin D Similar to those with calcium deficiency Vitamin D3 3,000-6,000 IU daily
Vitamin D2 50,000 IU 1-3 times weekly
Iron Fatigue, koilonychia, pica, brittle hair, anemia 150-200 mg of elemental iron daily
Consider IV supplementation in refractory cases
Folate (folic acid) Macrocytic anemia, palpitations, fatigue, neural 1,000 mg daily
tube defects
Calcium Tetany, tingling, cramping, metabolic bone disease 1,200-1,500 mg daily
Zinc Growth retardation, delayed sexual maturity, 60 mg elemental zinc orally twice a day
impotence, impaired immune function
Copper Microcytic anemia, neutropenia, ataxia Mild to moderate deficiency (including low hematologic indices): 3-8 mg
daily oral copper gluconate or sulfate until indices return to normal
Severe deficiency: 2-4 mg daily IV copper can be initiated for 6 d or until
serum levels return to normal and neurologic symptoms resolve
Abbreviations: IM, intramuscularly; IV, intravenously.

RYGB. Predictors of severe symptoms include younger age and for SIBO. Breath testing involves ingestion of a carbohydrate
a lower body mass index. substrate (glucose or lactulose); its metabolism when exposed to
Late dumping is also known as postprandial hyperinsulinemic gut bacteria leads to the production of hydrogen and methane.
hypoglycemia (PHH). The pathophysiologic mechanism of However, postsurgical anatomy makes breath testing difficult to
PHH is complex and not completely understood but includes interpret.
alterations in multiple hormonal and glycemic patterns.
Incretin and insulin production increase, an effect that leads Management. Management of SIBO involves use of anti
to hypoglycemia. Patients with PHH present with postprandial biotics for bacterial eradication. The most studied and effica-
neuroglycopenic symptoms, including dizziness, diaphoresis, cious agent is rifaximin, which also has the advantage of being
and weakness. These symptoms occur 1 to 3 hours after inges- gut specific and nonsystemic. Other agents that have been proved
tion of a carbohydrate-rich meal. PHH generally presents at least efficacious include ciprofloxacin, norfloxacin, and metronida-
1 year after RYGB. It is a very uncommon phenomenon and zole. Dietary approaches such as a low-FODMAP (fermentable
occurs in less than 0.5% of cases. oligosaccharides, disaccharides, monosaccharides, and polyols)
diet and elemental diet have been tried with limited success and
Management. The initial management of early and late data. Many patients (up to 50%) may experience a recurrence in
dumping syndrome is similar and revolves around dietary symptoms. Management for this group includes the following:
modifications. These include multiple small meals throughout • Identification of offending organism with bacterial culture and use
the day and separating solid from liquid intake by 30 minutes. of targeted antibiotics
Meals should be high in fiber and protein and low in simple • Addressing any additional risk factors such as avoiding medications
carbohydrates that can be rapidly absorbed. A multidisciplinary that delay gut transit, reducing proton pump inhibitor and opioid
team including an experienced bariatric dietitian can be invalu- use, and improving glycemic control
able in the management of dumping syndrome. Early dumping is • Cyclical monthly low-dose antibiotic therapy with 2 or 3 antibiotics
generally mild and resolves spontaneously over time. PHH may • Trial of prokinetic agents
persist; in patients with refractory symptoms, pharmacotherapy • In rare instances, surgical or endoscopic revision of blind limb
or gastrostomy tube with feeding into the remnant stomach may
be attempted. Drugs that have been shown to have some ther- Gastrogastric Fistula
apeutic benefit include nifedipine, acarbose, diazoxide, and
octreotide. Partial pancreatectomy is not recommended. Surgical A gastrogastric fistula (GGF) is an abnormal communication
or endoscopic revision of RYGB is an option that can be explored between the gastric pouch and the excluded stomach remnant,
in refractory cases. allowing ingested food to enter the bypassed foregut (stomach
and duodenum). Historically, RYGB involved creation of a
nondivided or partially divided gastric pouch, which resulted
Nephrolithiasis in GGF formation in close to 50% of patients. Contemporary
The risk of nephrolithiasis is increased in patients who have techniques involve complete transection of the gastric segments,
had RYGB: a 2-fold increased risk in patients without a pre- an approach that has led to a decrease in the incidence of GGF,
vious history of stones and a 4-fold increased risk in patients now ranging from 1% to 3%.
with a previous history of stones. RYGB is associated with sev- There are multiple reasons for formation of GGF. As men
eral changes in the metabolic processing of calcium and oxalate tioned above, surgical technique or incomplete transection is a
in the urine, including an increase in urinary oxalate excretion, common iatrogenic reason for GGF formation. Anastomotic
supersaturation of calcium oxalate, a low urine citrate level, and leaks from the gastrojejunal anastomosis or pouch staple-line dis-
lower urine volume. All of these factors predispose patients to ruption can also lead to GGF formation. Perforation of marginal
nephrolithiasis after RYGB. Most patients can be managed with ulcers and erosion of foreign bodies such as nonabsorbable suture
dietary modifications (use of a low-fat, low-oxalate diet) and use material and preanastomotic rings may also cause GGF.
of calcium as an oxalate binder. Rarely, chronic deposition of
calcium oxalate in the renal parenchyma can result in oxalate Clinical Presentation and Diagnosis. GGF most com-
nephropathy and chronic kidney disease after RYGB. monly presents with weight regain or intractable marginal ulcer-
ation leading to recurrent GI hemorrhage or pain. For differential
diagnosis, GGF should be strongly considered in a patient with
Small Intestinal Bacterial Overgrowth weight regain after a period of stable weight after RYGB. GGF
RYGB is a common predisposing factor for small intestinal bac- can be diagnosed with upper GI series or computed tomog-
terial overgrowth (SIBO). This condition is thought to occur raphy with oral contrast agent. It can also be visualized on upper
because of the intestinal bypass, with the pancreatobiliary limb endoscopy.
acting as a relatively blind loop. This blind loop has abnormal
motility and ineffective clearance of secretions, factors leading to Management. Asymptomatic patients can be managed
bacterial stasis and overgrowth. conservatively with proton pump inhibitor therapy and close
follow-up. For symptomatic patients, GGF can be managed en-
Clinical Presentation and Diagnosis. SIBO presents with doscopically or surgically. Endoscopic repair can be performed
vague and nonspecific symptoms, including abdominal pain, in multiple ways, including fibrin sealant, endoscopy clips, and
bloating, diarrhea, distention, and flatulence. It can be diagnosed endoscopic suturing systems. It is safe and feasible and can be
with either noninvasive breath testing or culture of small-bowel used with good success for small fistulas or in the short term.
aspirates obtained during endoscopy. Small-bowel cultures are Surgical repair in the form of laparoscopic fistula excision with or
considered more accurate in terms of testing; a threshold of more without revision of gastrojejunostomy anastomosis remains the
than 103 colony-forming units per milliliter is a positive test result definitive therapy.
Candy Cane Syndrome bowel obstruction and complications including ischemia, per-
This rare complication develops in patients with an abnormally foration, pancreatitis, and biliary obstruction. A classic feature
long blind afferent Roux limb. The blind limb fills with food described on computed tomography is the C-loop sign (seen in
after meals and acts like an obstructed loop; the associated ab- the right upper quadrant, representing the dilated afferent limb).
dominal pain is relieved by vomiting or passage of food into An upper GI series can also be used for the diagnosis of afferent
the Roux limb. It occurs in patients with excessive length of the loop syndrome and may show failure of contrast agent to enter
blind Roux limb just distal to the gastrojejunostomy; this length the afferent limb; however, this finding is nonspecific.
was reported to be 8 to 15 cm in one study. Other predisposing Management. Most cases of acute afferent limb syndrome
factors include GI dysmotility and progressive dilatation of the should be managed surgically. Nasojejunal decompression and
blind afferent limb. intravenous fluids can be used as temporizing measures preop-
Clinical Presentation and Diagnosis. Patients present with eratively. Endoscopic therapy is emerging as a safe and effective
postprandial epigastric abdominal pain. This may occur either rel- option for many patients. This includes stent placement, anasto-
atively early after surgery (as soon as 2-3 months postoperatively) motic stricture dilation, and endoscopic ultrasound-guided crea-
or even years after surgery. Patients may also have nausea and tion of a gastrojejunostomy.
symptoms of reflux or regurgitation. The pain is generally re-
lieved after vomiting. Suggested Reading
Candy cane syndrome should be suspected in patients with Al Harakeh AB, Kallies KJ, Borgert AJ, Kothari SN. Bowel obstruc-
postprandial pain relieved by vomiting. It can be confirmed by tion rates in antecolic/antegastric versus retrocolic/retrogastric Roux
upper GI contrast studies, which show contrast spillage into the limb gastric bypass: a meta-analysis. Surg Obes Relat Dis. 2016
blind afferent limb before passing into the Roux limb. Endoscopic Jan;12(1):194–8.
visualization shows that the afferent limb is the direct outlet of Almby K, Edholm D. Anastomotic strictures after Roux-en-Y gastric by-
the gastrojejunostomy, rather than the Roux limb. pass: a cohort study from the Scandinavian Obesity Surgery Registry.
Obes Surg. 2019 Jan;29(1):172–7.
Management. Surgical revision of the RYGB is the mainstay Aryaie AH, Fayezizadeh M, Wen Y, Alshehri M, Abbas M, Khaitan L.
of treatment for candy cane syndrome. This generally includes “Candy cane syndrome:” an underappreciated cause of abdominal
laparoscopic resection of the afferent limb. Surgeons should pain and nausea after Roux-en-Y gastric bypass surgery. Surg Obes
attempt to minimize the length of the blind afferent limb and Relat Dis. 2017 Sep;13(9):1501–5.
place the blind limb toward the right side to favor drainage by Blouhos K, Boulas KA, Tsalis K, Hatzigeorgiadis A. Management of
afferent loop obstruction: reoperation or endoscopic and percutaneous
gravity as a means to prevent this complication.
interventions? World J Gastrointest Surg. 2015 Sep 27;7(9):190–5.
Canales BK, Hatch M. Kidney stone incidence and metabolic urinary
Afferent Loop Syndrome changes after modern bariatric surgery: review of clinical studies, ex-
perimental models, and prevention strategies. Surg Obes Relat Dis.
Afferent loop syndrome refers to a partial or complete obstruc- 2014 Jul-Aug;10(4):734–42.
tion of the biliopancreatic (afferent) limb along its course or at the Chahine E, Kassir R, Dirani M, Joumaa S, Debs T, Chouillard E. Surgical
anastomosis. It presents with symptoms of bowel obstruction but management of gastrogastric fistula after Roux- en- Y gastric by-
can also cause biliary dilatation or acute pancreatitis due to back pass: 10-year experience. Obes Surg. 2018 Apr;28(4):939–44.
pressure. It occurs after Billroth II or Roux-en-Y reconstruction; Chowbey P, Baijal M, Kantharia NS, Khullar R, Sharma A, Soni V.
the reported incidence is 0.3% to 1%. Causes of afferent loop Mesenteric defect closure decreases the incidence of internal hernias
following laparoscopic Roux-en-Y gastric bypass: a retrospective co-
syndrome include entrapment and kinking of the afferent loop by
hort study. Obes Surg. 2016 Sep;26(9):2029–34.
postoperative adhesions, internal herniation, volvulus and intus- Grotewiel RK, Cindass R. Afferent loop syndrome. Statpearls [internet].
susception of the afferent loop, and stenosis due to ulceration at StatPearls Publishing; 2022.
the gastrojejunostomy site. Rarely, enteroliths, bezoars, and for- Parrott J, Frank L, Rabena R, Craggs-Dino L, Isom KA, Greiman L.
eign bodies are responsible for the afferent loop. American Society for Metabolic and Bariatric Surgery integrated
health nutritional guidelines for the surgical weight loss patient 2016
Clinical Presentation and Diagnosis. Afferent loop syn- update: micronutrients. Surg Obes Relat Dis. 2017 May;13(5):727–41.
drome may be acute or chronic. Acute cases generally occur Ramos-Andrade D, Andrade L, Ruivo C, Portilha MA, Caseiro-Alves
early postoperatively and present with sudden onset of abdom- F, Curvo-Semedo L. Imaging the postoperative patient: long-term
inal pain, nausea, and vomiting. In severe cases with ischemia complications of gastrointestinal surgery. Insights Imaging. 2016
and perforation, patients may have peritonitis and shock. Patients Feb;7(1):7–20.
may also have jaundice due to biliary obstruction and features of Termsinsuk P, Chantarojanasiri T, Pausawasdi N. Diagnosis and
acute pancreatitis. treatment of the afferent loop syndrome. Clin J Gastroenterol. 2020
Chronic afferent loop syndrome typically presents in the Oct;13(5):660–8.
Vargas EJ, Abu Dayyeh BK, Storm AC, Bazerbachi F, Matar R, Vella A,
late postoperative period with postprandial abdominal pain and
et al. Endoscopic management of dumping syndrome after Roux-en-
weight loss. The postprandial abdominal pain may lead to food Y gastric bypass: a large international series and proposed manage-
aversion and malabsorption. ment strategy. Gastrointest Endosc. 2020 Jul;92(1):91–6.
Afferent loop syndrome should be suspected in a patient with Zafar SN, Miller K, Felton J, Wise ES, Kligman M. Postoperative
acute or chronic abdominal pain after RYGB. It can be diagnosed bleeding after laparoscopic Roux-en-Y gastric bypass: predictors and
with abdominal computed tomography, which can show the consequences. Surg Endosc. 2019 Jan;33(1):272–80.
14
Endoscopy for the Gastroenterology

Board Examination
TAREK SAWAS, MD
DAVID H. BRUINING, MD
ANDREW C. STORM, MD
Quality Metrics for Colonoscopy include advanced age, male sex, obesity, non-English speaking,
enrolled in Medicaid insurance, inpatient, single, polypharmacy,
Colonoscopy is a widely used diagnostic and therapeutic tool.
and comorbidities such as diabetes mellitus, cerebrovascular ac-
The goal of a screening colonoscopy is to detect and remove
cident, Parkinson disease, and dementia. An important nonpatient
early neoplastic lesions to prevent the development of colorectal
determinant of a poor preparation is a long interval between the
cancer in asymptomatic patients. Performing a high-quality co-
end of preparation and the start of the procedure.
lonoscopy with comprehensive mucosal visualization is essen-
Patients should be carefully educated and instructed about the
tial. The following metrics have been proposed as indicators
preparation process. Appropriate cleansing incorporates a combi-
for high-quality examinations: colon preparation, cecal intuba-
nation of diet modification and a cathartic agent. Patients should
tion rate, withdrawal time, and adenoma detection rate (ADR)
be advised to follow a clear-liquid or low-residual diet the day
(Table 14.1).
before the procedure. Consuming the colon preparation in a split
dose results in higher-quality examinations, higher adenoma de-
Colon Preparation tection rates, and improved patient tolerance. The quality of the
colon preparation should be documented for each procedure.
The yield of screening colonoscopy is dependent on the quality of
One of the proposed validated scoring tools is the Boston bowel
the colon preparation. The American College of Gastroenterology
preparation scale (Table 14.2). This scale has been shown to be
and the American Society for Gastrointestinal Endoscopy Task
positively associated with the ADR and procedural insertion and
Force on Quality in Endoscopy defined adequate examination
withdrawal times. Screening colonoscopy with inadequate prepa-
as one that allows detection of lesions larger than 5 mm (Am J
ration should be repeated in 1 year or less.
Gastroenterol. 2002 Jun;97[6]‌:1296-308). Inadequate colon prep-
aration is the most common cause of incomplete colonoscopy and
has been associated with missed neoplasia, prolonged procedure Table 14.1. Quality Metrics for Colonoscopy
time, and a higher rate of adverse events. Preparation is inade-
quate in about 15% of colonoscopies. Multiple factors have been Quality measure Recommended target
identified as predictors of poor colon cleansing. Patient factors Adequate colon preparation ≥90% of all colonoscopies
Cecal intubation rate ≥95% of screening colonoscopies
≥90% of all colonoscopies
Adenoma detection rate ≥25%
Abbreviations: ADR, adenoma detection rate; CHA2DS2-VASc, car-
≥20% in women
diac failure or dysfunction, hypertension, age 65-74 years or older than
≥30% in men
75 years, diabetes mellitus, and stroke, transient ischemic attack, or Withdrawal time ≥6 minutes
thromboembolism-vascular disease, and sex category (female); ERCP,
endoscopic retrograde cholangiopancreatography; EUS, endoscopic ul- Data from Rex DK, Schoenfeld PS, Cohen J, Pike IM, Adler DG, Fennerty
trasonography; FNA, fine-needle aspiration; GI, gastrointestinal; INR, MB, et al. Quality indicators for colonoscopy. Gastrointest Endosc. 2015
international normalized ratio; PEP, post-ERCP pancreatitis. Jan;81(1):31-53.
167
Table 14.2. Boston Bowel Preparation Scale aged 50 years or older undergoing screening colonoscopy who
have 1 or more precancerous polyps detected. The ADR is in-
Score Description
versely associated with the risk of colorectal cancer. The goal
0 Unprepared colon segment with solid stool preventing mucosal ADR is 25% or more (men ≥30% and women ≥20%). An ADR
visualization less than 20% is associated with a higher risk for post-colonoscopy
1 Portion of the mucosal segment is not seen because of staining, colorectal cancer.
solid stool, or opaque liquids
2 Minor amount of residual staining, residual stool, or opaque
liquids but mucosa is well visualized Management of Antithrombotic Agents
3 Entire mucosa is well visualized without residual staining,
stool, or opaque liquid Antithrombotic medications can be categorized according to their
mechanism of action into anticoagulants and antiplatelet agents.
Data from Lai EJ, Calderwood AH, Doros G, Fix OK, Jacobson BC. The Boston Anticoagulants prevent thrombosis by blocking the clotting
bowel preparation scale: a valid and reliable instrument for colonoscopy-oriented
cascade, whereas antiplatelet agents affect platelet function by
research. Gastrointest Endosc. 2009 Mar;69(3 Pt 2):620-5.
preventing platelet aggregation. Management of antithrombotic
agents in patients undergoing endoscopic procedures is challenging.
Cecal Intubation Rate Interrupting antithrombotic therapy increases the risk of thrombo-
Cecal intubation is defined as advancement of the colonoscope embolic events. Conversely, some endoscopic procedures are as-
tip proximal to the ileocecal valve to ensure adequate visuali- sociated with a high risk of bleeding. Periprocedural management
zation of the cecal base. Low cecal intubation rates are associ- should consider 4 factors: 1) the risk of bleeding associated with
ated with higher post-colonoscopy proximal colon cancer. The the endoscopic procedure, 2) a patient’s personal risk for thrombo-
current quality guidelines recommend a cecal intubation rate of embolic events, 3) the urgency of the procedure, and 4) the phar-
95% for screening colonoscopies and 90% for all colonoscopies. macokinetics of the antithrombotic agent.
Endoscopists are expected to photographically document ana-
tomical landmarks (ileocecal valve and appendiceal orifice). Step 1: Determine the Risk of Bleeding
(High vs Low)
Withdrawal Time The risk of bleeding is mainly driven by the need for therapeutic
The goal withdrawal time is an average of 6 or more minutes. intervention (Box 14.1). Most diagnostic endoscopy is associated
Longer withdrawal time is associated with a higher ADR. with a low risk of bleeding (<1%) and does not require interruption
of anticoagulation or antiplatelet therapy. The most common low-
risk procedures are upper endoscopy with biopsies, colonoscopy
Adenoma Detection Rate with biopsies, endoscopic retrograde cholangiopancreatography
The ADR is the single most important quality measure for (ERCP) without sphincterotomy, and endoscopic ultrasonog-
screening colonoscopy. It is defined as the percentage of patients raphy (EUS) without fine- needle aspiration (FNA). High- risk
Box 14.1. Procedure Risk for Bleeding

High bleeding risk Low bleeding risk
Varices treatment Diagnostic EGD or colonoscopy with biopsy
Dilation Enteral stent (controversial)
Polypectomy Barrett esophagus ablation
ERCP with biliary or pancreatic ERCP with stent or papillary balloon dilation
sphincterotomy Capsule endoscopy
Ampullectomy EUS without FNA
EUS with FNA EUS with FNA of solid masses and patient is
Cystgastrostomy receiving ASA or NSAIDs
PEG and PEJ tube placement PEG placement and patient is receiving ASA
Therapeutic BAE (except APC) or clopidogrel
Endoscopic mucosal resection or Diagnostic BAE

endoscopic submucosal dissection APC
Abbreviations: APC, argon plasma coagulation; ASA, aspirin; BAE, balloon- assisted enteroscopy; EGD,
esophagogastroduodenoscopy; ERCP, endoscopic retrograde cholangiopancreatography; EUS, endoscopic ultra-
sound; FNA, fine-needle aspiration; NSAIDs, nonsteroidal anti-inflammatory drugs; PEG, percutaneous endoscopic
gastrostomy; PEJ, percutaneous endoscopic jejunostomy.
Adapted from ASGE Standards of Practice Committee, Acosta RD, Abraham NS, Chandrasekhara V, Chathadi
KV, Early DS, et al. The management of antithrombotic agents for patients undergoing GI endoscopy. Gastrointest
Endosc. 2016 Jan;83(1):3-16; used with permission.
14. Endoscopy for the Gastroenterology Board Examination 169
procedures require holding and possibly reversing the effect high-risk conditions include placement of drug- eluting coro-
of antithrombotics to minimize the risk of bleeding. High-risk nary stents in the past year or bare metal stents within the pre-
procedures include esophageal dilation, variceal banding, percuta- vious month. In these situations, endoscopic procedures should
neous feeding-tube placement, ERCP with sphincterotomy, EUS be delayed, if possible, until it is safe to withhold antiplatelet
with FNA, and colonoscopy with removal of large polyps (>1 cm). therapy. Patients with a history of an occluded coronary artery
The risk of bleeding after polypectomy ranges from 0.3% stent are at high risk for a second stent occlusion (20%) and car-
to 10%. Factors associated with increased postpolypectomy diac death (28%) even after 1 year from stent placement.
bleeding include large polyp size (>10 mm), polyp location
(higher risk in the right side), morphologic features (large sessile
Step 3: Determine the Urgency of
polyps and pedunculated thick-stalk polyps), resection technique
the Procedure
(lower risk of delayed bleeding with cold snare polypectomy),
and type of cautery used (higher risk with pure cutting mode of Urgent situations include but are not limited to active gastroin-
electrosurgical current). testinal (GI) bleeding and acute cholangitis. Patients receiving
warfarin who have life- threatening GI bleeding may require
reversal of the effect of anticoagulation, whereas those with
Step 2: Determine the Risk of a
minor bleeding may be managed by withholding warfarin but
Thromboembolic Event
not reversing its effect. For patients with active GI bleeding,
If a procedure is deemed to be associated with a high risk of some experts recommend a goal international normalized ratio
bleeding, the next step is to determine the risk for a thromboem- (INR) of less than 2.5. One study suggested that the success rate
bolic event and thus the need for a bridging agent (Table 14.3). of endoscopic hemostasis for patients with an INR between 1.3
The risk depends on the underlying indication for anticoagulation and 2.7 is comparable to that of patients who are not receiving
or antiplatelet therapy. Patients receiving anticoagulation anticoagulants, and the study was not powered to determine the
who have a low thromboembolic risk do not require bridging. success rate for an INR of more than 2.7 (Am J Gastroenterol.
Conversely, high-risk patients undergoing high-risk procedures 2007 Feb;102[2]‌:290-6). Accordingly, endoscopic therapy for se-
require bridging with a short-acting anticoagulant before and rious GI bleeding should not be delayed in patients with an INR
after the procedure. Conditions that are associated with a low less than 2.5.
thromboembolic risk include nonvalvular atrial fibrillation with
a CHA2DS2-VASc (cardiac failure or dysfunction, hypertension,
Step 4: Determine the Appropriate Duration to
age 65-74 years [1 point] or ≥75 years [2 points], diabetes mel-
Withhold Medication
litus, and stroke, transient ischemic attack, or thromboembolism
[2 points]-vascular disease [2 points], and sex category [female]) The risk of bleeding in patients taking a low-dose aspirin is
risk score of 0 or 1, having a bileaflet aortic valve prosthesis low, and use of this medication does not need to be stopped
without atrial fibrillation, and venous thromboembolism for more even for patients undergoing a procedure associated with a
than 6 months before the procedure. High-risk conditions in- high risk of bleeding. Other antiplatelet agents can be withheld
clude having any prosthetic mitral valve or a caged-ball or tilting on the basis of their elimination time: clopidogrel (5-7 days),
disk aortic valve prosthesis; cerebrovascular accident or transit prasugrel (5-7 days), ticagrelor (3-5 days), and ticlopidine (10-
ischemic attack within the past 6 months; venous thromboembo- 14 days). Warfarin should be withheld for 5 days before high-risk
lism in the past 3 months; and severe thrombophilia (protein C, procedures. Because low-molecular-weight heparin has a short
protein S, and antithrombin deficiency and the antiphospholipid half-life, its use can be stopped 24 hours before the procedure.
antibody syndrome). For patients receiving antiplatelet therapy, Novel oral anticoagulants include direct factor Xa inhibitors and
Table 14.3. Risk Stratification for Thromboembolic Event in Patients With Mechanical Valve or VTE
Risk
Valve or condition High Medium Low

Mitral valve Any mitral prosthesis NA NA
Aortic valve Caged-ball or tilting disk aortic Bileaflet aortic valve prosthesis and 1 of Bileaflet aortic valve without
valve prosthesis the following: AF, prior CVA or TIA, risk factors
hypertension, diabetes, CHF, age ≥75 y
Cerebrovascular accident TIA or CVA within past 6 months NA NA
VTE VTE within 3 mo VTE in past 3-12 mo VTE >12 mo and no other risk
Recurrent VTE factors
Active cancer (treatment in the past 6 mo
or palliative)
Thrombophilia Severe thrombophilia (deficiency Nonsevere thrombophilia (heterozygous NA
protein C/S/antithrombin, factor V Leiden)
antiphospholipid antibodies)
Abbreviations: AF, atrial fibrillation; CHF, congestive heart failure; CVA, cerebrovascular accident; NA, not applicable; TIA, transient ischemic attack; VTE,
venous thromboembolism.
Adapted from Douketis JD, Spyropoulos AC, Spencer FA, Mayr M, Jaffer AK, Eckman MH, et al. Perioperative management of antithrombotic
therapy: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines.
Chest. 2012 Feb;141(2 Suppl):e326S-e50S; used with permission.
Table 14.4. Perioperative Management of Novel Oral Table 14.5. Antibiotic Prophylaxis in Cardiac Conditions
Anticoagulant Agentsa
Cardiac condition Indication for antibiotics
Electiveb Hemodialysis
All cardiac conditions No
Novel oral (Cr clearance (massive GI Highest risk of IE If established GI tract infection and for those
anticoagulant >90 mL/min) Reversal agent bleeding) who receive antibiotic therapy to prevent
Direct thrombin NA NA NA wound infection or sepsis associated with
inhibitor a GI procedure, use an antibiotic regimen
Dabigatran Hold 2-3 d Idarucizumab Yes with an agent active against enterococci
Direct Xa inhibitors NA Recombinant NA Prosthetic cardiac valve NA
factor Xa History of IE
Rivaroxaban Hold 1 d NA No Cardiac transplant with
Apixaban Hold 1-2 d NA No valvulopathy
Edoxaban Hold 1 d NA No CHD
Unrepaired cyanotic CHD
Abbreviations: Cr, creatinine; GI, gastrointestinal; NA, not applicable. Repaired CHD (first 6 mo)
a
Based on procedural urgency and high-risk procedure. Repaired CHD with
residual defects
b
See guidelines for impaired renal function.
Abbreviations: CHD, congenital heart disease; GI, gastrointestinal; IE, infective
c
Approved apixaban and rivaroxaban.
endocarditis; NA, not applicable.
Data from ASGE Standards of Practice Committee, Acosta RD, Abraham
Adapted from ASGE Standards of Practice Committee, Khashab MA, Chithadi
NS, Chandrasekhara V, Chathadi KV, Early DS, et al. The management of
KV, Acosta RD, Bruining DH, Chandrasekhara V, et al. Antibiotic prophylaxis for
antithrombotic agents for patients undergoing GI endoscopy. Gastrointest Endosc.
GI endoscopy. Gastrointest Endosc. 2015 Jan;81(1):81-9; used with permission.
2016 Jan;83(1):3-16.
direct thrombin inhibitor agents. The discontinuation duration Endoscopic Ultrasonography

varies according to kidney function. For most of these agents, EUS is both a diagnostic and a therapeutic tool. The diagnostic
an average of 1 to 2 days is appropriate in patients with normal role includes evaluation and staging of GI mucosal and submu-
creatinine clearance (Table 14.4). Patients with impaired renal cosal lesions and of pancreas and bile duct abnormalities and
function may require longer discontinuation times. Use of novel performance of EUS-guided FNA and biopsy. The wall of the
oral anticoagulants can be restarted once hemostasis is con- GI tract is lined by 5 layers. Layers that contain muscle appear
firmed. Idarucizumab is a reversal agent for direct thrombin in- darker (hypoechoic) on EUS. The 5 layers from the inside out are
hibitor (dabigatran), and recombinant factor Xa (Andexxa) is a as follows (Figure 14.1):
reversal agent for apixaban and rivaroxaban. 1. Mucosa/epithelium (bright)
2. Muscularis mucosa (dark)
Antibiotic Prophylaxis for Endoscopy
Although bacteremia is common after endoscopy, clinically sig-
nificant infections are rare. Antibiotic prophylaxis to solely pre- Table 14.6. Antibiotic Prophylaxis Before Endoscopic
vent infectious endocarditis is not recommended for most GI Procedures
procedures, even in patients with high-risk cardiac conditions.
Procedure Indication for antibiotics
Similarly, patients with synthetic vascular grafts or an ortho-
pedic prosthesis who are undergoing GI endoscopic procedures ERCP without cholangitis (complete No
do not require antibiotic prophylaxis. The only exceptions are drainage)
patients with high- risk cardiac conditions (Table 14.5) and ERCP for obstruction without Yes; continue after procedure
cholangitis (incomplete drainage)
those with an established GI tract enterococcus infection such Liver transplant Yes; continue after procedure
as cholangitis. Prophylactic antibiotics effective against gram- EUS-FNA of solid lesion (upper or No
positive skin flora should be given before percutaneous endo- lower GI tract)
scopic gastrostomy or jejunostomy tube placement. Patients EUS-FNA of mediastinal cysts Suggested
who are having peritoneal dialysis and will undergo lower en- EUS-FNA of pancreatic or Suggested
doscopy should receive antibiotic prophylaxis with ampicillin peripancreatic cysts
and an aminoglycoside. PEG or PEJ initial placement Yes
Cirrhosis with GI bleeding Yes
Antibiotic prophylaxis should be administered before ERCP Synthetic vascular graft OR prosthetic No
in the following: 1) liver transplant recipients, 2) patients in joints
whom biliary obstruction is suspected who have a possibility of Lower endoscopy in patient Yes; ampicillin +aminoglycoside
incomplete biliary drainage, and 3) patients with primary scle- undergoing peritoneal dialysis
rosing cholangitis (Table 14.6). The antibiotic chosen should be
Abbreviations: ERCP, endoscopic retrograde cholangiopancreatography; EUS,
effective against biliary or enteric flora, including enteric gram-
endoscopic ultrasound; FNA, fine-needle aspiration; GI, gastrointestinal;
negative organisms and enterococci. Patients undergoing EUS PEG, percutaneous endoscopic gastrostomy; PEJ, percutaneous endoscopic
or EUS with FNA of a solid lesion do not require prophylaxis. jejunostomy.
However, prophylactic antibiotics are suggested for EUS with
Adapted from ASGE Standards of Practice Committee, Khashab MA, Chithadi
FNA of mediastinal, pancreatic, and peripancreatic cystic lesions KV, Acosta RD, Bruining DH, Chandrasekhara V, et al. Antibiotic prophylaxis for
(Table 14.7). GI endoscopy. Gastrointest Endosc. 2015 Jan;81(1):81-9; used with permission.
Table 14.7. Endoscopic Ultrasonography of Subepithelial Lesions

Lesion Layer Pattern Stain Miscellaneous
Carcinoid 2,3 Hypoechoic or isoechoic NA NA
Duplication cyst or Cyst: 2,3,4,5 Anechoic NA Duplication cyst: Doppler
varices Varices: 3 (can course negative
through all layers) Varices: Doppler positive
Pancreatic rest 2,3,4 Hypoechoic (usually) NA Central umbilication
Lipoma 3 Hyperechoic NA Pillow sign
Schwannoma 3,4 Hypoechoic +S100 NA
Glomus tumor 3,4 Hypoechoic (usually) +Vimentin NA
Leiomyoma 4 (usually) Hypoechoic +Desmin, +SMA, NA
2,3 (rare) −CD117
GIST 4 (usually) Hypoechoic +CD117 (c-Kit) NA
2,3 (rare) +PDGFRa
Abbreviations: GIST, gastrointestinal stromal tumor; NA, not applicable; PDGFRa, platelet-derived growth factor receptor alpha; SMA,
smooth muscle actin.
3. Submucosa (bright) recurrent pancreatitis, suspected sphincter of Oddi dysfunction,

4. Muscularis propria (dark) young age, absence of chronic pancreatitis, normal serum bili-
5. Serosa (bright) rubin value, difficult cannulation, repetitive pancreatic guidewire
Subepithelial tumors are identified in layers 2, 3, or 4. The cannulation, pancreatic injection, pancreatic sphincterotomy,
appearance and location of the most commonly identified and and papillary large- balloon dilation of an intact sphincter.
important lesions are listed in Table 14.7. Administration of rectal nonsteroidal anti-inflammatory drugs in
high-risk patients substantially reduces the incidence and severity
of PEP. Additional methods to reduce PEP involve placement of
Endoscopic Retrograde a prophylactic pancreatic plastic stent and periprocedural intrave-
Cholangiopancreatography nous hydration.
ERCP is the cornerstone for management of pancreaticobiliary Post-ERCP bleeding complicates less than 2% of procedures
diseases. Familiarity with the following concepts is important for and most commonly is a result of sphincterotomy. Other less
the board examination: common causes of post-ERCP bleeding include stricture dila-
tion, biopsy, and ablative therapy. Bleeding might be immediate
1. Adverse events associated with ERCP or delayed up until several weeks after ERCP. Risk factors for
2. High-yield cholangiograms
post-ERCP bleeding include coagulopathy, active cholangitis, the
3. Biliary stents
use of anticoagulants within 3 days from the procedure, and the
endoscopist’s ERCP case volume. The length of sphincterotomy,
periampullary diverticulum, and aspirin use have not been shown
ERCP-Associated Adverse Events to increase the risk of bleeding.
It is essential for gastroenterologists to understand the possible Other possible adverse events associated with ERCP include
adverse events associated with ERCP. Post-ERCP pancreatitis cholangitis, cholecystitis, and perforation. Abdominal computed
(PEP) is the most common adverse event (5% of cases). Factors tomography with an oral contrast agent is the most reliable
associated with a high risk for PEP include prior PEP, female sex, method to assess for perforation.
Figure 14.1. Normal Gastric Wall Layers Shown on Ultrasonography.

High-Yield Cholangiograms or Pancreatograms Biliary Stents

The following conditions are important to recognize on cholangio Biliary stents can be either plastic or metal. All plastic stents are
grams or pancreatograms: radiopaque. They have a small diameter and require exchange
1. Primary sclerosing cholangitis: the multifocal short biliary strictures every 2 to 3 months. The 2 main adverse events associated with
and upstream dilatation result in the characteristic appearance of plastic stents are migration and occlusion. Metal stents have a
beads on a string. larger diameter with longer patency time and a low risk for ob-
2. Abnormal pancreaticobiliary junction: the junction of the biliary struction. Metal stents are either fully covered or uncovered.
duct and pancreatic duct is outside the wall of the duodenum with a Uncovered metal stents are prone to tissue ingrowth, which makes
long common channel (Figure 14.2). stent extraction or manipulation extremely difficult after insertion.
3. Post-cholecystectomy biliary leak: contrast extravasation from the Covered metal stents prevent tissue ingrowth but are more likely
cystic duct stump (most commonly) or within the gallbladder bed. to migrate. Self-expanding metal stents are preferred over plastic
4. Pancreatic divisum (Figure 14.3): characterized by the presence stents in selected patients with nonresectable malignant biliary
of a short ventral duct at the major papilla and the dorsal pancre-
obstruction given their longer patency and might be more cost
atic duct draining separately from the tail to the head at the minor
papilla. effective in patients with a longer life expectancy and no metas-
5. Annular pancreas (Figure 14.4): the ventral pancreatic duct encircles tasis and who have early occlusion of the plastic biliary stents.
the duodenum.
6. Recurrent pyogenic cholangitis (Figure 14.5): the classic finding is ✓ ADR is the single most important quality measure for screening
the arrowhead sign. This sign results from multiple changes caused colonoscopy and is inversely associated with the risk of post-
by periductal fibrosis, including dilated intrahepatic and extrahepatic colonoscopy colorectal cancer. The goal ADR is 25% or more.
ducts, straightened intrahepatic ducts with less acute angled ✓ The goal withdrawal time for screening colonoscopy is an average
branching, and decreased branching with acute tapering of the pe- of 6 minutes or more. Longer withdrawal times are associated
ripheral ducts. with higher ADRs.
Figure 14.2. Anomalous Pancreaticobiliary Junctions on Endoscopic Retrograde Cholangiopancreatography. A, Anomalous pancreaticobiliary
junction (APBJ, arrow) with a bile duct stricture (arrowhead) caused by gallbladder cancer in a 32-year-old with obstructive jaundice. APBJ is a risk
factor for development of gallbladder cancer. Note the absence of a bile duct cyst. B, Anomalous pancreaticobiliary junction with a cyst of the common
bile duct. Bile drains to the duodenum via the minor papilla (inset). (Adapted from Topazian MD. Pancreas divisum, biliary cysts, and other congen-
ital anomalies. In: Baron TH, Kozarek RA, Carr-Locke DL, eds. ERCP. 3rd ed. Elsevier; 2018:335-45; Figure 2B courtesy of Naoki Takahashi, MD,
Diagnostic Radiology, Mayo Clinic; used with permission.)
Figure 14.4. Annular Pancreas on Endoscopic Retrograde

Cholangiopancreatography. The ventral pancreatic duct encircles the
second duodenum (arrow). This patient also has a stricture of the main
pancreatic duct, caused by pancreatic adenocarcinoma. (Adapted from
Topazian MD. Pancreas divisum, biliary cysts, and other congenital
anomalies. In: Baron TH, Kozarek RA, Carr-Locke DL, eds. ERCP. 3rd
ed. Elsevier; 2018:335-45; used with permission.)
✓ Repeat colonoscopy within 1 year after a colonoscopy for which

preparation was inadequate.
✓ Continue use of antithrombotics for procedures with a low
bleeding risk. There is no need to interrupt the use of aspirin, even
for procedures with a high bleeding risk.
✓ There is no need for prophylactic antibiotics for most GI
procedures, even in the presence of high-risk cardiac conditions.
✓ Antibiotic prophylaxis should be used in the following cases: be-
fore ERCP in liver transplant recipients or patients with ongoing
Figure 14.3. Pancreatic Divisum on Endoscopic Retrograde biliary obstruction, before EUS with FNA of a cystic lesion, be-
Cholangiopancreatography. A, Cannulation of the major papilla fore percutaneous endoscopic gastrostomy or jejunostomy tube
demonstrates an arborizing ventral pancreatic duct that does not cross placement, in patients who are having peritoneal dialysis and
the midline or give rise to an uncinate branch. B, Cannulation of the will undergo lower endoscopy, in patients with high-risk cardiac
minor papilla demonstrates a dominant dorsal pancreatic duct, with conditions, and in patients with established GI tract enterococcus
no communication to the ventral pancreas. The uncinate branch arises infection.
from the dorsal pancreatic duct. (Adapted from Topazian MD. Pancreas ✓ Administration of rectal nonsteroidal anti-inflammatory drugs in
divisum, biliary cysts, and other congenital anomalies. In: Baron TH, high-risk patients substantially reduces the incidence and severity
Kozarek RA, Carr-Locke DL, eds. ERCP. 3rd ed. Elsevier; 2018:335-45; of post-ERCP pancreatitis.
used with permission.)
Figure 14.5. Recurrent Pyogenic Cholangitis. This condition is characterized by recurrent and progressively severe attacks of cholangitis with
associated intrahepatic stones, secondary strictures, and upstream duct dilatation. These features often lead to segmental or lobar atrophy, as shown on
magnetic resonance cholangiopancreatograpy (A), endoscopic retrograde cholangiography (B), computed tomography (C), and gross specimen (D).
When disease is unilateral, isolated left lobe involvement is most common.
Suggested Reading ASGE Standards of Practice Committee, Khashab MA, Chithadi KV,
Acosta RD, Bruining DH, Chandrasekhara V, et al. Antibiotic prophy-
ASGE Standards of Practice Committee, Acosta RD, Abraham NS, laxis for GI endoscopy. Gastrointest Endosc. 2015 Jan;81(1):81–9.
Chandrasekhara V, Chathadi KV, Early DS, et al. The management ASGE Standards of Practice Committee, Saltzman JR, Cash BD, Pasha
of antithrombotic agents for patients undergoing GI endoscopy. SF, Early DS, Muthusamy VR, et al. Bowel preparation before colon-
Gastrointest Endosc. 2016 Jan;83(1):3–16. oscopy. Gastrointest Endosc. 2015 Apr;81(4):781–94.
ASGE Standards of Practice Committee, Chandrasekhara V, Rex DK, Boland CR, Dominitz JA, Giardiello FM, Johnson DA,
Khashab MA, Muthusamy VR, Acosta RD, Agrawal D, et al. Kaltenbach T, et al. Colorectal cancer screening: recommendations
Adverse events associated with ERCP. Gastrointest Endosc. 2017 for physicians and patients from the US Multi-Society Task Force on
Jan;85(1):32–47. Colorectal Cancer. Gastrointest Endosc. 2017 Jul;86(1):18–33.
Questions He takes daily ibuprofen for tennis elbow. His medical history
also includes a diagnosis of fatty liver disease and alcohol use
Abbreviations used: disorder during his teenaged and college years. What is the
ALT, alanine aminotransferase most likely cause of the GI tract bleeding?
ANCA, antineutrophil cytoplasmic antibody
AST, aspartate aminotransferase a. Diverticular bleeding
BAE, balloon-assisted endoscopy b. Cameron lesions
CE, capsule endoscopy c. PUD
CI, colonic ischemia d. Small-bowel angiectasia
CT, computed tomography e. Esophageal varices
CTA, computed tomographic angiography IV.2. A 75-year-old man presents with a 3-month history of inter-
CTE, computed tomographic enterography mittent melena. His current hemoglobin level is 10.1 g/dL.
DBE, double-balloon endoscopy He had an ileal carcinoid tumor resected 10 years earlier. He
EGD, esophagogastroduodenoscopy has daily bloating and intermittent distention when he eats
ERCP, endoscopic retrograde cholangiopancreatography high-fiber foods. EGD and colonoscopy are performed, but a
GAVE, gastric antral vascular ectasia bleeding source is not identified. He does not use NSAIDs or
GI, gastrointestinal anticoagulants, and he has no history of kidney disease. What
HSP, Henoch-Schönlein purpura is the most appropriate next test for this patient?
INR, international normalized ratio
IRCI, isolated right colonic ischemia a. Antegrade BAE
MRA, magnetic resonance angiography b. Retrograde BAE
MRCP, magnetic resonance cholangiopancreatography c. CE
NSAID, nonsteroidal anti-inflammatory drug d. CTA
PAN, polyarteritis nodosa e. CTE
PEG, percutaneous gastrostomy IV.3. A 44-year-old woman presents with a 3-day history of melena.
PEJ, percutaneous jejunostomy Four years earlier, when EGD was performed for reflux, a
PUD, peptic ulcer disease 2-cm hiatal hernia was identified. The patient takes NSAIDs
RYGB, Roux-en-Y gastric bypass daily for chronic pain in her lower back. EGD for the present
SSc, systemic sclerosis history of melena shows a large (1.5-cm diameter) ulcer with
a 1-mm nonbleeding vessel in the lateral wall of the second
Multiple Choice (choose the best answer) portion of the duodenum. What is the most appropriate man-
agement plan?
IV.1. A 53-year-old man presents with a 7-day history of melena.
Four years earlier, when EGD was performed for reflux, a 3- a. High doses of proton pump inhibitor and no endoscopic
cm hiatal hernia was identified. Since then the patient has lost intervention
6.8 kg with daily exercise, and he stopped taking omeprazole 1 b. Epinephrine injection only
year ago (he says that he does not have reflux symptoms now). c. Hemostatic powder application
175
d. Epinephrine injection and bipolar probe therapy

e. Immediate referral to the interventional radiology service for
embolization
IV.4. A 24-year-old man presents with a 3-day history of melena.
The hemoglobin concentration is 7.6 g/dL. The patient’s past
medical history is unremarkable, and he has not had any sur-
gical procedures. He does not use NSAIDs, and he has not had
diarrhea or abdominal pain. EGD and colonoscopy do not
show evidence of the source of the bleeding. What is the most
appropriate next test?
a. Meckel scan
b. Antegrade DBE
c. Retrograde DBE
d. Follow-up EGD
e. Capsule endoscopy
IV.5. A 70-year-old man is admitted to the hospital with sudden onset
of cramping right lower quadrant abdominal pain of moderate
severity. Several hours later, he has bloody bowel movements. He
has hypertension and coronary artery disease; his medications
are atorvastatin, metoprolol, and low-dose aspirin. On physical
examination, he appears comfortable. Vital signs are normal.
The abdomen is nondistended, and bowel sounds are normal.
On deep palpation of the right lower quadrant, he has moderate
tenderness with no rebound or guarding. CT without a contrast
agent shows thickening of the ascending colon. Colonoscopy
shows a segment with subepithelial hemorrhage, edema, and
erythema from the cecum to the ascending colon. Which of the
following is the most appropriate test to perform next?
a. Selective catheter angiography
b. MRA
c. CTA The patient is admitted to the hospital with a diagnosis of
d. Duplex ultrasonography of mesenteric vessels ischemic colitis. In addition to giving him nothing by mouth
and providing intravenous fluids and narcotic analgesia, what
IV.6. A 75-year-old woman is evaluated for early satiety, postpran- else should be done?
dial abdominal pain, and an unintentional 13.6- kg (30-
lb)
weight loss over the past 2 months. She also has coronary ar- a. Perform mesenteric CTA
tery disease and hypertension and a 50 pack-year smoking b. Initiate therapy with intravenous broad-spectrum antibiotics
history. Her medications are low- dose aspirin, metoprolol, c. Start total parenteral nutrition
lisinopril, hydrochlorothiazide, sublingual nitroglycerin, and d. Perform flexible sigmoidoscopy
rosuvastatin. On physical examination, her vital signs are IV.8. A 70-year-old woman with cerebrovascular and peripheral
normal, and body mass index is 20. The patient appears ca- vascular disease presents to the emergency department for
chectic with temporal wasting. An abdominal bruit is heard, further evaluation of worsening abdominal pain and weight
and mild epigastric tenderness is noted. Laboratory test loss. She reports postprandial abdominal bloating and dis-
results are as follows: hemoglobin, 11 g/dL; mean corpuscular comfort for the past 6 months associated with a 13.6-kg (30-lb)
volume, 90 fL; white blood cell count, 9.0×109/L; and platelet weight loss. She describes variable occurrence of abdominal
count within the reference range. Ultrasonography of the mes- distention and cramping with onset 20 to 40 minutes after
enteric vessels shows increased velocity in the celiac and supe- eating. The postprandial pain gradually increases in severity
rior mesenteric arteries, which is consistent with high-grade and then slowly resolves over the next 1 to 3 hours. She does
stenosis of these vessels. Subsequent CTA shows severe ste- not use NSAIDs. Findings were unremarkable from previous
nosis of the celiac and superior mesenteric arteries and pos- laboratory testing, including Helicobacter pylori serology,
sible enlargement of pancreatic head. Which of the following is liver biochemical tests, abdominal radiography, and carbohy-
the most appropriate management? drate antigen 19-9. Findings from upper endoscopy, colonos-
a. Catheter angiography with stenting of the celiac artery copy, and capsule endoscopy have been unremarkable. What
b. Vascular surgery consultation for mesenteric arterial bypass should be the next step in management?
c. Four-hour solid meal gastric emptying study a. Duplex ultrasonography of the mesenteric vessels
d. Endoscopic ultrasonography of the pancreas with fine-needle b. Ultrasonography of the right upper quadrant
aspiration c. Mesenteric CTA
IV.7. A 73-year-old man with hypertension presents with abrupt d. Gastric emptying study
onset of mild, cramping abdominal pain in the left lower IV.9. A 25-year-old woman presents for evaluation of recurrent
quadrant and subsequent bloody diarrhea several hours later. episodes of severe abdominal pain of prolonged duration
On physical examination, he is afebrile with normal hemody- that have required admissions to the hospital for intrave-
namic status. On abdominal examination he has mild abdom- nous fluids and narcotic analgesia. The pain episodes began
inal tenderness in the left lower quadrant without rebound or 6 months previously after she underwent Roux-en-Y gas-
guarding. Laboratory study results include a white blood cell tric bypass surgery for medically complicated obesity.
count of 12×109/L and normal values for hemoglobin, lactate, During these episodes, she also has upper extremity pain,
serum urea nitrogen, and creatinine. CT of the abdomen and nausea, vomiting, and constipation. On review of the med-
pelvis is performed (see image). ical records, other presenting conditions were hypertension
and tachycardia. Laboratory studies done during pain found Which of the following diagnoses likely explains the
mild hyponatremia. Upper endoscopy and cross-sectional patient’s abdominal pain?
imaging of the abdomen performed during the pain crises
a. HSP
had unremarkable findings. Between episodes, she is without
b. Granulomatosis with polyangiitis
symptoms. Currently, she feels well and is without symptoms.
c. PAN
On physical examination, she is a well-appearing, slightly
d. Eosinophilic granulomatosis with polyangiitis
overweight woman with normal vital signs. Results of ab-
dominal and anorectal examinations are normal. What is the IV.12. A 78-year-old woman presents with a 1-year history of iron
most likely diagnosis? deficiency anemia with intermittent melena. She denies heart-
burn, regurgitation, dysphagia, and abdominal pain. Physical
a. Systemic mastocytosis
examination shows multiple facial telangiectasias, patchy vit-
b. Adrenal insufficiency
iligo on the upper extremities, and hand sclerodactyly. Stool
c. Recurrent small-bowel obstruction
obtained on digital rectal examination is positive for occult
d. Acute intermittent porphyria
blood. Which GI manifestation of systemic disease is the most
IV.10. A 60-year-old man presents with an 18-month history of pro- likely cause of her iron deficiency anemia?
gressively worsening, nonbloody diarrhea with multiple stools
a. Gastroesophageal reflux
per day of varying volume. He reports a 16-kg weight loss
b. Wide-mouth colonic diverticula
since onset of the diarrhea and infrequent episodes of urge
c. GAVE
fecal incontinence. His medical history includes atrial fibrilla-
d. Mesenteric vasculitis
tion with onset at age 40 years and bilateral surgical release for
carpal tunnel syndrome. On physical examination, he is a thin- IV.13. A 56-year-old woman with a past medical history significant
appearing man with an unremarkable abdomen. Anorectal in- for type 2 diabetes mellitus and severe obesity (body mass
spection shows intact perianal sensation and adequate resting index, 52) undergoes RYGB and is admitted for observation.
and squeeze anal sphincter tones. A stool pathogen panel is On postoperative day 3, she is asymptomatic and appears well.
negative. A 72-hour quantitative stool collection result is 55 g On review of her medical record, you note that she has had
of fecal fat/24 hours. mild tachycardia (heart rate 111 beats/min) during the past
Given the patient’s history and the presence of chronic 24 hours and one recorded episode of a low-grade fever (37.2
fatty diarrhea, which of the following is the most appropriate °C). She requests dismissal from the hospital. What do you do
next step for evaluating this patient’s diarrhea? next?
a. Small-bowel aspiration and culture a. Order blood cultures and chest radiograph
b. Empirical trial of pancreatic enzyme replacement b. Order CT of abdomen with oral contrast agent
c. Upper endoscopy with duodenal biopsy c. Continue observation overnight
d. Colonoscopy with random biopsies d. Dismiss with close follow-up
IV.11. A 26- year-old woman presents with 5 days of persistent IV.14. A 45- year-
old man underwent RYGB for severe obesity 2
abdominal pain associated with nausea, vomiting, and months ago. He did very well postoperatively for the first
nonbloody stools that developed 2 weeks after an upper month. During the past 1 month, he has noticed nausea and
respiratory infection. Her only medication is ibuprofen for early satiety. On seeking medical attention, his bariatric team
joint pain. Physical examination is notable for right lower obtained an upper GI series, which confirmed an anastomotic
quadrant tenderness and fullness. Laboratory examination stricture measuring 10 mm. What is the best next step in
indicates a mild leukocytosis. CT of the abdomen and pelvis management?
shows circumferential wall thickening of the terminal ileum
a. Endoscopic balloon dilation to 15 mm
(arrow, image below). Stool studies are negative for infec-
b. Endoscopic balloon dilation to 20 mm
tion. Colonoscopy shows normal colonic mucosa; however,
c. Endoscopic stricturotomy with needle knife
in the ileum there is diffuse, circumferential ulceration and
d. Surgical revision of gastrojejunostomy
subepithelial hemorrhage that extends 15 cm. Ileal biopsies
are interpreted as ulceration with ischemic- like changes. IV.15. A 47-year-old woman undergoes RYGB for obesity compli-
Three days after hospital admission, palpable purpura cated by type 2 diabetes. She has an uneventful postoperative
develops on the lower extremities, and a leukocytoclastic vas- course. At her 6-month follow-up, she reports that she has
culitis with IgA deposits is detected with immunofluorescence had severe diarrhea since her surgery. This is most prominent
of a skin biopsy specimen. Urinalysis results are mild pro- about an hour after meals and associated with mild dizziness.
teinuria, leukocytes, and red cell casts. She has not noticed any blood in her stools. She has lost 50 lb
(22.68 kg) since her surgery. She has no other symptoms. What
is the best next step?
a. Reassure the patient that this is an expected outcome after
RYGB
b. Refer the patient to a dietitian
c. Obtain stool studies to rule out infection
d. Order EGD and colonoscopy with random biopsies
IV.16. A 54-year-old man undergoes RYGB for super-obesity (body
mass index, 54). He has an uneventful postoperative course
and loses 53% of his excess body weight in the first year after
surgery. He presents for follow-up 3 years after surgery. He has
now regained about 15% of his weight. On review of his med-
ical record, he was noted to have increased his weight by 5%
at his 2-year appointment. The patient reports that there have
been no changes in his dietary habits and that he is adhering
to his diet. What is the best next step in evaluation?
a. Continue to monitor closely because the weight gain is an ex- regarding PEG placement. She experienced a cerebrovas-
pected stabilization of weight after initial weight loss cular accident 7 days ago and failed a swallow evaluation
b. Refer him to a dietitian for further evaluation (oropharyngeal dysfunction with aspiration). She is receiving
c. Obtain a thyroid function test clopidogrel 75 mg daily through a nasogastric tube. What is
d. Obtain an upper GI series the correct recommendation regarding peri-procedural use of
clopidogrel before PEG placement?
IV.17. A 58- year-
old woman presented with severe right upper
quadrant abdominal pain associated with fever, nausea, and a. Continue administration of clopidogrel (low risk if not used as
vomiting that had been present for 1 day. Her medical history dual-antiplatelet therapy)
was clinically significant for coronary artery disease for which b. Withhold clopidogrel for 3 days before the procedure
she was receiving aspirin and clopidogrel and for atrial fibril- c. Withhold clopidogrel for 5 days before the procedure
lation for which she was receiving warfarin. On presentation, d. Withhold clopidogrel for 5 days before the procedure and start
her vital signs were as follows: temperature, 39.4 °C; blood aspirin therapy now
pressure, 75/50 mm Hg; and heart rate, 120 beats per minute. e. Withhold clopidogrel for 5 days before the procedure and start
Laboratory results were as follows: white blood cell count, 22 heparin therapy as bridge
× 109/L; ALT, 420 IU/L; AST, 250 IU/L; total bilirubin, 5.2 mg/
dL; alkaline phosphatase, 350 IU/L; and INR, 3.5. On abdom-
inal ultrasonography, cholelithiasis and a dilated common bile Answers
duct (16 mm) with an obstructing stone at the distal end were
found. The patient was admitted to the intensive care unit and IV.1. Answer c.
received fluid resuscitation and wide- spectrum antibiotics. A patient presentation with melena is most consistent with a
What is the best next step in her management? bleeding source in the upper GI tract. Patients with diverticular
bleeding are more likely to present with painless hematochezia.
a. Perform ERCP with sphincterotomy for stone extraction
The history provided (no ascites or encephalopathy) does not
b. Perform MRCP
c. Refer to surgery for cholecystectomy suggest decompensated cirrhosis, so esophageal varices as a
d. Perform ERCP for stent placement bleeding source are less likely. While patients with Cameron
e. Continue administration of fluid and antibiotics and delay lesions (history of hiatal hernia) or small-bowel angioectasia can
ERCP until clopidogrel and warfarin have been discontinued present with melena, the most likely cause of melena in this pa-
for 1 week tient (who is taking NSAIDs) would be PUD.
IV.18. A 35-year-old woman with no clinically significant medical IV.2. Answer e.
history presented to the emergency department with right
Small-bowel bleeding should be suspected in this patient who
upper quadrant abdominal pain associated with nausea and
vomiting. Her vital signs were as follows: temperature, 36.1 °C; has melena without abnormalities apparent on EGD and colon-
blood pressure, 120/80 mm Hg; and heart rate, 105 beats/min. oscopy. While BAE can be both diagnostic and therapeutic, it is
Laboratory results were as follows: white blood cell count, 13 typically performed after a target lesion has been identified with
× 109/L; ALT, 234 IU/L; AST, 178 IU/L; total bilirubin 4.2 mg/ capsule endoscopy, CTE, or CTA. This patient, who had small-
dL; and lipase, 60 IU/L. Ultrasonography showed cholelithi- bowel surgery and who now has symptoms of possible obstruc-
asis with a dilated common bile duct but no visual stone. The tion, should undergo a patency capsule test before CE. CTA is
patient underwent ERCP with difficult biliary cannulation in typically done if active bleeding is present (this patient has had
which the wire accessed the pancreatic duct multiple times. A intermittent melena for several months). Therefore, CTE would
few hours after ERCP, severe epigastric pain radiating to her be the most appropriate next test for this patient.
back developed. Her repeat lipase value was 980 IU/L. Which
of the following could have decreased her risk of post-ERCP IV.3. Answer d.
pancreatitis? In this patient, EGD showed an ulcer and a blood vessel with a high
a. She should not have had ERCP because it was not indicated risk of bleeding. Endoscopic intervention would be appropriate.
b. Administration of indomethacin 100 mg rectally after the Because of the bleeding risk, the use of epinephrine alone would
procedure be inferior to the use of epinephrine in combination with either
c. Performance of a sphincter balloon dilation instead of cautery (bipolar probe or heater probe) or hemoclip placement.
sphincterotomy Hemostatic powder is typically used for active bleeding that
d. Placement of a biliary stent after sphincterotomy
cannot be effectively managed with other modalities.
e. Administration of ibuprofen 800 mg orally for 3 days
IV.19. A 73-year-old man with a history of right knee replacement IV.4. Answer a.
surgery, aortic regurgitation, coronary artery disease, and The bleeding source is most likely in the small bowel since the
ischemic cardiomyopathy is referred for an inpatient gastro- findings from EGD and colonoscopy were unremarkable. Given
enterology consultation regarding PEG placement. He experi- the patient’s young age and lack of comorbidities, a Meckel di-
enced a cerebrovascular accident 10 days ago and had a recent verticulum would rank high in the differential diagnosis. BAE is
failed swallow evaluation (oropharyngeal dysfunction with as- typically performed after a lesion is identified on CE or CT.
piration). Which of the following indications is the strongest
for antibiotic prophylaxis with GI endoscopy? IV.5. Answer c.
a. Prosthetic joints CTA is the best next test for this patient, whose clinical presen-
b. PEG placement tation with sudden onset of right-sided cramping abdominal pain
c. Cardiomyopathy and a subsequent bloody bowel movement is typical of IRCI.
d. Aortic regurgitation The CT findings of thickening of the ascending colon and the
IV.20. An 84-year-old woman with a history of coronary artery dis colonoscopy features are helpful in confirming this diagnosis.
ease (stent placement 6 months ago) and atrial fibrillation The most common cause of CI is a nonocclusive low-flow state
is referred for an inpatient gastroenterology consultation in the colonic microvasculature. Most cases of CI involve the
left colon, which is supplied by the inferior mesenteric artery. this patient, limited colonoscopy (flexible sigmoidoscopy) would
As with IRCI, the diagnosis is clinical and supported by CT and be appropriate to confirm the nature of the CT abnormality given
colonoscopy. Patients with left-sided CI tend to heal well with the left-sided occurrence. The endoscopic procedure should be
conservative therapy alone. However, IRCI can be the harbinger stopped at the most distal extent of disease, and biopsies of the
of acute mesenteric ischemia caused by a focal thrombus or em- colonic mucosa should be obtained unless gangrene is present.
bolus of the superior mesenteric artery. This artery supplies both The pathophysiology of CI most often involves a nonocclusive,
the small intestine and the right colon, and the consequences of low-flow state in the colonic microvasculature, particularly when
acute mesenteric ischemia involving the small bowel are severe, the left colon is involved. CTA would be appropriate if the CI
with mortality rates that can approach 60%. Therefore, patients were isolated to the right colon because IRCI can be the har-
with IRCI require urgent noninvasive imaging of the mesenteric binger of acute mesenteric ischemia caused by a focal thrombus
vasculature to assess the extent of ischemia and nature of the or embolus of the superior mesenteric artery. This artery supplies
intervention. CTA is the recommended method of imaging for both the small intestine and the right colon, and the consequences
the diagnosis of acute mesenteric ischemia because results can of acute mesenteric ischemia involving the small bowel are se-
be obtained rapidly. CTA allows visualization of the origins and vere, with mortality rates that can approach 60%. This patient
length of the vessels, characterizes the extent of occlusion, and has mild CI and initiation of therapy with intravenous antibiotics
aids in planning revascularization. would not be indicated. In addition, starting total parenteral nutri-
MRA provides information about mesenteric arterial flow and tion would not be indicated.
avoids the potential harms of radiation and use of contrast agents
that are associated with CTA. However, MRA takes longer to per- IV.8. Answer c.
form than CTA, lacks the required resolution to identify arterial The patient presents with postprandial abdominal pain and
occlusion, and can lead to overestimation of the severity of ste- weight loss, which can be manifestations of chronic mesenteric
nosis. Selective catheter angiography was the standard method ischemia. However, the differential diagnosis of postprandial ab-
for diagnosing mesenteric ischemia. However, it is now used after dominal pain and weight loss includes more common conditions
a revascularization plan has been chosen, because CTA can be such as peptic ulcer disease, intestinal obstruction, upper GI ma-
obtained rapidly and is noninvasive. Duplex ultrasonography is lignancy, chronic pancreatitis, and hepatobiliary disease. This
an effective, low-cost tool that can be used to assess the proximal patient, though, has undergone a multitude of laboratory and im-
visceral vessels but with limited ability to visualize distal vessels. aging studies, so these more common conditions are less likely.
It is best reserved for the evaluation of patients who have chronic Demonstration of severe stenosis of the major mesenteric vessels
mesenteric ischemia, which typically presents with postprandial is a requirement for a diagnosis of chronic mesenteric ischemia.
abdominal pain, sitophobia, and weight loss. For patients with suggestive symptoms, as in this patient, the
American College of Radiology consensus opinion recommends
IV.6. Answer d. CTA as the preferred initial imaging modality because it reliably
The patient has postprandial abdominal pain and weight loss, identifies or excludes the presence of atherosclerotic vascular dis
which can be the manifestation of chronic mesenteric arteri- ease and can be used to rule out other abdominal disease as the
osclerotic disease. Mesenteric Doppler study and subsequent source of symptoms. Duplex ultrasonography of the mesenteric
CTA showed severe stenosis of the celiac and superior mes- vessels is a reasonable initial screening modality for the detection
enteric arteries, which in this clinical setting are suggestive of of high-grade celiac and superior mesenteric artery stenosis for
chronic mesenteric ischemia. However, the differential diagnosis patients examined in an office setting. When the results of duplex
for postprandial abdominal pain and weight loss include more ultrasonography are assessed, technical considerations should be
common conditions such as peptic ulcer disease, intestinal ob- kept in mind because they can limit the accuracy of the findings;
struction, upper GI tract malignancy, chronic pancreatitis, and these include the expertise of the examiner, large body habitus,
hepatobiliary pathology. CTA showed possible enlargement of intestinal gas, and previous abdominal surgery. Ultrasonography
the pancreatic head, which would be concerning for pancreatic of the right upper quadrant to assess for biliary pathology as a
adenocarcinoma causing malignant encasement and occlusion of source of symptoms would be a low-yield procedure given the
the celiac and superior mesenteric arteries. Therefore, the most normal results of the liver biochemical tests. A gastric emptying
appropriate next step in management would be to perform en- study would be helpful to assess for gastroparesis, which can be
doscopic ultrasonography with fine- needle aspiration of the an atypical manifestation of chronic mesenteric ischemia, but
pancreatic head to exclude malignancy. Selective catheter angi- this test would not be helpful in assessing for mesenteric vascular
ography with stenting of the celiac artery and surgical mesen- occlusion.
teric bypass would be potential treatment options if the cause
of the arterial occlusion were atherosclerotic and not cancer. IV.9. Answer d.
A 4-hour solid meal gastric emptying study would be helpful to The differential diagnosis of abdominal pain after gastric bypass
assess for gastroparesis, which can be an atypical manifestation surgery for obesity is broad and includes complications of sur-
of chronic mesenteric ischemia, but this test would not be helpful gery such as small-bowel obstruction and ischemic or thrombotic
in diagnosing the cause of mesenteric vascular occlusion. disease of the gut. In this case, appropriate studies, including
abdominal imaging and laboratory studies, ruled out many of
IV.7. Answer d. these conditions. The possibility of acute porphyria should be
This patient most likely has CI, which is the most common form considered in patients with recurrent, severe abdominal pain
of intestinal ischemia. CI is often self-limiting and transient. The when clinical evaluation has not found a cause. Features that
CT image shows thickening of the left colon without ominous may occur in association with attacks of acute porphyria and that
features that suggest gangrenous bowel, such as pneumatosis should increase suspicion for the diagnosis include systemic ar-
linearis. When CI is suspected, endoscopy should be performed terial hypertension, tachycardia, constipation, and hyponatremia
within 48 hours after presentation to confirm the diagnosis. For (due to syndrome of inappropriate antidiuretic hormone
secretion). Various factors can precipitate porphyria attacks, in- IV.12. Answer c.
cluding fasting, poor intake of carbohydrates and energy, use of This patient has SSc, which commonly affects the GI tract. GI
drugs or alcohol, smoking, infections, and other forms of stress. manifestations of SSc include gastroesophageal reflux, esoph-
This patient’s recurrent acute attacks were precipitated by the ageal aperistalsis, GAVE, intestinal pseudo- obstruction, wide-
negative energy balance resulting from bariatric surgery. The mouth colonic diverticula, pneumatosis cystoides intestinalis,
diagnostic study of choice is measurement of 5-aminolevulinic and anal incontinence. GAVE is associated with SSc and often
acid and porphobilinogen in urine or serum. The absence of ur- presents with low-grade GI bleeding and iron deficiency anemia,
ticaria pigmentosa and intermittent symptoms makes systemic as in this patient. SSc is the most common rheumatologic condi-
mastocytosis unlikely. Hyponatremia can occur with adrenal in- tion associated with GAVE. GAVE is also termed “watermelon
sufficiency, but the normal vital signs and intervening symptom- stomach” because of the characteristic endoscopic appearance of
free periods makes this diagnosis unlikely. longitudinal rows of red stripes radiating from the pylorus into
the antrum that resemble the stripes on a watermelon. These
IV.10. Answer c. red stripes represent ectatic mucosal vessels, which are prone to
With the history of young-onset atrial fibrillation and bilateral bleeding. Gastroesophageal reflux can cause erosive esophagitis,
carpal tunnel syndrome, clinical suspicion for an infiltrative dis- which can lead to iron deficiency anemia, but it is unlikely in the
order such as amyloidosis of the GI tract is high. The criterion absence of heartburn, regurgitation, and dysphagia. Wide-mouth
standard for the diagnosis of GI involvement by amyloidosis is colonic diverticula are a characteristic feature of colon involve-
pathologic confirmation with biopsy. The highest degree of amy- ment by SSc but would not present with iron deficiency anemia.
loid deposition in the GI tract is in the duodenum. Therefore, upper Mesenteric vasculitis can cause occult blood in the stool but
endoscopy with duodenal biopsy is the appropriate study to assess would be associated with abdominal pain and is not a GI man-
for GI involvement by amyloidosis. Small-bowel aspiration and ifestation of SSc.
culture is used for the evaluation of small intestinal bacterial over-
growth, which may complicate amyloidosis and other infiltrative IV.13. Answer b.
diseases of the gut. Although bacterial overgrowth in the small Anastomotic leaks are one of the most severe complications after
intestine is associated with steatorrhea, small- bowel aspiration RYGB. Often, they can present subtly, especially in patients who
would be of little utility in evaluating for suspected amyloidosis. have severe obesity. Postoperative tachycardia is a sensitive sign
Pancreatic enzyme replacement may be useful for reducing the de- of a potential anastomotic leak. Clinicians should have a strong
gree of steatorrhea in patients with steatorrhea due to pancreatic clinical suspicion for this complication and a low threshold for
insufficiency. An empirical trial of pancreatic enzyme replacement ordering contrast-enhanced imaging postoperatively.
has no role in the investigation of suspected GI involvement by
amyloidosis. The colon can be involved by amyloidosis; however, IV.14. Answer a.
because the presence of steatorrhea suggests intestinal malabsorp- Anastomotic strictures are a common complication after RYGB
tion, colonoscopy with biopsy is a less correct choice. and generally present within 2 to 3 months postoperatively. The
first line of treatment should be endoscopic balloon dilation,
IV.11. Answer a. which has proved to be a safe and effective therapy. Balloon
The clinical presentation and biopsy findings are diagnostic of dilation should be performed only up to 15 mm, because dila-
HSP, a systemic vasculitis characterized by cutaneous involvement tion to larger diameters may increase the risk of perforation and
with tissue deposition of IgA-containing immune complexes. It partly abolish the restrictive nature of the weight loss mechanism.
occurs more often in children than adults and presents with the Generally, serial dilations are needed to manage most strictures.
classic tetrad of rash, abdominal pain, arthralgias, and renal dis Surgical revision of gastrojejunostomy should be reserved for re-
ease. The rash is typically the initial manifestation, is purpuric, fractory cases.
and occurs in a symmetric distribution over the lower aspect of
the legs. GI symptoms occur in most patients and are due to a IV.15. Answer b.
local vasculitis causing intestinal ischemia. In the absence of the Postprandial diarrhea in the setting of recent RYGB is concerning
purpuric rash, the diagnosis of HSP may not be obvious. As in for early dumping syndrome. This occurs due to fluid shifts with
this patient, abdominal symptoms can precede the rash (15% of hyperosmolar food entering the small intestinal lumen. Patients
cases) and may initially obscure the diagnosis. present with diarrhea, abdominal pain, dizziness, and hypoten-
Granulomatosis with polyangiitis is a small-vessel vascu- sion a few minutes to an hour after eating. Most cases of early
litis that rarely involves the gut. Histology-confirmed features dumping syndrome are managed with dietary changes, including
of necrotizing granulomatous vasculitis facilitate a diagnosis avoiding simple sugars and a diet consisting of high-fiber, com-
of granulomatosis polyangiitis, which is frequently associ- plex carbohydrate, and protein-rich foods. A consultation with
ated with c- ANCA and proteinase- 3 antibodies. PAN is a an experienced dietitian is most appropriate in this situation.
non– ANCA- associated vasculitis that predominantly affects
muscular medium-sized arteries of any organ system except IV.16. Answer d.
the lungs. GI manifestations of PAN are variable but abdom- Regaining weight after RYGB can occur in up to 20% of patients.
inal pain, often due to ischemia resulting from mesenteric ar- One of the most common causes of weight regain is progressive
teritis, is the most common. Because PAN does not involve noncompliant eating or behavioral change. In this patient, who
small vessels, a leukocytoclastic vasculitis rash does not occur. reports adherence to diet, further evaluation for structural causes
Eosinophilic granulomatosis with polyangiitis, or Churg- of weight regain is warranted. These include enlargement of the
Strauss syndrome, although an important consideration in this gastric pouch, dilation of the gastrojejunal anastomosis, or devel-
case, is unlikely in the absence of concomitant asthma and pe- opment of a gastrogastric fistula. All of these causes result in a
ripheral eosinophilia. decrease in the restrictive nature of the gastric bypass procedure.
An upper GI series will help in further evaluation of anatomical IV.18. Answer b.

changes that may be promoting weight regain. The patient presented with symptomatic choledocholithiasis,
and ERCP is indicated for stone removal. She is at high risk for
IV.17. Answer d. post ERCP-pancreatitis because of difficult cannulation and mul-
At presentation, the patient had severe acute cholangitis and tiple accesses of the wire to the pancreatic duct. Rectal, not oral,
septic shock in the setting of an obstructing common bile duct NSAIDs have been shown to decrease the risk of post-ERCP
stone. After fluid resuscitation and administration of antibiotics, pancreatitis in patients who are at high risk. Other methods to
she needs urgent biliary drainage. Ideally, this is achieved by decrease post-ERCP pancreatitis include intravenous hydration
performing ERCP with sphincterotomy for stone extraction. and a pancreatic stent but not a biliary stent. Sphincter balloon
However, because she is receiving an antithrombotic, she is dilation increases the risk for post-ERCP pancreatitis.
at high risk for post-sphincterotomy bleeding. Alternatively,
ERCP with stent placement is the most appropriate next step IV.19. Answer b.
and is not contraindicated in the setting of antithrombotic Data support a reduction in peristomal infections when antibiotics
therapy. There is no role for MRCP because the diagnosis is al- are provided before the initial placement of PEG or PEJ tubes.
ready made based on the clinical picture and ultrasonographic The use of antibiotics solely to prevent endocarditis or septic ar-
findings. The patient is in septic shock, and delaying biliary thritis is not recommended for patients undergoing GI endoscopy.
drainage is inappropriate. Although the patient will need a IV.20. Answer a.
cholecystectomy, she is currently unstable to undergo surgery. Clopidogrel monotherapy (not when used as dual-antiplatelet
Once the patient is stable and not receiving an antithrombotic, therapy with aspirin) is considered a low bleeding risk for PEG
she can undergo another ERCP for stone extraction followed placement. In this case, stopping treatment, changing to therapy
by cholecystectomy. with aspirin, or bridging with heparin therapy is not indicated.
V
Colon
15
Inflammatory Bowel Disease: Clinical Aspects

VICTOR G. CHEDID, MD, MS
NAYANTARA COELHO-PRABHU, MBBS
Inflammatory bowel disease (IBD) is a disease process occurs between the fifth and seventh decades. Men and women
characterized by chronic idiopathic intestinal inflammation along generally have a similar risk for IBD, but the overall incidence
a spectrum that ranges from ulcerative colitis (UC) at one end of CD is higher among women. IBD is more common among
to Crohn disease (CD) at the other. UC affects the colonic mu- Ashkenazi Jews than among non-Jews. Historically, UC has been
cosa and extends proximally from the anal verge in an uninter- more common than CD.
rupted pattern that involves all or part of the colon. In contrast, The incidence of UC is 8.3 per 100,000 person- years in
CD is a transmural process that primarily affects the small bowel. Olmsted County, Minnesota, and 14.2 per 100,000 person-years
However, CD can occur anywhere in the gastrointestinal tract in Winnipeg, Manitoba. The prevalence in Olmsted County is 229
from mouth to anus, manifesting as patchy inflammation with per 100,000 persons. The proportion of patients with ulcerative
intervening areas of normal mucosa. Indeterminate colitis, now proctitis varies in different series from 17% to 49% of the totals.
termed IBD colitis, unclassified type, in the middle of the spec- The incidence of CD also varies among reporting centers. It
trum, affects a small number of patients who have chronic co- is 6.9 per 100,000 person-years in Olmsted County and 14.6 per
lonic inflammation with features consistent with both UC and 100,000 person-years in Winnipeg. The prevalence in Olmsted
CD. All IBD, regardless of where it lies on the spectrum, can be County is 133 per 100,000 persons.
associated with extraintestinal manifestations (EIMs). Mortality rates for persons with IBD may be slightly higher
than those for the general population. In a study from Stockholm,
✓ UC involves the colonic mucosa in a continuous distribution from Sweden, the standardized mortality ratio was 1.37 for UC and
the anal verge to all or part of the colon 1.51 for CD.
✓ CD involves transmural patchy inflammation with intervening
normal mucosa and can occur anywhere in the gastrointestinal ✓
Proctitis—inflammation isolated to the rectum
tract from the mouth to the anus
✓ Indeterminate colitis has features of UC and CD
✓ EIMs can be present in all forms of IBD

Genetics
The genetic influence on the development of IBD is a topic of
Epidemiology considerable interest. From 10% to 15% of patients with UC
have a relative with IBD, mainly UC and, less commonly,
Onset of IBD is most frequent among adolescents, with a peak CD. Approximately 15% of patients with CD have a relative
incidence between ages 15 and 25 years. A smaller second peak with IBD, mainly CD and, less commonly, UC. The pheno-
typic concordance appears to be higher for CD. Several genetic
Abbreviations: CD, Crohn disease; CT, computed tomographic; EIM, linkages have been identified, and specific genetic defects have
extraintestinal manifestation; IBD, inflammatory bowel disease; MR, been determined in IBD. The first to be characterized was the
magnetic resonance; PSC, primary sclerosing cholangitis; UC, ulcera- CARD15/NOD2 gene, present in the homozygous form in up
tive colitis to 17% of patients with CD. This genetic defect is associated
185
186 Section V. Colon
with fibrostenotic disease involving the distal ileum. Other in warmer climates, and it is more common in developed coun-
associations are with the IBD5 haplotype of chromosome 5 tries than in developing countries.
and the IL23R gene on chromosome 1p31. The IL23R gene
encodes a proinflammatory cytokine, interleukin 23. Three ge- ✓ Among patients with CD and UC, 10% to 15% have a relative
netic syndromes are associated with IBD: Turner syndrome; with CD or UC
Hermansky- Pudlak syndrome (oculocutaneous albinism, a ✓ CARD15/NOD2 gene—associated with fibrostenotic CD
✓ Patients with IBD—no specific dietary restrictions
platelet aggregation defect, and a ceroid-like pigment deposi-
✓ Women with active IBD—decreased fertility but able to conceive
tion); and glycogen storage disease type IB. ✓ Sulfasalazine causes reversible azoospermia in men
✓ UC is a disease of nonsmokers, but smoking increases the risk of
Diet symptomatic recurrences in patients with CD
Patients with IBD can often have food sensitivities, but only
those with complications such as strictures need to follow re-
stricted diets. Although lactose intolerance is more common Diagnosis
among patients with CD than among the general population, The basis for suspicion of IBD is clinical presentation in combi-
lactose and other milk components do not seem to influence nation with physical examination findings. The diagnosis is con-
the inflammatory disease. Elemental diets and parenteral hyper- firmed with findings from endoscopic, radiographic, serologic,
alimentation are useful for correction of malnutrition and for and histopathology studies.
growth failure in children with IBD. Parenteral nutrition has not
been found to be superior to enteral nutrition for CD. The use of
enteral nutrition or parenteral nutrition as primary therapy for
Clinical Presentations
CD is controversial; nutritional support is used primarily as an Ulcerative Colitis
alternative to corticosteroids. There is no convincing evidence
The onset of UC may be gradual or sudden, with an increase in
that elemental nutrition or parenteral nutrition is therapeutic for
bowel movements and bloody diarrhea, fecal urgency, cramping
UC. Increased interest has led to the exploration of the use of
abdominal pain, and fever. The course is variable, with periods of
anti-inflammatory diets for symptom management in patients
exacerbation, improvement, and remission that may occur with
with IBD, and large studies are underway to study the efficacy
or without specific medical therapy. About half the patients have
of these diets.
disease involving the left colon to some extent, including proc-
titis, proctosigmoiditis, and disease extending from the splenic
Pregnancy flexure distally. Constipation with rectal bleeding is a presenting
symptom in about 25% of patients with disease limited to the
Fertility is normal in patients with inactive IBD. Fertility is rectum. Diarrhea, which is usually worse in the morning and im-
decreased in some women with active IBD, but most patients mediately after meals, may vary from 1 to 20 or more loose or
can conceive. Sulfasalazine causes reversible infertility in men liquid stools daily; patients with moderate or severe symptoms
as a result of abnormalities of spermatogenesis and decreased often have nocturnal stools. Abdominal pain is usually cramping,
sperm motility. There is no clear evidence of birth defects in which is worse after meals or bowel movements. Anorexia,
the offspring of a parent with IBD. Most studies do not show an weight loss, and nausea in the absence of bowel obstruction are
increased risk in association with the disease or the treatments; common with severe and extensive disease but uncommon with
however, methotrexate is contraindicated during pregnancy mild to moderate disease or disease limited to the left colon. In
(its use should be discontinued ≥3 months before conception). children, urgency, incontinence, and upper gastrointestinal tract
The course of pregnancy is usually normal, although there is symptoms are more frequent and growth failure is common.
an increased chance of preterm delivery and decreased birth
weight. Two-thirds of women with IBD in remission before
pregnancy remain in remission through pregnancy and the post- Crohn Disease
partum period. Flares occur most commonly during the first Symptoms of CD depend on the anatomical location of the dis
trimester and the postpartum period. Previous colectomy with ease. Typical symptoms with ileocecal disease are abdominal
an end-ileostomy or with a continent ileal pouch does not pre- pain, diarrhea, and fever. With colonic disease, bloody bowel
clude pregnancy, and for some women, vaginal delivery is still movements with diarrhea, weight loss, and low-grade fever are
an option. Increased infertility has been reported in women after common. Patients with gastroduodenal CD often have burning
ileal pouch–anal anastomosis for UC. There is no definitive evi- epigastric pain and early satiety, and these symptoms usually
dence to support the idea that breastfeeding is a protective factor overshadow the symptoms from coexisting ileal or colonic dis
against later development of IBD. ease. The symptoms of oral or esophageal CD include dysphagia,
odynophagia, and chest pain, even without eating. The findings
in patients with perianal CD include perirectal abscesses, painful
Environmental Influences
and edematous external hemorrhoids, and anal and perianal
UC is primarily a disease of nonsmokers. Only 13% of patients fistulas. Enterovesical fistulas can cause pneumaturia and recur-
with UC are current smokers, and the rest are nonsmokers or rent polymicrobial urinary tract infections. Rectovaginal fistulas
former smokers. Pouchitis after proctocolectomy with an ileal J- occur in up to 10% of women with rectal CD and may cause gas
pouch–anal anastomosis for UC is less common among smokers. or stool to be passed from the vagina. In children, the onset of CD
In contrast, patients with CD are more likely to be smokers than is often insidious; weight loss occurs in up to 87% before the di-
the general population, and smoking increases the risk of sympto- agnosis is made, and 30% of children have growth failure before
matic recurrences. IBD is more common in colder climates than the onset of intestinal symptoms.
15. Inflammatory Bowel Disease: Clinical Aspects 187
Table 15.1. EIMs of IBD and Their Relationship With IBD weight loss, muscle wasting, abdominal tenderness (partic-
Activity ularly in the lower abdomen), and a palpable mass, usually in
the ileocecal region of the right lower quadrant of the abdomen.
Parallels Independent May or may
IBD of IBD not parallel
Rectal examination findings may include large, edematous, ex-
EIM activity activity IBD activity ternal hemorrhoidal tags; fistulas; anal canal fissures; and anal
stenosis. Patients with CD may have ulcers on the lips, gingiva,
Axial arthropathy ✓ or buccal mucosa.
Peripheral arthropathy
Type 1 (pauciarticular) ✓
Type 2 (polyarticular) ✓ Laboratory Findings
Erythema nodosum ✓
Pyoderma gangrenosum ✓ When patients have mild disease, laboratory test results may be
Sweet syndrome ✓ normal. Iron deficiency anemia due to gastrointestinal tract blood
Oral aphthous ulcers ✓ loss may occur in UC and in CD, and anemia of chronic disease,
Episcleritis ✓ presumably due to cytokine effects on the bone marrow, may occur
Uveitis ✓ with either disorder. Malabsorption of vitamin B12 or folate is an-
PSC ✓
other cause of anemia in patients with CD. Hypoalbuminemia,
Abbreviations: EIM, extraintestinal manifestation; IBD, inflammatory bowel hypokalemia, and metabolic acidosis can occur with severe dis
disease; PSC, primary sclerosing cholangitis. ease because of potassium and bicarbonate wasting with diarrhea.
An increased leukocyte count may be a consequence of active
IBD or a complicating abscess.
Extraintestinal Manifestations
Up to 36% of patients with IBD have EIMs. These may involve ✓ Toxic megacolon—total or segmental nonobstructive dilatation of
any organ system and can greatly affect the patient’s function and the colon with systemic toxicity in patients with IBD or infectious
quality of life. The most common EIM involves the joints as periph- colitis

eral or axial arthropathy. Peripheral arthropathies are classified as
type 1, with asymmetric involvement of fewer than 5 large joints Laboratory values of acute phase reactants, including the
(ie, pauciarticular), and type 2, with symmetric involvement of erythrocyte sedimentation rate and C- reactive protein, can
5 or more small joints (ie, polyarticular). Skin manifestations be increased but may also be normal in mildly active disease.
include erythema nodosum, pyoderma gangrenosum, Sweet Perinuclear antineutrophil cytoplasmic antibody test results are
syndrome, and aphthous stomatitis. Eye involvement includes positive in about two-thirds of patients with UC and in about one-
episcleritis and uveitis. Table 15.1 summarizes the EIMs and third of patients with CD. Anti–Saccharomyces cerevisiae anti-
their relationship to the IBD activity. body test results are positive in about two-thirds of patients with
Primary sclerosing cholangitis (PSC) is an EIM involving the CD and in about one-third of patients with UC. These antibody
hepatobiliary tract. Although PSC occurs in a relatively small tests may be used together to help distinguish between UC and
percentage of patients with UC (2.4%-7.5%), a large percentage CD. However, the positive predictive value of the 2 tests together
of patients with PSC (75%) typically have UC. When patients re- is 63.6% for UC and 80% for CD; thus, distinguishing the 2
ceive a diagnosis of PSC, they should undergo colonoscopy with diseases with these serologic tests is less than ideal (Table 15.2).
colonic biopsy to evaluate for concomitant IBD. In addition, for Several additional antimicrobial antibodies have been described,
patients with IBD, the presence of PSC is an independent risk including those to Escherichia coli outer membrane protein C,
factor for the development of colorectal dysplasia or cancer. Bacteroides caccae TonB- linked outer membrane protein W,
Therefore, annual surveillance colonoscopies are recommended CBir1 flagellin, and Pseudomonas fluorescens–related protein.
for patients who have IBD and PSC. The usefulness and role of these markers in IBD diagnostic and
management algorithms is being assessed. With new-onset IBD
✓ Diagnostic testing for IBD—endoscopy, radiology, serology, and or with relapse, infection should be ruled out with stool studies,
pathology including cultures for bacterial pathogens and examinations for
✓ Onset of UC—varies from mild and gradual to severe and sudden ova and parasites and Clostridioides difficile toxin. For patients
with bloody diarrhea, crampy abdominal pain, and fever with systemic symptoms such as fever, malaise, and myalgias,
✓ Half the patients with UC have disease involving the left colon
cytomegalovirus infection should be ruled out with mucosal bi-
✓ CD symptoms vary with anatomical location, severity of disease,
and patient’s phenotype opsy studies, particularly if the patient is receiving therapy with
immunosuppressive agents.
Physical Examination Table 15.2. Positive Predictive Value of Serologic Markers

in Patients With Indeterminate Colitis
When patients have mildly active UC, physical examination
findings are often normal or the patients may have abdominal Positive predictive
Disease Marker value, %
tenderness, particularly with palpation over the sigmoid colon.
Patients with more severe disease may have pallor (from anemia), Ulcerative colitis pANCA+ 63.6
tachycardia (from dehydration), fever, diminished bowel sounds, ASCA−
and diffuse abdominal tenderness with rebound. Tenderness with Crohn disease pANCA− 80
rebound is ominous and suggests toxic dilatation or perforation. ASCA+
When patients have CD, physical examination findings may Abbreviations: ASCA, anti–Saccharomyces cerevisiae antibody; pANCA,
be normal or may include 1 or more of the following: fever, perinuclear antineutrophil cytoplasmic antibody.
✓ In a patient with UC, abdominal rebound tenderness is an omi-

nous sign of possible toxic megacolon or perforation
✓ Thorough rectal examination in patients with CD may identify
fistulas, fissures, anal stenosis, or perianal abscesses
✓ Iron deficiency anemia may occur with either UC or CD
✓ Vitamin B12 deficiency occurs more commonly with CD than
with UC
✓ New-onset IBD or relapse—use stool studies to rule out infection,
especially with Clostridioides difficile
Endoscopy
Flexible proctosigmoidoscopy or colonoscopy can be used to
identify characteristic mucosal changes of UC, including loss
of the normal vascular markings and the presence of mucosal
granularity, friability, mucous exudate, and focal ulceration
(Figure 15.1). With colonoscopy, the extent of disease can be
determined and the terminal ileum can be examined for evi-
dence of backwash ileitis in UC or ileal involvement in CD.
Patients with left-sided UC may have inflammatory changes
around the appendix, referred to as a cecal patch, as a man- Figure 15.2. Crohn Disease. Colonoscopy shows linear ulcers and
surrounding mucosal erythema, edema, and granularity. These findings
ifestation of the disease; this finding should not be confused
are typical of Crohn disease.
with segmental colitis due to CD. Only a limited examination
of the rectosigmoid colon should be performed in patients with
severely active colitis because of the risk of perforation. In CD,
characteristic lesions at colonoscopy are deep linear ulcers of malignancy for patients with less extensive UC (with involve-
(rake ulcers) with surrounding erythema and granularity and ment of the colon distal to the splenic flexure) also is increased,
skip areas of normal-appearing mucosa between areas of in- but the magnitude of the risk has not been defined. The risk of
volvement (Figure 15.2). Endoscopy of the upper gastrointes- rectal cancer for patients with ulcerative proctitis without co-
tinal tract can be used to confirm the presence and distribution litis above the rectum does not appear to be increased. Patients
of disease in the upper gut and to define how severely the mu- with either form of colitis that involves more than one-third of
cosa is affected. the colon should have periodic surveillance biopsies after 8 to
Patients with IBD who have extensive, long-standing colonic 10 years of disease. The optimal interval between surveillance
inflammation have a risk for malignancy that is higher than that examinations has not been defined, and the examinations are
for the general population. For that reason, periodic colonoscopy usually performed at 1-to 2-year intervals.
with surveillance biopsies for dysplasia is indicated after 8 to
10 years of disease for patients who have extensive UC. The risk Radiologic Features
If patients have severely active colitis, plain abdominal films
with supine and upright views should be obtained to examine
for complications, including perforation with free air or toxic
dilatation. In CD, computed tomographic (CT) enterography
(Figure 15.3), magnetic resonance (MR) enterography (Figure
15.4), or abdominal ultrasonography can be used to assess the
location and extent of small-bowel disease and complications
such as fistulas, strictures, or abscesses. CT enterography has
been shown to have superior sensitivity and specificity compared
with traditional small-bowel follow-through images for detecting
active inflammation of the small intestine. MR enterography has
the advantage of avoiding exposure to ionizing radiation and is
safe in pregnancy (gadolinium should be avoided in the first tri-
mester). Wireless capsule endoscopy may be useful for evalua-
tion in some patients but should not be performed if obstructive
or stricturing disease is suspected, because of the risk of capsule
retention. A barium swallow may be useful for assessment of CD
that involves the esophagus, stomach, and duodenum. MR im-
aging is the preferred imaging method for identifying pelvic and
perianal abscesses.
Histology
Figure 15.1. Ulcerative Colitis. Colonoscopy shows diffuse changes
of colitis with mucosal granularity, erythema, and exudate. These Mucosal biopsy specimens from involved areas of the gastro-
findings are typical of moderately active ulcerative colitis. intestinal tract are useful for excluding self-limited colitis and
15. Inflammatory Bowel Disease: Clinical Aspects 189
Differential Diagnosis
UC and CD must be differentiated from infectious causes of colitis
and also from noninfectious causes of inflammation in the colon
and small intestine (Box 15.1). Microscopic colitis describes a syn-
drome of chronic watery diarrhea with characteristic histologic
abnormalities but without specific endoscopic or radiographic
features. Specific forms of microscopic colitis include lymphocytic
colitis, in which intraepithelial lymphocytes and chronic inflam-
matory cells are present in the lamina propria, and collagenous co-
litis, which includes the features of lymphocytic colitis and also
the presence of a subepithelial collagen band. Diverticular disease–
associated chronic colitis is a segmental colitis in which there are
chronic inflammatory changes of the mucosa limited to areas of the
sigmoid colon where diverticula are present.
Nonsteroidal anti-
inflammatory drugs can cause ulcerations
throughout the gastrointestinal tract, including the colon and
rectum, which can be confused with CD. Ischemia more com-
monly causes segmental colitis that may be confused with CD, but
occasionally it causes a diffuse colitis that can resemble UC. Injury
to the rectum from radiotherapy for prostate cancer or gyneco-
Figure 15.3. Computed Tomographic Enterography in Crohn
logic malignancy may appear similar to ulcerative proctitis or CD
Disease. This axial image shows wall thickening and mural enhance-
ment (arrow) in the terminal ileum of a patient with active Crohn
with fistulas and strictures. Injury to the small intestine and more
disease.
Box 15.1. Differential Diagnosis of Inflammatory

other infections and noninfectious causes of colitis, such as is- Bowel Disease
chemia, drug effect, radiation injury, and solitary rectal ulcer
Acute self-limited colitis
syndrome. Noncaseating granulomas are a feature of CD and
can be helpful in differentiating it from UC, but even when Bacteria
Toxigenic Escherichia coli
multiple specimens are taken, granulomas are identified in
only 30% of specimens of resected CD. The presence of focal, Salmonella
patchy inflammation is characteristic of CD but not invariably Shigella
identifiable. Campylobacter
Yersinia
✓ Granuloma— a structure formed during inflammation that
is present in many diseases; it is a collection of cells known as Mycobacterium
macrophages
Neisseria gonorrhoeae
Clostridioides difficile
Chlamydia
Parasites
Amebae
Viruses
Cytomegalovirus
Herpes simplex virus
Collagenous colitis and lymphocytic colitis
Diverticular disease–associated colitis
Medication-induced colitis
Nonsteroidal anti-inflammatory drugs
Gold
Ischemic colitis
Radiation enterocolitis
Diverticulitis
Appendicitis
Neutropenic enterocolitis
Solitary rectal ulcer syndrome
Malignancy
Carcinoma
Figure 15.4. Magnetic Resonance Enterography in Crohn
Disease. This axial image of a segment of ileum shows enhancement, Lymphoma
thickening, and dilated vasa recta (arrow) (the comb sign) in a patient Leukemia
with Crohn disease.
proximal colon from radiotherapy may cause chronic diarrhea, Suggested Reading
strictures, malabsorption, and other features that may mimic exten-
Fletcher JG, Fidler JL, Bruining DH, Huprich JE. New concepts in in-
sive CD. Solitary rectal ulcer syndrome may be confused with CD testinal imaging for inflammatory bowel diseases. Gastroenterology.
involving the rectum but can be differentiated on the basis of his- 2011 May;140(6):1795–806.
tologic features showing marked subepithelial fibrosis without in- Henckaerts L, Figueroa C, Vermeire S, Sans M. The role of ge-
flammation. Diverticulitis may be confused with CD when patients netics in inflammatory bowel disease. Curr Drug Targets. 2008
present with fistulas, localized abscesses, and a segmental colitis. May;9(5):361–8.
Joossens S, Reinisch W, Vermeire S, Sendid B, Poulain D, Peeters
✓ Endoscopic characteristics of UC— loss of normal vascular M, et al. The value of serologic markers in indeterminate co-
markings and the presence of mucosal granularity, friability, litis: a prospective follow- up study. Gastroenterology. 2002
exudates, and focal ulcerations May;122(5):1242–7.
✓ Left- sided UC can be associated with isolated inflammation Loftus EV, Jr. Clinical epidemiology of inflammatory bowel di-
around the appendix (known as a cecal patch) sease: Incidence, prevalence, and environmental influences.
✓ Endoscopic characteristics of CD—deep linear ulcers, erythema, Gastroenterology. 2004 May;126(6):1504–17.
granularity, and skip lesions Peyrin-Biroulet L, Loftus EV, Jr., Colombel JF, Sandborn WJ. The nat-
✓ Colonoscopy with surveillance biopsies for malignancy should be ural history of adult Crohn’s disease in population-based cohorts. Am
performed after 8 to 10 years from diagnosis with subsequent sur- J Gastroenterol. 2010 Feb;105(2):289–97.
veillance every 1 to 2 years Podolsky DK. Inflammatory bowel disease. N Engl J Med. 2002 Aug
✓ CT or MR enterography can be used to assess the location and 8;347(6):417–29.
extent of small-bowel disease in CD Rubin DT, Ananthakrishnan AN, Siegel CA, Sauer BG, Long MD. ACG
✓ MR imaging—the preferred method for evaluation of pelvic and clinical guideline: ulcerative colitis in adults. Am J Gastroenterol.
perianal abscesses 2019 Mar;114(3):384–413.
16
Inflammatory Bowel Disease: Therapy

DARRELL S. PARDI, MD
VICTOR G. CHEDID, MD, MS
There are many therapies available for patients with inflamma- left-sided UC (inflammation from the rectum to the splenic
tory bowel disease (IBD). Medical therapies include aminosali flexure), and extensive colitis or pancolitis (inflammation extends
cylate drugs such as sulfasalazine, olsalazine, balsalazide, and from the rectum to beyond the splenic flexure or involves the en-
various formulations of mesalamine; antibiotics; corticos tire colon). CD, however, can involve any location in the gastro-
teroids; immunosuppressive medications such as azathioprine, intestinal tract, from mouth to anus. Accordingly, it is divided
6-mercaptopurine (6-MP), methotrexate, and cyclosporine; and into ileitis, colitis, and ileocolitis; involvement of the jejunum or
biotechnology medications such as anti–tumor necrosis factor the upper gastrointestinal tract is much less common. A subset of
(TNF) agents, anti-interleukins, anti-integrins, and other newer patients has perianal disease with fissures, fistulas, abscesses, and
agents with different targets and mechanisms of action. This other findings.
chapter reviews these various treatments and where they fit in the
treatment algorithms for Crohn disease (CD) and ulcerative co-
Aminosalicylates
litis (UC). Many surgical therapies also are used in patients with
IBD, although a detailed review of these options is beyond the Sulfasalazine, oral mesalamine (Pentasa, Asacol, Delzicol,
scope of this chapter. Lialda, and Apriso), rectal mesalamine (Rowasa and Canasa),
Many of the treatments reviewed are used for both UC and olsalazine, and balsalazide (Colazal and Giazo) are drugs that de-
CD, with some notable exceptions. Some of the treatments act liver 5-aminosalicylate (5-ASA) to the bowel lumen (Table 16.1).
systemically, but others are designed to deliver medication to With the exception of the Pentasa formulation of mesalamine,
specific areas of the bowel, so a thorough understanding of the these medications primarily deliver drug to the colon.
anatomical distribution of inflammation is required in order to Sulfasalazine, the first drug developed in this class, combines
choose the optimal drug for a given patient. a 5-ASA molecule with sulfapyridine. This drug was originally
UC is classified according to the extent of involvement developed to treat rheumatoid arthritis, and for that indication,
as ulcerative proctitis (rectal involvement only), ulcerative the sulfapyridine moiety is thought to be the active component.
proctosigmoiditis (involving the rectum and sigmoid colon), Subsequently, sulfasalazine was discovered to be effective for
UC, with the active ingredient being 5-ASA. This discovery led
to the development of the newer generation of 5-ASA drugs that
have fewer adverse effects than the sulfa-containing parent drug.
Abbreviations: CD, Crohn disease; FDA, US Food and Drug Administration; In sulfasalazine, 5-ASA is linked to sulfapyridine by an azo bond,
5-ASA, 5-aminosalicylate; IBD, inflammatory bowel disease; Ig, immu-
which keeps the 5-ASA inactivated until the azo bond is cleaved
noglobulin; IL, interleukin; IPAA, ileal pouch–anal anastomosis; JAK,
janus kinase; MAdCAM-1, mucosal addressin cell adhesion molecule 1; by bacterial enzymes. Therefore, active drug is delivered prima-
NUDT15, nudix hydrolase 15; 6-MP, 6-mercaptopurine; SONIC, Study of rily to the colon.
Biologic and Immunomodulator Naive Patients in Crohn’s Disease; TNF, Olsalazine and balsalazide are prodrugs with 5-ASA bound
tumor necrosis factor; TPMT, thiopurine methyltransferase; UC, ulcerative by an azo bond. In addition, 5-ASA is available covered with a
colitis pH-dependent polymer that dissolves in the terminal ileum and
191
Table 16.1. Preparations of 5-Aminosalicylate (5-ASA) for Treatment of Ulcerative Colitis

Daily dose, ga
Proprietary
Generic name name Formulation Sites of delivery Active Maintenance
Mesalamine Rowasa Enema suspension From rectum to splenic flexure 4 4b
Canasa Suppository Rectum 1 1b
Pentasa Ethylcellulose-coated granules (controlled-release) Duodenum, jejunum, ileum, colon 2-4 1.5-4
Asacol Eudragit-S–coated tablets (dissolves at pH ≥7.0) Terminal ileum, colon 2.4-4.8 1.6-4.8
Delzicol Eudragit-S–coated tablets (dissolves at pH ≥7.0) Terminal ileum, colon 2.4-4.8 1.6-4.8
Apriso Enteric coating (dissolves at pH ≥6) around polymer Terminal ileum, colon 1.5 1.5
matrix
Lialda Enteric coating (dissolves at pH ≥7) around polymer Terminal ileum, colon 2.4-4.8 2.4
matrix with lipophilic and hydrophilic matrices
Olsalazine Dipentum 5-ASA dimer linked by azo bond Colon 2-3 1
Sulfasalazine Azulfidine 5-ASA linked to sulfapyridine by azo bond Colon 2-4 2-4
Balsalazide Colazal 5-ASA linked to inert carrier by azo bond Colon 6.75 4.5-6.75
Giazo 5-ASA linked to inert carrier by azo bond Colon 6.6 4.4-6.6
a
Dose ranges reflect those commonly used in clinical practice and are broader than those specifically studied in clinical trials.
b
When 5-ASA enemas or suppositories are used for maintenance therapy, the dose may be decreased to every second or third night.
cecum (Asacol and Delzicol), as ethylcellulose-coated granules Antibiotics

that release drug throughout the gastrointestinal tract (Pentasa);
Controlled trials of various antibiotics have not demonstrated effi-
or in more complex delivery systems that result in prolonged
cacy in treating UC. The data for use of antibiotics in CD are less
mesalamine release throughout the colon (Lialda and Apriso).
clear-cut. Three small studies suggested efficacy of metronidazole
Mesalamine can also be administered as an enema to treat left-
and ciprofloxacin; however, a placebo-controlled trial of metronida-
sided colitis or proctosigmoiditis (Rowasa) or as a suppository to
zole did not demonstrate efficacy for inducing remission in patients
treat proctitis (Canasa).
with active CD. Similarly, another trial did not demonstrate an ad-
All 5-ASA drugs are effective in inducing and maintaining
junctive role for antibiotics in patients receiving budesonide for
remission in mildly to moderately active UC. The choice of drug
active CD. Controlled trials of metronidazole and ornidazole after
therefore depends primarily on the distribution of inflammation.
ileal resection showed that postoperative endoscopic recurrence of
In contrast, the efficacy of 5-ASA drugs for CD is much less
disease could be delayed after resection for CD, although adverse
clear; the conclusion from a meta-analysis was that these drugs
effects were common; in a small pilot study of ciprofloxacin after
have little or no benefit over placebo. Drug-associated toxicity is
ileal resection, findings were negative. Because of these results, the
common with sulfasalazine, including headache, epigastric pain,
use of antibiotic therapy for CD is debated, and in the absence of
nausea and vomiting, and skin rash. Less common but severe
penetrating complications, such as a fistula or abscess, the role of
adverse events include hepatitis, fever, autoimmune hemolysis,
antibiotics as primary therapy in CD is limited.
bone marrow toxicity, and others. Folate deficiency is induced by
In contrast, uncontrolled studies and clinical experience in-
sulfasalazine, and therefore folate supplementation is required.
dicate that antibiotics such as metronidazole and ciprofloxacin
Sulfasalazine can cause reversible azoospermia leading to male
are effective for fistulizing CD, particularly perianal fistulas. No
infertility. Sulfasalazine may be taken during pregnancy and
controlled trials have been performed, but antibiotic therapy is
breastfeeding.
used widely for this treatment indication and is considered to be
Olsalazine, balsalazide, and mesalamine generally are better
the first-line therapy in combination with immunosuppressive or
tolerated than sulfasalazine. Commonly occurring adverse events
biological therapies.
include headache, rash, and alopecia. Less common is a hyper-
Small placebo-controlled and comparative trials have shown that
sensitivity reaction resulting in worsening diarrhea and abdom-
metronidazole and ciprofloxacin are effective for inducing remis-
inal pain that may be confused with a colitis flare. Rarely, patients
sion in patients with acute pouchitis after colectomy and ileoanal
have serious adverse events, including interstitial nephritis,
anastomosis for UC. Uncontrolled clinical observations have
pericarditis, pneumonitis, hepatitis, or pancreatitis. Periodic
suggested that metronidazole and ciprofloxacin may be effective
monitoring of kidney function is recommended with long-term
for maintaining remission in patients with chronic pouchitis.
treatment with any mesalamine formulation, although nephrotox-
Adverse effects with metronidazole include paresthesias, pe-
icity is rare. A secretory diarrhea can occur with olsalazine, which
ripheral neuropathy, yeast infections, anorexia, dyspepsia, nausea,
has limited its use. Olsalazine, balsalazide, and mesalamine may
a metallic taste, and intolerance to alcohol. Adverse effects with
be taken during pregnancy and breastfeeding.
ciprofloxacin are less common and include photosensitivity,
nausea, rash, increased liver enzyme levels, and tendinopathy,
✓ Medical therapies for IBD include oral or rectal 5-ASA drugs, rarely including tendon rupture. Ciprofloxacin should not be
immunomodulators, biologicals, and other newer agents with
taken during pregnancy or breastfeeding. Metronidazole can be
different targets and mechanisms of action
✓ For patients with mild to moderate UC, 5-ASA drugs are effective considered during pregnancy, but it is secreted in breast milk.
for achieving remission and maintenance
✓ Rarely, patients have serious adverse events with 5-ASA drugs Corticosteroids
(eg, interstitial nephritis, pericarditis, pneumonitis, hepatitis, or
pancreatitis) Corticosteroids are commonly used in patients with IBD.
A dose-response study of patients with active UC showed that
16. Inflammatory Bowel Disease: Therapy 193
a prednisone dosage of 40 or 60 mg daily is more effective than Before these medications are prescribed, consideration should
20 mg daily, and more adverse effects occur with 60 mg daily. be given to checking for TPMT activity in all patients and for
Doses larger than 60 mg provide little if any additional efficacy the NUDT15 genotype in certain populations (especially those
with more adverse effects, so they should not be used. Similar with Asian, Latino, American Indian, or Finnish ancestry);
data exist for corticosteroid therapy in patients with CD. Most patients with normal TPMT and NUDT15 activity may be treated
clinicians initiate oral corticosteroid therapy with prednisone at with full-dose azathioprine or 6- MP. Trials have shown that
a dosage of 40 to 60 mg daily. For patients with ileocolonic CD, azathioprine at dosages of 1.5 to 2.5 mg/kg daily is useful for its
controlled ileal-release budesonide is an alternative to predni- corticosteroid-sparing effects and for maintenance of remission
sone, and for patients with UC, a colonic-release formulation of in patients with UC. One study showed that azathioprine 2.0 mg/
budesonide (multimatrix system budesonide) is available. Both kg daily was more effective than oral mesalamine 3.2 g daily.
formulations of budesonide offer effective therapy with fewer Trials also have shown that azathioprine 2 to 3 mg/kg daily and 6-
corticosteroid-related adverse effects (owing to high first-pass MP 1.5 mg/kg daily are effective for inducing remission, closing
hepatic metabolism) but at a higher cost. fistulas, corticosteroid sparing, and maintaining remission in
Placebo-controlled trials have shown that corticosteroid patients with CD.
therapy is not effective for maintaining remission in patients Adverse effects with azathioprine and 6-MP include fever,
with UC or CD; thus, for patients who respond to corticosteroid nausea, allergic reactions, pancreatitis, arthralgias, bone marrow
therapy, the dose is typically tapered over 2 to 4 months while suppression, hepatitis, infectious complications, and an increased
use of another medication is begun for maintenance. Patients risk of lymphoma and skin cancer. Although azathioprine and 6-
with severely active disease who do not have a response to oral MP are classified as pregnancy category D drugs, several recent
corticosteroid therapy are often either hospitalized and given publications indicated that these drugs can be administered safely
corticosteroids intravenously (eg, methylprednisolone, 40-60 mg during pregnancy. They are also probably safe for use during
daily) or treated with a biological agent. breastfeeding.
Corticosteroid enemas are effective for inducing remis-
sion in left-sided UC or ulcerative proctosigmoiditis, and cor- ✓ Before azathioprine and 6-MP are administered, test all patients
ticosteroid suppositories are effective for ulcerative proctitis. for TPMT and NUDT15 activity
However, in clinical trials, topical mesalamine is superior to ✓ Patients with normal TPMT and NUDT15 activity may be treated
with full-dose azathioprine or 6-MP
topical corticosteroids, and thus topical corticosteroids are typ-
ically reserved for patients who do not tolerate or have no re-
sponse to mesalamine. Topical corticosteroids are not effective
for maintaining remission. Methotrexate
Short-and long- term adverse events occur frequently in Parenteral methotrexate at a dose of 25 mg weekly is effective for
patients receiving corticosteroids. Short-term adverse events in- inducing and maintaining remission in patients with CD. Adverse
clude weight gain, moon face, acne, ecchymoses, hypertension, events that may occur with methotrexate include rash, nausea,
hirsutism, petechial bleeding, striae, and psychosis. Long-term mucositis, diarrhea, bone marrow suppression, infections, pneu-
adverse events include type 2 diabetes, increased risk of infec- monitis, increased liver enzyme levels, and liver fibrosis or
tion, osteonecrosis, osteoporosis, myopathy, cataracts, and glau- cirrhosis. Some toxicity can be mitigated by the concomitant
coma among many others. Corticosteroids may be taken during administration of folic acid. Methotrexate is contraindicated for
pregnancy and breastfeeding. pregnant and lactating women.
Azathioprine and 6-MP Cyclosporine

Azathioprine is a prodrug that is converted rapidly to 6-MP, which Intravenous cyclosporine is effective for inducing remission in
is then either inactivated (to 6-thiouric acid by xanthine oxidase patients with severely active, corticosteroid-refractory UC. The
or to 6-methylmercaptopurine by thiopurine methyltransferase) efficacy of cyclosporine at a moderate dose (2 mg/kg) is similar
or activated through several enzyme steps to the active metabo- to that at a higher dose (4 mg/kg). Many patients who have a re-
lite 6-thioguanine nucleotide. The enzyme activity of thiopurine sponse to cyclosporine undergo a colectomy within a few years;
methyltransferase (TPMT) is determined genetically: 1 in 300 therefore, many clinicians do not feel that the risk is worth the
patients (0.3%) have no enzyme activity and have a very high long-term benefit. In placebo-controlled trials of oral cyclospo-
risk of serious toxicity, such that these drugs should not be used; rine, the drug was not efficacious for inducing or maintaining re-
10% have intermediate enzyme activity, with an increased risk of mission in patients with CD.
toxicity that can be mitigated in most patients by dose reduction Adverse events that may occur with cyclosporine therapy in-
and careful follow-up; and 90% have normal enzyme activity. clude headache, tremor, paresthesias, seizures, hypertrichosis,
The enzyme nudix hydrolase 15 (NUDT15) is directly involved gingival hyperplasia, kidney insufficiency, hypertension,
in the metabolism of thiopurines by catalyzing the conversion of infections, hepatotoxicity, and nausea and vomiting. Use of cy-
active metabolites to less toxic metabolites, thus preventing the closporine is generally avoided in pregnant women.
incorporation of toxic metabolites into DNA. The frequency of
the NUDT15 poor metabolizer phenotype is about 1 in every 50
patients of East Asian descent, so it is more common than the
Anti-TNF Agents
TPMT poor metabolizer phenotype in Europeans. NUDT15 defi- Infliximab is a mouse-human chimeric, intravenously admini
ciency is also more prevalent in individuals of Hispanic ethnicity, stered monoclonal antibody directed toward TNF-α. Adalimumab
particularly those with a high degree of American Indian genetic and golimumab are fully human monoclonal antibodies and
ancestry. certolizumab pegol is a pegylated humanized (mostly human)
Fab′ fragment; all 3 are administered by subcutaneous injec- Risankizumab

tion. Controlled trials have shown that infliximab is effective for
Risankizumab is a humanized monoclonal antibody directed
inducing and maintaining remission and closing fistulas in CD and
to the p19 subunit of IL-23. It has been recently approved for
for inducing and maintaining remission in UC. Controlled trials
the treatment of adults who have moderate to severe CD.
have shown that adalimumab and certolizumab pegol are effective
Risankizumab is also indicated for psoriasis and psoriatic ar-
for inducing and maintaining remission in CD and UC. Data also
thritis. In clinical trials risankizumab was safe, and patients had
indicate that use of adalimumab and certolizumab can result in
few adverse reactions. Drug-induced liver injury has been re-
fistula closure. Controlled trials have shown that golimumab is
ported, so pretreatment evaluation should include checking levels
effective for inducing and maintaining remission in UC.
of liver enzymes and bilirubin in addition to the usual labora-
Adverse events that may occur with anti-TNF therapy include
tory testing performed before administration of biologicals. Liver
formation of antibodies against the therapy, infusion or injection
enzyme and bilirubin levels should be checked again 8 weeks
site reactions, delayed hypersensitivity reactions, autoantibody
after initiation of risankizumab therapy and every 3 to 6 months
formation, drug-induced lupus, infection (particularly tubercu-
thereafter.
losis and fungal infections such as histoplasmosis), psoriasis, and
possibly lymphoma and skin cancers. Antibodies to infliximab
lead to higher rates of infusion reactions and loss of efficacy in Janus Kinase Inhibitors
patients receiving infliximab. The frequency of formation of these
The inhibition of the janus kinase (JAK) family, which
antibodies is decreased when patients receive 3 induction doses
includes JAK1, JAK2, JAK3, and TYK2, can block several
of infliximab and then maintenance infusions every 8 weeks, with
proinflammatory cytokines involved in immune function, such as
concomitant immunosuppressive therapy and pretreatment with
IL-6, IL-12, and IL-23, which are important in the pathophysi-
corticosteroids before each dose. There are fewer studies and
ology of UC and CD.
less experience with antibodies to adalimumab, certolizumab, or
Tofacitinib is a pan- JAK inhibitor (blocking all JAK
golimumab. Although data are limited, anti-TNF agents appear to
receptors) approved by the US Food and Drug Administration
be safe for use in pregnant women.
(FDA) for the treatment of UC. In the OCTAVE trials,
tofacitinib was effective for induction and maintenance of re-
Vedolizumab mission in patients with UC. Results from studies in patients
with CD were negative.
Vedolizumab is an immunoglobulin (Ig) G1 humanized mono-
Nonselective JAK inhibitors may have more safety concerns
clonal antibody that selectively inhibits the interaction between
related to the pan-JAK inhibition compared to selective JAK
α4β7 integrin and mucosal addressin cell adhesion molecule 1
inhibitors. Hematopoietic or blood cell–related adverse effects
(MAdCAM-1). It prevents lymphocyte translocation from the
such as anemia or neutropenia may occur with JAK2 inhibi-
blood into the inflamed gut tissue and thereby decreases local in-
tion. The biggest safety concern with tofacitinib thus far is
flammation. Vedolizumab is effective for the induction and main-
venous thromboembolism, which occurred in a large study of
tenance of remission in patients with UC and CD. It is approved
patients older than 50 years who had 1 or more cardiac risk
for those with an inadequate response to either standard therapies
factors. This has led the FDA to add a black box warning to
or anti-TNFα.
JAK inhibitors and restricted the use of tofacitinib to patients
With its gut- selective mechanism of action and no systemic
who have not had a therapeutic response to anti- TNFs or
effects, vedolizumab has a good safety profile with minimal im-
other biological therapies. However, increased rates of venous
munogenicity. Progressive multifocal leukoencephalopathy has not
thromboembolisms have not been reported for patients with UC
been observed in patients treated with vedolizumab as compared to
or CD who were treated with tofacitinib. Another concern with
those treated with the non–gut selective anti-integrin, natalizumab.
JAK inhibition is the reactivation of herpes zoster, which occurs
Vedolizumab is not associated with an increased risk of serious or op-
in a dose-dependent manner with tofacitinib. Therefore, patients
portunistic infections, does not increase the risk of malignancy, and
should be vaccinated with the recombinant shingles vaccine. In
is well tolerated by patients. There is no evidence for safety concerns
addition, patients beginning therapy with tofacitinib should be
regarding pregnancy outcomes associated with vedolizumab.
monitored with complete blood cell counts and lipid panels.
There are no data on safety during pregnancy, so tofacitinib is
Ustekinumab not recommended during pregnancy.
Ustekinumab is an IgG1 κ humanized monoclonal antibody that Upadacitinib, a selective JAK1 inhibitor, has been re-
binds to interleukin (IL)-12 and IL-23. These cytokines mod- cently approved by the FDA for UC (March 2022). It is only
ulate the function of lymphocytes, including T-helper-1 and T- approved in patients that have failed anti-TNF therapy due
helper-17 cell subsets. Ustekinumab is indicated for the treatment to safety concerns with the class of JAK inhibitors. The U-
of adult patients with moderate to severely active CD and UC. ACHIEVE and U-ACCOMPLISH trials have shown excellent
Ustekinumab has been found to be safe with minimal long-term clinical remission and response for induction and maintenance
risks. It has also shown favorable outcomes in treating perianal in UC. The overall safety signals have been very favorable for
disease in patients with CD. Safety data during pregnancy have upadacitinib, likely due to the selectivity of JAK1 inhibition.
been promising. Similar to tofacitinib, it is recommended to monitor complete
blood counts and lipid panels when starting upadacitinib and
✓ Infliximab and adalimumab—anti-TNF antibodies that patients be vaccinated with the recombinant shingles
✓ Vedolizumab—an antibody against α4β7 integrin vaccine if they are to be treated with upadacitinib. There is no
✓ Ustekinumab targets IL-12 and IL-23
data on safety during pregnancy, and thus it is not recommended
during pregnancy.
Ozanimod medical therapy, and patients who have a complication (eg, toxic
megacolon). Colectomy for low-grade dysplasia has been the
Ozanimod is a selective sphingosine 1-phosphate receptor ag-
subject of debate recently because of results from newer studies,
onist, which was approved for UC by the FDA in 2021. It is
and the procedure is dependent on other patient factors. Patients
effective in achieving clinical remission in induction and mainte-
who elect not to proceed with colectomy should have more in-
nance in UC. Ozanimod is contraindicated for patients who have
tensive surveillance colonoscopy and biopsies, ideally with
had a myocardial infarction, unstable angina, stroke, transient
chromoendoscopy, which increases the detection of dysplasia.
ischemic attack, or decompensated heart failure in the previous
The most common complication after IPAA for UC is pouchitis,
6 months. Other contraindications are Mobitz type II second or
which is characterized by diarrhea, cramps, urgency, and often
third degree atrioventricular block, sick sinus syndrome, or si-
fecal incontinence. The cumulative frequency of acute pouchitis
noatrial block unless the patient has a functioning pacemaker.
after IPAA for UC approaches 50% by 5 years. Most patients
Ozanimod is also not recommended for patients with severe un-
respond to a short course of antibiotics (often ciprofloxacin or
treated sleep apnea or for those receiving therapy with a monoa-
metronidazole), although some patients have a prompt recurrence
mine oxidase inhibitor.
after discontinuation of antibiotic therapy (termed antibiotic-
Patients should have a baseline complete blood cell count (to
dependent chronic pouchitis). In these patients, long-term use of
exclude lymphopenia) and liver enzyme testing, and they should
suppressive antibiotics can be helpful. A small subset of patients
be monitored for hypertension before and after initiation of
has antibiotic-refractory chronic pouchitis and requires treatment
therapy. Monitoring for signs and symptoms of macular edema is
with corticosteroids (eg, budesonide), immunomodulatory
recommended. Pregnancy should be avoided during therapy with
medications, biologicals, or surgery (pouch excision or diver-
ozanimod and for 3 months after stopping therapy.
sion). For these patients, the possibility of CD of the pouch must
be considered.
The need for surgical resection in patients with CD increases
Surgery
with time. By 15 years after diagnosis, 70% of patients have had
The original operation for UC consisted of a total proctocolectomy at least 1 operation, and half these patients have had 2 or more
with Brooke ileostomy (Figure 16.1). In the 1970s, the conti- operations, but much of the data on the surgical natural history
nent ileostomy, or Kock pouch, served as an alternative to the of CD are from the era before biologicals. Emerging data in-
conventional ileostomy (Figure 16.1). However, dysfunction dicate that these highly effective medications are changing the
of the pouch, often requiring reoperation, was common. In the natural history of this disease, resulting in fewer hospitalizations
1980s, the ileal pouch–anal anastomosis (IPAA) largely replaced and operations. In patients with extensive stricturing or numerous
the Kock pouch for patients with UC who required operation previous operations (or both), bowel-sparing techniques such as
and is now the standard procedure for the majority of patients stricturoplasty may be used (Figure 16.2). In patients with peri-
(Figure 16.1). anal fistulas, a fistulotomy or placement of setons or drains may
Colectomy is indicated for patients with UC who have colo- be used to control symptoms, enhance the effectiveness of med-
rectal cancer or dysplasia, patients who have disease refractory to ical therapies, and ultimately avoid proctectomy.
Figure 16.1. Surgical Options for Ulcerative Colitis.

Figure 16.2. Stricturoplasty for Crohn Disease.
Treatment Strategies for UC remission in UC. Prednisone is not effective for maintaining
remission, and patients who respond to this therapy require a
Induction of Remission
corticosteroid-sparing maintenance therapy such as azathioprine
The aminosalicylates are effective for inducing remission in or 6-MP or biological therapy. Anti-TNFs, vedolizumab, and
patients with mild to moderate UC. Patients with proctitis ustekinumab are effective for maintaining remission in patients
alone may be treated with mesalamine suppositories, and those who respond to these agents. In those with no response to anti-
with proctosigmoiditis or left-sided colitis may be treated with TNF therapy, a second agent should be considered such as
mesalamine enemas. Corticosteroid suppositories and enemas vedolizumab, ustekinumab, ozanimod, or one of the new JAK
can also be used in these situations, although clinical trials inhibitors.
and a meta-analysis have shown that mesalamine is superior to
corticosteroids.
In patients who do not respond to topical therapy or who Treatment Strategies for CD
cannot administer or tolerate it and in those with pancolonic UC, Induction of Remission
oral 5-ASA drugs can be used, either alone or in combination
In 2 older studies, sulfasalazine was modestly effective for
with topical therapy. When the choice is between sulfasalazine
inducing remission in patients with active CD and colitis or
and the other 5-ASA compounds, the trade-off between cost and
ileocolitis, although a recent meta-analysis indicated that the
adverse effects needs to be considered. In addition, for patients
effect size is small. Antibiotics and mesalamine are not consist-
with arthralgias, sulfasalazine may be used to treat the joints and
ently effective for inducing remission. Ileal-release budesonide
the colitis more effectively than other 5-ASA compounds. The
is more effective than mesalamine and is as effective as predni-
pH is less than 7 in some patients with active UC who are treated
sone (but with fewer adverse effects) in patients with ileocolonic
with a 5-ASA formulation that is pH dependent (Table 16.1);
disease. The colonic-release formulation of budesonide might be
thus, whole pills may pass in their stool. If this happens, an alter-
considered for induction of colonic CD.
native formulation should be used.
For patients who have moderate to severe disease and for
For patients with more severe disease and those with mod-
patients who had no response with budesonide or sulfasalazine,
erate disease who do not respond to 5-ASA products, short-term
the next therapy to consider may be prednisone, an anti-TNF
therapy with corticosteroids is considered along with planning the
biological agent, ustekinumab, risankizumab, or vedolizumab.
corticosteroid-sparing agent of choice for induction and mainte-
Data from meta-analyses and guidelines do not support the use of
nance of remission. Patients with moderately severe disease can
azathioprine and 6-MP as induction agents in patients with active
receive oral prednisone or an anti-TNF agent (eg, vedolizumab
CD. Methotrexate is sometimes considered as an induction agent
or ustekinumab) as an outpatient, while those with fulminant
in these patients.
colitis (acute severe UC) are often hospitalized and treated with
intravenous corticosteroids. Patients who respond to cortico-
steroid therapy require an alternative therapy for maintenance, Special Considerations
as discussed below. In hospitalized patients who do not respond
Combination Therapy
to intravenous corticosteroids, treatment with cyclosporine, an
anti-TNF, or colectomy is indicated. Azathioprine or 6-MP can In the pivotal trials of anti-TNF therapy in CD, outcomes were no
be considered, but usually neither is recommended for induction better for patients who were receiving an immunomodulator than
therapy because the data on efficacy are limited and the onset for those who were not. However, these were all post hoc, un-
of action is slow. In patients with moderate to severe UC not controlled observations and therefore not definitive conclusions.
requiring admission and with no response to anti-TNF therapy, The Study of Biologic and Immunomodulator Naive Patients in
a second agent should be considered such as vedolizumab, Crohn’s Disease (SONIC) compared azathioprine monotherapy,
ustekinumab, ozanimod, or one of the new JAK inhibitors. infliximab monotherapy, and combination therapy with both
agents in patients with CD who were naive to both. The efficacy
results showed that infliximab was superior to azathioprine and
Maintenance of Remission that combination therapy was superior to either treatment alone.
The 5-ASA drugs, including topical therapies in patients with In addition, the risk of serious adverse effects was not increased
proctitis and proctosigmoiditis, are effective for maintaining in the combination therapy group. Although the SONIC trial
assessed infliximab, the same results would probably be found performed, and the risk of recurrence is high after discontinua-
with the other anti-TNF agents. These data, together with several tion if no other therapy is used. Similarly, azathioprine and 6-MP
other lines of evidence showing benefits of combination therapy may be effective for perianal disease, but no controlled trials with
(eg, better efficacy and fewer antitherapeutic antibodies) has led fistula closure as the primary end point have been conducted.
to the recommendation to use combination therapy more often in However, uncontrolled studies, post hoc analyses, and clinical
patients with CD. experience have suggested that these treatments may be effective.
Anti-TNF agents and ustekinumab appear to be effective for
both inducing and maintaining fistula closure, although only
Top-Down Versus Step-Up
infliximab has been assessed in randomized trials with fistula clo-
The use of biological therapy earlier in the course of CD has sure as the primary end point.
become standard of care. Several lines of evidence support this
thinking, including the “top-down or step-up” study. Although
Conclusions
the design of this study was not ideal with respect to current prac-
tice paradigms, it did support the notion that early use of anti- Several treatment options are available for CD and UC. Many of
TNF therapy led to better outcomes than the traditional approach the drugs can be used for either condition, although some are used
of using corticosteroids first, immunomodulators second, and for only one or the other. Knowledge of the individual drugs and
then anti-TNF agents. Other evidence supporting the earlier use their characteristics with regard to whether the drug treats sys-
of anti-TNFs includes data from children and adults that show temic disease or local disease, and where in the gastrointestinal
high response and remission rates when treatment is started tract it releases active drug, is critical for successful treatment of
earlier in the course of the disease. Similar data are emerging for patients with IBD.
other biologicals.
Suggested Reading
Maintenance of Medically Induced Remission Colombel JF, Sandborn WJ, Reinisch W, Mantzaris GJ, Kornbluth A,
The 5-ASA drugs and prednisone are not effective for mainte- Rachmilewitz D, et al. Infliximab, azathioprine, or combination therapy
nance of medically induced remission. Budesonide prolongs the for Crohn’s disease. N Engl J Med. 2010 Apr;362(15):1383–95.
D’Haens G, Baert F, van Assche G, Caenepeel P, Vergauwe P, Tuynman
time to relapse, but a maintenance effect beyond 6 months has not
H, et al. Early combined immunosuppression or conventional man-
been shown. Azathioprine, 6-MP, methotrexate, anti-TNF agents, agement in patients with newly diagnosed Crohn’s disease: an open
ustekinumab, and vedolizumab are all effective for maintaining randomised trial. Lancet. 2008 Feb;371(9613):660–7.
remission. D’Haens G, Panaccione R, Baert F, Bossuyt P, Colombel JF, Danese S,
et al. Risankizumab as induction therapy for Crohn’s disease: results
from the phase 3 ADVANCE and MOTIVATE induction trials.
Postoperative Maintenance of Remission Lancet. 2022 May 28;399(10340):2015–30.
The 5-ASA drugs provide minimal benefit for maintaining surgi- Engel T, Ungar B, Yung DE, Ben-Horin S, Eliakim R, Kopylov U.
cally induced remission. Metronidazole and ornidazole have had Vedolizumab in IBD-lessons from real-world experience; a sys-
some efficacy in small studies, but adverse events are common. tematic review and pooled analysis. J Crohns Colitis. 2018
A pilot study of ciprofloxacin was negative. Azathioprine and 6- Jan;12(2):245–57.
Feagan BG, Macdonald JK. Oral 5-aminosalicylic acid for induction of
MP may be effective, but data are sparse and conflicting. A small
remission in ulcerative colitis. Cochrane Database Syst Rev. 2012
study of infliximab has suggested a possible large benefit for Oct;10:CD000543.
postoperative maintenance of remission. A large randomized Feagan BG, Macdonald JK. Oral 5-aminosalicylic acid for maintenance
trial showed that infliximab is not superior to placebo in of remission in ulcerative colitis. Cochrane Database Syst Rev. 2012
preventing clinical recurrence after CD-related resection; how- Oct;10:CD000544.
ever, infliximab decreased endoscopically observed recurrence. Ferrante M, Panaccione R, Baert F, Bossuyt P, Colombel JF, Danese S.
The current approach to postoperative maintenance therapy is Risankizumab as maintenance therapy for moderately to severely active
risk stratification of patients for the likelihood of postoperative Crohn’s disease: results from the multicentre, randomised, double-blind,
recurrence. Those deemed to be at high risk are offered treatment placebo-controlled, withdrawal phase 3 FORTIFY maintenance trial.
with azathioprine, 6-MP, or preferably infliximab. Patients not Lancet. 2022 May 28;399(10340):2031–46.
Feuerstein JD, Ho EY, Shmidt E, Singh H, Falck-Ytter Y, Sultan S, et al.
considered to be at high risk, and those who opt not to receive
AGA clinical practice guidelines on the medical management of
medical therapy, are offered a colonoscopy 6 to 12 months after moderate to severe luminal and perianal fistulizing Crohn’s disease.
surgery. Patients who show evidence of endoscopic recurrence Gastroenterology. 2021 Jun;160(7):2496–508.
are then offered treatment. Ford AC, Bernstein CN, Khan KJ, Abreu MT, Marshall JK, Talley
NJ, et al. Glucocorticosteroid therapy in inflammatory bowel di-
sease: systematic review and meta- analysis. Am J Gastroenterol.
Treatment of Perianal CD 2011 Apr;106(4):590–9.
Perianal fistulas can be divided into simple and complex fistulas. Ford AC, Kane SV, Khan KJ, Achkar JP, Talley NJ, Marshall JK, et al.
A simple fistula is below the sphincter complex, has a single Efficacy of 5-aminosalicylates in Crohn’s disease: systematic review
external opening, and does not have an associated abscess, and meta-analysis. Am J Gastroenterol. 2011 Apr;106(4):617–29.
rectovaginal fistula, anorectal stricture, or macroscopically evi- Hashash JG, Regueiro MD. The evolving management of postoper-
ative Crohn’s disease. Expert Rev Gastroenterol Hepatol. 2012
dent rectal inflammation. A complex fistula is high or has multiple
Sep;6(5):637–48.
external openings, a perianal abscess, rectovaginal fistula, ano- Honap S, Meade S, Ibraheim H, Irving PM, Jones MP, Samaan MA.
rectal stricture, or macroscopic evidence of rectal inflammation. Effectiveness and safety of ustekinumab in inflammatory bowel di-
Antibiotics may be effective for fistula closure, especially sease: a systematic review and meta-analysis. Dig Dis Sci. 2022
for a simple fistula, but no placebo-controlled trial has been Mar;67(3):1018–35.
Kornbluth A, Sachar DB; Practice Parameters Committee of the American Crohn’s disease after ileocolonic resection. Gastroenterology. 2016
College of Gastroenterology. Ulcerative colitis practice guidelines in Jun;150(7):1568–78.
adults: American College of Gastroenterology, Practice Parameters Sandborn WJ, Feagan BG, D’Haens G, Wolf DC, Jovanovic I, Hanauer
Committee. Am J Gastroenterol. 2010 Mar;105(3):501–23. SB, et al. Ozanimod as induction and maintenance therapy for ulcera-
Lichtenstein GR, Feagan BG, Cohen RD, Salzberg BA, Diamond RH, tive colitis. N Engl J Med. 2021 Sep;385(14):1280–91.
Price S, et al. Serious infection and mortality in patients with Crohn’s Sandborn WJ, Ghosh S, Panes J, Schreiber S, D’Haens G, Tanida S, et al.
disease: more than 5 years of follow-up in the TREAT registry. Am J Efficacy of upadacitinib in a randomized trial of patients with active
Gastroenterol. 2012 Sep;107(9):1409–22. ulcerative colitis. Gastroenterology. 2020 Jun;158(8):2139–49.
Lichtenstein GR, Hanauer SB, Sandborn WJ; Practice Parameters Sandborn WJ, Su C, Sands BE, D’Haens GR, Vermeire S, Schreiber S,
Committee of American College of Gastroenterology. Management of et al. Tofacitinib as induction and maintenance therapy for ulcerative
Crohn’s disease in adults. Am J Gastroenterol. 2009 Feb;104(2):465–83. colitis. N Engl J Med. 2017 May;376(18):1723–36.
Ng SW, Mahadevan U. Management of inflammatory bowel disease in Sands BE, Sandborn WJ, Panaccione R, O’Brien CD, Zhang H, Johanns
pregnancy. Expert Rev Clin Immunol. 2013 Feb;9(2):161–73. J, et al. Ustekinumab as induction and maintenance therapy for ulcer-
Pineton de Chambrun G, Peyrin-Biroulet L, Lemann M, Colombel JF. ative colitis. N Engl J Med. 2019 Sep;381(13):1201–14.
Clinical implications of mucosal healing for the management of IBD. Shen B. Acute and chronic pouchitis: pathogenesis, diagnosis and
Nat Rev Gastroenterol Hepatol. 2010 Jan;7(1):15–29. treatment. Nat Rev Gastroenterol Hepatol. 2012 Apr;9(6):323–33.
Regueiro M, Feagan BG, Zou B, Johanns J, Blank MA, Chevrier M, Wiese DM, Schwartz DA. Managing perianal Crohn’s disease. Curr
et al. Infliximab reduces endoscopic, but not clinical, recurrence of Gastroenterol Rep. 2012 Apr;14(2):153–61.
17
Inflammatory Bowel Disease: Extraintestinal

Manifestations and Colorectal Cancer
KEVIN P. QUINN, MD
LAURA E. RAFFALS, MD
Ulcerative colitis (UC) and Crohn disease (CD) are inflamma- arthritis can precede the diagnosis of IBD by many years. IBD
tory disorders that affect the gastrointestinal tract. However, these arthropathies are seronegative (negative for rheumatoid factor).
diseases are systemic disorders that may involve other organ The prevalence of peripheral and axial arthritis is similar in CD
systems. Extraintestinal manifestations can affect any organ and UC (5%-20%). However, inflammatory joint disease is more
system, and while in many cases these symptoms are believed common in patients who have CD with colonic involvement than
to be a result of the underlying intestinal inflammation, some in patients who have other CD phenotypes. IBD arthropathy also
extraintestinal manifestations are independent of the luminal appears to be less common in patients with ulcerative proctitis.
disease course. Extraintestinal manifestations may precede the
diagnosis of inflammatory bowel disease (IBD). Many patients
Peripheral Arthropathy
who have extraintestinal manifestations have colonic disease,
and in persons with 1 extraintestinal manifestation, another Patients with peripheral arthropathy have pain, increased local
extraintestinal symptom is more likely to develop. temperature, joint swelling, and stiffness. These patients gener-
This chapter reviews the most common extraintestinal ally have joint stiffness that improves with activity; this feature
manifestations, their relation to luminal disease activity, and their helps to differentiate IBD-associated arthropathy from osteoar-
treatment. Patients with IBD with colonic involvement (UC or thritis. Plain radiographs of involved joints typically do not show
CD involving the colon) are at increased risk for colorectal cancer
(CRC). This chapter also reviews risk factors associated with
CRC and provides guidelines for surveillance measures.
Box 17.1. Bone and Joint Manifestations of
Inflammatory Bowel Disease
Musculoskeletal Manifestations Spondyloarthropathy
Musculoskeletal symptoms (pain) are the most common Axial skeleton
extraintestinal manifestations of IBD, affecting up to 53% of Sacroiliitis
patients who have IBD (Box 17.1). Arthritis can affect the spine, Ankylosing spondylitis
the sacroiliac joints, or the peripheral joints. Peripheral and axial Peripheral
Type 1 (oligoarticular)
Type 2 (polyarticular) (rare)
Abbreviations: CD, Crohn disease; COX-2, cyclooxygenase 2; CRC, Metabolic bone diseases
colorectal cancer; DEXA, dual energy x-ray absorptiometry; EN, ery- Osteoporosis or osteopenia
thema nodosum; HLA, human leukocyte antigen; IBD, inflammatory
Osteomalacia (rare)
bowel disease; NSAID, nonsteroidal anti-inflammatory drug; PG, pyo-
derma gangrenosum; PSC, primary sclerosing cholangitis; TNF, tumor Osteonecrosis (rare)
necrosis factor; UC, ulcerative colitis; UDCA, ursodeoxycholic acid
199
destructive changes. Peripheral arthritis associated with IBD is Treatment of sacroiliitis is guided by the patient’s symptoms.
divided into 2 subtypes. Asymptomatic patients who have normal spinal mobility and
Type 1 peripheral arthritis is pauciarticular, involving fewer than who test negative for HLA-B27 do not need specific therapy.
5 joints. Larger joints are generally involved, and knees are the most However, symptomatic patients should be referred to a phys-
commonly involved joints. This arthritis is associated with disease ac- ical therapist and monitored for disease progression. First-line
tivity, generally in parallel with the severity of the luminal symptoms, therapy for ankylosing spondylitis is physical therapy and use of
and is also associated with other extraintestinal manifestations. Type NSAIDs, which have been shown to prevent radiographic pro-
1 peripheral arthritis is self-limited and typically resolves within 1 to gression of disease. COX-2 inhibitors are the preferred NSAID
2 months or as the bowel symptoms resolve. because they carry a lower risk of exacerbating underlying IBD.
Patients with type 2 peripheral arthritis have a polyarticular Treatment of ankylosing spondylitis has improved dramati-
arthritis (affecting ≥5 joints) that is independent of IBD activity. cally over recent years with the introduction of TNF antagonists.
The severity of type 2 peripheral arthritis is also independent of TNF antagonists have been shown to induce remission, par-
IBD severity. Smaller joints, such as metacarpophalangeal joints, ticularly in the earlier stages of ankylosing spondylitis; there-
are typically involved, and generally the distribution is sym- fore, TNF antagonists are preferred when NSAIDs have not
metrical. This is a chronic arthritis that can last years. Type 2 helped. The opportunity to treat and prevent disease progression
peripheral arthritis may be associated with uveitis, but it is not highlights the importance of early detection of ankylosing spon-
associated with other extraintestinal manifestations. dylitis. As with peripheral arthritis, the utility of vedolizumab for
Treatment of type 1 peripheral arthritis is generally aimed treating axial arthritis in IBD appears limited. Colectomy also has
at treating the underlying bowel disease. Nonsteroidal anti- no effect on axial arthritis.
inflammatory drugs (NSAIDs) may provide symptomatic relief,
although they are not commonly used because of the risk of flaring
Osteoporosis
bowel inflammation. Alternatively, cyclooxygenase 2 (COX- 2)
inhibitors may provide symptomatic relief and are less likely to Osteoporosis is common in patients with IBD, with a prevalence
worsen underlying IBD. Sulfasalazine, with its antiarthritic sulfa- rate of 22% to 70%. The overall fracture risk in IBD patients is
pyridine moiety, may provide some relief of arthritic symptoms. 40% higher than in the general population. Common risk factors
Methotrexate has also been used for the treatment of IBD-associated in this patient population include frequent use of corticosteroids,
arthropathy. A short course of corticosteroids can be considered for decreased physical activity, inflammation leading to increased
more immediate relief. In refractory cases, tumor necrosis factor cytokine release (interleukin 1, interleukin 6, and TNF-α) and
(TNF) antagonists may help relieve symptoms of peripheral ar- thereby contributing to bone resorption, malabsorption of cal-
thritis. Tofacitinib and ustekinumab may also have some efficacy cium and magnesium, vitamin D deficiency, and ileal resection.
in relieving symptoms of type 1 peripheral arthritis. Conversely, Patients who have been treated with corticosteroids for more than
vedolizumab, a gut-specific monoclonal antibody directed against 3 months or who have had recurrent courses of corticosteroids
α4β7 integrin, appears ineffective for treating peripheral arthritis. should be evaluated for osteoporosis. The diagnostic standard for
bone density measurement is dual energy x-ray absorptiometry
(DEXA). Patients who have a low-trauma or fragility fracture,
Axial Arthropathy patients with hypogonadism, postmenopausal women, and men
Axial arthritis is also associated with IBD but is independent of older than 50 years should also undergo DEXA. Despite the prev-
IBD disease activity. Sacroiliitis, which is often asymptomatic, alence rate of osteoporosis in patients with IBD, only 23% of
is more common than ankylosing spondylitis, which is present patients who have IBD and are at risk for osteoporosis undergo
in only 1% to 6% of patients with IBD. Men tend to be affected screening, which highlights the need for attention to this preven-
more commonly than women, although less than previously tive measure.
believed. More recent studies show a 2:1 to 3:1 male to female
ratio, compared with earlier studies that showed a 5:1 to 6:1 ratio. ✓ Two types of peripheral arthritis associated with IBD
Axial joint disease should be suspected if patients have in- • Type 1—affects fewer than 5 joints, typically involves larger
flammatory back pain. Inflammatory back pain is a clinical joints (knees are most common), and is associated with luminal
disease activity
diagnosis based on a history of back pain of insidious onset be-
• Type 2—affects 5 or more joints, typically involves smaller
fore the age of 40 to 45 years, pain with stiffness that improves joints with symmetrical distribution (joints of hands commonly
with exercise, pain that is not relieved with rest, and pain that involved), and is independent of IBD activity
has been present for at least 3 months. Axial arthritis is typically ✓ Axial arthritis is independent of IBD activity
classified as sacroiliitis or ankylosing spondylitis. Sacroiliitis is ✓ Treatment of axial arthropathies, including ankylosing spondylitis
more common and often remains undiagnosed. The majority of • First-line therapy—physical therapy and NSAIDs (preferably
the patients are asymptomatic. Sacroiliitis is detected in 24% of COX-2 inhibitors)
asymptomatic IBD patients who undergo magnetic resonance • If no response to initial therapy—TNF antagonists
imaging. In a subset of patients with sacroiliitis, the disease ✓ Indications for osteoporosis screening for patients with IBD—
progresses and ankylosing spondylitis develops. Patients with recurrent or persistent corticosteroid use (>3 months), low-trauma
or fragility fracture, hypogonadism, postmenopausal woman, or
sacroiliitis who test positive for human leukocyte antigen (HLA)-
man older than 50 years
B27 have a greater risk for progression to ankylosing spondylitis.
Sacroiliitis, spinal inflammation, and enthesitis are the character-
istic features of ankylosing spondylitis. Progressive ankylosing
spondylitis is measured by the presence of new bone formation
Dermatologic Manifestations
(syndesmophytes) and ankylosis of the sacroiliac joints and ver- Dermatologic manifestations are present in 10% of patients
tebral column. Patients with ankylosing spondylitis may have when IBD is diagnosed (Box 17.2). The incidence of skin
limited spinal mobility and decreased chest expansion. conditions increases over time among patients with CD and UC.
17. Inflammatory Bowel Disease: Extraintestinal Manifestations and Colorectal Cancer 201
Box 17.2. Dermatologic Manifestations of

Common
Pyoderma gangrenosum
Erythema nodosum
Cutaneous (“metastatic”) Crohn disease
Aphthous stomatitis
Less common
Bowel-associated dermatosis-arthritis syndrome
(bowel bypass syndrome)
Sweet syndrome (acute neutrophilic dermatosis)
Epidermolysis bullosa acquisita
Mucosal cobblestoning of buccal mucosa
and palate
Pyostomatitis vegetans
The most common dermatologic manifestations of IBD are er-

ythema nodosum (ED), pyoderma gangrenosum (PG), and oral
ulcerations. Metastatic CD and Sweet syndrome are less com-
monly associated with IBD.
EN is the most common cutaneous lesion in patients with
IBD. It occurs as deep, tender nodules on the extensor surfaces
of the lower extremities, although these lesions can also occur
on the arms and trunk. EN typically parallels bowel disease ac-
tivity, and treatment is directed toward the underlying IBD. In
patients with severe or refractory disease, corticosteroids can
Figure 17.1. Pyoderma Gangrenosum Involving Peristomal Skin.
be helpful. EN is associated with conditions other than IBD,
including Behçet syndrome and sarcoidosis. EN has also been
described in patients with various infections, including Yersinia Metastatic CD is a rare skin manifestation of IBD that is
infection, tuberculosis, coccidioidomycosis, histoplasmosis, characterized by ulcerating nodules typically present on the an-
and blastomycosis. terior abdominal wall, submammary area, arms, legs, or perianal
PG is a painful, ulcerating skin disorder that typically region. Biopsy specimens from these lesions show noncaseating
manifests initially as a pustule, papule, or nodule that eventually granulomas. The lesions may or may not parallel luminal activity.
breaks down into an ulcer with violaceous, undermined borders. If luminal activity is present, treatment of the underlying IBD
These lesions are most commonly encountered on the lower is generally helpful. Corticosteroids and immunosuppressives
extremities or peristomal region, but because this skin condition may also help alleviate these lesions. Case reports have described
is pathergic (similar to Behçet syndrome), these lesions can occur successful treatment of metastatic CD with metronidazole.
in any area that is frequently traumatized (Figure 17.1). PG may Sweet syndrome, also associated with IBD, occurs as raised,
or may not parallel disease activity. Because PG may be asso- tender nodules on the face, arms, or trunk (Figure 17.3). Patients
ciated with active IBD, it is important to treat any underlying
bowel inflammation when managing this condition. In addition
to receiving therapy for active IBD, patients generally require
therapy with corticosteroids at a high dose that is tapered. Topical
tacrolimus can also be helpful in treating these lesions. Milder
cases can be managed with dapsone. Despite these measures,
PG can be extremely difficult to treat. Other treatments that can
be considered for difficult-to-treat lesions include cyclosporine,
tacrolimus, azathioprine, and anti–TNF-α agents. Vedolizumab
appears to be less effective. Surgical measures should be avoided
because of the risk of exacerbating the lesion or inducing new
lesions from pathergy.
Oral lesions (aphthous stomatitis) are relatively common in
patients with IBD, affecting 10% of patients with UC and 20%
to 30% of patients with CD. Typical lesions are indistinguishable
from canker sores, and often these lesions resolve when the un-
derlying IBD is treated (Figure 17.2). Treatment is symptomatic.
Topical anesthetics may be helpful. In some instances, a topical
corticosteroid can be applied for more immediate relief. Figure 17.2. Aphthous Ulcers of the Lower Lip.
therefore, it is reasonable to refer all patients who have IBD

with ocular manifestations to an ophthalmologist for evaluation.
Treatment is aimed at controlling the underlying bowel disease,
but oral and topical corticosteroids are often required.
Anterior uveitis (iritis) is associated with other extraintestinal
manifestations, including peripheral and axial arthritis and
dermatologic manifestations (particularly EN). Test results are
positive for HLA-B27 in approximately 50% of patients who
have the acute form of uveitis. In these patients, uveitis does not
always parallel disease activity. It is associated with eye pain,
redness, visual blurring, photophobia, and headaches. This con-
dition should also prompt a referral to an ophthalmologist since
untreated uveitis can lead to complications such as cataracts or
glaucoma. Characteristic findings on examination include a cil-
iary flush (intense redness in the center of the eye that lessens
in intensity peripherally). Slit-lamp examination shows corneal
Figure 17.3. Sweet Syndrome Involving the Lower Extremity.
clouding and conjunctival injection. Treatment consists of oral
and topical corticosteroids. Anti–TNF-α agents have been used
also have constitutional symptoms, including fever. Biopsy for refractory cases.
specimens from these lesions show intense neutrophilic infiltrates Ocular complications may also develop from medical therapy
without underlying vasculitis. Treatment includes corticosteroids for IBD. Prolonged courses of corticosteroids can lead to the
and treatment of the underlying IBD. development of cataracts and glaucoma. Patients who have re-
ceived long courses of corticosteroids should undergo regular
✓ Erythema nodosum examinations by an ophthalmologist.
• Most common skin lesion in IBD
• Tender, subcutaneous nodules on extensor surfaces of lower ✓ Episcleritis
extremities • Eye redness and irritation or burning without a change in vision
• Parallels IBD activity • Parallels IBD activity and resolves with treatment of under-
✓ Pyoderma gangrenosum lying bowel inflammation
• Painful, violaceous skin ulcerations with irregular borders ✓ Eye redness or pain and a change in vision in a patient with IBD
• Often preceded by trauma warrants immediate ophthalmologic evaluation for scleritis or an-
• May or may not parallel IBD disease activity terior uveitis
Ocular Manifestations Hepatobiliary and Pancreatic Manifestations

Ocular manifestations of IBD are present in up to 5% of patients The most common hepatobiliary manifestation of IBD is primary
(Box 17.3). Most patients with ocular symptoms have colonic in- sclerosing cholangitis (PSC) (Box 17.4). PSC is an idiopathic,
volvement of IBD. Episcleritis is the most common ocular com- chronic inflammatory disorder of the biliary tree. The inflamma-
plication and parallels IBD activity. Patients with episcleritis tory process can result in stricturing and fibrosis of the medium-
present with acute redness in 1 or both eyes and a sensation of sized and large intrahepatic and extrahepatic bile ducts, which
irritation or burning of the eye. No change in vision is associated leads to the classic “beads-on-a-string” finding on endoscopic or
with this ocular manifestation. Episcleritis generally resolves magnetic resonance cholangiography. A strong association exists
with treatment of the underlying bowel disease, although topical between PSC and IBD. Although only 2% to 7% of patients with
corticosteroids can be helpful.
Scleritis, a more severe ocular manifestation, may impair
vision and warrants immediate evaluation by an ophthalmolo-
gist. The clinical presentation of scleritis is similar to episcleritis;
Box 17.4. Hepatobiliary Manifestations of
Biliary
Primary sclerosing cholangitis (large duct)
Box 17.3. Ocular Manifestations of Inflammatory Small duct primary sclerosing cholangitis (formerly
Bowel Disease known as pericholangitis)
Inflammatory Cholelithiasis or choledocholithiasis
Anterior uveitis (iritis) Cholangiocarcinoma (rare)
Scleritis Primary biliary cirrhosis (rare)
Episcleritis Hepatic
Retinitis (rare) Fatty liver or steatohepatitis
Treatment-related (corticosteroids) Autoimmune hepatitis
Cataracts Drug-induced liver injury (thiopurines, methotrexate,
Glaucoma 5-aminosalicylates)
UC have PSC, up to 80% of patients with PSC have IBD, most

commonly UC. Patients often have mild pancolitis, although Box 17.5. Miscellaneous Extraintestinal Manifestations
patients with PSC-associated colitis may also have rectal sparing and Complications of Inflammatory Bowel Disease
or predominantly right-sided colitis with backwash ileitis. This Renal
pattern of inflammation is most likely a unique PSC phenotype Nephrolithiasis (oxalate, urate)
of IBD. The majority of patients (approximately 80%) have
Glomerulonephritis (rare)
positive test results for perinuclear antineutrophil cytoplasmic
autoantibody. Right ureteral obstruction
PSC is often diagnosed after the onset of IBD, although Urinary system fistulas (eg, enterovesical, colovesical,
PSC may develop years before the onset of bowel symptoms. rectourethral)
The disease course of PSC is independent of IBD activity. PSC Tubulointerstitial nephritis (5-aminosalicylates)
is typically a progressive disease leading to end-stage liver Secondary amyloidosis
disease. The median survival time after diagnosis is 12 years. Hematologic
Patients with advanced disease may present with pruritus or
Anemia
jaundice. Earlier in the disease course, patients may be asymp-
Iron deficiency
tomatic and present with findings of mildly abnormal levels
of liver enzymes. Any patient with IBD and evidence of Vitamin B12 deficiency
cholestasis (high alkaline phosphatase level) warrants further Folic acid deficiency
evaluation to exclude a diagnosis of PSC. Patients with PSC Anemia of chronic disease
have an increased risk of cholangiocarcinoma, even in the ab- Autoimmune hemolytic anemia
sence of cirrhosis. The risk of CRC is also increased in this Neoplastic
patient population, so annual surveillance colonoscopies are Myelodysplastic syndrome (rare)
recommended.
Promyelocytic leukemia (rare)
No effective medical therapies are available for PSC.
Therapeutic trials of ursodeoxycholic acid (UDCA) have yielded Cardiopulmonary
inconsistent results. High dosages of UDCA (25-30 mg/kg daily) Pericarditis (extraintestinal manifestation or
may actually be harmful and should be avoided. Liver transplant drug-induced)
is often an effective therapy for PSC, but PSC can recur after Myocarditis
transplant. Conduction abnormalities
Although rare, autoimmune hepatitis is associated with IBD. Pneumonitis
An overlap syndrome of autoimmune hepatitis and PSC is
Eosinophilic pneumonia
also recognized. The serologic findings are characteristic of
autoimmune hepatitis (high levels of antinuclear antibodies, Cryptogenic organizing pneumonia
smooth muscle antibodies, and immunoglobulin G), and the Bronchiectasis, bronchiolitis, bronchitis, and subglottic
cholangiographic findings are typical of PSC. stenosis
Cholelithiasis is more common in patients with IBD than in Pancreatic
the general population. Patients with ileal CD (active inflamma- Acute pancreatitis
tion of the terminal ileum or resection of the ileum) are at par- Drug-induced (purine analogues,5-aminosalicylates)
ticular risk for cholelithiasis due to interruption of enterohepatic Duodenal Crohn disease
cycling of bile salts leading to disruption of the processing of Granulomatous involvement of pancreas (rare)
cholesterol and phospholipids. Cholesterol stones may form in
Chronic pancreatitis
these patients.
Pancreatitis also occurs in patients with IBD. Pancreatitis is Autoimmune pancreatitis
an adverse effect of thiopurine therapy and a less common ad- Thrombophilia
verse effect of 5-aminosalicylic acid or corticosteroid therapy. In Multifactorial
patients with CD involving the duodenum, pancreatitis may de-
velop if active disease disrupts the drainage of pancreatic juices
into the bowel. In patients with CD, a granulomatous inflamma-
tory process can involve the pancreas. Nephrolithiasis is a recognized problem for patients with
CD, particularly ileal CD. Disease or resection of the terminal
✓ Up to 80% of patients with PSC have IBD, most commonly UC ileum leads to bile salt malabsorption, and, in patients with ex-
✓ Any patient with IBD and a high alkaline phosphatase level tensive disease or resection, fat malabsorption. In patients with
warrants evaluation for PSC, with magnetic resonance cholangio
fat malabsorption, free calcium binds to fatty acids rather than
pancreatography being the test of choice
✓ Causes of pancreatitis in IBD oxalate within the intestinal lumen. The oxalate is then absorbed,
• Medications (thiopurines more often than 5-aminosalicylates) leading to increased urinary oxalate excretion and a risk of cal-
• Active CD involving the duodenum cium oxalate stone formation. In patients who have less extensive
• Autoimmune pancreatitis involvement of the terminal ileum and subsequent bile salt mal-
absorption, increased colonic permeability to small molecules
develops from the exposure of the bile salts to the colonic epi-
thelium. This increased permeability leads to absorption of oxa-
Miscellaneous Complications
late and increased urinary oxalate excretion. In patients with IBD,
Patients with IBD may have various miscellaneous extraintestinal uric acid stones may also develop as a result of hypovolemia and
manifestations and complications (Box 17.5). metabolic acidosis from diarrhea.
Secondary amyloidosis is a rare complication of many inflam-

matory diseases, including IBD. This complication more com- Box 17.6. Risk Factors for Colorectal Cancer in
monly affects patients with CD rather than UC. Patients may Inflammatory Bowel Disease
present with proteinuria or kidney failure. Treatment is aimed Extent of colitis
at the underlying bowel disease, but in some instances, kidney Duration of disease
transplant may improve survival.
Family history of colorectal cancer
Patients receiving 5- aminosalicylate therapy should be
monitored for interstitial nephritis, a rare idiosyncratic reaction Primary sclerosing cholangitis
to this class of medication. Kidney function should be monitored Medical nonadherence or lack of follow-up
on a regular basis in these patients. No use or minimal use of sulfasalazine or
Thromboembolism is also a complication of IBD. Compared 5-aminosalicylates
with the general population, patients with IBD have a 3-fold risk
of deep vein thrombosis or pulmonary embolism. IBD is a risk
factor for venous thromboembolism, whereas neither rheumatoid
arthritis nor celiac disease increases the risk of thromboembo- or prior dysplasia) should undergo annual colonoscopies. The
lism. One-third of IBD patients with a venous thromboembolism American Gastroenterological Association recommends colon-
have no risk factors for thromboembolism except a diagnosis oscopy every 1 to 3 years, with more frequent colonoscopies for
of IBD. Thromboembolic events are most common in patients patients at higher risk.
with active disease but can also occur in patients with disease Surveillance guidelines were developed with patients with
in partial or full remission. Prevention is of utmost importance. UC in mind. However, patients with CD involving the colon
All acquired risk factors for thrombosis should be addressed with also have an increased risk for neoplasia. Risk factors for neo-
any patient who has IBD. Effective treatment of luminal disease, plasia include younger age at diagnosis, longer disease course,
maintenance of hydration, mobilization, treatment of vitamin and greater intervals between colonoscopies. For all practical
deficiencies (folate, vitamins B12 and B6), and prophylaxis for purposes, patients with CD involving more than one-third of the
high-risk patients should be instituted. The American College of colon are considered to have a CRC risk that is similar to the risk
Chest Physicians recommends pharmacologic prophylaxis for for patients with UC.
any acutely ill hospitalized patient with IBD. Sequential com- Patients who have flat, high-grade dysplasia have a high risk
pression devices should be used only if pharmacologic prophy- for synchronous cancer and a great risk for a CRC diagnosis at
laxis is contraindicated. a subsequent examination. Given the high risk for CRC among
these patients, colectomy is the standard of care. There is some
✓ All acutely ill hospitalized patients with IBD have an increased debate on the most appropriate management when patients have
risk for thromboembolism and should receive pharmacologic flat, low-grade dysplasia. Colectomy is often offered to these
prophylaxis patients as well, but in some situations, patients are monitored
closely with surveillance colonoscopies every 3 to 6 months with
or without chromoendoscopy. The management of polypoid dys-
plasia also varies among practicing physicians. In the absence
Colorectal Cancer
of flat dysplasia in the mucosa surrounding the lesion, polypoid
Patients with IBD involving the colon have an increased risk for lesions may be removed endoscopically with close follow-up.
CRC compared with the general population (Box 17.6). This risk
increases as the duration of disease increases, with an estimated ✓ Surveillance colonoscopies should begin 8 years after diagnosis
incidence rate of 18% after 30 years of disease in patients with for patients with either of the following:
UC. Methods to identify patients at greatest risk for CRC are im- • UC extending beyond the rectum
• CD involving more than one-third of the colon
perfect. The current standard surveillance program includes mul-
✓ Patients with PSC should undergo screening colonoscopy yearly

tiple random biopsies obtained throughout the colon at regularly
scheduled intervals. This approach has been the preferred method
of surveillance for the past 30 years. Chromoendoscopy is also an
effective surveillance tool in the IBD population, but it is tedious Suggested Reading
and time-consuming, and it is not performed by most endoscopists. Bennett AN, McGonagle D, O’Connor P, Hensor EM, Sivera F, Coates
Furthermore, the benefit of chromoendoscopy compared with LC, et al. Severity of baseline magnetic resonance imaging-evident
targeted biopsies using high-definition colonoscopes has yet to be sacroiliitis and HLA-B27 status in early inflammatory back pain pre-
determined. As technology advances, strategies to detect neoplasia dict radiographically evident ankylosing spondylitis at eight years.
in patients with long-standing colitis will continue to evolve. Arthritis Rheum. 2008 Nov;58(11):3413–8.
The risk of CRC increases with the extent of disease and dis Chedid VG, Kane SV. Bone health in patients with inflammatory bowel
ease duration. Generally, initiation of surveillance colonoscopies diseases. J Clin Densitom. 2020 Apr-Jun;23(2):182–9.
should begin 8 to 10 years after diagnosis. Patients with disease Dubinsky MC, Cross RK, Sandborn WJ, Long M, Song X, Shi N, et al.
limited to the rectum do not have an increased risk for CRC and Extraintestinal manifestations in vedolizumab and anti-TNF-treated
patients with inflammatory bowel disease. Inflamm Bowel Dis. 2018
do not need to undergo surveillance colonoscopies. A minimum
Aug 16;24(9):1876–82.
of 32 biopsies should be obtained throughout the colon, and many Farraye FA, Melmed GY, Lichtenstein GR, Kane SV. ACG clinical
experts advocate 4-quadrant biopsies every 10 cm, with targeted guideline: preventive care in inflammatory bowel disease. Am J
biopsies of suspicious lesions. Gastroenterol. 2017 Feb;112(2):241–58.
The recommendations for interval surveillance colonoscopies Garber A, Regueiro M. Extraintestinal manifestations of inflammatory
vary among professional societies. There is agreement that bowel disease: epidemiology, etiopathogenesis, and management.
patients with the highest risk for CRC (eg, patients with PSC Curr Gastroenterol Rep. 2019 May 16;21(7):31.
Hagen JW, Swoger JM, Grandinetti LM. Cutaneous manifestations of colitis in remission: a randomized, placebo-controlled, pilot study.
Crohn disease. Dermatol Clin. 2015 Jul;33(3):417–31. Clin Gastroenterol Hepatol. 2006 Feb;4(2):203–11.
Hannuksela M. Human yersiniosis: a common cause of erythematous Shah J, Shah A, Hassman L, Gutierrez A. Ocular manifestations of inflam-
skin eruptions. Int J Dermatol. 1977 Oct;16(8):665–6. matory bowel disease. Inflamm Bowel Dis. 2021 Oct 20;27(11):1832–8.
Koutroumpakis EI, Tsiolakidou G, Koutroubakis IE. Risk of venous Tavarela Veloso F. Review article: Skin complications associated with
thromboembolism in patients with inflammatory bowel disease. inflammatory bowel disease. Aliment Pharmacol Ther. 2004 Oct;20
Semin Thromb Hemost. 2013 Jul;39(5):461–8. Suppl 4:50–3.
Lichtenstein GR, Loftus EV, Isaacs KL, Regueiro MD, Gerson LB, Umit H, Asil T, Celik Y, Tezel A, Dokmeci G, Tuncbilek N, et al. Cerebral
Sands BE. ACG clinical guideline: management of Crohn’s disease sinus thrombosis in patients with inflammatory bowel disease: a case
in adults. Am J Gastroenterol. 2018 Apr;113(4):481–517. report. World J Gastroenterol. 2005 Sep 14;11(34):5404–7.
Lofgren S. False positive seroreactions for syphilis in connection with Vavricka SR, Brun L, Ballabeni P, Pittet V, Prinz Vavricka BM, Zeitz J, et
erythema nodosum. Acta Derm Venereol. 1946 Jan;26:243–60. al. Frequency and risk factors for extraintestinal manifestations in the
Loftus EV, Jr., Harewood GC, Loftus CG, Tremaine WJ, Harmsen WS, Swiss inflammatory bowel disease cohort. Am J Gastroenterol. 2011
Zinsmeister AR, et al. PSC-IBD: a unique form of inflammatory Jan;106(1):110–9.
bowel disease associated with primary sclerosing cholangitis. Gut. Vavricka SR, Rogler G, Gantenbein C, Spoerri M, Prinz Vavricka
2005 Jan;54(1):91–6. M, Navarini AA, et al. Chronological order of appearance of
Mahadevan U, Loftus EV, Jr., Tremaine WJ, Sandborn WJ. Safety of se- extraintestinal manifestations relative to the time of IBD diagnosis
lective cyclooxygenase-2 inhibitors in inflammatory bowel disease. in the Swiss inflammatory bowel disease cohort. Inflamm Bowel Dis.
Am J Gastroenterol. 2002 Apr;97(4):910–4. 2015 Aug;21(8):1794–800.
Queiro R, Maiz O, Intxausti J, de Dios JR, Belzunegui J, Gonzalez C, Weismuller TJ, Trivedi PJ, Bergquist A, Imam M, Lenzen H, Ponsioen
et al. Subclinical sacroiliitis in inflammatory bowel disease: a clinical CY, et al. Patient age, sex, and inflammatory bowel disease phe-
and follow-up study. Clin Rheumatol. 2000 19(6):445–9. notype associate with course of primary sclerosing cholangitis.
Rubin DT, Ananthakrishnan AN, Siegel CA, Sauer BG, Long MD. ACG Gastroenterology. 2017 Jun;152(8):1975–84.
clinical guideline: Ulcerative colitis in adults. Am J Gastroenterol. Wester AL, Vatn MH, Fausa O. Secondary amyloidosis in inflamma-
2019 Mar;114(3):384–413. tory bowel disease: a study of 18 patients admitted to Rikshospitalet
Sandborn WJ, Stenson WF, Brynskov J, Lorenz RG, Steidle GM, University Hospital, Oslo, from 1962 to 1998. Inflamm Bowel Dis.
Robbins JL, et al. Safety of celecoxib in patients with ulcerative 2001 Nov;7(4):295–300.
18
Intestinal Infectionsa
SAHIL KHANNA, MBBS, MS
Intestinal infections are common. An estimated 180 million Another infection of the colon, acute diverticulitis, is common in
illnesses occur annually in the US and over 1 billion cases of in- adults older than 50 years.
fectious diarrhea occur annually worldwide. Despite advances in This chapter discusses common viral, bacterial, and protozoal
diagnosis, supportive care, and antibiotic guidance, the mortality enteric infections; C difficile infections (CDIs) in particular; and
from these infections remains extremely high, especially in the diverticulitis.
pediatric age group. Some estimates indicate that enteric infec-
tious diarrhea in children younger than 5 years leads to 1 death
Enteric Viral Infections
every 10 seconds. Infectious diarrhea from enteric pathogens is
more common in children and in resource-limited countries than In the US, most cases of gastroenteritis are viral and are usu-
in adults in industrialized countries. The clinical features of in- ally brief and self- limited. Viral gastroenteritis typically is
fectious diarrhea vary, depending on whether the organism is in- characterized by diarrhea with a brief duration and is often associ-
vasive and whether the infection occurs in the small bowel or ated with nausea and vomiting; affected persons do not have high
colon. Patients with small-bowel diarrhea have middle or diffuse fever, severe abdominal pain, or bloody diarrhea. Management
abdominal pain and large-volume watery diarrhea. Patients with is symptomatic with hydration, antiemetics, and antipyretics if
colonic infections typically have lower abdominal or rectal pain, needed.
and the stool is mucoid or bloody; the volume of stool is often
small. Most pathogens are managed with supportive treatment, Rotavirus
and antibiotics are indicated in a few instances. Infection from
an anaerobic pathogen, Clostridioides difficile, is more common Rotavirus, an enteric adenovirus, is a common cause of diarrhea
in industrialized countries than in resource- limited countries. in young children worldwide; the incidence has been decreasing
since the introduction of the rotavirus vaccine. Adult infections
are often the result of contact with a sick child or as part of a
a
I acknowledge the contributions of Conor G. Loftus, MD, author of local epidemic. Rotavirus infections occur year-round in tropical
“Gastrointestinal Infections, Clostridium difficile–Associated Disease, climates, whereas in temperate climates, the infections are more
and Diverticular Disease,” in previous editions of this text.
common in winter. Spread is by fecal-oral contamination, which
Abbreviations: CDI, Clostridioides difficile infection; EAEC, entero is promoted by prolonged survival in the environment along with
aggregative Escherichia coli; EHEC, enterohemorrhagic Escherichia resistance to many disinfectants. Typically, symptoms (mild fever,
coli; EIA, enzyme immunoassay; EIEC, enteroinvasive Escherichia
diarrhea, vomiting) occur within 72 hours after exposure and can
coli; EPEC, enteropathogenic Escherichia coli; ETEC, enterotoxigenic
Escherichia coli; FDA, US Food and Drug Administration; FMT, fecal last up to 5 days. Most adults are mildly symptomatic or asymp-
microbiota transplant; GDH, glutamate dehydrogenase; HLA, human tomatic, but the disease can be severe if the person is immuno-
leukocyte antigen; HUS, hemolytic uremic syndrome; PCR, polymerase compromised or malnourished or has multiple comorbidities.
chain reaction; TMP-SMX, trimethoprim-sulfamethoxazole; TTP, Diagnosis is made from a stool test (rather than a rectal swab)
thrombotic thrombocytopenic purpura that uses an enzyme immunoassay or a polymerase chain reaction
207
(PCR) test. Treatment focuses on rehydration, and oral rehydra- Coronavirus

tion is optimal because oral nutrition stimulates mucosal repair,
The novel SARS- CoV-2 is a respiratory pathogen that also
shortens the duration, and lessens the severity of the illness. Use
causes gastrointestinal symptoms because of the presence of
of antivirals is not recommended. Very young or elderly persons
angiotensin-converting enzyme 2 receptors in the intestines. The
can die of dehydration and acidosis. Symptoms may be pro-
nucleocapsid protein of this virus is present in gastric, duodenal,
longed because of a transient disaccharidase deficiency caused by
and rectal glandular epithelial cells. The viral RNA is found in
damage to small-bowel epithelial cells, with a resultant decrease
esophageal, gastric, duodenal, and rectal biopsies from patients
in brush border enzymes.
who have severe disease. About 50% of patients have detectable
Protective immunity may not develop after natural infections,
viral RNA and live virus in the stool, but the infectious potential
although reinfection tends to be less severe. A rotavirus vaccine
of the stool is unclear. Gastrointestinal symptoms include diar-
has been approved for use in infants. The vaccine should be
rhea, nausea and vomiting, and abdominal pain. These symptoms
administered to all infants who do not have a contraindication.
may appear earlier than respiratory symptoms and may delay the
Two orally administered rotavirus vaccines with a live, attenu-
diagnosis.
ated virus are available in the US: a pentavalent rotavirus vaccine
(RotaTeq; Merck) given in a 3-dose schedule at ages 2, 4, and
✓ Acute infectious diarrhea
6 months or a monovalent vaccine (Rotarix; GlaxoSmithKline
• Detailed clinical and exposure history should be obtained to
Biologicals) given in a 2-dose schedule at ages 2 and 4 months. ascertain causes
In the US, rotavirus vaccination is part of the recommended im- • Patient with fever or bloody diarrhea should be evaluated for
munization schedule. enteric pathogens, especially if antimicrobial agents would be
beneficial
✓ Traveler’s diarrhea
Norovirus • If uncomplicated and unless treatment is indicated, diagnostic
Norovirus (also known as Norwalk-like virus) is a calicivirus testing is not recommended
(small round-structured viruses) and is an important cause of • If diarrhea lasts 14 days or longer, stool testing should be
viral gastroenteritis in young children and adults. Since the in- performed (including testing for parasitic infections)
troduction of the rotavirus vaccine, norovirus is now the most ✓ Multiple-pathogen nucleic acid amplification test results should
be interpreted with caution and within the appropriate clinical
common cause of viral enteritis. Outbreaks from norovirus are
context—these assays detect DNA and not necessarily viable
associated with contaminated food (eg, shellfish) or water or organisms
with person-to-person spread. Norovirus is highly contagious, ✓ Testing for fecal leukocytes or lactoferrin is typically not useful
as it has a very low infectious dose (about 20 viral particles), because of low sensitivity and specificity
and the virus can withstand a wide range of temperatures and ✓ Postinfection and extraintestinal manifestations associated with
persists on environmental surfaces, in drinking water, and in var- enteric infections are common
ious food items. Interestingly, viral shedding precedes the onset
of illness and may continue long after symptoms have subsided.
The incubation period is less than 48 hours; the illness lasts up to Enteric Bacterial Infections
3 days. Diagnosis is made with a stool PCR assay. The infection
occurs in the proximal small bowel. Symptoms include vomiting Compared to viral infections, enteric bacterial infections are rela-
and nonbloody diarrhea lasting up to 2 or 3 days. A low-grade tively uncommon causes of acute diarrhea, and the indiscriminate
fever is present during the first 24 hours in 40% of infections. culturing of stool from patients with acute diarrhea produces few
Many strains exist, and cross-protection is lacking, so repeated positive findings, with an unacceptably high cost per culture with
infections are likely. Patients who are immunosuppressed, such positive results. Stool should be tested for bacterial pathogens
as those who have received an organ transplant and are receiving if patients have fever, bloody or mucoid stools, severe abdom-
immunosuppressive therapy or those who have common vari- inal cramping or tenderness, or signs of sepsis. If patients who
able immunodeficiency, can have chronic and severe norovirus are immunocompromised are at high risk for disease but do not
infection. have fever or bloody stools, testing should be considered, es-
pecially during an outbreak. In most laboratories, routine stool
cultures detect Salmonella, Shigella, and Campylobacter. Testing
Astrovirus for Escherichia coli O157:H7, Yersinia, Vibrio, and others often
Astrovirus is an important cause of diarrhea in infants and children, requires a special request. Some PCR-based assays have the po-
particularly in resource-limited countries because malnourishment tential to detect multiple bacterial and viral pathogens with 1 test.
is a risk factor. Nausea and vomiting are less commonly reported These tests are typically known as pathogen panels and should be
than with rotavirus infection, and diarrhea is the predominant interpreted with caution because of a risk of false-positive results.
symptom. The incubation period is 2 to 4 days. Illness is usually Stool studies help guide antimicrobial use in certain instances (eg,
mild and lasts up to 5 days. Salmonella, Shigella, and some Campylobacter infections). Stool
studies may also help prevent unnecessary additional testing and
imaging and unnecessary use of antibiotics.
Enteric Adenovirus In healthy adults, many bacterial causes of diarrhea do not
Most adenoviruses cause respiratory infection, although some require antibiotic therapy. Empirical use of antimicrobials is not
strains cause diarrhea. Respiratory symptoms may precede recommended for most patients who are immunocompetent, but
gastrointestinal manifestations. Diagnosis is made with an en- it should be considered for 1) patients younger than 3 months
zyme immunoassay or a PCR test. A long incubation period who may have a bacterial infection, 2) patients who are immuno-
(up to 10 days) and diarrhea of long duration (1-2 weeks) are compromised, 3) patients who are immunocompetent and appear
characteristic. ill if Shigella infection is suspected, or 4) recent travelers who are
18. Intestinal Infections 209
febrile or have signs of sepsis. Empirical antimicrobial therapy 25% of patients. A chronic carrier state is rare. Hemolytic uremic
in adults should be either a fluoroquinolone (eg, ciprofloxacin) syndrome (HUS), reactive arthritis (human leukocyte antigen
or azithromycin, depending on the local susceptibility patterns [HLA]-B27), and Guillain-Barré syndrome can occur.
and travel history. Antibiotics should be avoided for those In most healthy patients, symptoms are mild to moderate,
with the Shiga toxin–producing E coli O157 strain because of and by the time the slow-growing Campylobacter is identified,
evidence of harm. Antimicrobial treatment should be modi- the patient’s condition has begun to improve. A PCR assay will
fied or discontinued when a clinically plausible organism is provide a rapid result. For healthy patients, antibiotic therapy
identified. Common exposures and conditions that lead to diar- is unnecessary. Antibiotics are recommended for patients who
rhea are summarized in Table 18.1. Clinical presentations that have prolonged (>1 week) or worsening symptoms, dysentery,
suggest causes of infectious diarrhea are outlined in Table 18.2; high fever, or bacteremia and for pregnant women and persons
recommended antimicrobial agents for pathogens, in Table 18.3; at risk for complications (extremes of age, immunocompromised
and common postinfection manifestations associated with enteric state, or cirrhosis). The drug of choice is azithromycin because
pathogens, in Table 18.4. of increased resistance to quinolones, which are an alternative
therapy for Campylobacter infection.
Campylobacter jejuni
Salmonella
Most enteric bacterial infections are due to Campylobacter jejuni
and typically are acquired from contaminated poultry (up to Infection with Salmonella leads to a spectrum of diseases
90% of chickens may be colonized) or unpasteurized milk in the ranging from acute gastroenteritis to typhoid fever (Table 18.5).
summer or early fall. Infection is most common in very young The infection may get complicated by bacteremia resulting
children, teens, and young adults. Fever, myalgias, malaise, ab- in disseminated infection. Salmonella typhi and Salmonella
dominal pain, and headache occur after an incubation period of 1 paratyphi cause typhoid fever. The other serotypes (about
to 4 days. Diarrhea begins later, ranges from profuse and watery 2,000 have been described) cause nontyphoidal salmonellosis.
to bloody, and lasts up to 1 week. Prolonged carriage can occur Salmonella enteritidis and Salmonella typhimurium are the 2
for several months, and recurrent infection can occur in up to serotypes most often isolated in the US.
Table 18.1. Exposures and Conditions Associated With Pathogens That Cause Diarrhea
Exposure or condition Pathogen
Foodborne outbreaks at hotels, cruise ships, resorts, Norovirus, nontyphoidal Salmonella, Clostridium perfringens, Bacillus cereus, Staphylococcus
restaurants, or catered events aureus, Campylobacter species, ETEC, STEC, Listeria, Shigella, Cyclospora cayetanensis,
Cryptosporidium species
Consumption of unpasteurized milk or dairy products Salmonella, Campylobacter, Yersinia enterocolitica, S aureus, Cryptosporidium, STEC, Listeria
(infrequently associated with diarrhea), Brucella (goat milk cheese), Mycobacterium bovis,
Coxiella burnetii
Consumption of raw or undercooked meat or poultry STEC (beef), C perfringens (beef, poultry), Salmonella (poultry), Campylobacter (poultry), Yersinia
(pork, chitterlings), S aureus (poultry), Trichinella species (pork, wild game meat)
Consumption of fruits or unpasteurized fruit juices, STEC, nontyphoidal Salmonella, Cyclospora, Cryptosporidium, Norovirus, hepatitis A virus,
vegetables, leafy greens, or sprouts Listeria monocytogenes
Consumption of undercooked eggs Salmonella, Shigella (egg salad)
Consumption of raw shellfish Vibrio species, Norovirus, hepatitis A virus, Plesiomonas
Swimming in or drinking untreated fresh water Campylobacter, Cryptosporidium, Giardia, Shigella, Salmonella, STEC, Plesiomonas shigelloides
Swimming in recreational water facility with treated Cryptosporidium and other potentially waterborne pathogens when disinfectant concentrations are
water inadequately maintained
Health care, long-term care, prison exposure, or Norovirus, Clostridioides difficile, Shigella, Cryptosporidium, Giardia, STEC, Rotavirus
employment
Child care center (attendance or employment) Rotavirus, Cryptosporidium, Giardia, Shigella, STEC
Recent antimicrobial therapy C difficile, multidrug-resistant Salmonella
Travel to resource-limited countries Escherichia coli (enteroaggregative, enterotoxigenic, enteroinvasive), Shigella, Salmonella typhi,
nontyphoidal Salmonella, Campylobacter, Vibrio cholerae, Entamoeba histolytica, Giardia,
Blastocystis, Cyclospora, Cystoisospora, Cryptosporidium
Exposure to house pets with diarrhea Campylobacter, Yersinia
Exposure to pig feces in certain parts of the world Balantidium coli
Contact with young poultry or reptiles Nontyphoidal Salmonella
Visit to a farm or petting zoo STEC, Cryptosporidium, Campylobacter
Age Rotavirus (6-18 mo), nontyphoidal Salmonella (birth to 3 mo; adults >50 y with a history of
atherosclerosis), Shigella (1-7 y), Campylobacter (young adults)
Underlying immunocompromising condition Nontyphoidal Salmonella, Cryptosporidium, Campylobacter, Shigella, Yersinia
Hemochromatosis or hemoglobinopathy Yersinia enterocolitica, Salmonella
AIDS, immunosuppressive therapies Cryptosporidium, Cyclospora, Cystoisospora, microsporidia, Mycobacterium avium-intracellulare
complex, Cytomegalovirus
Anal-genital, oral-anal, or digital-anal contact Shigella, Salmonella, Campylobacter, E histolytica, Giardia lamblia, Cryptosporidium, agents of
sexually transmitted infections
Abbreviations: ETEC, enterotoxigenic Escherichia coli; STEC, Shiga toxin–producing Escherichia coli.
Adapted from Shane AL, Mody RK, Crump JA, Tarr PI, Steiner TS, Kotloff K, et al. 2017 Infectious Diseases Society of America clinical practice guidelines for the
diagnosis and management of infectious diarrhea. Clin Infect Dis. 2017 Nov 29;65(12):e45-e80; used with permission.
Table 18.2. Clinical Presentations That Suggest Causes of Infectious Diarrhea

Finding Likely pathogens and other comments
Persistent or chronic diarrhea Cryptosporidium spp, Giardia lamblia, Cyclospora cayetanensis, Cystoisospora belli,
Entamoeba histolytica
Visible blood in stool STEC, Shigella, Salmonella, Campylobacter, Entamoeba histolytica, noncholera Vibrio
species, Yersinia, Balantidium coli, Plesiomonas
Fever Not highly discriminatory: viral, bacterial, and parasitic infections can cause fever
In general, higher temperatures suggest bacterial agent or E histolytica
Patients infected with STEC usually are not febrile at presentation
Abdominal pain STEC, Salmonella, Shigella, Campylobacter, Yersinia, noncholera Vibrio species,
Clostridioides difficile
Severe abdominal pain, often grossly bloody stools STEC, Salmonella, Shigella, Campylobacter, Yersinia enterocolitica
(occasionally nonbloody), and minimal or no fever
Persistent abdominal pain and fever Y enterocolitica and Y pseudotuberculosis (findings may resemble those with appendicitis)
Nausea and vomiting lasting ≤24 h Ingestion of Staphylococcus aureus enterotoxin or Bacillus cereus (short-incubation emetic
syndrome)
Diarrhea and abdominal cramping lasting 1-2 d Ingestion of Clostridium perfringens or B cereus (long-incubation emetic syndrome)
Vomiting and nonbloody diarrhea lasting ≤2-3 d Norovirus (low-grade fever usually present during the first 24 h in 40% of infections)
Chronic watery diarrhea, often lasting ≥1 y Brainerd diarrhea (etiologic agent has not been identified)
Postinfectious irritable bowel syndrome
Abbreviation: STEC, Shiga toxin–producing Escherichia coli.
Adapted from Shane AL, Mody RK, Crump JA, Tarr PI, Steiner TS, Kotloff K, et al. 2017 Infectious Diseases Society of America clinical practice guidelines for
the diagnosis and management of infectious diarrhea. Clin Infect Dis. 2017 Nov 29;65(12):e45-e80; used with permission.
Outbreaks typically occur in the summer or autumn and Symptoms typically last 4 weeks, although antibiotic therapy
are associated with contaminated food (undercooked or raw can hasten recovery. Recurrent infection, occurring 7 to 10 days
poultry or eggs, meat, or dairy products), reflecting the high after apparent recovery, is not uncommon. The incidence of ty-
colonization rates of Salmonella in poultry and livestock. Pets, phoid fever is decreasing in the US.
including turtles, reptiles, cats, and dogs, can carry and transmit Prolonged asymptomatic fecal shedding of Salmonella is
the organism. Person- to-person spread is also important in common (average duration, about 5 weeks), although most
outbreaks and in resource-limited countries. Because typhoidal patients clear the organism within 3 months. Chronic carriage
Salmonella exists only in humans, a new case of typhoid fever (>1 year) occurs in less than 1% of patients with gastroenteritis
indicates exposure to a carrier. Attack rates are highest among and in up to 3% with typhoid fever. Risk factors include extremes
infants, elderly patients, and persons with decreased levels of of age and cholelithiasis (associated with chronic gallbladder
stomach acid. Conditions that predispose to Salmonella infec- infection).
tion, in addition to eating raw or undercooked eggs and poultry, Therapy for uncomplicated gastroenteritis includes rehy-
are listed in Box 18.1. dration and avoidance of antimotility agents. Antibiotics may
Gastroenteritis occurs in 75% of infections and typically prolong the carrier state and select for resistant organisms;
begins with nausea and vomiting within 48 hours after exposure they do not improve outcomes and are not indicated for healthy
with subsequent diarrhea and cramps. Diarrhea may range from patients with uncomplicated gastroenteritis. Commonly used
mild to severe and from watery to bloody. Fever and abdominal antibiotics include cephalosporins and quinolones; alternatives
pain are common. Localized tenderness can simulate an acute are amoxicillin and trimethoprim- sulfamethoxazole (TMP-
abdomen and is often localized to the right lower quadrant, re- SMX). Antibiotics are indicated for patients who have colitis,
flecting the ileal location of most infections. Gastroenteritis bacteremia or a risk for bacteremia (extremes of age, immuno-
usually lasts for no more than 7 days, although in unusual cases, compromised state [from HIV, medications, or malignancy], val-
primarily with colitis, symptoms can last for weeks. Bacteremia vular heart disease, hemoglobinopathy, or orthopedic implants),
occurs in 5% to 10% of infections, often resulting in distant or severe disease and for patients who are long-term carriers.
infections (eg, central nervous system infections, endocar- Multidrug resistance is becoming a problem; therapy should be
ditis, or osteomyelitis). Recurrent or persistent bacteremia can guided by sensitivity testing. Prolonged therapy is necessary for
occur in immunocompromised patients such as those with HIV metastatic infections.
or AIDS. For typhoid fever, therapy is recommended. Typically, a third-
Typhoid fever (enteric fever) is a systemic infection generation cephalosporin or a quinolone is given as empirical
characterized by an incubation period of 1 to 2 weeks and sub- therapy while sensitivity data are pending. In cases of fluoro-
sequent systemic symptoms that include fever, malaise, ar- quinolone resistance, azithromycin is the treatment of choice.
thralgia, myalgia, headache, and delirium. Gastrointestinal Chloramphenicol, TMP-SMX, and ampicillin are inappropriate
symptoms often have a delayed onset and include abdominal for empirical therapy because of resistance. Short-term use of
pain and constipation more frequently than diarrhea. Delayed corticosteroids may be beneficial for patients with severe dis
bowel perforation and bleeding can occur. Physical examination ease (eg, known enteric fever and severe systemic illness with
findings include relative bradycardia (pulse-temperature disso- delirium, coma, or shock). For long-term carriers, therapy with a
ciation), hepatosplenomegaly, lymphadenopathy, and a macular quinolone (eg, norfloxacin, 400 mg twice daily for 4 weeks) may
rash (rose spots). Typhoid fever is associated with recurrent or lead to clearance. If not, cholecystectomy may be needed to re-
sustained bacteremia, which results in metastatic infections. move the nidus of chronic infection.
Table 18.3. Recommended Antimicrobial Agents for Diarrhea

Pathogen First choice Alternative Comments
Bacteria a
Campylobacter Azithromycin Ciprofloxacin

Nontyphoidal Salmonella Usually not indicated for NA Antimicrobial therapy should be considered
entericab uncomplicated infection for groups at increased risk for invasive
infection: neonates (≤3 mo old); persons older
than 50 y with suspected atherosclerosis; persons
with immunosuppression, cardiac disease
(valvular or endovascular), or joint disease
If susceptible, treatment with ceftriaxone,
ciprofloxacin, TMP-SMX, or amoxicillin
Salmonella enterica Ceftriaxone or ciprofloxacin Ampicillin or TMP-SMX, or
Typhi or Paratyphib azithromycin
Shigellaa Azithromycinc or ciprofloxacina, TMP-SMX or ampicillin if Clinicians treating people with shigellosis for whom
or ceftriaxone susceptible antibiotic treatment is indicated should avoid
prescribing fluoroquinolones if the ciprofloxacin
MIC is ≥0.12 μg/mL even if the laboratory report
identifies the isolate as susceptibled
Vibrio cholerae Doxycyclinee Ciprofloxacin, azithromycin, or
ceftriaxone
Non–Vibrio choleraee For noninvasive disease: usually For noninvasive disease: usually not
not indicated, but single-agent indicated, but single-agent therapy
therapy if treated if treated
For invasive disease: ceftriaxone For invasive disease: TMP-SMX with
with doxycycline an aminoglycoside
Yersinia enterocolitica TMP-SMX Cefotaxime or ciprofloxacin
Parasites
Cryptosporidium spp Nitazoxanide (HIV-uninfected, Effective cART: immune reconstitution NA
HIV-infected in combination may lead to microbiologic and
with effective cART) clinical response
Cyclospora cayetanensis TMP-SMX Nitazoxanide (limited data) Patients with HIV infection may require higher doses
or longer durations of TMP-SMX treatment
Giardia lamblia Tinidazole (data from HIV- Metronidazole (data from Tinidazole—approved in US for children aged ≥3 y;
uninfected children) HIV-uninfected children) available in tablets that can be crushed
Nitazoxanide Metronidazole—high frequency of gastrointestinal
adverse effects; pediatric suspension is not
commercially available but can be compounded
from tablets; not FDA approved for treatment of
giardiasis
Cystoisospora belli TMP-SMX Pyrimethamine
Potential second-line
alternatives: ciprofloxacin,
nitazoxanide
Trichinella spp Albendazole Mebendazole Therapy less effective in late stage of infection when
larvae encapsulate in muscle
Abbreviations: cART, combination antiretroviral therapy; FDA, US Food and Drug Administration; MIC, minimum inhibitory concentration; NA, not applicable; TMP-
SMX, trimethoprim-sulfamethoxazole.
a
For information on susceptibility patterns in the US, see the National Antimicrobial Resistance Monitoring System for Enteric Bacteria (https://www.cdc.gov/narms/
index.html). Susceptibility testing should be considered when a therapeutic agent is selected.
b
If invasive disease is suspected or confirmed, ceftriaxone is preferred over ciprofloxacin because of increasing resistance to ciprofloxacin.
c
Most clinical laboratories do not test for azithromycin susceptibility.
d
For additional information, see https://emergency. cdc.gov/han/han00401.asp.
e
Primary therapy is aggressive rehydration; antibiotics are adjunctive therapy.
Adapted from Shane AL, Mody RK, Crump JA, Tarr PI, Steiner TS, Kotloff K, et al. 2017 Infectious Diseases Society of America clinical practice guidelines for the
diagnosis and management of infectious diarrhea. Clin Infect Dis. 2017 Nov 29;65(12):e45-e80; used with permission.
Shigella
Shigella has 40 serotypes in 4 species (Shigella dysenteriae, mildest disease and is the most common serotype in the US.
Shigella flexneri, Shigella boydii, and Shigella sonnei). Spread Symptoms characteristically begin within 48 hours after inges-
is typically person to person, facilitated by a low infective dose tion and include fever, malaise, abdominal pain, and watery
because of resistance to stomach acid. Outbreaks are related diarrhea. Rectal pain or burning can be a prominent symptom.
to contaminated food and water. Shigella sonnei produces the Respiratory symptoms are common, and children may have
Table 18.4. Postinfectious Manifestations Associated With

Enteric Pathogens Box 18.1. Conditions Predisposing to Salmonella
Infection
Manifestation Organisms
Hemolytic anemia
Erythema nodosum Yersinia, Campylobacter, Salmonella,
Sickle cell disease
Shigella
Glomerulonephritis Shigella, Campylobacter, Yersinia Malignancy
Guillain-Barré syndrome Campylobacter
Lymphoma
Hemolytic anemia Campylobacter, Yersinia
Hemolytic uremic syndrome STEC, Shigella dysenteriae serotype 1 Leukemia
Immunoglobulin A nephropathy Campylobacter Disseminated carcinoma
Reactive arthritisa Salmonella, Shigella, Campylobacter,
Yersinia, Giardia (rarely),
Immunosuppression
Cyclospora cayetanensis AIDS
Postinfectious irritable bowel Campylobacter, Salmonella, Shigella, Corticosteroids
syndrome STEC, Giardia
Meningitis Listeria, Salmonella (infants ≤3 mo Chemotherapy, radiotherapy
old are at high risk) Achlorhydria
Intestinal perforation Salmonella (including Salmonella Gastric surgery
Typhi), Shigella, Campylobacter,
Proton pump inhibitors
Yersinia, Entamoeba histolytica
Ekiri syndrome (lethal, toxic Shigella Idiopathic
encephalopathy) and/or seizure Ulcerative colitis
Aortitis, osteomyelitis, Salmonella, Yersinia
Schistosomiasis
extravascular deep tissue focus
Abbreviation: STEC, Shiga toxin–producing Escherichia coli. Adapted from Giannella RA. Infectious enteritis and proctocolitis and
bacterial food poisoning. In: Feldman M, Friedman L, Brandt LJ, eds.
a
Includes Reiter syndrome.
Sleisenger & Fordtran’s gastrointestinal and liver disease. Saunders/
Adapted from Shane AL, Mody RK, Crump JA, Tarr PI, Steiner TS, Kotloff K, Elsevier; 2010:1843-87; used with permission.
et al. 2017 Infectious Diseases Society of America clinical practice guidelines for
the diagnosis and management of infectious diarrhea. Clin Infect Dis. 2017 Nov
29;65(12):e45-e80; used with permission.
Treatment focuses on rehydration and avoidance of antimotility
agents. Antibiotics have been shown to decrease mortality and the
neurologic manifestations, including seizures. The diarrhea may duration of disease. Therefore, antibiotic therapy is indicated for
decrease and become bloody with mucus and pus (ie, dysentery). most patients, particularly those with chronic illnesses (including
The initial watery diarrhea is thought to be due to the Shiga toxin, malnutrition and HIV), elderly patients, day care or health care
whereas dysentery is due to mucosal invasion, which occurs pri- workers, and food handlers. Owing to increasing antimicrobial
marily in the colon. This classic progression occurs in a small resistance, selection of therapy should be guided, if possible, by
proportion of cases and is least common in S sonnei infections. results of antimicrobial susceptibility testing. Treatment options
Predictors of severity include extremes of age, malnutrition, include azithromycin, ciprofloxacin, or TMP-SMX. Before sus-
immunosuppression, and infection with S dysenteriae, which is ceptibility testing results are available, fluroquinolone therapy
most likely to cause complications such as HUS, dysentery, or can be initiated. Resistance to multiple antibiotics has been re-
toxic megacolon. Shigellosis typically lasts for 1 to 3 days in ported. Clinicians should avoid prescribing fluoroquinolones if
children and 5 to 7 days in adults. Although chronic carriage is the ciprofloxacin minimum inhibitory concentration is 0.12 μg/
unusual, prolonged infections can occur and may be difficult to mL or higher even if the laboratory report identifies the isolate
differentiate from ulcerative colitis. A delayed, asymmetric large- as susceptible.
joint arthritis can occur, usually in persons with HLA-B27.
Escherichia coli
Table 18.5. Clinical Syndromes of Salmonella Infection The different types of E coli are summarized in Table 18.6.
Syndrome Incidence, %
Enterohemorrhagic E coli
Gastroenteritis 75
Varies from mild to severe (dysentery) Enterohemorrhagic E coli (EHEC) produces Shiga toxin and
Bacteremia 5-10 causes colitis after an incubation period of 3 to 5 days. Escherichia
With or without gastroenteritis coli O157:H7 accounts for more than 90% of EHEC cases in the
Consider AIDS US; 100 other serotypes have been identified. Although several
Typhoid (enteric) fever 5-10
With or without gastroenteritis outbreaks have attracted considerable media attention, most cases
Systemic infection 5 of EHEC are sporadic. It has been estimated that 50% of cattle
Osteomyelitis, arthritis, meningitis, cholecystitis, abscess and 90% of hamburger lots are contaminated with EHEC. Thus,
Carrier state duration >1 y <1 EHEC is associated with the ingestion of undercooked hamburger
but also with the ingestion of salami, sprouts, and unpasteurized
Adapted from Giannella RA. Infectious enteritis and proctocolitis and bacterial
food poisoning. In: Feldman M, Friedman L, Brandt LJ, eds. Sleisenger & milk or juice. Although the infectious dose is low, EHEC is ef-
Fordtran’s gastrointestinal and liver disease. Saunders/Elsevier; 2010:1843-87; fectively killed at temperatures higher than 69 °C. A pink center
used with permission. in a hamburger is associated with lower temperatures and an
Table 18.6. Types of Escherichia coli Causing Infectious Diarrhea

Type of E coli Patients affected Pathophysiology Clinical features
Enteropathogenic (EPEC) Infants in resource-limited countries; Attachment alters brush border Watery diarrhea
some travelers
Enterotoxigenic (ETEC) Children in resource-limited countries; Enterotoxin-mediated secretion Watery diarrhea
travelers
Enteroinvasive (EIEC) All ages; rare; food and water outbreak Direct invasion Usually watery diarrhea; 10% have
dysentery
Enterohemorrhagic (EHEC) All ages; food (hamburger); sporadic or Shiga-like cytotoxins Watery then bloody diarrhea; HUS
(eg, E coli O157:H7) outbreak or TTP
Enteroaggregative (EAEC) Infants in resource-limited countries; Adherence; toxins Prolonged watery diarrhea
HIV-positive adults
Abbreviations: HUS, hemolytic uremic syndrome; TTP, thrombotic thrombocytopenic purpura.
Adapted from Giannella RA. Infectious enteritis and proctocolitis and bacterial food poisoning. In: Feldman M, Friedman L, Brandt LJ, eds. Sleisenger &
Fordtran’s gastrointestinal and liver disease. Saunders/Elsevier; 2010:1843-87; used with permission.
increased risk of infection. Irradiation of hamburger also effec- organism attaches to the small bowel and causes diarrhea through
tively kills EHEC, but whether the public will embrace irradiated enterotoxins. The disease ranges from mild to severe watery diar-
foods is not known. rhea and is often associated with mild upper gastrointestinal tract
EHEC typically produces watery diarrhea that progresses symptoms that last for 2 to 5 days. Rehydration is the mainstay
to bloody diarrhea after a few hours to a few days. One study of therapy. Routine antibiotic administration is not recommended
suggested that EHEC is the most common cause of bloody diar- because most cases are self-limiting and antibiotics would propa-
rhea in the US. Systemic symptoms (fatigue, myalgias, and head- gate the development of drug-resistant strains. Antibiotics may be
ache), severe abdominal pain, nausea, and vomiting are common, considered for patients who have severe diarrhea, who need hos-
but fever is not. Illness typically lasts 5 to 10 days. In the elderly, pitalization because of dehydration, or who are immunocompro-
EHEC may be misdiagnosed as ischemic colitis. mised. Azithromycin or a fluoroquinolone would be considered
EHEC can lead to HUS or thrombotic thrombocytopenic pur- the drug of choice.
pura (TTP) in 5% of patients, resulting in hemolytic anemia and
kidney failure, with or without central nervous system symptoms.
The pathophysiologic mechanism of EHEC appears to be vas- Enteropathogenic E coli
cular endothelial damage that leads to platelet aggregation and Enteropathogenic E coli (EPEC) is primarily a problem in
initiation of the coagulation cascade. This, in turn, leads to is- infants. It caused several epidemics with high mortality in neo-
chemia of the colon and results in hemorrhagic colitis. Some natal nurseries in the early 1970s. Currently, it occurs most often
cases of “ischemic colitis” probably are misdiagnosed cases of in resource-limited countries. EPEC attaches to the small-bowel
EHEC. Similarly, thrombi and ischemia in the kidney may be mucosa and causes watery mucoid diarrhea by producing struc-
the cause of kidney insufficiency in HUS. Morbidity and mor- tural changes in the microvilli. Most people recover spontane-
tality rates are high among patients with HUS or TTP, particu- ously and do not need antibiotic treatment. The importance of
larly among those who are very young or very old. antibiotics even in severe or persistent disease is unknown. If
In some laboratories, specific testing for E coli O157:H7 antibiotics are chosen, fluoroquinolones such as ciprofloxacin,
(with sorbitol-MacConkey agar or a newer stool toxin assay that macrolides such as azithromycin, or rifaximin may be used.
may be more sensitive) must be requested; thus, the condition
can be underdiagnosed. In several large series reported from
Enteroinvasive E coli
North America, E coli O157:H7 was the second to fourth most
identified bacterium in acute diarrheal illnesses. Antibiotics do Enteroinvasive E coli (EIEC) is a rare cause of diarrhea associ-
not appear to be beneficial and may increase toxin production ated with fever and abdominal pain. The diarrhea is usually watery,
or release (or both). This, in turn, may increase the risk of HUS but it can be accompanied by fever and leukocytes (ie, dysentery).
or TTP and, perhaps, death. Also, antimotility agents, including EIEC is similar to Shigella in its ability to invade the colonic mu-
narcotics, may increase the risk of HUS. Thus, use of antibiotics cosa and produce a Shiga-like toxin. Data are limited on the benefit
and antimotility agents should be avoided if EHEC infection is of antibiotic therapy because patients do recover spontaneously.
suspected clinically (eg, absence of fever in a patient with bloody If antibiotics are chosen, fluoroquinolones such as ciprofloxacin,
diarrhea of suspected infectious origin). macrolides such as azithromycin, or rifaximin may be used.
Contact isolation precautions are necessary for patients with
EHEC, and any personal contacts who have gastrointestinal tract
Enteroaggregative E coli
symptoms should be tested for EHEC. It has been recommended
that children, food handlers, and health care workers delay their Enteroaggregative E coli (EAEC) is primarily a problem in
return to school or work until they are asymptomatic and have infants in resource-limited countries and in adults infected with
had several stool cultures negative for EHEC. HIV, although it also can cause traveler’s diarrhea. EAEC causes
persistent diarrhea that can be watery or bloody. Testing for
EAEC requires a tissue culture adherence assay or a PCR assay.
Enterotoxigenic E coli Quinolones are an effective therapy, suggesting that empirical
Enterotoxigenic E coli (ETEC) is a common cause of diarrhea treatment with these agents may be reasonable for patients with
in travelers and in children in resource-limited countries. The HIV who have diarrhea and negative findings on evaluation.
Vibrio ulcers, arthralgias, and erythema nodosum), and right lower

quadrant tenderness with mesenteric lymphadenitis can simulate
Vibrio species are halophilic and associated with the consump-
appendicitis.
tion of raw or undercooked saltwater fish or shellfish (oysters,
crabs, and mussels) or contamination of food with seawater.
Vibrio parahaemolyticus is a common cause of diarrhea in the Parasitic Intestinal Infections
coastal US and Japan, particularly during warm months. Several Stool evaluation for ova and parasites is helpful when patients are
toxins can be produced, resulting in various clinical presentations. immunocompromised or have an appropriate exposure or travel
The incubation period is less than 1 to 2 days, and the primary history. Most parasites are shed intermittently, and a single stool
symptom is watery diarrhea. Abdominal pain, vomiting, and evaluation is relatively insensitive. To increase sensitivity, 3 or
headaches are also common. Uncommonly, V parahaemolyticus more separate stools should be analyzed. Newer antigen-based
may cause frank dysentery and mucosal ulceration. The illness and molecular PCR-based assays have higher sensitivity than
typically lasts 2 to 5 days, and antibiotics usually are not nec- stool microscopic assays.
essary. The importance of antibiotics is uncertain, even for
patients with severe or prolonged symptoms. If antibiotics are
administered, a reasonable choice is doxycycline. Giardia lamblia
Vibrio cholerae infection is not common in the US, although Giardia lamblia (also known as Giardia intestinalis or Giardia
sporadic cases occur along the Gulf Coast and in travelers re- duodenalis), the most common parasitic infection in the US, is
turning from endemic areas (Latin America, Africa, and Asia). acquired by the ingestion of water or food contaminated with
The infectious dose is large, although hypochlorhydria decreases cysts or by person-to-person spread (eg, day care centers and
it. Cholera toxin can cause profound dehydration from profuse nursing homes). Cysts can survive for months in the environment
diarrhea (>1 L/h in some cases) and vomiting. However, milder and are resistant to chlorination. In the US, the peak incidence
cases (and asymptomatic carriage) are possible. In severe cases, occurs in the summer and early autumn. Excystation occurs in
stools are described as “rice water” because of the watery con- the small bowel, where the trophozoites attach to and damage the
sistency with flecks of mucus. Hypotension, kidney failure, mucosa. High-risk groups are travelers to endemic areas, children
and hypokalemic acidosis occur in severe cases and, without in day care, patients with immunoglobulin deficiencies, and men
aggressive rehydration, often lead to death. Oral rehydration who have sex with men. Symptoms, including watery diarrhea,
solution can be lifesaving, but severe cases usually require in- cramps, nausea, bloating, and flatulence, occur 1 to 2 weeks after
travenous fluids, with attention to potassium and bicarbonate ingestion. Patients initially may have acute disease, although di-
replacement. Infection can be treated with various antibiotics, arrhea may be intermittent, leading to a delay in seeking medical
which most commonly include tetracycline or doxycycline. attention. Chronic symptoms also may occur and can be asso-
Azithromycin, erythromycin, or even a single dose of quino- ciated with malabsorption. Some persons become asymptomatic
lone therapy can be effective, although resistance patterns are carriers with long-term cyst passage.
emerging. Examination of multiple stools for trophozoites or cysts is in-
Vibrio vulnificus also can cause diarrhea, and hemorrhagic sensitive. Preferred methods are fecal analysis for Giardia an-
bullae may appear. The organism can be acquired through wound tigen, nucleic acid assay, or duodenal aspirate and biopsy (to
contamination from contaminated seawater or by direct con- confirm presence of organisms or lack of plasma cells). First-line
sumption, particularly in the summer months. In patients who therapy is with tinidazole (single 2-g dose) or nitazoxanide; use
are immunocompromised or those with chronic liver disease, of metronidazole (250 mg 3 times daily for 5-7 days) is an alter-
systemic infection with sepsis is a risk, and the mortality rate is native. Paromomycin is the treatment of choice if the patient is
high. These patients should be instructed not to eat or handle raw pregnant. Treatment of asymptomatic carriers provides no benefit
seafood, particularly oysters. for the patient but may help prevent outbreaks (eg, among day
care or health care workers).
Yersinia
Yersinia enterocolitica is less common in the US than in northern
Cryptosporidium
Europe. Yersinia typically is acquired in cold months from Although Cryptosporidium increasingly has been recognized as
contaminated food, milk, or water and has an incubation period a pathogen in patients with AIDS, it also can cause diarrhea in
of 4 to 7 days. Many animals can harbor the organism and be a hosts who are immunocompetent. Infection commonly is ac-
source of infection, which occurs primarily in the terminal ileum. quired from contaminated water or person-to-person spread. The
Symptoms range from mild (fever, diarrhea, nausea, and cramps) parasite can resist chlorination, resulting in outbreaks even in
to severe (reflecting invasion). Uncommonly, Yersinia causes industrialized areas. Several US outbreaks have been attributed
bacteremia with sepsis or distant infection. Arthralgias and rash to contaminated water sources. Cryptosporidium invades the
are more common in adults than in children. Postinfectious ar- small-bowel mucosa and causes inflammation, villous blunting,
thritis also can occur (HLA-B27). and malabsorption. In most healthy patients, disease is mild and
In healthy patients, symptoms typically last 1 to 3 weeks. self-limited, with watery diarrhea, nausea, cramps, and flatu-
Antibiotic therapy has not been shown to be of benefit in uncom- lence developing 7 to 10 days after ingestion. Stools may be
plicated disease. Patients at risk for sepsis (those with cirrhosis, intermittent and mucoid but should not contain much blood or
iron overload, or an immunocompromised state) and those with pus. Diarrhea can last 6 weeks or longer. Headaches, fevers,
severe or prolonged symptoms, bacteremia, or distant infections or myalgias are common. The diagnosis can be made by stool
may benefit from antibiotic therapy (TMP-SMX, a cephalosporin, analysis (immunoassays are more sensitive than microscopy)
or a quinolone). Ileocolitis from Yersinia infection can simulate or small-bowel biopsy. In healthy patients, treatment usually is
Crohn disease (including extraintestinal manifestations: aphthous not necessary.
Entamoeba histolytica Symptoms typically begin several days after the person arrives
in the area and last for 3 to 5 days. Watery diarrhea, bloating, fa-
Amebiasis is the most common parasitic diarrhea in the world,
tigue, and cramps are common. Bloody diarrhea and high fever
although it is less common in the US. Most cases in the US occur
are uncommon; their presence suggests an invasive organism and
in travelers or immigrants from endemic areas (Latin America,
should prompt an evaluation for a specific organism. For most
Africa, and India) and in men who have sex with men. Infection
travelers, antibiotic prophylaxis is not recommended. Bismuth
is acquired through the ingestion of contaminated food or water.
subsalicylate (2 tablets 4 times daily) is a possible prophylaxis.
Amebic cysts undergo excystation in the small bowel and infect
Mild cases of traveler’s diarrhea can be treated with rehydra-
the colon. Symptoms begin 7 to 21 days after ingestion and in-
tion and antidiarrheals or bismuth (if no fever, severe pain, or
clude bloody diarrhea, abdominal pain, fever, and tenesmus, con-
bloody diarrhea) for 1 to 3 days. The recommendation for mod-
sistent with invasive colitis. Amebic colitis can vary from mild
erate to severe diarrhea is azithromycin, a quinolone, or rifaximin,
to fulminant, with severe bleeding or perforation. Because the
often in combination with an antidiarrheal. Azithromycin has ac-
risk of perforation is increased by corticosteroid use, it is im-
tivity against fluoroquinolone- resistant Campylobacter, which
portant to differentiate amebic colitis from ulcerative colitis.
may be encountered during travel in South and Southeast Asia.
Amebic ulcers are caused by mucosal invasion by trophozoites.
The ulcers vary from mild to severe, with the classic descrip-
tion being that of undermined edges leading to a flask-shaped Food Poisoning
ulcer. Amebae can penetrate the bowel wall, enter the portal cir- Common symptoms of food poisoning and typical offending
culation, and cause liver or splenic abscesses. Patients with liver agents are listed in Table 18.7.
abscesses tend to be male, and they may not have a discernible Staphylococcus aureus toxin causes 1 to 2 days of severe
history of colitis. Distant infection (peritonitis, empyema, or vomiting, cramps, and diarrhea that begin 2 to 6 hours after in-
central nervous system infection) also can occur. A localized ingestion of contaminated food (eg, cream-filled pastries, meat, or
fection surrounded by granulation tissue or a dense fibrous coat potato or egg salad). Severe infection can cause dehydration.
(ameboma) can resemble colon cancer. Clostridium perfringens toxin produces 1 to 2 days of abdom-
Diagnosis is made by stool examination. Three or more inal pain and watery diarrhea that usually begin 8 to 24 hours
samples may be needed to make the diagnosis with micros- after ingestion of foods typically prepared in advance and left
copy, although stool antigen testing and the PCR assay for E to sit unrefrigerated (eg, beef, poultry, or gravy). An uncommon
histolytica DNA are more sensitive. Metronidazole (750 mg 3 strain of C perfringens produces the potentially fatal enteritis
times daily for 7-10 days) is the drug of choice for treating co- necroticans, or pigbel, a condition that occurs primarily in poor
litis or liver abscesses. Cysts are relatively resistant to metroni- tropical regions.
dazole and require a second agent such as diloxanide furoate, Bacillus cereus toxin causes nausea and vomiting that usu-
paromomycin, or iodoquinol. Drainage of liver abscesses is not ally occur within 2 to 6 hours after ingestion of contaminated
recommended unless rupture is imminent or medical therapy is food (eg, pork, creams or sauces, or fried rice) and last 6 to 10
ineffective. hours. Diarrhea may occur later, probably from a toxin formed in
The human colon can be inhabited by numerous nonpathologic vivo. In healthy hosts, antibiotic therapy is not necessary for these
amebae, including Entamoeba coli, Entamoeba hartmanni, and acute forms of food poisoning due to preformed enterotoxins.
Endolimax nana. Distinguishing between these organisms and E Listeria monocytogenes can be found in many foods (eg, hot
histolytica can be difficult with routine microscopy, even for ex- dogs, lunch meat, and cheeses), and its growth is not substantially
perienced examiners, although serologic testing and stool PCR inhibited by refrigeration. It can cause gastroenteritis, often with
assay should help. fever, that is typically mild and self-limited, lasting 1 to 2 days.
However, in chronically ill or immunosuppressed patients and in
Blastocystis hominis patients who are very young, elderly, or pregnant, Listeria also
can cause severe disease, with bacteremia and disseminated in-
Blastocystis hominis is found occasionally on routine stool fection associated with a high mortality rate. Therapy, usually
examinations for ova and parasites. Its pathogenicity is uncertain, with ampicillin and gentamicin, is indicated.
particularly in hosts who are immunocompetent. However, if no
other cause for a patient’s symptoms is found, a trial of metroni-
dazole or tinidazole can be considered.
Table 18.7. Food Poisoning Syndromes
Traveler’s Diarrhea Incubation
Infectious diarrhea affects 40% to 60% of travelers to high-risk Symptoms period, h Possible agents
areas of Southeast Asia, the Middle East, India, Africa, and Acute nausea, 6 Preformed toxins of Staphylococcus
South America. The incidence of diarrhea varies depending on vomiting aureus, Bacillus cereus
the specific area visited (eg, urban or rural), the traveler’s age, Watery diarrhea 6-72 Clostridium perfringens, B cereus, ETEC,
time of year, and local conditions, such as flooding or a cholera Vibrio cholerae, Giardia
Inflammatory 16-72 Salmonella, Shigella, Campylobacter,
outbreak. Bacteria cause 80% to 90% of cases of traveler’s diar-
ileocolitis EIEC, EHEC (O157:H7), Vibrio
rhea, and the other 10% to 20% are due to parasites, viruses, or (“dysentery”) parahaemolyticus, Yersinia
toxins. ETEC is a common cause. The unusual case of prolonged
traveler’s diarrhea is more likely to be caused by a parasite such Abbreviations: EHEC, enterohemorrhagic Escherichia coli; EIEC, enteroinvasive
as G intestinalis or Cyclospora cayetanensis. The risk of infec- Escherichia coli; ETEC, enterotoxigenic Escherichia coli.
tion can be decreased by avoiding uncooked foods, local water Data from Guerrant RL, Bobak DA. Bacterial and protozoal gastroenteritis.
(including ice), and unpasteurized drinks. N Engl J Med. 1991 Aug 1;325(5):327-40.
C difficile Infection abdomen and localized rebound tenderness, no diarrhea, and

normal findings on sigmoidoscopy. The overall mortality rate is
Clostridium difficile, recently renamed and reclassified as
low (2%-3%), although it is higher among elderly or debilitated
Clostridioides difficile, is a spore-forming toxigenic bacterium
patients (10%-20%) and patients with fulminant colitis or toxic
that causes diarrhea and colitis, typically after antibiotic therapy.
megacolon (30%-80%).
It is the most common health care infection in industrialized
Despite successful treatment, 20% to 30% of patients have
countries, and the number of cases of CDI in the community has
a recurrence after a first infection; 40% to 50%, after a second
increased sometimes in the absence of prior antibiotic exposure.
infection; and more than 60%, after a third infection even after
Risk factors that predispose persons to CDI include age older
receiving guideline-based therapy.
than 65 years, antibiotic exposure, health care exposure, immu-
nosuppression, chemotherapy, chronic kidney disease, surgery,
malnutrition, proton pump inhibitor use, and critical illness. Diagnostic Testing
These risk factors lead to disruption of the gut microbiome and An accurate diagnosis of CDI is based on a combination of
predispose a person to colonization and active infection with C risk factors, clinical findings, and stool testing. Endoscopy and
difficile. The acquisition and germination of spores, and an over- biopsies have negligible value in the diagnosis of CDI owing to
growth of C difficile owing to a disrupted microbiome, leads to excellent sensitivity of available tests and a decreased incidence
toxin production. Toxin A binds to mucosal receptors and causes of pseudomembranes. Stool culture and cell cytotoxicity assays
cytotoxicity by disrupting cytoplasmic microfilaments and inducing for C difficile are not used in clinical practice owing to the ex-
apoptosis. Toxin B can then enter the damaged mucosa and cause pense and the time required for the tests. An enzyme-linked im-
further cytotoxicity, resulting in hemorrhage, inflammation, and munosorbent assay for the detection of toxin A or B is limited by
cellular necrosis. The toxins also interfere with protein synthesis, its lower sensitivity and is not used as an assay independently.
stimulate granulocyte chemotaxis, increase capillary permeability, Testing for fecal leukocytes lacks sensitivity and specificity.
and promote peristalsis. In severe cases, inflammation and necrosis Stool testing for CDI should not be performed in the ab-
may involve deeper layers of the colon and result in toxic dilatation sence of symptoms that suggest CDI, and a test of cure is not
or perforation. recommended after resolution of symptoms. Treatment of asymp-
The spectrum of disease associated with CDI ranges from mild tomatic carriers is not recommended because it may prolong the
to moderate infection at 1 end to fulminant infection with sepsis carrier state and increase the risk of future CDI.
or shock at the other. Colitis may range from minimal erythema or The most common test for CDI is a PCR assay, which has a
edema to ulceration, often with nodular exudates that may coalesce sensitivity greater than 95% for a single stool sample. A PCR-
and form yellow pseudomembranes consisting of mucus and fibrin based assay has limitations, including the inability to distinguish
filled with dead leukocytes and mucosal cells (Figure 18.1). colonization from active infection because toxin production is
not measured. Practice guidelines suggest that if PCR alone is
Clinical Presentation used as an assay, it should be performed only when patients have
otherwise unexplained diarrhea and CDI is a strong possibility.
The time between the initiation of antibiotic therapy and the
A test with negative results should not be repeated.
appearance of clinical symptoms varies from 1 day to 6 weeks
Most treatment guidelines now recommend a 2-step assay for
and can be up to 12 weeks after antibiotic exposure. The clin-
an accurate diagnosis of CDI. The first step is to perform a gluta-
ical presentation ranges from only loose stools to toxic megacolon
mate dehydrogenase (GDH) assay and then an enzyme immuno-
(nausea, vomiting, high-grade fever, and ileus) and colonic perfo-
assay (EIA) for toxins A and B. If results are positive for both GDH
ration. Typically, the disease manifests with watery or mucoid di-
and EIA, the diagnosis is CDI. If results are negative for both GDH
arrhea, abdominal pain, and low-grade fever. Diarrhea may cause
and EIA, CDI is ruled out. If the test results are discordant (ie, pos-
dehydration and electrolyte depletion. Rarely, disease is localized
itive for GDH and negative for EIA), a PCR assay is performed.
to the proximal colon; affected patients may present with an acute
Interpretation of this testing algorithm is shown in Figure 18.2.
Treatment
Supportive therapy includes rehydration and, if possible, discon-
tinuation of treatment with the offending antibiotic. Antidiarrheal
agents and narcotics should be avoided because they may prolong
exposure to toxins and result in more severe colitis. For severe
disease, hospitalization for therapy and intravenous hydration
may be necessary. If CDI is a strong possibility, empirical antibi-
otic therapy should be started after collecting a stool sample and
before test results are known. Treatment options for CDI include
therapy with antibiotics, a monoclonal antibody, and microbiome
restoration. A management algorithm for CDI is included in
Figure 18.3. Dosing regimens for CDI are included in Table 18.8.
Treatment of Primary Nonfulminant CDI

The preferred option for primary nonfulminant CDI is fidaxomicin
Figure 18.1. Pseudomembranous Colitis. Typical histologic 200 mg twice daily for 10 days. Fidaxomicin is as effective as
appearance is shown (hematoxylin-eosin). vancomycin for clearing C difficile initially and is associated with
Figure 18.2. Algorithm for Clostridioides difficile Infection. Stepwise performance of 2-step testing algorithm for C difficile infection starts with glu-
tamate dehydrogenase (GDH) assay, which is sensitive but not specific for C difficile infection, and subsequent enzyme immunoassay (EIA) for C difficile
toxins. A polymerase chain reaction (PCR) test for C difficile is used to arbitrate discordant results. One asterisk (*) indicates that in most instances a nega-
tive result for GDH is not used to rule out C difficile infection; subsequent EIA for toxins A and B is performed (the diagnostic kits check for both GDH and
the C difficile toxins). In some instances, a negative result for GDH may be used to rule out C difficile infection. (Adapted from Khanna S. My treatment
approach to Clostridioides difficile infection. Mayo Clin Proc. 2021 Aug;96[8]:2192-204; used with permission.)
a lower likelihood of recurrent disease (recurrence rate, 25% with microbiota transplant (FMT) (which has been successful in more
vancomycin and 15% with fidaxomicin). The use of fidaxomicin than 80%-90% of patients, as described below).
is limited by cost. An alternative to fidaxomicin is vancomycin at
a dose of 125 mg 4 times daily for 10 days. Oral vancomycin is Treatment of Fulminant CDI
poorly absorbed, and a high concentration can be achieved in the
stool without systemic adverse effects. If fidaxomicin and van- Fulminant CDI (such as in patients with sepsis, shock, or
comycin are not available, metronidazole can be used (500 mg 3 megacolon) is managed with a multidisciplinary approach, in-
times daily for 10 days). cluding a prompt surgical consultation. Vancomycin (500 mg
Recurrences after CDI are common, and recurrent infection 4 times daily) is administered orally or through a nasogastric
must be distinguished from developing postinfection irritable tube supplemented with a vancomycin enema, especially in
bowel syndrome. After resolution of CDI, postinfection irri- instances of paralytic ileus. In addition, intravenous metronida-
table bowel syndrome develops in about 20% to 25% of patients, zole 500 mg 3 times daily is recommended. Diverting ileostomy
and symptoms may be overlapping. Patients with postinfection or colectomy is performed for severe refractory disease or for
symptoms have fewer instances of diarrhea and may have inter- complications such as perforation or megacolon. Because the risk
mittent constipation; their bowel habits are related to food, and of complications increases markedly after several days of inef-
their abdominal pain is relieved with defecation. fective therapy, some advocate surgery for patients with severe
disease that does not respond after 2 to 7 days of treatment.
Treatment of First Recurrence of CDI Antibody-Based Treatment

Most recurrences happen within 8 weeks of an initial infection. A 1-time dose of intravenous bezlotoxumab (10 mg/kg) can help
For a first recurrence, the general principle is to avoid repeating with recurrent CDI. This treatment, approved by the US Food and
the course of antibiotics that was used for an initial infection. One Drug Administration (FDA), is not used as a sole treatment of
option is a prolonged course of vancomycin therapy with a sub- CDI but as an adjunct to antibiotics during the antibiotic therapy.
sequent gradual tapering (eg, 125 mg 4 times daily for 2 weeks, Bezlotoxumab is beneficial if at least 1 of the following risk
125 mg twice daily for 1 week, 125 mg daily for 1 week, 125 mg factors is present: age older than 65 years, recent CDI (ie, in the
every other day for 1 week, and 125 mg every 3 days for 2 weeks). past 6 months), immunosuppression, or presence of severe CDI
Other options include fidaxomicin, which can be given as a 10-day (defined as a white blood cell count >15,000/µL or a creatinine
course or as an extended regimen (200 mg twice daily on days 1-5, value >1.5 mg/dL). A history of heart failure is a contraindication
none on day 6, and 200 mg once every other day on days 7-25). to the use of bezlotoxumab.
Treatment of Multiply Recurrent CDI Microbiome-Based Therapies

Multiply recurrent CDI is managed with a course of antibiotics Microbiome-based therapies, with FMT being the most common
and subsequent microbiome restoration therapy, such as fecal way to perform microbiome restoration, have shown promise in
Figure 18.3. Management Algorithm for Nonfulminant Clostridioides difficile Infection. See Table 18.8 for dosing details. One asterisk
(*) indicates use of oral vancomycin (standard) or fidaxomicin (standard or extended) and consideration of intravenous bezlotoxumab in patients at
high risk for recurrence. Two asterisks (**) indicate use of oral vancomycin (taper and pulse) or fidaxomicin (standard or extended) while avoiding use
of the same regimen as for the first episode and considering use of intravenous bezlotoxumab. Three asterisks (***) indicate use of a standard course
of antibiotics with subsequent use of microbiota restoration therapies such as fecal microbiota transplant; alternatively, vancomycin (taper and pulse)
or rifaximin chaser or fidaxomicin (extend) may be used. (Adapted from Khanna S. My treatment approach to Clostridioides difficile infection. Mayo
Clin Proc. 2021 Aug;96[8]:2192-204; used with permission.)
Table 18.8. Dosing Regimens for Clostridioides difficile Infection

Regimen Dosage
Vancomycin standard regimen Vancomycin 125 mg orally 4 times daily for 10 d
Fidaxomicin standard regimen Fidaxomicin 200 mg orally 2 times daily for 10 d
Fidaxomicin extended regimen Fidaxomicin 200 mg orally 2 times daily for 5 d; then 200 mg once every other day
on days 7-25 (20 doses)
Vancomycin taper and pulse Vancomycin 125 mg orally 4 times daily for 14 d; then 2 times daily for 7 d, once
daily for 7 d, once every other day for 8 d, and once every 3 d for 15 d (86 doses)
Rifaximin chaser regimen Vancomycin 125 mg orally 4 times daily for 10-14 d; then rifaximin 550 mg orally
twice daily for 10-14 d
Fulminant C difficile regimen Vancomycin 500 mg orally 4 times daily in combination with IV metronidazole
500 mg 3 times daily (vancomycin 500 mg can be added rectally for ileus or
suboptimal response)
Bezlotoxumab One-time IV dose (10 mg/kg body weight) administered during an antibiotic course
Abbreviation: IV, intravenous.
Adapted from Khanna S. My treatment approach to Clostridioides difficile infection. Mayo Clin Proc. 2021 Aug;96(8):2192-204; used
with permission.
the treatment of multiply recurrent CDI. Even though it is not an to colonic obstruction. Jaundice or hepatic abscesses suggest
FDA-approved therapy, FMT is used commonly in this situation pylephlebitis. A massively dilated (>10 cm) cecum, signs of cecal
after completion of antibiotic therapy for an acute episode. FMT necrosis (ie, air in the bowel wall), or marked tenderness mandate
is dependent on the availability of stool from donors who have immediate surgical consultation. Colovesical and, less frequently,
undergone screening for overall health and infectious diseases. colovaginal and colocutaneous fistulas may occur.
Donors are excluded if they are very young or very old or if they
have a disease associated with microbiome alterations. FMT is a Diagnosis
heterogeneous practice, and recent FDA alerts warn of possible
transmission of diarrheagenic and multidrug-resistant E coli and The initial evaluation when diverticulitis is suspected should in-
SARS-CoV-2. clude a clinical evaluation and appropriate laboratory evaluation
including a complete blood cell count. Computed tomography,
✓ CDI—increased number of cases in the community with and the standard test for a diagnosis of diverticulitis, is used to assess
without antibiotic exposure disease severity and the risk of complications. If the clinical
✓ CDI diagnosis— 2-
step algorithm (glutamate dehydrogenase features are highly suggestive of mild uncomplicated diverticu-
assay; then enzyme immunoassay for toxins A and B) with subse- litis, imaging studies may not be needed if patients have a history
quent PCR if results are discordant of diverticulitis.
✓ CDI treatment
• Fidaxomicin—first-line treatment; fewer recurrences compared
to vancomycin Treatment
• For first recurrence—vancomycin with a tapering dose; then
pulse therapy Treatment is influenced by severity, ability to tolerate oral intake,
• Metronidazole—not recommended in most instances previous history of diverticulitis or bleeding, and complications.
• Intravenous bezlotoxumab— helps prevent recurrences in Mild diverticulitis can be treated without antibiotics and with
patients with high risk for recurrence bowel rest. Moderate or severe infections (including those with
✓ Microbiome restoration by fecal microbiota transplant— abscesses smaller than 3 cm) are managed with antibiotic courses.
experimental therapy with high efficacy for multiply recur- Percutaneous drainage is usually recommended for patients in
rent CDI stable condition who have an abscess larger than 3 cm. After an
episode of acute complicated diverticulitis has resolved, a colon-
oscopy should be performed at around 6 to 8 weeks to exclude
Diverticulitis neoplasm.
If surgical treatment can be deferred until the acute inflamma-
In Western societies, colonic diverticulosis affects 5% to 10% of tion heals, a single-stage primary resection and reanastomosis,
the population older than 45 years and 80% of those older than perhaps laparoscopically, can be accomplished with minimal mor-
80 years. Diverticulosis affects predominantly the sigmoid colon bidity and mortality. Indications for elective surgery include recent
but may involve the entire colon. There is an association between diverticulitis with abscess or diverticulitis complicated by fistula,
diverticulosis and a Western diet high in refined carbohydrates obstruction, or stricture. Elective surgical resection on the basis of
and low in dietary fiber; whether this is a causal association is a patient’s young age at presentation is no longer recommended,
unproved. Patients with uninflamed and nonbleeding diver- and elective sigmoid colectomy after recovery from uncomplicated
ticula are usually asymptomatic. Diverticulitis is one of the most acute diverticulitis should be an individualized decision.
common gastrointestinal diagnoses in hospitals in the US. Indications for emergency surgery include diffuse peritonitis
Approximately 20% of patients with diverticula have an epi- and failure of nonoperative management of acute diverticulitis.
sode of symptomatic diverticulitis. If the neck of a diverticulum For emergency indications, the first stage of a 2-stage procedure
is obstructed, it may distend and lead to bacterial overgrowth and involves resection of the diseased segment and creation of an end
invasion, sometimes perforation, which is generally walled off by colostomy with oversewing of the distal colonic or rectal stump
the adjacent mesocolon or appendices epiploicae. Stage I diver- (Hartmann procedure). Colonic continuity may be reestablished
ticulitis is characterized by small confined pericolonic abscesses, in a second operation.
and stage II disease includes larger confined pericolonic
collections. Stage III involves generalized suppurative peritonitis
(perforated diverticulitis); because the diverticular neck is gener- Prevention
ally obstructed by a fecalith, peritoneal contamination by feces A high-fiber diet, decreased intake of red meat, adequate water
may not occur. Stage IV indicates fecal peritonitis. intake, and measures to avoid constipation may help prevent di-
verticulitis. The avoidance of nuts and popcorn does not prevent
Clinical Features diverticulitis. Smoking cessation, physical activity, and weight
loss are recommended to possibly decrease the risk of divertic-
Symptoms of diverticulitis include lower abdominal pain, fever, ulitis. The use of mesalamine, rifaximin, or probiotics does not
and altered bowel habits (typically, diarrhea). Dysuria, urinary decrease the risk of diverticulitis.
frequency, and urinary urgency reflect bladder irritation, whereas
pneumaturia, fecaluria, and recurrent polymicrobial urinary tract ✓ Diverticular disease
infection suggest a colovesical fistula. Physical findings include • Common, and incidence increases with age
fever, tenderness in the left lower quadrant of the abdomen, or • Diverticulitis—most common complication
a mass. ✓ Computed tomography of the abdomen and pelvis—most appro-
Rupture of a peridiverticular abscess or uninflamed divertic- priate initial imaging when diverticulitis is suspected
✓ Treatment of diverticulitis
ulum causes peritonitis, occurs more commonly in elderly and
• No antibiotics for mild uncomplicated diverticulitis
immunosuppressed persons, and is associated with a high mor- • Percutaneous drainage for abscesses larger than 3 cm
tality rate. Repeated episodes of acute diverticulitis may lead
guidelines for the treatment of left-sided colonic diverticulitis. Dis

• Most cases do not need surgical intervention
Colon Rectum. 2020 Jun;63(6):728–47.
• Decisions related to surgery should be individualized on the
Johnson S, Lavergne V, Skinner AM, Gonzales-Luna AJ, Garey KW,
basis of recurrent episodes and immunosuppression
Kelly CP, et al. Clinical practice guideline by the Infectious Diseases
• Elective colectomy is recommended for diverticulitis compli-
Society of America (IDSA) and Society for Healthcare Epidemiology
cated by fistula, obstruction, or stricture
of America (SHEA): 2021 focused update guidelines on management
• Urgent partial colectomy is recommended for diffuse perito-
of Clostridioides difficile infection in adults. Clin Infect Dis. 2021
nitis or for failure of nonoperative management
Sep 7;73(5):755–7.
✓ After resolution of acute diverticulitis, a colonoscopy should
Khanna S. My treatment approach to Clostridioides difficile infection.
be performed 6 to 8 weeks later if one has not been performed
Mayo Clin Proc. 2021 Aug;96(8):2192–204.
recently
McDonald LC, Gerding DN, Johnson S, Bakken JS, Carroll KC, Coffin
✓ Prevention—high-fiber diet; nuts and popcorn do not need to be
SE, et al. Clinical practice guidelines for Clostridium difficile infec-
limited
tion in adults and children: 2017 update by the Infectious Diseases
Society of America (IDSA) and Society for Healthcare Epidemiology
of America (SHEA). Clin Infect Dis. 2018 Mar 19;66(7):e1–e48.
Shane AL, Mody RK, Crump JA, Tarr PI, Steiner TS, Kotloff K,
Suggested Reading et al. 2017 Infectious Diseases Society of America clinical practice
Hall J, Hardiman K, Lee S, Lightner A, Stocchi L, Paquette IM, et al. guidelines for the diagnosis and management of infectious diarrhea.
The American Society of Colon and Rectal Surgeons clinical practice Clin Infect Dis. 2017 Nov 29;65(12):e45–e80.
19
Colorectal Neoplasmsa
DEREK W. EBNER, MD
JOHN B. KISIEL, MD
Colorectal cancer (CRC) is primarily a disease of urban, and adenocarcinomas of the breast, ovary, prostate, lung,
industrialized societies. In the US, the lifetime risk of CRC is and stomach. Because of the relative rarity of the other pri-
similar for men (4.4%) and women (4.1%). Recent data have mary malignancies, the term CRC is used throughout the rest
suggested that the incidence rates of CRC may be decreasing of this chapter to refer to primary colon adenocarcinoma.
gradually in some subgroups of the population but increasing The term colorectal neoplasia is used to refer to either malig-
in adults younger than 50 years. However, the mechanisms un- nant adenocarcinomas or premalignant precursor lesions, as
derlying these trends have not been defined completely. Several described in more detail below.
national organizations have endorsed screening and surveillance
guidelines, which undoubtedly have contributed to more effective ✓ Colorectal cancer—primary adenocarcinoma; can also include
prevention of CRC. neuroendocrine, sarcomatous, and lymphomatous malignancies
primary to the colon, but excludes metastasis
✓ Colorectal neoplasia—malignant adenocarcinoma or premalig-
Clinical Features nant precursor lesions
✓ Advanced colorectal neoplasia— cancers and premalignant
Definitions lesions with advanced features
Most cases (>95%) of CRC are adenocarcinomas. Less common ✓ Advanced features—high-grade dysplasia, 1 cm or larger, and
cancer subtypes include lymphoma, neuroendocrine, and villous features
leiomyosarcoma. Metastatic lesions to the colorectum can in- ✓ High-risk features—advanced features or 3 or more premalig-
nant precursors (or both); predictive of future advanced colorectal
clude lymphoma, leiomyosarcoma, malignant melanoma,
neoplasia

a
Portions previously published in Limburg PJ, Ahlquist DA. Colorectal
adenocarcinoma. In: Johnson LR, ed. Encyclopedia of gastroenterology.
Academic Press; 2004:457-66 and Hawk ET, Limburg PJ, Viner JL. Presentation
Epidemiology and prevention of colorectal cancer. Surg Clin North Am. Clinical manifestations of CRC are often related to tumor size
2002 Oct;82(5):905-41; used with permission.
and location. Common signs and symptoms with proximal
Abbreviations: CMS, consensus molecular subtype; COX- 2, neoplasms (cecum to splenic flexure) include ill-defined abdom-
cyclooxygenase 2; CRC, colorectal cancer; CT, computed tomography; inal pain, weight loss, and occult bleeding. Patients with distal
EGFR, epidermal growth factor receptor; FAP, familial adenomatous pol-
neoplasms (descending colon to rectum) may present with altered
yposis; FOLFIRI, 5-fluorouricil, leucovorin, and irinotecan; FOLFOX,
5-
fluorouracil, leucovorin, and oxaliplatin; HNPCC, hereditary bowel habits, decreased stool caliber, hematochezia, or a com-
nonpolyposis colorectal cancer; MAP, MUTYH-associated polyposis; bination of these features. Colonoscopy is the test of choice for
MMR, mismatch repair; MSI, microsatellite instability; NCCN, National the diagnostic evaluation of any signs or symptoms suggestive
Comprehensive Cancer Network; SEER, Surveillance, Epidemiology, of CRC because tissue specimens can be obtained at the time
and End Results; SSL, sessile serrated lesion of visual inspection. Up to 7% of patients with CRC may have
221
additional, synchronous malignancies in the colon or rectum at called microsatellites. In addition to microsatellite instability
the time of the index cancer diagnosis. At the initial diagnosis of (MSI), CMS1 CRCs have aberrant hypermethylation in CpG is-
CRC, 37% of patients have localized disease, 35% have regional lands, BRAF (OMIM 164757) sequence variants, and immune
metastases, and 21% have distant metastases. Distant metastases cell infiltration. CMS2 (canonical) tumors are characterized by
typically occur in the liver, peritoneal cavity, and lungs. Less chromosomal instability and activation of Wnt by APC (OMIM
common sites of metastases are the adrenal glands, ovaries, and 611731) variation or other mechanisms. CMS3 (metabolic)
bones. Central nervous system metastases are rare. CRCs harbor KRAS (OMIM 190070) variants and are typically
low in DNA methylation. CMS4 (mesenchymal) cancers show
stromal infiltration and transforming growth factor β activation.
Adenoma-Carcinoma Sequence
These features are useful for prognosis and selection of specific
Most CRCs are thought to develop through an ordered series of therapies (discussed below).
events: Normal colonic mucosa develops into mucosa at risk,
which develops into an adenoma, which develops into adenocar-
Polyp Subtypes
cinoma. Indirect evidence to support this adenoma-carcinoma se-
quence includes the following: 1) prevalence rates cosegregate Adenomatous polyps are considered to have malignant poten-
within populations, 2) subsite distribution patterns within the tial, whereas hyperplastic, inflammatory, and hamartomatous (ju-
colorectum are similar, 3) benign adenomatous tissue is often venile) polyps generally do not. Sessile serrated lesions (SSLs)
juxtaposed with invasive cancer in early- stage malignancies, confer an increased risk of future CRC and are implicated in being
and 4) incidence rates of CRC are decreased by endoscopic precursor lesions for microsatellite-unstable CRC (Figure 19.2).
polypectomy. Adenomas can be classified further as tubular (70%-85%), villous
A diverse group of molecular alterations has been associated (<5%), or tubulovillous (10%-25%) on the basis of their glandular
with the adenoma-carcinoma sequence (Figure 19.1). Rather than histologic features and as low-grade or high-grade on the basis of
a sequential progression through all these molecular alterations, their degree of dysplasia. “Advanced” adenomas are associated
several aberrancies commonly cluster together. The consensus with an increased risk of CRC and usually are defined by 1) large
molecular subtype (CMS) classification was developed to account size (≥1 cm), 2) any villous histologic features, or 3) high-grade
for this molecular heterogeneity. CMS1 (immune) tumors show dysplasia. Multiple (≥3) synchronous adenomas also are associ-
sequence variations or instability in normally repetitive regions ated with an increased risk of CRC.
Figure 19.1. Adenoma-Carcinoma Sequence and the Associated Molecular Alterations Involved in Colon Cancer Development. APC
indicates adenomatous polyposis coli tumor suppressor gene; CIN, chromosomal instability; COX-2, cyclooxygenase 2; DCC, deleted in colorectal
cancer gene; MSI, microsatellite instability. (Adapted from Van Schaeybroeck S, Lawler M, Johnston B, Salto-Tellez M, Lee J, Loughlin P, et al.
Colorectal cancer. In: Niederhuber JE, Armitage JO, Doroshow JH, Kastan MB, Tepper JE, editors. Abeloff’s clinical oncology. 5th ed. Philadelphia
[PA]: Elsevier Churchill Livingstone; c2014. p. 1278-335.e14; used with permission.)
19. Colorectal Neoplasms 223
Figure 19.2. Colon Polyp Architecture. A, Tubular adenoma resembles normal colonic architecture but has irregular, crowded, and hyperchromatic
nuclei (arrow). B, Villous adenoma has epithelial fingerlike projections (bracket) formed by fibrovascular cores and lined with dysplastic epithelium.
C, High-grade dysplasia has architectural complexity, loss of nuclear polarity, and prominent nucleoli (arrow). D, Sessile serrated lesions (SSLs) often
occur in the right colon. They have serrations that extend the length of the crypt (bracket) and boot-shaped deformity at the crypt base (arrow). E,
Traditional serrated adenomas have “ectopic” crypts, which appear to be free-floating rather than anchored to the muscularis mucosae (frame). These
lesions have malignant potential, are often in the left colon, and are much less common than SSLs. F, A hyperplastic polyp has serrations in only the
upper half of the crypt (bracket). These are typically rectosigmoid in location and have no malignant potential. (Photos A, B, and C courtesy of Rondell
P. Graham, MBBS, Anatomic Pathology, Mayo Clinic. Photos D, E, and F adapted from Sweetser S, Smyrk TC, Sinicrope FA. Serrated colon polyps
as precursors to colorectal cancer. Clin Gastroenterol Hepatol. 2013 Jul;11[7]‌:760-7; used with permission.)
Staging and Prognosis ✓ Presenting symptoms of CRC

The American Joint Commission on Cancer system is com- • Proximal colon: ill-defined abdominal pain, weight loss, and
monly used to stage colon and rectal cancers (Table 19.1). It occult bleeding
• Distal colon: altered bowel habits and decreased stool caliber
subcategorizes the pathologic stage of the tumor to correlate
with or without hematochezia
with prognosis. This classification system subdivides pathologic • Diagnostic colonoscopy is required for evaluation
stages further to account for worse prognosis on the basis of the ✓ Adenoma carcinoma sequence
depth of tumor invasion, number of metastatic regional nodes, and • Up to 10 years for malignant transformation from early pre-
number of metastatic sites. For colon cancers, the preoperative, cursor to invasive cancer
or clinical, stage typically is determined by physical examination, • Accumulation of molecular events that promote tumorigenesis
computed tomography (CT), and chest radiography. For rectal • Molecular events aggregate into subtypes that have therapeutic
cancer, endoscopic ultrasonography or pelvic magnetic resonance and prognostic implications
imaging can provide additional information about the depth of ✓ Precursor polyp lesions have different levels of risk for future ad-
tumor invasion and regional lymph node status. The final CRC vanced neoplasia
• Removal of premalignant polyps results in lower population in-
stage incorporates pathology review (lowercase letter p) of the
cidence of CRC
resected tumor (T) tissue, lymph nodes (N), and biopsy of distant ✓ Staging and prognosis
metastatic (M) disease. Before neoadjuvant radiochemotherapy, • Pathologic stage is best predictor of survival
rectal cancers may be given a clinical stage according to imaging • Five-year survival rate: 64% (localized, 90%; regional, 71%;
findings and designated by a lowercase letter c, or a lowercase and distant, 14%)
u for endorectal ultrasonography, noted before the TNM scores;
pathologic staging determined after neoadjuvant radiotherapy is
designated by the lowercase letter y. Pathologic stage is the best
predictor of survival. The overall 5-year survival rates for colon Epidemiologic Factors
cancer and rectal cancer are generally similar (64%). By stage,
General Distribution
5-year survival rates are as follows: localized, 90%; regional
(invaded nearby tissue or spread to nearby lymph nodes), 71%; Worldwide, CRC ranks third in cancer incidence for men and
and distant metastatic, 14%. second for women. However, the incidence rates vary by global
Table 19.1. Colorectal Cancer Staging incidence rates also differ, and the proportion of cases of CRC
located in the proximal colon appears to be increasing compared
Stage TNM Classification a,b
with the proportion of cases in the distal colon and rectum.
0 Tis N0 M0
I T1 or T2 N0 M0
IIA T3 N0 M0 Age
IIB T4a N0 M0
IIC T4b N0 M0
As with most malignancies, the incidence rates of CRC increase
IIIA T1-T2 N1/N1c M0 with advancing age. Less than 7% of cases occur among persons
T1 N2a M0 younger than 45 years. SEER data suggest that age-specific inci-
IIIB T3-T4a N1/N1c M0 dence rates of CRC begin to increase more rapidly during the fifth
T2-T3 N2a M0 decade. The prevalence of adenomatous polyps also increases
T1-T2 N2b M0 with age, with estimates of 30% at 50 years, 40% to 50% at
IIIC T4a N2a M0 60 years, and 50% to 65% at 70 years. Also, several important
T3-T4a N2b M0
clinical features of adenomas may be age-related. In the National
T4b N1-N2 M0
IVA Any T any N M1a
Polyp Study, the risk of having a polyp with high-grade dysplasia
IVB Any T any N M1b was 80% higher among participants 60 years or older than among
IVC Any T any N M1c younger participants.
a
T category (primary tumor): Tis, tumor confined to mucosa; T1, tumor invades the
submucosa; T2, tumor invades through the submucosa and into the muscularis propria; Personal History of Colorectal Neoplasia
T3, tumor invades through the muscularis propria and into pericolorectal tissues; T4,
tumor invades through the entire colorectal wall and into nearby tissues and organs. Persons with a personal history of colorectal adenomas or
adenocarcinomas are at increased risk (up to 6-fold) for ad-
b
Prognosis varies with the following: 1) Depth of tumor penetration: T4a
ditional, or metachronous, neoplasms. Adenoma characteris-
penetrates the surface of the visceral peritoneum and T4b invades into or adheres
to other organs. 2) Number of nodes: N0 (no nodal metastases); N1a (metastasis in tics associated with future tumor development include large
1 regional node); N1b (metastasis in 2-3 regional nodes); N1c (no regional nodes size (≥1 cm), villous histology, and 3 or more lifetime co-
but tumor in subserosa, mesentery, or nonperitonealized pericolic, or perirectal lonic adenomas. Neither rectosigmoid hyperplastic polyps nor
or mesorectal tissue); N2a (metastasis in 4-6 nodes); and N2b (metastasis in ≥7 small, solitary tubular adenomas are strong risk factors for
nodes). 3) Metastatic sites: M0 (no distant metastasis); M1a (single metastatic
site); M1b (multiple metastatic sites); and M1c (peritoneal carcinomatosis).
metachronous neoplasms. After resection of CRC, the annual in-
cidence rate of a second primary colon or rectal cancer has been
Adapted from Jessup J, Goldberg R, Asare E, Benson A, Brierly J, Chang G, et al. estimated at 0.35%.
Colon and rectum. In: Amin MB, Edge SB, Greene FL, American Joint Committee
on Cancer, eds. AJCC cancer staging manual. 8th ed. 2017:251-74; used with
permission. Family History of Colorectal Neoplasia
Familial clustering occurs in approximately 20% of all cases of
region (10-fold difference); most cases occur in industrialized CRC, including patients with heritable cancer syndromes (see
regions. Areas with the highest reported incidence rates of CRC below). In the absence of an identifiable syndrome, a strong
include North America, Australia and New Zealand, Western family history of colorectal neoplasia (typically defined as having
Europe, and Japan. Conversely, most parts of Africa and Asia 1 first-degree relative with colorectal neoplasia diagnosed before
report low incidence rates. In the US, both the incidence and the age 60 years or ≥2 first-degree relatives with colorectal neoplasia
mortality for CRC decreased approximately 2% annually from diagnosed at any age) appears to confer an approximately 1.5-to
2007 to 2016. However, the incidence has increased among per- 2-fold increase in the risk of CRC.
sons younger than 50 years. In the US, CRC is projected to
account for 8% of new cancer diagnoses and for 9% of cancer-
associated deaths among men and 8% among women in 2023.
Chronic ulcerative colitis and Crohn colitis are associated with
an increased risk of CRC. In the US and Europe, the incidence
Race and Ethnicity of colitis-associated cancers appears to have decreased in re-
Of the 5 major racial-ethnic population subgroups monitored by cent decades but remains strongly correlated to the duration of
the Surveillance, Epidemiology, and End Results (SEER) pro- chronic colitis. The extent of colitis has been positively associ-
gram, Blacks in the US have the highest incidence and mortality ated with CRC risk (ie, the risk with pancolitis is greater than the
rates for CRC. Although this likely is explained, at least partly, risk with distal colitis, which is greater than the risk with proc-
by differences in the stage of disease at the time of diagnosis, titis), but the effects of disease activity have not been defined
the survival gap persists when within- stage comparisons are completely. Primary sclerosing cholangitis and a family history
made. Racial disparities in CRC burden are likely exacerbated of CRC are additional risk factors. However, the effects of dis
by limited access to screening and lack of access to high-quality ease activity on the risk of CRC are not conclusively known.
treatment. Screening for dysplasia is encouraged at 8 to 10 years after diag-
nosis of colonic inflammatory bowel disease and repeated every
1 to 5 years. Fewer data are available on the association between
Anatomical Subsite Crohn disease and CRC, but the risk appears to be comparable to
Anatomical subsites of the colorectum differ in their embryologic that of chronic ulcerative colitis when more than one-third of the
origin, physiologic function, and vascular supply. Differences colon has been involved after a similar duration. Current data do
in the morphology, histology, and genetics of CRC have been not support an increased CRC risk for patients with lymphocytic
observed across regions within the large bowel. Subsite-specific or collagenous colitis.
Dietary Components Other

Excess body weight has been associated with a 1.5-to 2-fold In a meta-analysis of data from 15 observational studies, patients
increase in the risk of CRC, although not all observational with type 2 diabetes had a 30% increase in the risk for CRC
studies have had consistent results. Red meat, particularly when compared with those without diabetes. Insulin resistance has
consumed with a heavily browned surface, has been proposed as been proposed as the underlying mechanism of tumorigenesis.
a risk factor for both benign and malignant colorectal neoplasia. Persons with acromegaly may be predisposed metabolically
Meats processed by salting, curing, fermentation, or smoking or anatomically to higher risks for CRC. Because of the relative
are listed by the World Health Organization as carcinogenic to rarity of this condition, most observational studies have lacked
humans. adequate statistical power, but the preponderance of evidence
Vegetables and fruits contain a wide array of potentially supports a positive risk association.
anticarcinogenic substances that may function through 1 or sev- Cholecystectomy results in an altered fecal bile acid compo-
eral independent or codependent mechanisms. Generally, vege- sition. Two meta-analyses have reported moderately increased
table consumption has been 1 of the most consistent predictors of risks of 11% to 34% for CRC (mainly in the proximal colon)
reduced risk of CRC, but fruit consumption appears to be associ- after gallbladder surgery.
ated less strongly with reductions in large-bowel tumorigenesis.
Fiber enhances stool bulk, decreases the concentration of ✓ CRC epidemiology
procarcinogenic secondary bile acids, and increases the concen- • Third most common and fatal cancer in men (after lung and
tration of anticarcinogenic short-chain fatty acids. Although mul- prostate cancers), third most common and fatal cancer in
tiple case-control studies initially suggested a protective effect women (after lung and breast cancers), second most common
from increased intake of dietary fiber, subsequent intervention and fatal cancer in men and women combined
• Incidence and mortality are increasing among persons younger
trials have not shown appreciable reductions in the risk of CRC.
than 50 years
Calcium binds to intraluminal toxins and also influences • Blacks in the US have the highest incidence and mortality
mucosal proliferation within the colorectum. In 1 clinical • Incidence increases with age and male sex
trial, calcium supplementation was associated with a statisti- • Personal history of advanced or high-risk colorectal neoplasia
cally significant 19% decrease in the recurrence of adenoma is the strongest risk factor for subsequent (metachronous) ad-
in postpolypectomy patients after 4 years. However, in another vanced neoplasia, including cancer
large, randomized, controlled trial of postmenopausal women, • Family history of CRC is identified in about 20% of all cases
calcium and vitamin D supplementation for 7 years had no ap- • Inflammatory bowel disease involving the colon is a strong risk
preciable effect on incident CRC. factor that increases the lifetime incidence by 2-to 3-fold
Antioxidants (including retinoids, carotenoids, ascorbic acid, • Weaker risk factors: sedentary lifestyle, obesity, type 2 dia-
betes, alcohol, tobacco, and processed meat consumption
α-tocopherol, and selenium) have been hypothesized to prevent
carcinogen formation by neutralizing free radical compounds. So
far, observational and experimental data have been unimpressive,
with the exception that selenium decreased the risk of CRC by Heritable Syndromes
58% when measured as a secondary end point in a skin cancer Well-
defined hereditary CRC genetic syndromes account for
prevention study. approximately 2% to 5% of all large-bowel malignancies. An
Folate and methionine supply methyl groups necessary for important point is that patients with gene variations are also at
critical cellular functions such as nucleotide synthesis and gene increased risk for target organ cancers outside the colorectum.
regulation. Particularly in the context of excess alcohol con-
sumption, dietary deficiencies of these compounds may be a risk
factor for CRC. Nonetheless, in a recent multicenter clinical trial Familial Adenomatous Polyposis
of participants with a previous history of benign colorectal neo- Germline mutations in the APC gene form the basic molecular
plasia, folic acid 1 mg daily was associated with an increased risk foundation for familial adenomatous polyposis (FAP) (an auto-
of both recurrent advanced adenomas and noncolorectal cancers. somal dominant condition). As many as 1 in 5 cases may result
from new-onset spontaneous mutations. The estimated preva-
lence is 1 per 5,000 to 7,500 persons. Additional but unidenti-
Lifestyle
fied genetic and environmental factors seem likely to influence
Alcohol induces cellular proliferation, blocks methyl group do- the clinical manifestations of FAP because phenotypic features
nation, and inhibits DNA repair. Many observational studies have vary widely despite similar inherited APC alterations. The hall-
suggested a 2-to 3-fold increase in the risk of CRC with excess mark lesion of FAP is diffuse colorectal polyposis, and, typically,
alcohol consumption, although a meta-analysis of 27 case-control hundreds to thousands of adenomas develop during adolescence.
and cohort studies found only a 10% increase in risk among daily Other findings include duodenal adenomas, gastric (fundic)
alcohol users. gland hyperplasia, mandibular osteomas, and supernumerary
Tobacco smoke contains numerous putative carcinogens, in- teeth. In the absence of prophylactic colectomy, CRC inevitably
cluding polycyclic aromatic hydrocarbons, nitrosamines, and ar- is diagnosed in patients with FAP at a mean age of approximately
omatic amines. On the basis of data from several large cohort 40 years. Even after colectomy, patients have an increased risk
studies, smoking appears to be a risk factor for CRC after a pro- for cancer, particularly in the periampullary region of the duo-
longed latency of 20 or more years. denum and in the retained rectal remnant (if partial colectomy
Physical activity has been associated consistently with a 40% was performed).
to 50% decrease in the risk for CRC, particularly in the distal Gardner syndrome is a variant of FAP in which patients with
colon, through the stimulation of intestinal transit, decreased APC alterations have the same phenotypic features as in classic
prostaglandin E2 levels, or other undefined mechanisms. FAP, but they also can have osteomas of the skull and long bones,
congenital hypertrophy of the retinal pigmented epithelium, des- which maintain nucleic acid sequence integrity during replica-
moid tumors, epidermoid cysts, fibromas, and lipomas. tion. According to the NCCN, the specific germline variant can
be used to further individualize the frequency of endoscopic
screening and surveillance. Adenomas are believed to precede
Attenuated FAP
carcinomas in most instances, and CRC develops in 75% to 80%
Compared with classic FAP, attenuated FAP is associated with of patients with Lynch syndrome, at a median age of 46 years.
relatively fewer adenomas (<100) and a later onset of CRC (ap- It has been reported that for persons with Lynch syndrome, reg-
proximate age at onset, 55 years). About 40% of these cases ularly performed colonoscopy with polypectomy can decrease
are associated with germline APC alterations. Because both the the risk of large-bowel adenocarcinoma by approximately 60%.
adenomas and the cancers appear to arise in the proximal colon, Patients who receive a diagnosis of CRC with Lynch syndrome
at-risk family members should have screening with full colonos- are often treated with subtotal colectomy rather than segmental
copy rather than with flexible sigmoidoscopy, as recommended surgical resection. Women with Lynch syndrome have a very
for screening in classic FAP kindreds. high risk for endometrial cancer and should be offered total
hysterectomy or endometrial biopsy every 1 to 2 years. Not all
Lynch Syndrome patients with HNPCC have Lynch syndrome. Patients who meet
the Amsterdam criteria for HNPCC and have MMR-proficient
Hereditary nonpolyposis CRC (HNPCC) is a clinical phenotype, tumors are considered to have familial CRC type X, and those who
and family history suggests that it is an autosomal dominant syn- have MMR-deficient tumors but no somatic or germline MMR
drome; features include early-onset CRC, usually located in the gene variations are considered to have Lynch-like syndrome.
proximal colon, and increased risk of extracolonic malignancies
(in the uterus, ovaries, stomach, urinary tract, small bowel, and
bile duct). The clinical criteria for considering a person to be at Turcot Syndrome
risk for HNPCC are the Amsterdam criteria (Box 19.1). Lynch Turcot syndrome is a familial predisposition for both colonic
syndrome is a common cause of HNPCC. Lynch syndrome is polyposis and central nervous system tumors. It likely is a con-
genetically defined by the presence of a germline alteration in the stellation of molecular features that can be variants of either FAP
DNA mismatch repair (MMR) genes or EPCAM gene (OMIM or Lynch syndrome. Patients with early-onset colonic polyposis
185535). Because the Amsterdam criteria are not sufficiently sen- associated with APC variations tend to have medulloblastomas
sitive to identify all cases of Lynch syndrome, and because MMR (an FAP variant), whereas those with DNA mismatch repair
expression has therapeutic value, the National Comprehensive gene variations are prone to the development of glioblastoma
Cancer Network (NCCN) recommends that all colorectal primary multiforme (a Lynch syndrome variant). Of interest, glioblas-
tumors should be tested for phenotypes MMR deficiency (ei- toma multiforme that arises in Turcot syndrome tends to occur
ther MSI testing or MMR expression testing) (see the Universal at an earlier age and carry a better prognosis than the sporadic
Molecular Testing of Colon Cancer section below). If results are form of the tumor.
positive, germline variations should be sought in the DNA MMR
genes (MLH1 [OMIM 120436], MSH2 [OMIM 609309], MSH6
Muir-Torre Syndrome
[OMIM 600678], and PMS2 [OMIM 600259]) and EPCAM,
Patients with Muir-Torre syndrome have sebaceous neoplasms, uro-
genital malignancies, and gastrointestinal tract adenocarcinomas in
association with defective DNA mismatch repair. The ratio of af-
Box 19.1. Amsterdam Clinical Criteria for Hereditary fected men to women is 2:1.
Nonpolyposis Colorectal Cancer Syndrome
✓ Hereditary nonpolyposis colorectal cancer (HNPCC)— clin-
At least 3 relatives have had Lynch syndrome–related ical phenotype of young-onset colon cancer, familial cancers as-
cancersa sociated with Lynch syndrome, and family history suggesting an
At least 1 relative is a first-degree relative of 2 other autosomal dominant syndrome (Amsterdam criteria describe the
affected persons clinical criteria)
At least 2 successive generations have been ✓ Lynch syndrome—1 of several diseases causing HNPCC; defined
affected by germline variations in 1 of 4 DNA mismatch repair (MMR)
genes (MLH1, MSH2, MSH6, PMS2) or EPCAM
At least 1 relative received diagnosis before
✓ Deficient MMR—phenotypic feature of Lynch syndrome and other
age 50 y
forms of HNPCC, which is measured by immunohistochemistry
Familial adenomatous polyposis should be excluded for MMR proteins or by microsatellite instability polymerase chain
in the colorectal cancer case(s) if any reaction testing and can be due to somatic (nonhereditary) events
Tumors should be verified by pathologic ✓ Lynch-like syndrome—deficient MMR phenotype but negative
examination results with genetic testing for germline Lynch mutations and so-
matic (primary tumor) mutations in MMR genes
a
Including cancer of the colorectum, endometrium, small bowel, ✓ Familial CRC type X—meets pedigree phenotype of HNPCC but
ureter, or renal pelvis. has MMR-proficient tumors
✓ Turcot syndrome— familial predisposition for CRC and brain
Adapted from Vasen HF, Watson P, Mecklin JP, Lynch HT. New clin- tumors and is likely a variant of FAP (medulloblastomas) or Lynch
ical criteria for hereditary nonpolyposis colorectal cancer (HNPCC, syndrome (glioblastomas)
Lynch syndrome) proposed by the International Collaborative Group ✓ Muir-Torre syndrome—sebaceous neoplasms, urogenital malig
on HNPCC. Gastroenterology. 1999 Jun;116(6):1453- 6; used with nancies, and gastrointestinal tract adenocarcinomas in association
permission. with deficient MMR

MUTYH-Associated Polyposis Cowden Disease

MYH is a DNA base excision repair enzyme coded for by the Cowden disease is an autosomal dominant condition in which per-
gene MUTYH (OMIM 604933). MUTYH-associated polyposis sons with variations in the PTEN gene (OMIM 158350) may have
(MAP) is an autosomal recessive syndrome with a wide-ranging trichilemmomas, other skin lesions, and alimentary tract polyps
phenotype. The colorectal adenoma burden in MAP can be sim- that are histologically similar to the polyps of juvenile polyposis
ilar to that in attenuated FAP, but there are reports of patients syndrome. Patients with Cowden disease are at increased risk for
with MAP who have more than 100 adenomas. Also, duodenal breast cancer (often bilateral) and papillary thyroid cancer. The
and periampullary adenomas can be found in patients with MAP, risk of CRC is not well-defined in this syndrome, but colonos-
although the true incidence of upper gastrointestinal tract neo- copy should be included in the original diagnostic evaluation.
plasia is not known. Biallelic carriers, or persons with variations
in both MUTYH alleles, have an 80% cumulative risk of CRC by Cronkhite-Canada Syndrome
age 70 years, but monoallelic carriers do not appear to have an
Cronkhite-Canada syndrome is a noninherited condition mani
increased risk for CRC.
fested by signs and symptoms of malnutrition or malabsorption.
Characteristic clinical features include alopecia and hyperker-
Hamartomatous Polyposis Syndromes atosis of the fingernails and toenails. In the US and Europe,
Peutz-Jeghers Syndrome
Cronkhite-Canada syndrome typically develops in men, whereas
in Asian countries, women appear to be affected more often.
Peutz-Jeghers syndrome is an autosomal dominant condition The neoplastic potential of gastrointestinal tract hamartomas
characterized by multiple hamartomatous polyps scattered in Cronkhite-Canada is uncertain; case reports of CRC in these
throughout the gastrointestinal tract. Up to 60% of cases of patients suggest involvement of both typical adenomatous and
the syndrome are related to germline variations in the LKB1 serrated lesion pathways.
(STK11) gene (OMIM 602216). Melanin deposits usually
can be seen around the lips, buccal mucosa, face, genitalia,
Prevention
hands, and feet, although occasionally the skin and intestinal
lesions are inherited separately. Foci of adenomatous epithe- Screening and Surveillance
lium can develop within Peutz-Jeghers polyps and may be as- For patients with average risk (defined as asymptomatic adults
sociated directly with an increased risk of CRC. Extracolonic who are 45-75 years old [screening is individualized for patients
malignancies include other gastrointestinal tract cancers (in 76-85 years old] and who do not have other known CRC risk
the duodenum, jejunum, ileum, pancreas, biliary tree, and factors), the US Multi-Society Task Force on Colorectal Cancer
gallbladder), ovarian sex cord tumors, Sertoli cell testicular has endorsed the following screening options:
tumors, and breast cancer.
• Colonoscopy every 10 years
• Fecal immunochemical test annually
Tuberous Sclerosis • Stool DNA test every 3 years
Tuberous sclerosis (an autosomal dominant condition) is associ- • Flexible sigmoidoscopy every 5-10 years
• CT colonography every 5 years
ated with hamartomas, intellectual disability, epilepsy, and ade-
• Capsule colonoscopy every 5 years
noma sebaceum. Adenomatous polyps may occur, particularly in
the distal colon. Diagnostic colonoscopy should be performed in follow-up of any
noninvasive screening test with positive findings.
For patients with a strong family history of colorectal neo-
Juvenile Polyposis Syndrome
plasia (excluding FAP, Lynch syndrome, and other identifiable
Juvenile polyposis syndrome is an autosomal dominant con- syndromes), colonoscopy is advised every 5 years beginning at
dition in which juvenile mucous retention polyps (misnamed age 40 years (or 10 years before the youngest age at diagnosis
hamartomata) can arise in the colon, stomach, or elsewhere in in the family, whichever is earlier). Strong family history refers
the gastrointestinal tract. Variations of genes in the transforming to patients with 1 first-degree relative who received a diagnosis
growth factor β pathway (SMAD4 [OMIM 600993], BMPR1A of CRC or advanced adenoma when younger than 60 years or
[OMIM 601299], and ENG [OMIM 131195]) have been 2 second- degree relatives with CRC or advanced adenomas
implicated as genetic causes of the syndrome. Symptoms diagnosed at any age.
of bleeding or obstruction may arise during childhood and Recommendations for patients with high risk are shown in
may warrant surgery on the affected intestinal segments for Table 19.2.
treatment of anemia or obstruction or for cancer prevention.
The risk of CRC is increased when synchronous adenomas or History of Colorectal Neoplasia in Persons
mixed juvenile-adenomatous polyps are present. If prophylactic Without High-Risk Diseases
or therapeutic colonic resection is performed, ileorectostomy
or total proctocolectomy should be considered because of an After a complete clearing colonoscopy (ie, the bowel preparation
increased risk of recurrent juvenile polyps within the retained was adequate and all colonic polyps were removed), subsequent
colorectal segment. Of note, the presence of fewer than 5 ju- examinations are determined according to polyp histology, size,
venile polyps (including solitary polyps) in a person with no and number.
family history of juvenile polyposis syndrome does not indicate
a heritable syndrome and, on the basis of current knowledge, ✓ Risk-stratified intervals for follow-up colonoscopy
• Lowest risk (10 years): normal colonoscopy or no more than 20
does not warrant further diagnostic testing or aggressive cancer
hyperplastic polyps smaller than 10 mm
surveillance.
Table 19.2. Screening and Surveillance Recommendations for Patients With High Risk for Colorectal Cancer
Condition Gene(s) Clinical features Cancer risk reduction strategy
Lynch syndrome MLH1 Accelerated adenoma-carcinoma Colonoscopy: baseline as early as age 20-25 y; follow-up varies with
MSH2 and sequence germline mutation (may be as short as every 1-2 y)
EPCAM Microsatellite instability (MSI) EGD: starting at age 30-40 y; repeated every 2-4 y
MSH6 Risk of extracolonic cancers Consider prophylactic hysterectomy and bilateral salpingo-oophorectomy
PMS2 after childbearing
Skin examination (annually)
Consider pancreatic cancer evaluation (except for PMS2 carriers)
Familial APC ≥100 Cumulative adenomas (10-99 Baseline colonoscopy at puberty; individualized time to colectomy;
adenomatous in attenuated form and right-side then ileorectal evaluation, pouchoscopy, or ileoscopy every 6-12 mo
polyposis (FAP) predilection) EGD: baseline at age 20-25 y with follow-up pending findings
Risk of gastric, duodenal, and ampullary Thyroid evaluation (every 2-5 y)
carcinoma
MUTYH-associated MUTYH Similar to attenuated FAP Colonoscopy: baseline at age 25-30 y; repeat every 1-2 y
polyposis (MAP) EGD: baseline at age 30-35 y with follow-up pending findings
Peutz-Jeghers STK11 Clinical diagnosis if ≥2 of the following: Colonoscopy and EGD: baseline at age 8-10 y; repeat every 2-3 y
syndrome (PJS) ≥2 PJS polyps in GI tract pending findings
Mucocutaneous pigmentation Small bowel: video capsule or enterography every 2-3 y
Family history Pancreatic cancer evaluation (annually)
Additional extraintestinal screening
Juvenile polyposis SMAD4 Clinical diagnosis if ≥5 juvenile polyps Colonoscopy and EGD: baseline at age 12-15 y; repeat every 2-3 y
syndrome (JPS) BMPR1A of the colon or multiple juvenile pending findings
polyps throughout GI tract or any in Screen for features associated with HHT among those with SMAD4 at
patient with family history of JPS first diagnosis
HHT with SMAD4
Serrated polyposis Unknown ≥5 Serrated lesions proximal to rectum, Surveillance colonoscopy every 1-3 y
syndrome (SPS) all ≥5 mm in size (≥2 being ≥10 mm
in size) or >20 serrated lesions of any
size throughout the colon with ≥5
proximal to rectum
Polyp count is cumulative over lifetime
Cowden syndrome PTEN Macrocephaly Colonoscopy: baseline at age 35 y; repeat every 5 y
Trichilemmomas EGD: no screening recommendation
Marked esophageal glycogenic Clinical breast examination and annual mammography
acanthosis Endometrial cancer screening with discussion of prophylactic
hysterectomy
Evaluation of skin (annually), thyroid (annually), and kidneys (every 1-2 y)
Inflammatory bowel NA Ulcerative colitis and Crohn disease Colonoscopy: baseline screening for flat dysplasia 8-10 y after
disease (IBD) involving ≥33% of colon symptom onset
Random 4-quadrant biopsies every 10 cm
Targeted biopsies should be handled separately
Colonoscopy annually for patients with primary sclerosing cholangitis;
otherwise, every 1-5 y according to cumulative risk factors (extent and
duration of inflammation, family history, personal history of colorectal
dysplasia)
Pouch surveillance annually for patients with primary sclerosing
cholangitis and personal history of colorectal cancer
Abbreviations: EGD, esophagogastroduodenoscopy; GI, gastrointestinal; HHT, hereditary hemorrhagic telangiectasia; NA, not applicable.
• Low-risk adenomas (7-10 years): 1 or 2 adenomas smaller

be treated endoscopically, particularly for pedunculated polyps.
than 10 mm However, for sessile polyps with endoscopic features suggesting
• Low-risk sessile serrated lesions (SSLs) (5-10 years): 1 or 2 submucosal invasion (depression, disrupted vessels, or amorphous
SSLs smaller than 10 mm pattern) there is greater risk for nodal metastases; biopsy, tattooing,
• Moderate increased risk (3-5 years): 3 or 4 adenomas or SSLs and referral to surgery should be pursued preferentially in an other-
smaller than 10 mm; large (≥10 mm) hyperplastic polyps (may wise surgically fit patient. The success of endoscopic management
be a misdiagnosed SSL) depends on 1) complete excision of the lesion and thorough exami-
• High-risk (3 years): 5 to 10 adenomas or SSLs (even if small); nation (ideally en bloc) by a pathologist; 2) the depth of invasion and
adenoma or SSL 10 mm or larger; villous architecture or high- grade of differentiation; 3) the absence of high-risk features (poor
grade dysplasia; traditional serrated adenoma
differentiation, vascular invasion, and lymphatic involvement); and
• Highest risk (1 year): more than 10 adenomas; serrated polyp-
osis syndrome
4) the margin of excision being free of cancer cells by at least 1 mm.
Follow-up colonoscopy should be performed at 3 months for malig-
nant polyps that meet these favorable prognostic criteria.
Malignant polyps, defined as neoplasms with dysplastic cells Patients with potentially curable colon or rectal cancer
invading through the muscularis mucosa into the submucosa, can should have a clearing colonoscopy preoperatively or within 3 to
6 months postoperatively if obstructive lesions prevented preop- surgical resection; it may be considered for selected patients who
erative colonoscopy. After clearing colonoscopy, subsequent sur- have advanced disease or if local cancer is inoperable. Extended
veillance examinations can be performed at 1 year, 3 years, and segmental resection is performed to ensure sufficient sampling of
5 years if no additional colorectal neoplasia is found. In addition, a minimum of 12 lymph nodes for accurate staging. The proce-
histologically favorable tumor stage 1 rectal cancers treated en- dure, if feasible, is preferentially performed laparoscopically as
doscopically or by transanal excision (without complete surgical opposed to an open incision because of faster recovery and oth-
staging to obtain lymph nodes) should be assessed with endo- erwise comparable morbidity and mortality. Subtotal colectomy
scopic ultrasonography or magnetic resonance imaging of the or total proctocolectomy may be performed in patients who have
pelvis every 6 months for 5 years. colorectal neoplasia in multiple colonic segments or in patients
who have familial cancer syndromes. Operative intervention also
may be considered for selected patients who have isolated liver
Chemoprevention
or lung metastases. For surgically incurable patients, resection of
Chemoprevention is the use of chemical compounds to pre- the primary cancer is usually indicated only if there is bleeding,
vent, inhibit, or reverse carcinogenesis before the invasion of obstruction, or impending obstruction. Postoperative, or adju-
dysplastic epithelial cells across the basement membrane. In its vant, cytotoxic chemotherapy is recommended for patients with
broadest sense, chemoprevention includes both nutritional and stage III (lymph node involvement) colon cancer. It should be
pharmaceutical interventions. With regard to pharmaceutical considered also for patients with stage II colon cancer who have
agents, nonsteroidal anti-inflammatory drugs are structurally di- poor prognostic factors (poor differentiation, lymphovascular
verse, yet they appear to share abilities to decrease proliferation, or perineural invasion, T4 primary cancer, perforation, inde-
slow cell cycle progression, and stimulate apoptosis. Extensive terminate or positive margins, or tumor budding) according
epidemiologic data uphold a negative risk (40%-60%) associa- to pathology review. The preferred regimen is FOLFOX (5-
tion between the regular use of nonsteroidal anti-inflammatory fluorouracil, leucovorin, and oxaliplatin) for 6 months.
drugs and colorectal tumors. The chemopreventive effects of Rectal adenocarcinoma should be managed through a mul-
these drugs are thought to be derived through cyclooxygenase tidisciplinary surgical, radiation, and medical oncology team.
2 (COX-2) inhibition. In several large clinical trials, agents that Adenocarcinomas in the middle and upper rectum usually are
selectively block this enzyme isoform (celecoxib and rofecoxib) removed by a sphincter-sparing endoscopic resection or surgery.
have been shown to decrease the recurrence rates of adenoma. Cancers in the lower rectum (0-5 cm above the anal verge) often
However, selective COX-2 inhibitors have been associated also require abdominoperineal resection, with a permanent colos-
with increased cardiovascular toxicity, which has limited their tomy. However, sphincter-sparing procedures may be offered if
chemopreventive applications to high- risk clinical settings. complete resection is possible, if small rectal tumors are present,
Emerging research suggests that combining COX-2 inhibitors or while waiting for the response of large or invasive tumors to
with targeted epidermal growth factor receptor (EGFR) inhibitors preoperative chemoradiotherapy or radiotherapy. Preoperative,
(eg, erlotinib) may greatly decrease the duodenal polyp burden in or neoadjuvant, treatment with 5- fluorouracil–
based chemo-
patients with FAP. therapy in combination with radiotherapy generally is indicated
for patients with tumors that are staged as T3 and higher or
N1 and higher by CT of the chest abdomen and pelvis, retro-
Universal Molecular Testing of Colon Cancer grade endoscopic ultrasonography, or magnetic resonance im-
At the time of CRC diagnosis, testing of the primary tumor aging of the pelvis. Adjuvant chemotherapy with 5-fluorouracil
for deficiency of MMR enzymes is recommended by the US and leucovorin (with or without oxaliplatin) is recommended
Preventive Services Task Force and the NCCN. The phenotypes for patients with stage II or stage III rectal cancer. For pallia-
of MMR deficiency include MSI marker polymerase chain reaction of metastatic disease, both FOLFOX and FOLFIRI (a reg-
tion and deficient expression by immunohistochemistry. Either imen containing irinotecan in place of oxaliplatin) are accepted
test may be ordered depending on local expertise. Positive results as first-line cytotoxic regimens. Molecularly targeted therapies
require confirmation with germline sequencing of Lynch syn- have shown benefits for subsets of patients with metastatic or
drome causative variations; if those results are negative, other advanced CRC; emerging data show benefit for those with early-
causes of MMR deficiency, MLH1 hypermethylation and BRAF stage rectal cancer. Bevacizumab is a humanized monoclonal an-
alteration, should be investigated. Testing for these are advised to tibody that targets vascular endothelial growth factor, impairing
confirm that these sporadic events (not requiring genetic testing the proliferation of endothelial cells and formation of new
of relatives) caused the MMR deficiency phenotype. Universal blood vessels. Cetuximab and panitumumab are monoclonal
testing is used 1) to diagnose Lynch syndrome and refer family antibodies that target EGFR. Pembrolizumab and nivolumab are
members for genetic testing and 2) to select therapy for patients monoclonal antibodies that act as immune checkpoint inhibitors,
with metastatic disease. which bind to programmed cell death 1 on T cells and promote
immune-mediating destruction of cancer cells. Ipilimumab is
also a monoclonal antibody checkpoint inhibitor that binds to
Treatment of CRC
cytotoxic T-lymphocyte antigen-4, activating antitumor immu-
Treatment of tumors above the peritoneal reflection differ from nity. Checkpoint inhibitors are most likely beneficial in those
treatment of those in the rectum. The approaches are therefore with MSI high/MMR-deficient CRC. KRAS tumor testing is
described separately. used to select which patients will respond best to an EGFR in-
For most patients who have colon cancer proximal to the hibitor, which may improve outcomes for patients with advanced
rectum, in the absence of known distant metastases or prohibitive tumors with wild-type KRAS. In contrast, mutant KRAS constitu-
comorbid conditions, surgical excision is the initial treatment. tively activates the RAS-RAF-ERK pathway downstream from
Chemotherapy with or without radiotherapy is not provided before EGFR, resulting in resistance to anti-EGFR therapy.
Suggested Reading Ma H, Brosens LAA, Offerhaus GJA, Giardiello FM, de Leng WWJ,
Montgomery EA. Pathology and genetics of hereditary colorectal
American Cancer Society. Colorectal cancer facts & figures. American cancer. Pathology. 2018 Jan;50(1):49–59.
Cancer Society; 2023. Murthy SK, Feuerstein JD, Nguyen GC, Velayos FS. AGA clinical
Cooper K, Squires H, Carroll C, Papaioannou D, Booth A, Logan practice update on endoscopic surveillance and management of co-
RF, et al. Chemoprevention of colorectal cancer: systematic re- lorectal dysplasia in inflammatory bowel diseases: expert review.
view and economic evaluation. Health Technol Assess. 2010 Gastroenterology. 2021 Sep;161(3):1043–51.
Jun;14(32):1–206. National Cancer Institute. Cancer stat facts: colorectal cancer. https://
Gbolahan O, O’Neil B. Update on systemic therapy for colorectal seer.cancer.gov/statfacts/html/colorect.html
cancer: biologics take sides. Transl Gastroenterol Hepatol. Rex DK, Boland CR, Dominitz JA, Giardiello FM, Johnson DA,
2019 4:9. Kaltenbach T, et al. Colorectal cancer screening: recommendations
Giardiello FM, Allen JI, Axilbund JE, Boland CR, Burke CA, Burt RW, for physicians and patients from the US Multi-Society Task Force
et al. Guidelines on genetic evaluation and management of Lynch on Colorectal Cancer. Am J Gastroenterol. 2017 Jul;112(7):1016–30.
syndrome: a consensus statement by the us multi-society task force Syngal S, Brand RE, Church JM, Giardiello FM, Hampel HL, Burt RW,
on colorectal cancer. Am J Gastroenterol. 2014 Aug;109(8):1159–79. et al. ACG clinical guideline: genetic testing and management of he-
Guinney J, Dienstmann R, Wang X, de Reynies A, Schlicker A, Soneson reditary gastrointestinal cancer syndromes. Am J Gastroenterol. 2015
C, et al. The consensus molecular subtypes of colorectal cancer. Nat Feb;110(2):223–62.
Med. 2015 Nov;21(11):1350–6. US Preventive Services Task Force, Davidson KW, Barry MJ,
Gupta S, Lieberman D, Anderson JC, Burke CA, Dominitz JA, Mangione CM, Cabana M, Caughey AB, et al. Screening for colo-
Kaltenbach T, et al. Recommendations for follow-up after colon- rectal cancer: US Preventive Services Task Force recommendation
oscopy and polypectomy: a consensus update by the US Multi- statement. JAMA. 2021 May 18;325(19):1965–77.
Society Task Force on Colorectal Cancer. Gastrointest Endosc. 2020 Wolpin BM, Mayer RJ. Systemic treatment of colorectal cancer.
Mar;91(3):463–85. Gastroenterology. 2008 May;134(5):1296–310.
20
Irritable Bowel Syndrome

PRIYA VIJAYVARGIYA, MD
DAVID O. PRICHARD, MB, BCH, PHD
Irritable bowel syndrome (IBS) is characterized by abdominal practice, this can be helpful. The more criteria a patient meets, the
pain and altered bowel habits in the absence of detectable bio- more likely the patient is to have IBS.
chemical or structural abnormalities. The goal of therapy is to
improve the patient’s symptoms, prevent suffering, and improve
Epidemiology
quality of life. Altered bowel habits and abdominal pain may
need to be treated independently. The bidirectional relationship IBS is a common condition, affecting 10% to 20% of the popu-
between gastrointestinal symptoms and psychological issues is lation in industrialized countries. Not everyone with IBS seeks
well established, and behavioral therapies are effective. medical care, so incidence data are difficult to obtain. One es-
timate of the incidence of clinically diagnosed IBS is 196 per
100,000 person-years. However, about 10% of the general pop-
Definition ulation reports the onset of IBS symptoms over a 1-year period.
The current symptom criteria for the diagnosis of IBS, based The difference between the clinical incidence and onset figures
on the Rome IV criteria, are presented in Box 20.1. The Rome likely reflects the limited use of health care by some persons with
criteria were developed in conjunction with the World Congress IBS and the fluctuating pattern of IBS symptoms. Still, this is
of Gastroenterology held in Rome, Italy, in 1988 and were re- much higher than the incidence of colon cancer (50 per 100,000
vised in 1999 (Rome II), 2006 (Rome III), and 2016 (Rome
IV). The Rome criteria are similar to the criteria established by
Manning and colleagues in 1978. However, the Rome criteria in- Box 20.1. Diagnostic Criteria for Irritable Bowel
corporate constipation-type symptoms into the definition. The Syndromea
dominant bowel pattern of patients is used to classify IBS into
Recurrent abdominal pain on an average of
4 categories: diarrhea-predominant IBS (IBS-D), constipation-
≥1 d/wk with ≥2 of the following:
predominant IBS (IBS-C), mixed-type IBS (IBS-M), and unclas-
sified IBS (IBS-U) (Figure 20.1). a. Pain related to defecation
As with any set of criteria, there is a trade-off between sensi- b. Associated with a change in frequency of stool
tivity and specificity, depending on the threshold used. In clinical c. Associated with a change in form (appearance)
of stool
a
Criteria fulfilled for the past 3 months, with symptom onset at least 6
Abbreviations: FDA, US Food and Drug Administration; FODMAP, months before diagnosis.
fermentable oligosaccharides, disaccharides, monosaccharides, and
polyols; HLA, human leukocyte antigen; IBS, irritable bowel syndrome; Adapted from Lacy BE, Mearin F, Chang L, Chey WD, Lembo AJ,
IBS-C, constipation-
predominant irritable bowel syndrome; IBS- D, Simren M, et al. Bowel disorders. Gastroenterology. 2016;150(6):1393-
diarrhea-predominant irritable bowel syndrome; IBS-M, mixed-type ir- 407; used with permission.
ritable bowel syndrome; IBS-U, unclassified irritable bowel syndrome.
231
Figure 20.1. Relationship Between Predominant Bowel Habit and Subtypes of Irritable Bowel Syndrome (IBS). A, The Bristol Stool Form
Scale recognizes 7 types of stool consistency. B, The stool type in the bowel movement (BM) is used to classify IBS subtypes as constipation-
predominant IBS (IBS-C), diarrhea-predominant IBS (IBS-D), mixed-type IBS (IBS-M), or unclassified IBS (IBS-U). (Adapted from Lacy BE, Mearin
F, Chang L, Chey WD, Lembo AJ, Simren M, et al. Bowel disorders. Gastroenterology. 2016;150[6]‌:1393-407; used with permission.)
person-years) and inflammatory bowel disease (10 per 100,000 medical centers, likely reflecting the severity of IBS or person-
person-years). ality traits (or both).
Many patients with IBS report that a family member also
has the condition. Familial aggregation of IBS exists, and twin
Risk Factors
studies have suggested a genetic component. Other studies have
Multiple risk factors have been proposed for IBS. In clinic-based shown that health care for gastrointestinal problems is sought
studies, there is a strong association with sex. However, the fe- more frequently among children of parents who have gastroin-
male to male ratio in the community is approximately 2:1. Thus, testinal symptoms. Additional study is needed to characterize the
sex may have a role not only in the onset of IBS but also in influence of nature and nurture in the development of IBS.
health care–seeking behavior. Even though the prevalence of Postinfectious IBS is a well-recognized subtype of IBS that
IBS decreases slightly with age, new symptoms may occur in develops de novo after bacterial or viral gastroenteritis. The pro-
the elderly. Prevalence estimates are available from around the pensity for postinfectious IBS to develop is associated with fe-
world, but no consistent racial or ethnic differences have been male sex, duration of illness, and the psychological state (anxiety
identified. and depression) of the person at the time of infection. It usually
Multiple studies have assessed the role of personality char- develops into a diarrhea-predominant phenotype.
acteristics, psychiatric illness, and physical and sexual abuse Food sensitivities also may have a role in the development
in the development of IBS. These associated characteristics are of IBS. Patients with IBS symptoms report more sensitivity to
seen more frequently in patients with IBS evaluated in academic food than people without symptoms. This could potentially be
20. Irritable Bowel Syndrome 233
secondary to increased colonic contractions after eating asso- A symptom-based diagnosis is recommended when patients
ciated with the gastrocolic reflex, alteration in the microbiome, fulfill the diagnostic criteria, clinical examination findings are
insoluble foods that may result in increased gas production and normal, and the patient does not have warning symptoms (no
water secretion, or changes in intestinal epithelial barrier function. overt blood within the stool, weight loss, recent change in bowel
To date, the data on exclusion diets have not convincingly shown habits, nocturnal pain or passage of stools, family history of co-
that food is a cause of the symptoms. Moreover, only 25% of lorectal cancer or inflammatory bowel disease, palpable abdom-
patients who completed a double-blind reintroduction of known inal mass or lymphadenopathy, or iron deficiency anemia). Only
symptomatic foods experienced a return of abdominal symptoms. limited investigation should be performed. A complete blood cell
count, celiac serology, and C-reactive protein can be evaluated
for all patients. Thyrotropin test, fecal calprotectin test, and stool
Pathogenesis culture and microscopy can be considered. Colonoscopy should
The cause of IBS is unknown. In the past, the predominant be offered to patients older than 50 years who are not current with
pathophysiologic mechanisms in IBS were perceived to be high-quality colon cancer screening.
abnormalities intrinsic to the smooth muscle of the gut, visceral Some patients who have pronounced symptoms despite em-
hypersensitivity, and psychological stress. Current models of pirical therapy (discussed below) will seek further care. For these
pathophysiology suggest a role for altered motility, intraluminal patients, an approach that considers the patient’s predominant
intestinal irritants such as maldigested carbohydrates or fats, ex- symptom is recommended (Figure 20.2). For patients with IBS-
cess bile acids, gluten intolerance, visceral hypersensitivity, au- C, a detailed rectal examination should be performed to exclude a
tonomic dysfunction, immune activation, and alterations in gut functional defecatory disorder or other anorectal pathology. Tests
microbiome and epithelial permeability. A bidirectional asso- to consider for patients with IBS-D include measurement of fecal
ciation between the brain and gut has been established. Where bile acids, duodenal aspirate or hydrogen breath testing for bacterial
conditions involving both are present, the psychiatric and psycho- overgrowth, and colonic biopsies for microscopic colitis. The yield
logical conditions preceded gastrointestinal symptoms in 50% of of these tests is low, but they are useful for evaluating patients who
patients, and gastrointestinal symptoms preceded psychiatric and have chronic diarrhea with increased stool volume. Rarely, stool
psychological conditions in the other 50%. chemistry tests for surreptitious laxative abuse may be considered.
Slow colonic transit occurs in 25% of patients with IBS- If pain is predominant, a plain radiograph of the abdomen when the
C. Disorders of rectal evacuation, such as functional defeca- patient is having severe pain may help to exclude obstruction.
tory disorders and descending perineum syndrome, may mimic
symptoms of IBS-C and are important to consider in the differ- ✓ IBS—symptom-based diagnosis defined by recurrent abdominal
ential diagnosis. pain associated with 2 or more of the following:
Rapid colon transit occurs in up to 45% of patients with IBS-D. • Pain associated with defecation
• Change in stool frequency
Disorders that mimic IBS-D include disaccharidase deficiencies,
• Change in stool consistency
celiac disease, microscopic colitis, gluten intolerance without ce- ✓ IBS—in the absence of alarm features, only limited investigations
liac disease, and idiopathic bile acid malabsorption. In selected should be performed
studies, approximately 25% of patients with IBS-D had high
concentrations of fecal bile acids; whether this is the cause or the
consequence of accelerated colonic transit is unclear.
There is an association between ingestion of food and the Prognosis
induction of gastrointestinal symptoms in IBS. The fat content The natural history of IBS is becoming better understood. In
of the meal appears to have a key role in provoking gastroin- approximately 30% of patients, the symptoms resolve within a
testinal symptoms in IBS by inducing high-amplitude colonic year. This contributes to the placebo response rate, which has
contractions. In addition, ingestion of poorly absorbed, fer- made evaluation of investigative agents difficult. Although IBS
mentable oligosaccharides, disaccharides, monosaccharides, symptoms may resolve, symptoms of another functional gas-
and polyols (FODMAP) may induce symptoms of IBS. Studies trointestinal disorder develop in almost half the patients. Thus,
have demonstrated that patients with human leukocyte antigen the degree to which the gastrointestinal symptoms resolve com-
(HLA)-DQ2 or HLA-DQ8 genotypes without celiac disease pletely is not clear. A pattern of the condition coming, going, and
are more likely to respond to gluten withdrawal than patients changing over time is quite common. Ten years after diagnosis,
without these genotypes. 50% to 70% of patients continue to have symptoms.
Alterations in the intestinal microbiome may be a relevant
pathophysiologic mechanism in IBS. Small intestinal bacterial
overgrowth may be the cause of IBS-like symptoms.
Management
Management of IBS requires an integrative approach based
on an understanding of the patient’s desired outcomes (ie, what
Diagnosis
symptoms are most bothersome). Patients must be educated about
The diagnosis of IBS is symptom based (Box 20.1). IBS can be IBS and reassured about the low probability of organic disease.
categorized according to the patient’s predominant bowel habits Simple investigations, as described above, should be performed.
or most bothersome symptom (Figure 20.1). IBS-D is strictly de- Abnormal bowel habits and abdominal pain should be treated with
fined as type 6 or 7 on the Bristol Stool Form Scale. IBS-C is the simplest and safest agents. However, physicians must be aware
characterized by stools described as type 1 or 2. The presence that altering stool frequency or consistency may not reduce ab-
of other functional gastrointestinal disorders (eg, functional dominal pain; each may require independent treatment. Coexisting
dyspepsia), nongastrointestinal disorders (eg, fibromyalgia or psychological factors must be addressed with appropriate pharma-
chronic fatigue), or psychological comorbidities (eg, depression cologic and nonpharmacologic means. Until an initial therapeutic
or anxiety) support the diagnosis of IBS. trial is complete (ie, 3-6 weeks), further investigations should be
Figure 20.2. Management of Irritable Bowel Syndrome. ESR indicates erythrocyte sedimentation rate; sTSH, sensitive thyrotropin. (Adapted
from Drossman DA, Whitehead WE, Camilleri M. Irritable bowel syndrome: a technical review for practice guideline development. Gastroenterology.
1997 Jun;112[6]‌:2120-37; used with permission.)
deferred. The hope is that the patient will be reassured about the diarrhea, constipation, or bloating. Based on the observation
diagnosis and will have a response to the initial therapy. that food can trigger or exacerbate symptoms, 4 specific dietary
interventions can be offered to patients with IBS: general dietary
advice, soluble fiber, low-FODMAP, and a gluten-free diet.
Exercise
General dietary recommendations are to consume small meals,
Moderate to vigorous exercise (eg, walking, aerobics, and cy- regularly spaced throughout the day, and avoid insoluble fiber,
cling) can decrease the severity of IBS symptoms. Patients who fatty foods, and caffeine. Soluble fiber (eg, psyllium) but not in-
continue to exercise frequently can also experience long-term im- soluble fiber (eg, wheat bran) reduces global symptoms in both
provement in sleep, energy, and physical functioning. Different IBS-D and IBS-C. Greater response rates are seen in patients with
exercises may offer different benefits. For example, yoga and IBS-C. When only a limited number of food triggers are present,
walking both decrease gastrointestinal symptoms. However, specific avoidance is the simplest restriction diet. When dietary
yoga may be more beneficial for reducing somatic symptoms (eg, triggers are numerous or unclear, a low-FODMAP or gluten-free
nausea, dizziness, and fatigue), while walking may be more bene- diet, undertaken with the help of a dietician, may be beneficial.
ficial for depression and anxiety. It is not known whether exercise A low-FODMAP diet has been found to decrease abdominal
benefits 1 type of IBS more than others. A small proportion of bloating and gas production. Correctly undertaking this diet
people have worse symptoms with exercise. requires the complete elimination of all FODMAPs to determine
symptomatic response, with subsequent stepwise reintroduction
of FODMAP groups to identify those that provoke symptoms.
Dietary Management Only FODMAPs associated with symptoms should be excluded
For every patient, a dietary history is important to ensure that the thereafter. Notably, the low-FODMAP diet has not been shown
patient is not consuming products that may inadvertently cause to be superior to conventional, less restrictive diets. A gluten-free
20. Irritable Bowel Syndrome 235
diet may offer similar benefit but is predominantly beneficial for anticholinergic effects, decreased bowel motion frequency,
patients with HLA-DQ2 and HLA-DQ8 haplotypes. The long- increased stool consistency, and decreased abdominal pain in
term consequences for patients with IBS continuing to eat a low- small clinical trials involving patients with IBS-U. It worsened
FODMAP or gluten-free diet are unknown. symptoms in patients with constipation. Eluxadoline, a novel μ-
and κ-opioid receptor agonist and δ-opioid receptor antagonist,
showed efficacy for decreasing abdominal pain and improving
Alterations of the Microbiome stool consistency on the same day for at least 50% of the days.
In randomized controlled trials, the minimally absorbed anti- The effects on stool frequency and form were greater than the
biotic rifaximin relieved bloating, abdominal pain, and watery effect on abdominal pain. Owing to an increased risk of pan-
stools in patients with IBS-D. The mechanism underlying the creatitis, eluxadoline should be prescribed only to patients who
beneficial effect is unclear. Symptoms recur in a high propor- have an intact gallbladder and minimal alcohol intake. The use
tion of patients, and retreatment may be required. Rifaximin is of diphenoxylate (a µ-and δ-opioid receptor agonist) in combi-
approved by the US Food and Drug Administration (FDA) for the nation with atropine (an antimuscarinic) is approved by the FDA
treatment of IBS-D. There are insufficient data from patients with only for the treatment of diarrhea.
IBS to support the use of prebiotics or probiotics. In patients with IBS- D, the type 3 serotonin receptor
antagonists ondansetron and alosetron decreased symptom se-
verity, urgency, and frequency to a greater extent than placebo. In
Medications for Abdominal Pain
addition, ondansetron reduced the severity of bloating. Alosetron,
Several medications can be used to treat IBS-associated abdom- but not ondansetron, is approved by the FDA for the treatment
inal pain. No randomized controlled trials have directly compared of IBS. In approximately 0.3% of patients receiving alosetron,
their clinical efficacy. ischemic colitis develops, so patients must be counseled about
The antispasmodics hyoscyamine and dicyclomine promote this risk.
smooth muscle relaxation by antagonism of acetylcholine at the Bile acid sequestrants can be used to treat diarrhea. Use of
muscarinic receptor. The data supporting the efficacy of these cholestyramine, available only in a powder formulation, carries
medications is low to moderate, but both demonstrate a good the highest rates of nausea, but the drug is most readily covered
safety profile. These medications can be given to treat existent by insurance companies. Colesevelam and colestipol are avail-
pain (eg, hyoscyamine sublingually) or prophylactically (eg, 20 able in pill formulation. In patients with IBS-D, colesevelam
minutes before eating) to decrease postprandial symptoms. These increased stool consistency but had no effect on stool frequency.
medications inhibit intraluminal fluid secretion and may offer In general, bile acid sequestrants have few serious adverse
greater benefit to patients with IBS-D. Peppermint oil, which effects. Constipation and bloating can be avoided by starting at a
inhibits smooth muscle contraction through calcium channel low dose and increasing it slowly to the lowest dose that relieves
blockade, has shown more efficacy than placebo in reducing the symptoms. Patients should be advised that bile acid sequestrants
symptom burden in patients who have IBS-D or IBS-M. will also bind other medications and therefore should be taken 2
Neuromodulators can provide considerable pain relief to hours before or 4 hours after other medications. None has FDA
patients with IBS. The choice of antidepressant should consider the approval for the treatment of bile acid diarrhea or IBS.
underlying subtype of IBS and other psychological and physical In truly refractory cases, treatment with clonidine, vera-
factors. Tricyclic antidepressants (eg, amitriptyline, nortriptyline, pamil, or octreotide may be considered. However, use of these
and desipramine) are associated with a reduction in IBS symptom treatments is off-label.
severity, particularly pain, discrete from alterations in mood. They
prolong intestinal transit and are preferentially used in patients with
Medications for Constipation
IBS-D. They may also improve sleep and anxiety. A serotonin nor-
epinephrine reuptake inhibitor such as duloxetine may reduce vis- Simple laxatives (ie, osmotic or stimulant) are first-line therapy
ceral pain in patients with fibromyalgia and depression. Pooled data for the treatment of IBS-C, although they do not have FDA ap-
suggest that selective serotonin reuptake inhibitors (eg, citalopram, proval for this indication. Osmotic laxatives (eg, polyethylene
paroxetine, and fluoxetine) do not improve global symptoms. glycol, magnesium, sodium phosphate, and nonabsorbable
However, where anxiety or stress are exacerbating symptoms, carbohydrates such as lactulose or sorbitol) retain fluid in the in-
these medications may be of benefit. Selective serotonin reuptake testinal lumen and accelerate colonic transit. Use of lactulose and
inhibitors can shorten intestinal transit time and may be more ap- sorbitol should be avoided in patients with IBS because of the
propriate for patients with IBS-C. These medications do not have bloating associated with these medications. Stimulant laxatives
FDA approval for the treatment of IBS, so care should be taken (eg, Senokot [Avrio Health LP], bisacodyl, and glycerin) induce
when counseling patients on potential benefits and adverse effects. high-amplitude propagated colonic contractions. There is little
Pregabalin, a structural derivative of the neurotransmitter evidence to suggest that patients become dependent on these
γ‐aminobutyric acid, showed more efficacy than placebo in a medications with long-term use. Stimulant laxatives are best used
double-blind placebo-controlled trial for reducing abdominal pain as rescue agents when the patient has not had a bowel movement
and overall symptom severity in patients with IBS-D, IBS-C, or for several days.
IBS-M. In addition, subscores were lower for diarrhea and bloating Three secretagogues have FDA approval for IBS-C. By stim-
but not constipation. Similar to the situation with antidepressants, ulating a net efflux of ions and water into the intestinal lumen,
pregabalin is not approved by the FDA for the treatment of IBS. these secretagogues accelerate transit and facilitate defecation.
Lubiprostone, a bicyclic fatty acid derivative of prostaglandin
E1, works mainly by activating apical type 2 chloride channels.
Medications for Diarrhea Nausea, a common adverse effect of lubiprostone, may be
Loperamide and eluxadoline are approved by the FDA for the lessened by ingestion with food. Linaclotide and plecanatide
treatment of IBS. Loperamide, a μ-opioid receptor agonist with are guanylate cyclase-C agonists that induce opening of cystic
fibrosis transmembrane regulator chloride channels on intestinal with IBS, although a survey of gastroenterologists indicated that
mucosa cells. At high doses (290 µg daily), linaclotide reduces 28% of their patient population had IBS. Expenditures account-
abdominal pain; the effect is greater in patients with more se- able to IBS are difficult to determine. Recent estimates suggest
vere pain. that the additional costs of health care for patients with IBS,
The type 4 serotonin receptor agonist prucalopride, recently when compared with control groups, are approximately $2,250
approved for the treatment of chronic idiopathic constipation, has for patients with IBS-D and $3,850 for patients with IBS-C. For
not been approved by the FDA for the treatment of IBS. both, 78% was from medical costs and 22% was from prescription
costs. Additionally, IBS is associated with higher absenteeism,
which is 75% higher among patients with IBS-D compared with
Alternative Therapies
control groups. These direct and indirect costs make the total cost
The bidirectional association between psychological distress and of IBS considerable.
IBS is well established. When formal psychiatric disorders are
present, appropriate therapy is mandatory. Even when a psychi-
Summary
atric disorder has not been diagnosed, the use of psychological
intervention is helpful in the management of IBS. Cognitive be- The diagnosis of IBS is symptom based. Routine serologic
havioral therapy, dynamic psychotherapy, and hypnotherapy are screening for celiac disease in patients with IBS is recommended.
effective psychological therapies in the management of IBS. These Initial treatment involves lifestyle and dietary modifications with
may be particularly beneficial when established precipitants of symptomatic remedies. Patients with persistent gastrointestinal
anxiety or stress worsen gastrointestinal symptoms. Overall, the symptoms despite these initial measures should undergo tests to
number needed to treat for psychological therapies is 4 (95% CI, identify causative factors.
3-5). Psychology-based self-aid (ie, education) has been shown to
be beneficial for treating all subtypes of IBS. In addition, patients Suggested Reading
with IBS may benefit from formal pain management approaches.
Camilleri M. Peripheral mechanisms in irritable bowel syndrome. N Engl
✓ Patient education about the underlying disease process of IBS (eg, J Med. 2012 Oct 25;367(17):1626–35.
visceral hypersensitivity or central sensitization) increases accept- Canavan C, West J, Card T. The epidemiology of irritable bowel syn-
ance of the diagnosis and decreases the use of health care drome. Clin Epidemiol. 2014 6:71–80.
✓ Initial treatment of IBS—lifestyle and dietary modifications with Dionne J, Ford AC, Yuan Y, Chey WD, Lacy BE, Saito YA, et al. A sys-
symptomatic remedies tematic review and meta-analysis evaluating the efficacy of a gluten-
✓ Pain and bowel symptoms in IBS may require independent treatment free diet and a low FODMAPs diet in treating symptoms of irritable
✓ A bidirectional association exists between psychological distress bowel syndrome. Am J Gastroenterol. 2018 Sep;113(9):1290–300.
and IBS Enck P, Aziz Q, Barbara G, Farmer AD, Fukudo S, Mayer EA, et al.
• Cognitive behavioral therapy and hypnotherapy are effective Irritable bowel syndrome. Nat Rev Dis Primers. 2016 Mar 24;2:16014.
psychological therapies Ford AC, Lacy BE, Talley NJ. Irritable bowel syndrome. N Engl J Med.
• Formal psychiatric disorders (eg, depression) should be treated 2017 Jun 29;376(26):2566–78.
concurrently by an appropriately trained physician Ford AC, Quigley EM, Lacy BE, Lembo AJ, Saito YA, Schiller LR, et al.
✓ Patients with persistent gastrointestinal symptoms despite empir- Effect of antidepressants and psychological therapies, including hyp-
ical therapies may require tests to identify causative factors notherapy, in irritable bowel syndrome: systematic review and meta-
analysis. Am J Gastroenterol. 2014 Sep;109(9):1350–65.
Lacy BE, Mearin F, Chang L, Chey WD, Lembo AJ, Simren M, et al.
Bowel disorders. Gastroenterology. 2016;150(6):1393–407.
Health Care Use Locke GR, 3rd. Natural history of irritable bowel syndrome and du-
rability of the diagnosis. Rev Gastroenterol Disord. 2003 3 Suppl
Older data suggest that IBS accounts for 3.5 million physician 3:S12–7.
visits, 2.2 million prescriptions, and 35,000 hospitalizations an- Saito YA, Mitra N, Mayer EA. Genetic approaches to functional gas-
nually. Primary care physicians provide most care for patients trointestinal disorders. Gastroenterology. 2010 Apr;138(4):1276–85.
21
Constipation and Fecal Incontinencea

ADIL E. BHARUCHA, MBBS, MD
Constipation conduit, whereas the rectum and anal canal are responsible for
continence and defecation. The ileocolic sphincter regulates the
Colonic Motor Physiology and Pathophysiology:
intermittent transfer of ileal contents into the colon, a process
Salient Aspects
that normalizes in response to augmented storage capacity in the
Function residual transverse and descending colon within 6 months after
Colonic functions include the absorption of water and electrolytes, right hemicolectomy.
storage of intraluminal contents until elimination is socially
convenient, and nutrient salvage from bacterial metabolism of Motor Patterns
carbohydrates that are not absorbed in the small intestine. The
Colonic motor activity is extremely irregular, ranging from qui-
colon absorbs all but 100 mL of fluid and 1 mEq of sodium and
escence (particularly at night) to isolated contractions, bursts of
chloride from approximately 1,500 mL of chyme received over 24
contractions, or propagated contractions. This activity is in con-
hours. Absorptive capacity can increase to 5 to 6 L of fluid and 800
trast to that of the small intestine, where rhythmic migrating
to 1,000 mEq of sodium and chloride daily. In a healthy person,
motor complexes occur. Colonic contractions are tonic or sus-
the average mouth-to-cecum transit time is approximately 6 hours,
tained, lasting several minutes to hours, and shorter or phasic.
and average regional transit times through the right, left, and sig-
Propagated phasic contractions propel colonic contents over
moid colon are about 12 hours each, with an average total colonic
longer distances than nonpropagated phasic contractions. High-
transit time of 36 hours. (The physiology of defecation is discussed
amplitude propagated contractions are more than 75 mm Hg in
in the “Disorders of Pelvic Floor Function” section below.)
amplitude, occur about 6 times daily (frequently after awakening
and after meals), are responsible for mass movement of colonic
Regional Differences in Colonic Motor Function contents, and frequently precede defecation. Stimulant laxatives
The right colon is a reservoir that mixes and stores contents such as bisacodyl (Dulcolax; Sanofi Consumer Health Inc) and
and absorbs fluid and electrolytes. The left colon is primarily a glycerol induce high-amplitude propagated contractions.
a
Portions of this chapter have been adapted from Bharucha AE. Treatment Colonic Contractile Response to a Meal
of severe and intractable constipation. Curr Treat Options Gastroenterol. Neurohormonal mechanisms are responsible for increased co-
2004 Aug;7(4):291-8; used with permission and Bharucha AE, Knowles lonic motor activity beginning within a few minutes after inges-
CH, Mack I, Malcolm A, Oblizajek N, Rao S, et al. Faecal incontinence
tion of a meal of 500 kcal or more. The term gastrocolic reflex is
in adults. Nat Rev Dis Primers. 2022 Aug 10;8(1):53.
a misnomer because this response, induced by gastric distention
Abbreviations: DD, defecatory disorder; 5-HT, 5-hydroxytryptamine and chemical stimulation by nutrients, is observed even after
(serotonin); IBS, irritable bowel syndrome; MR, magnetic resonance;
gastrectomy. This response may explain postprandial urgency
MRI, magnetic resonance imaging; NASHA/Dx, nonanimal stabilized
hyaluronic acid/dextranomer; PNTML, pudendal nerve terminal motor and abdominal discomfort in patients with irritable bowel syn-
latency drome (IBS).
237
Colonic Relaxation release of acetylcholine and enhances contractility, whereas 5-

Colonic relaxation resulting from sympathetic stimulation or opiates HT4 receptor–mediated stimulation of inhibitory neurons releases
may cause acute colonic pseudo-obstruction, or Ogilvie syndrome. inhibitory neurotransmitters (eg, nitric oxide or vasoactive intes-
Stimulation of α2-adrenergic receptors decreases the release of ace- tinal polypeptide), which relax smooth muscle.
tylcholine from excitatory cholinergic terminals in the myenteric Sensory effects involve the 5-HT3 and 5-HT4 receptors located
plexus, thereby inhibiting gastrointestinal motility. Conversely, on intrinsic primary afferent neurons, which initiate peristaltic
reduced tonic inhibition of the sympathetic system impairs the and secretory reflexes. The 5- HT3 receptors are located also
net absorption of water and electrolytes and accelerates transit in on extrinsic sensory afferents and vagal afferents, which partly
patients who have diabetic neuropathy, thus explaining their diar- explains why 5-HT3 antagonists reduce nausea.
rhea. Clonidine restores the sympathetic brake, reducing diarrhea.
Assessment of Colonic Transit
Colocolonic Inhibitory Reflexes Colonic transit can be measured with commercially available
Peristalsis is a local reflex mediated by intrinsic nerve pathways radiopaque markers (Sitzmarks; CMX Medical Imaging), scin-
and characterized by contraction proximal to the distended tigraphy, or a wireless pH and pressure-sensing capsule. These
segment and relaxation distal to the distended segment. In techniques entail counting the number of orally ingested markers
addition, rectal or colonic distention can inhibit motor activity in that remain in the colon as seen on plain radiographs of the ab-
the stomach, small intestine, or colon. These inhibitory reflexes domen. One approach is to administer a capsule containing 20
are mediated by extrinsic reflex pathways with synapses in the markers on day 1. Delayed colonic transit is indicated if 8 or more
prevertebral ganglia, independent of the central nervous system. markers are seen on plain films on day 3 or if 5 or more markers
They may account for delayed left colonic transit or small intes- are seen on day 5. With scintigraphy, the isotope (generally tech-
tinal transit (or both) in patients with obstructive defecation. netium Tc 99m or indium In 111) is delivered into the colon by
orocecal intubation or within a delayed- release capsule. The
delayed-release capsule contains radiolabeled activated charcoal
Serotonin and the Gut covered with a pH-sensitive polymer (methacrylate) designed to
About 95% of the body’s serotonin (5-hydroxytryptamine [5- dissolve in the alkaline pH of the distal ileum. This releases the
HT]), a monoamine neurotransmitter, is in the gut: 90% in radioisotope within the ascending colon. Gamma camera scans
enterochromaffin cells and 10% in enteric neurons. The effects of taken 4, 24, and, if necessary, 48 hours after ingestion of the iso-
5-HT are mediated by receptors located on gut neurons, smooth tope show the colonic distribution of isotope. Regions of interest
muscle, and enterochromaffin cells. There are 7 families of 5-HT are drawn around the ascending, transverse, descending, and sig-
receptors. The 5-HT3 and 5-HT4 receptors and, to a lesser degree, moid colon and the rectum; counts in these areas are weighted by
the 5-HT1p, 5-HT1a, and 5-HT2 receptors are important targets of factors 1 through 4, respectively, and stool counts are weighted
pharmacologic modulation in the gut. Cisapride, prucalopride, by a factor of 5. Thus, colonic transit may be summarized as an
and tegaserod maleate (Zelnorm; Alfasigma USA, Inc) are 5-HT4 overall geometric center (Figure 21.1). The 4-hour scan identifies
receptor agonists. Alosetron is a more potent 5-HT3 receptor an- rapid colonic transit, and the 24-hour and 48-hour scans show
tagonist than ondansetron. slow colonic transit. Assessments of colonic transit made with
The effects of 5-HT are motor and sensory. Motor effects in- radiopaque markers, scintigraphy, and the pH and pressure cap-
volve stimulation of serotoninergic 5-HT4 receptors, which facili- sule are comparable. The radiopaque marker technique is simpler
tate both components of the peristaltic reflex: proximal excitation and more widely available. However, with scintigraphy, colonic
coordinated with distal inhibition. Thus, stimulation of 5-HT4 transit can be assessed in 48 hours, compared with 5 to 7 days
receptors located on cholinergic enteric neurons induces the for radiopaque markers. Moreover, gastric, small intestinal, and
Figure 21.1. Scintigraphic Assessment of Colonic Transit. Images show progression of isotope through cecum and ascending colon at 1 hour
(A), ascending and transverse colon at 4 hours (B), and ascending, transverse, descending, and rectosigmoid colon at 24 hours (C). D, Numbers rep-
resent average isotope distribution corresponding to a geometric center of 1 to 5. In this patient, the geometric center at 24 hours was 2.2 (normal,
1.6-3.8). (Adapted from Bharucha AE, Klingele CJ. Autonomic and somatic systems to the anorectum and pelvic floor. In: Dyck PJ, Thomas PK, eds.
Peripheral neuropathy. 4th ed. Philadelphia [PA]: Elsevier; 2005: 279-98; used with permission.)
21. Constipation and Fecal Incontinence 239
colonic transit can be assessed simultaneously with scintigraphy dietary intake of calories and fiber; 3) a history of phys-
and the wireless pH and pressure capsule. ical, emotional, or sexual abuse; and 4) obstructive defeca-
tion. Bowel diaries are more accurate than self-reporting for
characterizing bowel habits, particularly stool frequency. As
Constipation
characterized by the Bristol Stool Form Scale, stools that are
Definition and Classification hard, small pebbles correlate with delayed colonic transit, and
Chronic constipation may be classified on the basis of symptoms stools that are watery (at the other extreme) correlate strongly
or according to colonic transit and anorectal functions. The with accelerated colonic transit. In contrast to stool frequency
symptom-based criteria (ie, the Rome criteria), which were de- recorded in diaries, frequency reported from recall alone does
veloped by a committee of experts, are essential for clinical trials not correlate with colonic transit. Certain symptoms (prolonged
and research studies but are also useful in clinical practice. By straining, sense of anorectal blockage, tendency to facilitate
convention, these symptom criteria need to be present for at least defecation by assuming different positions, difficult evacuation
3 months, with a total symptom duration of at least 6 months. of soft stool, and digital maneuvers to facilitate defecation) are
Functional constipation is defined by 2 or more of the suggestive but not diagnostic of functional defecatory disorders
following symptoms: 1) fewer than 3 defecations per week, (DDs). The examination may identify anismus, inadequate per-
2) straining, 3) lumpy or hard stools, 4) sensation of incomplete ineal descent, or, conversely, ballooning of the perineum with
evacuations, 5) sensation of anorectal obstruction or blockage, excessive descent.
and 6) manual maneuvers to facilitate defecation. For symptoms
2 through 6 (as listed above) to be considered present, they should
Practical Classification of Constipation
occur with one-fourth of defecations.
Constipation-predominant IBS is defined by abdominal dis- A practical approach to classifying and managing chronic con-
comfort and at least 2 of the following 3 symptoms: 1) abdom- stipation is shown in Figure 21.2. After secondary causes of
inal discomfort associated with change in stool form (ie, hard constipation have been excluded, anorectal functions should be
stools), 2) abdominal discomfort associated with change in stool assessed in patients who have constipation that does not respond
frequency (ie, less frequent stools), and 3) abdominal discomfort to dietary fiber supplementation or over-the-counter laxatives
relieved by defecation. (or both in combination). Anorectal tests are necessary because
However, many patients satisfy criteria for functional constipa- symptoms alone cannot be used to distinguish among constipa-
tion and constipation-predominant IBS. Hence, a more practical tion resulting from DDs, normal transit, and slow transit. DDs,
approach is to characterize constipation as painful or painless. which are characterized by symptoms of constipation and ano-
Patients with painful constipation report more abdominal pain, dis- rectal test results indicative of disordered defecation, should be
ability, somatic symptoms, and urinary urgency than those with primarily managed with pelvic floor retraining (biofeedback
painless constipation. (Diarrhea-predominant syndrome is defined therapy). When anorectal test results are normal, colonic transit
by loose and less frequent stools instead of hard and more frequent should be assessed to distinguish normal from slow transit consti-
stools.) Table 21.1 summarizes the salient differences between pation. When anorectal test results are abnormal (ie, they indicate
functional constipation and constipation-predominant IBS. a DD), it is not essential to evaluate colonic transit before bio-
feedback therapy because the management is the same, regard-
less of whether colonic transit is normal or slow; 50% of patients
Clinical Assessment with DD have slow colonic transit. However, colonic transit
Clinical assessment of constipation should focus on identifying should be evaluated in patients with DD who do not respond to
1) secondary causes (Table 21.2 and Box 21.1); 2) inadequate biofeedback therapy.
Table 21.1. Differences Between Functional Constipation and Constipation-Predominant IBS

Variable Functional constipation Constipation-predominant IBS
Symptom criteria Symptoms for ≥6 mo and for >25% of Recurrent abdominal pain or discomfort ≥3 d/mo in the
defecations during preceding 3 mo: preceding 3 mo associated with ≥2 of the following:
• Straining • Improvement with defecation
• Lumpy or hard stools • Onset associated with change in frequency of stool
• Sensation of incomplete evacuation • Onset associated with change in form (appearance) of stool
• Sensation of anorectal obstruction/blockade • <25% of bowel movement were loose stools
• Manual maneuvers to facilitate defecations
<3 defecations/wk
• Loose stools not present and insufficient
criteria for IBS
Upper gastrointestinal tract symptoms Less commona More commona
(eg, heartburn, dyspepsia), anxiety
and depression, urinary symptoms
Prevalence of defecatory disorder About 50% of patients About 50% of patients
Prevalence of increased rectal sensation Less commonb More commonb
Abbreviation: IBS, irritable bowel syndrome.

a
The prevalence of these symptoms varies by individual symptom; hence, specific figures are not provided.
b
The prevalence of increased rectal sensation varies among studies.
Adapted from Bharucha AE, Wald A. Chronic constipation. Mayo Clin Proc. 2019 Nov;94(11):2340-57; used with permission.
Table 21.2. Medications Associated With Constipation

Box 21.1. Medical Conditions Associated With
Class Examples
Constipation
5-HT3 receptor antagonists Ondansetron Drug effects
Analgesics
Opiatesa Morphine Mechanical obstruction
NSAIDsa Ibuprofen Colon cancer
Anticholinergic agents Librax, belladonna External compression from malignant lesion
Tricyclic antidepressantsa Amitriptyline > nortriptyline
Strictures: diverticular or postischemic
Antiparkinsonian drugs Benzatropine
Antipsychotics Chlorpromazine Rectocele (some)
Antispasmodicsa Dicyclomine Metabolic conditions
Antihistaminesa Diphenhydramine
Type 2 diabetes
Anticonvulsantsa Carbamazepine
Antihypertensives Hypothyroidism (severe)
Calcium channel blockers Verapamil, nifedipine Hypercalcemia (severe)
Diureticsa,b Furosemide
Hypokalemia
Centrally acting Clonidine
Antiarrhythmics Amiodarone Hypomagnesemia
β-Adrenoceptor antagonist Atenolol Heavy metal poisoning
Bile acid sequestrants Cholestyramine, colestipol
Myopathies
Cation-containing agents
Aluminuma Antacids, sucralfate Amyloidosis
Calcium Antacids, supplements Scleroderma
Bismuth Neuropathies
Iron supplements Ferrous sulfate
Lithium Parkinson diseasea
Chemotherapy agents Spinal cord injury or tumora
Vinca alkaloids Vincristine Cerebrovascular disease
Alkylating agents Cyclophosphamide
Miscellaneous compounds Barium sulfate, oral contraceptives, Multiple sclerosisa
polystyrene resins Other conditions
Endocrine medications Pamidronate and alendronic acid Depression
Other antidepressants Monoamine oxidase inhibitors
Other antipsychotics Clozapine, haloperidol, risperidone Autonomic neuropathy
Other antiparkinsonian drugs Dopamine agonists Cognitive impairment
Other antispasmodics Mebeverine, peppermint oil
Immobilitya
Sympathomimetics Ephedrine, terbutaline
Abbreviations: 5-HT, 5-hydroxytryptamine (serotonin); NSAID, nonsteroidal a

Condition frequently encountered in clinical practice and associated
anti-inflammatory drug. with constipation.
a
Drugs associated with constipation in community-based studies.
b
Perhaps related to electrolyte disturbances. Adapted from Bharucha AE, Wald A. Chronic constipation. Mayo Clin
Proc. 2019 Nov;94(11):2340-57; used with permission.
Adapted from Branch RL, Butt TF. Drug-induced constipation. Adverse Drug
React Bull. 2009 (257):987-90; used with permission.
Normal transit constipation includes IBS and functional Medical Therapy. A stepwise approach that begins with die-
constipation. In IBS, abdominal pain is associated with defe- tary fiber supplementation and osmotic or stimulant laxatives
cation or a change in bowel habits (ie, harder or less frequent should be used to manage constipation. These agents are rela-
stools). Patients with functional constipation also may have ab- tively safe, inexpensive, and widely used, and, in many cases,
dominal pain, but by definition the pain is not relieved by def- efficacy has been proved in controlled trials. Further testing to
ecation or associated temporally with harder or less frequent identify the pathogenesis of constipation is warranted if patients
stools. Most patients with DD also have delayed colonic transit. do not have a response to these agents (Table 21.3). This evalu-
Consequently, delayed colonic transit does not imply slow ation should be considered earlier if DDs are strongly suspected
transit constipation. clinically. For normal transit and slow transit constipation,
Colonic inertia refers to severe colonic motor dysfunction that treatment with laxatives or a secretagogue (ie, lubiprostone), or
is identified by reduced colonic contractile responses to a meal both, should be considered.
and stimulants such as bisacodyl or neostigmine, as assessed with Increasing dietary fiber either with food or a fiber supple-
intraluminal measurements of pressure activity or tone. ment increases stool weight and accelerates colonic transit.
Fiber intake should be increased gradually to 12 to 15 g daily
with products such as the following: 1) psyllium (Konsyl, Konsyl
Management of Constipation Pharmaceuticals, Inc; Metamucil, Procter & Gamble), daily with
Principles. Reassurance and education about normal bowel fluid, or methylcellulose (Citrucel, Haleon Group), 1 teaspoon up
habits, the need for adequate caloric intake and dietary fiber sup- to 3 times daily; 2) calcium polycarbophil (FiberCon, Foundation
plementation, and the absence of a “serious disorder” are vital. Consumer Brands), 2 to 4 tablets daily; or 3) bran, 1 cup daily.
Deficient caloric intake can cause or exacerbate constipation, Fiber supplements are more effective in normal transit or “fiber-
whereas refeeding may restore colonic transit. deficiency” constipation than in slow transit constipation or
Figure 21.2. Approach for Managing Chronic Constipation. OTC indicates over-the-counter. (Adapted from Bharucha AE, Lacy BE. Mechanisms,
evaluation, and management of chronic constipation. Gastroenterology. 2020; 158[5]‌:1232-49; used with permission.)
Table 21.3. Classification of Chronic Constipation

Category
Feature Normal transit constipation Slow transit constipation Defecatory disorder

Colon transit Normal Slow Normal or slow
Anorectal function Normal Normal Abnormal
Management Fiber supplementation Fiber supplementation Anorectal biofeedback
Laxatives Laxatives therapy
Surgery
pelvic floor dysfunction. Fiber supplementation should start at a Stimulant laxatives affect mucosal transport and motility
small dose administered twice daily (morning and evening) with and include surface- active agents (docusate sodium [Colace,
fluids or meals, increasing the dose gradually after 7 to 10 days. Avrio Health LP], 100 mg orally twice daily), diphenylmethane
Patients should be reassured that although fiber supplements may derivatives, ricinoleic acid, anthraquinones, glycerin (supposi-
increase gaseousness, this often subsides with time. A response to tory), and bisacodyl (10-mg tablet or suppository). Stool softeners
fiber supplements is evident over several weeks, not days as with such as docusate sodium have limited efficacy. Glycerin and
a laxative. Bloating may be reduced by gradually titrating the bisacodyl, taken up to once every other day, work by inducing
dose of dietary fiber to the recommended dose or by switching colonic high- amplitude propagated contractions. Bisacodyl
to a synthetic fiber preparation such as methylcellulose. Bran tablets take effect in 6 to 8 hours, and suppositories should be
impairs absorption of iron and calcium. Fiber supplements are administered 30 minutes after eating to maximize synergism
contraindicated for patients with intestinal obstruction, fecal im- with the gastrocolic reflex. Of the diphenylmethane derivatives,
paction, or severe vomiting. phenolphthalein was withdrawn from the US market after an-
imal studies suggested that it may be carcinogenic; however, no
✓ Dietary fiber content should be increased gradually to 12 to 15 g epidemiologic evidence supports this claim. The anthraquinone
daily for patients with constipation compounds may cause allergic reactions, electrolyte depletion,
✓ In normal transit constipation, 80% of patients have a sympto- melanosis coli, and cathartic colon. Melanosis coli refers to
matic response to dietary fiber supplementation brownish black colorectal pigmentation of unknown composition
associated with apoptosis of colonic epithelial cells. Cathartic
Hyperosmolar agents, such as sorbitol or lactulose (15- 30 colon refers to altered colonic structure observed on barium
mL once or twice daily), are nonabsorbable disaccharides enema studies and associated with long-term use of stimulant
metabolized by colonic bacteria into acetic and other short-chain laxatives. The altered structure includes colonic dilatation, loss
fatty acids. Sorbitol and lactulose accelerate proximal colonic of haustral folds, strictures, colonic redundancy, and wide gaping
transit in healthy patients. Both agents may cause transient ab- of the ileocecal valve. Early reports implicating laxative-induced
dominal cramps and flatulence. They are equally effective for destruction of myenteric plexus neurons in cathartic colon have
treating constipation in elderly patients. However, lactulose is been disputed. Although anthraquinones may induce colorectal
extremely sweet and generally more expensive than sorbitol. tumors in animal models, several cohorts and a recent case-
A controlled study showed that polyethylene glycol (MiraLAX; control study did not find an association between anthraquinones
Bayer Consumer Health), 17 g daily for 6 months, is superior to and colon cancer.
placebo for improving symptoms in chronic constipation. Oral
sodium phosphate solution is used for bowel cleansing, occa- ✓ Bisacodyl and glycerin facilitate defecation by inducing colonic
sionally by patients with severe constipation. However, acute high-amplitude propagated contractions
phosphate nephropathy (acute nephrocalcinosis), a type of acute ✓ Melanosis coli indicates recent laxative use, but the evidence
linking anthraquinones to colon cancer and destruction of the my-
kidney failure, which rarely progresses to chronic kidney impair-
enteric plexus is inconclusive
ment and long-term dialysis, has occurred in patients who took
oral sodium phosphate. Kidney tubular injury occurs from the
deposition of calcium phosphate crystals in the distal tubules and The secretagogues lubiprostone, linaclotide, and plecanatide
collecting ducts, as shown histologically. Crystals form because increase the intestinal secretion of chloride; tenapanor, which
of an abnormally high concentration of calcium phosphate from is a locally acting, selective small-molecule inhibitor of the in-
oral sodium phosphate–induced dehydration, decreased intra- testinal sodium- hydrogen exchanger 3 increases luminal so-
vascular volume, and hyperphosphatemia, which is compounded dium. As a result, all these drugs promote the efflux of fluid
further by reabsorption of water from kidney tubules. Risk factors into the gut lumen and maintain osmotic balance. The US
for acute phosphate nephropathy include older age (greater se- Food and Drug Administration has approved these 4 drugs for
verity for patients 57 years or older), decreased intravascular treating constipation-predominant IBS in adults; lubiprostone
volume (eg, congestive heart failure, cirrhosis, or nephrotic and linaclotide are also approved for treating chronic idiopathic
syndrome), acute or chronic kidney disease, and concomitant constipation, and lubiprostone is also approved for treating
use of drugs that affect kidney perfusion or function (diuretics, opioid-induced constipation in adult patients who have chronic,
angiotensin-converting enzyme inhibitors, angiotensin receptor noncancer pain.
blockers, and possibly nonsteroidal anti-inflammatory drugs).
A saline laxative, milk of magnesia (15-30 mL once or twice ✓ Lubiprostone stimulates intestinal secretion by activating chlo-
daily), draws fluid osmotically into the lumen, stimulates the re- ride channels; it also improves stool consistency and relieves
lease of cholecystokinin, and accelerates colonic transit. It may constipation
cause hypermagnesemia, particularly in patients with kidney
insufficiency. Lubiprostone is a bicyclic fatty acid derivative that promotes
intestinal secretion by activating intestinal chloride channels.
✓ Patients with slow transit constipation can take saline laxatives Lubiprostone accelerates colonic transit in healthy patients but
or hyperosmolar agents daily and stimulant laxatives on an as- not in those with chronic constipation. The effects of lubiprostone
needed basis are more pronounced on stool consistency and frequency than on
✓ Sorbitol is as effective as lactulose but less expensive and less
abdominal bloating, discomfort, and straining. Lubiprostone is
sweet
✓ Oral sodium phosphate solution should be used with care be- well tolerated; nausea and headache are the most common ad-
cause rarely it can cause acute phosphate nephropathy and kidney verse effects. In clinical trials, 33% of patients reported nausea,
failure which generally was mild and could be reduced by taking the
medication with meals.
Similar to the natriuretic peptides uroguanylin and guanylin as-needed basis (eg, if a patient does not have a bowel movement
and the heat-stable enterotoxins of Escherichia coli that cause for 2 days) with stimulant laxatives administered orally or as
traveler’s diarrhea, linaclotide and plecanatide are peptide-based suppositories. In patients with chronic functional (ie, painless)
guanylate cyclase-C receptor agonists that increase the synthesis constipation, these simple laxatives are as effective and much
of cyclic guanosine monophosphate. In turn, these effects stim- less expensive than newer agents (eg, secretagogues or prokinetic
ulate chloride and bicarbonate secretion through cystic fibrosis agents). When patients do not have a response to simple laxatives,
transmembrane conductance regulator channel–dependent and, secretagogues, which may also have antinociceptive effects,
to a lesser extent, channel-independent mechanisms. Linaclotide should be considered, especially in patients with marked abdom-
also acts on a sodium proton exchanger and thereby inhibits inal bloating or pain (ie, painful constipation or constipation-
the absorption of sodium from the lumen. Linaclotide and predominant IBS), and anorectal testing should be considered,
plecanatide are comparably effective; there are minor differences especially when the clinical features suggest a DD.
between these drugs. The activation of guanylate cyclase-C is pH
independent, and the activation of linaclotide and plecanatide is Surgical Therapy. Subtotal colectomy with ileorectal anas-
pH dependent, but the consequences of these differences on the tomosis is effective and occasionally indicated for patients
beneficial and adverse effects is unclear. Evidence that the drugs with medically refractory, severe slow transit constipation,
decrease nociception during colonic distention in animal models provided that pelvic floor dysfunction has been excluded or
and in humans is stronger for linaclotide than for plecanatide and treated. In patients with megarectum, the rectum is also resected.
is absent for tenapanor. In contrast to lubiprostone, linaclotide Postoperative ileus and delayed mechanical small- bowel ob-
accelerates colonic transit in constipation- predominant IBS. struction each occur in approximately 10% of patients. Diarrhea
Diarrhea is the most common adverse effect of all drugs in this is common shortly after the operation but tends to resolve with
class. In constipation-predominant IBS trials, 10% of patients time. It is extremely important to identify and treat pelvic floor
discontinued use of linaclotide because of troublesome diarrhea. dysfunction with biofeedback therapy preoperatively in patients
Newer serotoninergic 5-HT4 agonists are more specific for 5- with slow transit constipation.
HT4 receptors and have fewer cardiovascular effects than older
✓ Subtotal colectomy is necessary and beneficial for patients with
5-HT4 agonists (eg, cisapride). Prucalopride and tegaserod accel- slow transit constipation who do not have a response to medical
erate colonic transit in patients with constipation; prucalopride management
also accelerates gastric emptying. In the US, prucalopride is
approved for treating chronic idiopathic constipation; tegaserod
is approved for treating constipation-predominant IBS in women
younger than 65 years. Disorders of Pelvic Floor Function
Other pharmacologic approaches that have been used to manage Disorders of pelvic floor function include functional DDs and
constipation include colchicine and misoprostol (Cytotec, Pfizer fecal incontinence. Fecal incontinence, or involuntary leakage of
Inc). Colchicine, 0.6 mg orally 3 times daily, and misoprostol, stool from the anus, is a common symptom, particularly in the
1,200 mg daily, cause diarrhea. Colchicine should be used cau- elderly. In community-based surveys, the prevalence of fecal in-
tiously, if at all, for treating constipation, because long-term use continence among women 50 years or older is nearly 15%. The
may be associated with neuromyopathy. Other adverse effects in- prevalence among nursing home residents is as high as 40%. At
clude hypersensitivity reactions, bone marrow suppression, and Mayo Clinic, 50% of patients who had chronic constipation also
kidney damage. Misoprostol should not be used to treat constipa- had a component of pelvic floor dysfunction.
tion because it is expensive, may cause miscarriage in pregnant
women, and may exacerbate abdominal bloating. Moreover, its
beneficial effects appear to decrease with time.
Physiology of Defecation
Rectal distention evokes the desire to defecate and induces re-
✓ Colchicine and misoprostol are unproven, potentially deleterious laxation of the internal anal sphincter by an involuntary reflex
agents for treating slow transit constipation (Figure 21.3). Defecation is completed by adoption of a suit-
able posture, contraction of the diaphragm and abdominal mus-
cles to increase intra-abdominal pressure, and relaxation of the
Enemas, which are especially useful in patients with fecal
puborectalis muscle and external anal sphincter, both striated
impaction in the rectosigmoid colon, as may occur in obstruc-
muscles. Relaxation of the puborectalis muscle allows widening
tive defecation, include mineral oil retention enema, 100 to 250
and lowering of the anorectal angle, with perineal descent
mL daily per rectum; phosphate enema (Fleet; C B Fleet Co,
(Figure 21.4). The coordination between abdominal contraction
Inc), 1 unit per rectum; tap water enema, 500 mL per rectum;
and pelvic floor relaxation is crucial to the process. Although
and soapsuds enema, 1,500 mL per rectum. All the preparations
colonic high-amplitude propagated contractions may precede
are contraindicated for patients with rectal inflammation,
defecation, the contribution of rectal contraction to defecation
and phosphate enemas are contraindicated for patients with
is unclear.
hyperphosphatemia or hypernatremia. Mineral oil taken orally
is associated with lipid pneumonia, malabsorption of fat-soluble
vitamins, dehydration, and fecal incontinence. Functional DDs
Functional DDs (also called obstructive defecation, pelvic floor
✓ Enemas may be used judiciously on an as-
needed basis for dyssynergia, and pelvic floor dysfunction) are characterized by
constipation
disordered defecation caused by functional obstruction that
results from impaired relaxation of the external anal sphincter,
In summary, management should initially include dietary impaired relaxation of the puborectalis muscle, or inadequate
fiber supplements and osmotic laxatives, supplemented on an propulsive forces (ie, intrarectal pressure), or a combination of
Figure 21.3. Physiology of Defecation. HAPC indicates high- amplitude propagated contraction. (Adapted from Bharucha AE, Camilleri
M. Physiology of the colon. In: Zuidema GD, Yeo CJ, eds. Shackelford’s surgery of the alimentary tract. 5th ed. Philadelphia [PA]: WB Saunders
Company; 2002: 29-39; used with permission.)
these. Although certain symptoms are considered suggestive of by perineal descent (2-4 cm) and relaxation of the puborectalis
DDs (eg, frequent straining, a sensation of incomplete evacua- muscle. In patients with functional DDs, digital rectal examina-
tion, dyschezia, and digital evacuation of feces), symptoms alone tion may show 1) increased resting pressure or 2) increased or
are not sufficiently specific for distinguishing between functional decreased perineal descent or 3) both. When rectal prolapse is
DDs and other causes of constipation (ie, normal transit and suspected, patients should be examined in the seated position on
slow transit constipation). A thorough digital rectal examination a commode.
with assessment of anal resting tone and anorectal motion when
patients contract their muscles (ie, squeeze) and simulate evacua-
tion is useful for identifying DDs. Anal resting pressure is gauged Tests
by the resistance to the insertion of a finger in the anal canal. Anorectal tests are necessary because DDs cannot be identified
When patients squeeze, the anal sphincter and puborectalis mus- from clinical features alone. Anorectal manometry and rectal
cles contract; the latter lifts the palpating finger toward the um- balloon expulsion tests usually are sufficient to confirm or ex-
bilicus. Conversely, simulated evacuation should be accompanied clude functional DDs. Defecography with barium or magnetic
Figure 21.4. Magnetic Resonance Fluoroscopic Images of the Pelvis. A, At rest. B, During simulated defecation. Defecation is accompanied by
opening of the anorectal junction (arrow), pelvic descent, and widening of the anorectal angle from 101° at rest to 124° during defecation. The rectum
was filled with ultrasound gel.
resonance (MR) imaging (MRI) may be necessary in selected to defecate (average volume, 183 mL), which may compensate
patients (eg, when findings from manometry and the balloon ex- for reduced rectal sensation of some patients with DD. Moreover,
pulsion test are discrepant or these test results differ from the an abnormal result on the rectal balloon expulsion test predicts
clinical impression, or when a rectocele is suspected). Because the response to pelvic floor retraining by biofeedback therapy.
false-
positive and false-negative results may occur, anorectal
function tests need to be interpreted in the context of the clinical Barium or MR Proctography. During dynamic (ie, barium or
features. MR) proctography, anorectal anatomy and pelvic floor motion are
recorded with the patient at rest and while coughing, squeezing,
Anorectal Manometry. Anorectal manometry can be con and straining to expel barium from the rectum. The anorectal
ducted with traditional (ie, water-or air-perfused or solid-state) angle and position of the anorectal junction are tracked during
or high-resolution manometric catheters. The advantage of high- these maneuvers, as are the retention and evacuation of contrast
resolution manometric catheters is that sensors are evenly distrib- material. Dynamic imaging can identify inadequate or exces-
uted along the catheter. Hence, when the catheter is positioned sive perineal descent, internal rectal intussusception, rectoceles,
appropriately, the sensors straddle the entire anal canal, allowing sigmoidoceles, and enteroceles. Also, puborectalis muscle dys-
pressures to be assessed without a pull-through maneuver, in con- function can be characterized during squeeze and evacuation.
trast to traditional manometry. MR proctography is preferred to barium proctography because
Patients with DD may have 1 or more of several abnormalities. 1) it does not entail radiation exposure, 2) it is easier to visu-
Arguably, the most useful parameter is a smaller rectoanal alize the bladder and uterus together with the anorectum, and
pressure gradient (ie, rectal pressure minus anal pressure), which 3) the bony landmarks (pubis and sacrococcygeal junction)
may result from a low rectal pressure or a high anal pressure (or necessary to measure anorectal descent are visualized more
both), during simulated defecation. Other disturbances include distinctly during MRI. Therefore, measurements of anorectal
high resting anal sphincter pressure and reduced rectal sensa- motion are more reproducible with MR proctography than with
tion (Figure 21.5). Normal values for anal pressures measured barium proctography. However, proctography findings need to be
with manometry are technique- dependent and influenced by interpreted in the overall clinical context. For example, rectoceles
age, sex, and perhaps parity. Anal pressures are lower in women are particularly common in multiparous persons. Clinically im-
than in men and decrease with age, even in asymptomatic per- portant rectoceles are generally large (>3 cm) or do not empty
sons. Hence, the pressures must be compared against appropriate completely during defecation. Moreover, women with clinically
normal values. important rectoceles often apply posterior vaginal pressure to
facilitate defecation. Rectoceles usually are due to inadequate
Rectal Balloon Expulsion Test. Rectal expulsion can be pelvic floor relaxation rather than to the primary abnormality.
evaluated by asking patients to expel from the rectum a balloon
filled with water. While the patient is seated on a commode chair Colonic Transit. Delayed colonic transit is common in DD.
behind a privacy screen, the time required to expel a rectal balloon Hence, the finding of slow colonic transit does not exclude the
is measured. Depending on the technique, patients with normal diagnosis of DD.
pelvic floor functions can expel a rectal balloon within 1 to 2
minutes. The rectal balloon expulsion test is highly sensitive and ✓ Anorectal manometry and the rectal balloon expulsion test gener-
ally are sufficient for diagnosing functional DDs; proctography is
specific (>85%) for identifying functional DDs. In 1 study, for
necessary in selected cases only
the diagnosis of a DD, the positive predictive value was 64% and ✓ Rectal balloon expulsion test
the negative predictive value was 97%. However, in this study the • Highly sensitive and specific for diagnosis of functional DDs
rectal balloon was not inflated to a fixed volume, which is the typ- • Abnormal test result predicts the response to biofeedback therapy
ical approach; instead, it was inflated until patients felt the desire
Figure 21.5. Rectoanal Pressure Profiles During Defecation in Health and Functional Defecatory Disorders (Dyssynergia and Impaired
Propulsion). In contrast to patients with a normal pattern (left) (ie, increased rectal pressure and anal relaxation) during simulated evacuation, patients
with defecatory disorders may either paradoxically contract the anal sphincters (center) or generate inadequate rectal propulsive forces (right).
• Some patients with a DD may have normal results on balloon

constipation may strain excessively during defecation and cause
expulsion test, so defecography should be performed when stretch injury to the pudendal nerve, soft tissue laxity, and exces-
clinically indicated sive perineal descent. Eventually, sphincter weakness develops,
✓ Colonic transit is delayed in the majority of patients who have predisposing to fecal incontinence.
functional DDs
✓ Anorectal function tests Neurologic Causes. Neurologic causes include multiple
• False-positive and false-negative results may occur, so results sclerosis, Parkinson disease, Alzheimer disease, stroke, dia-
must be interpreted in the context of the clinical features betic neuropathy, and cauda equina or conus medullaris lesions.
• In up to 20% of healthy persons, the anal sphincter paradoxi- Cauda equina lesions that cause fecal incontinence usually are
cally contracts instead of relaxes during evacuation accompanied by other neurologic symptoms and signs.
Other Local Causes. Examples of other local causes are pe-
rianal sepsis, radiation proctitis, and systemic sclerosis. In radia-
Treatment tion proctitis, the entry of stool into a noncompliant (stiff) rectum
Pelvic floor retraining with biofeedback therapy improves symptoms may overwhelm continence mechanisms and cause inconti-
in 70% of patients who have a functional DD. Biofeedback therapy nence. Scleroderma is associated with fibrosis of the internal anal
is conducted with sensors that measure surface electromyographic sphincter and weak resting pressures.
activity or pressures in the anorectum. By providing auditory or
Diarrhea. Fecal incontinence is a common complication of
visual feedback of this activity, patients are taught to relax the
pelvic floor and improve coordination between abdominal wall and IBS, cholecystectomy, and inflammatory bowel disease.
diaphragmatic contraction and pelvic relaxation during defecation.
Measures to contract the pelvic floor muscle (eg, Kegel exercises) Assessment
are not appropriate for obstructive defecation. Strong rapport be- Patients with diarrhea must be asked specifically about fecal
tween patients and therapists is critical for biofeedback therapy. incontinence because they may not volunteer the information.
Controlled trials have shown that pelvic floor retraining is superior The severity, risk factors, and circumstances of fecal inconti-
to laxatives for relieving constipation in patients with obstructive nence and its effect on lifestyle should be assessed. Patients with
defecation. This symptomatic improvement has been sustained for urge incontinence generally are incontinent only for liquid or
2 years. Biofeedback therapy also normalizes colonic transit and semiformed stools, have a brief warning time, and cannot reach
anal relaxation during defecation. the toilet in time. In contrast, patients with passive incontinence
are aware of stool leakage only after the episode. Patients with
Fecal Incontinence urge incontinence have a decreased anal squeeze pressure or
squeeze duration (or both), whereas those with passive inconti-
Fecal continence is maintained by anatomical factors and com-
nence have a reduced anal resting pressure. Some patients with
plex sensory and motor interactions among the sphincters, the
urge fecal incontinence also may have rectal hypersensitivity,
anorectum, central and peripheral awareness, and the physical
perhaps from a stiffer rectum. Nocturnal fecal incontinence
ability to get to a toilet. Fecal incontinence is defined as the invol-
occurs in patients with type 2 diabetes or scleroderma and is
untary leakage of liquid or solid stool from the anus; anal incon-
suggestive of weakness of the internal anal sphincter. A com-
tinence also includes leakage of gas. Up to 40% of nursing home
plete physical examination should include perianal assessment
residents have fecal incontinence, which is also common in the
to identify common causes of perianal soiling, such as hemor-
community. Up to 1 in 10 of all women and 1 in 5 women 40 years
rhoidal prolapse, perianal fistula, rectal mucosal prolapse, fecal
or older in the community have fecal incontinence. Patients with
impaction, anal stricture, and rectal mass. The perianal area must
chronic fecal incontinence lead a restricted lifestyle, are afraid
be inspected closely with the patient in the left lateral decubitus
of having an embarrassing episode, and often miss work. The
position and with the patient seated on the toilet. A thorough
symptom frequently coexists with urinary incontinence and
digital examination, as described above, should be performed.
contributes to institutionalization. People with fecal incontinence
Flexible sigmoidoscopy, with or without anoscopy, is the final
are embarrassed to admit to their family and physician that they
component in this phase of evaluation.
have this condition, even though their symptoms may affect their
quality of life. Therefore, it is essential to ask patients with diar-
rhea or type 2 diabetes whether they have incontinence. Tests
A combination of tests is necessary to evaluate the various
Etiology components of anorectal anatomy and function. For each patient,
In most patients, fecal incontinence is attributable to disordered the intensity of investigation depends on the patient’s age, se-
anorectal continence mechanisms compounded by bowel verity of fecal incontinence, clinical assessment of risk factors
disturbances, generally diarrhea. Several important diseases con- and anal sphincter pressures, and response to previous therapy
tribute to fecal incontinence. (Figure 21.6).
Sphincter Damage. Sphincter damage includes obstetric and Anorectal Manometry. Frequently, anal resting and squeeze
surgical (eg, hemorrhoidectomy) damage. Known obstetric risk pressures are decreased in fecal incontinence. Anal pressures
factors for sphincter damage include forceps delivery, median should be compared with normal values obtained with the same
episiotomy, and high birth weight. technique in age-and sex- matched asymptomatic persons.
Among patients with weak or normal anal pressures, other factors
Pudendal Neuropathy. Pudendal neuropathy may be attrib- (eg, diarrhea or disturbances of rectal compliance or sensation)
utable to obstetric trauma or type 2 diabetes. Also, patients with also may contribute to fecal incontinence.
Figure 21.6. Diagnostic Approach for Fecal Incontinence. MRI indicates magnetic resonance imaging; SeHCAT, selenium homocholic acid tau-
rine test. (Adapted from Bharucha AE, Knowles CH, Mack I, Malcolm A, Oblizajek N, Rao S, et al. Faecal incontinence in adults. Nat Rev Dis Primers.
2022 Aug 10;8[1]‌:53.)
Anal Ultrasonography. Anal ultrasonography reliably chronic constipation. Pudendal nerve terminal motor latency
identifies anatomical defects or thinning of the internal anal (PNTML) can be measured by placing the examining finger, cov-
sphincter and defects of the external anal sphincter that often ered by a glove containing stimulating and recording electrodes,
are unrecognized clinically or are amenable to surgical repair as close as possible to the pudendal nerve as it courses around
(or both). However, compared with the interpretation of images the pelvic brim. PNTML measures the function of the fastest
of the internal sphincter, the interpretation of images of the ex- conducting fibers. Initial studies showed prolonged PNTML
ternal anal sphincter is more subjective, operator-dependent, and in fecal incontinence. However, PNTML measurements are
confounded by normal anatomical variations of the external anal operator-dependent and lack adequate sensitivity and specificity
sphincter. Even asymptomatic women may have an external anal for identifying pudendal nerve damage. Patients with prolonged
sphincter defect after a vaginal delivery. Therefore, it can be PNTML may have normal anal canal squeeze pressures. In con-
challenging to interpret the clinical significance of anal sphincter trast to data from earlier studies, recent data have suggested that
defects (ie, the extent to which a sphincter defect explains anal prolonged PNTML does not predict success after surgical repair
weakness). Among women with obstetric injury, isolated injury of sphincter defects. According to a position statement from the
of the external sphincter is more common; internal anal sphincter American Gastroenterological Association, PNTML should not
injury, in addition to external sphincter injury, increases the risk be used to evaluate fecal incontinence. Needle electromyographic
for fecal incontinence. examination of the external anal sphincter provides a sensitive
measure of denervation and usually can identify myopathic, neu-
Evacuation Proctography. Dynamic proctography is indi- rogenic, or mixed injury.
cated for fecal incontinence when clinical features suggest ex-
cessive perineal descent, a clinically significant rectocele (eg, in Rectal Compliance and Sensation. Sensation is assessed
patients who splint the vagina to facilitate rectal emptying), an by asking patients to report when they perceive the first detect-
enterocele, or internal rectal intussusception. able sensation, the desire to defecate (or urgency), and maximal
tolerable discomfort during rectal balloon distention, generally
Sphincter Denervation Measurements. The pudendal with a handheld syringe. Alternatively, a balloon can be in-
nerve may be injured (with or without damage to the sphincter) flated at a controlled rate with a barostat, which is a continuous-
during vaginal delivery or by repetitive straining in patients with infusion pump. During distention with a barostat, rectal pressures
and volumes and, thus, rectal compliance (pressure- volume therapy with a low dose of psyllium and loperamide reduced the
relationships) and capacity also can be assessed. Rectal sensation frequency of fecal incontinence compared with use of placebo,
may be normal, decreased, or increased in fecal incontinence. but differences were not statistically significant. However, a rec-
When rectal sensation is decreased, stool may leak before the ommendation to increase fiber intake in patients with diarrhea
external anal sphincter contracts. By improving rectal sensation, may be counterintuitive since increased fiber intake is commonly
sensory retraining can restore the coordinated contraction of the advised for treating constipation. Further study is necessary.
external anal sphincter and improve fecal continence. Conversely, It is sensible to recommend limiting intake of caffeine, al-
some patients with fecal incontinence have exaggerated rectal cohol, fatty foods, fructose, and lactose, which predispose to
sensation, perhaps because of a stiffer or smaller rectum. loose stools and fecal incontinence. Weight loss may be attempted
for patients who are overweight or who have obesity. Scheduled
Pelvic MRI. MRI is a relatively new method for imaging anal toileting may also be helpful, particularly for patients who have
sphincter anatomy and pelvic floor motion during defecation limited mobility.
and squeeze without radiation exposure. The anal sphincters Diarrhea should be managed by treatment of the underlying
also can be visualized, preferably with an endoanal MRI coil. condition (eg, antibiotics for small intestinal bacterial over-
MRI is superior to ultrasonography for visualizing morphologic growth and dietary restriction for carbohydrate malabsorption) or
features, particularly atrophy, of the external anal sphincter. In with antidiarrheal agents, which must be prescribed in adequate
contrast to evacuation proctography, dynamic MRI does not en- doses. Loperamide hydrochloride (2 mg; maximal dose, 16 mg
tail radiation exposure and it provides direct visualization of the daily), diphenoxylate hydrochloride with atropine sulfate (5 mg),
pelvic floor, including the anterior (bladder) and middle (uterus) or codeine sulfate (30-60 mg) may need to be taken regularly,
compartments. preferably 30 minutes before meals, perhaps up to several times
daily. Loperamide not only delays gastrointestinal transit but also
Treatment improves anal resting tone. Similarly, amitriptyline improves
Much can be accomplished by regulating bowel habits in patients fecal continence by restoring stool consistency and reducing
who have diarrhea or constipation (Figure 21.7). The use of die- rectal irritability. The bile acid–binding resins cholestyramine
tary fiber supplementation (eg, psyllium 15 g daily) has been and colesevelam are useful for patients with postcholecystectomy
shown to decrease episodes of loose or liquid fecal incontinence diarrhea. Scheduled rectal emptying with suppositories or enemas
compared to placebo or other dietary fibers. In a crossover study, is often useful for fecal impaction and overflow incontinence.
Figure 21.7. Treatment of Fecal Incontinence. (Adapted from Bharucha AE, Knowles CH, Mack I, Malcolm A, Oblizajek N, Rao S, et al. Faecal
incontinence in adults. Nat Rev Dis Primers. 2022 Aug 10;8[1]‌:53.)
When individualized to the underlying anorectal dysfunction, Continence improves in 80% to 90% of patients shortly after
pelvic floor rehabilitation may improve anal sphincter contrac- repair of anal sphincter defects but then worsens over time; less
tions, sensory dysfunction, and coordination, and rehabilitation than 20% of patients are continent at 5 years after the opera-
may be supplemented with biofeedback to augment training tion. Hence, sphincteroplasty is typically reserved for younger
through visual or auditory electronically amplified feedback. women (eg, younger than 45 years) who often have a sphincter
Among patients who did not respond to education and med- defect shortly after obstetric injury. The risks include a high risk
ical management, biofeedback-assisted pelvic floor rehabilita- of minor wound infection (>50%), a moderate risk (about 20%)
tion provided additional benefit beyond pelvic floor exercises of wound breakdown, and a small risk (about 5%) of complete
alone. By contrast, results with biofeedback were not different breakdown with iatrogenic fistulation or cloacal defect, which
from results with education among 300 women who had fecal in- may necessitate a diverting stoma.
continence. In another randomized controlled trial, biofeedback A colostomy is often the last resort for patients with medi-
improved fecal incontinence symptoms more than attention- cally refractory fecal incontinence. Conservative measures, in-
control therapy. Together, these data justify biofeedback therapy cluding management of bowel disturbances, often can improve
when the response to dietary modifications and bowel manage- fecal continence.
ment is insufficient. In patients with coexisting rectal evacuation
disorders, biofeedback may provide the added benefit of teaching ✓ Patients who do not benefit from conservative measures alone
pelvic floor relaxation. may benefit from pelvic floor retraining
If initial therapies are unsuccessful, transanal irrigation or bar- ✓ After surgical repair of anal sphincter defects, fecal continence
initially improves but then worsens
rier devices may be considered. Patients with neurogenic bowel
disorders or chronic constipation and fecal retention may benefit
from transanal irrigation to facilitate rectal cleansing and pre-
vent unwanted stool leakage. Barrier devices (eg, Renew anal Suggested Reading
insert [Renew Medical Inc] and Eclipse vaginal bowel-control Bharucha AE. Pelvic floor: Anatomy and function. Neurogastroenterol
system [Laborie Medical Technologies Corp]) are well tolerated Motil. 2006 Jul;18(7):507–19.
and have improved symptoms in open-label trials. In 1 open- Bharucha AE, Basilisco G, Malcolm A, Lee TH, Hoy MB, Scott SM, et al.
label trial, 62% of patients treated with Renew inserts completed Review of the indications, methods, and clinical utility of anorectal
therapy and had a decrease in the frequency of fecal incontinence manometry and the rectal balloon expulsion test. Neurogastroenterol
of at least 50%. In an open-label trial of the Eclipse vaginal in- Motil. 2022 Sep;34(9):e14335.
Bharucha AE, Dunivan G, Goode PS, Lukacz ES, Markland AD,
sert, of the 55% of patients who were successfully fitted, 79%
Matthews CA, et al. Epidemiology, pathophysiology, and classifi-
had a decrease in the frequency of fecal incontinence episodes cation of fecal incontinence: state of the science summary for the
of at least 50%. National Institute of Diabetes and Digestive and Kidney Diseases
In patients whose symptoms are refractory to rigorously (NIDDK) workshop. Am J Gastroenterol. 2015 Jan;110(1):127–36.
implemented conservative therapy, the key surgical options are Bharucha AE, Knowles CH, Mack I, Malcolm A, Oblizajek N, Rao S,
sacral neuromodulation, sphincteroplasty, some implantable et al. Faecal incontinence in adults. Nat Rev Dis Primers. 2022 Aug
biomaterials and, as a final resort, colonic stoma. Artificial anal 10;8(1):53.
sphincter and dynamic graciloplasty are associated with consid- Bharucha AE, Lacy BE. Mechanisms, evaluation, and management of
erable morbidity, particularly wound infections, and are not used chronic constipation. Gastroenterology. 2020 Apr;158(5):1232–49.
in the US. In large observational cohorts and national registries, Bharucha AE, Sharma M. Painful and painless constipation: all roads
lead to (a change in) Rome. Dig Dis Sci. 2018 Jul;63(7):1671–4.
success rates after sacral neuromodulation have been about
Oblizajek NR, Gandhi S, Sharma M, Chakraborty S, Muthyala A,
50% at 5 to 10 years. Serious harm is very unlikely to occur. Prichard D, et al. Anorectal pressures measured with high-resolution
However, the process is a 2-stage procedure that entails a life- manometry in healthy people-normal values and asymptomatic pelvic
long commitment to use the device, potentially a battery charge floor dysfunction. Neurogastroenterol Motil. 2019 Jul;31(7):e13597.
or change, and other troubleshooting interventions, which are not Rao SSC, Bharucha AE, Chiarioni G, Felt- Bersma R, Knowles
uncommon. C, Malcolm A, et al. Anorectal disorders. Gastroenterology.
Especially for patients with an internal sphincter defect and 2016;150(6):1430–42.
reduced anal resting tone who often have predominantly passive Wald A, Bharucha AE, Limketkai B, Malcolm A, Remes- Troche
incontinence, injectable biomaterials may be considered (ie, JM, Whitehead WE, et al. ACG clinical guidelines: manage-
nonanimal stabilized hyaluronic acid/ dextranomer [NASHA/ ment of benign anorectal disorders. Am J Gastroenterol. 2021
Oct;116(10):1987–2008.
Dx], which is the only approved submucosal agent). In 1 study,
Whitehead WE, Rao SS, Lowry A, Nagle D, Varma M, Bitar KN, et al.
NASHA/Dx was superior to placebo but not to pelvic floor bio- Treatment of fecal incontinence: state of the science summary for
feedback therapy. The potential adverse effects with NASHA/Dx the National Institute of Diabetes and Digestive and Kidney Diseases
include proctalgia, bleeding, and infection. workshop. Am J Gastroenterol. 2015 Jan;110(1):138–46.
22
Gastrointestinal Disease and Pregnancya

SUNANDA V. KANE, MD
Pharmacotherapy for the management of common gastrointes- are presented, and the clinician must decide which information
tinal illnesses continues to evolve. Women with chronic illnesses should be discussed with each particular patient. However, the
who would have been unwilling or unable to conceive in the rating system is still cited and thus is included here.
past are now healthy enough to consider pregnancy. In addition, This chapter covers the treatment of common gastrointestinal
many women are deferring childbearing until later in life, when and liver diseases, the management of common gastrointestinal
polypharmacy and illness may be more common. This chapter symptoms, and the use of medications during endoscopy. The
discusses the use of medications during pregnancy according to majority of medications can be categorized on the basis of ex-
the best available evidence. Because the amount of high-quality isting reports; the categories are summarized in Table 22.1.
controlled data in pregnancy is limited, absolute safety is not
guaranteed with any medication. Instead, the risk of the under- Table 22.1. US Food and Drug Administration (FDA)
lying condition and the safety of the medications used to treat it Categories for the Use of Medications in Pregnancya
should be balanced against the overall health of the mother and
the fetus in each case. All conversations about medications, along FDA category Definition
with possible consequences of not treating the disease during A Controlled studies in animals and women have shown
pregnancy, should be documented carefully. Communication no risk in the first trimester, and possible fetal harm
with the patient’s obstetrician during this time is also paramount. is remote
The US Food and Drug Administration (FDA) has moved away B Either animal studies have not demonstrated a fetal risk,
from its safety rating system and now expects manufacturers but there are no controlled studies in pregnant women,
to include paragraphs in the prescribing information related to or animal studies have shown an adverse effect that
fertility, pregnancy, and lactation. Any animal and human data was not confirmed in controlled studies in women in
the first trimester
C No controlled studies in humans have been performed, and
animal studies have shown adverse events, or studies
a
Portions of this chapter were adapted from Mahadevan U, Kane in humans and animals are not available; give the
S. American Gastroenterological Association Institute technical review medication if the potential benefit outweighs the risk
on the use of gastrointestinal medications in pregnancy. Gastroenterology. D Positive evidence of fetal risk is available, but the benefits
2006 Jul;131(1):283-311 and Mahadevan U. Gastrointestinal medications may outweigh the risk if the disease is life-threatening
in pregnancy. Best Pract Res Clin Gastroenterol. 2007;21(5):849-77; or serious
used with permission. X Studies in animals or humans show fetal abnormalities;
Abbreviations: ERCP, endoscopic retrograde cholangiopancreatography; the drug is contraindicated
FDA, US Food and Drug Administration; HBV, hepatitis B virus; H2,
histamine; IBD, inflammatory bowel disease; IBS, irritable bowel syn-
a
The categories are now considered historical.
drome; Ig, immunoglobulin; OR, odds ratio; SSRI, selective serotonin Adapted from Mahadevan U, Kane S. American Gastroenterological Association
reuptake inhibitor; TREAT, Crohn’s Therapy, Resource, Evaluation, and Institute technical review on the use of gastrointestinal medications in pregnancy.
Assessment Tool; UDCA, ursodeoxycholic acid Gastroenterology. 2006 Jul;131(1):283-311; used with permission.
251
✓ The FDA no longer uses a rating system for safety of medications

women prior to the labor period, unless in the judgment of the
and expects all prescribing information to include sections on fer- physician the potential benefits outweigh the possible risks, be-
tility, pregnancy, and lactation cause safe use in pregnancy prior to labor has not been established
relative to possible effects on fetal development.” Meperidine
is preferred to diazepam or midazolam as an endoscopic pre-
medication during pregnancy. The meperidine dosage should
Endoscopy be titrated to produce calmness, restfulness, and mild analgesia
Endoscopy constitutes a large portion of the gastroenterologist’s without somnolence.
role in patient care. Although many pregnant women have appro-
priate indications for endoscopy, fetal drug safety is a major con-
Fentanyl
sideration in the choice and dosage of endoscopic medications.
For particularly high-risk endoscopy, such as therapeutic endo- Fentanyl is rated a category C drug during pregnancy, and
scopic retrograde cholangiopancreatography (ERCP), an anes- accumulated anecdotal experience suggests that it may be used in
thesiologist may be helpful in titration of medications and patient low doses for endoscopy. Fentanyl is sometimes used as an alter-
monitoring. For patients who present with gastrointestinal tract native to meperidine during endoscopy because of its more rapid
hemorrhage, in which diagnosis and therapeutic intervention onset of action. In several human studies, administration of fen-
are necessary, therapeutic scopes should be used. The use of tanyl to the mother during labor produced no neonatal toxicity.
medications for endoscopy is summarized in Table 22.2.
Propofol
Meperidine
Propofol is a category B drug and is now a preferred agent for
Meperidine is transferred rapidly across the placenta. Physicians sedation in some endoscopy centers. However, it has not been
have extensive experience prescribing meperidine during preg- studied extensively in women in the first and second trimesters
nancy, particularly during labor. Two large studies did not show and, thus, is not recommended for use during this time because
teratogenicity from the administration of meperidine during the of the dearth of studies in the obstetric literature. Propofol rap-
first trimester. The Collaborative Perinatal Project, a national idly transfers across the placenta near term. In 1 study, 20
study with the primary aim of documenting the teratogenicity infants exposed to propofol during parturition had depressed
of drugs taken during the first 4 months of pregnancy, followed Apgar scores at birth compared with unexposed controls, but
more than 50,000 women in 12 US centers between 1959 and the neurodepression rapidly reversed. Numerous other studies
1965 and reported no teratogenicity from meperidine use in 268 have not demonstrated any neonatal toxicity when propofol was
mothers with first-trimester exposure. Meperidine is preferred administered during parturition; however, the safety of exposure
to morphine for obstetric pain because meperidine crosses the in the first trimester has not been studied adequately.
fetal blood-brain barrier more slowly. Meperidine can cause di-
minished fetal beat-to-beat cardiac variability that lasts for ap-
Naloxone
proximately 1 hour after being administered intravenously to the
mother and is a common cause of decreased fetal cardiac vari The FDA classifies naloxone as a category B drug during preg-
ability during endoscopy. nancy. In opiate-dependent patients, small doses of naloxone
The labeling approved by the FDA for meperidine carries the precipitate a syndrome resembling that produced by opiate
following warning: “Meperidine should not be used in pregnant withdrawal. Symptoms include restlessness, anxiety, insomnia,
Table 22.2. Medications Used for Endoscopy

Drug FDA category Recommendations for pregnancy Recommendations for breastfeeding
Ampicillin B Safe to use when required Compatible
Benzocaine C Avoid unless benefit outweighs risk No human data: potential toxicity
Diatrizoate D Minimal use for therapeutic ERCP Limited human data: probably compatible
Diazepam D Midazolam is the preferred benzodiazepine Limited human data: potential toxicity
Electricity None Use for therapeutic ERCP No human data: potential toxicity
Epinephrine C Avoid unless for hemostasis No human data: potential toxicity
Fentanyl C Use in low doses Compatible
Flumazenil C Only for severe benzodiazepine overdose No human data: probably compatible
Glucagon B Avoid except for ERCP No human data
Lidocaine B Gargle and spit (oral form) Limited human data: probably compatible
Meperidine B Use in low doses Compatible
Midazolam D Use in low doses Limited human data: potential toxicity
Naloxone B Only for severe narcotic overdoses No human data: probably compatible
Piperacillin-tazobactam B Useful in cholangitis or biliary sepsis Safe
Polyethylene glycol electrolyte C No human studies available Probably safe
Propofol B Avoid in first and second trimesters Limited human data: probably compatible
Simethicone C Can be avoided but low risk No human data: probably compatible
Sodium glycol electrolyte C Low risk with 1-time use No human data
Abbreviations: ERCP, endoscopic retrograde cholangiopancreatography; FDA, US Food and Drug Administration.
Adapted from Mahadevan U, Kane S. American Gastroenterological Association Institute technical review on the use of gastrointestinal medications in
pregnancy. Gastroenterology. 2006 Jul;131(1):283-311; used with permission.
22. Gastrointestinal Disease and Pregnancy 253
irritability, hyperalgesia, nausea, and muscle cramps. Because Simethicone use carries a low risk during endoscopy because it is
opiates cross the placenta, the administration of naloxone is not absorbed systemically.
dangerous and contraindicated in a pregnant patient who is
specifically opiate dependent. The FDA-approved labeling for
Glucagon
naloxone has the following precaution about use during preg-
nancy: “Naloxone should be used in pregnancy only if clearly The FDA classifies glucagon as a category B drug during preg-
needed.” The administration of naloxone is appropriate, however, nancy. However, no adequate and well-controlled studies have
for pregnant patients who have serious signs of potential meper- involved pregnant women. Thus, this drug should be used during
idine toxicity, such as respiratory depression, systemic hypoten- pregnancy only if clearly needed. Although fetal risk has not
sion, or unresponsiveness. been characterized completely, the administration of glucagon
appears to be justified to decrease intestinal motility to help re-
duce procedure time and to aid in cannulation of the bile duct and
Benzodiazepines sphincterotomy during therapeutic ERCP, which is performed be-
Diazepam and midazolam, category D drugs, should have re- cause of the high risk of untreated maternal cholangitis. If elec-
stricted use during endoscopy, particularly during the first tri- trocautery is used, the grounding pad should be positioned so that
mester. Benzodiazepines, including diazepam and midazolam, the uterus is not directly between the electrical catheter and the
are commonly administered before gastrointestinal endoscopy grounding pad.
to reduce anxiety, induce brief amnesia, and produce muscle re-
laxation. Diazepam freely and rapidly crosses the placenta and
Antibiotics
accumulates in the fetal circulation at levels equal to or higher
than those of maternal serum. The FDA- approved labeling Ampicillin
for diazepam carries the following warning about use in preg- The FDA classifies ampicillin as a category B drug during
nancy: “An increased risk of congenital malformations associated pregnancy. This penicillin antibiotic may be used when
with the use of minor tranquilizers . . . during the first trimester Enterococcus infection is a concern. Ampicillin rapidly crosses
of pregnancy has been suggested in several studies. Because the placenta, and fetal serum levels equilibrate with those of the
use of these drugs is rarely a matter of urgency, their use during maternal serum within 3 hours after the drug is administered to
this period should almost always be avoided.” Diazepam is not the mother.
recommended by the American Academy of Pediatrics because
it, along with its metabolite N-demethyldiazepam, can accumu-
late in breastfed infants. Piperacillin-Tazobactam
Many endoscopists prefer midazolam to diazepam for en- Piperacillin-tazobactam, in FDA category B, is a good choice
doscopic premedication because of faster onset and recovery for pregnant patients who present with features of cholangitis or
time, more intense transient antegrade amnesia, and lower risk biliary sepsis. It may also be used before ERCP as prophylaxis
of thrombophlebitis. Midazolam crosses the human placenta, but against biliary sepsis when an obstructed biliary tree is suspected.
fetal serum levels increase to only about one-third to two-thirds Piperacillin-tazobactam covers most biliary and enteric pathogens
of those of maternal serum after oral, intramuscular, or intrave- (eg, Escherichia and Klebsiella) and also covers Enterococcus
nous administration in the mother. Midazolam appears to be pref- species. The drug does cross the placenta but is deemed safe in
erable to diazepam for endoscopy during pregnancy because of all trimeters of pregnancy. This antibiotic may also be used in
the potential association between diazepam and oral clefts and women who breastfeed.
neonatal neurobehavioral abnormalities. Because the mechanism
of action is similar to that of diazepam, midazolam should be
used cautiously and in low doses during pregnancy, particularly Colonic Lavage Preparations
during the first trimester. Dosages should be titrated carefully to Polyethylene glycol electrolyte solution has not been studied
an end point of relaxation and calmness but not somnolence. extensively in pregnancy, and it is not known whether it can
cause fetal harm. A study of 225 patients showed that the agent
Flumazenil was safe when used to treat constipation. Because full colonos-
copy rarely is indicated during pregnancy, tap water enemas are
Flumazenil, a category C drug, is a benzodiazepine antagonist
recommended as bowel preparation for lower endoscopy.
that rapidly reverses the central effects of benzodiazepines. Little
is known about the safety of flumazenil during pregnancy or in
infants; thus, it should be used during pregnancy only if the poten- Topical Anesthetics
tial benefit clearly outweighs the risks. The need for flumazenil
Lidocaine
can be prevented by carefully and slowly titrating the benzodiaz-
epine dosage and by using the minimal benzodiazepine dosage Lidocaine, an FDA category B drug, can be applied topically to
required for endoscopic examination. the oropharynx before upper endoscopy and ERCP, although it
is rarely needed. Additionally, lidocaine gel can be used topi-
cally around the perianal area before lower endoscopy in patients
Simethicone with painful hemorrhoids and fissures. No fetal harm was noted
The FDA has classified simethicone as a category C drug. Many during parturition in the Collaborative Perinatal Project, in which
endoscopists use simethicone to reduce gastric foam before upper 293 infants were exposed in the first trimester. The pregnant pa-
endoscopy. A surveillance study of Michigan Medicaid patients tient who is administered topical lidocaine should be instructed
did not show a statistically significant difference between preg- to gargle and spit out the preparation, rather than swallow it, to
nant women exposed to the drug and those not exposed to it. minimize systemic absorption.
Table 22.3. Medications Used for Nausea and Vomiting During Pregnancy
Dolasetron B No human studies No human data: probably compatible
Domperidone C Safety unknown Limited human data: probably compatible
Granisetron B No human studies No human data: probably compatible
Metoclopramide B No teratogenicity; low risk (population-based study) Limited human data: potential toxicity
Ondansetron B No teratogenicity; low risk (controlled trial) No human data: probably compatible
Prochlorperazine C No teratogenicity; low risk (large database study) No human data: potential toxicity
Promethazine C No teratogenicity; low risk (large database study) No human data: probably compatible
Pyridoxine A Considered safest therapy for nausea and vomiting; Compatible
available without prescription
Trimethobenzamide C No teratogenicity; low risk (case series) No human data: probably compatible
Abbreviation: FDA, US Food and Drug Administration.
Benzocaine use of antiemetic medications during pregnancy is summarized

Benzocaine aerosols, gels, and solutions are used to anes- in Table 22.3.
thetize the oropharynx before upper endoscopic procedures.
However, benzocaine is an FDA category C drug and should be Ginger
considered only if the benefit of the medication outweighs the
Ginger extract, which comes in many forms, is popular for homeo
risk to the fetus.
pathic treatment of nausea and vomiting during pregnancy. At least
4 randomized controlled trials have compared ginger with placebo,
Therapeutic Agents for Hemostasis and another 4 have compared ginger with pyridoxine. All these
Epinephrine is injected during endoscopy to achieve hemostasis trials have shown that ginger is beneficial for symptoms without
of actively bleeding lesions. During therapeutic endoscopy, epi- raising clinically significant safety concerns.
nephrine is used to stop active bleeding; in this clinical scenario,
the benefit outweighs the potential risk of its use. Pyridoxine
Electricity is transferred readily across the uterus because am-
First-line therapy for nausea and vomiting during pregnancy is
niotic fluid is an excellent conductor. Fetal risk depends on the
pyridoxine (vitamin B6). Several randomized controlled trials
voltage and on the current amplitude, duration, and frequency
have demonstrated its effectiveness at 10 to 25 mg every 8
time as well as on the location on the body. Fetal mortality is rare
hours in the treatment of nausea and vomiting during pregnancy.
from electroconvulsive therapy or direct current cardioversion
Pyridoxine in combination with doxylamine has also been shown
during pregnancy. During endoscopy, bipolar electrocautery
to be effective and safe and is classified in FDA category A.
should be used because no grounding pad is necessary.
Metoclopramide
Contrast Dye
The use of metoclopramide as an antiemetic usually is con-
Diatrizoate, a contrast agent injected into the biliary tree, has
fined to the first trimester, but it also is used to enhance gastric
been used in diagnostic and therapeutic amniography without
emptying throughout pregnancy. A Danish study compared, over
harming the fetus. Although it has been documented to impair
a 5-year period, 309 women who had singleton pregnancies and
fetal thyroid function and is an FDA category D medication, the
prescriptions for metoclopramide with 13,327 controls. The
risk of its use for cholangiography is less than for amniography
study reported no major differences in the risk of malformations
because of the doses used. In the appropriate clinical setting, the
(odds ratio [OR], 1.11; 95% CI, 0.6-2.1); low birth weight (OR,
risk of maternal cholangitis likely outweighs the theoretical risk
1.79; 95% CI, 0.8-3.9); or preterm delivery (OR, 1.02; 95% CI,
of transient fetal hypothyroidism.
0.6-1.7). While metoclopramide is an FDA category B medica-
✓ Indications for endoscopy in pregnant women are the same as tion, the risk of metoclopramide-induced movement disorders
those in women who are not pregnant with long-term use needs to be considered.
✓ Propofol—the preferred agent for sedation (if sedation is to
be used)
Prochlorperazine
Prochlorperazine, a category C drug, readily crosses the placenta.
However, most studies have not found an increased risk of ad-
Nausea and Vomiting
verse outcomes in pregnancy.
Nausea and vomiting are extremely common during preg-
nancy and have multiple causes. Most women can be supported
Promethazine
through episodes without the use of antiemetics. However, for
women who have a protracted course or underlying conditions Promethazine is another category C drug. It is an antihistamine
that may predispose to nausea and vomiting, medical therapy is that is used occasionally as an antiemetic during pregnancy and
warranted to prevent complications from volume depletion. The also as adjunctive therapy for narcotics during labor.
Table 22.4. Medications Used for Gastroesophageal Reflux and Peptic Ulcer Disease
Antacids
Aluminum-containing antacids None Most safe: minimal absorption Low risk
Calcium-containing antacids None Most safe: minimal absorption Low risk
Magnesium-containing antacids None Most safe: minimal absorption Low risk
Magnesium trisilicates None Avoid long-term use or high doses Low risk
Sodium bicarbonate None Not safe: alkalosis Low risk
Mucosal protectants
Sucralfate B Safe No human data: probably compatible
Histamine receptor antagonists
Cimetidine B Controlled data: low risk Compatible
Famotidine B Paucity of safety data Limited human data: probably compatible
Nizatidine B Limited human data (low risk in Limited human data: probably compatible
animals)
Ranitidine B Low risk Limited human data: probably compatible
Proton pump inhibitors
Dexlansoprazole B Limited data: low risk No human data: potential toxicity
Esomeprazole B Limited data: low risk No human data: potential toxicity
Lansoprazole B Limited data: low risk No human data: potential toxicity
Omeprazole C Embryonic and fetal toxicity Limited human data: potential toxicity
Pantoprazole B Limited data: low risk No human data: potential toxicity
Rabeprazole B Limited data: low risk No human data: potential toxicity
Promotility agents
Cisapride C Controlled study: low risk, limited Limited human data: probably compatible
availability
Metoclopromide B Low risk Limited human data: potential toxicity
Treatment of Helicobacter pylori infection
Amoxicillin B Safe Compatible
Bismuth C Not safe: teratogenicity No human data: potential toxicity
Clarithromycin C Avoid in first trimester No human data: probably compatible
Metronidazole B Low risk: avoid in first trimester Limited human data: potential toxicity
Tetracycline D Not safe: teratogenicity Compatible
Trimethobenzamide Domperidone
Trimethobenzamide is a category C drug. Three studies have Domperidone, a category C drug, is a dopamine antagonist
followed outcomes among women who took trimethobenzamide used for short-term treatment of nausea and vomiting and for its
during the first trimester for nausea and vomiting. In all 3 studies, prokinetic properties. Currently, it is not available in the US by
there was no increase in the incidence of malformations with the prescription. Whether it crosses the placenta is not known, but its
use of trimethobenzamide. bioavailability after oral ingestion is low.
✓ Nausea and vomiting—extremely common during pregnancy

Ondansetron ✓ Natural entities such as ginger and pyridoxine are effective first-
line therapy for mild symptoms related to nausea and vomiting
Ondansetron, a category B drug, is used for the prevention
and treatment of chemotherapy-induced nausea and vomiting
and for hyperemesis gravidarum. A randomized, double-blind
study compared intravenous ondansetron with promethazine for Gastroesophageal Reflux Disease
hyperemesis. Ondansetron was well tolerated and efficacious with Heartburn is estimated to occur in 30% to 50% of pregnancies.
no adverse effects; however, outcomes among infants were not For mild symptoms, only lifestyle and dietary modifications
reported. Results from teratogen information services databases may be required. Medications for treating gastroesophageal
do not show an increase in major malformations in comparison reflux disease have not been tested routinely in randomized
with exposure to other antiemetics or healthy controls. controlled trials with pregnant women. The medications used to
treat gastroesophageal reflux disease and peptic ulcer disease are
summarized in Table 22.4.
Granisetron and Dolasetron
Both granisetron and dolasetron are category B drugs. There
have not been any studies on pregnant women exposed to these
Antacids
agents. However, studies of pregnant rats and rabbits that were Antacids that contain magnesium, aluminum, or calcium are not te-
given up to 146 times the human dose did not show any adverse ratogenic in animal studies. Although 1 case-control study reported
outcomes. a significant increase in major and minor congenital abnormalities
in infants exposed to antacids during the first trimester of preg- Therefore, maternal doses of 45 mg or less daily should not have
nancy, no analysis of individual agents was done and, currently, adverse effects on a breastfeeding infant.
most antacids at normal therapeutic doses are considered accept-
able during pregnancy. Magnesium trisilicate, found in alginic
Cisapride
acid, can lead to fetal nephrolithiasis, hypotonia, and respiratory
distress if used long term and in high doses. Antacids containing Cisapride is a category C drug. A prospective, multicenter study
sodium bicarbonate should not be used because they can cause compared the outcomes of 129 Canadian women who took
maternal or fetal metabolic alkalosis and fluid overload. Excessive cisapride between November 1996 and November 1998 with
intake of calcium carbonate can result in milk-alkali syndrome, those of matched controls. No differences in the rates of major or
characterized by hypercalcemia, kidney impairment, and meta- minor congenital malformations were reported for the 2 groups.
bolic alkalosis. None of the antacids have been shown to concen- In July 2000, Janssen Pharmaceuticals, Inc, removed cisapride
trate in breast milk, so they are acceptable when breastfeeding. from the market because of concern about cardiovascular effects,
and it is available only through a limited-access program.
Sucralfate
Omeprazole
Sucralfate, a category B drug, is a nonabsorbable drug that exerts a
local rather than systemic effect and has been tested in a prospec- Omeprazole, the first proton pump inhibitor, is a category C
tive randomized controlled trial. Women with gastroesophageal drug. This drug has been shown to produce dose-related embry-
reflux disease treated with sucralfate had a higher frequency of onic and fetal mortality in pregnant rats and rabbits administered
symptomatic remission than controls (90% vs 43%, P<.05). doses similar to those for humans. However, several prospective
database studies have shown the safety of omeprazole. The in-
cidence of major abnormalities in pregnant women exposed to
Cimetidine omeprazole was 5.1%, compared with 3.1% for those taking H2
Cimetidine is a category B drug. Multiple large cohort studies blockers and 3.0% for the untreated group. Because of the pau-
have shown that the rate of major birth defects among pregnant city of data about their effects, proton pump inhibitors are not
women taking cimetidine is the same as that for healthy controls. recommended for mothers who are breastfeeding.
Ranitidine Lansoprazole
Ranitidine, like the other histamine (H2) blockers, is a category B Lansoprazole is a category B drug. In 1 nonobservational cohort
drug. In the most recently published study of ranitidine use during study, 6 pregnant patients exposed to lansoprazole during the first
pregnancy, data were collected prospectively from a large network da- trimester delivered 7 healthy newborns. The relative risk for a
tabase for teratology information. The study reported on 335 pregnant congenital malformation was 1.6 (95% CI, 0.1-5.2); for low birth
women exposed to ranitidine, 113 to cimetidine, 75 to famotidine, and weight, 1.8 (95% CI, 0.2-13.1).
15 to nizatidine. The incidence of premature deliveries was higher in
the exposed group than in the control group, but there was no increase
Pantoprazole
in the incidence of major malformations. The authors concluded that
there was no indication of an increased risk of major malformations Pantoprazole is also a category B drug. In a European cohort
after the use of H2 blockers during pregnancy. study, 53 pregnant women were exposed to pantoprazole, and
the rate observed for congenital anomalies was 2.1%. Although
the newer proton pump inhibitors rabeprazole and esomeprazole
Famotidine and Nizatidine are also category B drugs, no controlled data are available about
Although both famotidine and nizatidine are category B drugs, the them; thus, their use is not recommended during pregnancy.
relatively smaller amount of data available from animal and human
studies compared with that for other H2 blockers makes the choice of Esomeprazole
another agent prudent. Studies of animals treated with nizatidine, at
300 times the recommended human dose, reported more abortions, Esomeprazole is a category B drug. Most of its safety data come
lower fetal weight, and fewer live fetuses among the treated ani- from studies done with its isomer, omeprazole. The single study
mals than among the controls. Another study showed a higher rate that used esomeprazole showed a nonsignificant increase in the
of abortions in rabbits treated with large doses of the drug. incidence of birth defects when the drug was used 4 weeks before
pregnancy or in the first trimester.
Promotility Agents
Dexlansoprazole
Metoclopramide
Dexlansoprazole is a category B drug as well. To date, no
Metoclopramide is a category B drug. No congenital controlled studies have been performed with humans. In reproduc-
malformations or other neonatal toxicities in humans have been tive studies with rodents given up to 40 times the recommended
reported with the use of metoclopramide. Reproductive studies human dose, there was no evidence of adverse events.
of mice, rats, and rabbits that received up to 250 times the
recommended human dose have not demonstrated any increase
in fetal toxicity. Metoclopramide has been used as a lactation Rabeprazole
stimulant, and the total daily dose that would be consumed by a Compared with studies of other proton pump inhibitors,
nursing infant if the mother took 30 mg daily is much less than rabeprazole studies have the least amount of human data. Studies
the maximum daily dose of 500 µg/kg recommend for infants. with rodents given doses considered supratherapeutic for humans
did not show any increase in adverse events. Thus, rabeprazole is Acute and Chronic Pancreatitis
a category B drug.
Acute pancreatitis often resolves with supportive care. If an-
✓ Heartburn— extremely common during pregnancy, particularly algesia is required, meperidine and fentanyl are the preferred
during later stages medications (discussed above in the Endoscopy section). If the
✓ Omeprazole—the only proton pump inhibitor that is discouraged patient cannot tolerate nutrition by mouth because of ongoing
as treatment according to early animal data pain or ileus, early enteral feedings are recommended.
✓ Avoid use of heartburn remedies that contain sodium bicarbonate, Chronic pancreatitis is managed with alcohol cessation, small
calcium carbonate, or trisilicates low-fat meals, analgesia, and pancreatic enzyme supplements.
Pancreatic enzymes are a category C drug because animal re-
production studies have not been performed. The data on safety
Peptic Ulcer Disease during pregnancy and lactation are limited. Generally, unless
these medications are essential, their use should be avoided.
Treatment of peptic ulcer disease involves the use of proton However, in patients with cystic fibrosis and pancreatic insuf-
pump inhibitors or H2 blockers, which are discussed above in the ficiency, maintenance of nutritional status is a critical factor in
Gastroesophageal Reflux Disease section. If peptic ulcer disease pregnancy outcome. In a study of 23 women with 33 pregnancies,
is related to Helicobacter pylori infection, treatment of the in- 91% of the women received pancreatic supplementation during
fection can be deferred until after pregnancy. The most common pregnancy. The severity of lung disease predicted preterm de-
regimen involves triple therapy with a proton pump inhibitor, livery, and no congenital malformations were noted.
amoxicillin, and clarithromycin. Alternatively, metronidazole,
bismuth, and tetracycline may be used if needed. In the unusual
case when treatment is warranted during the gravid period, tetra- Biliary Tract Disease
cycline and bismuth should not be used. Cholecystitis and Choledocholithiasis
Laparoscopic cholecystectomy has become the standard of
Amoxicillin care for the management of cholecystitis and symptomatic
Amoxicillin is a category B drug. A population-based study of choledocholithiasis. Surgical intervention during pregnancy does
401 women treated with amoxicillin did not show any increased not appear to be associated with an increase in complications,
risk of congenital malformation or any other adverse event and if cholecystectomy is indicated during pregnancy, the
compared with pregnant women not treated with amoxicillin. second trimester is the best time. Nonsurgical approaches, such
as oral chenodeoxycholic acid, oral ursodiol (ursodeoxycholic
acid [UDCA]), and extracorporeal shock wave lithotripsy,
Clarithromycin
have not been used in pregnancy and are not recommended.
Clarithromycin, a category C drug, has a higher rate of placental Chenodeoxycholic acid and UDCA have been used with limited
passage than other macrolide antibiotics. In a prospective study success in the treatment of cholesterol gallstones in the general
of clarithromycin in pregnancy, no increased risk of congenital population. No data are available about chenodeoxycholic acid
malformations was reported; however, the rate of spontaneous in pregnancy (UDCA is discussed below with primary sclerosing
abortions was higher than in the unexposed group. A retrospective cholangitis).
surveillance study of clarithromycin exposure within 270 days
of delivery showed no increase in congenital malformations
compared with that of the general population of pregnant women. Primary Sclerosing Cholangitis
There is no effective medical therapy for primary sclerosing
Tetracycline cholangitis. The medication that has been used most commonly
is UDCA, a category B drug. Its safety during lactation is not
Tetracycline, a category D drug, is possibly unsafe to use during known. Human fetotoxicity from UDCA has not been reported;
lactation. It is discussed below in the Infectious Diarrhea section. however, the data are not sufficient to determine risk in the first
trimester. Therapeutic trials with UDCA have yielded incon-
Metronidazole sistent results, and high doses (25-30 mg/kg daily) may actually
be harmful and should be avoided. UDCA can be administered
Metronidazole is a category B drug and carries a low risk during during pregnancy, especially after the first trimester, to reduce
lactation. It is discussed below in the Infectious Diarrhea section. cholestasis and accompanying sequelae such as pruritus.
Bismuth Diseases of the Liver

Bismuth, a category C drug, is one of the most commonly used The use of medications for diseases of the liver, including liver
over-the-counter antacids. Fetotoxicity from bismuth has been transplant, is summarized in Table 22.5.
described for animals. Exposure to bismuth subsalicylate during
late pregnancy may increase the risk of closure or constriction of
the fetal ductus arteriosus, resulting in pulmonary hypertension. Viral Hepatitis
Bismuth is considered as possibly unsafe during lactation.
Hepatitis A is a self-limited condition, and the treatment of
✓ Unless H pylori infection has been diagnosed in a patient with pregnant women is similar to that of nonpregnant women. Both
acute bleeding in the gastrointestinal tract, it is reasonable to defer the inactivated vaccine against hepatitis A and postexposure
treatment until after delivery immune globulin prophylaxis are safe to administer during
pregnancy.
Table 22.5. Medications Used in the Treatment of Diseases of the Liver

Adefovir dipivoxil C Minimal data: no teratogenicity No human data: probably compatible
(hepatitis B)
Antithymocyte globulin C Human-specific agent Safety unknown
Cyclosporine C Safest of immunosuppressants Limited human data: potential toxicity
Entecavir B Not recommended: alternatives available No human data
Interferon C Not recommended: defer treatment until after delivery Limited human data: probably compatible
Lamivudine C Low risk Contraindicated
Muromonab-CD3 C No pregnancy data but probably low risk Contraindicated
(Orthoclone OKT3a)
Mycophenolate mofetil D Not recommended Contraindicated
Nadolol C: First trimester Prolonged half-life, so use alternative Limited human data: potential toxicity
D: Second and third Risk of IUGR in second or third trimester
trimesters
Obeticholic acid No rating Acceptable to use if appropriate Likely compatible
Penicillamine D Severe embryopathy No human data: potential toxicity
If required, decrease dose to 250 mg daily 6 wk
before delivery
Propranolol C: First trimester Fetal bradycardia Limited human data: potential toxicity
D: Second and third IUGR in second and third trimesters
trimesters
Ribavirin X Contraindicated No human data: potential toxicity
Severe fetal neurotoxicity
Sirolimus C Not recommended No human data: potential toxicity
Tacrolimus C Use if mother’s health mandates Limited human data: potential toxicity
Tenofovir B Safe for use during pregnancy Probably compatible (hepatitis B)
Trientine C Limited human data: alternative to penicillamine No human data: potential toxicity
Ursodiol B Low risk No human data: probably compatible
Used for intrahepatic cholestasis of pregnancy
Abbreviations: FDA, US Food and Drug Administration; IUGR, intrauterine growth retardation.
a
Janssen-Cilag.
Adapted from Mahadevan U, Kane S. American Gastroenterological Association Institute technical review on the use of gastrointestinal medications in pregnancy.
Gastroenterology. 2006 Jul;131(1):283-311; used with permission.
Hepatitis B infection carries a high rate of vertical trans- but this was not statistically higher than expected. Lamivudine is
mission, and the indications to treat are much greater during contraindicated during breastfeeding because it is excreted into
pregnancy. The vaccine is safe to use. Passive and active immu- milk in high concentrations.
nization, given together, are very effective in preventing neonatal
transmission, reducing the carrier state of infants born to women
Adefovir Dipivoxil
who test positive for hepatitis B e antigen and hepatitis B surface
antigen (carrier state decreases from 70% to 90% to almost zero). Adefovir dipivoxil is a category C drug. No adequate well-
controlled studies have been conducted on the use of adefovir
dipivoxil in pregnant women. This drug is indicated for the
Lamivudine
treatment of chronic hepatitis B in adults who have evidence of
The FDA has classified lamivudine as a category C drug. For active viral replication and evidence of either persistent increase
women with chronic hepatitis B, studies have documented the in the serum levels of aminotransferases or histologically active
safety of lamivudine for continued treatment during pregnancy. disease. During clinical trials with this agent, 16 pregnancies
Standard doses of lamivudine have been continued through with known outcomes were reported. Ten women had a thera-
pregnancy with a hepatitis B virus (HBV)-DNA seroconver- peutic abortion, 2 had a spontaneous abortion, 3 delivered healthy
sion rate of 92%, with no reported complications or congenital babies, and 1 delivered a live infant at 25 weeks’ gestation who
abnormalities. In an earlier study, investigators treated 8 highly died 4 days later. Studies conducted with adefovir dipivoxil
viremic women with 150 mg lamivudine in the third trimester administered orally in doses up to 23 times that achieved in
of pregnancy in an attempt to prevent perinatal transmission of humans have not shown any embryotoxicity or teratogenicity in
HBV infection. One child was delivered early because of in- laboratory animals. No human studies have been performed on
trauterine growth retardation. All but 1 woman had a marked the use of this drug during lactation, and its use during lactation
decrease in HBV DNA levels before delivery, and vertical trans- is not recommended.
mission occurred in only 1 child.
In the medical literature on HIV, the Antiretroviral Pregnancy
Tenofovir
Registry contains 526 live births that were exposed to lamivudine
during the first trimester, with a congenital defect rate of 1.7%. Of Tenofovir is a nucleotide reverse transcriptase inhibitor. In a re-
1,256 live births, 25 had a history of exposure during pregnancy cent review, tenofovir was determined to provide more benefit
and showed a slightly higher rate, 2.5% (95% CI, 1.3%-3.0%), than harm during pregnancy, and it is a reasonable choice when
the viral load is greater than 200,000 U/mL at 26 to 28 weeks’ pregnancy. For women who are pregnant and have hepatitis C
gestation. virus infection, the guidance from the American Association for
the Study of Liver Diseases and the Infectious Diseases Society
of America is that “treatment can be considered during pregnancy
Telbivudine
on an individual basis after a patient-physician discussion about
Telbivudine is a nucleoside reverse transcriptase inhibitor that is the potential risks and benefits.”
not available in the US. It can be used if the viral load is greater
than 200,000 U/mL at 26 to 28 weeks’ gestation, but, as with ✓ Generally, there is no need to use drug therapy for hepatitis C
other drugs in this class, lactic acidosis and kidney insufficiency during pregnancy because the risks outweigh the benefits
can occur.
Entecavir Wilson Disease

Entecavir is a cyclopentyl guanosine analogue used to treat active Penicillamine
hepatitis B. It is not recommended for use during pregnancy be- Penicillamine, a category D drug, is a chelating agent that is first-
cause animal data have shown a teratogenic effect. line therapy for Wilson disease. Only a few reports are available
about the outcome of pregnancies in women with Wilson disease.
Interferon The largest recent case series is from India, where 59 pregnancies
in 16 women were studied retrospectively. This group included
Interferon, a category C drug, is contraindicated during preg-
24 spontaneous abortions, 3 stillbirths, 2 terminations, and
nancy because of its antiproliferative activity. When interferon
30 successful pregnancies. The majority of the spontaneous
was administered to pregnant rhesus monkeys, they had a statisti-
abortions were in women who were not receiving therapy. Other
cally significant increase in the number of spontaneous abortions.
case reports have documented severe embryopathy characterized
No teratogenic effects were observed in this species when doses
by micrognathia, diffuse cutis laxa, and agenesis of the corpus
of 1 million to 25 million IU/kg daily were administered during
callosum in addition to transient fetal myelosuppression. It is
the early-fetal to mid-fetal period. To date, only 27 pregnancies
debated whether penicillamine therapy should be continued
have been reported after exposure to interferon. The majority of
during pregnancy; various authors have disagreed on whether to
these women were being treated for essential thrombocythemia
use the agent and, if so, how much to administer.
and not hepatitis B. Premature delivery occurred in 15% and in-
trauterine growth retardation in 22% of the patients (6 of 27).
A total of 8 children have been born to mothers receiving inter- Trientine
feron who were thought to be at high risk for chronic hepatitis
Trientine is a category C drug and is used if no other alternatives
infection. With the advent of effective direct- acting antiviral
are appropriate to treat the mother’s liver disease. This chelating
therapy, interferon is no longer used for the treatment of hepatitis
agent is an alternative to penicillamine and is available only as
C. Interferon is rarely indicated for treatment of chronic hepatitis
an orphan drug for use in Wilson disease. Because there are few
B and should not be given during pregnancy because of the risk
other options, the benefit is thought to outweigh the risk.
of teratogenicity.
Primary Biliary Cirrhosis

Ribavirin
Ursodeoxycholic Acid
Ribavirin is indicated in some situations along with direct-
acting antiviral therapy for treatment of hepatitis C. However, UDCA is a category B drug. Because of the paucity of data
ribavirin is known to cause dose-related teratogenic effects and about its safety in the first trimester, its use during this time is
embryolethality in all animal species tested. It is a category X not recommended unless essential. It has been administered to
drug and is contraindicated in pregnancy. Furthermore, the risk women during the second and third trimesters without apparent
of teratogenicity persists for up to 6 months after drug cessation deterioration of liver function. No fetal loss or unfavorable
in women taking ribavirin and in female partners of men taking outcomes were reported among 10 women receiving the drug.
ribavirin. In a randomized controlled trial of UDCA in women with
intrahepatic cholestasis of pregnancy, UDCA improved pruritus
✓ Hepatitis B infection during pregnancy—use of passive and active and liver enzyme levels, and it allowed for delivery closer to
immune therapy at birth is recommended term. A second randomized controlled trial, which compared
✓ Agents for treatment of hepatitis B that pose a low risk during UDCA with cholestyramine, reported similar results: Among
pregnancy—lamivudine, tenofovir, and telbivudine the patients treated with UDCA, symptoms were alleviated and
✓ Treatment of hepatitis B should be provided when the viral load
babies were delivered much closer to term.
exceeds 200,000 U/mL
✓ Interferon, adefovir, and entecavir are not recommended for use
during pregnancy Obeticholic Acid
The FDA recently approved obeticholic acid to treat primary bil-
While there are several FDA-approved regimens for hepatitis iary cirrhosis. The drug is used when the response to ursodiol
C with sustained viral response, the indications for treatment is inadequate or as monotherapy for patients unable to tolerate
during pregnancy are individualized. Very small studies have ursodiol. Animal data did not demonstrate a risk of adverse
demonstrated safety. However, there are not enough safety outcomes, so obeticholic acid can be used during pregnancy if
data to recommend use of direct-acting antiviral therapy during the maternal benefit outweighs the risk of fetal harm.
Portal Hypertension abortion rate was 12%, the stillbirth rate was 3%, and 59% of the
infants were premature. Malformations occurred in 4 neonates,
Propranolol
with no consistent defects. More recent data from the National
Propranolol, a category C drug, is a nonselective β-adrenergic Transplantation Pregnancy Registry showed a birth defect rate
blocking agent used for prophylaxis against variceal bleeding in of 4.2% among live births with exposure to tacrolimus, which
patients with cirrhosis. It has been administered during pregnancy was not different from the background rate of birth defects in the
to treat maternal thyrotoxicosis, arrhythmias, and hypertension. It US (3%-5%). Tacrolimus is the most commonly used immuno-
readily crosses the placenta and, thus, is used also to treat fetal suppressive drug after liver transplant and is generally used at
arrhythmias. Adverse outcomes have not been clearly linked to its the lowest acceptable dose during pregnancy to prevent rejection.
use, but daily doses greater than 160 mg appear to produce more Tacrolimus is contraindicated during lactation because of the
serious fetal cardiac complications. No data have been reported high concentrations found in breast milk.
for outcomes among women who took this drug for variceal pro-
phylaxis. Propranolol is not a teratogen, but fetal and neonatal
toxicity may occur. Maternal use after the second trimester can
Sirolimus
result in marked weight reductions in the infant. Therefore, it is Sirolimus is a category C drug. Little is known about its effect
not recommended for use after the first trimester unless the unin humans. Sirolimus is another agent used for immunosup-
derlying condition of the mother requires continued β-blockade. pression in transplant recipients. Three patients in the National
Transplantation Pregnancy Registry were treated with sirolimus,
but they were kidney recipients. Because of the relative paucity of
Nadolol
information, and the reasonable alternatives for immunosuppres-
Nadolol, a category C drug, is another nonselective β-adrenergic sion, this agent is not recommended during pregnancy.
blocker. It is an alternative to propranolol. Nadolol is used pre-
dominantly as an antihypertensive, and no data are available
for its use for variceal prophylaxis. Because the characteristics Mycophenolate Mofetil
of nadolol include a long half-life, low protein binding, and Mycophenolate mofetil, a category D drug, has been shown to
lack of metabolism, the use of alternative agents in this class is have teratogenic properties in laboratory animals. In a single
recommended if treatment is strongly indicated. case report in the obstetric literature, a kidney transplant recip-
ient was treated with mycophenolate mofetil before conception
Liver Transplant and during the first trimester of pregnancy. The fetus had facial
dysmorphology and multiple midline anomalies. The molecular
The best data available about medications for transplant recipients weight of this agent is low enough that it most likely crosses the
are from the National Transplantation Pregnancy Registry. Every placenta. Its use is contraindicated in pregnancy. The manufac-
year, an updated report is presented with the results from a pro- turer recommends that women use effective contraception before
spective database of all transplant recipients. In a recent report, and during therapy and for 6 weeks after therapy has stopped.
the rate of live births was 77% for women receiving cyclosporine,
82% for those receiving cyclosporine as Neoral (Novartis), and
72% for those receiving tacrolimus. Two patients were receiving Irritable Bowel Syndrome
mycophenolate mofetil therapy and delivered healthy infants. Irritable bowel syndrome (IBS) is a heterogeneous disorder without
The mean gestational age was 37 weeks, and the rate of low birth a standardized therapeutic regimen. No large epidemiologic
weight was 29% to 42%. The conclusion of the advisory board studies have been conducted with pregnant women who have pre-
was that “the majority of pregnancy outcomes reported to the existing IBS. If possible, medications should be avoided and die-
Registry appear favorable for parent and newborn.” tary alterations and fiber supplementation should be the first step
for symptoms of constipation. The following summarizes available
Cyclosporine safety data about drugs for IBS if medication is required. However,
most drug therapies for the treatment of this syndrome have not
Cyclosporine is a category C drug. A meta-analysis of 15 studies demonstrated efficacy over placebo. The use of medications for
of pregnancy outcomes after cyclosporine therapy reported on IBS during pregnancy is summarized in Table 22.6.
410 patients. For major malformations, the calculated OR (3.83;
95% CI, 0.75-19.6) was not statistically significant, and the rate of ✓ For any symptom in a patient with IBS, dietary modification
malformations (4.1%) was not different from that of the general should always be tried before medications
population. The conclusion from the study was that cyclosporine
did not appear to be a major human teratogen. The American
Academy of Pediatrics considers cyclosporine contraindicated
Constipation
during breastfeeding because of the potential for immunosup-
pression and neutropenia. For a pregnant woman with constipation, first-line therapy should
be fiber supplements, introduced gradually to avoid excessive
gas and bloating, and adequate water intake. New-onset consti-
Tacrolimus
pation during early pregnancy is often due to iron therapy, and
Tacrolimus is another category C drug. The earliest experience symptomatic relief can be achieved with docusate, now a com-
with this medication was in 1997, with a report of 27 pregnancies ponent of some prenatal vitamins. When these methods are in-
with exposure to tacrolimus. Another study from Germany re- adequate, an osmotic laxative should be considered, particularly
ported on 100 pregnancies in transplant recipients followed from a polyethylene glycol solution. Osmotic laxatives include saline
1992 to 1998. The live birth rate was 68%, the spontaneous osmotics (magnesium and sodium salts), saccharated osmotics
Table 22.6. Medications Used in the Treatment of Irritable Bowel Syndrome

Alosetron B Avoid: restricted access No human data: potential toxicity
Amitriptyline C Avoid: no malformations, but worse outcomes Limited human data: potential toxicity
Bisacodyl C Safe with short-term use Safety unknown
Bismuth subsalicylate C Not safe: teratogenicity No human data: potential toxicity
Castor oil X Uterine contraction and rupture Possibly unsafe
Cholestyramine C Low risk, but can lead to infant coagulopathy Compatible
Desipramine C Avoid: no malformations, but worse outcome Limited human data: potential toxicity
Dicyclomine B Avoid: possible congenital anomalies Limited human data: potential toxicity
Diphenoxylate-atropine C Teratogenic in animals; no human data Limited human data: potential toxicity
Docusate C Safe Compatible
Hyoscyamine C No available data No human data: probably compatible
Imipramine D Avoid: no malformations, but worse outcomes Limited human data: potential toxicity
Kaopectate (bismuth subsalicylate)a C Unsafe; now contains bismuth subsalicylate No human data: probably compatible
Lactulose B No human studies No human data: probably compatible
Linaclotide B Low risk if appropriate Limited human data: probably compatible
Loperamide B Low risk: possibly increased cardiovascular defects Limited human data: probably compatible
Lubiprostone C Limited human data: use when benefit outweighs risk No human data: not recommended
Magnesium citrate B Avoid long-term use: hypermagnesemia, Compatible
hyperphosphatemia, dehydration
Mineral oil C Avoid: neonatal coagulopathy and hemorrhage Possibly unsafe
Nortriptyline D Avoid: no malformations, but worse outcomes Limited human data: potential toxicity
Paroxetine D Avoid: twice as many birth defects as other Potential toxicity
antidepressants
Plecanatide B Low risk if indicated Low risk
Polyethylene glycol C First-choice laxative in pregnancy Low risk
Senna C Safe with short-term use Compatible
Selective serotonin reuptake C Avoid: no malformations, but increased adverse fetal Limited human data: potential toxicity
inhibitors (except paroxetine) events
Simethicone C No available data No human data: probably compatible
Low risk
Sodium phosphate None Avoid long-term use: hypermagnesemia, Safety unknown
hyperphosphatemia, dehydration
Tegaserod B Low risk: human data negative for malformations Safety unknown

a
Kramer Laboratories.
(lactulose and sorbitol), and polyethylene glycol. Saline os- vitamin absorption and lead to neonatal coagulopathy and
motic laxatives such as magnesium citrate (category B) and hemorrhage.
sodium phosphate have rapid onset of action but are intended Tegaserod (category B), a type 4 serotonin receptor agonist,
for short-term intermittent relief. Long-term use can result in was approved by the FDA for the treatment of constipation-
hypermagnesemia, hyperphosphatemia, and dehydration. No predominant IBS and chronic constipation. It was withdrawn
human studies are available on the use of lactulose (category B) from the market in 2007 because of concern about an increased
during pregnancy. Polyethylene glycol (category C) is negligibly risk of cardiac events with its use, but it has been reintroduced
absorbed and metabolized in humans, making it unlikely to cause and is available. Current guidelines suggest that it not be used in
malformations. Also, it is effective and well tolerated compared patients who have risk factors for cardiac disease.
with lactulose. The results of animal teratogenesis studies have Lubiprostone is a chloride channel activator that is approved
been negative. A consensus meeting on the management of con- by the FDA to treat chronic constipation and constipation-
stipation in pregnancy considered polyethylene glycol to meet predominant IBS. It is a category C drug with limited human
the criteria for an ideal laxative in pregnancy: effective, not ab- data, and animal studies have shown adverse events with expo-
sorbed (nonteratogenic), well tolerated, and safe. However, the sure. It is not recommended for use when breastfeeding.
consensus members thought that current data were insufficient Linaclotide and plecanatide are both guanylate cyclase-C re-
to demonstrate conclusively whether absorption of polyethylene ceptor agonists approved for treatment of chronic constipation.
glycol affects the fetus. However, these are relatively new therapies, and few data are
Stimulant laxatives such as senna (category C) and bisacodyl available from studies of pregnant women, so agents with other
(category C) are considered safe for short-term use, but long- mechanisms of action should be used.
term use is not recommended. Because senna is excreted in
breast milk, it should be used with caution during lactation. ✓ Fiber should be the first- line therapy for constipation during
Docusate (category C), a stool softener, is generally considered pregnancy
safe. Castor oil (category X) should be avoided because it is as- ✓ Short-term use of stimulant laxatives is acceptable
✓ Castor oil is absolutely contraindicated because of the risk of
sociated with uterine contraction and rupture. Mineral oil also
uterine rupture
should be avoided because it can impair maternal fat-soluble
Diarrhea solely to treat symptoms of IBS and not an associated major de-
pression, strong consideration should be given to stopping the
In a trial of 105 women exposed to loperamide (category B) during
drug therapy during the gravid period.
pregnancy, loperamide was not associated with an increased risk
Antispasmodics are prescribed frequently for the management
of congenital malformations, although 20% of the infants were
of abdominal pain in IBS. Dicyclomine (category B), in com-
200 g smaller than infants in the control group. At least 187 cases
bination with pyridoxine and doxylamine (Bendectin; Merrell
of first-trimester exposure have been reported, with no evidence
Dow Pharmaceuticals, Inc), has been associated with multiple
of developmental toxicity. Cholestyramine (category C), an
congenital anomalies, but the studies have not been conclusive.
anion exchange resin, is often used to treat cholestasis of preg-
Hyoscyamine (category C) has not been studied in pregnancy.
nancy and can be used to manage diarrhea resulting from ileal
resection or cholecystectomy. However, fat-soluble vitamin de- ✓ During pregnancy, antidiarrheal agents containing salicylates
ficiency, including coagulopathy, can occur, so it should be used should be avoided
with caution. Kaolin in combination with pectin (Kaopectate; ✓ Loperamide, eluxadoline, and tricyclic antidepressants are ac-
Kramer Laboratories) (category B) was an antidiarrheal of choice ceptable to use for diarrhea caused by IBS
because it was not absorbed and did not cross the placenta, but
concern arose over the potential for kaolin-induced iron defi-
ciency anemia. In 2003, Kaopectate was reformulated to contain Infectious Diarrhea
bismuth subsalicylate (category C). Bismuth subsalicylate, alone
or in Kaopectate, should be avoided in pregnancy because the Diarrhea can be described as acute (<14 days), persistent
salicylates can be absorbed and lead to increased perinatal mor- (>14 days), or chronic (>30 days). Although most episodes of
tality, premature closure of the ductus arteriosus, neonatal hem- diarrhea are self-limited and treatment is not required, certain
orrhage, decreased birth weight, prolonged gestation and labor, pathogens require treatment. The common medications used to
and possible teratogenicity. Alosetron (category B) has restricted treat infectious diarrhea are summarized in Table 22.7.
access because of concern about ischemic colitis. Its use gener-
ally should be avoided during pregnancy. Albendazole
Eluxadoline is approved to treat diarrhea associated with IBS.
Although data from studies with pregnant women are limited, Albendazole, a category C drug, is used in the treatment of
eluxadoline is considered low risk for use during pregnancy and microsporidial infection, cysticercosis, helminth infection, and
breastfeeding. hydatid disease. The drug is embryotoxic and teratogenic (skel-
For pregnant women with diarrhea, dietary modification, with etal malformations) in rats and rabbits. Human data are limited.
reduction of fats and dairy, can improve symptoms. Although Albendazole therapy for the eradication of helminths during
human data are limited, both loperamide and diphenoxylate are pregnancy is associated with significantly less maternal anemia
considered “low risk” and can be used with discretion. and no increase in adverse pregnancy outcomes, prompting the
Tricyclic antidepressants (amitriptyline and desipramine, World Health Organization to recommend antihelminthic therapy
both category C drugs, and nortriptyline and imipramine, both in pregnancy.
category D drugs) and selective serotonin reuptake inhibitors
(SSRIs) (generally category C drugs) are frequently used in Ampicillin
the management of IBS. Overall, the newer antidepressants
Ampicillin, a category B drug, is not considered teratogenic. It
(citalopram, escitalopram, fluoxetine, fluvoxamine, sertraline,
is second-line treatment of Shigella infection. Ampicillin passes
reboxetine, venlafaxine, nefazodone, trazodone, mirtazapine,
through the placenta by simple diffusion and is excreted into
and bupropion) are not associated with an increased rate of
breast milk in low concentrations.
major malformations compared with that of the general popula-
tion. Recently, however, an unpublished GlaxoSmithKline study
of 3,500 pregnant women noted twice as many birth defects Azithromycin
with paroxetine than with other antidepressants (Table 22.6). Azithromycin, a macrolide antibiotic, is in pregnancy cate-
In the first trimester, for paroxetine users the absolute rate of gory B and is a second-line treatment of Cryptosporidium and
major congenital malformations was 4% and the absolute rate Entamoeba histolytica infections. In pregnant women with
of cardiovascular malformations was 2%. Infants exposed to traveler’s diarrhea, azithromycin or a third- generation ceph-
antidepressants are also at higher risk for other adverse events. In alosporin is considered the treatment of choice. A study of 20
a large Swedish study of 997 infants exposed to antidepressants women who received the drug for Chlamydia trachomatis infec-
during pregnancy, the infants had an increased risk of preterm tion noted that 40% reported moderate to severe gastrointestinal
birth, low birth weight, low Apgar score, respiratory distress, adverse effects. A trial of 94 pregnant women with Trichomonas
neonatal convulsions, and hypoglycemia. The data suggested that vaginalis treated with a combination of azithromycin, cefixime,
outcomes were worse with tricyclic antidepressants compared and metronidazole demonstrated increased rates of infant low
with SSRIs. Multiple studies with SSRIs have confirmed that birth weight, preterm birth, and 2-year mortality compared with
the rate of congenital malformations for infants exposed to these rates for the children of 112 infected mothers who were not
drugs is similar to that for the general population; however, the treated for the same infection.
studies also have noted a higher rate of premature delivery, res-
piratory difficulty, cyanosis on feeding, and jitteriness as well
Doxycycline and Tetracycline
as low birth weight and neonatal convulsions among infants
exposed to SSRIs. The effect of SSRI exposure through the pla- Doxycycline and tetracycline are both category D drugs.
centa on neonatal adaptation and long-term neurocognitive de- Doxycycline is used as second-line treatment of infections with
velopment is debated. If the antidepressant is being administered Vibrio cholerae, Campylobacter, and enterotoxigenic Escherichia
Table 22.7. Medications Used for the Treatment of Infectious Diarrhea

Albendazole C Embryotoxic in animals No human data: probably compatible
Avoid in first trimester
Human data support improved pregnancy
outcomes with helminth eradication
Ampicillin B Safe Compatible
Azithromycin B Low risk Limited human data: probably compatible
Ciprofloxacin (all quinolones) C Potential toxicity to cartilage: avoid Limited human data: probably compatible
Doxycycline D Contraindicated: teratogenic Compatible
Fidaxomicin B Low risk but expensive No human data: potential toxicity
Furazolidone C Low risk No human data: potential toxicity
Limited data
Metronidazole B Low risk: question of increased risk of cleft Limited human data: potential toxicity
lip with or without cleft palate
Rifaximin C Animal teratogen No human data: probably compatible
No human data
Tetracycline D Not safe: teratogenicity Compatible
Tinidazole C Low risk Unsafe
Limited data
Trimethoprim-sulfamethoxazole C Teratogenic Compatible
Vancomycin C Low risk Limited human data: probably compatible
coli. Similar to tetracycline, this class of medications crosses the of cleft lip, with or without cleft palate. This increase was slight
placenta and is bound by chelating with calcium in developing and not thought to be clinically significant.
bone and teeth. This results in discoloration of the teeth, hypoplasia
of enamel, and inhibition of skeletal growth. A population-based
Quinolones
study found a higher rate of congenital anomalies in the infants
of mothers who used doxycycline during pregnancy; however, the Quinolones (eg, ciprofloxacin, levofloxacin, and norfloxacin),
case-control pair analysis did not show a significantly higher rate category C drugs, are used to treat infections with Shigella,
of doxycycline treatment in the second and third months of gesta- Campylobacter, Yersinia, enterotoxigenic and enteroinvasive E
tion in any group of congenital abnormalities. coli, and V cholerae. Quinolones have a high affinity for bone
tissue and cartilage and may cause arthropathies in children.
The manufacturer reports damage to cartilage in weight-bearing
Fidaxomicin joints after quinolone exposure in immature rats and dogs.
Fidaxomicin, a category B drug, recently received FDA approval However, a prospective controlled study of 200 women exposed
for treatment of Clostridioides difficile infection. Its use is lim- to quinolones and a population-based cohort study of 57 women
ited by its cost, and it has not been studied in large numbers of exposed to quinolones did not find an increased risk of congen-
pregnancies to date. ital malformations. Overall, the risk is thought to be minimal,
but because safer alternatives are available, quinolones should be
avoided in pregnancy.
Furazolidone
Furazolidone, a category C drug, is second-line treatment of giar-
Rifaximin
diasis. Few data are available on the safety of furazolidone in preg-
nancy, but the Collaborative Perinatal Project monitored 50,282 Rifaximin, a category C drug, can be used to treat traveler’s
mother-child pairs, and 132 had exposure to furazolidone in the diarrhea, although azithromycin is the antibiotic of choice for
first trimester with no association with congenital malformations. pregnant patients with traveler’s diarrhea. Little information
exists about the safety of rifaximin in pregnancy. Rifaximin
has not been found to affect fertility or pregnancy outcome
Metronidazole
in rats or, in 1 study, to cause teratogenic complications in
Metronidazole, a category B drug, is used to treat C difficile rats and rabbits. However, other studies have noted teratoge-
infection, amebiasis, and giardiasis. Multiple studies have nicity in rats and rabbits, including cleft palate and incomplete
suggested that exposure to metronidazole prenatally is not asso- ossification.
ciated with birth defects. These studies include 2 meta-analyses,
2 retrospective cohort studies, and a prospective controlled study
Tinidazole
of 228 women exposed to metronidazole during pregnancy.
A population-based case-control study found that overall terato- Tinidazole, a category C drug, is a second-line treatment of giar-
genic risk was low, but infants of women exposed to metronida- diasis and amebiasis. Placental transfer of tinidazole occurs early
zole in the second to third months of pregnancy had higher rates in pregnancy, raising concern about its use in the first trimester.
A population-based study from Hungary did not note an increased ✓ Quinolones should be avoided as alternatives are available for
rate of congenital malformations when the drug was administered treating infectious diarrhea
during pregnancy; however, the number of women treated with
tinidazole was small.

Trimethoprim-Sulfamethoxazole
For patients with Crohn disease and ulcerative colitis, disease ac-
Trimethoprim-sulfamethoxazole, a category C drug, is first-line tivity at the time of conception can be associated with a higher
treatment of infections with Cystoisospora (previously known as risk of spontaneous abortion, and disease activity during the
Isospora) or Cyclospora and second-line treatment of infections course of pregnancy can be associated with higher rates of low
with Shigella, Yersinia, or enterotoxigenic E coli. Trimethoprim birth weight and premature infants. It is advisable that the disease
has antifolate effects, increasing the potential for congenital be in remission when patients are considering pregnancy, and
anomalies. A study of 2,296 Michigan Medicaid recipients with for the majority, this requires continued use of the medications.
first-trimester exposure to trimethoprim noted an increased risk of Medications used to treat inflammatory bowel disease (IBD) are
birth defects, particularly cardiovascular defects. A population- summarized in Table 22.8.
based case-control study in Hungary noted a higher rate of mul-
tiple congenital anomalies and cardiovascular malformations. On
the basis of these data, use of trimethoprim-sulfamethoxazole Aminosalicylates
should be avoided in pregnancy. All aminosalicylates (sulfasalazine, mesalamine, and
balsalazide) are category B drugs except olsalazine, and
the mesalamine products Asacol and Asacol HD (AbbVie),
Vancomycin which are in category C. A population- based study using
Vancomycin, a category C drug, is used in the treatment of se- the Hungarian Case- Control Surveillance of Congenital
vere C difficile colitis, or C difficile infection that is refractory to Abnormalities database did not show a significant increase in
treatment with metronidazole. Studies in rats and rabbits have not the prevalence of congenital abnormalities in the children of
demonstrated teratogenic effects. No cases of congenital defects women treated with sulfasalazine. Because of concern about
attributable to vancomycin have been located, and the drug is potential antifolate effects of sulfasalazine, it is recommended
considered low risk in pregnancy. that women take folic acid 1 mg twice daily in the
Table 22.8. Medications Used in the Treatment of Inflammatory Bowel Disease (IBD)
Adalimumab B Limited human data: low risk No human data: probably compatible
Amoxicillin-clavulinic acid B Low risk Probably compatible
Azathioprine and 6-mercaptopurine D Data in IBD and transplant literature suggest low risk No human data: potential toxicity
Balsalazide B Low risk No human data: potential diarrhea
Certolizumab pegol B Low risk No human data
Ciprofloxacin C Avoid: potential toxicity to cartilage Limited human data: probably compatible
Corticosteroids C Low risk: possibly increased risk of cleft palate, adrenal Compatible
insufficiency, premature rupture of membranes
Cyclosporine C Low risk Limited human data: potential toxicity
Fish oil supplements None Safe No human data
Possible benefit
Golimumab B Low risk Human data: probably compatible
Infliximab B Low risk No human data: probably compatible
Mesalamine B Low risk Limited human data: potential diarrhea
Methotrexate X Contraindicated: teratogenic Contraindicated
Metronidazole B Avoid: limited efficacy in IBD and risk of cleft palate Limited human data: potential toxicity
Natalizumab B Low risk No human data
Olsalazine C Low risk Limited human data: potential diarrhea
Ozanimod No rating Animal risk; no human data No human data: possible toxicity
Rifaximin C Animal teratogen No human data: probably compatible
No human data
Sulfasalazine B Considered safe Limited human data: potential diarrhea
Give folate 2 mg daily
Tacrolimus C Use if mother’s health mandates Limited human data: potential toxicity
Thalidomide X Contraindicated: teratogenic No human data: potential toxicity
Upadacitinib No rating Possible teratogen Limited human data: probably compatible
Ustekinumab No rating Human data: low risk Limited human data: probably compatible
Vedolizumab No rating Human data: low risk Limited human data: probably compatible
prenatal period and throughout pregnancy. Unlike with other Methotrexate

sulfonamides, bilirubin displacement and, thus, kernicterus do Methotrexate, a category X drug, is clearly teratogenic and should
not occur in the infant. Sulfasalazine has been clearly associ- not be administered to women or men who are considering con-
ated with infertility in men. Abnormalities in sperm number, ception. Methotrexate is a folic acid antagonist, and its use during
motility, and morphology have been noted. This effect appears the critical period of organogenesis (6-8 weeks postconception) is
to be reversible: When mesalamine was substituted for sulfa- associated with multiple congenital anomalies collectively called
salazine, semen quality returned to normal. An association has methotrexate embryopathy or fetal aminopterin-methotrexate
been described between sulfasalazine use in the parent and syndrome. This syndrome is characterized by intrauterine growth
congenital malformations in the progeny. Because the lifespan retardation; decreased ossification of the calvarium; hypoplastic
of sperm is 120 days, men considering conception should ei- supraorbital ridges; small, low- set ears; micrognathia; limb
ther stop taking sulfasalazine or switch to mesalamine at least abnormalities; and, occasionally, intellectual disability. Exposure
3 months before attempting conception. in the second and third trimesters may be associated with
Case series of mesalamine use in pregnancy do not suggest an fetal toxicity and death. Methotrexate may cause reversible
increased risk to the fetus. This has been supported by a prospec- oligospermia in men. No case reports have been published on
tive controlled trial of 165 women exposed to mesalamine who congenital anomalies occurring in the offspring of men receiving
were compared with matched controls with no exposure and by a methotrexate therapy. Methotrexate may persist in tissues for
population-based cohort study from Denmark. The formulations long periods, and it has been suggested that patients wait at least
of Asacol and Asacol HD have been changed, so dibutyl phthalate 3 to 6 months after discontinuation of treatment with the drug be-
is no longer present in any mesalamine products. fore attempting conception.
Antibiotics Azathioprine and 6-Mercaptopurine

Metronidazole, the quinolones, and rifaximin are covered in the The drug 6-mercaptopurine and its prodrug azathioprine are in
Infectious Diarrhea section above. Because of the limited evi- category D. Animal studies have demonstrated teratogenicity,
dence of the effectiveness of these agents in treating IBD and the with increased frequencies of cleft palate and open-eye and skel-
extended duration of use in the treatment of Crohn disease and etal anomalies in mice exposed to azathioprine and cleft palate
ulcerative colitis, use of these drugs should be avoided during and skeletal and urogenital anomalies in rats. Transplacental and
pregnancy. Short courses for the treatment of pouchitis can be transamniotic transmission of azathioprine and its metabolites
considered on the basis of the safety data presented above. An from the mother to the fetus can occur. The oral bioavailability of
alternative antibiotic for pouchitis is amoxicillin-clavulanic acid, azathioprine (47%) and 6-mercaptopurine (16%) is low, and the
a category B drug. early fetal liver lacks the enzyme inosinate pyrophosphorylase,
which is needed to convert azathioprine to 6-mercaptopurine.
Corticosteroids Both features may protect the fetus from toxic drug exposure
during the crucial period of organogenesis. The largest evi-
Corticosteroids are category C drugs. A case-control study of dence on safety comes from transplant studies, in which rates of
corticosteroid use during the first trimester of pregnancy noted anomalies ranged from zero to 11.8%, and no evidence emerged
an increased risk of oral clefts in newborns. This was confirmed for recurrent patterns of congenital anomalies. Multiple case se-
by a large case-control study and a meta-analysis, which re- ries of IBD have not noted an increase in congenital anomalies.
ported a summary OR for case-control studies examining the On the basis of the large experience with transplant patients and
risk of oral clefts (OR, 3.35; 95% CI, 1.97-5.69). However, the body of evidence in IBD, use of the drugs is often continued
the population was treated for various conditions, and the during pregnancy to maintain remission in the mother. A flare of
overall risk of major malformations was low (OR, 1.45; 95% disease during pregnancy may be more deleterious to neonatal
CI, 0.80-2.60). A prospective controlled study of 311 women outcome than any potential risk from the medication.
who received corticosteroids during the first trimester did
not note an increased rate of major anomalies, and cases of
oral cleft were not noted. The study was powered to find a Cyclosporine and Tacrolimus
2.5-fold increase in the overall rate of major anomalies. An These agents are considered in the Liver Transplant section. For
increased risk of premature rupture of membranes and adrenal severe corticosteroid-refractory ulcerative colitis, cyclosporine
insufficiency in the newborn has been reported for transplant may be a better treatment option than colectomy, which is asso-
patients. Overall, the use of corticosteroids poses a small risk ciated with a considerable morbidity rate for mother and fetus.
to the developing infant, and the benefit of treating active dis
ease outweighs the fetal risk. Systemic corticosteroids should
be used at the lowest effective dose because prolonged expo- Thalidomide
sure leads to increased risk of gestational diabetes and prema- Thalidomide, a category X drug, has some anti–tumor necrosis
ture lung maturity in the fetus. A small retrospective review of factor effects and has been used successfully for the treatment of
patients with IBD treated with budesonide during pregnancy Crohn disease. However, its teratogenicity has been documented
did not document congenital malformations or an increase in extensively and includes limb defects, central nervous system
adverse outcomes. effects, and abnormalities of the respiratory, cardiovascular,
gastrointestinal, and genitourinary systems. Thalidomide is
contraindicated during pregnancy and for women of childbearing
Immunomodulators
age who are not using 2 reliable methods of contraception for
The immunomodulators are the most controversial agents used to 1 month before starting therapy, during therapy, and for 1 month
treat IBD in pregnant women. after stopping therapy.
✓ Immunomodulators safe to use in pregnancy include thiopurines

category B drug. Few postmarketing data are available about its
and calcineurin inhibitors use in pregnancy. Currently, there are no firm recommendations
✓ Methotrexate and thalidomide—contraindicated in pregnancy
about its use in treating IBD in pregnant women, but given the
availability of more targeted anti-integrins, this agent is not com-
monly used for Crohn disease.
Biological Therapy
Vedolizumab
Infliximab
Vedolizumab is a more targeted IgG1 monoclonal antibody to α
Infliximab, a category B drug, is used in the management of Crohn
integrins. It is approved for the treatment of both Crohn disease
disease and ulcerative colitis. A growing body of evidence suggests
and ulcerative colitis. While it does cross the placenta, it is thought
that infliximab is low risk in pregnancy. The 2 largest studies are from
to present only low risk during pregnancy, so therapy should not
the Crohn’s Therapy, Resource, Evaluation, and Assessment Tool
be discontinued before conception or during pregnancy.
(TREAT) Registry and the infliximab safety database maintained
by Janssen Biotech, Inc. The TREAT Registry is a prospective reg-
istry of patients with Crohn disease, and the patients may or may Ustekinumab
not be treated with infliximab. Among the 5,807 patients enrolled, Ustekinumab is an IgG1 monoclonal antibody targeted toward
66 pregnancies were reported, and 36 of the 66 had prior exposure interleukins 12 and 23. It is approved for the treatment of both
to infliximab. Fetal malformations have not occurred in any of the Crohn disease and ulcerative colitis. It also crosses the placenta,
pregnancies. The rates of miscarriage (11.1% vs 7.1%, P=.53) and but in retrospective studies and registries, it is considered safe to
neonatal complications (8.3% vs 7.1%, P=.78) were higher for use before and during pregnancy, so therapy should not be stopped.
infliximab-treated patients than for infliximab-naïve patients, but
the differences were not statistically significant. ✓ All biologicals except certolizumab cross the placenta but are not
In the infliximab safety database, a retrospective data collection, associated with an increase in adverse outcomes
pregnancy outcome data are available for 96 women who had direct ✓ All biologicals should be continued before and during pregnancy
exposure to infliximab. The 96 pregnancies resulted in 100 births. to maintain maternal health
The expected outcomes and the observed outcomes for women
exposed to infliximab were not different from those of the general
population. In a series of 10 women who received maintenance Small Molecules
therapy with infliximab throughout pregnancy, all 10 pregnancies
ended in live births and no congenital malformations were reported. Tofacitinib
Infliximab probably crosses the placenta, beginning at ap- Tofacitinib is a nonselective Janus kinase inhibitor that is
proximately week 20. Currently, if maternal health warrants approved to treat ulcerative colitis. Because of its potential
infliximab therapy, it is continued through pregnancy. effect on the placenta and the relative lack of safety data, it is not
recommended for use in women actively interested in starting a
Adalimumab family. For women receiving tofacitinib whose disease is in re-
mission and who are pregnant, the recommendation is that they
Adalimumab, a category B drug, is approved for induction and continue therapy but be monitored closely.
maintenance therapy for both Crohn disease and ulcerative co-
litis. It is an immunoglobulin (Ig)G1 molecule that crosses the
placenta, but retrospective and prospective data show its safety Upadacitinib
during pregnancy. Upadacitinib is a selective Janus kinase 1 inhibitor that is
approved to treat ulcerative colitis. As with tofacitinib, because of
Certolizumab Pegol its potential effect on the placenta and the relative lack of safety
data, it is not recommended for use in women actively interested
Certolizumab is a pegylated Fabʹ fragment of IgG1 antibody in starting a family. For women receiving upadacitinib whose di-
against tumor necrosis factor α and is approved to treat Crohn sease is in remission and who are pregnant, the recommendation
disease. Studies have shown the lack of placental transfer of is that they continue therapy but be monitored closely.
certolizumab, and it may thus have an advantage for use in preg-
nancy. Certolizumab pegol therapy is warranted during preg-
nancy for active IBD or maintenance of remission. Ozanimod
Ozanimod is a sphingosine-1-phosphate receptor modulator re-
Golimumab cently approved to treat ulcerative colitis. Animal data suggest
that fetal harm can occur with exposure, so it is not recommended
Golimumab is an IgG1 monoclonal antibody approved for ulcer- for women interested in childbearing.
ative colitis. Like the other anti–tumor necrosis factor molecules,
it crosses the placenta but is not associated with any adverse ✓ The effect of small molecules in pregnancy is unclear, so therapy
outcomes in pregnancy and should be continued before concep- that uses other mechanisms of action should be used
tion and during pregnancy.
Natalizumab Fish Oil Supplements

Natalizumab is a monoclonal antibody of the IgG4 class directed Many patients who have IBD take fish oil supplements as an ad-
against α integrins and approved for the treatment of Crohn dis junct to standard medical therapy. Because fish oil is a supple-
ease. On the basis of animal and trial data, it is listed as an FDA ment and not a drug, it is not rated by the FDA. A randomized
controlled trial of fish oil supplementation showed a prolongation Deshpande NA, James NT, Kucirka LM, Boyarsky BJ, Garonzik-Wang
of pregnancy without detrimental effects on the growth of the JM, Cameron AM, et al. Pregnancy outcomes of liver transplant
fetus or the course of labor. Fish oil supplementation may help recipients: a systematic review and meta-analysis. Liver Transpl.
prevent miscarriage associated with the antiphospholipid anti- 2012 Jun;18(6):621–9.
Diav-Citrin O, Shechtman S, Gotteiner T, Arnon J, Ornoy A. Pregnancy
body syndrome. In women with IBD who may be at increased
outcome after gestational exposure to metronidazole: a prospective
risk for preterm birth and miscarriage, fish oil supplementation is controlled cohort study. Teratology. 2001 May;63(5):186–92.
not harmful and may provide some benefit. Garbis H, Elefant E, Diav- Citrin O, Mastroiacovo P, Schaefer C,
Vial T, et al. Pregnancy outcome after exposure to ranitidine and
Suggested Reading other H2-blockers: a collaborative study of the European Network
of Teratology Information Services. Reprod Toxicol. 2005
Akbari M, Shah S, Velayos FS, Mahadevan U, Cheifetz AS. Systematic Mar-Apr;19(4):453–8.
review and meta- analysis on the effects of thiopurines on birth Hasler WL. The irritable bowel syndrome during pregnancy. Gastroenterol
outcomes from female and male patients with inflammatory bowel Clin North Am. 2003 Mar;32(1):385–406.
disease. Inflamm Bowel Dis. 2013 Jan;19(1):15–22. Lu EJ, Curet MJ, El-Sayed YY, Kirkwood KS. Medical versus surgical
American Academy of Pediatrics Committee on Drugs. Transfer of drugs and management of biliary tract disease in pregnancy. Am J Surg. 2004
other chemicals into human milk. Pediatrics. 2001 Sep;108(3):776–89. Dec;188(6):755–9.
Antiretroviral Pregnancy Registry Steering Committee. Antiretroviral Mahadevan U, Kane S. American Gastroenterological Association
pregnancy registry interim report for 1 January 1989 through 31 July Institute technical review on the use of gastrointestinal medications
2022. Registry Coordinating Center.www.APRegistry.com. in pregnancy. Gastroenterology. 2006 Jul;131(1):283–311.
Armenti VT, Radomski JS, Moritz MJ, Gaughan WJ, McGrory CH, Mahadevan U, Robinson C, Bernasko N, Boland B, Chambers C, Dubinsky
Coscia LA. Report from the National Transplantation Pregnancy M, et al. Inflammatory bowel disease in pregnancy clinical care
Registry (NTPR): outcomes of pregnancy after transplantation. Clin pathway: a report from the American Gastroenterological Association
Transpl. 2003:131–41. IBD Parenthood Project Working Group. Gastroenterology. 2019
ASGE Standard of Practice Committee, Shergill AK, Ben-Menachem T, Apr;156(5):1508–24.
Chandrasekhara V, Chathadi K, Decker GA, et al. Guidelines for en- Majithia R, Johnson DA. Are proton pump inhibitors safe during preg-
doscopy in pregnant and lactating women. Gastrointest Endosc. 2012 nancy and lactation? Evidence to date. Drugs. 2012 Jan;72(2):
Jul;76(1):18–24. 171–9.
Bradley CS, Kennedy CM, Turcea AM, Rao SS, Nygaard IE. Niebyl JR. Clinical practice: nausea and vomiting in pregnancy. N Engl J
Constipation in pregnancy: prevalence, symptoms, and risk factors. Med. 2010 Oct;363(16):1544–50.
Obstet Gynecol. 2007 Dec;110(6):1351–7. Papadakis EP, Sarigianni M, Mikhailidis DP, Mamopoulos A,
Briggs GG, Freeman RK, Yaffe SJ. Drugs in pregnancy and lactation: a Karagiannis V. Acute pancreatitis in pregnancy: an overview. Eur J
reference guide to fetal and neonatal risk. 7th ed. Lippincott Williams Obstet Gynecol Reprod Biol. 2011 Dec;159(2):261–6.
& Wilkins; 2005: 1,858 pages. Ramin KD, Ramsey PS. Disease of the gallbladder and pancreas in preg-
Brown RS, Jr., Verna EC, Pereira MR, Tilson HH, Aguilar C, Leu CS, nancy. Obstet Gynecol Clin North Am. 2001 Sep;28(3):571–80.
et al. Hepatitis B virus and human immunodeficiency virus drugs Su GG, Pan KH, Zhao NF, Fang SH, Yang DH, Zhou Y. Efficacy and
in pregnancy: findings from the antiretroviral pregnancy registry. J safety of lamivudine treatment for chronic hepatitis B in pregnancy.
Hepatol. 2012 Nov;57(5):953–9. World J Gastroenterol. 2004 Mar 15;10(6):910–2.
Questions random biopsy samples of the transverse colon. What is the

best next step in management?
Abbreviations used:
ALT, alanine aminotransferase a. Change the therapy to a different biological
CD, Crohn disease b. Perform chromoendoscopy now
CRC, colorectal cancer c. Refer her to a colorectal surgeon now
CT, computed tomographic d. Perform follow-up colonoscopy in 6 months
DD, defecatory disorder e. Do nothing since she is asymptomatic
ERCP, endoscopic retrograde cholangiopancreatography V.2. A 34-year-old man who was previously healthy presents with
HBV, hepatitis B virus a 2-month history of recurrent fevers, abdominal pain in the
HLA, human leukocyte antigen right lower quadrant, and weight loss. He also reports having
IBD, inflammatory bowel disease intermittent, nonbloody diarrhea for the past 6 months. He has
IBS, irritable bowel syndrome not traveled outside the US. He is not taking any medications.
MRCP, magnetic resonance cholangiopancreatography He has no family history of colorectal cancer or IBD. On phys-
MRI, magnetic resonance imaging ical examination he has tachycardia, a cachectic appearance,
PCR, polymerase chain reaction and a scaphoid abdomen with tenderness in the right lower
PSC, primary sclerosing cholangitis quadrant but no guarding or rebound tenderness. Laboratory
UC, ulcerative colitis test results are notable for the following: leukocytes, 19×109/L;
hemoglobin, 8.6 g/dL; mean corpuscular volume, 73 fL; and
Multiple Choice (choose the best answer) C-reactive protein, 95 mg/L. CT enterography with an intra-
venous contrast agent shows severe inflammation in the ter-
V.1. A 44-year-old woman who received a diagnosis of UC 20 years minal ileum connecting to a 3-cm abscess in the right iliopsoas
ago is receiving therapy with a fourth biological after having a muscle. No areas of inflammation are apparent in the small
lack of response to previous agents because of antibody forma- bowel. What is the most likely diagnosis?
tion. She has been having 6 to 8 nonbloody bowel movements
(Bristol type 4-6) daily for 6 months. Her weight has been a. UC with backwash ileitis
stable. On surveillance colonoscopy, she has evidence of severe b. Mycobacterium tuberculosis infection
inflammation characterized by erosions, erythema, friability, c. CD
granularity, and loss of vascularity in all the examined colon d. Acute appendicitis
(Mayo score 3). Surveillance biopsies from the cecum and the V.3. A 62-year-old man has a 30-year history of UC. His disease has
ascending, transverse, descending, and rectosigmoid areas been well controlled for the past 5 years with infliximab every
show moderate, active chronic colitis with ulcerations and no 8 weeks. Previous chromoendoscopy for dysplasia surveillance
granulomas. Additionally, low-grade dysplasia is identified in showed a large number of pseudopolyps extending throughout
random biopsy samples from the cecum and the ascending and the descending and sigmoid colon. Random biopsies were neg-
rectosigmoid areas, and high-grade dysplasia is identified in ative for dysplasia. A 15-mm lesion (Paris classification type Is)
269
was removed en bloc with endoscopic mucosal resection from tofacitinib. What are important considerations related to
the transverse colon; the lesion was a tubular adenoma with tofacitinib?
low-grade dysplasia. There was no active inflammation. What
a. She should be evaluated for sleep apnea
is the most appropriate recommendation?
b. She should be evaluated by an ophthalmologist
a. Perform high-definition white-light colonoscopy in 5 years c. She should undergo electrocardiography before she begins
b. Refer to the surgery service for colectomy therapy
c. Increase the dose of infliximab d. She should receive the recombinant shingles vaccine
d. Perform high-definition colonoscopy in 1 year
V.9. A 36-year-old man returns for follow-up after he received
e. Perform chromoendoscopy now
a diagnosis of extensive UC 6 months ago. He is receiving
V.4. A 45-year-old woman presents to the IBD clinic for her annual adalimumab monotherapy. He feels well with 1 or 2 nonbloody
follow-up. She has a 30-year history of mild, uncomplicated UC bowel movements daily. However, follow-up colonoscopy shows
involving the left colon. She has been receiving mesalamine, mild inflammation from the sigmoid colon to the cecum with
and the disease has been in histologic remission for over 10 relative sparing of the rectum. The terminal ileum appears
years. Findings from her most recent colonoscopy 1 year ago normal. Laboratory test results are notable for an alkaline
were normal. For several years, she has also had pain bilat- phosphatase value of 176 U/L (reference range, 40-129 U/L);
erally in her metacarpophalangeal and metatarsophalangeal other liver enzyme results are normal. What is the best next
joints and in her ankles. She has not had back or hip pain. step?
What is the most likely cause of the arthritis?
a. Perform MRCP
a. Parvovirus b. Perform liver biopsy
b. Fibromyalgia c. Repeat liver enzyme testing in 6 months
c. Type 1 IBD–related arthritis d. Perform ERCP
d. Osteoarthritis
V.10. A 52-year-old woman with CD and ileocolitis for the past 4
e. Type 2 IBD–related arthritis
years returns for her annual follow-up. She has been treated
V.5. A 25-year-old man with a history of stricturing ileocolonic CD with vedolizumab every 8 weeks for the past 12 months. When
underwent an ileocecal resection for a stricture at the ileocecal she previously used adalimumab, antibodies developed. Her
valve. Before surgery, he was treated with azathioprine as a current symptoms include 3 or 4 loose stools daily with ab-
single agent. What would be the best approach for treatment dominal cramping. Within the past several months, she has
after surgery? also had pain, swelling, and stiffness in her left knee and right
ankle. Those symptoms improve with activity. Laboratory test
a. Monitor symptoms for recurrence of disease, and treat if
results are normal. Colonoscopy shows mild inflammation
symptomatic
with scattered aphthous ulcerations in the terminal ileum and
b. Initiate infliximab therapy now for prevention of postoperative
mild, patchy inflammation throughout the transverse colon.
CD
What is the best next step in management?
c. Offer colonoscopy at 12 months after surgery to assess for
postoperative recurrence a. Increase the frequency of vedolizumab to every 4 weeks
d. Initiate budesonide treatment now for prevention of postopera- b. Perform MRI of the affected joints
tive CD c. Discontinue the use of vedolizumab and prescribe infliximab
d. Continue the use of vedolizumab at the current dosage
V.6. A 30-year-old man with a diagnosis of mild to moderate UC
achieved and maintained remission with sulfasalazine about V.11. A 60-year-old man with UC and PSC returns for his annual
4 years ago. He has been doing well with no recurrence of examination. The UC is currently in remission with his use of
disease and continues to take sulfasalazine daily. He and his oral mesalamine. Surveillance colonoscopy shows a normal-
partner have been trying to get pregnant for over a year and appearing terminal ileum and colon without inflammation or
have not been successful. How would you counsel him about polyps. Biopsies are obtained in 4 quadrants every 10 cm for
fertility? surveillance. Histopathology shows high-grade dysplasia in
the cecum and descending colon. What is the best next step in
a. UC is associated with higher rates of infertility in men
management?
b. The partner might have infertility issues, and they should seek
care from an infertility specialist a. Repeat the colonoscopy in 6 months with chromoendoscopy
c. His medication should be switched to mesalamine b. Repeat the surveillance colonoscopy in 1 year
d. His medication should be switched to vedolizumab c. Repeat the colonoscopy in 3 months with chromoendoscopy
d. Perform a colectomy
V.7. A 28-year-old woman is admitted to the hospital with acute
severe UC. Clostridioides difficile infection has been ruled out, V.12. Which of the following is associated with IBD activity and
and therapy was started with intravenous methylprednisolone. is likely to respond to treatment of the underlying bowel
On the third day after admission, she continues to have 10 inflammation?
bloody bowel movements daily and abdominal pain, and
a. Peripheral arthritis involving joints of the hands bilaterally
her C-reactive protein level is still high. She is otherwise he-
b. Erythema nodosum
modynamically stable with no involuntary guarding on ab-
c. Ankylosing spondylitis
dominal examination. What would be the best next step in
d. Scleritis
management?
V.13. A 28-year-old man, a second-year resident in internal med-
a. Initiate infliximab therapy
icine, presents in the emergency department with nausea,
b. Refer her for a total proctocolectomy
vomiting, and diarrhea along with crampy abdominal pain
c. Initiate azathioprine treatment
that started 2 days ago during a flight. He had traveled to
d. Increase the dose of intravenous methylprednisolone
Cancun, Mexico, to present research findings. He is other-
V.8. A 35- year-
old woman received a diagnosis of moderate to wise healthy, has a normal body mass index, and exercises 5
severe UC, but she has not responded to treatment with times per week. Before the trip, he missed an appointment in
infliximab and vedolizumab. You plan to begin therapy with the travel medicine clinic because of his clinical schedule. He
appears dehydrated and has blood in his stool. He says that he c. Outpatient management with antibiotics, colonoscopy in 6 weeks,
ate “quite a bit” of street food on the trip. On physical examina- and surgical referral for sigmoid colectomy
tion he has tachycardia (other vital signs are normal), and his d. Hospital admission, bowel rest, intravenous antibiotics, and
abdomen is tender. What is the next step in his management? colonoscopy in 3 days
a. Initiate loperamide for traveler’s diarrhea V.17. Which of the following statements correctly describes the epi-
b. Perform a stool multiplex PCR panel for enteric pathogens demiology of CRC?
c. Perform a stool PCR assay for Clostridioides difficile
a. The incidence of CRC is increasing for adults of all ages in
d. Admit him to the hospital for intravenous antibiotics
the US
e. Begin empirical therapy with an oral outpatient antibiotic for
b. In the US, the mortality of CRC is higher for Blacks than
traveler’s diarrhea
Whites, even when adjusted for stage
V.14. A 60-year-old woman with a history of hypertension and re- c. The incidence of CRC is decreasing in resource- limited
flux disease (treated with atenolol and omeprazole) presents countries
to the outpatient clinic with diarrhea for the past 9 days. d. Cigarette smoking decreases the risk for CRC
Previously she had not had consistent diarrhea that required
V.18. A 62-year-old woman is found to have colon cancer during
evaluation. She has daytime and nighttime stools and abdom-
routine screening colonoscopy. Mismatch repair enzyme ex-
inal pain but no blood in the stool. She has lost 1.8 kg (4 lb)
pression testing by immunohistochemistry shows an absence
since the onset. About 3 weeks before the diarrhea began,
of MLH1 and PMS2. Staging CT scans of the chest, abdomen,
she had received amoxicillin for routine dental cleaning. On
and pelvis do not show obvious lymph node involvement or
physical examination, she has normal vital signs and mild
metastatic disease. Her mother had endometrial cancer at age
tenderness on deep palpation of the abdomen. On laboratory
48 years and her brother had a cancer of the upper urothelial
evaluation, results are normal for hemoglobin, white blood
tract. What is the best next step in management?
cell count (8,500 cells/µL), electrolytes, and serum creatinine.
PCR test results are positive for Clostridioides difficile. What a. Refer for prophylactic hysterectomy
treatment would you recommend for clinical cure with a low b. Initiate annual colonoscopy for all first-degree relatives older
chance of recurrence? than 20 years
c. Refer for germline genetic testing
a. Metronidazole 500 mg 3 times daily for 10 days
d. Order PCR testing for microsatellite instability
b. Vancomycin 125 mg 4 times daily for 10 days
c. Fidaxomicin 200 mg 2 times daily for 10 days V.19. A 48-year-old man says that he has had hematochezia every
d. Vancomycin 125 mg 4 times daily for 10 days in combination 1 to 3 days for the past 6 weeks. At colonoscopy, a 2.5-cm
with intravenous bezlotoxumab 10 mg/kg pedunculated polyp is found in the rectum 10 cm from the
anal verge; the polyp is removed with a snare with electro-
V.15. A 60-year-old woman with a history of hypertension and re-
cautery. Pathology examination of the polyp shows a poorly
flux disease (treated with atenolol and omeprazole) received
differentiated adenocarcinoma with a focus of invasion into
a diagnosis of a first episode of mild Clostridioides difficile in-
the submucosa. Although the margins are clear by at least 2
fection after receiving amoxicillin for routine dental cleaning.
mm, lymphovascular invasion is present. Staging CT scans do
When she was treated with a course of fidaxomicin, her di-
not show distant metastasis. Which of the following is the best
arrhea symptoms resolved on day 5, and she completed the
next step in management?
10-day course. She returns to the clinic 2 weeks after finishing
treatment because she has gastrointestinal distress with occa- a. Refer for transanal excision of the polyp at the base
sional loose stools. She has regained the 1.8 kg (4 lb) that she b. Refer for low anterior resection and lymph node staging
had lost, but she thinks that the infection has not resolved. On c. Do not refer for surgery now, but repeat the colonoscopy in 1 year
physical examination in the office, she has normal vital signs d. Do not refer for surgery now, but perform endoscopic ultraso-
and minimal abdominal tenderness. A resident physician or- nography in 6 months
ders a C difficile stool PCR test, and the results are positive.
V.20. During colonoscopy for a 53-year-old man, you find 4 sessile
What is the next step in her management?
serrated polyps in the right colon; the diameters are 6 to 9
a. Repeat the course of fidaxomicin because the infection has not mm. At the patient’s first screening colonoscopy 3 years ago, 2
completely resolved sessile serrated lesions (12-15 mm in diameter) were removed
b. Prescribe vancomycin 125 mg 4 times daily for 10 days from the ascending colon; no residual polyp tissue is seen near
c. Perform a 2-step toxin-based assay for C difficile infection the well-healed scars from the previous polypectomy. When
d. Obtain a detailed symptom history to evaluate for a postin should he return for his next surveillance examination?
fection state
a. In 1 year
V.16. A 41-year-old man with obesity (body mass index, 27) is re- b. In 3 to 5 years
ceiving therapy for hyperlipidemia and reflux disease and c. In 7 years
presents to the emergency department with abdominal pain in d. In 10 years
the left lower quadrant that has worsened in the past 3 days.
V.21. A 17-year-old adolescent girl presents with abdominal pain
He has felt feverish but has not had diarrhea or blood in the
associated with defecation. She describes having 1 bowel
stool. On examination, he has mild tenderness in the left lower
movement every 4 days that is Bristol type 1 or 2. She says that
quadrant of the abdomen but no peritoneal signs. The white
she does not have any warning symptoms. She has received
blood cell count is 8,500/µL. CT with oral and intravenous
a diagnosis of constipation-predominant IBS and now wants
contrast agents shows inflammation and stranding around di-
to try further management options. Which of the following
verticula in the sigmoid region and changes consistent with di-
tests should be completed before further empirical treatment
verticulitis. No abscess or perforation is seen. What is the best
options are offered?
a. Celiac disease testing
a. Outpatient management with a liquid diet, no antibiotics, and
b. Colonoscopy
colonoscopy in 6 weeks
c. CT of the abdomen and pelvis
b. Outpatient management with antibiotics and colonoscopy in 6
d. Colonic transit study
weeks
V.22. A 45-year-old man presents with abdominal pain and diar- vaginal delivery with anal sphincter tear 20 years ago. She does
rhea. He has a past surgical history of cholecystectomy. He not take any medications. Dietary fiber supplementation ag-
says that he does not have any warning symptoms. He has gravated her diarrhea. On digital rectal examination she has
tried to increase his fiber intake, and he has received loper- normal anal resting tone, a weak squeeze response, and normal
amide and antispasmodic therapy without any improvement anorectal descent during evacuation. Results were normal from
in the diarrhea or the abdominal pain. What treatment option a complete blood cell count, serologic tests for celiac disease,
should not be offered to this patient? and flexible sigmoidoscopy. What is the best next step?
a. Tricyclic antidepressants a. Perform endoanal ultrasonography and refer her to a colorectal
b. Diphenoxylate-atropine surgeon for anal sphincteroplasty
c. Eluxadoline b. Recommend that she limit her intake of caffeine and foods
d. A serotonin-norepinephrine reuptake inhibitor containing artificial sugars, and if diarrhea persists, try lopera-
mide (2 mg) beginning with 1 tablet 30 minutes before break-
V.23. A 23-year-old woman with constipation presents with diarrhea
fast and lunch and titrated thereafter to a maximum of 16 mg
and abdominal pain associated with defecation. The diarrhea
daily
is characterized by 3 bowel movements daily, which are Bristol
c. Perform anal manometry
type 6 and contain some blood. The symptoms have been pres
d. Recommend anorectal biofeedback therapy
ent for the past 12 months. Her abdominal pain gets worse
after bowel movements and is associated with eating. Blood V.27. Which of the following statements about isolated slow transit
test results were normal for hemoglobin, iron, C-reactive pro- constipation is most accurate?
tein, fecal calprotectin, and a celiac panel, and a fecal sample
a. Every patient who has constipation with slow transit has slow
was negative for Clostridioides difficile. Celiac genotype testing
transit constipation
identified HLA-DQ1 and HLA-DQ4 haplotypes. What is the
b. Opioids do not delay colon transit
c. Patients with DDs may also have slow colon transit
a. Trial treatment with dietary fiber supplementation d. All patients with slow transit constipation need a colectomy
b. Colonoscopy
V.28. Which statement correctly describes anorectal tests for chronic
c. No further testing or treatment because the symptoms will re-
constipation?
solve on their own
d. Trial treatment with a gluten-free diet a. A rectal balloon expulsion test is the preferred initial test for
diagnosing DDs
V.24. A 24-year-old woman returns to your clinic. At her initial visit
b. In healthy people, the rectoanal gradient during evacuation
6 months ago, she described a 6-month history of weekly ab-
measured with high-resolution manometry is positive
dominal pain and bloating associated with harder, less fre-
c. A negative rectoanal gradient is not associated with an ab-
quent stool. The pain was reportedly relieved by satisfactory
normal result on the rectal balloon expulsion test
defecation. A symptom- based diagnosis of constipation-
d. Anorectal high-resolution manometry is the gold standard test
predominant IBS was made. In the past 6 months her symptoms
for the diagnosis of DDs
have not improved with increased aerobic exercise, increased
consumption of soluble fiber, and use of osmotic and stimu- V.29. A 24-year-old woman presents to your office at 13 weeks’
lant laxatives. She describes feeling frustration because of her gestation. She is having a little heartburn, particularly after
symptoms and her doubts about the diagnosis. What is the she eats spicy foods. She does not have dysphagia, nausea, or
next step in management? vomiting. She is otherwise healthy and does not have a history
of heartburn or gastroesophageal reflux disease before this
a. Digital rectal examination
pregnancy. Which of the following should you recommend for
b. Colonoscopy
her heartburn symptoms?
c. Therapy with rifaximin
d. Therapy with prucalopride a. Calcium carbonate 4 times daily
b. Sodium bicarbonate 3 times daily
V.25. A 40-year-old woman presents to your office with chronic
c. Magnesium trisilicate twice daily
constipation for the past 20 years. She describes having hard
d. Famotidine once daily
stools, straining excessively to defecate, and having a sense
of anal blockage during defecation and a sense of incomplete V.30. A 28-year-old female immigrant from Southeast Asia presents
evacuation thereafter. Her symptoms have not responded to your clinic at 16 weeks’ gestation and tells you that she has
to several laxatives or linaclotide. She does not have alarm hepatitis B. Results for hepatitis B serology are positive for hep-
symptoms or a family history of colon cancer. What is the best atitis B surface antigen and hepatitis B e antigen and negative
response at this point? for anti-hepatitis B e antigen. Her viral load, checked by her
obstetrician last week, was 190,000 IU/mL; the ALT level was
a. Perform defecography
110 U/L. She does not have cirrhosis. You counsel her about
b. Prescribe a cyclic guanosine monophosphate agonist (eg,
the use of hepatitis B immune globulin at the time of delivery.
lubiprostone or plecanatide)
Which drug should be used now to treat her hepatitis B?
c. Perform a careful digital rectal examination, anorectal manom-
etry, and rectal balloon expulsion test a. Tenofovir
d. Perform a colonoscopy b. Adefovir
c. Interferon
V.26. A 45-year-old woman presents to your office with fecal in-
d. Entecavir
continence for the past 15 years. She describes having acci-
dental bowel leakage of a moderate amount of semiformed V.31. A 30-year-old woman at 26 weeks’ gestation comes to your
stool preceded by marked urgency once weekly. The symptom office because of constipation. She did not have constipation
is embarrassing and has prompted her to withdraw from so- before her pregnancy. She is gaining weight appropriately,
cial activities. She describes having postprandial abdominal she works full-time, and she exercises 4 times weekly. Every
discomfort and rectal urgency that are relieved by passing 3 other day she has a bowel movement that is type 1 or 2 on the
semiformed to loose stools daily. Her past medical history is Bristol Stool Form Scale, but she feels uncomfortable on the
notable for diarrhea- predominant IBS and a complicated days when she does not have a bowel movement. She says that
she does not have bleeding, excessive straining, or abdominal were completely removed. The yield of chromoendoscopy is
pain. What should you recommend that she try first? decreased when inflammation or pseudopolyposis is promi-
a. Daily senna nent. The most appropriate approach would be surveillance with
b. Fiber supplementation high-definition white-light endoscopy with random and targeted
c. Castor oil biopsies of lesions of interest.
d. Eluxadoline
V.4. Answer e.
V.32. A 24-year-old woman with a history of UC who had a hyper-
The most likely cause is type 2 IBD–related arthritis, which is
sensitivity reaction to mesalamine is currently taking delayed-
release budesonide. She is contemplating pregnancy and wants
polyarticular, involves smaller joints, is symmetrical, and does
your advice about a safe therapy for UC if she were to stop not parallel the IBD activity. Parvovirus is unlikely because the
taking budesonide. She is currently asymptomatic with once- patient has no other symptoms that would suggest that infection.
daily budesonide. What should you recommend for therapy? While fibromyalgia is possible, her symptoms suggest an inflam-
matory cause and are known extraintestinal manifestations. Type
a. Continue budesonide indefinitely until she is pregnant
b. Use a biological as a steroid-sparing agent
1 IBD–related arthritis typically is pauciarticular and not sym-
c. Use tofacitinib as it is another oral agent that is convenient metrical and usually parallels the IBD activity. She is too young
d. Stop the use of budesonide and evaluate the response for the development of osteoarthritis.
V.5. Answer b.
This patient should begin infliximab therapy now. The current
Answers approach to postoperative maintenance therapy is risk stratification
V.1. Answer c. of patients for the likelihood of postoperative recurrence. Those
This patient should be referred to a colorectal surgeon now for a deemed to be at high risk are offered treatment with azathioprine,
total proctocolectomy since she has evidence of multifocal dys- 6-mercaptopurine, or preferably infliximab. The patient in this vi-
plasia of the colon in addition to UC. The patient would also be gnette is a young man with a history of stricturing CD, which are
a candidate for total proctocolectomy instead of a segmental co- high risk features. Patients not considered to have a high risk and
lectomy since dysplasia is involving the rectum as well. While those who opt not to receive medical therapy are offered colonos-
therapy with a different biological would be appropriate to help copy 6 to 12 months after surgery. Patients who show evidence of
achieve remission, the presence of multifocal dysplasia poses a endoscopic recurrence are then offered treatment.
high risk of progression to colorectal cancer. Also, since therapy V.6. Answer c.
with other agents has already failed, the likelihood of endoscopic Sulfasalazine is associated with reversible azoospermia and
remission is much lower. The performance of chromoendoscopy thus is the cause of infertility in this patient. Since he has been
to detect dysplastic lesions is limited by the presence of severe in deep remission with sulfasalazine, it would be reasonable to
inflammation and hence would not be helpful in this patient. switch him to mesalamine at this point to maintain remission.
Although follow-up colonoscopy in 6 months might be appro- Mesalamine therapy does not pose the reversible azoospermia
priate, it would carry a high risk that the disease would progress risk. A switch to vedolizumab would not be necessary since he is
to colorectal cancer or that high-grade dysplasia or carcinoma in in remission with an aminosalicylate. UC is not associated with
situ would be missed. Doing nothing would not be an appropriate higher rates of male infertility, and seeking care from an infer-
option as this time. tility specialist would not be necessary at this point.
V.2. Answer c. V.7. Answer a.
The history and imaging findings are most consistent with CD, This patient was admitted to the hospital for management of
and the patient most likely has severe fistulizing CD that involves acute severe UC. If patients have not responded to intravenous
the terminal ileum with abscess formation. He does not have methylprednisolone by the third day after admission, it is reason-
UC because there is no evidence of colonic inflammation, and able to try infliximab therapy before referring them for surgery. A
UC does not typically result in fistulas or abscesses. He does surgical consultation is also indicated at this point, but a trial of
not have risk factors for Mycobacterium tuberculosis infection. infliximab should be considered first since the patient is hemody-
Tuberculosis can involve the terminal ileum and mimic CD but namically stable with no signs of toxic megacolon. Initiation of
does not commonly cause a communicating abscess. Acute ap- azathioprine at this point would not be indicated because it has a
pendicitis does not involve the terminal ileum, so that is not the slow onset of action. Use of a higher dose of methylprednisolone
diagnosis. now would not have an added benefit and would increase the risk
V.3. Answer d. of infections and possible surgical complications.
The patient has colonic pseudopolyposis with UC. Patients who V.8. Answer d.
have a long history of UC should undergo colonoscopy with Janus kinase inhibition is associated with reactivation of herpes
high-definition white-light endoscopy or chromoendoscopy for zoster, which occurs with dose-dependent increases of tofacitinib.
dysplasia surveillance. This should be performed every 1 to 3 Patients should receive the recombinant shingles vaccine if they
years (not every 5 years) when adenomatous dysplasia has been will be treated with tofacitinib. Sleep apnea and heart blocks are
identified. Pseudopolyps are irregularly shaped islands of re- contraindications for ozanimod but not tofacitinib. Also, macular
sidual colonic mucosa that are the result of the mucosal ulcer- edema is associated with ozanimod but not tofacitinib.
ation and regeneration that occur in IBD. These lesions are not
precancerous by themselves. Surgery should be discussed with V.9. Answer a.
patients, but it would not be performed because pseudopolyps In a patient with IBD and an increased alkaline phosphatase
are not precancerous and because the adenomatous lesions level, further evaluation for possible PSC is warranted. MRCP
is the diagnostic test of choice for PSC because it is sensitive blood in the stool. He does not have risk factors for Clostridioides
for detecting characteristic bile duct changes and is noninva- difficile, and testing for C difficile alone would not be sufficient.
sive. Liver biopsy findings may support a diagnosis of PSC, but A decision to admit to the hospital would be based on the overall
they are often nondiagnostic, and liver biopsy is rarely neces- clinical picture, and in most instances intravenous antibiotics are
sary if a patient has characteristic findings with cholangiography. not needed. If there is no access to a stool test, empirical therapy
However, a liver biopsy may be necessary if there is a strong with an antibiotic for traveler’s diarrhea may be considered.
possibility of small duct PSC or an overlap condition with au-
toimmune hepatitis. Repeating liver enzyme testing in 6 months V.14. Answer c.
would be inappropriate without further evaluation because it This patient is having a first episode of mild Clostridioides
could delay the diagnosis of PSC. While ERCP is also sensitive difficile infection. The use of fidaxomicin has high rates of clin-
for detection of PSC, it is invasive and typically not used as the ical cure (similar to those with vancomycin) but lower rates
initial diagnostic test. of recurrence compared to vancomycin. Metronidazole is no
longer recommended, even in mild cases, owing to high rates of
V.10. Answer c. treatment failure and adverse effects. Use of vancomycin has a
This patient has type 1 peripheral arthritis, which tends to higher rate of recurrence compared to fidaxomicin. The addition
affect fewer than 5 joints and often involves larger joints such of intravenous bezlotoxumab to vancomycin therapy would not
as the knees. Type 1 peripheral arthritis tends to parallel IBD improve cure rates in this situation because of the absence of risk
activity. In this patient with evidence of active CD, starting factors (which include age >65 years), C difficile infection in the
infliximab therapy would help to treat underlying IBD and ar- past 6 months, immunosuppression, and the presence of severe C
thritis. Vedolizumab, a gut-specific monoclonal antibody directed difficile infection.
against α4β7 integrin, is thought to have less benefit in treating
extraintestinal manifestations of IBD. Therefore, increasing the V.15. Answer d.
frequency of vedolizumab to every 4 weeks would be unlikely to This patient has had 1 episode of Clostridioides difficile infec-
provide effective treatment of her arthritis. Her symptoms, which tion and is at a risk for recurrent infection. She is also at risk for
improve with activity, are most consistent with inflammatory ar- postinfection symptoms, which include occasional loose stools,
thritis. MRI is unlikely to aid in diagnosis. Since she is sympto- sometimes with alternating constipation, and symptoms related
matic and has evidence of active inflammation on colonoscopy, to meals. A detailed symptom history is important. A stool PCR
a change in management is warranted rather than continuing assay can have false-positive results in up to 30% to 50% of
therapy with vedolizumab at the current dosage. infections after successful treatment. Treatment with antibiotics
is not indicated, and treatment with vancomycin may increase
V.11. Answer d. the risk for future C difficile infection. While performing a 2-step
This patient, who has UC and PSC and an increased risk for co- toxin-based assay would be reasonable, it should be done only if
lorectal cancer, appropriately underwent surveillance colonos- a patient has clinical signs and symptoms of C difficile infection.
copy. The presence of multifocal, high-grade dysplasia suggests
a high risk for synchronous cancer or development of colorectal V.16. Answer a.
cancer, especially with PSC. Therefore, colectomy is the most This patient presents with a first episode of acute uncomplicated
appropriate next step in management. Further surveillance with diverticulitis. Since he is tolerating oral intake without diffi-
or without chromoendoscopy would not be appropriate for this culty, outpatient management would be recommended. Recent
patient who has multiple high-risk features. guidelines suggest that patients with uncomplicated acute diver-
ticulitis be managed without antibiotics as outcomes are sim-
V.12. Answer b. ilar to those for patients treated with antibiotics in this situation.
Patients with erythema nodosum, the most common cutaneous Hospital admission for bowel rest and intravenous antibiotics
manifestation of IBD, have tender subcutaneous nodules on the should be reserved for patients who have evidence of a compli-
anterior extensor surfaces of the lower extremities. The status cation (abscess) or for patients who cannot tolerate oral intake.
of erythema nodosum tends to parallel IBD luminal activity Colonoscopy is contraindicated during an episode of acute diver-
and improves with treatment of the underlying disease. Type 2 ticulitis and is not recommended until 6 to 8 weeks after the acute
peripheral arthritis typically involves more than 5 small joints episode has resolved. Surgical referral for colectomy because a
(polyarticular) and is independent of IBD activity. Similarly, patient is young at onset is no longer recommended.
axial arthropathies associated with IBD, including ankylosing
spondylitis and sacroiliitis, are independent of IBD activity. V.17. Answer b.
However, therapy with anti–tumor necrosis factor may induce re- In the US, Blacks have a disproportionately high mortality rate
mission in patients with ankylosing spondylitis, especially in the from CRC, which persists when adjusted for stage at diagnosis.
early stages. Among the extraintestinal manifestations involving Owing largely to population-level screening, the incidence of
the eye, scleritis and anterior uveitis are independent of IBD ac- CRC in the US is decreasing for most age groups. However, CRC
tivity, while episcleritis may parallel luminal disease. incidence and mortality are progressively increasing for per-
sons younger than 50 years. While decreasing in industrialized
V.13. Answer b. nations, the incidence of CRC is increasing in many resource-
The correct response is to perform stool testing when acute in- limited countries. This is thought to be due to lifestyle factors that
fectious diarrhea is suspected and the patient has fever, bloody or increase risk; these factors include cigarette smoking, obesity,
mucoid stools, severe abdominal tenderness, or signs of sepsis. and diets high in saturated fat or red (especially processed) meat.
Positive stool study results would help determine antimicrobial
use (eg, for Salmonella, Shigella, or Campylobacter, in certain V.18. Answer c.
cases) and may prevent unnecessary additional testing and im- Lynch syndrome should be suspected in patients with an auto-
aging. Loperamide would not be indicated because the patient has somal dominant pedigree of familial cancers. While mismatch
repair deficiency is a hallmark of Lynch syndrome, there are other colonic transit testing should be completed after a functional def-
somatic events that can result in this phenotype. Therefore, ge- ecatory disorder has been ruled out because patients with defeca-
netic testing to confirm a germline mutation in 1 of the genes tory disorders can have slow colonic transit, which will normalize
coding for mismatch repair enzymes is required for a diagnosis after the pelvic floor is rehabilitated.
of Lynch syndrome. Additionally, the patient’s primary tumor
should be tested for BRAF variation and hypermethylation of V.22. Answer c.
MLH1. The Amsterdam criteria are useful for identifying patients Eluxadoline increases the risk of pancreatitis in patients who have
with hereditary nonpolyposis CRC who should be tested for liver disease, who consume more than 3 alcoholic drinks daily, or
mismatch-repair deficiency to direct genetic testing for a diag- who have had a cholecystectomy. The mechanism of action is
nosis of Lynch syndrome. This diagnosis may lead to a subtotal believed to be related to a dysfunction of the sphincter of Oddi
colectomy rather than segmental resection. Women who have due to partial delta opioid antagonism. The other medications
Lynch syndrome and have completed childbearing can con- listed are appropriate for both abdominal pain and diarrhea.
sider hysterectomy, but this patient’s diagnosis is not yet con-
V.23. Answer b.
firmed. When Lynch syndrome is diagnosed, cascade genetic
The patient describes having blood in her stool, which is a con-
testing should be offered to first-degree relatives to rule out the
cerning warning symptom, and requires a more thorough eval-
disease and offer surveillance to confirmed mutation carriers.
uation, including a colonoscopy to rule out IBD. If she did not
Since the patient’s tumor shows deficient mismatch repair phe-
have warning symptoms, trying supplementation with dietary
notype by immunohistochemistry for mismatch repair enzymes,
fiber or foregoing further testing or treatment would be reason-
microsatellite instability testing does not offer any additional
able. A trial with a gluten-free diet has helped patients who have
information. Use of immunohistochemistry or microsatellite
genes permissive for celiac disease (ie, HLA-DQ2 or HLA-DQ8)
instability testing depends on local availability and laboratory
but would not be appropriate in this situation.
expertise.
V.24. Answer a.
V.19. Answer b. This patient has persistent, bothersome symptoms despite an
The patient has a malignant rectal polyp. Although the histologic appropriate symptom-based diagnosis and appropriate therapy.
margin is clear, the poor tumor differentiation and lymphovascular Further investigation can be considered at this time. Functional
invasion are both strong predictors of lymph node involvement defecatory disorders can mimic constipation-predominant IBS.
and are associated with distant metastatic recurrent disease. In A digital rectal examination should be performed to exclude
this situation, complete surgical staging by low anterior resection organic anal pathology and to evaluate for a functional defeca-
with pathologic lymph node staging is recommended by National tory disorder. Anorectal manometry can be considered there-
Comprehensive Cancer Network guidelines. Transanal excision after. A colonoscopy is not indicated in the absence of alarm
may be offered to patients with low-risk T1 rectal cancers. After symptoms. Rifaximin is approved for the treatment of only
transanal excision, surveillance by endoscopic ultrasonography diarrhea-predominant IBS. Prucalopride is not approved by the
and MRI should be performed every 6 months with colonoscopic US Food and Drug Administration for the diagnosis of IBS and
surveillance at 1-, 3-, and 5-year intervals. Colonoscopy or endo- may not affect her abdominal pain.
scopic ultrasonography alone is not advised because the patient
requires surgical staging. V.25. Answer c.
Defecatory disorders are managed with pelvic floor biofeedback
V.20. Answer a. therapy rather than with laxatives. Although symptoms and dig-
The patient has a lifetime history of 5 or more sessile serrated ital rectal examination findings may prompt a suspicion of DDs,
lesions (2 were confirmed at a previous colonoscopy, and 4 are anorectal tests are necessary because a clinical assessment alone
presumed according to the endoscopic features and polyp loca- does not suffice for identifying a DD. In patients with a DD, anal
tion), and all are 5 mm or larger in diameter with at least 2 lesions inspection may disclose an anal fissure or hemorrhoids; digital
10 mm or larger in diameter; he therefore meets 1 of 2 World rectal examination may disclose anismus (ie, high anal resting
Health Organization phenotypes for serrated polyposis syndrome pressure), reduced or excessive perineal descent, or rectal pro-
(the second phenotype is >20 serrated lesions or polyps of any lapse. The puborectalis muscle may not relax normally, or para-
size distributed throughout the large bowel, with ≥5 being prox- doxically it may contract during simulated evacuation. Initially,
imal to the rectum). Although surveillance may be personalized to anal manometry and a rectal balloon expulsion test are preferred
include longer intervals, most guidelines recommend annual sur- to barium defecography, which entails radiation exposure, or
veillance. A surveillance interval of 3 to 5 years is appropriate for magnetic resonance defecography, which is more expensive. If
patients with 3 or 4 serrated lesions that do not meet the criteria a patient with long-standing constipation does not have alarm
for serrated polyposis syndrome. An interval of 7 to 10 years is symptoms or a family history of colon cancer, a colonoscopy is not
recommended for patients with 1 or 2 small adenomas. A 10-year warranted. Since symptoms have not responded to lubiprostone,
interval is recommended if colonoscopy findings are normal or if which is a secretagogue, anorectal tests rather than a trial with
only small hyperplastic lesions are found. lubiprostone or plecanatide is the appropriate next step.
V.21. Answer a. V.26. Answer b.
Up to 30% of patients with celiac disease present with consti- If patients do not have organic disease (eg, UC), the use of
pation. All patients with IBS should be evaluated for celiac dis symptomatic measures to manage bowel disturbances is the
ease. This patient does not have warning symptoms, so she does preferred initial step and is often effective for managing fecal
not require further evaluation with colonoscopy or CT of the ab- incontinence. If fecal incontinence persists despite the use of
domen and pelvis. A colonic transit study could be considered adequate measures to manage the bowel disturbances, anal
if conservative therapy does not help the patient. Additionally, manometry and then anorectal biofeedback therapy should be
considered. Less than 20% of patients are continent at 5 years mild heartburn and can be used for the duration of the preg-
after anal sphincteroplasty. Hence, sphincteroplasty is typically nancy if needed.
reserved for younger women who often have a sphincter defect
identified shortly after obstetric injury. V.30. Answer a.
Treatment of hepatitis B depends on the viral load and ALT level.
V.27. Answer c. This patient should be treated. She has chronic hepatitis B in the
Many patients with DDs also have slow colon transit. Hence, immune-active phase and meets treatment thresholds (independent
the diagnosis of slow transit constipation applies to patients of pregnancy) with high levels of HBV DNA (>20,000 IU/mL)
who do not have impaired rectal evacuation. Because opioids and ALT (≥2 times the upper limit of the reference range). Women
delay colonic transit, their use should be discontinued when fea- who have an undetectable viral load can defer treatment and be
sible in patients with constipation. Colectomy is reserved for a monitored. To reduce the risk of maternal-fetal transmission, HBV
small fraction of patients with slow transit constipation whose DNA should be checked at 26 to 28 weeks’ gestation, and antiviral
symptoms are most likely explained by slow colon transit and do therapy should be initiated if the viral load exceeds 200,000 IU/
not respond to laxatives. mL. Of the drugs listed in the answer choices, tenofovir has the
most evidence for safety during pregnancy. Adefovir and entecavir
V.28. Answer a. are considered less safe, and interferon is contraindicated.
The rectal balloon expulsion test is the preferred initial test for
diagnosing DDs. Failure to expel a rectal balloon in 60 seconds V.31. Answer b.
is considered to be abnormal. Measured with manometry, the Constipation is common during pregnancy, particularly in ad-
rectoanal gradient (ie, rectal pressure minus anal pressure) during vanced stages. First-line therapy is fiber supplementation because
evacuation is typically negative even in healthy women and men. it is safe and effective for most patients. Senna can be used for
Hence, this gradient is abnormal only if it is more negative than a short duration, but as a stimulant laxative, it can cause cramps.
the lower limit of normal. A more negative rectoanal gradient is Castor oil is contraindicated as it is associated with uterine rup-
associated with an abnormal balloon expulsion test. ture. Eluxadoline is safe during pregnancy but should be used
only after other modalities, such as fiber and osmotic laxatives,
V.29. Answer d. have been tried.
Heartburn is a common symptom during pregnancy and can get
worse as the pregnancy progresses. Over-the-counter calcium V.32. Answer b.
supplements are appropriate for mild heartburn during preg- Prolonged use of corticosteroids, including budesonide, is not
nancy, but they should not be taken more than 3 times daily an optimum strategy for conception or during pregnancy. All the
because higher amounts of carbonate can cause metabolic de- biologicals currently approved for UC carry a low risk and would
rangement. Similarly, sodium bicarbonate should not be used be appropriate to use to control the disease and to spare continued
because it can cause milk-alkali syndrome. Trisilicates also can use of the corticosteroid. Tofacitinib is currently not suggested as
cause metabolic derangement and should not be used for ex- first-line therapy for use in a patient contemplating pregnancy be-
tended periods. Histamine blockers are appropriate therapy for cause data from animal studies suggest a teratogenic effect.
VI
Liver
23
Approach to the Patient With Abnormal Liver Test

Results and Acute Liver Failurea
JOHN J. POTERUCHA, MD
Abnormal Liver Test Results ✓ Chronic liver disease—elevation of liver enzymes for more than
3 months
Definitions and Prevalence
Abnormal liver test results are defined as abnormal results for Aminotransferases (ALT and AST)
aminotransferases (aspartate aminotransferase [AST] or alanine
aminotransferase [ALT]) or hepatic alkaline phosphatase (ALP). ALT and AST are in hepatocytes, and elevated serum levels are
Determination of currently used “normal” values most likely in- an indication of hepatocellular disease. Injury of the hepatocyte
cluded patients who had clinically unrecognized liver disease membrane allows these enzymes to “leak” out of hepatocytes,
such as nonalcoholic fatty liver disease. It has been suggested and within a few hours after liver injury, the serum levels of the
that the upper limit of the normal value for ALT should be 33 U/L enzymes increase. ALT elevation is more specific for liver injury
for men and 25 U/L for women. Population-based studies suggest than is AST elevation, although severe muscle injury may result
that 25% of the population has an abnormal ALT value and 33% in serum elevations of both enzymes. ALT has a longer half-life
an abnormal ALP value. Abnormal liver test results are generally than AST; thus, improvements in ALT levels lag those of AST.
defined as acute if the duration is less than 3 months or chronic if
the duration is more than 3 months. Alkaline Phosphatase
✓ Hepatocellular disease—predominant elevation of ALT ALP is an enzyme located on the hepatocyte membrane bordering
✓ Cholestatic liver disease—predominant elevation of ALP the bile canaliculus. Because ALP is found also in bone and pla-
✓ Acute liver disease—elevation of liver enzymes for less than 3 months centa, an increase in its level without other indication of liver
disease should prompt further testing to discover whether the in-
crease is from liver or from other tissues. One way of doing this is
a
Portions previously published in Poterucha JJ. Fulminant hepatic failure. to determine the concentration of ALP isoenzymes. Another way
In: Johnson LR, editor. Encyclopedia of gastroenterology. Vol 2. Elsevier is to determine the level of γ-glutamyltransferase, an enzyme of
Academic Press; 2004: 70-4; Poterucha JJ. Hepatitis. In: Bland KI, Sarr MG, intrahepatic biliary canaliculi.
Buchler MW, Csendes A, Garden OJ, Wong J, editors. General surgery: princi-
ples and international practice. 2nd ed. Springer; 2009: 921-32; and Poterucha
JJ, Gunneson TJ. Liver biopsy and paracentesis. In: Talley NJ, Lindor KD, Bilirubin
Vargas HE, editors. Practical gastroenterology and hepatology: liver and bil-
Bilirubin is the water- insoluble product of heme metabolism
iary disease. Wiley-Blackwell; 2010: 80-6; used with permission.
that is taken up by hepatocytes and conjugated with glucuronic
Abbreviations: ALP, alkaline phosphatase; ALT, alanine aminotransferase; acid to form monoglucuronides and diglucuronides through the
AST, aspartate aminotransferase; INR, international normalized ratio;
activity of the enzyme uridine diphosphate glucuronosyltrans
MELD, Model for End-stage Liver Disease; MELD-Na, Model for End-
stage Liver Disease with determination of sodium; PBC, primary biliary
ferase. Conjugation makes bilirubin water-soluble, allowing it
cholangitis; PSC, primary sclerosing cholangitis to be excreted into the bile canaliculus. The serum concentration
279
280 Section VI. Liver
of bilirubin is measured in direct (conjugated) and indirect Table 23.1. Child-Turcotte-Pugh Score
(unconjugated) fractions. Diseases characterized by overpro-
Number of pointsa
duction of bilirubin, such as hemolysis or resorption of a hema-
toma, are characterized by hyperbilirubinemia that is 20% or less Measure 1 2 3
conjugated bilirubin. Hepatocyte dysfunction or impaired bile
Encephalopathy None Stage 1 or 2 Stage 3 or 4
flow produces hyperbilirubinemia that is usually 20% to 80% Ascites None Mild or moderate Severe
conjugated bilirubin. Patients with an inherited disorder of bili- Bilirubin, mg/dL <2 2-3 >3
rubin excretion into the canaliculus, such as Dubin-Johnson syn- Albumin, g/dL >3.5 2.8-3.5 <2.8
drome or Rotor syndrome, have hyperbilirubinemia that is more INR <1.7 1.7-2.3 >2.3
than 80% conjugated. Because conjugated bilirubin is water-
Abbreviation: INR, international normalized ratio.
soluble and may be excreted in urine, patients with conjugated
hyperbilirubinemia may note dark urine. In these patients, the a
Interpretation: class A (compensated disease), 5 or 6 points; class B (functional
stools are lighter in color because of the absence of pigments that compromise), 7-9 points; class C (decompensated disease), 10-15 points.
result from the presence of bilirubin in the intestine.
for deceased donor liver transplant, and to assess surgical risk
Prothrombin Time and Albumin for patients with cirrhosis. Online tools are available to calcu-
Abnormalities of prothrombin time and albumin occur with liver late scores for MELD and MELD-Na to help stratify outcome for
dysfunction and should prompt immediate evaluation. Prothrombin patients with chronic liver disease.
time is a measure of the activity of coagulation factors II, V, VII,
and X, all of which are synthesized in the liver. These factors are Hepatocellular Disorders
dependent also on vitamin K for synthesis. Vitamin K deficiency
Acute Hepatitis
may be caused by antibiotics, prolonged fasting, small-bowel mu-
cosal disorders such as celiac disease, or severe cholestasis with Symptoms of acute hepatitis include malaise, anorexia, abdom-
an inability to absorb fat-soluble vitamins. Liver dysfunction is inal pain, and jaundice. Common causes of acute hepatitis are
characterized by an inability to synthesize clotting factors despite listed in Table 23.2.
adequate stores of vitamin K. Administration of vitamin K improves Acute hepatitis caused by viruses or drugs usually produces
prothrombin time within 48 hours in a patient with vitamin K defi- a marked increase in aminotransferase levels (often >1,000 U/
ciency but has little effect if the prolonged prothrombin time is due L). Aminotransferase levels of more than 5,000 U/L usually are
to liver disease with poor hepatocellular function. due to acetaminophen hepatotoxicity, ischemic hepatitis (shock
Because albumin has a half-life of 21 days, decreases due to liver liver), or, rarely, hepatitis caused by unusual viruses, such as
dysfunction do not occur suddenly; however, the serum level of al- herpesvirus. Ischemic liver injury occurs after an episode of hy-
bumin can decrease relatively quickly in a patient who has an acute potension and is seen most often in patients with preexisting car-
inflammatory illness such as bacteremia. This rapid decrease likely diac dysfunction. Lactate dehydrogenase is also often markedly
is caused by the release of cytokines, which accelerate the metabo- elevated. In patients with ischemic liver injury, aminotransferase
lism of albumin. Other causes of hypoalbuminemia include urinary levels increase quickly and improve within a few days. Acute and
or gastrointestinal tract losses, and these should be considered in a transient increases in aminotransferase levels (as high as 1,000
patient who has hypoalbuminemia in the absence of liver disease. U/L) may also be caused by a sudden increase in intrabiliary
pressure, usually from a common bile duct stone. In patients with
pancreatitis, a transient increase in ALT is suggestive of gallstone
Platelet Count and Other Tests
pancreatitis. Alcoholic hepatitis is characterized by more modest
Although most patients with significant liver injury have ab- increases in aminotransferase levels, nearly always less than 400
normal levels of liver enzymes, occasionally patients with cir- U/L, with an AST:ALT ratio greater than 2:1. If muscle injury has
rhosis may have normal liver enzyme levels and preserved liver been excluded, the higher the AST:ALT ratio, the more likely a
function. A decreased platelet count due to hypersplenism may be patient is to have alcoholic liver disease. Patients with alcoholic
a clue to the presence of significant liver injury, and the presence
of thrombocytopenia requires exclusion of portal hyperten-
sion even when the results of other liver tests are normal. Most Table 23.2. Common Causes of Acute Hepatitis
patients with thrombocytopenia due to portal hypertension have
splenomegaly and, often, other features of portal hypertension Disease Clinical clue Diagnostic test
such as esophageal varices. Hepatitis A Exposure history IgM anti-HAV
Hepatitis B Risk factors HBsAg, IgM anti-HBc
Hepatitis C Risk factors HCV RNA more reliable
Scoring Systems to Assess Liver Disease Severity than anti-HCV
The Child- Turcotte-Pugh score (Table 23.1) uses encepha- Drug-induced Compatible medication Improvement after agent is
lopathy, ascites, bilirubin, albumin, and prothrombin time (or withdrawn
Alcoholic History of alcohol Liver biopsy, improvement
international normalized ratio [INR]). The measurement of as-
hepatitis excess, AST:ALT with abstinence
cites and encephalopathy is subjective, leading to interobserver >2:1, AST <400 U/L
variation. Ischemic History of severe Rapid improvement of
The Model for End-stage Liver Disease (MELD) with deter- hepatitis hypotension aminotransferase levels
mination of sodium (MELD-Na) is based on measurements of
INR, bilirubin, creatinine, and sodium and is used to predict sur- Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase;
HAV, hepatitis A virus; HBc, hepatitis B core; HBsAg, hepatitis B surface
vival of patients with chronic liver disease, to prioritize patients antigen; HCV, hepatitis C virus.
23. Approach to the Patient With Abnormal Liver Test Results and Acute Liver Failure 281
hepatitis frequently have an increase in bilirubin level that is out primary biliary cholangitis [PBC]), large bile ducts (eg, pancreatic
of proportion to the increase in aminotransferase levels. cancer obstructing the common bile duct), or both (eg, primary
When common causes of acute hepatitis have been excluded, sclerosing cholangitis [PSC]). In these disorders, the predomi-
considerations should include cytomegalovirus or Epstein-Barr nant abnormality is the level of ALP rather than ALT. A markedly
virus, hepatitis E, severe cardiovascular disease, seronegative increased ALP level (>1,000 U/L) suggests an intrahepatic rather
autoimmune hepatitis, and a previously unrecognized drug than obstructive problem. Some causes of cholestasis are listed
or toxin. in Table 23.4.
PBC usually occurs in women and can cause fatigue or pru-
ritus. Of the patients with PSC, 70% to 80% also have ulcerative
Chronic Hepatitis
colitis. Patients with PBC or PSC often are asymptomatic but
In chronic hepatitis, the increase in the ALT level is generally may have jaundice, fatigue, or pruritus. Large bile duct obstruc-
more modest (1.5-5 times the upper limit of the reference range) tion often is due to stones or to benign or malignant strictures.
than that in acute hepatitis. Usually the ALT is higher than the Acute bile duct obstruction from a stone is accompanied by
AST, although as the disease progresses to advanced fibrosis, abdominal pain and often fever and, as noted above, may pro-
the AST may be higher than the ALT. The most important and duce marked increases in the ALT level. Because ALP must be
common disorders that cause chronic hepatitis are listed in synthesized before excretion, acute biliary obstruction may not
Table 23.3. cause an elevated ALP level. Gradual onset of biliary obstruc-
Patients with nonalcoholic fatty liver disease usually have tion, such as that caused by a malignant stricture, is initially
obesity and type 2 diabetes or hyperlipidemia. Risk factors for painless and not accompanied by fever. Infiltrative disorders such
hepatitis C include a history of intravenous drug use or expo- as amyloidosis, sarcoidosis, or lymphoma may produce a mark-
sure to blood products. Most patients with hepatitis B are from edly increased ALP level with a normal bilirubin concentration.
an area where the disease is endemic, such as parts of Asia or Any systemic inflammatory process such as infection or immune
Africa, or they have a history of illegal drug use or multiple disorder may produce nonspecific liver test result abnormalities.
sexual contacts. A complete history is needed to help diagnose The abnormalities usually show a mixed cholestatic (ALP) and
drug-induced or alcohol- induced liver disease. Autoimmune hepatocellular (ALT or AST) pattern, and patients often have
hepatitis may manifest as acute or chronic hepatitis. Patients usu- jaundice.
ally have an ALT serum level of 200 to 800 U/L, higher than that
in other disorders that cause chronic hepatitis. Autoantibodies,
Hyperbilirubinemia
hypergammaglobulinemia, and other autoimmune disorders are
helpful clues to the diagnosis of autoimmune hepatitis. Jaundice may be the initial manifestation of hepatobiliary dis
When the most common causes of liver disease have been ease and occurs when the bilirubin concentration is more than
excluded, other diseases that should be considered are chronic 2.5 mg/ dL. A common disorder that produces unconjugated
drug-induced liver injury, celiac disease, and nonalcoholic fatty hyperbilirubinemia (but not usually jaundice) is Gilbert syn-
liver disease that is not apparent on imaging. About 30% to 50% drome due to an inherited deficiency of uridine diphosphate
of patients with celiac disease have elevated aminotransferase glucuronosyltransferase. In Gilbert syndrome, total bilirubin is
levels, and these abnormalities often improve with a gluten-free generally less than 3.0 mg/dL, whereas direct bilirubin is 0.5 mg/
diet. Celiac disease may also accompany immune-mediated liver dL or less. The bilirubin level usually is highest when a patient
diseases such as autoimmune hepatitis, primary biliary cirrhosis, is ill or fasting. A presumptive diagnosis of Gilbert syndrome
and primary sclerosing cholangitis. Chronic liver disease due to can be made in an otherwise well patient who has unconjugated
drug-induced liver injury is uncommon, although it should be hyperbilirubinemia, normal liver enzyme values, and a normal
considered if a patient has a history of severe cholestatic drug- concentration of hemoglobin (to exclude hemolysis). Genetic
induced liver injury. testing for Gilbert syndrome is available but usually unnecessary
for diagnosis.
Direct hyperbilirubinemia can result from a nonobstructive
Cholestatic Disorders
condition or from an obstructive condition. Obstruction is
Diseases that affect predominantly the biliary system are termed suggested by abdominal pain, fever, or a palpable gallbladder
cholestatic diseases. These can affect the microscopic ducts (eg, (or a combination of these). Jaundice due to hepatocellular
dysfunction is suggested by risk factors for viral hepatitis, re-
cent ingestion of a potentially hepatotoxic drug, a bilirubin
concentration of more than 15 mg/dL, and persistently high
Table 23.3. Common Causes of Chronic Hepatitis aminotransferase levels. In patients with resolving acute hep-
Disease Clinical clue Diagnostic test atitis, improvement in bilirubin concentration occurs more
slowly than improvement in ALT level. In diseases resulting in
Hepatitis C Risk factors Anti-HCV, HCV RNA
Hepatitis B Risk factors HBsAg large bile duct obstruction, extrahepatic and intrahepatic biliary
Nonalcoholic fatty Obesity, type 2 diabetes, Ultrasonography, liver dilatation can be identified on imaging studies, especially if the
liver disease hyperlipidemia biopsy bilirubin concentration is more than 10 mg/dL and the patient
Alcoholic liver History, AST:ALT >2:1 Liver biopsy, improvement has had jaundice for more than 2 weeks. Acute large bile duct
disease with abstinence obstruction, usually from a stone, may not cause dilatation of
Autoimmune ALT 200-1,500 U/L, Antinuclear or anti–smooth the bile ducts, and if the clinical suspicion is strong for bile
hepatitis usually female, other muscle antibody, biopsy duct obstruction even though ultrasonography or computed to-
autoimmune disease
mography shows normal-sized bile ducts, the biliary tree should
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; be imaged with magnetic resonance cholangiopancreatography,
HBsAg, hepatitis B surface antigen; HCV, hepatitis C virus.
Table 23.4. Common Causes of Cholestasis

Disease Clinical clue Diagnostic test
Primary biliary cholangitis Woman Antimitochondrial antibody
Primary sclerosing cholangitis Association with ulcerative colitis MRCP
Large bile duct obstruction Jaundice and pain are common Ultrasonography, CT, MRCP, ERCP
Drug-induced Compatible medication or timing Improvement after agent is withdrawn
Infiltrative disorder History of malignancy, amyloidosis, sarcoidosis Ultrasonography, CT, MRI
Inflammation-associated Symptoms of underlying inflammatory disorder Blood cultures, appropriate antibody tests
Abbreviations: CT, computed tomography; ERCP, endoscopic retrograde cholangiopancreatography; MRCP, magnetic resonance
cholangiopancreatography; MRI, magnetic resonance imaging.
endoscopic retrograde cholangiopancreatography, or endo- ✓ Thrombocytopenia— often the first manifestation of cirrhosis
scopic ultrasonography. with portal hypertension
✓ ALT level greater than 5,000 U/L—usually due to hepatic ischemia,
General Approach to Abnormal Liver acetaminophen drug-induced liver disease, or herpes hepatitis
✓ Acute biliary obstruction from a common duct stone may increase
Test Results
ALT up to 1,000 U/L
Disease in a patient with abnormal liver test results can usually be ✓ An AST:ALT ratio greater than 2 suggests liver disease associated
categorized into 1 of the clinical syndromes in Box 23.1, although with alcohol; an AST:ALT ratio greater than 1 in patients with
overlap among these categories is considerable. The approach to hepatitis C or NASH suggests advanced hepatic fibrosis
patients with acute hepatitis, chronic hepatitis, cholestasis, and ✓ Infiltrative disorders such as amyloidosis or sarcoidosis cause an
elevated ALP with a normal bilirubin level
jaundice is outlined above. Patients with a “first-time,” often inci-
✓ Patients with acute hepatitis without a common cause identified
dental, increase in liver enzyme levels are usually asymptomatic. often have an unrecognized drug-or toxin-induced liver injury,
Observation is reasonable, with the test repeated in a few months, infection, or cardiovascular disease
if 1) the patient is asymptomatic, 2) risk factors for liver disease ✓ Patients with a chronic liver injury without a readily identifiable
are not identified, 3) liver enzyme levels are less than 3 times cause often have nonalcoholic fatty liver disease
normal, and 4) liver function is preserved. About 30% of patients ✓ Acute severe drug-induced liver injury may lead to a long-term
with incidental elevations of liver test results have normal values increase in the ALP level
on subsequent testing. If the subsequent test results are still ab- ✓ Ultrasound-and MRI-based elastography have largely replaced
normal, the patient’s condition fits the category of chronic hepa- liver biopsy for assessment of hepatic fibrosis
titis or cholestasis, and appropriate evaluation should be initiated.
A similar approach can be taken with incidentally discovered ab-
normal results from patients who are taking medications that only Liver Biopsy
rarely cause liver disease.
Patients also may present with cirrhosis or portal hypertension. Technique and Safety
Most patients with portal hypertension have cirrhosis, although Most liver biopsies are performed percutaneously and guided
occasionally patients present with noncirrhotic portal hyperten- by imaging, usually ultrasonography. In patients with ascites or
sion that is idiopathic or due to portal vein thrombosis. The evalu- coagulopathy, specimens may also be obtained with transvenous
ation of a patient who has cirrhosis is like that of a patient who has access from the jugular vein. Transvenous approaches also allow
chronic hepatitis and cholestasis (as discussed above). In patients for measurement of the wedged hepatic vein pressure gradient
with α1-antitrypsin deficiency, genetic hemochromatosis, alco- to assess for sinusoidal portal hypertension. If open or laparo-
holic liver disease, or nonalcoholic fatty liver disease, cirrhosis is scopic abdominal surgery is necessary for another indication, bi-
frequently the first manifestation of liver disease. opsy specimens may also be obtained under direct visualization.
Finally, an increasing number of biopsies are done at the time of
✓ Upper limit of normal ALT value: for men, 33 U/L; for women, endoscopic ultrasonography. The most common complication of
25 U/L
liver biopsy is pain, which can usually be controlled with simple
✓ ALT has a longer half-life than AST; therefore, improvements in
ALT lag behind those of AST
analgesics. The most serious risk is bleeding, which occurs in
0.1% to 0.3% of all liver biopsies. Bleeding usually subsides
without the need for transfusion or other intervention. Persistent
bleeding may require transarterial embolization. Immediate se-
vere pain after liver biopsy is suggestive of a bile leak.
Box 23.1. Abnormal Liver Test Results: Clinical
Syndromes General Utility
“First-time” increase in liver enzymes
Liver histopathologic findings are often nonspecific. A common re-
Acute hepatitis port might include a lymphoplasmacytic portal infiltrate consistent
Chronic hepatitis with viral, drug, or autoimmune hepatitis. Clinical information is
Cholestasis without hepatitis or jaundice then required to help differentiate a cause. When the liver biopsy
Jaundice is done for diagnostic reasons, the pathologist and clinician should
Cirrhosis or portal hypertension
communicate, when possible, to allow an exchange of relevant in-
formation. This kind of dialogue is much more effective than if
the clinician merely relies on the biopsy report or the pathologist ✓ Acute liver failure—severe liver injury, including international
relies on printed clinical information, much of which may be in- normalized ratio greater than 1.5 and hepatic encephalopathy,
complete. In patients with acute liver disease, a diagnosis is usually developing within 26 weeks after onset of symptoms without
forthcoming with the help of the clinical history and blood tests for evidence of preexisting liver disease
infections and inherited and metabolic disorders; therefore, biopsy
is generally not performed. Occasionally, liver biopsy is needed Presentation
to help in the diagnosis of a sudden onset of autoimmune hepa-
titis, drug-induced liver injury, diffuse intrahepatic malignancy not The presenting symptoms of patients with acute liver failure are
identified on imaging, Wilson disease, alcoholic liver disease when usually those of acute hepatitis, including malaise, nausea, and
clinical history is uncertain, and unusual infections such as herpes jaundice. Hepatic encephalopathy is a required feature of the
or Q fever. Liver biopsy may detect clinically unsuspected chronic syndrome, and manifestations may range from subtle mental
liver disease in a patient presenting with acute hepatitis. status changes, such as difficulty with concentration, to coma
Patients with long-term liver enzyme elevations and negative or (Table 23.5). Because encephalopathy in a patient with acute
normal results on blood tests are frequently referred to hepatology liver disease is an ominous sign, the mental status of patients with
clinics for evaluation for causes of chronic liver disease. Studies acute hepatitis should be assessed frequently. Laboratory features
incorporating liver biopsy show that most of these patients have non- are consistent with severe liver dysfunction. Aminotransferase
alcoholic fatty liver disease with mild histologic changes. About 19% levels are variably increased, although they usually are more
of patients have normal liver histology or minimal abnormalities. than 1,000 U/L. Acetaminophen hepatotoxicity usually causes
Predictors of minimal changes are female sex and body mass index ALT to be more than 3,500 U/L. Fulminant Wilson disease is
(calculated as weight in kilograms divided by height in meters characterized by only modest increases in aminotransferase
squared) less than 25. Predictors of significant fibrosis are tobacco levels and a low or normal ALP level despite clinical evidence
use, body mass index less than 25, and presence of type 2 diabetes. of liver failure, such as a prolonged prothrombin time and high
The availability of noninvasive tests for fibrosis (eg, blood bilirubin concentration. An ALP to total bilirubin ratio less than
test panels and scoring systems, transient elastography, shear- 4 is suggestive of Wilson disease.
wave elastography, and magnetic resonance elastography) have The encephalopathy associated with acute liver failure, unlike
decreased the need for liver biopsy to assess degree of fibrosis. that of chronic liver disease, has a propensity to progress to ce-
rebral edema. The mechanisms for the development of cerebral
edema have not been clarified but may involve disruption of the
blood-brain barrier and interference with mechanisms of cellular
Acute Liver Failure osmolarity. Clinically, the encephalopathy often is associated
Definition and Etiology with a marked increase in the serum level of ammonia, although
alterations in unidentified neurotransmitters likely are involved
Acute liver failure is the development of severe acute liver injury,
in causing mental status changes. Ammonia levels of more than
including INR greater than 1.5 and encephalopathy, developing
150 µmol/L have been associated with intracranial hypertension
within 26 weeks after the onset of symptoms in a patient without
and a poor outcome.
a previous history of chronic liver disease. Patients with an acute
Cerebral edema and superimposed infection are the more
presentation of Wilson disease or a flare of hepatitis B may be
common causes of death when patients have acute liver failure.
still characterized as having acute liver failure even if they have
Cerebral edema leads to death by causing brain ischemia and ce-
histologic features of chronic liver injury. About 2,000 cases of
rebral herniation. Patients with acute liver failure are predisposed
acute liver failure occur annually in the US. Because many of the
to infections likely due to severe illness and the need for numerous
patients are young and previously healthy, a poor outcome of this
interventions and monitoring. The clinical features typical of in-
relatively unusual condition is particularly tragic.
fection, such as fever and leukocytosis, may not occur in patients
Determining the cause of acute liver failure is important for 2 with acute liver failure, so a high level of awareness for infection
reasons: 1) specific therapy may be available, as for acetamino- needs to be maintained. Any clinical deterioration should man-
phen hepatotoxicity or herpes hepatitis, and 2) the prognosis differs date a search for infection, and the threshold for antimicrobial
depending on the cause. For instance, the spontaneous recovery rate therapy should be low.
for patients with acute liver failure due to acetaminophen or hepa- Hypoglycemia occurs frequently and is a poor prognostic
titis A is more than 50%; consequently, a more cautious approach sign. It is likely due to both inadequate degradation of insulin and
would be advised before proceeding with liver transplant. In com- diminished production of glucose by the diseased liver.
parison, spontaneous recovery from acute liver failure due to Wilson A hyperdynamic circulation and a decrease in systemic vas-
disease is unusual and early liver transplant would be recommended. cular resistance are seen in patients with acute liver failure. These
In the US, the most common identifiable causes are acetaminophen features may be well tolerated by patients, but occasionally he-
hepatotoxicity, idiosyncratic drug reactions, Wilson disease, hepa- modynamic compromise can develop. Monitored parameters
titis B, and ischemia. Acetaminophen-protein adducts have also been
identified in about 20% of patients with idiopathic acute liver failure, Table 23.5. Stages of Hepatic Encephalopathy
suggesting that acetaminophen hepatotoxicity may have a role in this
patient subset. History should be obtained promptly, before mental Stage Features
status declines and a reliable history cannot be obtained. A history I Changes in behavior, with minimal change in level of consciousness
of prescription and nonprescription drugs, use of illicit substances, II Gross disorientation, gross slowness of mentation, drowsiness,
and alcohol use is important in making a decision about the patient’s asterixis, inappropriate behavior, maintenance of sphincter tone
candidacy for liver transplant. If the cause of acute liver failure III Sleeping most of the time, arousable to vocal stimuli, marked
cannot be determined from the history and blood tests, biopsy can be confusion, incoherent speech
IV Comatose, unresponsive to pain, decorticate or decerebrate posturing
considered to exclude malignancy and autoimmune hepatitis.
may mimic sepsis. Fluid resuscitation usually is necessary, al-

though caution is advised because the administration of excessive Box 23.2. King’s College Criteria for Liver Transplant
fluid may worsen intracranial pressure. in Fulminant Liver Failurea
Kidney and electrolyte abnormalities occur because of under-
1. Fulminant liver failure due to Wilson disease or
lying disease such as Wilson disease, functional kidney failure
Budd-Chari syndrome
due to sepsis or hepatorenal syndrome, or acute tubular necrosis.
Kidney dysfunction is particularly common in acetaminophen- 2. Acetaminophen-induced if either of the following
are met:
induced acute liver failure. Monitoring of electrolytes, including
sodium, potassium, bicarbonate, magnesium, and phosphorus, is a. pH <7.3 at 24 h after overdose
important, and the presence of acidosis is a risk factor for poor b. Creatinine >3.4 mg/ dL, prothrombin time >100 s,
outcome in acute liver failure and has been incorporated into and stage III or IV encephalopathy
some prognostic models. 3. Non– acetaminophen-
induced if either of the
following are met:
a. INR >6.5 or
Management
b. Any 3 of the following: INR >3.5, >7 d from jaundice
The appearance of encephalopathy precedes cerebral edema; to encephalopathy, indeterminate or drug-induced
therefore, patients with acute hepatitis and evidence of liver cause, age <10 y, age >40 y, bilirubin >17.5 mg/dL
failure need to be monitored carefully for mental status changes.
Lactulose is less effective in encephalopathy associated with Abbreviation: INR, international normalized ratio.
acute liver failure compared with encephalopathy associated with a
Any 1 of the 3 criteria.
chronic liver disease and may not prevent cerebral edema from
developing later; nevertheless, it is often given with monitoring
for gaseous distention of the intestines. Rifaximin may also be
In patients with acute liver failure, the prothrombin time is a
used, although its benefit has not been proved. Patients with stage
simple noninvasive measure to follow, and coagulopathy is not
II encephalopathy usually are admitted to an intensive care unit
corrected unless there is bleeding or an intervention is planned
for close monitoring of mental status and vital signs. Sedatives
(eg, placement of a monitoring device). If bleeding occurs or an
should be avoided initially to allow close monitoring of mental
invasive procedure is necessary, fresh frozen plasma usually is
status. Computed tomography or magnetic resonance imaging of
administered first, although platelets, fibrinogen, and even re-
the head is performed to exclude an alternative cause of mental
combinant activated factor VII may be necessary. Continuous
status changes.
infusion of 5% or 10% dextrose is used to keep the plasma glu-
Patients who reach stage III encephalopathy are at consid-
cose level between 100 and 200 mg/dL. The plasma glucose level
erable risk for progression to cerebral edema. Because clinical
should be monitored at least twice daily. Both bacteremia and
signs and computed tomography are insensitive for detecting
fungemia are sufficiently frequent that periodic blood cultures are
increased intracranial pressure, many centers institute intracranial
advised and prophylaxis with antimicrobials may be initiated, al-
pressure monitoring when patients reach stage III encephalop-
though this practice has not been shown to affect survival.
athy. Endotracheal intubation and mechanical ventilation usually
One randomized trial suggested that administration of N-
precede placement of the intracranial pressure monitor. Various
acetylcysteine may be beneficial in some patients who have acute
monitors are used, but infection and bleeding can complicate any
liver failure even when acetaminophen hepatotoxicity has been
monitoring. The goal of intracranial pressure monitoring is to
excluded. Patients with early-stage encephalopathy treated with
allow treatment of high pressure and to identify which patients
N-acetylcysteine had better transplant- free survival than un-
are too ill for liver transplant because of a prolonged period of
treated patients.
excessively high intracranial pressure. Generally, the goal is to
Models to predict the outcome of acute liver failure have been
maintain intracranial pressure less than 40 mm Hg and cere-
developed to facilitate the optimal timing of liver transplant be-
bral perfusion pressure (the difference between mean arterial
fore the patient becomes so ill that transplant is contraindicated
pressure and intracranial pressure) between 60 and 100 mm Hg.
yet still allow time for spontaneous recovery. The most well-
Excessively high cerebral perfusion pressures (>120 mm Hg) can
known and widely used model is the King’s College criteria (Box
increase cerebral edema.
23.2). A MELD score higher than 32 is also associated with a
Maneuvers that cause straining, including endotracheal
poor liver transplant-free survival. Acute liver failure is the indi-
suctioning, should be avoided or limited. Paralyzing agents and
cation for 6% of liver transplants in the US. Even though 1-year
sedatives may be necessary, although they may limit further
survival with transplant for acute liver failure is lower than that
assessment of neurologic status. Administration of hypertonic sa-
for transplant for other indications, outcomes are an improvement
line until the serum sodium level is 145 to 155 mmol/L decreases
over the dismal survival rates for patients with acute liver failure
the risk of intracranial hypertension. If intracranial pressure is
who meet poor prognostic markers such as the King’s College
more than 20 mm Hg or cerebral perfusion pressure less than
criteria, and long-term survival after transplant is excellent.
60 mm Hg, the following steps are advised: elevation of the head
to 20°, hyperventilation to a Paco2 of 25 mm Hg, and admin- ✓ Patients with acute hepatic failure who are potential transplant
istration of mannitol (if kidney function is intact). Barbiturate- candidates should be promptly referred to a liver transplant center
induced coma can be used for refractory cases. Glucocorticoids ✓ Clues to the diagnosis of acute liver failure due to Wilson disease
are ineffective. A prolonged increase in intracranial pressure include a low ALP and evidence of hemolysis
above mean arterial pressure may signify brain death and gener- ✓ Encephalopathy associated with acute liver failure predisposes to
ally is a contraindication to liver transplant. A sudden decrease in cerebral edema and responds less well to lactulose than that asso-
intracranial pressure may indicate brain herniation. ciated with chronic liver disease
and minimal lesions in patients with persistent unexplained elevated

✓ Cerebral edema and infections are common causes of death in
transaminases: a prospective multicenter study. J Hepatol. 2006
patients with acute liver failure
Oct;45(4):592–9.
✓ The prognosis with acute liver failure due to acetaminophen hepa-
Flamm SL, Yang YX, Singh S, Falck-Ytter YT, AGA Institute Clinical
totoxicity and hepatitis A is better than that from other causes; the
Guidelines Committee. American Gastroenterological Association
prognosis with acute liver failure associated with Wilson disease
Institute guidelines for the diagnosis and management of acute liver
and drugs other than acetaminophen is particularly poor
failure. Gastroenterology. 2017 Feb;152(3):644–7.
Kwo PY, Cohen SM, Lim JK. ACG clinical guideline: evaluation of ab-
normal liver chemistries. Am J Gastroenterol. 2017 Jan;112(1):18–35.
Suggested Reading Lee WM, Hynan LS, Rossaro L, Fontana RJ, Stravitz RT, Larson AM,
et al. Intravenous n-acetylcysteine improves transplant-free survival in
Biggins SW, Kim WR, Terrault NA, Saab S, Balan V, Schiano T, et al. early stage non-acetaminophen acute liver failure. Gastroenterology.
Evidence-based incorporation of serum sodium concentration into 2009 Sep;137(3):856–64.
meld. Gastroenterology. 2006 May;130(6):1652–60. O’Grady JG, Alexander GJ, Hayllar KM, Williams R. Early indicators
Chalasani N, Bonkovsky HL, Fontana R, Lee W, Stolz A, Talwalkar of prognosis in fulminant hepatic failure. Gastroenterology. 1989
J, et al. Features and outcomes of 899 patients with drug-induced Aug;97(2):439–45.
liver injury: the DILIN prospective study. Gastroenterology. 2015 Stravitz RT, Lee WM. Acute liver failure. Lancet. 2019 Sep 7;394(10201):
Jun;148(7):1340–52. 869–81.
de Ledinghen V, Ratziu V, Causse X, Le Bail B, Capron D, Renou C, Tapper EB, Lok AS. Use of liver imaging and biopsy in clinical practice.
et al. Diagnostic and predictive factors of significant liver fibrosis N Engl J Med. 2017 Aug 24;377(8):756–68.
24
Viral Hepatitisa,b
MICHAEL D. LEISE, MD
Viral infections are important causes of liver disease worldwide. causes acute hepatitis, but only hepatitis B, C, and D viruses
The 5 primary hepatitis viruses that have been identified are A, cause chronic hepatitis, although chronic hepatitis E can develop
B, C, D (or delta), and E. Other viruses, such as cytomegalovirus in the context of immunosuppression.
and Epstein-Barr virus, also can result in hepatitis as part of a The purpose of this chapter is to review the primary hepa-
systemic infection. In addition, medications, toxins, autoimmune titis viruses. More comprehensive discussions of acute hepatitis
hepatitis, or Wilson disease may cause acute or chronic hepatitis. are found in other chapters. The 4 common hepatitis viruses are
It is useful to divide hepatitis syndromes into acute and chronic compared in Table 24.1, and the disease burden of the 3 most im-
forms. Acute hepatitis can last from a few weeks to 6 months portant viruses in the US is summarized in Table 24.2.
and is often accompanied by jaundice. Symptoms of acute hepa-
titis tend to be similar regardless of cause and include anorexia, Hepatitis A
malaise, dark urine, fever, and mild abdominal pain. In chronic
hepatitis, patients are often asymptomatic but may complain of Epidemiology
fatigue. Occasionally, they have manifestations of advanced liver The incidence of acute hepatitis A virus (HAV) infection is
disease (ascites, variceal bleeding, or encephalopathy) at the in- decreasing in the US owing to the recommendation for uni-
itial presentation with chronic hepatitis. Each hepatitis virus versal childhood vaccination. However, outbreaks resulting in
37,000 new cases from 2016 through 2021 were identified pri-
a
Portions previously published in Poterucha JJ. Hepatitis. In: Bland marily among persons experiencing homelessness and those with
KI, Sarr MG, Buchler MW, Csendes A, Garden OJ, Wong J, eds. a history of injection or noninjection drug use. Common routes
General surgery: principles and international practice. 2nd Ed. London of transmission of HAV are ingestion of contaminated food or
(England): Springer-Verlag; 2009: 921-32; used with permission. water and contact with an infected person. Groups at particularly
b
I acknowledge John J. Poterucha, MD, for his contributions to this high risk include people living in or traveling to resource-limited
chapter in previous editions of this text. countries, children in day care centers, men who have sex with
Abbreviations: AASLD, American Association for the Study of Liver men, and perhaps persons who ingest raw shellfish. The incuba-
Diseases; ALT, alanine aminotransferase; anti-HAV, antibody to hepa- tion period for HAV is 2 to 6 weeks.
titis A virus; anti-HBc, antibody to hepatitis B core antigen; anti-HBs,
antibody to hepatitis B surface antigen; anti-HCV, antibody to hepatitis
C virus; APRI, aspartate aminotransferase to platelet ratio index; DAA, Clinical Presentation and Natural History
direct-acting antiviral; HAV, hepatitis A virus; HBeAg, hepatitis B e an-
The most important determinant of the severity of acute hepatitis
tigen; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; HCC,
hepatocellular carcinoma; HCV, hepatitis C virus; HDV, hepatitis D A is the age at which infection occurs. Persons infected when
virus; IDSA, Infectious Diseases Society of America; Ig, immunoglob- younger than 6 years have nonspecific symptoms that rarely
ulin; MELD, Model for End-stage Liver Disease; MR, magnetic reso- include jaundice. Adolescents or adults who acquire HAV in-
nance; RAS, resistance-associated substitution; SVR, sustained virologic fection usually have jaundice. Hepatitis A is almost always a self-
response; ULRR, upper limit of the reference range limited infection. There may be a prolonged cholestatic phase
287
Table 24.1. Comparison of the 4 Primary Hepatitis Viruses

Feature HAV HBV HDV HCV
Incubation, d 15-50 30-160 Unknown 14-160
Jaundice Common 30% of patients Common Uncommon
Course Acute Acute or chronic Acute or chronic Acute or chronic
Transmission Fecal-oral Parenteral Parenteral Parenteral
Test for diagnosis IgM anti-HAV HBsAg Anti-HDV HCV RNA
Abbreviations: anti-HAV, antibody to hepatitis A virus; anti-HDV, antibody to hepatitis D virus; HAV, hepatitis
A virus; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; HCV, hepatitis C virus; HDV, hepatitis D
virus; Ig, immunoglobulin.
characterized by persistence of jaundice for up to 6 months. Hepatitis B

Rarely, acute hepatitis A manifests as acute liver failure that may
Epidemiology
require liver transplant. HAV does not cause chronic infection and
should not be in the differential diagnosis of chronic hepatitis. Hepatitis B virus (HBV) is a DNA virus that causes about 30% of
the cases of acute viral hepatitis and 15% of the cases of chronic
viral hepatitis in the US. Most persons with chronic infection in
Diagnostic Tests
the US are immigrants from Asia and Africa, where infection
The diagnosis of acute hepatitis A is established by the presence is acquired at birth or in early childhood. Major risk factors for
of immunoglobulin (Ig)M antibody to hepatitis A virus (anti- adult disease acquisition in the US are sexual contact with an
HAV), which appears at the onset of the acute phase of the illness infected person and intravenous drug use.
and becomes undetectable in 3 to 6 months. During the acute
phase, IgG anti-HAV is also present, but it persists for decades Clinical Presentation and Natural History
and is a marker of immunity from further infection. A patient
with IgG anti-HAV, but not IgM anti-HAV, has had an infection The incubation period after HBV infection ranges from 60 to
in the remote past or has been vaccinated. 150 days. About 30% of adolescents or adults with acute hepa-
titis B have icterus. Complete recovery with subsequent lifelong
immunity occurs in 95% of infected adults. Chronic infection,
Treatment defined as persistence of hepatitis B surface antigen (HBsAg) for
The treatment of acute hepatitis A is supportive. For those exposed more than 6 months, develops in about 5% of infected adults.
to an infected person or contaminated food, postexposure pro- Immunosuppressed persons with acute HBV infection are more
phylaxis with hepatitis A vaccine or immune serum globulin (or likely to become chronically infected, presumably because of an
both) is advised, depending on the patient’s age and overall health insufficient immune response against the virus.
status. Patients with chronic hepatitis B infection present in 1 of 4
phases (Figure 24.1). An immune tolerant phase is recognized in
many Asian patients who are infected perinatally. This phase, usu-
Prevention
ally encountered in patients younger than 35 years, is characterized
Immunization with hepatitis A vaccine is recommended for all by the presence of hepatitis B e antigen (HBeAg) and very high
children at 12 months of age. Hepatitis A vaccine should be HBV DNA levels yet normal levels of alanine aminotransferase
offered also to travelers to areas with an intermediate or high (ALT). Generally, liver biopsy specimens from these patients
prevalence of hepatitis A, to men who have sex with men, to in- show minimal changes except for ground- glass hepatocytes.
travenous drug users, to recipients of clotting factor concentrates, The immune tolerant phase evolves under immune pressure into
and to patients with chronic liver disease. the HBeAg-positive chronic hepatitis B phase, characterized by
increased ALT levels, persistence of HBeAg, and more than 104
✓ Atypical presentation of hepatitis A— a relapsing -remitting IU/mL of HBV DNA. Active inflammation and often fibrosis,
cholestatic course lasting up to 6 months seen in liver biopsy specimens, lead to progressive liver injury. At
a rate of about 10% per year, patients mount enough of an immune
response to achieve a decrease in ALT levels, clearance of HBeAg
Table 24.2. Clinical Effects of Hepatitis Viruses in the USa and development of antibody to HBeAg (seroconversion), and a
decrease in HBV DNA to less than 104 IU/mL. The resulting inac-
Feature HAV HBV HCV tive carrier phase usually is not accompanied by progressive liver
Acute hepatitis, No. of 11,000 12,000 2,900 damage. In cross-sectional studies, about 60% of patients with
clinical cases annually chronic hepatitis B are in the inactive carrier phase. Many patients
Fulminant hepatitis, No. of 50 100 Rare remain in this phase for many years and have a better prognosis
deaths annually than those with active liver inflammation and HBV DNA levels of
Chronic hepatitis, No. of 0 800,000-1.4 million 2.7-3.9 million
more than 104 IU/mL.
clinical cases annually
Chronic liver disease, No. 0 3,000 12,000
About one-third of inactive carriers have a reactivation of
of deaths annually active hepatitis characterized by abnormal ALT levels and HBV
DNA levels of more than 104 IU/mL. This may be associated with
Abbreviations: HAV, hepatitis A virus; HBV, hepatitis B virus; HCV, hepatitis a reversion to the HBeAg-positive state, but more commonly it is
C virus. due to a precore or core promoter variant. This HBeAg-negative
a
Data from the Centers for Disease Control and Prevention (2008 data). chronic hepatitis B phase is associated with progression of liver
24. Viral Hepatitis 289
Figure 24.1. Phases of Chronic Hepatitis B Virus Infection. Black arrows indicate histopathologic changes; gray arrows, changes in serologic
markers between phases. White arrows indicate increase or decrease of DNA level (↑, low increase;↑↑, moderate increase;↓↓, moderate decrease;↑↑↑,
high increase). ALT indicates alanine aminotransferase; HBeAg, hepatitis B e antigen. (Adapted from Pungpapong S, Kim WR, Poterucha JJ. Natural
history of hepatitis B virus infection: an update for clinicians. Mayo Clin Proc. 2007 Aug;82[8]‌:967-75; used with permission of Mayo Foundation for
Medical Education and Research.)
damage. Patients with HBeAg-negative chronic hepatitis B are virus (HCV), HIV, or hepatitis D virus (HDV); hepatitis B geno-
more likely to have a fluctuating course than patients with HBeAg- type C; longer duration of infection; high HBV DNA levels; and
positive chronic hepatitis B. Also, the patients generally are alcohol use. Many of these factors, including HBV DNA level,
older and have more advanced fibrosis because HBeAg-negative are associated also with an increased risk of HCC.
chronic hepatitis B tends to occur later in the course of infection. Patients with chronic hepatitis B and cirrhosis are at high
Patients with chronic hepatitis B may experience sponta- risk for the development of HCC, and surveillance every 6 to
neous flares of disease characterized by markedly abnormal ALT 12 months is advised. Surveillance also is advised for patients
levels, deterioration in liver function, and often seroconversion of without cirrhosis who meet 1 of the following criteria: family
HBeAg. The differential diagnosis for acute hepatitis in patients history of HCC, Asian man older than 40 years, Asian woman
with chronic hepatitis B is listed in Table 24.3. Because disease older than 50 years, Black African older than 20 years, and per-
activity changes in patients with chronic hepatitis B, even after sistent increase in ALT level together with an HBV DNA value of
years in the inactive carrier state, periodic monitoring with liver more than 104 IU/mL. The method of surveillance varies among
tests and hepatitis B markers is necessary. Each year HBsAg centers, but many use ultrasonography at 6-month intervals with
clears spontaneously in about 1% of patients who have chronic or without monitoring serum alpha fetoprotein levels.
infection. Eight hepatitis B genotypes, labeled A through H, have been
In about 15% to 40% of patients with chronic HBV infection, identified, and the genotype for a patient is determined largely
serious sequelae develop—either decompensated liver disease or by the country in which infection is acquired. All genotypes have
hepatocellular carcinoma (HCC). Factors associated with the de- been identified in the US. Asian patients who have genotype B
velopment of cirrhosis are older age; coinfection with hepatitis C have a better prognosis than those with genotype C, including
a higher rate of clearance of HBeAg, a slower rate of progres-
sion to cirrhosis, and a lower likelihood of the development of
Table 24.3. Causes of Acute Hepatitis in Patients With hepatocellular cancer.
Chronic Hepatitis B
Cause Clinical clues Diagnostic Tests
Spontaneous “reactivation” of Seroconversion of HBeAg, reappearance A brief guide to serologic markers for hepatitis B is provided in
hepatitis B of IgM anti-HBc Table 24.4. The interpretation of serologic patterns is shown in
Flare due to immunosuppression Chemotherapy, antirejection therapy,
Table 24.5. Rarely, a patient with acute hepatitis B (usually with
corticosteroids, anti–tumor necrosis
a severe presentation such as acute liver failure) lacks HBsAg
factor agents
Induced by antiviral therapy Interferon (common), oral agents (rare) and has only IgM antibody to hepatitis B core antigen (anti-
Superimposed infection with Exposure to HDV (usually due to illicit HBc) as the marker for recent infection. Patients with an acute
other viruses, especially HDV drug use), HAV, or HCV flare of chronic hepatitis B may redevelop IgM anti-HBc. Most
Other causes of acute hepatitis History of excessive use of alcohol, patients with HBsAg have detectable serum levels of HBV DNA.
medications, or illegal drugs HBV DNA levels greater than 104 IU/mL are associated with an
Abbreviations: anti-HBc, antibody to hepatitis B core antigen; HAV, hepatitis A
increased risk of cirrhosis and HCC.
virus; HBeAg, hepatitis B e antigen; HCV, hepatitis C virus; HDV, hepatitis D Occasionally, patients have IgG anti-HBc as the only posi-
virus; Ig, immunoglobulin. tive hepatitis B serologic marker. A common explanation for a
Table 24.4. Hepatitis B Serologic Markers 2,000 IU/mL. All patients with cirrhosis should be treated with
an oral antiviral regardless of the phase of the disease or the HBV
Test Interpretation of positive result
DNA level. Acute liver failure due to acute hepatitis B should be
Hepatitis B surface antigen (HBsAg) Current infection treated with an oral agent. In some patients, oral antiviral therapy
Antibody to hepatitis B surface Immunity (immunization or can reverse liver failure.
antigen (anti-HBs) resolved infection) Patients with hepatitis B generally do not require liver biopsy
IgM antibody to hepatitis B core Recent infection or “reactivation”
before a decision about the need for treatment. Liver biopsy is
antigen (IgM anti-HBc) of chronic infection
IgG antibody to hepatitis B core Remote infection helpful for patients who otherwise do not meet clear criteria for
antigen (IgG anti-HBc) treatment. In those who do not meet treatment criteria, treatment
Hepatitis B e antigen (HBeAg) or Active viral replication (high should still be initiated if they have a fibrosis stage of F2 or higher
hepatitis B virus DNA >104 IU/mL infectivity) on liver biopsy or considerable inflammation. Liver biopsy also
(or both) can be used to diagnose advanced fibrosis, which could mandate
a change in management, such as evaluation for esophageal var-
Abbreviation: Ig, immunoglobulin.
ices or surveillance for HCC. Noninvasive testing such as tran-
sient or magnetic resonance (MR) elastography can also be used
population without risk factors for disease acquisition is a false- instead of liver biopsy.
positive test result (the results are often repeatedly positive). Hepatitis B can be treated with peginterferon or an oral
Another explanation is a previous, resolved HBV infection in agent (preferably entecavir or tenofovir). Peginterferon has
which the level of antibody to hepatitis B surface antigen (anti- replaced standard interferon because of its once-weekly dosing
HBs) has decreased below the limit of detection. This can be and perhaps better efficacy, and 1 year of treatment is advised.
supported by demonstrating an anamnestic type of response to Seroconversion may occur months or even years after comple-
hepatitis B vaccine. Rarely, patients with hepatitis B may have tion of treatment. Predictors of a greater likelihood of response
HBsAg levels that are below the level of detection, so that IgG to peginterferon include higher ALT level, lower HBV DNA
anti-HBc is the only marker of infection. Although the impor- level, shorter duration of disease, genotype A or B, and female
tance of this low-level infection is unclear, these patients can be sex. Patients treated with peginterferon may experience a flare
identified by the presence of HBV DNA in serum or liver. of hepatitis (likely due to immune system activation) about 4 to
The accuracy of serologic and nucleic acid tests obviates 8 weeks after beginning treatment. Treatment should be con-
the need for liver biopsy in the diagnosis of hepatitis B; how- tinued despite this flare unless there is clinical or biochemical
ever, liver biopsy is useful for grading inflammatory activity evidence of decompensation. Patients with Child-Turcotte-Pugh
and determining the stage of fibrosis. Histologic features of class B or C cirrhosis should not be treated with interferons
hepatitis B are inflammation that is usually around the portal because of the risk of precipitating decompensation with this
tract, variable fibrosis that initially is also portocentric, and the flare. Adverse effects of peginterferon are common and are
presence of ground-glass hepatocytes. Ground-glass hepatocytes considered below (in the Hepatitis C section). Peginterferon is
are hepatocytes with cytoplasm that has a hazy, eosinophilic not used often.
appearance. With immunostaining, these cells are positive for The oral agents are prescribed more frequently than peginter
HBsAg (Figure 24.2). Even though liver biopsy is the gold feron for chronic hepatitis B. They are compared in Table 24.6.
standard for diagnosing cirrhosis, it usually is not necessary These oral agents are well tolerated, and they are useful partic-
for patients who have other features of cirrhosis, such as portal ularly in patients with decompensated cirrhosis because these
hypertension. drugs may improve liver function. The flare of hepatitis that may
occur during interferon therapy is unusual with the oral agents.
Because of their high barrier to resistance, tenofovir and entecavir
Treatment
are the agents most commonly prescribed for hepatitis B. About
Generally, hepatitis B is treated if the patient is at risk for disease 15% to 20% of patients with HBeAg-positive disease who are
progression. This includes patients who have HBeAg-positive treated with oral agents have seroconversion and are positive for
chronic hepatitis B with ALT at least twice the upper limit of the antibody to HBeAg after 1 to 2 years of therapy; treatment should
reference range (ULRR) and HBV DNA greater than 20,000 IU/ be continued for 12 months after seroconversion. Patients without
mL and patients who have HBeAg-negative chronic hepatitis B seroconversion of HBeAg need to continue treatment indefi-
with ALT at least twice the ULRR and HBV DNA greater than nitely. Seroconversion of HBsAg with the oral agents is unusual;
Table 24.5. Interpretation of Hepatitis B Serologic Patterns

HBsAg Anti-HBs IgM anti-HBc IgG anti-HBc HBeAg Anti-HBe HBV DNA, IU/mL Interpretation
+ − + − + − + Acute infection or, less commonly, acute
flare of chronic hepatitis B
− + − + − ± − Previous infection with immunity
− + − + − − − Vaccination with immunity
+ − − + − + <104 Hepatitis B inactive carrier state
+ − − + + − >104 Chronic hepatitis B
+ − − + − + >104 HBeAg-negative chronic hepatitis B (often
“precore” or “core promoter” variants)
Abbreviations: anti-HBc, antibody to hepatitis B core antigen; anti-HBe, antibody to hepatitis B e antigen; anti-HBs, antibody to hepatitis B surface antigen; HBeAg,
hepatitis B e antigen; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; Ig, immunoglobulin.
for patients who have cirrhosis. Tenofovir alafenamide is as-

sociated with lower risk of bone and kidney complications as
compared to tenofovir disoproxil fumarate. Oral agents are pre-
ferred also for patients who are undergoing immunosuppression,
for example, after organ transplant or infection with HIV.
Patients who test positive for HBsAg and need chemo-
therapy or immunosuppression are at risk for disease flare, and
treatment with an oral agent is advised during therapy and for at
least 6 months after therapy has been completed. Patients with
isolated anti-HBc positivity are also at risk, although the risk
is much smaller than for those with HBsAg positivity. Patients
with isolated anti-HBc positivity who are treated with rituximab
or hematologic stem cell transplant are at high enough risk for
disease activation to warrant prophylactic HBV treatment, which
should be continued for 12 months after the last dose of rituximab
or other B-cell–depleting agents. For others with isolated anti-
HBc positivity, monitoring of ALT and HBV DNA levels during
immunosuppression therapy is advised, and treatment with oral
agents should be given if HBV DNA becomes detectable.
For patients with end-stage liver disease or HCC due to hep-
atitis B, liver transplant results in excellent outcomes. Patients
with hepatitis B who have HBeAg or high HBV DNA levels
(or both) before liver transplant are at particularly high risk for
recurrence after transplant. For these patients, oral agents are
recommended before transplant, and a combination of hepatitis B
immune globulin and an oral agent after transplant. Even among
patients without detectable HBV DNA, recurrence rates are suffi-
ciently high that most transplant groups still give an oral agent for
both preoperative therapy and postoperative therapy.
Prevention
Hepatitis B immune globulin should be given to nonimmune
household and sexual contacts of patients who have acute hep-
atitis B. All infants should receive hepatitis B vaccine. Neonates
Figure 24.2. Liver Biopsy Specimen From Patient With Hepatitis often acquire hepatitis B perinatally if the mother is infected;
B. A, Ground- glass hepatocyte (arrow) (hematoxylin- eosin). B, therefore, all pregnant women should undergo HBsAg testing.
Immunostain for hepatitis B surface antigen shows positive staining of Infants born to women who have HBsAgpositivity should re-
hepatocyte cytoplasm. ceive both hepatitis B immune globulin and hepatitis B vaccine.
In addition, oral agents can be administered during the third tri-
mester to pregnant women who have HBV DNA levels higher
therefore, most patients with HBeAg-negative chronic hepatitis than 200,000 IU/mL. Tenofovir is a category B drug for pregnant
will require prolonged or even indefinite therapy. women and is a safe choice for treatment during pregnancy.
The choice of therapeutic agent for hepatitis B depends on sev-
eral factors. Peginterferon is reasonable for patients without cir- ✓ HCC can develop without cirrhosis in patients with hepatitis B
✓ Surveillance is advised for patients without cirrhosis who meet 1
rhosis who have an ALT level greater than 200 U/L and who can
of the following criteria:
tolerate the numerous adverse effects of the drug. Peginterferon • Family history of HCC
is most effective against hepatitis B genotypes A and B; thus, • Asian man older than 40 years
genotyping is advised for patients for whom peginterferon • Asian woman older than 50 years
therapy is being considered. Entecavir or tenofovir is preferred
Table 24.6. Oral Agents for Treatment of Hepatitis B

Feature Lamivudine Adefovir Entecavir Telbivudine Tenofovir
Monthly charge, $ a
150 1,086 970 890 860
HBeAg seroconversion, % of patients 20 12 21 22 20
Loss of HBV DNA, % of patients 40 21 67 60 90
Resistance, % of patients 20 at 1 y 0 at 1 y Naive: <1 at 2 y 4 at 1 y None
70 at 5 y 29 at 5 y Lamivudine resistance: 7 at 1 y 21 at 2 y
Durability of response, % of responding patients 50-80 90 69 80 Unknown
Abbreviations: HBeAg, hepatitis B e antigen; HBV, hepatitis B virus.

a
Data from http://cashcard.lc.healthtrans.com (2012).
• Black African older than 20 years

infection. Historically, HCV: infection was the most common
• Persistent increase in ALT level and HBV DNA value greater chronic bloodborne infection in the US, with about 70% of infected
than 104 IU/mL patients having abnormal ALT levels. With the advent of direct-
✓ A simplified approach to determine who requires hepatitis B acting antiviral (DAA) therapy, the prevalence of chronic hepa-
treatment titis C is decreasing owing to the effectiveness of these therapies.
• ALT values at least twice the ULRR While hepatitis C was once the most common indication for liver
• Presence of cirrhosis, acute liver failure, fibrosis stage of F2 or transplant, it is now the third leading indication behind alcohol-
higher, or significant inflammation on liver biopsy associated liver disease and nonalcoholic fatty liver disease.
✓ Treatment of hepatitis B in most patients—entecavir or tenofovir
✓ Tenofovir alafenamide— associated with fewer adverse events
affecting kidneys or bones compared to other tenofovir formulations Clinical Presentation and Natural History
✓ Use tenofovir to treat pregnant women at gestational weeks 26
through 28 who have HBV DNA levels greater than 200,000 IU/mL
The incubation period of HCV ranges from 2 to 23 weeks (mean,
7.5 weeks). Patients infected with HCV rarely present clinically
with acute hepatitis, although retrospective studies have suggested
that 10% to 20% of patients have an icteric illness with acute infec-
Hepatitis D tion. Of those who acquire hepatitis C, chronic infection develops
HDV requires the presence of HBsAg to replicate. HDV infection in 60% to 85% (Figure 24.3). Once chronic infection has been
can occur simultaneously with HBV (coinfection) or as a super- established, subsequent spontaneous loss of the virus is rare.
infection in persons with established hepatitis B. Hepatitis D is Consequently, most patients with hepatitis C present with chronic
diagnosed with antibodies to HDV and should be suspected if a hepatitis, with a mild to moderate increase in ALT levels. For
patient has acute hepatitis B or an acute exacerbation of chronic patients with abnormal ALT levels, the degree of increase does not
hepatitis B. In the US, intravenous drug users are the group of correlate with the histologic severity of disease.
HBV patients at highest risk for acquiring HDV. Although HDV Up to 30% of patients with chronic HCV infection have a per-
does not commonly require treatment (indication for treatment is sistently normal level of ALT. As a group, these patients generally
elevated ALT and HDV RNA levels), peginterferon for 12 months have less aggressive histologic features and a lower risk for disease
can be used with sustained virologic clearance in about 30% of progression than patients with hepatitis C and abnormal ALT levels,
treated patients. but it is recommended that patients with normal ALT levels and
patients with abnormal ALT levels be managed similarly and un-
dergo biopsy when necessary to help make management decisions.
Hepatitis C Cirrhosis accounts for nearly all mortality and most morbidity
associated with hepatitis C. In about 20% to 30% of patients
Epidemiology
with chronic hepatitis C, cirrhosis develops over a 20-year pe-
As of 2016, HCV infection was estimated to affect 3.5 million riod (Figure 24.3). Factors that lead to a higher risk for advanced
Americans; estimates included 41,200 acute cases per year and fibrosis are duration of infection, alcohol intake of more than 50
20,000 deaths per year. In 2013, the annual age-adjusted mortality g daily, steatosis, coinfection with HIV or HBV, and male sex.
from hepatitis C surpassed that of a combination of 60 other re- Patients with cirrhosis due to HCV generally have had the disease
portable infectious diseases, which included hepatitis B and HIV longer than 20 years.
Figure 24.3. Natural History of Hepatitis C. Percentage values refer to patients. ALT indicates alanine aminotransferase; HCC, hepatocellular
carcinoma.
An important predictive factor for the development of cirrhosis Diagnostic Tests

is the severity of the histologic features of the liver at presenta-
Antibody to HCV (anti-HCV) indicates either current infection
tion. Liver biopsy specimens need to be interpreted with knowl
or a previous infection with subsequent clearance. Even after
edge of the duration of infection (if known). Patients who have
clearance of the infection, anti-HCV is no longer detectable in
only mild portal hepatitis without fibrosis, despite many years of
only about 10% of patients. The diagnosis of hepatitis C infection
infection, have a significantly lower risk of progression to cir-
is confirmed by the presence of HCV RNA in serum. Levels of
rhosis than those who have more advanced disease with a sim-
HCV RNA do not correlate with either disease severity or prog-
ilar duration of infection. Histologic markers of more advanced
nosis; the main use of HCV RNA quantitation is to help stratify
disease include moderate degrees of inflammation and necrosis
response to therapy. Patients with viral levels higher than 800,000
and septal fibrosis. Biopsy is not necessary before hepatitis C
IU/mL are less likely to have a response to treatment than those
treatment but may be helpful for decisions about the timing of
with lower HCV RNA levels.
treatment and surveillance for varices and HCC.
Identification of the HCV genotype is necessary to help deter-
mine the optimal treatment regimen. Liver biopsy is not necessary
Screening for the diagnosis of hepatitis C but may be helpful in assessing
Risk factors that require testing for hepatitis C are shown in Box the severity of disease for making decisions about treatment and
24.1. Initial screening recommendations were applied to patients screening. Typical biopsy findings include a mononuclear (pre-
born between 1945 and 1965, as this population was projected to dominantly lymphocytic) portal hepatitis with lymphoid follicles
have a 5-fold increase in risk for hepatitis C as compared to other and mild steatosis (Figure 24.4). Patients with risk factors for
populations. However, the most recent screening recommendation nonalcoholic fatty liver disease and those with HCV genotype
from the American Association for the Study of Liver Diseases 3 have more prominent steatosis than other patients with HCV.
(AASLD) and the Infectious Diseases Society of America (IDSA) Staging of fibrosis is often done with a 5-point scale, from 0 (no
is for universal screening for all persons 18 to 79 years old. This is fibrosis) to 4 (cirrhosis).
particularly important for persons 20 to 39 years old because of the
increase in acute hepatitis C infections due to the opioid epidemic Treatment
in this age group. Furthermore, a 1-time screening is recommended
The treatment of hepatitis C has improved dramatically since
for persons younger than 18 years who have behaviors, exposures,
2013 but continues to evolve. Nomenclature used to define
or circumstances that increase their risk for hepatitis C infection.
outcomes of hepatitis C treatment is shown in Table 24.7. Patients
Periodic follow-up hepatitis C testing should be offered to all per-
who respond to treatment and remain HCV RNA negative 24
sons who have ongoing behaviors, exposures, or circumstances
weeks after completion of therapy (ie, they have a sustained
that increase their risk for hepatitis C infection. Annual hepatitis
virologic response [SVR]) are cured of hepatitis C infection and
C testing is recommended for all persons who inject drugs and for
have improved outcomes compared with those who do not clear
men with HIV infection who have unprotected sex with men.
the virus. However, patients with cirrhosis remain at risk for HCC
despite having an SVR, and continued monitoring is advised.
The treatment of hepatitis C has become more straightforward
with the advent of DAA therapies. According to the AASLD-
Box 24.1. Risk Factors That Require Testing for IDSA guidelines, treatment is recommended for all patients
Hepatitis C who have chronic hepatitis C infection except those who have
Use of injection drugs or illicit intranasal drugs (at a short life expectancy that cannot be improved by treatment of
any time in life) hepatitis C with transplant or other directed therapy. The care of
Long-term treatment with hemodialysis (at any time
in life)
Percutaneous or parenteral exposure to HCV in an
unregulated setting
Needlesticks, sharps, or mucosal exposures to HCV-
infected blood
Child of an HCV-infected mother
Receipt of blood or blood components, transfusion,
or organ transplant before July 1992
Receipt of clotting factor concentrates produced
before 1987
History of incarceration
HIV infection
Sexually active person who will begin preexposure
prophylaxis for HIV
Person with undiagnosed chronic liver disease
Abnormally high level of ALT
Living organ donor or deceased liver donor Figure 24.4. Biopsy Specimen From Patient With Hepatitis C.
Specimen shows portal infiltrate, lymphoid follicle (arrow), and mild
Abbreviation: ALT, alanine aminotransferase; HCV, hepatitis C virus. steatosis.
Table 24.7. Hepatitis C Treatment Response Definitions important because hepatitis B reactivation can occur during DAA
therapy, particularly in patients with HBsAg positivity and de-
Virologic response Definition
tectable but not quantifiable hepatitis B DNA levels or low levels
End-of-treatment response HCV RNA negative at end of treatment of hepatitis B DNA. The HCV RNA level and genotype should
Sustained virologic response HCV RNA negative 24 wk after end of be checked. Additionally, fibrosis should be assessed and, if
treatment available, transient elastography or MR elastography should be
Breakthrough Reappearance of HCV RNA during
performed. If transient or MR elastography is not available, non-
treatment
Relapse End-of-treatment response without invasive blood-based assessments of fibrosis can be used. These
sustained response include the aspartate aminotransferase to platelet ratio index
Nonresponder Failure to clear HCV RNA during (APRI), Fibrosis-4 index, FibroTest (BioPredictive SAS), and
treatment Enhanced Liver Fibrosis (ELF) test (Siemens Medical Solutions
Null responder Usually used for peginterferon-ribavirin USA, Inc).
dual therapy; failure to decrease HCV The 3 main classes of DAA therapies for hepatitis C are shown
RNA by week 12 of therapy in Figure 24.5, and Table 24.8 shows how these classes of DAA
Partial responder Usually used for peginterferon-ribavirin
therapies are used together. Although several regimens are avail-
dual therapy; 2 log10 decrease in HCV
RNA by week 12 of therapy, but still
able, a streamlined approached has been published.
HCV RNA positive at 24 wk For patients who are treatment naïve and have genotype 1
hepatitis with or without cirrhosis, the preferred regimen (in
Abbreviation: HCV, hepatitis C virus. no particular order) is glecaprevir-pibrentasvir for 8 weeks or
Adapted from Ghany MG, Strader DB, Thomas DL, Seeff LB; American sofosbuvir-velpatasvir for 12 weeks. For patients with geno-
Association for the Study of Liver Diseases. Diagnosis, management, and type 2 or 3 with or without compensated cirrhosis, the preferred
treatment of hepatitis C: an update. Hepatology. 2009 Apr;49(4):1335-74; used treatment (in no particular order) is glecaprevir-pibrentasvir for 8
with permission. weeks or sofosbuvir-velpatasvir for 12 weeks.
The recommendation for patients with genotype 3 is to un-
patients with a short life expectancy should be managed by an ex- dergo resistance- associated substitution testing for the Y93H
pert specialist. After candidacy for hepatitis C treatment is deter- variant before treatment with sofosbuvir-velpatasvir. If the pa-
mined, requisite pretreatment testing should include a complete tient tests positive for the Y93H variant, the recommendation
blood cell count; liver tests; creatinine level; HBsAg, anti-HBs, is to add ribavirin to the regimen or use sofosbuvir-velpatasvir-
and anti-HBc testing; and HIV screening. Hepatitis B testing is voxilaprevir for 12 weeks.
Figure 24.5. Direct-Acting Antivirals for Hepatitis C. ER indicates endoplasmic reticulum; LD, lipid droplet. (Courtesy of Stacy A. Rizza, MD,
Department of Infectious Diseases, Mayo Clinic, Rochester, Minnesota; used with permission.)
Table 24.8. Combinations of Direct-Acting Antivirals Used for Hepatitis C Therapy

Drug class (combination includes drugs in same row)
NS5B non-nucleoside
NS3/4A protease inhibitor NS5A inhibitor polymerase inhibitor NS5B-nucleotide polymerase Trade name of combination
(suffix previr) (suffix asvir) (suffix buvir) inhibitor (suffix buvir) (manufacturer)
Grazoprevir Elbasvir Zepatier (Merck & Co, Inc)
Paritaprevir Ombitasvir Dasabuvir Viekiraa (AbbVie, Inc)
Simeprevir (Olysio; Janssen Sofosbuvir (Sovaldi; Gilead None
Therapeutics) Sciences, Inc)
Daclatasvir Sofosbuvir Daklinza (Bristol-Myers Squibb Co)
Ledipasvir Sofosbuvir Harvoni (Gilead Sciences, Inc)
Velpatasvir Sofosbuvir Epclusa (Gilead Sciences, Inc)
Voxilaprevir Velpatasvir Sofosbuvir Vosevi (Ameripharma Specialty Care)
Glecaprevir Pibrentasvir Mavyret (AbbVie Inc)
a
Viekira also includes ritonavir.
Genotypes 4, 5, and 6 are less common in the US and are un- Among patients who receive a liver transplant for hepatitis C,
likely to be tested, so they are not discussed here. posttransplant viremia is nearly universal and posttransplant hep-
Although 2 regimens are effective for all genotypes atitis C should be treated in all patients.
(glecaprevir-pibrentasvir and sofosbuvir- velpatasvir), only Patients with hepatitis C–associated type 2 mixed cryoglo
regimens containing sofosbuvir are safe in patients who have bulinemia usually have a vasculitic rash on the lower extremities,
decompensated cirrhosis. Regimens that contain an NS3/ 4A but they also may have a membranoproliferative glomerulone-
protease inhibitor are not safe to use in patients who have de- phritis or polyneuropathy. Mild cryoglobulinemia and its associ-
compensated cirrhosis because of the risk of worsening jaundice ated complications usually respond to the treatment of hepatitis
and worsening hepatic decompensation. All regimens are safe in C; more severe disease may require immunosuppressive therapy,
patients who have chronic kidney disease stage 4 or 5 or who such as corticosteroids and rituximab. Porphyria cutanea tarda is
are receiving hemodialysis. Many of the DAAs interact with manifested as a rash on sun-exposed areas, particularly the back
statins and calcineurin inhibitors. The most important drug-drug of the hands. Most patients also have abnormal iron test results,
interaction with DAA therapy is between sofosbuvir-containing and phlebotomy improves the rash of porphyria cutanea tarda.
regimens and amiodarone, which can cause life-threatening brad- The response of porphyria cutanea tarda to hepatitis C therapy is
ycardia and, in some patients, has resulted in pacemaker implan- more uncertain than the response of cryoglobulinemia.
tation and even death.
Generally, in patients with decompensated cirrhosis, treatment
Hepatitis C and Pregnancy
of hepatitis C should be overseen by an experienced hepatologist
or a transplant hepatologist. The best candidates are usually those The risk of hepatitis C vertical transmission ranges from 5% to
with a Model for End-stage Liver Disease (MELD) score that is 15%, and concomitant HIV infection increases the risk. The in-
no higher than 15 to 18 and those who are aware that their MELD cidence between 2011 and 2014 was increasing to 29,000 cases
score may improve, but they may have persistent symptoms such of vertical transmission per year. Of the children born to mothers
as ascites. Recent data have suggested that patients with HCC who are positive for hepatitis C, 3% to 5% have chronic infection.
who derive survival benefit from DAA therapy for hepatitis C The recommendation is to avoid obstetric procedures if possible.
have had interval follow-up studies that show no residual disease The use of DAAs in pregnancy is not recommended because
after ablative or surgical therapy. the data are limited. Breastfeeding does not seem to be a risk
Resistance-associated substitution (RAS) is indicated in a few factor for transmission for a child born to a mother with hepatitis
scenarios: 1) Patients who have genotype 1a hepatitis C with or C. HCV antibody should be checked at or after 18 months of age,
without cirrhosis should have RAS testing before therapy is initiated and if results are positive, the HCV RNA level should be checked
with sofosbuvir-ledipasvir. If results from RAS testing are positive, at 3 years to confirm chronicity.
a different regimen should be selected. 2) Patients who have gen- Recent recommendations from the AASLD- IDSA call for
otype 1a hepatitis and who will undergo therapy with grazoprevir- universal hepatitis C screening for mothers at the initial pre-
elbasvir, whether they are treatment naïve or experienced, should natal visit. An important point to remember for women who take
be tested for NS5A RAS; if results are positive, an alternative reg- ribavirin and for women whose male partners take ribavirin is that
imen should be used. 3) Patients who have genotype 3 hepatitis C the teratogenic effects of ribavirin can persist for 6 months after
with cirrhosis or who are treatment experienced should be tested for the last dose. Hepatitis C poses an increased risk for intrahepatic
NS5A if they are being considered for treatment with sofosbuvir- cholestasis of pregnancy. Spontaneous clearance of hepatitis C
velpatasvir or sofosbuvir-daclatasvir. If the Y93H substitution is post partum occurs in up to 10% of patients; the recommendation
detected, ribavirin can be added. The preferred treatment, how- is to recheck the HCV RNA level before treatment.
ever, is to use sofosbuvir-velpatasvir-voxilaprevir, which is highly
effective against baseline or treatment-emergent RAS. Prevention
Patients with hepatitis C and decompensated cirrhosis (in-
cluding those with HCC) should be considered for liver transplant. No vaccine is available for hepatitis C. Transmission by needlestick
injury is unusual, although monitoring after inadvertent exposure
is advised. Baseline anti-HCV testing is recommended with sub- ✓ Hepatitis E is usually acute and self-limited but can be chronic in
sequent determination of the HCV RNA level 4 weeks after ex- recipients of solid organ transplants; treatment is immunosuppres-
posure. Antiviral therapy is more effective for acute hepatitis C sion reduction and ribavirin
than for chronic hepatitis C. For patients with documented acute ✓ Pregnant women with hepatitis E can present with fulminant liver
hepatitis C, the current recommendation is to begin DAA therapy failure
without waiting for spontaneous resolution.
Blood donation is prohibited for patients infected with HCV,
and precaution should be taken when caring for open sores of
patients infected with HCV. Sexual transmission is unusual, but Viral Hepatitis and HIV
condoms are advised for those with multiple sex partners. For Because of shared risk factors, patients with viral hepatitis are
patients in a monogamous long-term relationship, the partner also at risk for infection with HIV. About 10% to 15% of patients
should be tested and the couple counseled about the possibility of with HIV infection are positive for HBsAg. Compared with
transmission. The decision about the use of condoms is left to the patients who are negative for HIV, patients with HIV infection
infected person and partner. are at increased risk for chronic HBV infection after an acute
HBV infection. Patients infected with HIV and HBV have higher
✓ Hepatitis C screening—recommended for persons 18 to 79 years HBV DNA levels and increased mortality from liver disease than
old and for pregnant women
patients infected with HBV and not with HIV.
✓ The presence of both HCV antibody and HCV RNA indicates
active infection, but HCV antibody persists even after a sustained
The response to treatment of HBV infection with peginterferon
virologic response at 24 weeks after treatment in patients infected with HIV is low, and treatment with oral
✓ Sofosbuvir-velpatasvir and glecaprevir-pibrentasvir are pangeno agents generally is advised. Tenofovir in combination with
typic and are used to treat most patients with HCV; sofosbuvir- emtricitabine has an antiviral effect on both HIV and HBV and is
velpatasvir-voxilaprevir is used predominately when other DAAs often used. For the rare patient who requires treatment of HBV
have not helped but not HIV, lamivudine, entecavir, or tenofovir should not be
✓ Genotype 3 hepatitis C—the most difficult to treat and most likely given as monotherapy because of the risk of resistance devel-
to lead to cirrhosis and HCC oping to later treatment of HIV disease.
✓ Patients with stage 3 or 4 cirrhosis should be monitored for About 45% of patients infected with HIV are also infected
hepatocellular carcinoma even after a sustained virologic response
with HCV. Compared with patients who have HCV infection
✓ Patients with hepatitis C and mixed cryoglobulinemia who pre-
sent with the Meltzer triad (purpura, myalgia, and weakness) or
without HIV infection, patients infected with both HCV and
glomerulonephritis are usually cured with successful hepatitis C HIV have higher HCV RNA levels and increased risks for
therapy vertical and sexual transmission of HCV, cirrhosis, and HCC.
✓ DAAs have not been shown to be safe in pregnancy Treatment should be considered for patients infected with both
✓ Sofosbuvir-containing regimens should never be used in patients HCV and HIV. The HIV disease should be controlled, and
receiving amiodarone because of the risk for lethal bradycardia treatment generally is recommended only if the HIV level is
less than 1,000 copies/mL and the CD4 cell count is more than
200/mL.
Hepatitis E
Hepatitis E causes large outbreaks of acute hepatitis in resource- Suggested Reading
limited countries. Infection with a different strain of hepatitis E has Ghany MG, Morgan TR, AASLD-IDSA Hepatitis C Guidance Panel.
been identified in relatively affluent countries, including the US. Hepatitis C guidance 2019 update: American Association for the
Of the 4 genotypes, genotypes 1 and 2 are found outside the US Study of Liver Diseases- Infectious Diseases Society of America
and are transmitted by the fecal-oral route, and genotypes 3 and 4 recommendations for testing, managing, and treating hepatitis C
are transmitted zoonotically (in contaminated food). Genotype 3 virus infection. Hepatology. 2020 Feb;71(2):686–721.
Morgan TR, Ghany MG, Kim HY, Snow KK, Shiffman ML, De Santo JL,
hepatitis E is identified in the US, where the prevalence of hepa-
et al. Outcome of sustained virological responders with histologically
titis E virus antibodies is 6% to 18%. Clinically, hepatitis E virus advanced chronic hepatitis C. Hepatology. 2010 Sep;52(3):833–44.
infection is similar to HAV infection. Spontaneous resolution of Nimgaonkar I, Ding Q, Schwartz RE, Ploss A. Hepatitis E
the hepatitis is typical, although prolonged cholestasis, with jaun- virus: advances and challenges. Nat Rev Gastroenterol Hepatol. 2018
dice and pruritus for more than 3 months, can occur in 60% of Feb;15(2):96–110.
patients. Chronic hepatitis E can occur in solid organ transplant Pungpapong S, Kim WR, Poterucha JJ. Natural history of hepatitis B
recipients and is treated with immunosuppression reduction and virus infection: an update for clinicians. Mayo Clin Proc. 2007
ribavirin. Women who acquire hepatitis E during pregnancy may Aug;82(8):967–75.
present with fulminant liver failure. van der Meer AJ, Veldt BJ, Feld JJ, Wedemeyer H, Dufour JF, Lammert
F, et al. Association between sustained virological response and all-
cause mortality among patients with chronic hepatitis C and advanced
✓ Hepatitis E with prolonged cholestasis, with jaundice and pruritus hepatic fibrosis. JAMA. 2012 Dec 26;308(24):2584–93.
for more than 3 months, occurs in 60% of patients
25
Clinical Approach to Liver Mass Lesionsa

LEWIS R. ROBERTS, MB, CHB, PHD
The clinical approach to liver mass lesions requires attention to the chapter describes the overall approach to the evaluation and diag-
clinical context within which the mass is identified, the symptoms nosis of liver mass lesions and summarizes the clinical features
of the patient, and the physical examination, laboratory tests, and and management of the most common benign and malignant liver
imaging studies. With the advent of frequent ultrasonographic or masses (Box 25.1).
cross-sectional imaging of the abdomen for various abdominal
symptoms, many liver mass lesions are now discovered inciden-
Evaluation
tally during imaging performed for unrelated symptoms. These
incidentally discovered lesions should be evaluated fully because History
a large proportion of them indicate the presence of malignant or A history should be obtained of potential risk factors for different
premalignant disease that requires appropriate management. This types of liver masses to inform the subsequent evaluation and to
limit unnecessary testing. The age and sex of the patient, a history
of oral contraceptive use, geographic residence and travel his-
a
Portions previously published in Alberts SR, Gores GJ, Kim GP, Roberts tory, and comorbid illnesses often provide important clues to the
LR, Kendrick ML, Rosen CB, et al. Treatment options for hepatobiliary diagnosis. A history of previous imaging studies should always
and pancreatic cancer. Mayo Clin Proc. 2007 May;82(5):628-37; used with be sought because information about whether the mass is new,
permission; and Roberts LR. Liver and biliary tract tumors. In: Goldman
previously seen and stable in size, or enlarging over time can be
L, Schafer AI, eds. Goldman’s Cecil Medicine. 24 ed. W.B. Saunders;
2012:1297-303. useful in the differential diagnosis of liver masses.
Pain can be an important presenting symptom. A rapidly
Abbreviations: BCLC, Barcelona Clinic Liver Cancer; CA19-9, car-
enlarging liver mass tends to distend the liver capsule and cause
bohydrate antigen 19- 9; CT, computed tomography; DEB- TACE,
drug-eluting bead transarterial chemoembolization; ERCP, endoscopic right upper quadrant abdominal pain, whereas a slowly growing
retrograde cholangiopancreatography; FDG, 18F-fluorodeoxyglucose; mass can reach a substantial size that almost completely occupies
FISH, fluorescence in situ hybridization; HBV, hepatitis B virus; HCA, the liver without causing noticeable symptoms. The liver mass
hepatocellular adenoma; HCC, hepatocellular carcinoma; HCV, hepa- may come to attention only when it becomes a visible abdominal
titis C virus; H-HCA, HNF1A-inactivated hepatocellular adenoma; IL, protuberance or causes mass effect on other organs such as the sto-
interleukin; JAK, Janus kinase; LI-RADS, Liver Imaging Reporting mach, leading to early satiety (Figure 25.1). Pain associated with
and Data System; MELD, Model for End-stage Liver Disease; MODY, tumor growth is usually dull, relatively diffuse, and persistent. It
maturity- onset diabetes of the young; MRCP, magnetic resonance may or may not be associated with tenderness in the epigastrium
cholangiopancreatography; MRI, magnetic resonance imaging; MWA, and right upper quadrant of the abdomen. Subcapsular lesions,
microwave ablation; NASH, nonalcoholic steatohepatitis; PEI, percu-
whether benign or malignant, frequently cause a pleuritic pain syn-
taneous ethanol injection; PET, positron emission tomography; PSC,
primary sclerosing cholangitis; PTC, percutaneous transhepatic cho- drome of abdominal pain accompanied by right shoulder discom-
langiography; RFA, radiofrequency ablation; STAT, signal transducer fort exacerbated by breathing. Lesions that have the propensity
and activator of transcription; TACE, transarterial chemoembolization; for intralesional rupture or hemorrhage can first become apparent
TARE, transarterial radioembolization with the sudden onset of severe abdominal pain. This is most
297
Box 25.1. Clinical Classification of Liver Mass Lesions

Benign lesions typically requiring no further
treatment
Cavernous hemangioma
Focal nodular hyperplasia
Simple liver cysts
Focal fatty change or focal sparing in a fatty liver
Angiolipoma
Benign lesions requiring further follow-up and
management
Hepatic adenoma
Pyogenic liver abscess
Nodular regenerative hyperplasia
Biliary cystadenoma
Inflammatory pseudotumor
Granulomatous abscesses
Amebic liver abscess
Echinococcal cysts
Malignant lesions requiring appropriate therapy
Liver metastases
Primary hepatocellular carcinoma
Cholangiocarcinoma
Mixed hepatocellular-cholangiocarcinoma
Cystadenocarcinoma
Hemangioendothelioma
Epithelioid angiomyolipoma
Mixed epithelial and stromal tumors
Sarcomas
typical of benign hepatic adenomas or hepatocellular carcinomas

(HCCs), which are highly vascular. If the rupture involves the liver
capsule, it can be associated with life-threatening intra-abdominal
hemoperitoneum, shock, and risk of exsanguination.
A history of an underlying liver disease that predisposes to Figure 25.1. Large Cavernous Hemangioma With the Manifestation
of an Abdominal Mass. A, Arterial phase shows peripheral nodular en-
malignancy is often an important diagnostic clue. Patients with
hancement. B, Venous phase shows fill-in of contrast agent from the pe-
nonalcoholic steatohepatitis (NASH) or viral, alcoholic, autoim- riphery toward the center of the mass.
mune, metabolic, or other causes of cirrhosis are at increased risk
for HCC and intrahepatic cholangiocarcinoma. These patients
may have had complications of cirrhosis, including ascites, spon- Primary sclerosing cholangitis (PSC), which can be sub-
taneous bacterial peritonitis, bleeding esophageal varices, or he- clinical in patients with ulcerative colitis or other inflammatory
patic encephalopathy. In addition, patients with long-standing bowel disease, is a major risk factor for cholangiocarcinoma.
chronic hepatitis B virus (HBV) infection are at risk for HCC A history of sudden hepatic decompensation, cholangitis, or
even in the absence of cirrhosis. Consequently, for patients who the development of a new dominant stricture in a patient with
have cirrhosis from any cause or who acquired chronic HBV in- known PSC can presage the development of cholangiocarcinoma.
fection at birth or in early life, current recommendations are to Approximately a third of the cholangiocarcinomas that occur in
begin a regular program of surveillance with ultrasonography of patients with PSC are diagnosed within 2 years after the diag-
the liver, with or without measurement of serum alpha fetoprotein, nosis of PSC; therefore, this should be a period of heightened sur-
every 6 months. Persons with chronic HBV infection without cir- veillance. Current expert screening recommendations for persons
rhosis who were born in sub-Saharan Africa should undergo sur- with PSC are for annual magnetic resonance imaging (MRI) with
veillance for HCC beginning at the age of 20 years. For persons MR cholangiopancreatography (MRCP) and measurement of the
born in Asia, surveillance should be initiated at age 40 years for serum carbohydrate antigen 19-9 (CA19-9).
men and 50 years for women (Figure 25.2). Regular surveillance General, nonspecific symptoms associated with malignancy
should also be recommended for persons with a family history of include fatigue, loss of appetite, unintended weight loss, low-
HCC, those with high HBV viral loads (HBV DNA >2,000 IU/ grade fever, night sweats, and frailty. A recent history of iron de-
mL), and those with a persistent or intermittent increase in the ficiency anemia should raise suspicion of colorectal cancer with
level of alanine aminotransferase. liver metastases; a long- standing history of gastroesophageal
25. Clinical Approach to Liver Mass Lesions 299
be due to advanced chronic liver disease or to biliary obstruc-

tion from cholangiocarcinoma. Peripheral edema may be as-
sociated specifically with chronic liver disease or with tense
ascites causing compression of the inferior vena cava and loss
of intravascular oncotic pressure due to hypoalbuminemia, or
it may be nonspecific from general debility. Rarely, large liver
cysts will cause a mass effect on the central bile ducts and in-
ferior vena cava, resulting in jaundice or bilateral leg edema
(or both). Frequently, cancer is associated with an acute phase
response syndrome, and because albumin is a negative acute
phase reactant, a cancer-associated hypoalbuminemia typically
contributes to peripheral edema. Many cancers are associated
with a prothrombotic tendency; consequently, it is important to
evaluate new-onset lower extremity edema, particularly if it is
unilateral, for deep vein thrombosis.
Laboratory Tests
Laboratory tests often provide evidence of chronic liver disease
or of the underlying tumor that is metastatic to the liver. A com-
plete blood cell count may show thrombocytopenia from chronic
liver disease with splenomegaly, or it may show anemia from gas-
trointestinal blood loss related to colon or other primary gastroin-
Figure 25.2. Surveillance Ultrasonography of the Liver. A small
1.3-cm mass (arrow) was identified in an at-risk patient during ultrason-
testinal cancer. Typically, aspartate aminotransferase and alanine
ographic screening for hepatocellular carcinoma. aminotransferase levels are increased from active inflammatory
liver disease or from neoplastic diseases infiltrating the liver. An
increase in the bilirubin and alkaline phosphatase concentrations
reflux and new-onset dysphagia should prompt consideration of usually reflects either a bile duct obstruction from a primary bil-
esophageal adenocarcinoma; the recent onset of type 2 diabetes iary tumor or a mass effect from an intrahepatic mass or from
should elicit a search for pancreatic adenocarcinoma; and a his- enlarged lymph nodes in the porta hepatis. The serum albumin
tory of breast cancer should be sought and the breasts should be level is often low and the prothrombin time increased in patients
examined and imaged to rule out metastatic breast cancer. In the with cirrhosis.
absence of other localizing symptoms, occult lymphoma should Potentially useful tests that may identify the specific cause
be considered. of liver disease include tests for viral markers (antibodies to
Various paraneoplastic syndromes can be helpful in the di- hepatitis C virus [HCV] or polymerase chain reaction for
agnosis of liver masses. A history of flushing, hypotension, and HCV RNA), hepatitis B surface antigen, antibodies to hepa-
diarrhea is classic for metastatic neuroendocrine tumors such as titis B core antigen, antibodies to hepatitis B surface antigen,
carcinoids. Diarrhea alone occurs most frequently with HCC as a and hepatitis D antibodies or hepatitis D virus RNA in all per-
consequence of the secretion of vasoactive intestinal polypeptide sons who have positive results for hepatitis B surface antigen.
and gastrin by the tumor. HCCs can also be associated with hy- Iron levels typically are increased in patients with hereditary
poglycemia and erythrocytosis. hemochromatosis and low in those with anemia from colon
cancer–related gastrointestinal blood loss. Tumor markers such
as carcinoembryonic antigen for colon cancer, CA19-9, and
Physical Examination
alpha fetoprotein are helpful if results are positive, but they fre-
The physical examination may provide clues to the underlying quently are negative if patients have early-stage cancer. Also,
cause of a liver mass. Most frequently, patients have stigmata these markers are not entirely specific for the primary site. For
of chronic liver disease, including temporal muscle wasting, example, the carcinoembryonic antigen level is often increased
spider angiomas, palmar erythema, ascites, splenomegaly, and in cholangiocarcinomas and pancreatic cancers, and the alpha
caput medusae from recanalization of the umbilical vein. The fetoprotein level can be increased in patients with primary
cirrhotic liver may be palpably nodular and often associated cancers of the upper gastrointestinal tract outside the liver,
with bilobar enlargement of the liver or isolated hypertrophy such as esophageal adenocarcinoma. With advances in geno-
of the caudate lobe. Large liver masses may give rise to pal- mics, proteomics, and metabolomics, there is substantial on-
pable hepatomegaly, and subcapsular masses may be palpable going innovation in cancer biomarker development, including
if located anteriorly or inferiorly in the liver. Abdominal lym- several new models that integrate clinical variables with bio-
phadenopathy or peritoneal carcinomatosis may be palpable. marker levels and a new generation of multicancer early detec-
Tumors may have associated tenderness in the epigastrium tion tests that are being deployed in clinical practice. Primary
or right upper quadrant of the abdomen. Vascular masses hepatic lymphomas or secondary lymphoma metastases can
such as primary HCCs may have an audible vascular bruit masquerade as primary liver cancers; the serum level of lac-
on auscultation. Pallor may be due to anemia from colon ad- tate dehydrogenase usually is increased and can be an important
enocarcinoma with chronic blood loss, from portal hyperten- clue to the diagnosis. The urine 24-hour 5-hydroxyindoleacetic
sive gastropathy in patients with cirrhosis, or from anemia of acid concentration is helpful in cases of suspected carcinoid
chronic disease related to other malignancies. Jaundice may syndrome.
Imaging Studies hemangiomas are multicentric in up to 30% of cases and fre-

quently coexist with focal nodular hyperplasia.
The imaging studies most frequently helpful in the differential di-
agnosis of liver mass lesions include abdominal ultrasonography,
cross-sectional imaging modalities such as computed tomography Histologic Features
(CT) and MRI, 18F-fluorodeoxyglucose (FDG)–positron emis- Cavernous hemangiomas are characterized by an extensive net-
sion tomography (PET), and fused PET/CT (most useful for im- work of vascular spaces lined by endothelial cells and separated
aging metastatic disease). More specialized contrast agents are by thin, fibrous stroma. Large hemangiomas may have areas of
now available, particularly for MRI. For example, both gadoxetate thrombosis, scarring, and calcification.
disodium (Eovist; Bayer HealthCare Pharmaceuticals Inc) and
gadobenate dimeglumine (MultiHance; Bracco Diagnostics Inc)
undergo biliary and kidney excretion, behaving as nonspecific gad- Clinical Features
olinium chelates in the first minutes after administration and as Patients with hemangiomas are most often asymptomatic. Large,
liver-targeted agents in later phases. This allows further delineation subcapsular hemangiomas may cause abdominal pain or dis-
of lesion characteristics in MRI scans obtained 20 minutes after comfort. Giant hemangiomas (>10 cm) may cause systemic
injection of gadoxetate disodium or 60 to 120 minutes after injec- features of inflammation such as fever, weight loss, and anemia.
tion of gadobenate dimeglumine and can be particularly helpful for Kasabach-Merritt syndrome may occur with disseminated intra-
distinguishing between focal nodular hyperplasias and adenomas vascular coagulation, most commonly in children. Cavernous
and for identifying small HCC nodules. The use of nuclear imaging hemangiomas do not undergo malignant transformation, and rup-
studies, including tagged red blood cell studies (for cavernous ture is exceedingly rare.
hemangiomas) and technetium Tc 99m sulfur colloid imaging (to
distinguish focal nodular hyperplasias from adenomas), has been
Imaging Characteristics
largely replaced by MRI with gadoxetate or gadobenate. For neu-
roendocrine tumors, newer imaging tests that can illuminate tumor Ultrasonography. On ultrasonography, hemangiomas are
somatostatin receptors throughout the body include gallium Ga 68 well-circumscribed, homogeneously hyperechoic lesions with
dotatate PET and copper Cu 64 dotatate PET. These are superior smooth margins.
to the earlier generation of octreotide scans, which used indium In
Dynamic Contrast-
Enhanced Multiphasic CT. On CT,
111 pentetreotide as the standard of care.
there is peripheral nodular enhancement during the arterial phase,
✓ Most common solid tumors in the liver: hepatic hemangioma, focal with later fill-in toward the center of the lesion (Figure 25.3).
nodular hyperplasia, hepatic adenoma, HCC, cholangiocarcinoma,
MRI With Gadolinium Contrast. On contrast-enhanced MRI,
liver metastases
hemangiomas are typically homogeneous, with low signal inten-
sity on T1-weighted images and sharply demarcated, hyperintense
✓ Hepatic hemangioma—benign tumor consisting of a 3-dimensional lesions on T2-weighted images. As in other contrast imaging
network of blood-filled spaces (much like a sponge); on contrast- studies, there is peripheral enhancement in the arterial phase, with
enhanced images it fills in gradually from the outside toward the later fill-in toward the center of the lesion.
middle, similar to how a squeezed sponge absorbs water from the
edges toward the center when placed in water Technetium Tc 99m–Labeled Red Blood Cell Scintigraphy.
✓ Focal nodular hyperplasia—benign tumor thought to arise around Scintigraphy can be used to confirm the diagnosis of lesions that
a malformed artery in the liver; has all the elements of the normal are atypical on other imaging studies. There is low perfusion on
portal triad, including hepatocytes, biliary ductules, and stromal early images, and the isotope gradually accumulates to a high
cells and no tendency to transform into a cancer concentration within the lesion on late images. With the advances
✓ Hepatic adenoma—benign tumor within the liver, histologically in dynamic cross-sectional imaging CT and MRI, scintigraphy is
consisting of sheets of cells supplied by arterial branches (ie, rarely used now in the diagnosis of hemangiomas.
“naked arteries”) without bile ductules; some subtypes, particularly
those with oncogenic β-catenin variants, can transform into HCCs
✓ Hepatocellular carcinoma—cancer arising in primary liver cells Biopsy
or hepatocytes, which are the primary cells that carry out the key
functions of the liver Biopsy seldom is needed. It may be useful for small lesions
✓ Cholangiocarcinoma—cancer arising in the bile ducts that collect that show uniform enhancement and resemble primary tumors
bile produced by the hepatocytes and transport it to the gall- or metastases and also for large lesions that have pronounced
bladder and ultimately to the intestines; cholangiocarcinomas are scarring and atypical imaging features. Biopsy specimens are
subclassified anatomically as intrahepatic, perihilar, and distal typically a relatively acellular “dry aspirate,” with occasional vas-
✓ Liver metastases—malignant masses in the liver that originated in cular elements seen on histologic study.
a cancer at a different site but have spread through the bloodstream
to the liver

Management
Most cavernous hemangiomas do not require intervention and
Benign Liver Masses can be observed. Symptomatic giant cavernous hemangiomas re-
quire surgical enucleation or resection.
Cavernous Hemangioma
Cavernous hemangiomas are the most common benign liver
tumors, occurring in 7% of adults in autopsy series. They are
Hepatic Adenoma
seen predominantly in women, with a female to male ratio Hepatic adenomas are benign tumors of the liver that occur
ranging from 1.5:1 to 5:1; they are diagnosed most frequently predominantly in young women between the third and fourth
in multiparous women in their third to fifth decades. Cavernous decades of life. Key features of hepatic adenomas are that they can
more likely to have multiple adenomas and to have progressive

growth of adenomas if they do not lose weight. Excessive use
of alcohol has been associated with the development of inflam-
matory hepatocellular adenomas (HCAs). Hepatic adenomas
also occur in a familial pattern associated with the variety of
type 2 diabetes known as maturity-onset diabetes of the young
(MODY) type 3, which is associated with germline variations in
the HNF1A gene (OMIM 600496); however, in patients with gly-
cogen storage disease type 1A or 3, most genetic variations in
HCAs appear to be somatic alterations. Persons who take the an-
drogenic hormones methandrostenolone and methyltestosterone
also have an increased risk for adenomas with subsequent ma-
lignant transformation. Adenomas are usually single, but they
may be multiple, especially in patients with MODY3 or glycogen
storage disease.
Advances in molecular classification have identified hepatic
adenomas as clonal tumors that are molecularly heterogeneous,
with different subtypes having particular etiologies and different
underlying genomic features, clinical presentations, radiologic
findings, histopathologic features, and risks of malignant trans-
formation or hemorrhage. Adenomas are subclassified into 5 mo-
lecular subgroups:
1. HNF1A-inactivated HCAs (H-HCAs) are characterized by inactiva-
tion of the HNF1A transcription factor and a highly steatotic mor-
phology. H-HCAs carry a low risk of hemorrhage or transformation
into HCC.
2. Telangiectatic or inflammatory HCAs are characterized by
activating variants of the interleukin (IL)-6/Janus kinase (JAK)/
signal transducer and activator of transcription (STAT) pathway,
such as the IL-6 signal transducer gene (IL6ST; OMIM 600694) or
the guanine nucleotide-binding protein alpha-stimulatory subunit
complex locus (GNAS; OMIM 139320). Inflammatory HCAs
are more common in persons who have obesity, inflamma-
tory cell infiltration on histology, and a tendency to malignant
transformation.
3. β-Catenin–activated HCAs encompass both noninflammatory and
inflammatory subgroups. These are subdivided into exon 3 mutated
adenomas and exon 7/ 8 mutated adenomas. Exon 3 mutated
Figure 25.3. Cavernous Hemangioma on Computed Tomography. adenomas show stronger β-catenin–pathway activation and are more
A, Arterial phase shows peripheral nodular enhancement of 1 large and prone to malignancy, while exon 7/8 mutated adenomas show weak
2 small cavernous hemangiomas (arrows). B, Venous phase shows fill-in β-catenin–pathway activation and no increase in risk for malig-
toward the center of the 3 masses, with almost complete contrast en- nancy, although they may carry an increased risk for bleeding.
hancement of the 2 small hemangiomas (arrows). 4. Sonic hedgehog pathway– activated HCAs are characterized by
the presence of a fusion between the inhibin beta E subunit gene
(INHBE; OMIM 612031) and the GLI1 gene (OMIM 165220) and
undergo malignant transformation or hemorrhage and sometimes appear to carry a higher risk for bleeding.
rupture, leading to hemoperitoneum. Epidemiologically, hepatic 5. Unclassified HCAs comprise small groups with less clearly defined
adenomas have been associated with long-term use of oral con- characteristics.
traceptive pills. In the past, when oral contraceptives contained Male sex, size greater than 5 cm, and strong β-catenin activation
relatively high amounts of estrogens, studies estimated the rel- as assessed by increased nuclear β-catenin staining are the major
ative risk for hepatic adenomas as 2.5 times greater for women risk factors for transformation to HCC.
who had taken oral contraceptive pills for 3 to 5 years compared
with women who had taken them for 1 year or less. After 5 years
of oral contraceptive use, the risk increased sharply to 25 times Histologic Features
greater after 9 or more years of use. The epidemiology of hepatic Adenomas are characterized by the presence of sheets of
adenomas is changing. Newer oral contraceptives contain less es- hepatocytes supplied by “naked” arteries (ie, arteries unaccompa-
trogen and are probably associated with a lower risk of hepatic nied by bile ductules, fibrous septa, portal tracts, or central veins).
adenomas; however, the overall incidence of hepatic adenomas
does not appear to have decreased concurrently.
With increasing rates of obesity worldwide, the prevalence of Clinical Features
obesity and the metabolic syndrome is high among patients with Patients with hepatic adenomas are most often asymptomatic.
hepatic adenomas, particularly the inflammatory or telangiectatic However, they may present with pain or discomfort of the upper
variant, suggesting that obesity and the metabolic syndrome in- abdomen or the right upper quadrant of the abdomen. Because
crease the risk for adenomas. Further, patients with obesity are these tumors have a propensity to rupture, patients may present
with intrahepatic hemorrhage and pain or with hemoperitoneum

and shock.
Adenomas frequently have nonspecific imaging characteristics.
Most often, they are heterogeneous because of the presence of
intralesional necrosis or hemorrhage, but frequently they are
homogeneous when small. The tumors typically take up the
contrast agent rapidly in the arterial phase of contrast CT or
MRI studies and then almost immediately become isointense
with the surrounding liver in the early portal phase. If contrast
studies are not optimally timed, this important imaging feature
may be missed. Adenomas often cannot be differentiated de-
finitively from HCC or hypervascular metastases with ultraso-
nography, CT, or MRI. Adenomas can be differentiated from
focal nodular hyperplasias in the delayed phase after MRI with
gadobenate dimeglumine or gadoxetate disodium, in which
adenomas show decreased retention of the contrast agent in
the biliary phase when compared with the surrounding liver
(Figure 25.4). On technetium Tc 99m sulfur colloid scintig-
raphy, there usually is no uptake because adenomas do not
contain Kupffer cells.
Biopsy
Because of the frequent uncertainty about the diagnosis after a
thorough noninvasive evaluation, biopsy often is required for
diagnosis. Biopsy is also helpful for immunohistochemical and
molecular classification to assess the risk of malignant trans-
formation. H-HCAs show loss of staining for liver fatty acid–
binding protein, indicating the functional loss of the HNF1A
gene; inflammatory HCAs show uniform expression of the in-
flammatory markers serum amyloid A protein or C-reactive pro-
tein; and β-catenin– exon 3 mutated adenomas show uniform
immunohistochemical staining for glutamine synthetase and nu-
clear staining for β-catenin, which is sometimes focal, while β-
catenin–exon 7/8 mutated adenomas show only faint glutamine
synthetase staining and no nuclear staining for β-catenin. A sonic
hedgehog pathway–activated HCA may develop areas of hemor-
rhage within the adenoma and show staining for prostaglandin
D2 synthase (PTGDS; OMIM 176803) and argininosuccinate
synthetase 1 (ASS1; OMIM 603470).
Management
Because of the risks of rupture or transformation to HCC, sur-
gical resection is recommended for large hepatic adenomas
(>5 cm), for hepatic adenomas of any size occurring in men,
for hepatic adenomas with β-catenin activation, and for hepatic Figure 25.4. Hepatic Adenoma. A, Arterial phase after intra-
adenomas that are histologically difficult to distinguish from venous injection of gadobenate dimeglumine shows heterogeneous
well-differentiated HCCs. hyperenhancement. B, Venous phase shows the adenoma almost
Patients generally are advised to discontinue the use of isoenhancing with the surrounding liver. C, Delayed hepatobiliary phase
oral contraceptive pills. Adenomas may decrease in size after shows the adenoma excluding the contrast agent and hypoenhancing
compared with the surrounding liver.
withdrawal of oral contraceptives, but they usually do not;
sometimes they increase in size. If the adenoma is larger than
5 cm, most experts advise against pregnancy until the lesion after withdrawal of estrogen, particularly in patients who do not
can be resected, although the evidence that pregnancy is asso- plan any future pregnancies.
ciated with a higher rate of complications is scant. Pregnancy
in patients with smaller adenomas can be managed by careful
Focal Nodular Hyperplasia
observation with intermittent ultrasonography. Small adenomas
located in the liver where they are technically difficult to re- Focal nodular hyperplasia is thought to develop as a reaction of
sect can be treated with radiofrequency ablation. Observation the liver to an intrahepatic arterial malformation. The arterial mal-
is recommended for smaller adenomas or for those that regress formation forms a vascular stellate scar that contains connective
tissue and bile ductules. The surrounding mass contains a pro-

liferation of hepatocytes separated by fibrous septa. Unlike he-
patic adenomas, focal nodular hyperplasias are polyclonal and do
not have a tendency for malignant transformation. Focal nodular
hyperplasia occurs predominantly in women of childbearing age
and is not considered to be related to oral contraceptive use. Focal
nodular hyperplasias may be multiple (10% of patients) or asso-
ciated with cavernous hemangiomas (20% of patients).
Histologic Features
Focal nodular hyperplasia is characterized by benign-appearing
hepatic parenchyma, with bile ductules in septal fibrosis.
Clinical Features
Most patients with focal nodular hyperplasia are asymptomatic.
Patients with large lesions may present with abdominal discom-
fort or an abdominal mass.
Ultrasonography. Focal nodular hyperplasia has a variable
ultrasonographic appearance, with lesions being hypoechoic,
hyperechoic, or isoechoic. Most commonly, the tumors are
hypoechoic except for the central scar. Color flow Doppler im-
aging may show increased blood flow in the central stellate scar.
Multiphasic CT. On multiphasic CT, the presence of an
avascular central scar or a feeding artery to the mass is highly
suggestive of focal nodular hyperplasia. The lesion shows rapid
and intense contrast enhancement during the arterial phase and
isointensity during the venous phase.
Contrast-Enhanced MRI. Contrast-
enhanced MRI shows
a rapid, intense contrast enhancement similar to the pattern
with multiphasic CT. Typically, focal nodular hyperplasia is
isointense on T1- weighted images and either isointense or
slightly hyperintense on T2-weighted images. The central scar
is usually hypointense on T1-weighted images but hyperintense
on T2-weighted images. Gadobenate dimeglumine or gadoxetate
disodium is taken up by the hepatocytes and partially excreted
into the immature bile ductules of focal nodular hyperplasias;
thus, they retain contrast medium in the biliary phase of imaging
(Figure 25.5).
Technetium Tc 99m Sulfur Colloid Scintigraphy. With
scintigraphy, 50% to 60% of cases of focal nodular hyperplasia
show hyperintense or isointense uptake, unlike the hypointensity
of adenomas, because of the presence of Kupffer cells.
Figure 25.5. Focal Nodular Hyperplasia. A, Arterial phase shows
Biopsy homogeneous hyperenhancement and a central scar. B, Venous phase
shows the tumor isoenhancing with the surrounding liver. C, Delayed
Focal nodular hyperplasia can be difficult to distinguish from ad- phase after intravenous injection of gadobenate dimeglumine shows the
enoma because fine-needle aspirates from both lesions may show contrast agent concentrated within the tumor.
only benign-appearing hepatocytes. Immunohistochemically,
focal nodular hyperplasia typically shows a patchy “map-like”
glutamine synthetase staining, which distinguishes it from he- discontinuation of oral contraceptives, although this has not been
patic adenoma. shown to result in regression of the tumor.
Management Simple Liver Cysts

Asymptomatic focal nodular hyperplasia can be monitored over Solitary or multiple liver cysts are common and usually asympto-
time, and surgery rarely is indicated. Some groups recommend matic, and they often coexist with other mass lesions in the liver.
The female to male ratio is 4:1. Liver cysts occur in 3.6% of the tetradecyl sulfate as a sclerosant to ablate the cyst. Large symp-
population, and the prevalence increases with age. tomatic cysts or smaller cysts that recur after aspiration and
attempted ablation should be treated with laparoscopic or open
Histologic Features surgical fenestration.
Cysts are thin-walled structures lined by cuboidal bile duct epi-

thelium and filled with isotonic fluid. Focal Fat or Fat Sparing
Fatty infiltration of the liver is common. Focal fatty infiltration
Clinical Features can give the appearance of a mass lesion on imaging studies; con-
versely, focal sparing in a liver with diffuse fatty infiltration also
Cysts are usually asymptomatic unless they are large and causing
can have the appearance of a mass. Fatty infiltration typically
symptoms through pressure on adjacent structures. Rarely, large
occurs in obese persons and in patients with type 2 diabetes, high
cysts may cause pain, produce biliary obstruction and present
alcohol consumption, or altered nutritional status because of che-
with jaundice, or exert pressure on the inferior vena cava, leading
motherapy regimens.
to lower extremity edema.
Histologic Features
Histologic specimens show areas of fatty infiltration with fat-
Ultrasonography. Ultrasonography is the best imaging method
laden cells.
for cysts. Classically, cysts are anechoic and have smooth, round
margins; a distinct far wall; and posterior acoustic enhance-
ment (Figure 25.6). Ultrasonography clearly shows the wall Clinical Features
thickness and, if present, internal septations. Thick-walled cysts Focal fat or fat sparing is asymptomatic and is usually discovered
with nodularity or irregular septations suggest the diagnosis of on abdominal imaging performed for other reasons.
cystadenoma or, rarely, cystadenocarcinoma.
Computed Tomography. On CT, cysts have the same density Imaging Characteristics
as water and do not change with contrast imaging.
Focal fat does not distort the contour of the liver. If normal
Magnetic Resonance Imaging. On MRI, cysts are hyper vessels, especially veins, can be seen coursing through the region,
intense on T2-weighted images. Small cysts may be difficult to the diagnosis of focal fat is likely. Also, focal fat typically occurs
differentiate from a cavernous hemangioma. in vascular watersheds, particularly along the falciform ligament.
“Skip areas” of normal liver in diffuse fatty infiltration typically
occur adjacent to the gallbladder fossa, in subcapsular areas, or in
Biopsy
the posterior aspect of segment 4 of the liver.
Biopsy usually is not necessary because of the distinctive im-
aging characteristics of simple cysts. Ultrasonography. Areas of fatty infiltration are hyperechoic.
Computed Tomography. On CT, fat is hypodense compared

Management with the spleen, but because the fat is dispersed in normal tissue, it
Smaller symptomatic simple cysts can be treated with percu- is not as low in density as adipose tissue. Venous structures coursing
taneous aspiration and instillation of ethanol or 3% sodium through the areas of focal fat are seen on venous phase studies.
Magnetic Resonance Imaging. On MRI, fat is occasionally
hyperintense on T1-and T2-weighted images. Decreased signal
intensity on out-of-phase gradient imaging is diagnostic of focal fat.
Biopsy
Biopsy can be used to exclude other lesions if the diagnosis
cannot be established confidently.
Management
No therapy is needed. Areas of focal fat may resolve if patients
lose weight or achieve better control of diabetes.
Malignant Liver Masses

Hepatocellular Carcinoma
The major risk factors for HCC include cirrhosis from chronic HBV
or HCV infection, alcohol use, nonalcoholic fatty liver disease, he-
reditary hemochromatosis, other causes of liver injury such as
Figure 25.6. Simple Liver Cyst. Ultrasonogram shows the charac- α1-antitrypsin deficiency, autoimmune hepatitis, primary biliary cir-
teristic changes of absence of echoes within the lesion, a distinct far wall, rhosis, and tyrosinema. Fungal aflatoxins that contaminate grains
and increased echogenicity posterior to the cyst. and legumes also have a synergistic effect with other causes of liver
injury and contribute to the development of liver cancer in parts of recommend that patients who have cirrhosis be evaluated with
sub-Saharan Africa and Asia. Approximately 80% to 90% of HCCs liver ultrasonography with or without measurement of serum alpha
occur with cirrhosis. The other 10% to 20% comprise 3 groups. fetoprotein every 6 months to screen for HCC. For those who have
One group includes patients who have chronic HBV infec- chronic hepatitis B without cirrhosis, screening should begin at
tion and HCC in the absence of cirrhosis, presumably because age 20 years for African-born persons, 40 years for Asian-born
of the oncogenic effects of HBV proteins and HBV integration, men, and 50 years for Asian-born women, and for patients with a
inherited familial tendency, and, in certain areas of the world, the family history of HCC, high HBV DNA level, and a persistent or
synergistic effect of exposure to dietary aflatoxin. These patients intermittent increase in the level of alanine aminotransferase. The
are often young, between 20 and 50 years old. high body mass index and central obesity of many US patients
Another group of patients without cirrhosis is characterized frequently render full ultrasonographic visualization of the liver
by older persons who live in countries where the incidence of difficult; hence, there is increasing interest in the development of
HBV infection is low and who present with sporadic-onset HCC additional blood-based biomarkers for surveillance for HCC.
occurring in a histologically normal liver in the absence of dis- Once a new mass is identified with ultrasonography or
cernible risk factors. In a proportion of these persons the adeno- suspected by biomarker elevation, it should be confirmed with
associated virus type 2 is integrated in their HCCs. cross-sectional imaging with multiphasic contrast-enhanced CT
The third group consists of an increasing number of people or MRI. The Liver Imaging Reporting and Data System (LI-
with NASH who have HCC without cirrhosis. Although the risk RADS) was developed by the American College of Radiology for
for HCC in this NASH population without cirrhosis is relatively systematic evaluation and reporting of liver lesions suspected of
low, since NASH is so prevalent in the population and has now being malignant that are imaged with CT or MRI. Combinations
become the most common cause of chronic liver disease in in- of arterial enhancement with washout in the portal venous phase
dustrial countries in North America and Europe, it contributes and an enhancing capsule in the delayed phase with or without
substantially to the overall number of HCC cases. Without sur- threshold growth of the lesion over time are used as diagnostic
veillance, most HCCs are diagnosed at an advanced stage, when criteria for early-stage HCC and are highly specific (Figure 25.7
radical treatment for cure is no longer feasible. Therefore, it is and Figure 25.8).
important that persons who are at risk for HCC be enrolled in a
surveillance program for early detection of new tumors. ✓ Persons eligible for HCC surveillance
• Patients with cirrhosis from any cause who would be a candi-
date for therapy
Surveillance and Diagnosis With Imaging, Biomarkers, • Patients with decompensated cirrhosis and end-stage liver dis
or Biopsy ease only if they are eligible for liver transplant
The best outcomes for treatment of HCC are achieved with ✓ Other persons eligible for HCC surveillance are those who have
liver transplant, surgical resection, or local ablative therapies chronic hepatitis B without cirrhosis
• If African born, begin surveillance at age 20 years
such as microwave ablation, radiofrequency ablation, laser abla-
• If Asian-born male, begin surveillance at age 40 years
tion, or percutaneous ethanol injection. Because these therapies • If Asian-born female, begin surveillance at age 50 years
are most effective when applied to early-stage HCC, there is a • Patient with high HBV DNA level
strong rationale for emphasizing a regular surveillance program • Patient with family history of HCC
to screen for the tumor in at-risk persons. Current guidelines • Patient with active inflammation and increased alanine
of the American Association for the Study of Liver Diseases aminotransferase level
Figure 25.7. Liver Imaging Reporting and Data System (LI-RADS). LI-RADS was developed for systematic evaluation and reporting of liver
lesions suspected of being malignant. CT indicates computed tomography; LR-3, indeterminate for malignancy; LR-4, suspicious for malignancy; LR-
5, definite for malignancy; MRI, magnetic resonance imaging. (Adapted from Cerny M, Chernyak V, Olivié D, Billiard J-S, Murphy-Lavallée J, Kielar
AZ, et al. LI-RADS version 2018 ancillary features at MRI. Radiographics. 2018 38[7]:1973-2001; used with permission.)
✓ LI-RADS criteria for noninvasive diagnosis of HCC

• Arterial phase enhancement
• Portal and delayed venous phase washout
• Rim enhancement in the delayed phase
• Threshold growth of mass
• Diffusion-weighted imaging on MRI
Management
The most comprehensive staging algorithm with associated
treatment strategy used in Western countries is the Barcelona
Clinic Liver Cancer (BCLC) staging and treatment system, which
incorporates assessment of the physical and biomarker characteris-
tics of the tumor, degree of underlying liver dysfunction, and cancer-
related performance status to help with developing an optimal
strategy for patient management (Figure 25.9). The BCLC strategy
is revised regularly and has an appropriate bias toward therapies
that have been proved effective in phase 3 studies; it therefore
provides robust, evidence-based guidance for clinicians. The 2022
update of the BCLC system incorporates the use of transarterial
radioembolization (TARE) for single tumors up to 8 cm in size.
Therapies that are almost certainly effective for some patients with
HCC, but which need a confirmatory base of evidence, include ster-
eotactic body radiation therapy, proton beam therapy, and carbon
ion therapy. In the past few years, the number of systemic therapy
options for patients with HCC has greatly increased.
Liver Transplant. Liver resection and transplant offer the
greatest chance of cure for patients with HCC. The decision to
choose resection or transplant is based on a careful evaluation of
the comorbid conditions of the patient, liver function, tumor size,
number of tumors, vascular invasion, candidacy for transplant,
and organ availability. Transplant is an effective treatment option
for HCC in patients with cirrhosis because it addresses both the
neoplasm and the underlying liver disease. Initially, the outcomes
of transplant for HCC were poor. However, with advances in pa-
Figure 25.8. Hepatocellular Carcinoma. A, Arterial phase shows tient selection using the Milan criteria (1 tumor ≤5 cm or 2 or 3
vascular enhancement (arrow). B, Portal phase shows venous washout tumors ≤3 cm, without vascular invasion or extrahepatic spread),
(arrow). the 5-year survival rate is 70% to 80% and the recurrence rate is
less than 15%. Despite the favorable results of transplant, organ
availability is less than the demand, and up to 15% of patients
HCC can be diagnosed noninvasively if a new nodule larger listed for transplant drop out because of tumor progression before
than 1 cm is found in a cirrhotic liver during surveillance and an organ becomes available. With treatment, intermediate-stage
shows typical arterial enhancement and venous washout on HCC can be downstaged to within the Milan criteria, and patients
triphasic CT or MRI. Additional MRI features of HCC include can undergo transplant successfully with excellent outcomes.
contrast exclusion in the delayed biliary phase of imaging with
gadoxetate disodium and hyperintensity on diffusion-weighted Surgery. Liver resection is the preferred treatment of HCC in
imaging. The main rationale for noninvasive diagnosis in early- patients without cirrhosis and in those with cirrhosis who have
stage HCC is to prevent tumor seeding and recurrence after powell-preserved liver function and little or no portal hypertension.
tentially curative treatment, including liver transplant. Patients For patients without cirrhosis, major liver resection carries a low
who present with newly discovered liver masses in the absence mortality rate (<5%) and a 5-year survival rate of 30% to 50%.
of cirrhosis should have a biopsy study to histologically confirm Bleeding and liver failure are the major causes of perioperative
HCC because conditions such as lymphomas and metastases mortality among patients with cirrhosis who undergo liver resec-
from other primary sites may appear to be HCC in a noncirrhotic tion. Limited liver resections are safe in patients with cirrhosis
liver. Determination of the alpha fetoprotein level may obviate who have preserved liver function (Child-Pugh class A) and no
the need for biopsy if the level is markedly increased, but it is im- portal hypertension. Multiple methods of assessing liver function,
portant to consider that malignancies at other primary sites, no- liver reserve, and perioperative mortality have been described
tably esophageal and gastric carcinomas, also can be associated and are important in selecting patients for resection. The Model
with a high level of alpha fetoprotein. HCCs diagnosed at inter- for End-stage Liver Disease (MELD) has been shown to pre-
mediate or advanced stages should be biopsied without hesitation dict perioperative mortality after liver resection. Patients with a
because genomic and immunohistochemical characterization of MELD score less than 9 have a perioperative mortality rate of
these tumors may provide valuable information to confirm the 0%, compared with 29% for those with a score of 9 or more. The
diagnosis and guide optimal therapy. albumin-bilirubin score, based on albumin and bilirubin levels,
Figure 25.9. Barcelona Clinic Liver Cancer System. This system provides staging and treatment recommendations for patients with hepatocellular carcinoma (HCC). AFP indicates alpha fetoprotein;
ALBI, albumin-bilirubin; BSC, best supportive care; LT, liver transplant; MELD, Model for End-stage Liver Disease; PS, performance status; TACE, transarterial chemoembolization. (Adapted from Reig
M, Forner A, Rimola J, Ferrer-Fabrega J, Burrel M, Garcia-Criado A, et al. BCLC strategy for prognosis prediction and treatment recommendation: the 2022 update. J Hepatol. 2022 Mar;76[3]:681-93;
used with permission.)
provides another objective measure of underlying liver function. • Liver transplant—for persons with underlying liver disease (eg,
After liver resection, the tumor recurs in approximately 70% of cirrhosis) who would not have sufficient liver function after
patients within 5 years and reflects both intrahepatic metastases surgical resection, the entire liver is removed and replaced with
and the development of de novo tumors in the diseased liver. the liver from a deceased donor or with a portion of the liver
Predictors of recurrence and survival after resection include from a living donor
tumor size and number and vascular invasion. The 5-year survival
rate after liver resection is 30% to 50%. For ideal candidates (ie,
they have a single tumor, preserved liver function, and absence Locoregional Therapies. Locoregional therapies include
of portal hypertension), the 5-year survival rate is as high as 50% transarterial chemoembolization (TACE), TARE, stereotactic
to 70%. body radiation therapy, and proton beam therapy. TACE involves
the angiographic injection of a combination of chemotherapy
Local Ablation. Local therapies for treating HCC include abla- agents with absorbable gelatin sponge particles (Gelfoam; Pfizer
tive methods such as microwave ablation (MWA), radiofrequency Inc) into the branch of the hepatic artery that supplies the tumor.
ablation (RFA), and percutaneous ethanol injection (PEI). MWA The goal is to deliver high concentrations of antitumor agents
and RFA are more effective ablative treatments and are used more and, simultaneously, to induce tumor necrosis by occluding the
often than PEI in clinical practice. Both MWA and RFA have sim- arterial supply to the tumor. The chemotherapy agents typically
ilar efficacy as surgical resection in treating single, small (<2 cm) used for TACE include cisplatin, doxorubicin, and mitomycin
HCCs, but MWA can be used to treat a larger volume in less time. C. Some centers use chemotherapy agents dissolved in iodized
Ablation is generally used for treatment of small HCCs (≤3 cm) oil (Lipiodol; Guerbet LLC); however, this iodinated contrast
in patients who are not candidates for liver transplant or when agent can interfere with subsequent detection of arterial enhance-
liver transplant is not available. In MWA, electromagnetic energy ment in residual tumor nodules. TACE is particularly effective
is applied at 915 MHz or 2.45 GHz; in RFA, the frequency ranges in the treatment of HCC because almost all the blood supply
from 375 to 500 KHz. RFA typically produces complete necrosis to the tumor is from branches of the hepatic artery. In contrast,
of a 3-to 4-cm radius of tissue during a single 10-to 15-minute the benign liver has a dual blood supply, with 70% to 80% of
treatment, while MWA can create a larger area of necrosis within the blood supply provided by the portal vein and 20% to 30%
a 5-minute treatment. RFA can be applied to overlapping fields by the hepatic artery. Consequently, occlusion of the branches
to treat lesions larger than 3 cm, but it is not as effective for these of the hepatic artery to the tumor can be achieved without sub-
lesions. RFA is not effective for the treatment of tumors close to stantially compromising the blood supply to the surrounding
major blood vessels because a heat-sink effect causes rapid con- cirrhotic liver. The major contraindication to TACE is complete
duction of heat away from the tumor. MWA achieves more rapid obstruction of the portal vein, in which case concomitant ob-
and homogeneous heating of the tumor and higher intratumoral struction of the arterial supply can lead to hepatic ischemia and
temperatures, rendering it more effective and less susceptible to induce liver decompensation. Randomized controlled trials have
the heat sink effect from nearby blood vessels. Both modalities shown that TACE improves survival of patients with unresectable
can damage the biliary tree or other extrahepatic structures such intermediate-stage HCC. TACE is an alternative treatment option
as the diaphragm, stomach, or bowel if applied too close to the for patients with early-stage HCC when ablative treatment cannot
structures. Several early studies raised concerns about increased be performed safely because of the location of the tumor. TACE
risks of tumor seeding after ablation. Advances in the ablation also is used frequently for downsizing the tumor or as a bridging
technique have lowered this risk substantially. Most often, sur- treatment before liver transplant.
face lesions are approached through the liver parenchyma rather Drug-eluting bead TACE (DEB-TACE) uses porous DEBs
than through direct puncture of the liver surface. In addition, loaded with doxorubicin for chemoembolization. The beads lodge
the probe track is cauterized as the probe is being removed; this in the tumor capillaries and gradually release doxorubicin into
destroys and prevents dissemination of any residual HCC cells. the local environment. Theoretically, treatment of intrahepatic
PEI is performed under ultrasonographic guidance. Ethanol tumors with DEB-TACE is more sustained and causes fewer sys-
induces tumor necrosis and is particularly effective in the cir- temic adverse effects. Most studies suggest that its efficacy is
rhotic liver because the surrounding fibrotic tissue limits the similar to that of conventional TACE.
diffusion of the injected ethanol. Usually 2 or 3 injection sessions TARE delivers intratumoral radiation by transarterial injec-
are needed for complete ablation of the tumor. The low cost of tion of yttrium 90 radioactive microspheres following the prin-
this treatment makes it attractive for use where resources are ciples of TACE. TARE has been confirmed to be effective for the
limited. treatment of unresectable unifocal HCCs up to 8 cm in size, and
Alternative means of local ablation that are being used more safety and tolerability have been acceptable.
frequently include laser ablation and irreversible electroporation.
Cryoablation can be useful when the extent of tissue injury must Systemic or Targeted Therapy. For more than a decade, the
be closely monitored in real-time, such as for tissue near nerves multitargeting kinase inhibitor sorafenib was the mainstay of
in the pelvis. therapy for patients with advanced unresectable HCC. However,
for patients with advanced HCC, the current standard of care,
✓ HCC treatments that have the potential for cure of the disease which is more effective than sorafenib, is 1) the immune check-
• Local ablation—usually uses microwave energy applied to the point inhibitor atezolizumab in combination with the anti–vascular
tumor tissue to destroy the tissue with heat energy; is usually endothelial growth factor A antibody bevacizumab or 2) the
most effective for tumors less than 3 cm in diameter immune checkpoint inhibitor durvalumab, an anti–programmed
• Surgical resection—operative removal of a section of liver cell death ligand 1 monoclonal antibody, in combination with
containing a tumor along with a surrounding rim of uninvolved the anti–cytotoxic T-lymphocyte antigen-4 inhibitor ipilimumab.
liver to ensure removal of the whole tumor; if the tumor is Bevacizumab is contraindicated in persons who are at risk for var-
large, the remaining portion of liver must have sufficient func-
iceal bleeding. These persons can have variceal banding to com-
tional reserve to prevent development of liver failure
pletion or should use a regimen that does not contain bevacizumab.
If 1 of these combinations cannot be used, acceptable options of intrahepatic cholangiocarcinomas has been increasing over
for first-line treatment are sorafenib, lenvatinib, or durvalumab. the past 30 years. The most common symptom of extrahepatic
Second-line therapy includes 1) regorafenib, which can be used cholangiocarcinoma is painless jaundice due to obstruction of
for patients who have tolerated sorafenib; 2) cabozantinib, which biliary ducts. With tumors of the intrahepatic bile ducts, patients
has been shown to be effective; and 3) ramucirumab, which can often have pain without jaundice. With perihilar or intrahepatic
be used in patients who have an alpha fetoprotein level of at least tumors, jaundice often occurs later in the disease course and
400 ng/mL. Cabozantinib is recommended for third-line therapy is a marker of advanced disease. Other common symptoms in-
for patients who have not yet been exposed to this agent and who clude generalized itching, abdominal pain, weight loss, and fever.
could alternatively be entered into clinical trials. Pruritis usually is preceded by jaundice, but it may be the initial
presenting symptom of cholangiocarcinoma. The pain associated
with cholangiocarcinoma is usually a constant dull ache in the
Cholangiocarcinoma
right upper quadrant of the abdomen. Biliary obstruction results
Cholangiocarcinomas are malignancies that arise from the in clay-colored stools and dark urine. Physical signs include jaun-
bile duct epithelium. In Western countries, PSC is the primary dice, hepatomegaly, and a palpable right upper quadrant mass.
identified risk factor for cholangiocarcinoma. In several coun- Patients with intrahepatic cholangiocarcinoma most often present
tries in Asia, liver fluke infestations of the biliary tract are an with dull right upper quadrant discomfort and weight loss.
important risk factor. Choledochal and other cystic disorders of
the biliary tract also are associated with cholangiocarcinoma.
Patients with cirrhosis due to chronic viral hepatitis, alcoholic
liver disease, nonalcoholic fatty liver disease, or other chronic Abdominal Ultrasonography. Cholangiocarcinomas are typi
liver diseases are also at increased risk for cholangiocarcinoma. cally hypoechoic on ultrasonography and sometimes are first
However, most patients with cholangiocarcinoma have no known visualized during an ultrasonographic examination of the liver for
risk factors. For patients with PSC, the risk of diagnosis of suspected gallstone disease causing right upper quadrant abdom-
cholangiocarcinoma is highest within the first 2 years after the inal discomfort.
diagnosis of PSC, suggesting that the development of cancer may
Multiphasic CT. Intrahepatic cholangiocarcinomas are usu-
be the event that triggers the diagnosis of PSC.
ally hypodense on noncontrast imaging, often with a rounded,
Cholangiocarcinomas are classified as intrahepatic or
smooth, nodular appearance. During the arterial phase, there is
extrahepatic tumors. The manifestation of intrahepatic cholangio
minimal enhancement that progressively increases through the
carcinomas is typically a large intrahepatic mass with or without
venous phase, often more prominent peripherally than centrally.
intrahepatic or regional lymph node metastases. Extrahepatic
Perihilar cholangiocarcinomas that preferentially affect 1 lobe of
cholangiocarcinomas may be perihilar tumors, which arise in the
the liver often lead to unilobar biliary obstruction for an extended
distal right or left hepatic duct or at the common hepatic duct bifur-
period, during which the patient has a normal bilirubin level be-
cation, or distal bile duct tumors arising in the common bile duct.
cause of adequate biliary drainage from the unaffected lobe of
The laboratory test most often used to confirm the diagnosis of
the liver. Eventually, the affected lobe undergoes atrophy, with
cholangiocarcinoma is measurement of the CA19-9 level. CA19-9
prominent biliary dilatation, while the unaffected lobe undergoes
(also called monosialylated Lewis) is a sialyl-LewisA blood group
compensatory hypertrophy. This syndrome is called the atrophy-
antigen that is used clinically as a tumor marker. A CA19-9 value
hypertrophy complex (Figure 25.10). Cross-sectional imaging is
greater than 100 U/mL is about 65% to 75% sensitive and 85% to
particularly helpful for assessing the degree of encasement of the
95% specific for the diagnosis of cholangiocarcinoma. CA19-9
also can be increased in pancreatic adenocarcinomas and other
upper gastrointestinal tract malignancies. CA19-9 values greater
than 1,000 U/mL usually are predictive of extrahepatic metastatic
disease. During evaluation for diagnosis or posttreatment follow-
up of patients with cholangiocarcinoma, those who test negative
for Lewis antigen (7%-10% of the general population) cannot
synthesize CA19-9 and may erroneously be presumed to lack the
tumor marker.
Histologic Features
Histologically, cholangiocarcinomas are adenocarcinomas. This
frequently leads to confusion about the primary site of the tumor.
Thus, cholangiocarcinoma can be misdiagnosed as metastatic ad-
enocarcinoma of unknown primary site.
Clinical Features
The clinical features of cholangiocarcinoma depend on its loca-
tion. Approximately 60% of these tumors are perihilar tumors Figure 25.10. Cholangiocarcinoma With Atrophy-Hypertrophy
located around the bifurcation of the hepatic duct; the rest occur Complex. Note cholangiocarcinoma with obstruction of the left biliary
in the distal extrahepatic (20%) or intrahepatic (20%) biliary tree. ductal system (arrow) and consequent marked dilatation of the bile ducts
While the incidence of extrahepatic cholangiocarcinomas has in the left lobe, with associated atrophy of the left lobe parenchyma. The
been stable over time, in most industrial countries the incidence right lobe shows compensatory hypertrophy.
hilar vasculature, a critically important part of the evaluation for and ERCP may be needed for successful passage through a dif-
surgical resectability. ficult stricture to accomplish internal biliary drainage, which is
preferred to external drainage.
MRI With Gadolinium. With contrast-enhanced MRI, intra
hepatic cholangiocarcinomas are hypointense on T1-weighted
images and hyperintense on T2-weighted images. There is pe- Biopsy and Cytology
ripheral contrast enhancement that progresses into the venous Intrahepatic mass- forming cholangiocarcinomas usually are
phase, similar to the pattern seen with multiphasic CT. MRCP is biopsied under ultrasonographic or CT guidance. Often, ductal
performed concomitantly with MRI and is now recommended cholangiocarcinomas are less amenable to percutaneous needle
as the optimal initial investigation for assessing the luminal biopsy. Also, immune-associated cholangitis can mimic a malig-
extent and resectability of suspected cholangiocarcinoma. nant biliary stricture, rendering the accurate diagnosis of biliary
MRCP is noninvasive and as accurate as direct cholangi- strictures even more difficult. Transpapillary forceps biopsies and
ography for assessing the level of biliary tract obstruction. cytologic brushings usually are obtained at ERCP or PTC to help
Often, the biliary tract peripheral to a biliary stenosis can be establish the diagnosis. Because many cholangiocarcinomas are
demonstrated better with MRCP than with endoscopic retro- highly desmoplastic, with a prominent fibrous stromal component
grade cholangiopancreatography (ERCP). separating small islands of malignant epithelium, histologic and
cytologic confirmation of their malignancy can be challenging.
Cholangiography. With the advent of MRI and MRCP, di- Advanced cytologic tests for chromosomal polysomy such as
rect cholangiography by means of ERCP and percutaneous fluorescence in situ hybridization (FISH) have been shown to im-
transhepatic cholangiography (PTC) are becoming less impor- prove substantially the sensitivity of brush cytology for diagnosing
tant as initial diagnostic methods; however, the resolution pro- malignancy in biliary strictures. Cytology samples with cells
vided by PTC and ERCP is still better in some cases than that of that show polysomy of 2 or more relevant chromosomal loci—
MRCP. In addition to providing tissue samples by brush cytology from chromosomal bands 1q21, 7p12, 8q24, and 9p21 in the
or biopsy, PTC and ERCP allow placement of therapeutic stents pancreatobiliary FISH probe set—are highly specific for cancer
for biliary decompression if needed and also can be used to de- (Figure 25.11). The combination of transpapillary forceps biopsy,
liver photodynamic therapy or RFA to unresectable tumors. In cytology, and pancreatobiliary FISH has been shown to have the
patients with PSC, PTC may be challenging technically because highest sensitivity for diagnosing malignancy in biliary strictures.
of peripheral strictures; for these patients, ERCP is the preferred
method. A completely occluded distal biliary tract may preclude Endoscopic Ultrasonography. Endoscopic ultrasonography
the use of ERCP, and either PTC or a combined approach of PTC with an ultrasound probe at the tip of a duodenoscope allows
Figure 25.11. Pancreatobiliary Fluorescence In Situ Hybridization (PB-FISH) for Diagnosis of Malignancy in Biliary Strictures. Fluorescent
DNA probes for chromosomal bands 1q21/MCL1 in yellow, 7p12/EGFR in green, 8q24/MYC in aqua, and 9p21/CDKN2A in red are hybridized to
brush cytology specimens obtained from biliary strictures at endoscopic retrograde cholangiopancreatography. The normal disomic cell has 2 copies
of each of the probes. The malignant polysomic cells have 6 copies of chromosomes 1q21/MCL1, 4 copies of 7p12/EGFR, 3 or 4 copies of 8q24/MYC,
and 2 copies of 9p21/CDKN2A. (Courtesy of Emily G. Barr Fritcher, CT[ASCP], MB[ASCP], and Benjamin R. Kipp, PhD, Department of Laboratory
Medicine and Pathology, Mayo Clinic; used with permission.)
high-resolution evaluation of the left lobe of the liver and appear to be acceptable for patients who have early- stage
fine-
needle aspiration of lymph nodes at the hepatic hilum. intrahepatic cholangiocarcinoma that has been mistaken for
This technique is extremely useful for assessing the presence HCC and who are enrolled in liver transplant protocols for HCC.
and malignancy of regional lymph nodules during staging of
cholangiocarcinomas.
Systemic Chemotherapy
Various chemotherapy agents have been evaluated for the treat
Management ment of cholangiocarcinoma, but for many years there was only
Surgery. Hilar cholangiocarcinoma accounts for two- a limited response to these agents. Until recently, the standard
thirds of all cases of extrahepatic cholangiocarcinoma. of care was gemcitabine given in combination with either cis-
Intrahepatic cholangiocarcinoma is treated with surgical re- platin or oxaliplatin. In a phase 3 clinical trial, the regimen of
section when feasible. Tumors in the mid bile duct can be gemcitabine in combination with cisplatin produced tumor con-
treated with resection and anastomosis of the bile duct. trol (complete or partial response or stable disease) in 81.4% of
Distal extrahepatic cholangiocarcinomas are treated with patients, but this response was not sustained, with a median sur-
pancreaticoduodenectomy. For hilar cholangiocarcinomas, vival of 11.7 months compared to 8.1 months for treatment with
surgical planning is more complex and preoperative evalua- gemcitabine alone. Recently, the use of durvalumab in combi-
tion of the local and regional extent of the tumor is critical. nation with gemcitabine and cisplatin was approved as first-line
Cross- sectional imaging and cholangiography (either direct treatment. The addition of durvalumab in a phase 3 trial (TOPAZ-
or MRCP) are necessary for appropriate patient selection and 1) led to a 12.8-month median overall survival compared to an
surgical planning. Current criteria that preclude resection in- 11.5-month overall survival with gemcitabine and cisplatin alone.
clude 1) bilateral ductal extension to secondary radicles; 2) en- Over the past few years, genomic analyses of cholangiocar
casement or occlusion of the main portal vein; 3) lobar atrophy cinomas have shown that intrahepatic cholangiocarcinomas have
with involvement of the contralateral portal vein, hepatic ar- a relatively high prevalence of targetable mutations or alterations,
tery, or secondary biliary radicles; 4) peripancreatic (head including fibroblast growth factor receptor 2 gene fusions in 10%
only), periduodenal, posterior pancreatoduodenal, periportal, to 20% and sequence variations in the isocitrate dehydrogenase
celiac, or superior mesenteric regional lymph node metastases; 1 gene (IDH1; OMIM 147700) in 15% to 20%. The fibroblast
and 5) distant metastases. The perioperative mortality rate of growth factor receptor inhibitors pemigatinib and infigratinib
hepatic resection for hilar cholangiocarcinoma is between 5% and the inhibitor of isocitrate dehydrogenase 1, ivosidenib, are
and 10% in major centers. The operation of choice for hilar approved for treatment of intrahepatic cholangiocarcinomas that
cholangiocarcinoma is cholecystectomy, lobar or extended lobar have the relevant sequence variations. Approximately 1% to
hepatic and bile duct resection, regional lymphadenectomy, and 2% of cholangiocarcinomas also have a defective mismatch re-
Roux-en-Y hepaticojejunostomy. With surgical resection, the 5- pair system, microsatellite instability, increased levels of tumor
year survival rate is 20% to 25%. Patients with PSC often have neoantigens, and a highly immune-infiltrative tumor microen-
cirrhosis and are not candidates for surgical resection because vironment, rendering them highly sensitive to treatment with
of concerns about postoperative hepatic decompensation. immune checkpoint inhibitors. Neurotrophic tyrosine receptor
kinase gene (NTRK) fusions of the C-terminal of the tropomy-
Liver Transplant. A protocol of neoadjuvant chemoradiotherapy osin receptor kinase with an N-terminal fusion partner, leading to
with subsequent liver transplant for patients with de novo hilar ligand-independent phosphorylation and activation, occur in less
cholangiocarcinoma or cholangiocarcinoma arising in associa- than 1% of cholangiocarcinomas, and the tropomyosin receptor
tion with PSC has been developed at Mayo Clinic in Rochester, kinase inhibitors entrectinib and larotrectinib show meaningful
Minnesota. The protocol is limited to patients who have a mass responses in these tumors.
with a radial diameter up to 3 cm and excludes patients who have
intrahepatic peripheral cholangiocarcinoma, metastases, or gall- Maintenance of Biliary Patency. For patients with unre
bladder involvement. Endoscopic ultrasonography is performed sectable tumor causing biliary obstruction, the maintenance of
with directed aspiration to rule out involvement of regional he- biliary patency is required for substantial survival. This usually is
patic lymph nodes. Patients are treated initially with preopera- achieved with the use of plastic endobiliary stents, which gener-
tive radiotherapy (40.5-45 Gy, given as 1.5 Gy twice daily) and ally remain patent for 8 to 12 weeks, or metal stents, which may
5-fluorouracil. This is followed by 20-to 30-Gy transcatheter ir- remain patent for more than a year. Unilateral drainage is gener-
radiation with iridium. Capecitabine is then administered until ally sufficient for palliation of biliary obstruction and is associated
transplant. Before transplant, patients undergo staging abdom- with fewer complications than bilateral stenting. Photodynamic
inal exploration. Regional lymph node metastases, peritoneal therapy is applied endoscopically through a glass fiber inserted
metastases, or locally extensive disease preclude transplant. At to the site of the malignant biliary stricture. The therapy is
the time of the last published review of patients treated since administered by intravenous infusion of the photosensitizer
1993, overall 5-year survival was 74% for patients with PSC porfimer sodium (Photofrin; Pinnacle Biologics, Inc) that pref-
and 58% for those with de novo perihilar cholangiocarcinoma. erentially accumulates in the proliferating tumor tissue, followed
These results exceed those achieved with surgical resection even 48 hours later with endoscopic or percutaneous application of a
though all the transplant protocol patients have unresectable laser light tuned to the appropriate wavelength. Overall, photody-
cholangiocarcinoma or cholangiocarcinoma arising in associa- namic therapy appears to be associated with increased survival,
tion with PSC. improved biliary drainage, and enhanced quality of life. However,
Attempts have been made to implement liver transplant the quality of evidence is low and additional randomized trials are
protocols for patients who have limited- stage intrahepatic warranted. More recently, RFA has also been used in the bile duct
cholangiocarcinoma. The rationale is that long-term outcomes to palliate unresectable biliary tract cancer.
Liver Metastases biliary strictures compared with patients with primary sclerosing cho-
langitis. Gastrointest Endosc. 2022 May;95(5):884–92.
Liver metastases from other primary cancer sites are the most Barr Fritcher EG, Voss JS, Brankley SM, Campion MB, Jenkins SM,
frequent malignant liver masses. Metastases are most com- Keeney ME, et al. An optimized set of fluorescence in situ hybridiza-
monly from colorectal adenocarcinomas but also frequently tion probes for detection of pancreatobiliary tract cancer in cytology
occur in patients with lung, pancreatic, esophageal, gastric, neu- brush samples. Gastroenterology. 2015 Dec;149(7):1813–24.
roendocrine, or breast cancer. Other potential primary tumors Bioulac-Sage P, Taouji S, Possenti L, Balabaud C. Hepatocellular ade-
include lymphomas, melanomas, thyroid cancers, and renal cell noma subtypes: the impact of overweight and obesity. Liver Int. 2012
carcinomas. Most often, liver metastases are multiple and dis- Sep;32(8):1217–21.
Bokemeyer A, Matern P, Bettenworth D, Cordes F, Nowacki TM,
tributed throughout both lobes of the liver. They tend not to have
Heinzow H, et al. Endoscopic radiofrequency ablation prolongs
a large dominant lesion with multiple smaller satellite lesions, a survival of patients with unresectable hilar cholangiocellular carci-
feature that is more characteristic of primary liver tumors such noma: a case-control study. Sci Rep. 2019 Sep 23;9(1):13685.
as HCC and cholangiocarcinoma. Liver metastases have various Bunchorntavakul C, Bahirwani R, Drazek D, Soulen MC, Siegelman ES,
imaging characteristics, depending on the degree of vascularity. Furth EE, et al. Clinical features and natural history of hepatocellular
Most commonly, they show persistent enhancement in the portal adenomas: the impact of obesity. Aliment Pharmacol Ther. 2011
venous and venous phases of multiphasic cross-sectional CT or Sep;34(6):664–74.
MRI studies. Some metastases also have a characteristic “halo” Chaiteerakij R, Yang JD, Harmsen WS, Slettedahl SW, Mettler TA,
of nonenhancing tissue around the nodule. For certain tumor Fredericksen ZS, et al. Risk factors for intrahepatic cholangio
types, such as colorectal adenocarcinomas, FDG-PET CT is ex- carcinoma: association between metformin use and reduced cancer
risk. Hepatology. 2013 Feb;57(2):648–55.
tremely valuable for characterizing the burden of metastatic di-
Choi BY, Nguyen MH. The diagnosis and management of benign hepatic
sease. Limited disease with only a few metastatic nodules can tumors. J Clin Gastroenterol. 2005 May-Jun;39(5):401–12.
be treated with surgical resection, local ablation, stereotactic El-Serag HB, Rudolph KL. Hepatocellular carcinoma: Epidemiology and
body radiotherapy, or proton beam therapy. For metastases that molecular carcinogenesis. Gastroenterology. 2007 Jun;132(7):2557–76.
are more diffuse within the liver, locoregional therapy with Finn RS, Qin S, Ikeda M, Galle PR, Ducreux M, Kim TY, et al.
TARE can be administered in combination with systemic che- Atezolizumab plus bevacizumab in unresectable hepatocellular car-
motherapy appropriate for the primary tumor. cinoma. N Engl J Med. 2020 May;382(20):1894–905.
Forner A, Vilana R, Ayuso C, Bianchi L, Sole M, Ayuso JR, et al.
Diagnosis of hepatic nodules 20 mm or smaller in cirrhosis: prospec-
Summary tive validation of the noninvasive diagnostic criteria for hepatocellular
A wide range of liver mass lesions initially may or may not pro- carcinoma. Hepatology. 2008 Jan;47(1):97–104.
Javle M, Roychowdhury S, Kelley RK, Sadeghi S, Macarulla T, Weiss
duce symptoms. Many masses are found incidentally during
KH, et al. Infigratinib (BGJ398) in previously treated patients with
imaging for nonspecific abdominal symptoms. Accurate differ- advanced or metastatic cholangiocarcinoma with FGFR2 fusions
entiation of benign lesions from malignant lesions depends on or rearrangements: mature results from a multicentre, open-label,
obtaining a complete history and performing a physical exam- single-arm, phase 2 study. Lancet Gastroenterol Hepatol. 2021
ination and appropriate laboratory tests. Most benign lesions Oct;6(10):803–15.
require no intervention, but an important subset requires mul- La Bella T, Imbeaud S, Peneau C, Mami I, Datta S, Bayard Q, et al.
tidisciplinary evaluation with subsequent surgical resection or Adeno-associated virus in the liver: natural history and consequences
other treatments. in tumour development. Gut. 2020 Apr;69(4):737–47.
La Vecchia C, Tavani A. Female hormones and benign liver tumours. Dig
Liver Dis. 2006 Aug;38(8):535–6.
Suggested Reading Lammert C, Toal E, Mathur K, Khungar V, House M, Roberts LR, et al.
Abou-Alfa GK, Sahai V, Hollebecque A, Vaccaro G, Melisi D, Al-Rajabi Large hepatic adenomas and hepatic adenomatosis: a multicenter
R, et al. Pemigatinib for previously treated, locally advanced or met- study of risk factors, interventions, and complications. Am J
astatic cholangiocarcinoma: a multicentre, open-label, phase 2 study. Gastroenterol. 2022 Jul;117(7):1089–96.
Lancet Oncol. 2020 May;21(5):671–84. Leggett CL, Gorospe EC, Murad MH, Montori VM, Baron TH, Wang KK.
Alberts SR, Gores GJ, Kim GP, Roberts LR, Kendrick ML, Rosen CB, Photodynamic therapy for unresectable cholangiocarcinoma: a compar-
et al. Treatment options for hepatobiliary and pancreatic cancer. ative effectiveness systematic review and meta-analyses. Photodiagnosis
Mayo Clin Proc. 2007 May;82(5):628–37. Photodyn Ther. 2012 Sep;9(3):189–95.
Asrani SK, Ghabril MS, Kuo A, Merriman RB, Morgan T, Parikh Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, et al.
ND, et al. Quality measures in HCC care by the Practice Metrics Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008
Committee of the American Association for the Study of Liver Jul;359(4):378–90.
Diseases. Hepatology. 2022 May;75(5):1289–99. Moreno-Luna LE, Yang JD, Sanchez W, Paz-Fumagalli R, Harnois DM,
Atassi B, Bangash AK, Bahrani A, Pizzi G, Lewandowski RJ, Ryu RK, Mettler TA, et al. Efficacy and safety of transarterial radioembolization
et al. Multimodality imaging following 90Y radioembolization: a versus chemoembolization in patients with hepatocellular carcinoma.
comprehensive review and pictorial essay. Radiographics. 2008 Jan- Cardiovasc Intervent Radiol. 2013 Jun;36(3):714–23.
Feb;28(1): 81–99. Nault JC, Bioulac- Sage P, Zucman- Rossi J. Hepatocellular benign
Azad AI, Rosen CB, Taner T, Heimbach JK, Gores GJ. Selected patients tumors-from molecular classification to personalized clinical care.
with unresectable perihilar cholangiocarcinoma (pCCA) derive Gastroenterology. 2013 May;144(5):888–902.
long-term benefit from liver transplantation. Cancers (Basel). 2020 Oseini AM, Chaiteerakij R, Shire AM, Ghazale A, Kaiya J, Moser CD,
Oct;12(11) et al. Utility of serum immunoglobulin G4 in distinguishing immu-
Banales JM, Marin JJG, Lamarca A, Rodrigues PM, Khan SA, noglobulin G4- associated cholangitis from cholangiocarcinoma.
Roberts LR, et al. Cholangiocarcinoma 2020: the next horizon in Hepatology. 2011 Sep 2;54(3):940–8.
mechanisms and management. Nat Rev Gastroenterol Hepatol. 2020 Parra-Robert M, Santos VM, Canis SM, Pla XF, Fradera JMA,
Sep;17(9):557–88. Porto RM. Relationship between CA 19.9 and the Lewis pheno-
Baroud S, Sahakian AJ, Sawas T, Storm AC, Martin JA, Abu Dayyeh type: options to improve diagnostic efficiency. Anticancer Res. 2018
BK, et al. Impact of trimodality sampling on detection of malignant Oct;38(10):5883–8.
Razumilava N, Gores GJ. Classification, diagnosis, and manage- Valle J, Wasan H, Palmer DH, Cunningham D, Anthoney A, Maraveyas
ment of cholangiocarcinoma. Clin Gastroenterol Hepatol. 2013 A, et al. Cisplatin plus gemcitabine versus gemcitabine for biliary
Jan;11(1):13–21. tract cancer. N Engl J Med. 2010 Apr;362(14):1273–81.
Reig M, Forner A, Rimola J, Ferrer-Fabrega J, Burrel M, Garcia-Criado Valls C, Iannacconne R, Alba E, Murakami T, Hori M, Passariello R,
A, et al. BCLC strategy for prognosis prediction and treatment rec- et al. Fat in the liver: diagnosis and characterization. Eur Radiol.
ommendation: the 2022 update. J Hepatol. 2022 Mar;76(3):681–93. 2006;16(10):2292–308.
Salem R, Johnson GE, Kim E, Riaz A, Bishay V, Boucher E, et al. Yttrium- Yang JD, Kim B, Sanderson SO, Sauver JS, Yawn BP, Larson JJ, et al.
90 radioembolization for the treatment of solitary, unresectable Biliary tract cancers in Olmsted County, Minnesota, 1976-2008. Am
HCC: the LEGACY study. Hepatology. 2021 Nov;74(5):2342–52. J Gastroenterol. 2012 Aug;107(8):1256–62.
Sempoux C, Chang C, Gouw A, Chiche L, Zucman-Rossi J, Balabaud C, Zhu AX, Macarulla T, Javle MM, Kelley RK, Lubner SJ, Adeva J, et al. Final
et al. Benign hepatocellular nodules: what have we learned using the overall survival efficacy results of ivosidenib for patients with advanced
patho-molecular classification. Clin Res Hepatol Gastroenterol. 2013 cholangiocarcinoma with IDH1 mutation: the phase 3 randomized clin-
Sep;37(4):322–7. ical ClarIDHy trial. JAMA Oncol. 2021 Nov 1;7(11):1669–77.
26
Alcohol-Related Liver Diseasea

ROBERT C. HUEBERT, MD
VIJAY H. SHAH, MD
Epidemiology and Clinical Spectrum (alcoholic hepatitis); and 3) end- stage chronic liver disease
(alcohol-related cirrhosis). Fatty liver can develop in response to
Public Health Significance
short, transient periods (ie, days) of alcohol misuse. It is gener-
Alcohol-related liver disease is a major cause of morbidity and ally asymptomatic or associated with nonspecific symptoms and
mortality worldwide. Globally, approximately 2 billion people con- is usually reversible with abstinence. This type of simple stea-
sume alcohol, and alcohol use disorder is diagnosed in more than 75 tosis develops in 90% to 100% of regular users of alcohol. More
million people—and these numbers are probably underestimates. advanced liver injury usually requires prolonged alcohol misuse
In the US, chronic liver disease is the 12th leading cause of death, over a period of years. Of note, more advanced lesions of alcohol-
and alcohol is implicated in approximately 50% of these deaths. related liver disease do not develop in the majority of people who
Also, alcohol-related liver disease is a major source of health care misuse alcohol for extended periods. However, alcohol-related
expenditures, accounting for nearly $5 billion annually. Alcohol- steatohepatitis develops in 20% of these people, and in approx-
related liver disease is the leading indication for liver transplant imately half of those the disease progresses further to alcohol-
in the US. Recent increases in deaths due to alcohol-related liver related cirrhosis. Overall, accounting for some improvement
disease are skewed toward younger age groups (25-34 years), and during periods of abstinence, end-stage alcohol-related liver dis
deaths due to alcohol-related liver disease are projected to increase ease develops in about 20% of people with alcohol use disorder.
in the coming years, particularly among women.
✓ Steatosis—simple fatty infiltration of the liver (most commonly
caused by metabolic disease)
Clinical Spectrum
✓ Steatohepatitis—fatty infiltration of the liver and associated in-
The clinical spectrum of alcohol-related liver disease includes 1) flammation with or without fibrosis
simple macrovesicular steatosis (fatty liver), with or without ✓ Nonalcohol-related fatty liver disease—liver disease in a person
abnormal results on liver tests; 2) severe acute steatohepatitis who consumes less than 20 g alcohol daily

a
Portions previously published in Menon KV, Gores GJ, Shah VH.
Pathogenesis, diagnosis, and treatment of alcoholic liver disease. Mayo Risk Factors
Clin Proc. 2001 Oct;76(10):1021- 9; used with permission of Mayo Alcohol Ingestion
Foundation for Medical Education and Research.
The most obvious and important factors in the development of
Abbreviations: ALT, alanine aminotransferase; AST, aspartate
aminotransferase; AUDIT, Alcohol Use Disorders Identification Test; alcohol-related liver disease are dose and duration of alcohol misuse.
CYP2E1, cytochrome P450 2E1 isozyme; GGT, γ-glutamyltransferase; Although alcohol-related fatty liver may develop in response to
HCV, hepatitis C virus; MDF, Maddrey discriminant function; MELD, short periods of alcohol misuse, such as for only a few days, more
Model for End- stage Liver Disease; MEOS, microsomal ethanol- advanced and morbid liver injury requires prolonged misuse of
oxidizing system; TNF, tumor necrosis factor alcohol. In general, the amount of ethanol consumption required
315
for the development of advanced forms of alcohol-related liver di- ✓ The global burden of alcohol- related liver disease is high,
sease is 60 to 80 g of alcohol daily for men, or the approximate accounting for considerable morbidity, mortality, and cost, and its
equivalent of 6 to 8 drinks daily for several years. In women, half prevalence is probably underestimated
this amount may cause clinically significant alcohol-related liver ✓ Alcohol- related liver disease encompasses a clinicohistologic
disease. The quantity of alcohol necessary for liver injury probably spectrum that includes fatty liver, alcohol-related hepatitis, and
does not depend on the type of alcohol consumed. However, there cirrhosis
is considerable individual variability in the threshold of alcohol ✓ Although fatty liver occurs nearly uniformly with excessive al-
necessary for advanced alcohol-related liver disease to develop. cohol consumption, more advanced liver injury occurs in only
Clearly, factors other than sex and absolute quantities of ethanol 15% to 20% of persons who continue to misuse alcohol
✓ While there is considerable variability among persons, the quan-
consumption are important in determining which persons develop
tity of alcohol necessary for advanced liver injury to develop is
alcohol-related liver disease, including ethnicity (eg, American probably 60 to 80 g (6-8 drinks) daily for several years, with a
Indians and Alaskan natives), metabolic comorbidities (eg, obe- much lower threshold for women
sity, iron overload, and type 2 diabetes), coexisting liver disease ✓ Genetic factors contribute to alcohol- related liver disease by
(eg, viral hepatitis), postsurgical anatomy (eg, Roux-en-Y gastric predisposing a person to alcohol use disorder and to alcohol-
bypass), and genetic factors (eg, PNPLA3 gene [OMIM 609567] induced liver injury
alterations and α1-antitrypsin heterozygosity).
Sex Ethanol Metabolism and Pathophysiology

Alcohol-related liver disease occurs more commonly in men More than 1 enzyme system is capable of metabolizing alcohol in
than in women, since men are statistically more likely to misuse the liver. Enzymes that have received the most attention include
alcohol. However, women are predisposed to the development alcohol dehydrogenase, aldehyde dehydrogenase, and the micro-
of this disease, and more severe disease develops in women somal ethanol-oxidizing system (MEOS) (Figure 26.1). Although
with less alcohol consumption than in men. The reason for this the peroxisomal catalase enzyme is also capable of ethanol me-
greater risk in women is multifactorial, but a similar level of tabolism, its physiologic role in alcohol metabolism appears to
alcohol consumption results in higher blood alcohol levels in be minor.
women than in men. Contributors to this phenomenon include a When physiologic circumstances are normal and blood levels
relative deficiency of gastric alcohol dehydrogenase in women, of alcohol are low, the most important enzyme is alcohol dehy-
sex differences in alcohol bioavailability, and female hormone– drogenase. This enzyme catalyzes the conversion of alcohol to ac-
related effects. etaldehyde, and aldehyde dehydrogenase subsequently catalyzes
the conversion of acetaldehyde to acetate. Alcohol dehydrogenase
catalysis changes the oxidation- reduction state in the cell by
Genetic and Hereditary Factors increasing the ratio of reduced nicotinamide adenine dinucleotide
The interindividual variability in the correlation between al- to the oxidized form, which has important implications for other
cohol consumption and development of liver disease emphasizes cellular processes, including the generation of free radicals, inhi-
that genetic factors may predispose a person to alcohol-induced bition of other enzyme systems, and accumulation of fat. Also,
liver toxicity. Specific genetic alterations have been detected in an isoform of alcohol dehydrogenase occurs within the gastric
patients who have alcohol-related liver disease, notably varia- mucosa. Although the clinical importance of the gastric compo-
tions in the HSD17B13 gene (OMIM 612127), the TM6SF2 gene nent of alcohol metabolism is debated, up to a quarter of alcohol
(OMIM 606563), the alcohol- metabolizing enzyme systems, metabolism may occur there, and sex-based differences in the
and the PNPLA3 gene. It also appears that milder phenotypes activity of this isoform may help to explain why women have a
of diseases known to cause chronic liver disease may predis- lower threshold for alcohol-induced liver damage.
pose individuals to alcohol-induced liver damage. Examples of The MEOS is localized in the endoplasmic reticulum of
this effect include compound heterozygosity at the hereditary the hepatocyte, whereas the alcohol dehydrogenase system
hemochromatosis locus or an MZ α1-antitrypsin phenotype. In operates in the cytosol. The MEOS appears to be more impor-
addition to the genetic factors predisposing certain persons who tant in alcohol metabolism when blood levels of alcohol are
misuse alcohol to liver disease, there also is strong evidence that moderate to high. Under normal conditions when alcohol levels
genetic factors predispose persons to alcohol use disorder itself. are low, the role of the MEOS is much smaller than that of the
Currently, however, no single genetic polymorphism has been alcohol dehydrogenase system. As explained by its enzyme ki-
shown definitively to contribute to alcohol-related liver disease. netics, the MEOS has a greater role in cases of chronic alcohol
Figure 26.1. Alcohol Metabolism. Alcohol is metabolized to acetaldehyde by alcohol dehydrogenase and cytochrome P450 2E1 isozyme
(CYP2E1). In most persons, the alcohol dehydrogenase pathway is dominant; however, in persons with alcohol use disorder and those with high blood
levels of alcohol, CYP2E1 is induced and has a major role in metabolism. Acetaldehyde derived from both these pathways is metabolized by aldehyde
dehydrogenase to acetate. MEOS indicates microsomal ethanol-oxidizing system.
26. Alcohol-Related Liver Disease 317
use because it is induced by alcohol, thereby allowing progres- This patient has clinical features suggestive of alcohol-related
sively increased ethanol metabolism in people with alcohol use fatty liver. The diagnosis and treatment are discussed below.
disorder. The MEOS also converts alcohol to acetaldehyde,
requiring aldehyde dehydrogenase for further metabolism.
History and Physical Examination
Importantly, the specific MEOS enzyme cytochrome P450 2E1
isozyme (CYP2E1) is responsible for the metabolism of var- Bland macrovesicular hepatic steatosis, without necroinflammatory
ious other compounds. The induction of CYP2E1 by alcohol activity, may develop in response to only a transient alcohol insult
affects blood levels of these compounds and accounts for the over a period of days. The most salient historic feature is an alcohol
increased tolerance to sedatives for persons who have alcohol binge. Liver steatosis results almost universally in those who con-
use disorder. Other compounds that are metabolized rapidly by sume alcohol regularly. Patients with fatty liver may be entirely
this process in persons with alcohol use disorder include isoni- asymptomatic or may complain of mild, nonspecific symptoms,
azid and, importantly, acetaminophen. including fatigue, malaise, abdominal discomfort, and anorexia.
Nearly half the people in eastern and southeastern Asia are On physical examination, tender hepatomegaly may be prominent.
deficient in aldehyde dehydrogenase activity because of the in- Stigmata of chronic liver disease are absent, and in many patients,
heritance of an allelic variation. This can result in excess accu- the physical examination findings are normal.
mulation of aldehyde, accounting for alcohol-induced flushing
symptoms in these persons. A similar flushing syndrome is Laboratory and Radiographic Features
observed in response to alcohol consumption when a person
ingests disulfiram, which is the basis for its use in the treatment Laboratory studies may show mild to moderate increases in the
of alcoholism. serum levels of aminotransferases, predominantly an increase in
Experimental evidence suggests that the alcohol metabo- AST. The classic 2:1 ratio of AST to ALT is not pathognomonic,
lite acetaldehyde may be a toxic mediator of alcohol-induced but since AST exists both in the cytosol and in the mitochondria
liver injury. The mechanism by which alcohol and acetaldehyde and since alcohol is a mitochondrial toxin, the AST level is
cause liver injury is being investigated. The initiation of fat ac- typically higher than the ALT level. In addition, ALT produc-
cumulation within the liver appears to occur in response to the tion requires vitamin B6, which is depleted during alcohol me-
decreased oxidation and increased accumulation of fatty acids. tabolism. Minor increases in alkaline phosphatase or bilirubin
These events may be linked to changes in the liver oxidation- (or both) may also be observed. Prothrombin time is generally
reduction state induced by ethanol metabolism. Other important normal. As in the above case, laboratory abnormalities often are
physiologic events that mediate liver injury include increased noted incidentally in an asymptomatic person.
oxidative stress, hepatocyte apoptosis and necrosis, and depo-
sition of collagen, with ensuing fibrosis through activation of Histologic Features
hepatic stellate cells. Various cytokines, transcription factors,
Generally, liver biopsy is not necessary to establish the diagnosis
and intracellular signaling pathways have been implicated in
of alcohol-related fatty liver because the condition is benign and
these events.
reversible. However, biopsy may be performed to determine
✓ Alcohol dehydrogenase is the primary alcohol- metabolizing whether the patient has more advanced alcohol-related liver dis
pathway, particularly when blood alcohol levels are low ease or another condition. The principal feature of alcohol-related
✓ The microsomal ethanol-oxidizing system is important in persons fatty liver in biopsy specimens is macrovesicular steatosis within
with alcohol use disorder, especially when blood levels of alcohol hepatocytes (Figure 26.2). There are no inflammatory cells or
are high, and induction of this system affects the metabolism of collagen deposition. Because biopsy specimens from patients
various xenobiotics, including sedatives and acetaminophen with other causes of chronic liver disease can also feature stea-
✓ Diminished activity of aldehyde dehydrogenase accounts for the tosis, an evaluation for these entities is sometimes advocated. It
flushing syndrome detected in a large proportion of Asians who is noteworthy that certain classic causes of microvesicular stea-
consume alcohol and in patients who take disulfiram tosis and macrovesicular steatosis can be identified in addition
to a mixed macrovesicular-microvesicular pattern (Box 26.1). An
evaluation of ceruloplasmin (to screen for Wilson disease), hepa-
Fatty Liver titis C status, α1-antitrypsin phenotype, and iron stores is reason-
able for young patients who have steatosis and abnormal levels
Clinical Presentation
of enzymes.
A 22-year-old male college student has a series of laboratory
tests performed during a routine checkup at the student health Prognosis and Treatment
clinic. He is asymptomatic, and the physical examination
findings are normal. He takes no medications and has no family No specific treatment other than abstinence is required for man-
history of liver disease. He is not sexually active and says he agement of alcohol-related fatty liver. If abstinence is achieved,
does not use intravenous or intranasal drugs, has not traveled re- alcohol-related fatty liver is usually reversible. However, 20%
cently, and has not had blood transfusions. Laboratory findings to 30% of patients who continue to drink excessive amounts of
include the following: aspartate aminotransferase (AST) 65 U/ alcohol chronically develop more advanced forms of alcohol-
L (reference range, 8-48 U/L); alanine aminotransferase (ALT) related liver disease, including alcohol-related hepatitis or cir-
43 U/ L (reference range, 7- 55 U/ L); γ-glutamyltransferase rhosis (or both).
(GGT) 336 U/L (reference range, 9-31 U/L); mean corpuscular
✓ Alcohol-related fatty liver may develop in response to short
volume, normal; and total bilirubin and alkaline phosphatase
periods of alcohol misuse, although it is more common with
levels, normal. On further questioning, the patient admits to chronic alcohol use disorder
having had 6 to 10 drinks daily over the past week during stu- ✓ Treatment—abstinence or more judicious consumption of alcohol

dent orientation.
Figure 26.2. Histopathologic Features of Alcohol-Related Liver Disease. A, Fatty liver. Note the macrovesicular steatosis and lack of inflamma-
tion and collagen deposition (hematoxylin-eosin). B, Alcohol-related hepatitis. Note the polymorphonuclear infiltrates, hepatocyte necrosis, steatosis,
Mallory bodies, and variable amounts of fibrosis (hematoxylin-eosin). C, Alcohol-related cirrhosis. Note the characteristic micronodular cirrhosis,
although a mixed nodularity pattern is often observed (trichrome). Frequently, there is prominent secondary hemosiderosis. (Adapted from Kanel GC,
Korula J. Liver biopsy evaluation: histologic diagnosis and clinical correlations. Philadelphia [PA]: WB Saunders Company; 2000:39, 89, 94; used with
permission.)
Severe Alcohol-Related Hepatitis This patient has the clinical features typical of severe alcohol-
related hepatitis. The diagnosis and treatment are discussed below.
A 36-year-old man describes having fatigue, dark urine, and ab-
History and Physical Examination
dominal swelling. He admits to drinking a few beers daily since
his teen years, but he has never had a major medical problem. A constellation of clinical symptoms, often nonspecific, are fre-
Recently, he has been drinking more heavily while unemployed. quently present in patients with more advanced lesions, such
He states that he has not had blood transfusions and does not use as alcohol-related hepatitis. Men who drink more than 60 to 80
intravenous drugs. Physical examination findings are remarkable g of alcohol daily for a period of years are at risk for alcohol-
for tachycardia and low-grade fever. He has prominent scleral related hepatitis; the threshold is approximately half this amount
icterus, and the abdominal examination shows shifting dullness. for women. Also, alcohol-related hepatitis may develop in the
The liver span is increased on percussion. presence or absence of underlying liver cirrhosis. The clinical
hyperdynamic circulation. Other findings depend on the severity

Box 26.1. Causes of Macrovesicular and Microvesicular of liver insult, the presence or absence of concomitant cirrhosis,
Steatosis and the presence or absence of portal hypertension. These findings
Causes of macrovesicular steatosis may include jaundice, splenomegaly, collateral vessels, hypogon-
Alcohol
adism, palmar erythema, hepatic bruit, asterixis, and ascites in
patients with severe alcohol-related hepatitis and portal hyper-
Metabolic disease–associated fatty liver
tension. Concern for concomitant infection is common because
Hepatitis C (especially genotype 3) of overlapping features of alcohol-related hepatitis and infections
Wilson disease (eg, fever, tachycardia, abdominal pain, and leukocytosis).
Lysosomal acid lipase deficiency
Starvation or rapid weight loss Laboratory and Radiographic Features
Long-term total parenteral nutrition
Laboratory abnormalities reflect the extrahepatic adverse effects
Medications: amiodarone, methotrexate, diltiazem, of alcohol and alcohol-induced liver injury (Box 26.2). Mean cor-
tamoxifen, corticosteroids, highly active puscular volume usually is increased, reflecting the adverse effect
antiretroviral therapy (HAART)
of alcohol on erythrocytes. The levels of triglycerides and uric acid
Causes of microvesicular steatosis also are frequently increased. Patients are prone to ketoacidosis.
Reye syndrome Peripheral polymorphonuclear leukocytosis is prominent, and
Acute fatty liver of pregnancy in some cases, a dramatic leukemoid reaction may be present
Inborn errors of metabolism with strikingly high white blood cell counts. Aminotransferase
levels are usually increased less than 5 to 10 times normal, but
Medications: valproate, tetracycline
they may be higher with concomitant acetaminophen toxicity.
Also, the level of AST is almost always higher than that of ALT,
which is opposite of the pattern seen in nonalcohol-related
presentation of patients with alcohol-related hepatitis includes steatohepatitis. This in combination with other variables deter
constitutional symptoms such as weakness, anorexia, and weight mines the alcohol-related liver disease—nonalcohol-related fatty
loss and other nonspecific symptoms such as nausea and vomiting. liver disease index (https://www.mayoclinic.org/medical-profes
Patients with severe alcohol-related hepatitis may have more ad- sionals/transplant-medicine/calculators/the-alcoholic-liver-dise
vanced symptoms related to portal hypertension, including gas- ase-nonalcoholic-fatty-liver-disease-index-ani/itt-20434726).
trointestinal bleeding, ascites, hepatorenal syndrome, and hepatic The index is a tool that helps distinguish metabolic fatty liver
encephalopathy. It is important to identify risk factors for con- disease from alcohol-related liver disease.
comitant or other forms of acute and chronic hepatitis, such as Abnormal results of some laboratory tests, including pro-
viral hepatitis, Wilson disease, and drug-induced hepatitis. thrombin time and bilirubin concentration, reflect the severity of
The diagnosis of alcohol-related hepatitis is contingent on de- alcohol-induced liver dysfunction and are prognostically useful
termining whether the patient is misusing alcohol. This is not al- (in contrast to aminotransferase levels). Attempts have been made
ways easy because patients with alcohol use disorder and their
family members often minimize or hide their alcohol use. An
independent history from multiple family members is often nec- Box 26.2. Abnormal Results of Laboratory Tests
essary to corroborate the patient’s alcohol history, and different in Alcohol-Related Hepatitis
caregivers may obtain a different history from the same inter-
Hematology
viewee. It is also critical to obtain this history early in the course
of the disease since the information is critical to subsequent Macrocytic anemia (increased MCV)
decisions, such as those related to transplant candidacy, and since Leukocytosis
encephalopathy may develop later and limit the ability to obtain Thrombocytopenia
these historic details. General chemistry
Questionnaires have been used to clarify alcohol use and Hyperglycemia
misuse syndromes; however, because of their length, many of
Hyperuricemia
them are limited to research purposes. One useful screening ques-
tionnaire in clinical practice is the CAGE questionnaire, which Hypertriglyceridemia
includes the following inquiries: Has the patient felt the need to Ketosis
cut down on alcohol use? Has the patient become annoyed with Liver function and injury
other persons’ concerns about the patient’s alcohol use? Does Hypoalbuminemia
the patient feel guilty about the patient’s alcohol use? Does the
Hyperbilirubinemia
patient use alcohol in the morning as an eye-opener? Although
2 positive responses have a high sensitivity and positive pre- Increased prothrombin time
dictive value for alcohol dependency, any positive response to Increased AST:ALT ratio (ratio, 1.5 to 2.5; total
these inquiries requires a more detailed investigation and should increase <10-fold)
increase suspicion for alcohol use disorder. The Alcohol Use Increased γ-glutamyltransferase
Disorders Identification Test (AUDIT) is a 10-item screening tool Increased alkaline phosphatase (mild increase)
developed by the World Health Organization to assess alcohol
drinking behaviors and related problems. Abbreviations: ALT, alanine aminotransferase; AST, aspartate amino
In patients with alcohol-related hepatitis, physical examina- transferase; MCV, mean corpuscular volume.
tion findings are most notable for tender hepatomegaly, fever, and
corpuscular volume. More recently, various sensitive alcohol

Box 26.3. Maddrey Discriminant Function (MDF) biomarkers, including ethyl glucuronide and phosphatidylethanol,
MDF = 4.6 × (PT –Control PT) +Serum Bilirubin are being used to detect surreptitious alcohol use in patients.
Concentration (mg/dL)
Histologic Features
Abbreviation: PT, prothrombin time.
With recent advances in noninvasive liver diagnostic capabilities,
the diagnosis of alcohol-related hepatitis is often made without
liver biopsy. However, liver biopsy is indicated if the diagnosis
to use bilirubin concentration, prothrombin time, and other lab- is in question after noninvasive evaluation. In particular, histo-
oratory variables to assess the prognosis of patients who have logic examination may be useful in distinguishing coexisting or
alcohol-related hepatitis. Of those assessments, the most his- alternative liver disorders, such as hereditary hemochromatosis
torically noted is the Maddrey discriminant function (MDF) in persons with high iron saturation levels, Wilson disease in
(Box 26.3). An MDF value greater than 32 effectively identifies younger persons with low to low-normal ceruloplasmin levels,
patients whose short-term risk of death exceeds 50% and for autoimmune hepatitis in persons with high titers of autoimmune
whom consideration of treatment with corticosteroids is justified. markers, and hepatitis C in persons with positive results for HCV
Among patients with alcohol-related hepatitis, a Model for antibody. Liver biopsy, if pursued, may require a transjugular
End-stage Liver Disease (MELD) score of 21 or more appears to route rather than a percutaneous route, depending on the degree
predict short-term risk of death as well as or better than the MDF of coagulopathy and thrombocytopenia.
threshold of 32. The MELD score and corresponding 90-day sur- In alcohol-related hepatitis, liver biopsy specimens show sev-
vival can be calculated on the basis of the patient’s international eral characteristic features, including centrilobular and some-
normalized ratio and bilirubin, creatinine, and sodium values times periportal polymorphonuclear infiltrates, centrilobular
at the following website: https://www.mayoclinic.org/medi hepatocyte swelling, ballooning degeneration, macrovesicular
cal-professionals/transplant-medicine/calculators/meld-score- steatosis, and Mallory bodies (Figure 26.2). Often, pericentral
and-90-day-mortality-rate-for-alcoholic-hepatitis/itt-20434719. and perisinusoidal fibrosis is detected with a trichrome stain. The
The general familiarity with MELD, the general availability of terminal hepatic venules frequently are obliterated, and indeed
its components, and the ease of its calculation have led to an the zone 3 region of the liver acinus shows the most prominent
increased use of MELD over MDF. injury. Mallory bodies (eosinophilic- staining condensed cyto-
The Lille score is another clinical prediction tool, driven skeletal structures) are not specific for alcohol-related hepatitis.
largely by the change in bilirubin levels after 1 week of medical However, their presence in association with other salient biopsy
therapy, that can help in the decision to discontinue corticosteroid features strongly suggests alcohol-related hepatitis. Prominent
therapy for patients who are not having a response. Other fre- neutrophilic infiltration of hepatocytes containing Mallory bodies
quently observed laboratory abnormalities that may cause diag- is termed satellitosis. Giant mitochondria (megamitochondria)
nostic confusion or suggest multifactorial liver disease include are another characteristic feature. In up to 50% of cases, concom-
increases in iron saturation indices and ferritin, hepatitis C virus itant cirrhosis may be present. Importantly, metabolic disease–
(HCV) antibody positivity, and increased levels of autoimmune associated steatohepatitis cannot be differentiated reliably from
markers, such as antinuclear antibody and anti–smooth muscle alcohol-related hepatitis with liver biopsy specimens because of
antibody. Rather than reflecting the concomitant presence of he- the overlap of histologic features.
reditary hemochromatosis or autoimmune hepatitis, increases in
iron indices and autoimmune markers more commonly reflect the Prognosis and Treatment
pathogenic role of iron deposition and autoimmunity in the devel-
opment of alcohol-related hepatitis. If the alcohol history is ques- Abstinence
tionable, a Doppler ultrasonographic study is useful to exclude Abstinence is the most important factor in both short-and long-
alternative diagnoses, such as cholecystitis, biliary obstruction, term survival of patients with alcohol- related hepatitis. For
and hepatic vein thrombosis, which may manifest like alcohol- patients who recover and remain abstinent, the disease may con-
related hepatitis. The false diagnosis of gallstone disease can be tinue to improve (ie, clinical sequelae and laboratory variables
catastrophic because of the high surgical morbidity and mortality improve) for as long as 6 months. Although the condition of
of patients with alcohol-related hepatitis. some patients continues to deteriorate even with abstinence, the
With the inherent difficulties in obtaining a reliable history of 5-year survival rate for this group is more than 60%. However,
alcohol use, several biochemical markers have been evaluated for for patients who continue to drink, the 5-year survival rate is less
the detection of surreptitious misuse of alcohol. Many traditional than 30%. While medications to reduce alcohol cravings, such as
serologic tests of alcohol misuse assess it indirectly by examining acamprosate or baclofen, are attractive options, their use has not
markers of liver injury such as AST, ALT, the AST:ALT ratio, been studied well, and they should be considered only in conjunc-
and GGT. However, because these tests assess alcohol misuse tion with an experienced addiction specialist. Recent trends also
indirectly by detecting liver injury, their sensitivity and spec- point to a role for cognitive behavioral therapy in maintaining
ificity generally are less than 70%. Mean corpuscular volume abstinence.
also indirectly assesses alcohol misuse by evaluating the bone
marrow toxicity of alcohol. Carbohydrate-deficient transferrin
reflects the desialylation of transferrin that occurs in response to Nutrition
high alcohol use, and mitochondrial AST is a specific isoform of Malnutrition is almost universal among patients with alcohol-
the enzyme that is released from hepatocytes injured by alcohol. related hepatitis because of concomitant poor dietary habits,
However, these tests have not been shown universally to be more anorexia, and encephalopathy. Although malnutrition was once
effective than the less expensive AST:ALT ratio, GGT, and mean thought to cause alcohol-related liver disease, it is no longer
considered to have a major role in the pathogenesis of the dis thistle, and N-acetylcysteine, have been evaluated but are not
ease. However, maintenance of a positive nitrogen balance and widely accepted.
provision of adequate energy requirements through nutritional
support are a vital supportive treatment approach. Patients with
Management of Portal Hypertension
alcohol-related hepatitis generally have greater protein and en-
ergy needs because of the stress of illness and underlying mal- Complications of portal hypertension may develop in patients
nutrition. Recommendations include caloric supplementation with alcohol-related hepatitis regardless of the presence or ab-
at 30 to 40 kcal/kg ideal body weight and protein supplemen- sence of underlying cirrhosis. This clinical observation is
tation at 1 to 1.5 g/kg ideal body weight. Provision of nutrients supported by studies showing that alcohol directly increases
in excess of calculated requirements is unlikely to be of benefit. portal pressure, and it emphasizes the importance of the vascular
Every attempt should be made to provide adequate calories en- component of intrahepatic resistance and portal hypertension.
terally. However, parenteral support may be necessary for some Hepatic encephalopathy, bleeding esophageal varices, ascites,
patients. Encephalopathy does not require protein restriction spontaneous bacterial peritonitis, and hepatorenal syndrome are
in most patients. For patients with severe encephalopathy that complications of portal hypertension commonly encountered in
is exacerbated by dietary protein, branched-chain amino acid patients with alcohol-related hepatitis. The management of these
supplements can be considered. Increased use of dietary vege- complications is discussed elsewhere in this book.
table protein may be better tolerated than animal protein. Amino
acid supplementation probably does not improve survival suffi- Treatment of Infection
ciently for the added cost.
Because of underlying malnutrition, liver cirrhosis, and iatrogenic
complications, infection is one of the most common causes of
Corticosteroids death among patients with alcohol-related hepatitis. The patients
Corticosteroids have been studied extensively for the treatment of must be evaluated carefully for infections, including sponta-
alcohol-related hepatitis. Although many of the initial controlled neous bacterial peritonitis, aspiration pneumonia, and lower ex-
trials did not show a benefit, further analysis suggested that tremity cellulitis. These infections should be treated aggressively
patients with encephalopathy and more severe disease may with antibiotics. However, fever and leukocytosis are common
benefit. Therefore, follow- up studies focused on the role of in patients with alcohol-related hepatitis, even without infection.
corticosteroids in the treatment of patients who had an MDF
function greater than 32 or hepatic encephalopathy (or both) Liver Transplant
but not kidney failure, infection, gastrointestinal tract bleeding,
or, in some studies, severe type 2 diabetes. Some studies and Recent studies have shown that early liver transplant improves
meta-analyses that used these criteria showed that corticosteroid survival among highly selected groups of patients not responding
therapy provided a survival benefit for patients with an MDF to medical therapy. While many patients with alcohol-related
greater than 32 or hepatic encephalopathy (or both); however, a hepatitis are not suitable candidates for liver transplant because
MELD score of 21 or more appears to be an acceptable alter- of psychosocial reasons, abstinence for less than 6 months is
native threshold. In 2015, a large randomized controlled study not itself an absolute contraindication to liver transplant. Thus,
did not show a statistically significant benefit with the use of patients who do not respond to medical therapy definitely warrant
prednisolone for alcohol-related hepatitis. Therefore, the use of discussion with a liver transplant center team that has the exper-
corticosteroid therapy for alcohol-related hepatitis is controver- tise and resources to determine whether an evaluation for liver
sial and varies among experienced hepatologists. transplant is appropriate.
✓ Alcohol-related hepatitis may occur with or without preexisting

Pentoxifylline liver cirrhosis
✓ Liver biopsy should be considered if the cause of hepatitis is
Kupffer cell– derived tumor necrosis factor (TNF)- α may be questioned and specific treatments for other entities are being
important in the pathogenesis of alcohol- related hepatitis. contemplated
Consequently, there has been interest historically in using the ✓ Histologic features cannot be used to reliably differentiate
phosphodiesterase inhibitor pentoxifylline, which inhibits TNF-α alcohol- related hepatitis from metabolic disease– associated
transcription, for treatment of alcohol-related hepatitis. However, steatohepatitis; the distinction is made best on the basis of the
additional studies have not supported its use, and it is no longer clinical history and the pattern of laboratory test results
considered appropriate therapy. Other anti-TNF therapies, such ✓ For most patients, the treatment of alcohol- related hepatitis
as infliximab and etanercept, have been studied, but the results includes abstinence, supportive care, and management of malnu-
have been similarly disappointing. trition, infection, and complications of portal hypertension
✓ Liver transplant evaluation can be considered for selected patients
who do not respond to medical management
Other Pharmacotherapies Being Studied
Alcohol induces oxidative stress in the liver, resulting in an im-
balance between oxidants and antioxidants. Looking for a way Alcohol-Related Cirrhosis
to decrease oxygen consumption by the liver, investigators have
studied the role of propylthiouracil in treating alcohol-related hep-
atitis, but the results have been inconclusive. Colchicine has also A 56-year-old salesman is admitted to the hospital with a 2-hour
been evaluated for treating alcohol-related hepatitis, but no clin- history of hematemesis and dizziness. His history is remarkable
ical benefit has been found. Other hepatoprotective compounds, for symptoms of fatigue and lower extremity edema. His wife
such as S-adenosyl-l- methionine, phosphatidylcholine, milk notes that his memory has been poor recently and that he has
been a “social drinker” for many years, having a few martinis Prognosis and Treatment
with clients and during business trips. Physical examination
A good prognosis depends on the absence of liver decompensa-
findings are notable for orthostasis, temporal wasting, spider
tion and complications of portal hypertension and on the patient’s
angiomas on the chest, and bilateral pitting edema of the lower
ability to maintain abstinence. The prognosis for patients with
extremities. His skin is jaundiced, and a liver edge is palpable
cirrhosis who are well compensated and able to maintain ab-
and firm. The tip of the spleen is palpable upon inspiration.
stinence is reasonably good (5-year survival rate >80%). Even
Rectal examination shows melena in the vault. There is prom-
for patients with decompensation, the 5-year survival rate with
inent asterixis.
abstinence is more than 50%. However, patients who continue to
This patient has the clinical features typical of alcohol-related
drink have a much worse prognosis (5-year survival rate <30%).
cirrhosis. The diagnosis and treatment are discussed below.
The only established effective therapy for alcohol-related cir-
rhosis is liver transplant. Currently, alcohol-related liver disease
History and Physical Examination is the most common indication for liver transplant in adults in the
Among persons with a clinical history of marked and prolonged US. However, less than 20% of patients with end-stage alcohol-
misuse of alcohol, liver cirrhosis eventually develops in only related liver disease undergo transplant. Despite perceptions to
about 20%. The presence or absence of symptoms is due largely the contrary, survival rates after transplant for alcohol-related
to the presence or absence of liver decompensation. Patients liver disease are comparable to those after transplant for other
with cirrhosis and compensated liver function may have min- indications. In fact, the risk of acute cellular rejection is actually
imal symptoms. The symptoms of patients with liver decompen- lower for persons undergoing transplant for alcohol-related liver
sation reflect the severity of portal hypertension, malnutrition, disease than for those with other conditions.
and degree of synthetic liver dysfunction and include nonspe- A major issue in maintaining excellent outcomes for this pop-
cific fatigue, weakness, and anorexia. More specific symptoms ulation focuses on identifying candidates with a low risk for re-
are related to the presence of specific complications of cir- cidivism after transplant. Alcohol relapse after transplant varies
rhosis and portal hypertension, including gastrointestinal tract among centers and is difficult to quantify accurately, but it is prob-
bleeding, ascites, encephalopathy, hepatorenal syndrome, and ably about 15% to 30%. Although detecting surreptitious alcohol
hepatocellular carcinoma. Physical examination findings may use after transplant can be difficult, the low incidence of graft loss
include stigmata of chronic liver disease (spider angiomas and from recurrent alcohol-related liver disease suggests that most
palmar erythema), complications of portal hypertension (as- patients who return to drinking after transplant do not drink to
cites, splenomegaly, asterixis, and pedal edema), signs of ex- the point of endangering the graft. However, heavy use of alcohol
cess estrogen (gynecomastia and hypogonadism), and signs of after liver transplant can cause rapid development of cirrhosis
systemic alcohol toxicity (peripheral neuropathy, dementia, and in the graft. Alcohol use also may interfere with compliance in
Dupuytren contracture). taking immunosuppressive medications and alter the perception of
the general public toward liver transplant, thus adversely affecting
potential organ donors. Therefore, selecting patients who are ap-
Laboratory and Radiographic Features propriate for liver transplant requires a multidisciplinary team
Prominent laboratory abnormalities include an increase in the involving a hepatologist, transplant surgeon, addiction specialist,
prothrombin time and bilirubin level and a decrease in the al- psychiatrist, and social worker. Currently, many transplant centers
bumin level, which are reflected in an increased Child-Turcotte- advocate 6 months of abstinence, appropriate addiction treatment,
Pugh score. Imaging findings may be suggestive of cirrhosis and aftercare with Alcoholics Anonymous attendance and sponsor-
ensuing portal hypertension, as indicated by heterogeneous liver ship, and demonstrated family and social support before per-
echotexture, splenomegaly, collateralization, and ascites on ul- forming a liver transplant for alcohol-related cirrhosis.
trasonography. Computed tomography may show changes in
liver contour, splenomegaly, collateralization, or ascites. Patients ✓ Alcohol causes micronodular or mixed micro-macronodular cir-
with cirrhosis are at risk for hepatocellular carcinoma and should rhosis in about 20% of people with prolonged, excessive use of
be evaluated biannually with ultrasonography, with or without alcohol
✓ Alcohol-related cirrhosis is currently the most common indication
serum alpha-fetoprotein levels, as should patients who have had
for liver transplant, which is the only curative treatment
recent clinical decompensation. Patients with cirrhosis are also ✓ Only a small proportion of patients with alcohol-related cirrhosis
at risk for esophageal varices, which, when large, can cause undergo transplant, because of various psychosocial barriers
life-threatening bleeding. Therefore, screening for esophageal ✓ Transplant outcomes for alcohol-related liver disease are compa-
varices with upper endoscopy is also indicated for patients who rable to those for most other indications
have cirrhosis.
Histologic Features Alcohol and Acetaminophen

Traditionally, alcohol-related cirrhosis is classified as a micro Patients who regularly use alcohol are at increased risk for
nodular cirrhosis (Figure 26.2). However, in many patients, larger acetaminophen-induced hepatotoxicity. An acetaminophen dosage
nodules also develop, leading to mixed micro-macronodular cir- of as little as 2.5 to 3 g daily may result in pronounced hepatotox-
rhosis. The earliest collagen deposition occurs around the ter- icity in patients who use alcohol. The reason for this is that both
minal hepatic venules, and progression to pericentral fibrosis alcohol and acetaminophen are metabolized in part by CYP2E1,
portends irreversible architectural changes. Hemosiderin deposi- an enzyme in the MEOS. With the induction of this enzyme by
tion is often prominent. In patients with alcohol-related cirrhosis alcohol, a greater proportion of acetaminophen is metabolized by
who continue to drink actively, many of the histologic features of this pathway than by the sulfation and glucuronidation detoxifi-
alcohol-related hepatitis also are present. cation pathways. The byproduct of acetaminophen metabolism
by CYP2E1 is N-acetyl-p-benzoquinone imine, which is toxic to Dominguez M, Rincon D, Abraldes JG, Miquel R, Colmenero J, Bellot P,
the liver. The accumulation of this compound in conjunction with et al. A new scoring system for prognostic stratification of patients with
diminished antioxidant defenses in the liver (glutathione) lowers alcoholic hepatitis. Am J Gastroenterol. 2008 Nov;103(11):2747–56.
the threshold of acetaminophen toxicity in patients using alcohol. Dunn W, Angulo P, Sanderson S, Jamil LH, Stadheim L, Rosen C, et al.
Utility of a new model to diagnose an alcohol basis for steatohepatitis.
The clinical presentation of regular alcohol users with ace-
Gastroenterology. 2006 Oct;131(4):1057–63.
taminophen toxicity is distinct from that of patients with Gramenzi A, Caputo F, Biselli M, Kuria F, Loggi E, Andreone P, et al.
alcohol-related hepatitis. Aminotransferase levels are markedly Alcoholic liver disease: pathophysiological aspects and risk factors.
increased—often exceeding 1,000 U/L—which is distinctly un- Aliment Pharmacol Ther. 2006 Oct 15;24(8):1151–61.
usual for alcohol-related hepatitis. This situation may arise when Haber PS, Warner R, Seth D, Gorrell MD, McCaughan GW. Pathogenesis
a regular alcohol user has a minor illness, discontinues alcohol and management of alcoholic hepatitis. J Gastroenterol Hepatol. 2003
use, and takes moderate doses of acetaminophen (the so-called Dec;18(12):1332–44.
therapeutic misadventure). Ironically, discontinuation of alcohol Hill DB, Deaciuc IV, Nanji AA, McClain CJ. Mechanisms of hepatic
perpetuates this problem since more cellular resources are then injury in alcoholic liver disease. Clin Liver Dis. 1998;2(4):703–21.
available for acetaminophen metabolism. Therefore, patients Julien J, Ayer T, Bethea ED, Tapper EB, Chhatwal J. Projected preva-
lence and mortality associated with alcohol-related liver disease in
who use alcohol regularly should not use acetaminophen without
the USA, 2019–40: a modelling study. Lancet Public Health. 2020
the supervision of a physician and should limit their intake. In Jun;5(6):e316–e23.
contrast, acetaminophen is the analgesic of choice for patients Kourkoumpetis T, Sood G. Pathogenesis of alcoholic liver disease: an
with cirrhosis, including alcohol-related cirrhosis, as long as the update. Clin Liver Dis. 2019 Feb;23(1):71–80.
patient is not currently using alcohol. However, patients with cir- Lucey MR, Mathurin P, Morgan TR. Alcoholic hepatitis. N Engl J Med.
rhosis should limit acetaminophen intake to a collective dosage 2009 Jun;360(26):2758–69.
that does not exceed 2 g every 24 hours. Maher JJ. Alcoholic steatosis and steatohepatitis. Semin Gastrointest
Dis. 2002 Jan;13(1):31–9.
Marsano LS, Mendez C, Hill D, Barve S, McClain CJ. Diagnosis and
Suggested Reading
treatment of alcoholic liver disease and its complications. Alcohol
Asrani S, Sanchez W. Epidemiology of alcoholic liver disease. In: Talley Res Health. 2003; 27(3):247–56.
NJ, Locke GR, Moayyedi P, West JJ, Ford AC, Saito YA, eds. GI Menon KV, Gores GJ, Shah VH. Pathogenesis, diagnosis, and treatment
epidemiology: diseases and clinical methodology, 2nd ed. John Wiley of alcoholic liver disease. Mayo Clin Proc. 2001 Oct;76(10):1021–9.
& Sons; 2014:332–43. Singal AK, Bataller R, Ahn J, Kamath PS, Shah VH. ACG clin-
Carithers R, McClain C. Alcoholic liver disease. In: Feldman M, ical guideline: alcoholic liver disease. Am J Gastroenterol. 2018
Friedman LS, Sleisenger MH, eds. Sleisenger & Fordtran’s gastroin- Feb;113(2):175–94.
testinal and liver disease: pathophysiology, diagnosis, management. Tome S, Lucey MR. Current management of alcoholic liver disease.
9th ed. Saunders; 2010:1383–400. Aliment Pharmacol Ther. 2004 Apr;19(7):707–14.
Ceccanti M, Attili A, Balducci G, Attilia F, Giacomelli S, Rotondo C, Zeng MD, Li YM, Chen CW, Lu LG, Fan JG, Wang BY, et al. Guidelines
et al. Acute alcoholic hepatitis. J Clin Gastroenterol. 2006 Oct;40(9): for the diagnosis and treatment of alcoholic liver disease. J Dig Dis.
833–41. 2008 May;9(2):113–6.
27
Vascular Diseases of the Livera

TASHA B. KULAI, MD
WILLIAM SANCHEZ, MD
Vascular diseases of the liver can be divided into disorders of he- off in the mesentery form a row of arterial arcades that terminate
patic inflow (ie, disorders of portal venous inflow and disorders of in the arteriae rectae of the wall of the small bowel. The inferior
hepatic arterial inflow) and disorders of hepatic venous outflow mesenteric artery arises 3 cm above the aortic bifurcation close
(Box 27.1). For a better understanding of the vascular diseases of to the inferior border of the duodenum. It branches into the left
the liver, a concise review of the vascular anatomy of the liver is colic artery and terminates as the superior rectal artery. The ve-
important. nous drainage has a similar pattern, with the venae rectae forming
a venous arcade that drains the small bowel and:
The arterial routes of the splanchnic circulation, except for the he-
Anatomy of the Splanchnic Circulation
patic artery, eventually empty into the portal venous system through
The splanchnic circulation comprises the arterial blood supply the splenic vein and superior and inferior mesenteric veins. The
and venous drainage of the entire gastrointestinal tract from the portal vein, formed by the convergence of the splenic and superior
distal esophagus to the midrectum and includes the spleen (which mesenteric veins, constitutes the primary blood supply to the liver.
is why splenomegaly and thrombocytopenia develop in the After perfusing the liver, venous blood reenters the systemic circu-
presence of portal hypertension), pancreas, gallbladder, and liver. lation through the hepatic veins and suprahepatic inferior vena cava.
The arterial system is derived from the celiac artery and the supe- The liver receives a dual blood supply. The 2 sources are portal
rior and inferior mesenteric arteries. The celiac artery arises from venous blood (derived from the mesenteric venous circulation, in-
the anterior aorta and typically gives rise to 3 major branches: cluding the digestive tract, spleen, and pancreas) and hepatic arterial
the left gastric artery, the common hepatic artery, and the splenic
artery. The superior mesenteric artery arises from the abdominal
aorta just distal to the celiac trunk. The superior mesenteric ar-
Box 27.1. Vascular Diseases of the Liver
tery gives off 3 sets of branches: 1) several small branches to the
pancreas and duodenum before entering the mesentery, 2) 3 large Disorders of portal venous inflow
arteries that supply the proximal two-thirds of the large bowel, Acute mesenteric or portal venous thrombosis
and 3) during its course through the mesenteric root, an arcade of Chronic mesenteric or portal venous thrombosis
arterial branches to the jejunum and ileum. The branches given Disorders of hepatic arterial inflow
Hepatic artery thrombosis
Hepatic arteriovenous fistula
a
Portions previously published in Menon KV, Shah V, Kamath PS. The Ischemic hepatopathy
Budd-Chiari syndrome. N Engl J Med. 2004 Feb;350(6):578-85; used
with permission. Disorders of hepatic venous outflow
Abbreviations: BCS, Budd- Chiari syndrome; HHT, hereditary hem- Venoocclusive disease
orrhagic telangiectasia; SOS, sinusoidal obstruction syndrome; TIPS, Budd-Chiari syndrome
transjugular intrahepatic portosystemic shunt
325
blood (usually from the celiac artery). Total hepatic blood flow shunts is present in a small number of referral centers. For refrac-
constitutes nearly 30% of total cardiac output. The portal venous in- tory variceal bleeding, gastroesophageal devascularization may be
flow comprises 65% to 75% of hepatic blood inflow, and the hepatic considered. For patients with thrombophilia, anticoagulation may be
artery comprises approximately 25% to 35%. The hepatic artery is initiated after the risk of bleeding has been decreased by the use of
the main blood supply to the biliary tree. Approximately 50% of the β-blockers or, if bleeding has occurred, surgical shunts.
liver’s oxygen requirements is delivered by hepatic arterial blood.
The hepatic vascular bed is a low-pressure system that can ✓ Patients with chronic mesenteric venous thrombosis—typically
maintain a large volume of blood. Sinusoidal blood collects asymptomatic or with chronic nonspecific symptoms
within terminal hepatic venules and reenters the systemic circula- ✓ Propranolol or other nonselective β-blockers are recommended to
prevent variceal bleeding in patients who have associated portal
tion through the hepatic veins and inferior vena cava. The caudate
hypertension
lobe of the liver maintains a separate venous drainage, accounting ✓ Endoscopic therapy—to control active bleeding and to prevent
for the compensatory hypertrophy of this lobe often observed in rebleeding
chronic liver disease associated with outflow obstruction of the ✓ Surgical shunts— only for patients whose bleeding cannot be
major hepatic veins (Budd-Chiari syndrome [BCS]). controlled with conservative measures and who have a patent cen-
tral vein
✓ Liver has a dual blood supply
• Portal venous blood (derived from the mesenteric venous circu-
lation)—70% of flow
• Hepatic arterial blood (usually from the celiac artery)—30% Disorders of Hepatic Arterial Inflow
of flow Hepatic Artery Thrombosis
✓ Hepatic vascular bed is a low-pressure system

Aside from patients who have had liver transplant, the prevalence of
hepatic artery thrombosis is not certain. Hepatic artery thrombosis
is the cause of considerable morbidity and mortality in approxi-
Disorders of Portal Venous Inflow
mately 3% to 7% of adult recipients of deceased donor transplants,
Acute Mesenteric Venous Thrombosis in up to 10% of adult recipients of living donor transplants, and in
Acute mesenteric venous thrombosis is discussed in Chapter 11, perhaps as many as 40% of pediatric patients undergoing orthotopic
“Vascular Disorders of the Gastrointestinal Tract.” liver transplant. The problem is more extensive in pediatric patients
because of the smaller caliber of the vessels involved and the prob-
ably greater fluctuation in the concentration of coagulation factors.
Chronic Mesenteric Venous Thrombosis Several risk factors are related to the development of hepatic
Chronic mesenteric venous thrombosis is very different from the artery thrombosis in adults, with the type of transplant (living
acute form. Lack of visualization of the superior mesenteric vein on donor or deceased donor) and the technical aspects of the arte-
computed tomography or duplex ultrasonography in conjunction with rial anastomosis being the most important risk factors for early
extensive collateral venous drainage suggests the diagnosis of chronic thrombosis. Other risk factors are older recipients, clotting
mesenteric venous thrombosis. Angiography can help confirm the di- abnormalities, tobacco use, and infections by agents such as cy-
agnosis but rarely is required. Although many patients present with tomegalovirus. Late hepatic artery thrombosis has been associ-
nonspecific symptoms of several months’ duration, an increasing ated with chronic rejection and blood type–incompatible grafts.
proportion are identified through imaging studies performed for un- The clinical presentation of hepatic artery thrombosis can vary
related reasons. These patients may be asymptomatic with respect from a mild increase in the serum level of aminotransferases to
to the primary event; hence, the time of the thrombotic event often fulminant hepatic necrosis. Early hepatic artery thrombosis has
is unclear. Patients in whom the thrombosis extends to involve the a more severe clinical course, and late hepatic artery thrombosis
portal vein or splenic vein (or both) may have portal hypertension generally has a milder course. There is no agreement about a
and esophageal varices, with the attendant complications of variceal time that distinguishes early from late hepatic artery thrombosis.
bleeding. They also may have splenomegaly and hypersplenism. However, the later that hepatic artery thrombosis develops after
Chronic mesenteric venous thrombosis should be differentiated liver transplant, the less severe the clinical presentation.
from isolated splenic vein thrombosis due to pancreatic neo- Early hepatic artery thrombosis results in massive injury to
plasm or chronic pancreatitis. Splenic vein thrombosis, often hepatocytes and bile duct epithelial cells. Ischemic damage to
called sinistral (or left-sided) portal hypertension, is related to a the bile ducts can lead to dehiscence of the biliary anastomosis,
local effect on the splenic vein and is not usually a disorder of the bile duct strictures (typically nonanastamotic), and intrahepatic
thrombotic pathway. Thus, anticoagulation is not warranted for abscesses. Thus, biliary sepsis may be a common presentation of
sinistral portal hypertension. early hepatic artery thrombosis. However, one-third of patients
Patients with isolated chronic mesenteric venous thrombosis with early hepatic artery thrombosis may be asymptomatic.
often remain asymptomatic because of the development of exten- Hepatic artery thrombosis can be diagnosed with duplex ul-
sive venous collaterals. Occasionally, some patients have gastroin- trasonography, but angiography may be necessary to confirm
testinal tract hemorrhage, and the use of a nonselective β-blocker the diagnosis. When hepatic artery thrombosis is detected early
is recommended to prevent variceal bleeding. Endoscopic therapy after liver transplant, surgical correction usually is recommended.
is used both to control active bleeding and to prevent rebleeding. Patients who have early hepatic artery thrombosis with graft dys-
Surgical intervention (eg, portosystemic shunts) is restricted to function should be listed for retransplant.
patients whose bleeding cannot be controlled with conservative
✓ Hepatic artery thrombosis is primarily a complication related to
measures and who have a patent central vein for shunting. When
liver transplant
thrombosis is extensive and no large vein is suitable for anastomosis, ✓ Hepatic artery thrombosis that occurs early after transplant usu-
nonconventional shunts (eg, anastomosis of a large collateral vein ally requires surgical correction, and relisting the patient for trans-
with a systemic vein) may be considered. Surgical expertise for such plant is necessary if acute graft dysfunction develops
27. Vascular Diseases of the Liver 327
Hepatic Artery Aneurysm Hepatic Artery–Portal Vein Fistulas

Although aneurysm of the hepatic artery (Figure 27.1) is rare, it Hepatic artery–portal vein fistulas are rare causes of portal hyper-
is the fourth most common abdominal aneurysm. The aneurysms tension. Although fistulas within the liver usually are iatrogenic
are usually small (<2 cm in diameter) and involve the main he- (the result of liver biopsy), they may be related to neoplasms or he-
patic artery. Causes of hepatic artery aneurysms include athero- reditary hemorrhagic telangiectasia (HHT) (Osler-Weber-Rendu
sclerotic vascular diseases, infections (eg, bacterial endocarditis, disease). A hepatic artery–portal vein fistula should be suspected
liver abscess, syphilis, and tuberculosis), and trauma from liver in a patient who has acute onset of abdominal pain and ascites,
biopsy. The hepatic artery commonly is involved in polyarteritis especially if associated with gastrointestinal tract bleeding, be-
nodosa, manifested as symptoms related to thrombosis, rupture, cause rupture of the artery into the portal vein causes an acute
or dissection of the aneurysm. increase in portal pressure. These fistulas may be accompanied
Most hepatic artery aneurysms are discovered incidentally. If by abdominal bruits in most patients. Hepatic artery–portal vein
they are symptomatic, the first and dominating symptom is se- fistulas are treated with coil embolization or surgical ligation.
vere abdominal pain, suggesting dissection. Vague abdominal If untreated, a hepatic artery–hepatic vein fistula may result in
pain in these patients is related to compression of surrounding high-output congestive heart failure. The best treatment is em-
structures. Rupture of a hepatic artery aneurysm causes massive bolization and occlusion of the fistula, except in the presence of
intraperitoneal hemorrhage or hemobilia manifested as abdom- HHT, when embolization is absolutely contraindicated. A hepatic
inal pain, jaundice, and gastrointestinal tract bleeding. Hemobilia artery–portal vein fistula can also result in high-output conges-
is usually a manifestation of an intrahepatic aneurysm. tive heart failure. Antibody therapy against vascular endothelial
The treatment of a ruptured aneurysm is emergency surgery growth factor (bevacizumab) has been shown to be beneficial in
or embolization of the aneurysm in patients who are not optimal patients who have HHT-related bleeding, but its utility in patients
candidates for surgery. For asymptomatic patients, treatment is with HHT-related liver disease is evolving.
debated. Clearly, aneurysms larger than 2 cm in diameter require
treatment, and those between 1 and 2 cm in diameter may be treated.
Ischemic Hepatopathy
For aneurysms smaller than 1 cm in diameter, follow-up at 6-month
intervals is reasonable. Treatment includes interventional radiologic In patients with congestive heart failure, portal blood flow is min-
approaches to embolize and occlude the aneurysm, ligation at sur- imal; thus, the major contribution of oxygenated blood to the liver
gery, or excision of the aneurysm and reconstruction of the artery. is from the hepatic artery. In congestive heart failure, episodes of
Intrahepatic aneurysms may also be treated with liver resection. hypotension, as associated with arrhythmias, diminish hepatic ar-
terial input and result in ischemic necrosis of the liver. Typical
✓ Hepatic artery aneurysms manifestations of ischemic hepatopathy are rapid increases (ie,
• If smaller than 1 cm—monitor with imaging every 6 months within 24-48 hours) in the serum levels of aminotransferases (as-
• If 1 to 2 cm, consider surgical repair partate aminotransferase and alanine aminotransferase) to several
• If larger than 2 cm, surgical intervention is required thousand units per liter (sometimes >10,000 U/L). These values
✓ Ruptured hepatic artery aneurysms
rapidly return to less than 100 U/L in 5 to 7 days. No specific
• Patient has severe abdominal pain
• Emergency surgery is required treatment is required other than control of the cardiac condition.
• Embolization can be considered if patient is not a surgical Extensive ischemic hepatopathy may result in acute liver failure.
candidate Ischemic hepatopathy may also result from hypovolemic shock
from any cause and obstructive sleep apnea. Postoperatively,
patients are especially prone to ischemic liver damage because
they often have coexisting arterial hypotension and hypoxemia.
Furthermore, hepatic blood flow may be reduced by anesthetic
agents. This problem may be of particular concern for patients
who have open heart surgery. The typical histologic finding in
these patients with ischemic liver damage is centrilobular hepatic
necrosis (zone 3). The severity of liver damage is related to the
duration of hypotension and the degree of hypoxemia.
Hereditary Hemorrhagic Telangiectasia

Three of the following criteria are required for the diagnosis of
HHT: 1) a history of epistaxis, 2) a family history of HHT, 3)
mucocutaneous telangiectasia, and 4) visceral involvement, which
can be hepatic, gastrointestinal, neurologic, or pulmonary.
The vascular malformation within the liver of patients with
HHT results in fistulas in 1 or more of the following locations: 1)
between the hepatic artery and the hepatic vein (the most common
abnormality), 2) between the hepatic artery and the portal vein,
or 3) between the portal vein and the hepatic vein. Previously, the
most common liver disease in patients with HHT was transfusion-
Figure 27.1. Aneurysm of the Hepatic Artery. Selective hepatic an- related viral hepatitis, but now the most common manifestation is
giogram shows an aneurysm (arrow) of the intrahepatic portion of the high-output cardiac failure resulting from hepatic artery–hepatic
hepatic artery. vein fistulas or hepatic artery–portal vein fistulas.
Additional abnormalities include 1) recurrent cholangitis due is a parenteral oligonucleotide mixture with fibrinolytic properties
to the diversion of hepatic arterial blood to the hepatic vein, 2) approved for the treatment of SOS. If there is no response to
portal hypertension as a result of hepatic artery–portal vein fistulas thrombolytic therapy, either a surgical shunt or a transjugular
or nodular regenerative hyperplasia, and 3) hepatic encephalop- intrahepatic portosystemic shunt (TIPS) may be used. Although
athy due to fistulas between the portal vein and the hepatic vein. the initial results with portosystemic shunts may be beneficial, the
Embolization of these fistulas is not recommended because of long-term outcome for patients who require shunts is poor because
the high risk of liver abscesses. This is probably related to most these patients usually have severe SOS and intervention generally
patients having some degree of a portal vein–hepatic vein fistula, delays, but does not prevent, a fatal outcome.
and once the hepatic artery is occluded, there is neither hepatic
arterial blood nor portal venous blood to the involved segment of ✓ Hepatic SOS results from occlusion of central and sublobular he-
the liver. Liver transplant has been performed to treat HHT and is patic veins, typically related to therapy for bone marrow transplant
best indicated for patients who have recurrent cholangitis. ✓ SOS generally resembles Budd-Chiari syndrome, but venous ob-
struction in SOS occurs more distally, closer to the liver
✓ SOS prophylaxis—heparin, prostaglandins, or ursodeoxycholic acid
Disorders of Hepatic Venous Outflow ✓ Established SOS—management is generally supportive; defibrotide
is approved treatment
Sinusoidal Obstruction Syndrome
Venoocclusive disease, or sinusoidal obstruction syndrome
(SOS), results from occlusion of the central and sublobular Budd-Chiari Syndrome
hepatic veins. In the US, the most common cause of SOS is
preconditioning therapy for bone marrow transplant. Other BCS is a heterogeneous group of disorders characterized by ob-
causes include radiation to the liver, antineoplastic drugs such struction of hepatic venous outflow. The site of obstruction may
as azathioprine and 6-mercaptopurine, and ingestion of alkaloids be at the level of small hepatic venules, large hepatic veins, or
containing pyrrolizidine. the inferior vena cava. Obstruction at the level of the central
The following discussion is predominantly about SOS of the and sublobular hepatic venules traditionally has been called
liver in relation to patients undergoing bone marrow transplant. SOS, as described above. In some countries, such as Japan and
For these patients, the incidence of SOS was approximately 50% India, people may have obstruction of the inferior vena cava by
when cyclophosphamide and total body radiotherapy were used membranes or webs or segmental narrowing of the vessel, which
as intensive conditioning therapy before transplant, and the mor- also may obstruct hepatic venous outflow.
tality rate was 20% to 40%. Currently, the incidence of SOS is
✓ Budd-Chiari syndrome—hepatic venous outflow tract obstruction
low because cyclophosphamide and high-dose radiotherapy are
from any cause

no longer used. Early changes are related to hemorrhage in zone
3, as seen in liver biopsy specimens. Diagnostic criteria include
subendothelial thickening of at least 1 terminal hepatic venule in
association with luminal narrowing. Etiology
The pathogenesis of SOS is not well defined. It probably The main predisposing causes of BCS include a hypercoagulable
results from a combination of endothelial injury and activation of state, tumor invasion of the hepatic venous outflow tract, and
clotting mechanisms. It has been hypothesized that the depletion miscellaneous causes. In some patients, no clear etiologic factor
of glutathione in zone 3 hepatocytes makes them more prone to is discernible. Increasingly, the presence of multiple underlying
damage by antineoplastic agents such as busulfan. The resulting disorders that cause BCS is being recognized.
accumulation of oxygen free radicals leads to zone 3 necrosis and Hematologic abnormalities, particularly myeloproliferative
subsequent endothelial damage. disorders, are detected in up to 87.5% of patients with BCS. Overt
The diagnostic criteria for SOS are listed in Table 27.1. Bilirubin polycythemia vera is the most common disorder encountered.
levels greater than 15 mg/dL are associated with poor outcome. Erythropoietin levels and demonstration of JAK variations
Treatment of SOS is difficult. Prophylactic strategies have included have been used to diagnose occult primary myeloproliferative
administration of heparin, prostaglandins, or ursodeoxycholic acid. disorders in patients otherwise thought to have idiopathic BCS.
Because of the lack of large, randomized studies, it is difficult to Both fulminant and chronic forms of the syndrome have been
determine the benefits of any of these therapies. The treatment of described for patients with paroxysmal nocturnal hemoglobi-
established SOS is also debated. Defibrotide has been approved nuria. Increasingly, inherited deficiencies of protein C, protein S,
for use in adult and pediatric patients, and tissue plasminogen and antithrombin are being reported in association with the syn-
activator and heparin have been administered to patients at high drome. Protein C and protein S are vitamin K–dependent proteins
risk for dying of complications of SOS. In addition, defibrotide that are synthesized in the liver and endothelial cells and act as
fibrinolytic agents. Antithrombin is a vitamin K–independent
protease inhibitor that is synthesized in the liver and neutralizes
Table 27.1. Diagnostic Criteria for Venoocclusive Disease activated clotting factors by forming a complex with a specific
Other required serine protease. Deficiencies of any of these proteins can result
Criteria Weeks after BMT Weight gain, % findings in both arterial thrombosis and venous thrombosis, but the cor-
relation between the levels of protein C and protein S and the
Baltimore ≤3 >5 Hepatomegaly
Ascites risk of thrombosis is not precise. In several patients with BCS,
Seattle ≤3 >2 Bilirubin >2 mg/dL protein C deficiency has also been associated with an underlying
Hepatomegaly myeloproliferative disorder. The diagnosis is sometimes diffi-
RUQ pain cult because these proteins can become deficient in patients with
impaired liver function. Normal levels of factors II and VII in
Abbreviations: BMT, bone marrow transplant; RUQ, right upper quadrant.
27. Vascular Diseases of the Liver 329
patients with BCS or deficiencies of protein C and protein S in

family members may point toward an inherited disorder. Box 27.2. Causes of Budd-Chiari Syndrome
The factor V Leiden variant has been reported in approxi- Common causes
mately 23% of patients with BCS. This alteration, caused by the Hypercoagulable states
substitution of an arginine residue by glutamine at position 506
Inherited
in the factor V molecule, abolishes a protein C cleavage site in
factor V and prolongs the thrombogenic effect of factor V ac- Factor V Leiden alteration
tivation. The term resistance to activated protein C is another Prothrombin gene alteration
name for this condition. Although about 2.9% to 6% of people Acquired
of European descent are believed to be heterozygous for this al- Myeloproliferative disorders
teration, the relative risk of thrombosis is thought to be low. In
Cancer
addition to being a sole cause of BCS, this alteration has been
reported to occur also in combination with other prothrombotic Pregnancy
disorders. Oral contraceptive use
Uncommon causes
Clinical Manifestations Hypercoagulable states
Inherited
The underlying pathophysiologic abnormality in BCS is an in-
crease in sinusoidal pressure caused by obstruction of hepatic ve- Antithrombin deficiency
nous outflow. This results in hypoxic damage to the hepatocytes Protein C deficiency
and increased portal venous pressure. Continued obstruction Protein S deficiency
of hepatic venous outflow leads to further hepatic necrosis, ul- Acquired
timately resulting in cirrhosis. Because the caudate lobe drains
Paroxysmal nocturnal hemoglobinuria
directly into the inferior vena cava, it is not damaged. In fact,
the caudate lobe hypertrophies, and this may, to various degrees, Antiphospholipid syndrome
obstruct the inferior vena cava. The clinical presentation of BCS Tumor invasion
depends on the extent and rapidity of the occlusion of the hepatic Hepatocellular carcinoma
vein and whether collateral circulation has developed to decom- Renal cell carcinoma
press the liver. Vague right upper quadrant abdominal pain is the Adrenal carcinoma
most common presenting symptom of the syndrome, and ascites
Miscellaneous
is the most common abnormality noted on physical examination.
Some patients with hepatic vein thrombosis are asymptomatic, Aspergillosis
presumably as a result of occlusion of only 1 or 2 hepatic veins Behçet syndrome
and decompression of the portal system through the development Inferior vena cava webs
of large intrahepatic and portosystemic collaterals. Trauma
Inflammatory bowel disease
Investigations Dacarbazine therapy
Doppler ultrasonography of the liver is the initial investigation of Idiopathic
choice for patients with suspected BCS; it provides visualization
of the hepatic veins, splenic vein, portal vein, and inferior vena Adapted from Menon KV, Shah V, Kamath PS. The Budd-Chiari syn-
cava. Areas of necrosis are seen better with contrast-enhanced drome. N Engl J Med. 2004 Feb;350(6):578-85; used with permission.
computed tomography and magnetic resonance imaging.
Venography or liver biopsy is not necessary after BCS has
been diagnosed with noninvasive studies. However, if clinical
suspicion is high for a diagnosis of BCS, especially if a patient and to relieve symptoms. Treatment options include medical
has a fulminant or acute presentation, contrast venography may management, surgical portosystemic shunting, TIPS, and liver
be necessary if noninvasive imaging is not diagnostic. The char- transplant (Table 27.2). Although most patients who have BCS
acteristic appearance of the hepatic veins in BCS is that of a spi- can be offered some form of definitive therapy, those in whom
derweb, with an extensive collateral circulation. Also, the inferior the syndrome is due to extensive malignant disease are offered
vena cava may be compressed by an enlarged caudate lobe, or it only palliative care because of the extremely poor prognosis with
may show thrombus. this condition.
In addition to establishing the diagnosis of hepatic vein throm- Medical management consists of diuretic therapy for the
bosis, it is important to identify an underlying cause to determine treatment of ascites, anticoagulation to prevent extension of
management strategies. An appropriate hematologic evaluation venous thrombosis, and treatment of the underlying cause.
should be performed to exclude the various disorders outlined in Approximately 20% of patients can be managed with this
Box 27.2, including evaluation for JAK2 alterations to determine approach. If this approach fails, intervention to enhance hepatic
whether the patient has a myeloproliferative disorder. venous outflow is the next step. Ideal candidates for angioplasty
include patients with inferior vena cava webs or focal hepatic
vein stenosis; thrombolytic therapy is used infrequently but is
Management administered best by direct infusion to the site of the clot.
The aims of treatment of BCS are to relieve obstruction of the The aim of portosystemic shunting is to use the portal
hepatic outflow tract, to identify and treat the underlying cause, vein to provide a venous outflow tract for the liver in order
Table 27.2. Management of Budd-Chiari Syndrome (BCS)

Treatment Indication Advantages Disadvantages
Thrombolytic therapy Acute thrombosis Reverses hepatic necrosis Risk of bleeding
No long-term sequelae Limited success
Angioplasty with and IVC webs Averts need for surgery High rate of restenosis or shunt
without stenting IVC stenosis occlusion
Focal hepatic vein stenosis
TIPS Possible bridge to transplant in fulminant BCS Low mortality High rate of shunt stenosis
Acute BCS Useful even with compression of IVC Extended stents may interfere with
Subacute BCS if portacaval pressure gradient by caudate lobe liver transplant
<10 mm Hg or IVC is occluded
Surgical shunt Subacute BCS Definitive procedure for many patients Risk of procedure-related death
Portacaval pressure gradient >10 mm Hg Low rate of shunt dysfunction with Limited applicability
portacaval shunt Limited availability of surgical
expertise
Liver transplant Fulminant BCS Reverses liver disease Risk of procedure-related death
Presence of cirrhosis May reverse underlying thrombophilia Need for long-term
Failure of portosystemic shunt immunosuppression
Abbreviations: IVC, inferior vena cava; TIPS, transjugular intrahepatic portosystemic shunt.
Adapted from Menon KV, Shah V, Kamath PS. The Budd-Chiari syndrome. N Engl J Med. 2004 Feb 5;350(6):578-85 with data from Ganguli SC, Ramzan NN,
McKusick MA, Andrews JC, Phyliky RL, Kamath PS. Budd-Chiari syndrome in patients with hematological disease: a therapeutic challenge. Hepatology. 1998
Apr;27(4):1157-61; used with permission.
to reverse hepatic necrosis and to prevent chronic sequelae of Darwish Murad S, Plessier A, Hernandez-Guerra M, Fabris F, Eapen CE,
obstruction of hepatic venous outflow. The optimal candidates Bahr MJ, et al. Etiology, management, and outcome of the Budd-
for surgical shunting are patients with a subacute presentation Chiari syndrome. Ann Intern Med. 2009 Aug;151(3):167–75.
in whom ascites is not severe, liver function is preserved, and Ganguli SC, Ramzan NN, McKusick MA, Andrews JC, Phyliky RL,
Kamath PS. Budd- Chiari syndrome in patients with hematolog-
the disease course is smoldering. Patients with acute BCS may
ical disease: a therapeutic challenge. Hepatology. 1998 Apr;27(4):
need a less invasive procedure, such as TIPS. Covered stents 1157–61.
have increased the long-term patency of TIPS, making this Garcia-Tsao G. Liver involvement in hereditary hemorrhagic telangiec-
the preferred method of performing a portosystemic shunt in tasia (HHT). J Hepatol. 2007 Mar;46(3):499–507.
most patients. Indications for liver transplant in patients with Kumar S, DeLeve LD, Kamath PS, Tefferi A. Hepatic veno-occlusive di-
BCS include 1) end-stage chronic liver disease, 2) fulminant sease (sinusoidal obstruction syndrome) after hematopoietic stem cell
liver failure, and 3) deterioration of liver function in spite of transplantation. Mayo Clin Proc. 2003 May;78(5):589–98.
portosystemic shunting. Kumar S, Sarr MG, Kamath PS. Mesenteric venous thrombosis. N Engl
J Med. 2001 Dec;345(23):1683–8.
McDonald GB. Hepatobiliary complications of hematopoietic cell trans-
✓ Budd-Chiari syndrome plantation, 40 years on. Hepatology. 2010 Apr;51(4):1450–60.
• Usually due to hematologic abnormalities (in >85% cases), Menon KV, Shah V, Kamath PS. The Budd-Chiari syndrome. N Engl J
most commonly polycythemia vera Med. 2004 Feb;350(6):578–85.
• Clinical presentation— depends on acuity and severity of Northup PG, Garcia-Pagan JC, Garcia-Tsao G, Intagliata NM, Superina
occlusion (most common is vague right upper quadrant abdom- RA, Roberts LN, et al. Vascular liver disorders, portal vein throm-
inal pain) bosis, and procedural bleeding in patients with liver disease: 2020
• Ascites—most common abnormality on physical examination practice guidance by the American Association for the Study of Liver
• Doppler ultrasonography—initial investigation of choice Diseases. Hepatology. 2021 Jan;73(1):366–413.
✓ When Budd- Chiari syndrome has been confirmed, evaluation Norton ID, Andrews JC, Kamath PS. Management of ectopic varices.
should focus on possible causes (Box 27.2) and management Hepatology. 1998 Oct;28(4):1154–8.
(Table 27.2) Pasha SF, Gloviczki P, Stanson AW, Kamath PS. Splanchnic artery
aneurysms. Mayo Clin Proc. 2007 Apr;82(4):472–9.
Plessier A, Darwish-Murad S, Hernandez-Guerra M, Consigny Y, Fabris
F, Trebicka J, et al. Acute portal vein thrombosis unrelated to cir-
Suggested Reading rhosis: a prospective multicenter follow-up study. Hepatology. 2010
Darwish Murad S, Kamath PS. Liver transplantation for Budd- Jan;51(1):210–8.
Chiari syndrome: when is it really necessary? Liver Transpl. 2008 Seeto RK, Fenn B, Rockey DC. Ischemic hepatitis: clinical presentation
Feb;14(2):133–5. and pathogenesis. Am J Med. 2000 Aug;109(2):109–13.
28
Portal Hypertension–Related Bleedinga

MOIRA HILSCHER, MD
DOUGLAS A. SIMONETTO, MD
Portal hypertensive bleeding encompasses a spectrum of varices. Wedged hepatic venous pressures can be measured di-
conditions that include esophageal, gastric, and ectopic varices rectly by a transjugular route, but expertise in this procedure is
and portal hypertensive gastroenteropathy. Esophageal variceal usually available only at large referral centers.
hemorrhage occurs through a combination of increased portal In cirrhosis, portal hypertension occurs through an increase in
pressure and local factors within the varix itself. Management of resistance to portal venous outflow early in the disease process.
esophageal varices includes primary prophylaxis of variceal hem- This increase is due to mechanical factors related to fibrotic dis-
orrhage, treatment of actively bleeding varices, and prevention tortion of liver architecture. However, approximately 30% of the
of variceal rebleeding (secondary prophylaxis). The choice of increase in intrahepatic resistance occurs through reversible vas-
therapy for primary prophylaxis depends on patient preferences cular factors that are potential targets of pharmacotherapy. Portal
and includes pharmacologic therapy with nonselective β-blockers hypertension is maintained through the development of systemic
(NSBBs) or variceal band ligation, especially if NSBB therapy hyperdynamic circulation and peripheral vasodilatation. Physical
fails or is not tolerated by the patient. Active bleeding is best examination findings in a patient in the hyperdynamic state in-
treated endoscopically. Pharmacologic therapy in combination clude relative hypotension and relative tachycardia; a cardiac out-
with endoscopic therapy is preferred for secondary prophylaxis. flow murmur may be present. The hyperdynamic circulation is
Surgical shunts or transjugular intrahepatic portosystemic shunts characterized in the splanchnic circulation by vasodilatation and
(TIPSs) are second-line therapy. Liver transplant is a treatment increased flow at the level of the splanchnic arterioles. This leads
option aimed at the underlying cause of portal hypertension but to increased portal venous inflow, which in turn exacerbates the
does not have a role in the management of acute bleeding. existing portal hypertension. Drugs such as octreotide and vaso-
pressin reduce splanchnic hyperemia and portal venous inflow.
Portal hypertension results in the development of collateral circu-
Pathogenesis of Portal Hypertension
lation, which may decrease portal pressure. In addition to esoph-
An increase in the hepatic venous pressure gradient (HVPG)— ageal and gastric varices, gastric and intestinal vascular ectasia
the difference between the wedged hepatic venous pressure and and portal hypertensive gastropathy occur in patients with portal
the free hepatic venous pressure—of at least 10 mm Hg is re- hypertension.
quired for the development of esophageal varices, and an HVPG
of 12 mm Hg or more is required for the rupture of esophageal
Esophageal Varices
Pathogenesis
a
The authors thank Patrick S. Kamath, MD, and William Sanchez, MD,
who authored previous versions of this chapter. Local factors that determine the risk of hemorrhage from esoph-
Abbreviations: BRTO, balloon-occluded retrograde transvenous obliter-
ageal varices include the radius of the varix, the thickness of the
ation; GOV, gastroesophageal varix; HVPG, hepatic venous pressure gra- varix wall, and the pressure gradient between the varix and the
dient; IGV, isolated gastric varix; NSBB, nonselective β-blocker; TIPS, esophageal lumen. Factors that determine the severity of bleeding
transjugular intrahepatic portosystemic shunt are the degree of liver dysfunction, the portal pressure, and the
331
size of the rent in the varix. Band ligation is an attempt to de- the day, and the lesser degree of β-blockade is not deleterious to
crease flow through the varix by inducing thrombosis and, ulti- the patient.
mately, to obliterate the varix. Carvedilol, an NSBB with additional α1-blocking properties,
is another agent that might be used for primary prophylaxis.
Because it has vasodilating effects, carvedilol can exacerbate ar-
Therapy terial hypotension and sodium retention, so it should be used with
The current recommendations for treatment of esophageal vari- caution in patients who have decompensated cirrhosis. Nitrates
ceal bleeding are summarized in Table 28.1. have no place in primary prophylaxis, either when administered
as single agents or in combination with NSBBs.
The goal of therapy is to decrease the HVPG to less than
Primary Prophylaxis
12 mm Hg or by 20% when compared with baseline. However,
Most patients with cirrhosis should undergo upper endoscopy to determination of the HVPG to assess the hemodynamic response
screen for the presence and size of esophageal varices. Patients is invasive and is not recommended in routine practice.
with a platelet count greater than 150×109/L and liver stiffness Although sclerotherapy is no longer used as a form of pri-
less than 20 kPa according to transient elastography have a low mary prophylaxis, variceal band ligation may be an alternative
risk for varices and thus can avoid screening endoscopy. Capsule approach to primary prophylaxis because it carries a lower rate
endoscopy and computed tomography are promising methods of esophageal ulceration and provides more effective obliteration
for detecting varices but, currently, are not recommended for of variceal structures compared with sclerotherapy. Currently,
screening. Varices should be characterized as either small esophageal variceal ligation is recommended for patients who
(≤5 mm in diameter) or large (>5 mm in diameter). Large varices have contraindications to therapy with NSBBs, who have not
are seen in 16% of patients who undergo screening by endos- had a decrease in the HVPG (if obtained), or who have had ad-
copy. In approximately 25% of patients with large varices, var- verse effects from NSBB therapy. A network meta-analysis of
iceal hemorrhage will develop within the ensuing 2 years. For 32 studies that compared NSBBs and endoscopic variceal liga-
patients with large varices and advanced liver disease (Child- tion showed a potential decrease in mortality risk with NSBB
Pugh class C), the risk of hemorrhage can be as high as 75%. therapy compared to band ligation, while both were effective in
Thus, prophylactic therapy is indicated for patients with large decreasing the risk of first variceal bleeding. Patient preference is
varices. The absence of endoscopic signs that indicate high risk often the factor that determines which therapy is used.
(eg, red wales) does not influence the decision to initiate therapy.
Prophylactic treatment may also be considered for patients with
Child-Pugh class C status and small varices. If only small var- Control of Esophageal Variceal Hemorrhage
ices are detected at endoscopy, the procedure should be repeated Active esophageal variceal bleeding is managed best by en-
in 1 year to assess for progression in size. If no varices are doscopic means, preferably variceal band ligation. After gas-
detected at endoscopy, the procedure should be repeated in 2 or trointestinal tract bleeding has been detected in patients with
3 years to screen for newly formed varices in patients who have cirrhosis, immediate initiation of pharmacologic therapy is
compensated cirrhosis and annually in those who have decom- beneficial—even before endoscopy has demonstrated variceal
pensated disease. bleeding. Pharmacologic therapy is continued for up to 5 days
The established primary prophylaxis is treatment with NSBBs, after endoscopic treatment of varices to reduce the risk of im-
such as propranolol and nadolol, or with endoscopic variceal mediate rebleeding.
band ligation. Only nonselective agents should be used rather Vasopressin is a potent splanchnic vasoconstrictor that decreases
than β1-selective agents (eg, metoprolol). β1-Blockade decreases portal venous inflow, thereby decreasing portal pressure, but it
cardiac output and splanchnic blood flow, whereas the additional is seldom used. Nitroglycerin is used only in conjunction with
β2-blockade allows unopposed α1-adrenergic constriction in the vasopressin to further decrease portal pressure and reduce the is-
splanchnic circulation. This decreases portal blood flow and, con- chemic adverse effects of vasopressin, which are pronounced and
sequently, portal pressure. Therapy is started at a low dose, with limit therapy in up to 30% of patients. Octreotide, a long-acting
slow upward titration of the dose until a resting pulse rate of 55 to synthetic somatostatin analogue, is the pharmacologic agent most
60 beats/min is achieved or hypotension develops (systolic blood commonly used in the US. It appears to decrease portal pressure
pressure <90 mm Hg). by inhibiting the release of glucagon and the ensuing postpran-
A long-acting preparation of propranolol administered as a dial hyperemia and by having a direct vasoconstrictive effect on
single dose in the early evening is preferred. This allows adequate splanchnic arteriolar smooth muscle. Octreotide is recommended
β-blockade at night, when the risk of bleeding is higher. With the for acute variceal bleeding and for prevention of early rebleeding.
long-acting preparation administered in the evening, β-blockade It is administered as an initial bolus of 50 µg, with a subsequent
is less during the following day, thus decreasing the side effect infusion at 50 µg hourly for up to 5 days, in conjunction with en-
of fatigue. At the same time, the risk of bleeding is lower during doscopic variceal band ligation. NSBBs should not be used in the
Table 28.1. Recommendations for Treatment of Esophageal Variceal Bleeding

Type of treatment First-line therapy Second-line therapy Other therapy
Primary prophylaxis NSBBs or endoscopic variceal band ligation
Control of bleeding Variceal band ligation and octreotide (or other TIPS
vasoactive pharmacologic agents)
Secondary prophylaxis Variceal band ligation and NSBBs TIPS Liver transplant
Abbreviations: NSBB, nonselective β-blocker; TIPS, transjugular intrahepatic portosystemic shunt.

28. Portal Hypertension–Related Bleeding 333
presence of acute bleeding since they will worsen hypotension, and gastric vascular ectasia. Because no evidence-based manage-
but use of NSBBs should be initiated once octreotide therapy is ment strategies are available for gastric sources of portal hyper-
discontinued and before hospital discharge. tensive bleeding, therapy often requires an empirical approach.
Supportive and resuscitative care includes early elective intu-
bation for airway protection, cautious volume replacement, and
Gastric Varices
vigorous surveillance and treatment of concomitant infection.
Maintenance of the hemoglobin level at 7 to 9 g/dL is appropriate The most common gastric varices are gastroesophageal varices
because aggressive transfusion of blood products may precipi- (GOVs) that extend into the lesser curve of the cardia of the stom
tate further bleeding by increasing portal pressure (transfusion ach (type 1 [GOV1]) and are readily treated with variceal band
threshold hemoglobin <7 g/dL). Antibiotic prophylaxis for 7 days ligation. The most common sources of gastric variceal bleeding
with a fluoroquinolone or third- generation cephalosporin is are cardiofundal varices, located in the greater curvature of the
recommended to decrease the incidence of bloodstream infection cardia and the fundus of the stomach, that are either extensions of
and spontaneous bacterial peritonitis, which commonly accom- esophageal varices (type 2 [GOV2]) or are isolated gastric varices
pany variceal hemorrhage. Antibiotic therapy is probably the most (IGVs) (cardiofundal varices; type 1 [IGV1]). Recent data have
important reason why the mortality rate among patients with var- suggested that the frequency of bleeding from gastric varices is
iceal bleeding has decreased from 50% to about 20%. Lactulose similar to that from large esophageal varices. Gastric varices are
therapy may be instituted to treat hepatic encephalopathy. more likely to be found in patients who have had bleeding from
TIPS may be used as preemptive, rescue, or salvage therapy esophageal varices than in those who have not had prior bleeding.
for variceal bleeding. Preemptive use of TIPS, placed within 72 The risk of bleeding from gastric varices is related to the size of
hours of presentation, has been shown to decrease the risk of the varix, the liver function according to the Child-Pugh classifi-
therapy failure or early rebleeding in high-risk patients; thus, it cation, and the presence of red signs on the varix.
may benefit those who have Child-Pugh class C or Child-Pugh NSBBs are recommended for primary prophylaxis of gastric
class B status with active bleeding on index endoscopy. Risk varices, although data are limited. Acute gastric variceal bleeding
of hepatic encephalopathy and 1-year mortality have not been is treated best endoscopically. GOV1 varices, like esophageal var-
shown to increase; however, the routine use of preemptive TIPS ices, can be treated with band ligation, while cardiofundal varices
has not been recommended because of the potential for liver dete- are treated best with injection of cyanoacrylate glue. Currently,
rioration and the uncertain effects on long-term survival. Salvage however, cyanoacrylate glue injection is not widely available
TIPS is indicated for patients with refractory bleeding, while in the US, and its use is considered off-label. Other options in-
rescue TIPS is recommended when bleeding recurs despite var- clude sclerotherapy with ethanolamine oleate or thrombin, but
iceal band ligation and vasoactive therapy. The use of TIPS is the success rate has varied. Thus, TIPS is still considered the
preferred to surgical intervention, particularly in patients with treatment of choice for bleeding cardiofundal varices.
Child-Pugh class B or C status. Since expertise with performing Although pharmacologic therapy (eg, NSBBs) may be used to
surgical shunts is limited to large referral centers, surgical in- prevent gastric variceal rebleeding, no studies support this prac-
tervention is impractical for acute bleeding. However, surgical tice. Thus, portosystemic shunt creation should be considered
shunts may be considered for recurrent bleeding in patients with for the prevention of rebleeding in patients with documented
Child-Pugh class A status and for patients for whom continued cardiofundal variceal bleeding if variceal obturation with cyano-
medical surveillance will be unlikely. TIPS requires close ultra- acrylate glue is not possible. TIPS is used for patients with poor
sonographic follow-up of the shunt to evaluate for restenosis, al- liver function, while patients with Child-Pugh class A status may
though the rate of TIPS stenosis has decreased with the adoption also be considered for portosystemic shunt surgery. Also, gastric
of covered stents. All potential transplant candidates who have varices can be obliterated concomitantly with TIPS placement
variceal hemorrhage should be referred to a transplant center for through the injection of gel foam or coils into the gastroesophageal
evaluation. collateral vessels. Balloon-occluded retrograde transvenous oblit-
eration (BRTO) may be an option for treatment of cardiofundal
varices in patients with spontaneous gastrorenal or splenorenal
Secondary Prophylaxis shunts; it involves sclerosant injection through cannulation of the
Secondary prophylaxis involves therapies to prevent rebleeding left renal vein to obliterate the cardiofundal varix and the shunt.
in patients who have already bled from esophageal varices.
Intervention is essential because up to 80% of patients who
Portal Hypertensive Gastropathy
have already bled from varices will bleed again within 2 years.
Treatments include pharmacotherapy with NSBBs, endoscopic Portal hypertensive gastropathy is a source of gastrointestinal
band ligation, TIPS, and surgical shunts. The use of variceal tract bleeding in some patients with cirrhosis and portal hyper-
band ligation in combination with NSBB therapy is first-line tension. The elementary lesion is a mosaic-like pattern of the
therapy to prevent recurrent bleeding. After acute bleeding has gastric mucosa, but this is not specific. The more specific lesion
been controlled with variceal ligation, the next ligation session is the red marking, which may be either a red point lesion less
should be scheduled in approximately 10 to 14 days. Subsequent than 1 mm in diameter or a cherry-red spot larger than 2 mm in
sessions should be scheduled every 3 to 4 weeks. Varices usually diameter. The presence of a mosaic-like pattern alone indicates
can be obliterated over several sessions. mild portal hypertensive gastropathy, whereas red markings
superimposed on the mosaic pattern suggest severe portal hy-
pertensive gastropathy. Portal hypertensive gastropathy tends to
Portal Hypertension Manifestations be more common in the proximal stomach, in patients who have
in the Stomach advanced stages of liver disease according to the Child-Pugh
Gastric consequences of portal hypertension that may lead to classification, and in those with gastric or esophageal varices.
bleeding include gastric varices, portal hypertensive gastropathy, Approximately 3% of patients who have severe gastropathy may
been high. Portosystemic shunts should be considered as rescue

treatment if vasoactive drug therapy fails. Patients who present
with chronic bleeding may be treated with iron supplementation
and NSBBs. For these patients, treatment should be continued
indefinitely or until liver transplant is performed. Portosystemic
shunts may be used as rescue treatment in patients who continue
to be transfusion-dependent in spite of adequate NSBB therapy.
Gastric Vascular Ectasia

A less common gastric mucosal lesion in portal hyperten-
sion is gastric vascular ectasia. In contrast to portal hyperten-
sive gastropathy, gastric vascular ectasia is characterized by
red markings in the absence of a mosaic-like pattern. The red
markings may be arranged in linear aggregates in the antrum,
for which the term gastric antral vascular ectasia (or water-
melon stomach) is used (Figure 28.1). If the red markings do
not have a typical linear arrangement, the lesion is designated
diffuse gastric vascular ectasia. Diffuse lesions that also involve
the proximal stomach may be difficult to differentiate from se-
vere portal hypertensive gastropathy. When the diagnosis is un-
certain, gastric mucosal biopsy, which usually is safe, may be
helpful. Liver dysfunction seems to be necessary for the path-
ogenesis of vascular ectasia because these lesions may resolve
with liver transplant.
Treatment of gastric vascular ectasia is difficult. Some
patients may be managed with only iron replacement therapy.
NSBBs do not seem to be effective for these lesions. Therapy
may be tried with thermoablation such as argon plasma coagu-
lation, radiofrequency ablation, and cryotherapy. Antrectomy is
effective, but the mortality and morbidity related to the operation
can be substantial for patients with cirrhosis. These lesions do not
respond to portosystemic shunts, either surgical or TIPS, but oc-
casionally they respond to estrogen-progesterone combinations
or intravenous bevacizumab.
Suggested Reading
Garcia-Tsao G, Abraldes JG, Berzigotti A, Bosch J. Portal hyperten-
sive bleeding in cirrhosis: risk stratification, diagnosis, and manage-
ment: 2016 practice guidance by the American Association for the
Study of Liver Diseases. Hepatology. 2017 Jan;65(1):310–35.
Garcia-Tsao G, Bosch J. Management of varices and variceal hemor-
rhage in cirrhosis. N Engl J Med. 2010 Mar 4;362(9):823–32.
Kamath PS, Lacerda M, Ahlquist DA, McKusick MA, Andrews
JC, Nagorney DA. Gastric mucosal responses to intrahepatic
portosystemic shunting in patients with cirrhosis. Gastroenterology.
2000 May;118(5):905–11.
Primignani M, Carpinelli L, Preatoni P, Battaglia G, Carta A, Prada A,
et al. Natural history of portal hypertensive gastropathy in patients
Figure 28.1. Gastric Antral Vascular Ectasia. A and B, Note the
with liver cirrhosis: The New Italian Endoscopic Club for the study
linear aggregates of red markings in the antrum and the absence of an
and treatment of esophageal varices (NIEC). Gastroenterology. 2000
underlying mosaic-like pattern.
Jul;119(1):181–7.
Shah V, Kamath P. Portal hypertension and variceal bleeding. In: Feldman
M, Friedman LS, Brandt LJ, Sleisenger MH, Fordtran JS, eds.
present with acute upper gastrointestinal tract bleeding, and ap-
Sleisenger and Fordtran’s gastrointestinal and liver disease: pathophys-
proximately 15% have chronic bleeding. iology, diagnosis, management. 11th ed. Elsevier; 2020:1442–70.
Anecdotally, acute bleeding from portal hypertensive Simonetto DA, Liu M, Kamath PS. Portal hypertension and related
gastropathy has been treated with vasoactive drugs such as vas- complications: diagnosis and management. Mayo Clin Proc. 2019
opressin, somatostatin, and octreotide, and the success rate has Apr;94(4):714–26.
29
Ascites, Hepatorenal Syndrome, and

Encephalopathya
TASHA B. KULAI, MD
DOUGLAS A. SIMONETTO, MD
The portal hypertension and hepatic synthetic dysfunction of changes from architectural distortion by fibrosis and nodular
cirrhosis cause 3 main complications as liver disease progresses regeneration, and 20% to 30% of the increased pressure is re-
from compensated to decompensated disease: variceal bleeding, lated to increased intrahepatic vascular tone due to vasoactive
ascites, and hepatic encephalopathy (HE). Variceal bleeding is factors. Increased hepatic sinusoidal pressure appears to be the
discussed in Chapter 27. primary event that leads to splanchnic (and eventually systemic)
vasodilatation, which in turn causes underfilling of the vascular
compartment and baroreceptor-mediated stimulation of the renin-
Ascites
angiotensin-aldosterone system, the sympathetic nervous system,
Ascites is the most common major complication of cirrhosis and antidiuretic hormone (ADH) release. The net result is reten-
and occurs within 10 years in about 50% of patients who have tion of sodium and water by the kidneys. Nitric oxide appears to
compensated cirrhosis. The development of ascites denotes the be an important factor in the regulation of intrahepatic vascular
transition from compensated to decompensated cirrhosis as it is tone. Considerable evidence shows that in persons with cirrhosis,
often the first decompensating event. Ascites is associated with the decreased availability of hepatic vascular nitric oxide impairs
morbidity from abdominal distention and increased mortality relaxation and increases hepatic perfusion pressure. However, the
from complications such as spontaneous bacterial peritonitis splanchnic and systemic vasculature markedly overproduce en-
(SBP) and kidney dysfunction, with 15% of patients dying in dothelial nitric oxide, which results in arterial vasodilatation and,
1 year and 44% in 5 years. subsequently, hyperdynamic circulation, which is characterized
by tachycardia, increased cardiac output, and decreased arterial
Pathogenesis of Ascites pressure.
Compared with other capillary beds, the hepatic sinusoids are
Persons with cirrhosis have increased hydrostatic pressure in the a very low-pressure hydrostatic system (vascular inflow is partly
liver. About 70% of this increased pressure is due to structural portal venous blood that has a hydrostatic pressure only slightly
higher than the systemic venous pressure). However, with portal
hypertension, increased pressure in the hepatic sinusoids causes
a
The authors thank J. Eileen Hay, MB, ChB, who authored previous
versions of this chapter. fluid to move into the tissue and to “weep” from the surface of the
liver as ascites. A minimum hepatic venous pressure gradient of
Abbreviations: AASLD, American Association for the Study of Liver
10 to 12 mm Hg is necessary for ascites to develop.
Disease; ADH, antidiuretic hormone; AKI, acute kidney injury; CTP,
Child-Turcotte-Pugh; HE, hepatic encephalopathy; HRS, hepatorenal
syndrome; MELD, Model for End- stage Liver Disease; NAKI, Evaluation of Patients With Ascites
nonacute kidney injury; PMN, polymorphonuclear neutrophil; PPCD,
postparacentesis circulatory dysfunction; SAAG, serum-ascites albumin The first step in the diagnostic approach to patients with ascites is
gradient; SBP, spontaneous bacterial peritonitis; TIPS, transjugular to determine the cause (Box 29.1). In 85% of patients, ascites is
intrahepatic portosystemic shunt due to cirrhosis and the diagnosis is usually obvious. About 15%
335
In addition to SBP, other complications of cirrhosis that may

Box 29.1. Diagnostic and Therapeutic Algorithm for worsen ascites, including malignancy, portal or hepatic venous
Patients With Ascites thrombosis, and active liver disease, should be sought with
Does the patient have cirrhosis? liver tests or imaging studies. Any active liver disease (alcohol-
If yes, are there any other complications of cirrhosis— related, autoimmune, or hepatitis B) must be treated appropri-
spontaneous bacterial peritonitis, portal vein ately. Kidney function and kidney sodium excretion should be
thrombosis, active liver disease, or malignancy? assessed because they are clinical predictors of a therapeutic re-
Prognostic factors for therapy—urinary sodium excre- sponse: Patients with normal serum urea nitrogen and creatinine
tion and kidney function levels and sodium excretion of more than 10 mEq/L (without
taking diuretics) generally are very sensitive to sodium restriction
Consideration of therapeutic options
and diuretic therapy. Patients with marked sodium retention, par-
ticularly those with abnormal urea and creatinine levels, require
much higher doses of diuretics.
have nonhepatic causes (malignancy, tuberculosis, constrictive
pericarditis, right-sided heart failure, myxedema, and kidney- ✓ Evaluation for new or worsening ascites
• Diagnostic paracentesis with cell count, including differential
related causes), and these must be differentiated from cirrhosis
cell count, and bacterial cultures
and treated appropriately. • Albumin levels of serum and ascitic fluid (for calculation of
Diagnostic paracentesis is mandatory and should be performed serum-ascites albumin gradient) and total protein level of as-
in all patients who present with new-onset ascites. If patients citic fluid for evaluation of new-onset ascites in patients who
have cirrhosis and ascites, diagnostic paracentesis should also do not have a clear diagnosis of cirrhosis
be performed if they are hospitalized or if they have a change • Doppler ultrasonography to rule out hepatocellular carcinoma
in clinical status, such as deterioration in liver function, fever, and portal or hepatic vein thrombosis
worsening encephalopathy, or kidney failure. Because bleeding • Evaluation for active liver disease (eg, consider alcohol use and
is uncommon, the routine prophylactic use of fresh frozen plasma autoimmune hepatitis)
or platelets before paracentesis is not recommended. For all • Serum sodium and creatinine levels
• Measurement of 24-hour urinary sodium excretion
patients, ascitic fluid analysis should include a cell count, with
both a total nucleated cell count and a polymorphonuclear neu-
trophil (PMN) count, and bacterial culture by bedside inocula-
tion of blood culture bottles. Ascitic fluid protein and albumin Therapy for Cirrhosis-Associated Ascites
levels are measured simultaneously with the serum albumin Sodium Restriction and Diuretic Therapy
level to calculate the serum-ascites albumin gradient (SAAG).
The albumin concentration in ascitic fluid is inversely propor- Cirrhosis-associated ascites is perpetuated by retention of sodium
tional to portal pressure. Usually, a high SAAG value (≥1.1 g/dL) and water by the kidneys. Therefore, treatment must produce a
confirms, with greater than 95% accuracy, the clinical suspicion negative sodium balance. About 10% of patients have a response
of portal hypertension–related ascites. The other main cause for a to salt restriction alone. Reversible factors that contribute to so-
high SAAG value is portal hypertension related to cardiac failure, dium retention should be identified and corrected (Box 29.2).
but in cardiac failure the total protein concentration in the ascitic Ascites is controlled in 65% of patients with the initiation of spi-
fluid is usually 2.5 g/dL or more (<2.5 g/dL in cirrhosis-related ronolactone therapy and in another 25% with the addition of a
portal hypertension) (Table 29.1). loop diuretic. Thus, ascites can be managed in 90% of patients,
Other tests should be performed only if a specific diagnosis is often as outpatients, with the sequential introduction of sodium
suspected clinically. Lactate dehydrogenase and glucose levels restriction, generally to 2 g daily (88 mEq), and then diuretic
should be determined if secondary peritonitis is suspected. Other therapy.
tests to consider are amylase (>1,000 U/L suggests pancreatic Spironolactone, an aldosterone antagonist, is an effective diu-
ascites), cytology (at least at the initial tap), and triglycerides (if retic in most patients who have nonazotemic cirrhosis with ascites
the ascitic fluid is cloudy; results are usually <100 mg/dL in cir- and is more effective than furosemide for single-agent therapy.
rhosis). Mycobacterial culture should be performed only if tu- Combination therapy with furosemide is generally used to
berculosis is strongly suspected. Other ascitic fluid indexes (eg, achieve natriuresis more rapidly and to maintain normokalemia.
lactate and pH) generally offer little or no additional information. Spironolactone is given at an initial dose of 100 mg daily, with
Gram staining is rarely positive. increases in 100-mg increments as appropriate to 400 mg daily,
Table 29.1. Ascitic Protein and Serum-Ascites Albumin

Box 29.2. Reversible Factors for Lack of Response
Gradient (SAAG)
to Diuretic Therapy in Cirrhosis-Associated Ascites
SAAG, g/dL Inadequate sodium restriction
Total protein,
g/dL ≥1.1 <1.1 Inappropriate use of diuretics or other medications
(eg, β-blockers)
<2.5 Cirrhosis Nephrotic syndrome
Nephrotoxic medications
Acute liver failure Myxedema
≥2.5 Congestive heart failure Peritoneal carcinomatosis Spontaneous bacterial peritonitis
Constrictive pericarditis Tuberculous peritonitis Portal or hepatic vein thrombosis
Budd-Chiari syndrome Pancreatic ascites
Untreated active liver disease
Veno-occlusive disease Chylous ascites
29. Ascites, Hepatorenal Syndrome, and Encephalopathy 337
according to the clinical response and adverse effects (particu- tolerable doses of diuretics but does not lose the desired weight
larly hyperkalemia). Furosemide usually is started at a dose of (ie, 24-hour urine sodium is less than intake). Patients who have
40 mg daily in combination with spironolactone and increased not had a response to spironolactone 400 mg daily and furo-
in 40-mg increments to 160 mg daily until the desired effect is semide 160 mg daily have diuretic-resistant ascites. Ascites is
achieved or adverse effects occur. termed diuretic-intolerant when therapy is prevented by diuretic-
Diuretic therapy is titrated to achieve optimal weight loss related complications.
without complications, which include 1) deterioration in kidney
function, 2) excessive weight loss in relation to ascites or edema, ✓ Refractory ascites— ascites unresponsive to sodium restriction
3) orthostatic symptoms, 4) encephalopathy, and 5) dilutional and diuretic therapy
hyponatremia unresponsive to fluid restriction. Generally, a daily ✓ Diuretic-resistant ascites—ascites unresponsive to the maximal
dose of diuretics
weight loss of 0.5 to 1.0 kg is optimal to avoid adverse effects be-
✓ Diuretic-intolerant ascites—ascites in patients who cannot
cause only 750 to 900 mL of fluid can be mobilized daily from the tolerate diuretic therapy because of adverse effects or related
abdomen into the general circulation. After the fluid is mobilized complications

by whatever method, diuretic therapy should be adjusted to keep
the patient free of ascites.
Treatment Options
Therapeutic Paracentesis For patients who have refractory ascites, the long-term prognosis
In randomized studies of patients with tense ascites and avid so- is dismal (1-year mortality rate >70%), and the only therapy ca-
dium retention, repeated large-volume paracentesis (with intra- pable of improving both quality of life and patient survival is
venous infusions of albumin), compared with diuretic therapy, liver transplant. Consequently, liver transplant should always be
is 1) more effective in eliminating ascites; 2) associated with a considered for an otherwise acceptable candidate who has ascites
lower incidence of hyponatremia (5% vs 30%), kidney impair- that cannot be controlled with adequate sodium restriction and
ment (3.4% vs 27%), and HE (10.2% vs 29%); and 3) associated diuretic therapy.
with shorter hospital stay and reduced cost of therapy without any Until a patient undergoes liver transplant or if a patient cannot
differences in survival, SBP, or causes of death. undergo liver transplant, therapeutic options for refractory ascites
Intravenous infusion of 25% albumin is an important measure are limited to repeated therapeutic paracentesis or insertion of a
to prevent postparacentesis circulatory dysfunction (PPCD) in transjugular intrahepatic portosystemic shunt (TIPS). According
patients with cirrhosis and tense ascites who are treated with to the treatment recommendations of the American Association
large-volume (>5 L) or total paracentesis. Complete mobiliza- for the Study of Liver Diseases (AASLD), first-line therapy for
tion of ascites without plasma volume expansion causes a dete- refractory ascites is therapeutic paracentesis, and TIPS is re-
rioration in systemic hemodynamics in 75% of patients; in 20%, served for patients who cannot tolerate paracentesis or who re-
hyponatremia or kidney dysfunction develops, which may be ir- quire large-volume paracentesis for refractory ascites for more
reversible. Generally, 6 to 8 g of albumin infused for every 1 L than 2 or 3 months. Peritoneovenous shunting may be considered
of ascitic fluid removed decreases the risk of PPCD to less than as a last resort for patients who are not candidates for repeated
20%. Dextran 70 and polygeline are less effective than albumin large-volume paracentesis, liver transplant, or TIPS. Diuretic
as plasma volume expanders and are not recommended. therapy should be discontinued for patients who have refractory
ascites when urine sodium excretion is less than 30 mmol daily.
Discontinuation of nonselective β-blockers may be considered if
Drugs to Avoid in Cirrhosis-Associated Ascites any of the following develops: circulatory dysfunction (systolic
For patients with cirrhosis-associated ascites, nonsteroidal anti- blood pressure <90 mm Hg), hyponatremia (<130 mmol/L), or
inflammatory drugs are contraindicated and aminoglycosides kidney injury (serum creatinine >1.5 mg/dL).
are generally avoided if alternative antibiotics may be effective.
Drugs that decrease arterial pressure or kidney blood flow should
TIPS in Refractory Ascites
be avoided (eg, angiotensin-converting enzyme inhibitors, an-
giotensin II receptor blockers, and α-adrenergic blockers). The hemodynamic effects of TIPS have been well described.
Pharmacologic acid suppression, which may increase the inci- Increased cardiac output (due to increased venous return) and a
dence of SBP, should also be avoided. further decrease in systemic vascular resistance occur temporarily
for 1 to 3 months, but increased urinary excretion of sodium starts
✓ Ascites can usually be managed with sodium restriction and diu- 7 to 28 days after the procedure. At the same time, renin activity
retic therapy and aldosterone levels decrease. Resolution of ascites is slow, and
✓ For patients with tense ascites, regular large-volume paracentesis diuretic therapy should be continued initially.
is best; if more than 5 L of fluid is removed, administer albumin TIPS effectively decreases ascites in about 50% of patients
(6-8 g for every 1 L fluid removed) but increases the incidence of encephalopathy by 20%. Overall
patient survival is unchanged by TIPS, although a potential ben-
efit has been suggested in recent studies. TIPS should be used
Refractory Ascites with caution in patients older than 70 years and in patients who
have clinically significant cardiopulmonary dysfunction, severe
Definition kidney failure, or advanced liver disease. Mortality increases
Refractory ascites is due to avid retention of sodium by the for patients with a pre- TIPS Child- Turcotte-
Pugh (CTP)
kidneys and occurs in about 10% of patients with decompensated score greater than 11 or a Model for End-stage Liver Disease
cirrhosis. Clinically, ascites is considered to be refractory when (MELD) score greater than 18. For patients with refractory as-
a patient has adequate sodium restriction and receives maximal, cites, survival after TIPS is lower than survival after TIPS for
variceal bleeding. Predictors of worsening encephalopathy are (92% of cases) are caused by a single organism, and 8% are
age older than 65 years, pre-TIPS encephalopathy, sarcopenia, polymicrobial. The use of norfloxacin prophylaxis has caused
hyponatremia, or a TIPS gradient less than 5 mm Hg. The use epidemiologic changes in the bacterial flora, with a shift toward
of expanded polytetrafluoroethylene–covered stents is preferred more gram-positive infections. The main pathogenic mechanism
to bare stents because patients have less shunt dysfunction and leading to SBP is generally considered to be intestinal bacterial
better survival. However, the optimal hepatic venous pressure translocation, by which bacteria move from the gut to mesen-
gradient for control of ascites is not known. Expansion- teric lymph nodes and, hence, into the systemic circulation before
controlled stents, which are now available, allow for a gradual infecting the peritoneal membranes.
increase in the stent diameter (starting at 8 mm). The clinical presentation and severity of SBP can be ex-
tremely variable and range from chills, fever, and abdominal
pain to no symptoms. Unless paracentesis is performed, the di-
Hepatic Hydrothorax
agnosis may be missed. Often, the clinical picture is a lack of
Hepatic hydrothorax is a complication of cirrhosis-associated as- response to diuretics, deteriorating kidney function, or worsening
cites in 5% to 10% of patients. Management is the same as for portosystemic encephalopathy. Patients with cirrhosis who are at
patients with ascites (sodium restriction and diuretic therapy). particular risk for SBP are those with more advanced cirrhotic-
TIPS is effective in some patients. Thoracentesis is recommended stage liver disease, a low concentration of ascitic fluid protein
only if the diagnosis is uncertain, if infection is strongly suspected, (<1 g/dL), bilirubin level higher than 3.2 mg/dL, or gastrointes-
or if symptomatic relief is needed. The use of chest tubes and tinal tract hemorrhage. Kidney impairment is common in these
pleurodesis should be avoided. patients and is a clinical predictor of poor outcome.
Spontaneous Bacterial Peritonitis Diagnosis

SBP occurs in 10% to 30% of patients with cirrhosis-associated Ascitic fluid analysis is essential for the diagnosis of SBP (Figure
ascites and frequently is recurrent (1-year recurrence rate, 70%). 29.1). However, the clinical presentation of this condition can
In the past, the infecting organisms were normal bowel flora, be subtle and easily missed clinically. Diagnostic paracentesis
with 70% of cases caused by gram-negative bacilli (especially should be performed in all hospitalized or emergency department
Escherichia coli and Klebsiella) and 30% by gram- positive patients who have cirrhosis-associated ascites and in patients who
cocci (mainly Streptococcus and Enterococcus species), with present with signs of infection, encephalopathy, deteriorating
anaerobes being very uncommon (<5% of cases). Most infections kidney function, or gastrointestinal tract bleeding. Bedside
Figure 29.1. Diagnostic Algorithm for Spontaneous Bacterial Peritonitis (SBP). CNNA indicates culture-negative neutrocytic ascites; PMN,
polymorphonuclear neutrophil.
inoculation of blood culture bottles with 10 mL of ascitic fluid is nosocomial infections with invasive procedures and in patients in
essential for maximizing the likelihood of positive cultures. intensive care units. In 50% of patients who received norfloxacin
A presumptive diagnosis of SBP is made if the ascitic fluid prophylaxis and in 16% of patients who did not receive prophy-
PMN count is more than 250 cells/µL in a patient who has laxis, SBP was caused by quinolone- resistant gram- negative
cirrhosis-associated ascites and no secondary source of infec- bacilli; these organisms often are resistant also to trimethoprim-
tion. Blood cultures are performed before antibiotic therapy is sulfamethoxazole therapy.
started. A positive bacterial culture of the ascitic fluid confirms
the diagnosis; if the bacterial culture is negative, the diagnosis of
culture-negative neutrocytic ascites is made if there is no recent Albumin Infusions
history of antibiotic therapy and no other cause of neutrocytic About 30% of patients with cirrhosis who have SBP develop
ascites (cholecystitis, pancreatitis, hemorrhage, recent abdom- kidney impairment, an important predictor of mortality for these
inal surgery, or carcinomatosis). Patients with culture-negative patients. In a randomized trial, albumin infusion on day 1 (1.5
neutrocytic ascites have clinical and biochemical features iden- g/kg) and day 3 (1 g/kg) prevented this complication; a meta-
tical to those of patients with microbiologically confirmed SBP, analysis of 4 randomized trials (288 patients) confirmed that al-
and they are assumed to have SBP that was missed with current bumin infusion prevented acute kidney injury (AKI) and reduced
culture techniques. Bacterascites is defined by ascitic fluid with mortality. AASLD guidelines state that albumin infusions should
a PMN count less than 250 cells/µL and a positive bacterial cul- be reserved for very ill patients who are most at risk (ie, serum
ture. It usually indicates the transient residence of bacteria in the creatinine >1 mg/dL, serum urea nitrogen >30 mg/dL, or total
ascitic fluid. Patients with bacterascites generally have less severe bilirubin >4 mg/dL).
liver disease than those with SBP. Although bacterascites may
progress to SBP, it usually clears spontaneously without antibi-
otic therapy. Follow-up Paracentesis
Diagnostic paracentesis after 48 hours of antibiotic therapy in
✓ Culture-negative neutrocytic ascites—ascitic fluid PMN count a recovering patient is often considered unnecessary. However,
greater than 250 cells/µL and a negative culture; treatment should follow-up paracentesis is mandatory for patients who do not
be as for SBP show clinical improvement. If the PMN count is greater than the
✓ Monomicrobial nonneutrocytic bacterascites—ascitic fluid PMN
baseline, the patient must be reexamined carefully for secondary
count less than 250 cells/µL and a positive culture; most resolve
spontaneously, but follow-up paracentesis should be performed sites of infection, including follow-up abdominal radiography
within 72 hours or, for symptomatic patients, antibiotic therapy for free air, computed tomography of the abdomen, and surgical
may be considered
consultation.
Differential Diagnosis
✓ SBP often occurs without symptoms
✓ PMN count greater than 250 cells/µL in a patient with cirrhosis- The main differential diagnosis for SBP is secondary bacterial
associated ascites and no secondary source of infection is suffi- peritonitis (5%-10% of cases of bacterial peritonitis in patients
cient for a diagnosis of SBP (culture-negative neutrocytic ascites) with cirrhosis), most commonly from a perforated viscus or occa-
sionally an abscess. Secondary bacterial peritonitis appears to be
a chance occurrence but is suspected in patients with liver disease
Treatment less severe than SBP. The operative mortality rate for patients
with cirrhosis who have infected ascites is about 85%, but for
Antibiotic Therapy patients with secondary bacterial peritonitis who do not have sur-
With the finding of a high PMN count in ascitic fluid, empirical gery, mortality is close to 100%.
therapy for SBP must be instituted and directed against aerobic SBP and secondary bacterial peritonitis cannot be distin-
enteric bacteria. Cefotaxime, 2 g intravenously every 8 hours, is guished on the basis of clinical features. Factors that suggest a
the first choice of antibiotic for empirical therapy and is started secondary infection are a high leukocyte count in ascites (>10,000
when the PMN count in ascitic fluid is more than 250 cells/µL. cells/µL), multiple or unusual organisms (fungi or anaerobes) in
This therapy is more effective (86%) than ampicillin in combina- ascitic fluid culture, ascitic fluid protein less than 1 g/dL, glucose
tion with an aminoglycoside and is associated with less kidney level less than 50 mg/dL, lactate dehydrogenase level more than
toxicity in patients with cirrhosis. Aztreonam is less effective the upper limit of the reference range for serum, and an increase
because of its lack of activity against gram-positive organisms; in the number of PMNs in ascitic fluid despite antibiotic therapy.
parenteral amoxicillin-clavulanic acid and quinolones have been Radiologic imaging is mandatory.
clinically effective. After the organism has been identified, anti-
biotic therapy can be adjusted accordingly. Uncomplicated SBP
in patients not already receiving quinolones may be treated ef- Primary Prophylaxis
fectively in an outpatient setting with oral ciprofloxacin. Patients Episodes of bleeding in patients with CTP class C cirrhosis
with an ascitic fluid PMN count less than 250 cells/µL but with or recurrent bleeding in patients with cirrhosis are factors that
signs of infection (fever, abdominal pain, or tenderness) should predict infection and SBP, which are often severe. Intravenous
receive antibiotic therapy until culture results are available. ceftriaxone is the prophylactic antibiotic of choice and should be
Epidemiologic changes in bacterial infections have occurred given for 7 days to all patients with advanced cirrhosis who have
with norfloxacin prophylaxis, and these must be considered an episode of gastrointestinal tract bleeding. Patients with less
for each patient. In a recent study of bacterial infections in severe liver disease and bleeding may receive an oral quinolone.
patients with cirrhosis who received norfloxacin prophylaxis, Long-term oral antibiotic prophylaxis is recommended for
53% of infections were due to gram-positive cocci, especially in patients with cirrhosis who have a very low ascitic fluid protein
level (<1.5 g/dL), especially if they also have a serum creatinine of ADH increases. The increased secretion of ADH eventually
level of 1.2 mg/dL or more, serum urea nitrogen 25 mg/dL or impairs water excretion, resulting in increased total body water and
more, serum sodium level 130 mmol/L or less, or a CTP score of dilutional hyponatremia. Splanchnic vasodilatation also continues
9 or higher with a bilirubin level of 3 mg/dL or more. to increase as liver disease worsens. As ascites progresses to type
2 HRS (HRS–non-AKI [NAKI]), arterial hypotension begins to
affect blood flow to the kidneys, brain, liver, and adrenals.
Secondary Prophylaxis
Initially, cardiac output increases in cirrhosis. However, as he-
Because SBP has a 1-year recurrence rate of more than 50%, pro- modynamic changes worsen, cardiac output decreases because of
phylactic measures are warranted for patients who have survived cirrhotic cardiomyopathy with systolic and diastolic dysfunction,
an episode of SBP. Rarely can the underlying liver disease be further worsening the blood flow to extrasplanchnic organs and
treated (except with liver transplant), and only occasionally does potentiating kidney impairment.
diuretic therapy completely clear the ascites. Treatment with
ciprofloxacin can be used to eliminate the gram-negative flora (and
reduce gram-negative infection), but it will not affect the other Hyponatremia
aerobic and anaerobic flora. Trimethoprim-sulfamethoxazole has The severity of water retention varies considerably among
also been effective for prophylaxis. Daily dosing is preferable to patients, but dilutional hyponatremia occurs in about 30% of
intermittent dosing. hospitalized patients who have cirrhosis-associated ascites and
is associated with increased morbidity and mortality. However,
symptoms are rare until sodium levels are very low (<110-
Bacterascites
115 mmol/L). Treatment is fluid restriction, which should be
When diagnostic paracentesis shows no evidence of neutrocytic implemented if serum sodium levels are less than 125 mmol/
ascites (PMNs <250 cells/µL), but the ascitic fluid culture grows L. Rarely, patients need infusion of hypertonic (3%) saline,
organisms that are not contaminants, the diagnosis is bacterascites. which is administered only to patients with severe, symptomatic
Paracentesis should be repeated within 72 hours and a decision hyponatremia. The vaptans are new aquaretic drugs (selective
about therapy should be based on the following: 1) if PMNs are vasopressin V2 receptor antagonists) and may be considered
more than 250 cells/µL, treat as SBP; 2) if PMNs are fewer than for severe hypervolemic hyponatremia. Oral tolvaptan is now
250 cells/µL but again culture-positive, treat with antibiotics; and available and causes marked increases in kidney water excre-
3) if PMNs are fewer than 250 cells/µL but cultures are negative, tion and serum sodium levels. Therapy with tolvaptan, which
do not treat. must be started when the patient is in the hospital, requires close
monitoring and slow titration of the dose to avoid a rapid increase
✓ Treatment of SBP in serum sodium; fluid restriction is avoided, and doses of other
• Cefotaxime 2 g intravenously every 8 hours for 5 days diuretics are adjusted accordingly. The safety and efficacy of
• If serum creatinine is greater than 1 mg/dL, serum urea ni- long-term tolvaptan use are undefined.
trogen is greater than 30 mg/dL, or total bilirubin is greater
than 4 mg/dL, patients should also receive albumin infusion on
day 1 (1.5 g/kg) and day 3 (1.0 g/kg) Major Diagnostic Criteria for HRS
✓ Patients who survive an episode of SBP should be treated with
secondary prophylactic antibiotics The International Club of Ascites proposed that all the following
✓ Indications for primary prophylaxis for SBP (≥1 of the following): major criteria must be present for the diagnosis of HRS:
• Ascitic fluid protein less than 1.5 g/dL
• Cirrhosis with ascites
• Impaired kidney function (creatinine ≥1.2 mg/dL, serum urea
• Serum creatinine level >1.5 mg/dL
nitrogen ≥25 mg/dL, or serum sodium ≤130 mmol/L)
• No improvement after diuretic withdrawal and plasma volume ex-
• Liver dysfunction (CTP score ≥9 and bilirubin ≥3 mg/dL)
pansion with 25% albumin (1 g/kg of dry body weight daily; max-
imum 100 g daily) for 2 days
• Absence of shock
• No current or recent nephrotoxic drugs or vasodilators
Kidney Function Abnormalities in Cirrhosis
• Absence of parenchymal kidney disease, with proteinuria <500 mg/
and Hepatorenal Syndrome dL, and no ultrasonographic evidence of obstructive uropathy or
Kidney dysfunction, a common complication of cirrhosis, is fre- microhematuria
quently progressive and severe and is an important predictor of The diagnosis is usually made on the basis of the serum creat-
mortality, especially when AKI develops after hospitalization. In inine level, which is a specific but relatively insensitive index of
1 series, about half of all patients had volume-responsive prerenal kidney function in this situation. Additional supportive features,
azotemia, with acute tubular necrosis in 32% and hepatorenal syn- which may help in making the diagnosis but are not considered
drome (HRS) in 20%. Infection is a common precipitant in many essential, are low urine volume (<500 mL daily), low urine so-
patients. The hemodynamic changes in chronic liver disease indium level (<10 mEq/L), urine osmolality greater than plasma
creasingly worsen, with the progression from compensated cir- osmolality, and low serum sodium level (<130 mmol/L).
rhosis to ascites (with a high incidence of AKI) to HRS.
Mild to severe sodium retention by the kidneys, mainly due
to increased tubular resorption of sodium, is a key factor in the HRS Types 1 and 2
pathogenesis of ascites in patients with cirrhosis. This occurs Type 2 HRS (HRS-NAKI) is kidney failure that progresses slowly
with activation of the renin-angiotensin-aldosterone system and over a long time, and the main consequence is refractory ascites;
the sympathetic nervous system and increased secretion of ADH. the creatinine level generally increases less than 0.5 mg/dL daily.
As liver disease worsens, the activity of the renin-angiotensin- In comparison, type 1 HRS (HRS-AKI) is rapidly progressive
aldosterone and sympathetic systems increases and the secretion kidney failure. It usually occurs in patients with refractory ascites
and results from a precipitating factor such as infection or gastro- In chronic liver disease, noxious substances, presumed ni-
intestinal tract bleeding. trogenous compounds from protein breakdown, are ineffectively
detoxified or bypassed (or both) by the diseased liver; they affect
✓ Hepatorenal syndrome—functional kidney failure that develops in the brain and cause HE, a neuropsychiatric syndrome. The path-
persons who have cirrhosis and ascites with no identified kidney ophysiologic mechanism is not well understood, but ammonia is
pathologic changes
thought to be of central importance.
Clinical Features
Treatment
HE is a constellation of neuropsychiatric features (dominated by
Kidney dysfunction in cirrhosis-associated ascites is more easily considerable psychomotor slowing) that fluctuate greatly over
prevented than treated. All factors that may potentiate kidney dys- time and range from a trivial impairment in cognition to frank
function should be avoided, including nephrotoxic drugs (espe- confusion, drowsiness, and coma.
cially nonsteroidal anti-inflammatory drugs and aminoglycosides), The 4 stages of overt HE (West Haven criteria) are well known:
excessive use of diuretics or lactulose, and large-volume paracen-
tesis without intravenous albumin. Complications such as bac- • Grade 1—Confused; altered mood or behavior; psychometric defects
• Grade 2—Drowsy; inappropriate behavior
terial infection, gastrointestinal tract bleeding, dehydration, or
• Grade 3—Stuporous but with inarticulate speech and able to obey
hypotension must be treated aggressively. SBP should be treated simple commands; marked confusion
with antibiotics and intravenous albumin when indicated. Sepsis • Grade 4—Coma; unable to be roused
is a strong risk factor for AKI in a person with cirrhosis and is
associated with arterial underfilling and kidney vasoconstriction. For patients with advanced coma (grade 3 or 4), the Glasgow
To reduce the risk of HRS, ciprofloxacin is recommended for Coma Scale allows more accurate assessment of progression.
patients with low-protein ascites and a CTP score of 9 or higher, Patients with cirrhosis who have no overt HE can be classified as
bilirubin level 3 mg/dL or more, serum creatinine level 1.2 mg/dL those with normal cognitive function and those with minimal HE
or more, or serum sodium level 130 mmol/L or less. characterized by changes in psychomotor speed, visual percep-
The only therapy proven effective for HRS is liver transplant. In tion, and attention. Studies have shown that even minimal HE can
HRS-NAKI, discontinuation of diuretics and plasma volume ex- greatly affect a patient’s functioning both at home and at work;
pansion are usually effective, at least temporarily. Ongoing use of recent evidence confirms attention deficit, impaired driving skills
nonselective β-blockers for prophylaxis against variceal bleeding with an increased accident rate, and increased risk of falls with
is controversial, but increasing evidence supports their discontin- increased morbidity.
uation in patients who have hypotension, AKI, or hyponatremia. No laboratory test can confirm the diagnosis, which rests on
These patients require an expedited referral for liver transplant. typical neuropsychiatric features in patients with established
There is increasing evidence for the efficacy of vasoconstrictor chronic liver disease. Other causes of encephalopathy in patients
therapy in combination with plasma volume expansion with 25% with cirrhosis must be excluded. If a diagnosis is difficult, mag-
albumin (20-40 g daily) in HRS-AKI. Terlipressin is the most netic resonance imaging of the head is useful to identify alterna-
widely studied drug; it is safe, and it has been administered in tive diagnoses, and imaging of the portosystemic circulation may
doses of 0.5 mg every 4 hours, up to 12 mg daily. Terlipressin is identify large portosystemic shunts.
superior to placebo for partial or complete reversal of HRS-AKI. Neuropsychometric testing is necessary to diagnose minimal
Response to terlipressin is more likely when the bilirubin level HE, which is particularly important for patients at risk for accidents
is less than 5 mg/dL and there is an early sustained increase in and may be useful to monitor cognitive decline in patients with
arterial pressure with therapy. Norepinephrine, an α1-adrenergic low-grade HE. No superior method of cognitive assessment has
agonist, has also been used with similar benefit to terlipressin, al- been identified. Testing may include paper-pencil psychomotor
though it requires intensive care unit admission for monitoring in tests (eg, number connection tests), computerized psychomotor
most centers. In a small number of patients, the use of midodrine tests (eg, inhibitory control test), and neurophysiologic perfor-
in combination with octreotide showed potential benefit in mance tests (eg, critical flicker frequency, mismatch negativity
HRS-AKI; however, this has not been demonstrated in placebo- analysis, and electroencephalography). The psychometric HE
controlled trials. Therapy for HRS should be introduced as soon score combines clinical impression with neuropsychologic per-
as the diagnosis is suspected, before the creatinine is markedly formance and may prove more sensitive than the West Haven
increased or the urine output is low. criteria. Asterixis is a nonspecific clinical sign, which generally,
A few small studies have suggested that kidney function but not invariably, occurs in the early stages of HE. Although
improved in select patients with HRS-AKI after TIPS; how- asterixis is associated with an increased arterial level of am-
ever, in line with AASLD guidelines, controlled trials are re- monia, there is no correlation between the degree of encephalop-
quired before TIPS can be recommended for this indication. athy and the ammonia level. Recent studies have suggested that
Kidney replacement therapy, either hemodialysis or contin- electroencephalographic alterations are associated with severity
uous venovenous hemofiltration, is used, especially in patients of liver disease and HE.
awaiting liver transplant.
Management
Hepatic Encephalopathy Identification of Precipitants
HE is a debilitating complication of cirrhosis for which therapies To treat HE and to avoid precipitants of HE in patients who have
are still limited and nonspecific. Furthermore, no weight is given advanced cirrhosis, the following general measures must be
for this complication in the MELD system for organ allocation, considered:
resulting in considerable morbidity for patients and a burden for 1. Avoid use of analgesics, sedatives, and tranquilizers.
families and the health care system.
2. Control gastrointestinal tract bleeding and purging of blood from the Therapies With Indeterminate Efficacy. Zinc is a cofactor of
gastrointestinal tract. urea cycle enzymes, and its deficiency is implicated in HE. Trials
3. Screen and initiate early aggressive therapy for any infection; this is of zinc therapy in HE have been inconclusive, but therapy benefits
especially important in advanced coma. some patients. Substrate for urea and glutamine synthesis (the 2
4. Correct acidosis, alkalosis, hypoxia, or electrolyte abnormalities
major routes of ammonia clearance) is provided by l-ornithine-l-
(especially hyponatremia).
5. Prevent constipation and intravascular volume depletion; dehy- aspartate, which lowers plasma ammonia levels and improves HE
dration secondary to aggressive diuretic or lactulose therapy is a in patients with cirrhosis. Ammonia levels are reduced by sodium
common precipitant. Diuretic use must be stopped, and albumin in- benzoate and phenylacetate, and some studies have shown benefit
fusion has been found to be beneficial. in HE; however, limitations of their use have prevented US Food
6. Ensure adequate intake of glucose to treat hypoglycemia and pre- and Drug Administration approval for HE. Probiotics, especially
vent endogenous protein breakdown. with lactobacilli and bifidobacteria, have shown some efficacy in
7. Correct nutritional deficiencies, and provide adequate vitamin sup- HE, but their therapeutic role has not been defined. Fecal trans-
plementation, including thiamine and folate. plant is emerging as a potential therapy for HE; however, large
8. Screen and correct for sarcopenia. randomized trials are still needed to confirm efficacy and safety.
Portosystemic Encephalopathy After TIPS. Most post-TIPS
Treatment
HE is maximal during the first 3 months and can be controlled by
Lactulose. Lactulose is the mainstay of therapy for most the above measures. For the approximately 8% of patients who
patients for treatment of an acute episode; it has been shown to have no response to medical treatment, the options are liver trans-
reduce the recurrence of HE. Lactulose is a nonabsorbable syn- plant and occluding the stent or decreasing its diameter. Stent ma-
thetic disaccharide metabolized by colonic bacteria to organic nipulation is not without morbidity (recurrent variceal bleeding,
acids. It decreases the absorption of ammonia by acting as an ascites, and even death) and should be considered only for se-
osmotic laxative, altering colonic pH, and trapping ammonia as verely refractory cases. Decreasing the diameter of the stent is
ammonium in the gastrointestinal tract. The starting dose is 30 safer than occluding it.
mL 2 or 3 times daily, titrated to produce 2 to 4 loose stools
daily. If patients are comatose, lactulose is given by feeding Liver Support Devices. The molecular adsorbent recirculating
tube or rectally. Excessive therapy can cause dehydration and system (MARS; Gambro) has been used to treat patients who have
hypernatremia. Lactitol is equivalent to lactulose but is not avail- acute decompensation of cirrhosis and HE. A US multicenter trial
able in the US. showed that the treated patients had earlier and more frequent im-
provement in HE but no mortality benefit.
Antibiotics. Rifaximin is a minimally absorbable antibiotic with
broad-spectrum antimicrobial activity that presumably modulates Liver Transplant. Liver transplant is the ultimate therapy for
the bacterial flora. It has shown efficacy in the treatment of HE, HE. Recurrent or difficult-to-treat HE is but one manifestation
and multicenter randomized controlled trials have shown that, at of deteriorating liver function and is an indication to consider
doses of 550 mg twice daily (with lactulose in many patients), orthotopic liver transplant.
it reduced the risk of recurrent episodes of HE better than lac-
HE and Spontaneous Portosystemic Shunts. Large sponta-
tulose alone. In 2 small randomized trials of patients with min-
neous portosystemic shunts have been identified in some patients
imal HE, rifaximin improved driving simulator performance in
who have recurrent or persistent HE out of proportion to the se-
1 trial and psychometric testing in the other. It is as effective as,
verity of their liver disease. These shunts may be amenable to
and safer than, neomycin or metronidazole. Neomycin can be ab-
embolization with improvement in HE.
sorbed to some extent (1%-3%) and may lead to ototoxicity and
nephrotoxicity. ✓ HE occurs in persons with hepatic dysfunction or portosystemic
shunting (or both)
Dietary Protein. Recent studies have shown improvements in
✓ Management of overt HE
HE in patients who have better nutritional status and increased • Identification and mitigation of precipitating factors
protein intake. Thus, patients with HE should avoid protein re- • Lactulose as first-line therapy and for ongoing secondary pro-
striction. In patients with advanced coma, protein may be withheld phylaxis after overt HE has resolved
for a short time while an adequate level of glucose is maintained • Rifaximin can be added to prevent recurrence
with intravenous infusion; the precipitating cause for the HE can
then be identified and lactulose therapy initiated. It is critical,
however, to maintain a positive nitrogen balance long-term in
Suggested Reading
these patients, particularly if they already have muscle wasting.
Protein intake of 1.0 to 1.5 g/kg (based on ideal or dry weight) Bass NM, Mullen KD, Sanyal A, Poordad F, Neff G, Leevy CB, et al.
is essential. Protein is best tolerated if the amount is distributed Rifaximin treatment in hepatic encephalopathy. N Engl J Med. 2010
evenly throughout the day rather than given in large doses. Also, Mar;362(12):1071–81.
Belcher JM, Garcia-Tsao G, Sanyal AJ, Bhogal H, Lim JK, Ansari N, et al.
the composition of the protein may make a difference: Vegetable
Association of AKI with mortality and complications in hospitalized
proteins may be more beneficial (less ammoniagenic) than animal patients with cirrhosis. Hepatology. 2013 Feb;57(2):753–62.
proteins. Furthermore, toxicity increases among animal proteins Cordoba J. New assessment of hepatic encephalopathy. J Hepatol. 2011
in ascending order as follows: dairy proteins, fish proteins, meat May;54(5):1030–40.
proteins, and blood proteins (red meat). Despite the absence of European Association for the Study of the Liver. EASL clinical prac-
proven clinical benefit in trials, some patients appear to tolerate tice guidelines on the management of ascites, spontaneous bacterial
preparations of branched-chain amino acids better than other peritonitis, and hepatorenal syndrome in cirrhosis. J Hepatol. 2010
proteins. Sep;53(3):397–417.
Garcia-
Tsao G. The transjugular intrahepatic portosystemic shunt Riggio O, Ridola L, Angeloni S, Cerini F, Pasquale C, Attili AF,
for the management of cirrhotic refractory ascites. Nat Clin Pract et al. Clinical efficacy of transjugular intrahepatic portosystemic
Gastroenterol Hepatol. 2006 Jul;3(7):380–9. shunt created with covered stents with different diameters: results
Gifford FJ, Morling JR, Fallowfield JA. Systematic review with meta- of a randomized controlled trial. J Hepatol. 2010 Aug;53(2):
analysis: vasoactive drugs for the treatment of hepatorenal syndrome 267–72.
type 1. Aliment Pharmacol Ther. 2017 Mar;45(5):593–603. Salerno F, Navickis RJ, Wilkes MM. Albumin infusion improves
Gines P, Guevara M. Hyponatremia in cirrhosis: pathogenesis, clinical outcomes of patients with spontaneous bacterial peritonitis: a meta-
significance, and management. Hepatology. 2008 Sep;48(3):1002–10. analysis of randomized trials. Clin Gastroenterol Hepatol. 2013
Gluud LL, Christensen K, Christensen E, Krag A. Systematic review of Feb;11(2):123–30.
randomized trials on vasoconstrictor drugs for hepatorenal syndrome. Singh V, Singh A, Singh B, Vijayvergiya R, Sharma N, Ghai A, et al.
Hepatology. 2010 Feb;51(2):576–84. Midodrine and clonidine in patients with cirrhosis and refractory or
Lucero C, Verna EC. The role of sarcopenia and frailty in hepatic en- recurrent ascites: a randomized pilot study. Am J Gastroenterol. 2013
cephalopathy management. Clin Liver Dis. 2015 Aug;19(3):507–28. Apr;108(4):560–7.
Martin-Llahi M, Guevara M, Torre A, Fagundes C, Restuccia T, Gilabert Sola E, Gines P. Renal and circulatory dysfunction in cir-
R, et al. Prognostic importance of the cause of renal failure in patients rhosis: current management and future perspectives. J Hepatol.
with cirrhosis. Gastroenterology. 2011 Feb;140(2):488–96. 2010 Dec;53(6):1135–45.
Moller S, Henriksen JH. Cirrhotic cardiomyopathy. J Hepatol. 2010 Wiest R, Schoelmerich J. Secondary peritonitis in cirrhosis: “oil in fire.”
Jul;53(1):179–90. J Hepatol. 2010 Jan;52(1):7–9.
30
Metabolic Liver Diseasesa

ANGELA C. CHEUNG, MD
WILLIAM SANCHEZ, MD
Metabolic liver disease refers to inherited disorders of metabo-

lism that manifest prominently with liver disease. The 3 major Box 30.1. Metabolic Liver Diseases
inherited disorders that cause liver disease in adults are α1- Inborn errors of carbohydrate metabolism
antitrypsin (A1AT) deficiency (A1ATD), Wilson disease (WD), Glycogen storage disease
and hereditary hemochromatosis. All are multisystem disorders
Inborn errors of protein metabolism
that cause liver injury by various mechanisms but which can ulti-
mately lead to cirrhosis and complications of liver failure. Also, Tyrosinemia
various inborn errors of metabolism that cause liver disease man- Urea cycle defects
ifest during childhood (Box 30.1). These inborn errors of me- Inborn errors of lipid metabolism
tabolism are, in aggregate, a major indication for pediatric liver Gaucher disease
transplant. As more patients who have childhood syndromes with
Niemann-Pick disease
liver involvement survive into adulthood, gastroenterologists who
treat adults will need to become familiar with their care; however, Inborn errors of bile acid metabolism
the childhood syndromes rarely manifest initially in adulthood. Byler disease
Benign recurrent cholestasis
α1-Antitrypsin Deficiency Inborn errors of copper metabolism
Wilson disease
A1ATD is an inherited disorder characterized by the development
of liver disease or lung disease (or both) in children and adults. Inborn errors of iron metabolism
Clinical manifestations include cirrhosis and emphysematous ob- Hereditary hemochromatosis
structive lung disease. The presence of emphysema—especially Non-HFE hereditary iron overload disorders
among nonsmokers—in conjunction with chronic liver disease Unclassified
should prompt an evaluation for A1ATD. α1-Antitrypsin deficiency
Cystic fibrosis
a
David J. Brandhagen, MD (deceased), John B. Gross Jr, MD, and John
J. Poterucha, MD, are gratefully acknowledged as authors of this chapter
Adapted from Ghishan FK. Inborn errors of metabolism that lead
in the previous editions of the book (parts of which appear in this edition).
to permanent liver injury. In: Boyer TD, Manns MP, Sanyal AJ, eds.
Abbreviations: A1AT, α1-antitrypsin; A1ATD, α1-antitrypsin deficiency; Zakim and Boyer’s Hepatology: a textbook of liver disease. 6th ed.
ATPase, adenosine triphosphatase; PAS, periodic acid-Schiff; UNOS, Saunders; 2012: 1155-201; used with permission.
United Network for Organ Sharing; WD, Wilson disease
345
Inheritance and Gene Function an increased prevalence of the Pi*MZ phenotype among those
undergoing orthotopic liver transplant for cryptogenic cirrhosis
A1AT is a member of the serine protease supergene family. The
compared with those having orthotopic liver transplant for other
function of A1AT is to protect tissues from the proteolytic ac-
indications. Adults with cirrhosis due to A1ATD have a greatly
tivity of serum proteases such as neutrophil elastase. The gene for
increased risk for hepatocellular carcinoma, with some studies
A1AT (SERPINA1; OMIM 107400) is located on the long arm of
reporting a prevalence of primary liver cancer of up to 30%.
chromosome 14.
A1ATD is inherited as an autosomal codominant disorder.
This deficiency is characterized on the basis of phenotype rather Diagnosis and Evaluation
than genotype. The normal protein is labeled M, and abnormal The diagnosis of A1ATD is made by A1AT phenotyping or
phenotypes include S, Z, and null. Phenotypes are reported as genotyping. Serum levels of A1AT are not useful for diagnosing
the combination of alleles present; therefore, the wild-type phe- the deficiency because they may be falsely increased (in inflam-
notype is Pi*MM (Pi indicates protease inhibitor), and abnormal matory conditions, malignancy, or pregnancy or with estrogen
phenotypes include Pi*MZ, Pi*SS, and Pi*ZZ. supplementation) or spuriously decreased (in nephrotic syn-
For liver disease, the Z phenotypes are the most clinically rel- drome or protein-losing enteropathy). Also, the serum levels of
evant. The normal Pi*MM phenotype is present in 95% of the A1AT do not correlate with liver damage, although they do pre-
population and is associated with normal serum levels of A1AT. dict lung damage.
Patients with the Pi*MZ phenotype have an intermediate defi- Liver disease due to A1ATD is confirmed by characteristic
ciency, and patients with Pi*ZZ have a severe deficiency. The Z findings in liver biopsy samples. Biopsy is also useful in staging
allele has a heterozygote frequency of 1:30 (Pi*MZ) and a homo- the degree of hepatic fibrosis. The characteristic finding is the
zygote frequency of 1:2,000 (Pi*ZZ). presence of eosinophilic, periodic acid- Schiff (PAS)- positive,
diastase-resistant (ie, PAS-diastase–positive) globules in the en-
Pathophysiology doplasmic reticulum of periportal hepatocytes. Because these
globules may be present also in persons who are heterozygous or
It is important to recognize that A1ATD causes disease by
homozygous without liver disease, their presence alone does not
different mechanisms in the lung and liver. Pulmonary disease
imply liver disease. Furthermore, because the globules may be
is caused by unopposed activity of neutrophil elastase and other
distributed variably throughout the liver, their absence does not
proteolytic enzymes that produce tissue damage. In contrast, in
exclude the diagnosis of A1ATD. The histologic features of the
the liver, A1ATD is a storage disease. The abnormally folded
liver in A1ATD are shown in Figure 30.1.
A1AT protein cannot be exported from hepatocytes into the cir-
Patients with cirrhosis due to A1ATD should be enrolled in
culation, so globules of A1AT accumulate in the endoplasmic re-
a surveillance program for hepatocellular carcinoma (typically
ticulum of hepatocytes, resulting in cell injury and death.
with ultrasonography every 6 months). Patients with diagnosed
liver disease due to A1ATD should be evaluated also for the
Clinical Features presence of coexisting lung disease, especially if they have
phenotype Pi*ZZ or are smokers. Baseline pulmonary function
The classic presentation of A1ATD is premature emphysema (es-
testing and chest radiography are recommended.
pecially in nonsmokers) and liver disease. This deficiency is also
an important cause of childhood liver disease, often presenting as
a neonatal hepatitis. The clinical manifestations of the deficiency Treatment
are affected by the phenotype and by environmental factors, such No effective medical therapy is available for liver disease due
as tobacco exposure and alcohol use. to A1ATD. Although recombinant A1AT infusions are available,
In the only population-based study performed, the Swedish their use is limited to patients with A1ATD-related lung disease
neonatal screening study identified 127 children deficient for (because infusions of A1AT do not help decrease the accumu-
A1AT who were followed prospectively through age 18 years. lation of abnormal A1AT protein globules within hepatocytes).
Neonatal cholestasis developed in 11%, and 6% had other liver The mainstay of therapy is avoidance of alcohol and other
disease without jaundice. Liver test results were abnormal 1 to hepatotoxins and maintenance of a healthy weight. Furthermore,
2 months after birth and usually normalized by 6 months. A small patients should be advised to refrain from smoking to decrease
proportion of children either had end- stage liver disease or their risk for obstructive lung disease.
presented with acute liver failure in infancy. Most of the children
(83%) were healthy throughout childhood, although most had ab-
normal liver test results in early life. ✓ A1ATD— an autosomal codominant disease with phenotypes
In adolescents and adults, A1ATD may cause chronic hepatitis ranging from Pi*MM (wild-type) to Pi*ZZ (severe deficiency)
or cirrhosis. This deficiency should be considered as a cause of ✓ Typically, Pi*MZ causes liver disease only in the presence of other
abnormal liver enzyme levels in patients for which other common risk factors (eg, nonalcohol-related fatty liver disease, alcohol-
causes of liver disease, such as viral hepatitis, have been excluded. related liver disease, and viral hepatitis)
For adults with the Pi*ZZ phenotype, it has been estimated that ✓ A1ATD can cause hepatic abnormalities at any age, including
cirrhosis will develop in 2% of those between 20 and 50 years old neonatal cholestasis, neonatal hepatitis, and liver failure and
end-stage liver disease in childhood
and in 19% of those older than 50 years. Patients with the Pi*MZ
✓ Liver transplant—the only curative therapy for cirrhosis due to
phenotype, which produces an intermediate degree of deficiency, A1ATD
are at some risk for chronic liver disease. It is more likely, how-
ever, that the Pi*MZ phenotype is a cofactor for the development Once advanced liver disease develops, liver transplant is the
of liver disease, along with other forms of liver injury such as only definitive therapy. A1ATD is the most common metabolic in-
nonalcohol-related fatty liver disease. Several studies have noted dication for liver transplant in adults. Liver transplant corrects the
30. Metabolic Liver Diseases
Figure 30.1. Histologic Features of the Liver in α1-Antitrypsin Deficiency. A, Low-power view. B, High-power view. Characteristic periodic
acid-Schiff–positive, diastase-resistant globules (arrows) have accumulated in hepatocytes.
consequences of portal hypertension, and the recipient assumes biliary canalicular membrane of hepatocytes. Although WD is a
the Pi phenotype of the donor. Long-term outcomes for A1ATD rare disorder, it is probably underdiagnosed. Approximately 1 per
after liver transplant are excellent. 30,000 persons are homozygous and 1 per 100 are heterozygous
A1ATD may be amenable to somatic gene therapy. Gene carriers of a WD gene alteration. To date, more than 600 variants
therapy probably would be beneficial for only the lung disease of ATP7B have been described. Attempts to correlate genotype
unless a method of delivering the corrected gene product to the with phenotype have not shown a consistent pattern and are not
endoplasmic reticulum of hepatocytes were available. Gene clinically useful. Approximately 30% to 40% of North American
therapy continues to be an area of research, but it is not routinely and European patients with WD have the H1069Q gene (OMIM
clinically available. 277900) variant.
Unlike hereditary hemochromatosis, in which approximately
Wilson Disease 90% of persons are homozygous for the C282Y alteration (see
the Hereditary Hemochromatosis section below), the majority of
WD is an inherited disorder of intrahepatic copper metabolism patients with WD are compound heterozygous (ie, they have 1
characterized by the deposition of excess copper in the liver, brain, copy of 2 different alterations). The number of clinically impor-
cornea, and other organs. This rare disorder typically manifests in tant alterations makes genetic testing less useful for this disease
children, adolescents, and young adults. Patients with WD may than for hereditary hemochromatosis. Genetic testing is most val-
present with various disease manifestations, including acute liver uable for screening the siblings of an affected proband in whom
failure, chronic liver disease, hemolytic anemia, or neuropsychi- the specific alterations are known.
atric symptoms (or a combination of these).
Inheritance and Gene Function Copper Metabolism and Pathophysiology

WD is an autosomal recessive disorder. The gene (ATP7B; OMIM Copper is an essential trace element that is necessary as a co-
606882) associated with the disease is on chromosome 13 and factor for many proteins. Dietary copper is absorbed in the prox-
codes for a copper-transporting P-type adenosine triphosphatase imal small bowel. Copper homeostasis is maintained through
(ATPase) located predominantly in the endoplasmic reticulum and the biliary excretion of excess copper by active transport with a
metal-transporting ATPase. Any disease that impairs biliary ex- performance for children and adolescents. Children are often
cretion (eg, chronic cholestatic biliary disorders such as primary classified as having behavioral problems or learning disabilities
biliary cholangitis or primary sclerosing cholangitis) can cause until progressive and sometimes irreversible neurologic
increases in the level of hepatic copper. In WD, intestinal copper symptoms begin to develop.
absorption is normal but biliary excretion of copper is decreased,
leading to marked copper overload and ultimately end-organ
Hematologic Manifestations
toxicity.
Copper toxicity has a major role in the pathogenesis of the Patients may present first with a Coombs-negative hemolytic
disease. Copper accumulates in the liver and eventually appears anemia, frequently seen in association with acute, severe, or
in other organs, particularly the brain and the eye (specifically, fulminant hepatitis. A young patient with severe liver dysfunc-
the cornea). Excess copper exerts its toxic effect by the gener- tion and hemolytic anemia should be assumed to have WD until
ation of free radicals that result in lipid peroxidation, similar to proved otherwise.
the mechanism proposed for iron-induced damage in hereditary
hemochromatosis. Deficiency of ceruloplasmin is not the cause Ocular Manifestations
of WD; rather, it is an effect of the abnormal cellular trafficking
of copper. Occasionally, WD is identified because of incidental eye findings,
or the ocular manifestations may be noted during the evaluation of
patients with suspected WD. Kayser-Fleischer rings result from
Clinical Features copper deposition in the periphery of the cornea. These rings are
WD has various clinical manifestations ranging from patients frequently present in patients with neurologic manifestations of
who are asymptomatic to those who have crippling neurologic WD, but the absence of the rings does not exclude the disease.
symptoms or acute liver failure. WD is a disease of young per- Prominent Kayser-Fleischer rings may be seen on direct exami-
sons; the typical age at presentation is 12 to 23 years. Hepatic nation, but more subtle rings may require slit-lamp examination.
manifestations tend to be more common in childhood, whereas Sunflower cataracts are seen only with a slit lamp and do not in-
neurologic symptoms tend to appear in the second and third terfere with vision. The ocular manifestations in WD are shown
decades of life. Although age alone should not be used to exclude in Figure 30.2.
WD, its initial presentation in patients older than 40 years is ex-
tremely rare.
The 5 main categories of clinical presentation are hepatic,
neurologic, psychiatric, hematologic, and ophthalmologic. In a
large clinical series, the initial clinical manifestations were he-
patic in 42% of patients, neurologic in 34%, psychiatric in 10%,
and hematologic in 12%.
Hepatic Manifestations
Patients with WD can present with any form of liver disease,
including asymptomatic abnormalities in liver test results,
chronic hepatitis, and cirrhosis. Reports of hepatocellular
cancer in patients with WD are rare even though many patients
have advanced fibrosis at a young age. Although WD should be
considered in all young patients with liver disease, it is respon-
sible for less than 5% of cases of chronic hepatitis in persons
younger than 35 years.
Acute liver failure is a catastrophic manifestation and may be
the initial presentation of patients with WD. Acute liver failure
due to this disease is 4 times more common in female patients
than male patients. Fulminant WD should be suspected in any
young patient with acute liver failure, especially if it is associated
with hemolytic anemia. Patients with fulminant WD require ur-
gent liver transplant because there is no other effective therapy. In
the US, patients with fulminant WD awaiting liver transplant are
given a high priority for deceased donor organ allocation (United
Network for Organ Sharing [UNOS] status 1).
Neuropsychiatric Manifestations
The typical neurologic manifestations of WD are dominated by
extrapyramidal motor symptoms, including rigidity or spasticity, Figure 30.2. Ocular Manifestations in Wilson Disease. A, Kayser-
tremor, ataxia, dysarthria, drooling, and involuntary movements. Fleischer ring (arrow). B, Sunflower cataract. (Adapted from Zucker
Dementia and seizures are rare. Psychiatric problems may be SD, Gollan JL. Wilson’s disease and hepatic copper toxicosis. In: Zakim
dramatic, with psychosis or depression, or they may be subtle D, Boyer TD, eds. Hepatology: a textbook of liver disease. 3rd ed. WB
and manifested as behavioral problems or declining school Saunders; 1996:1405-39; used with permission.)
30. Metabolic Liver Diseases 349
Other Manifestations Treatment

WD is associated also with proximal or distal renal tubular aci- Treatment of WD is lifelong. Because many patients with WD
dosis and nephrolithiasis. Another manifestation is azure lunulae, are adolescents or young adults, adherence to therapy can be
a blue discoloration of the base of the fingernails that is an un- challenging, especially among asymptomatic patients. Therapies
common but characteristic finding. for WD can be divided broadly into 2 categories: chelating agents
that remove copper from the body and agents that inhibit intes-
Diagnosis and Evaluation tinal absorption of dietary copper. Liver transplant also is indi-
cated as a treatment of fulminant WD (acute liver failure often
The diagnosis of WD requires a strong clinical suspicion be- associated with hemolysis) or for patients with complications of
cause of the multitude of potential manifestations. The disease cirrhosis from the disease.
should be considered in any person younger than 30 years who
has liver disease. The presence of liver disease in combination
with extrapyramidal motor abnormalities should strongly suggest Chelating Agents
WD, and the presence of severe liver disease in combination with Patients with symptomatic or clinically evident disease should
nonimmune hemolytic anemia should be considered WD until be treated initially with chelating agents. Penicillamine and
definitively proved otherwise. trientine are metal chelators that induce the urinary excretion
Liver chemistry values are frequently abnormal in patients of copper. Both agents have been approved for the treatment of
with WD, and characteristic patterns may serve as a clinical clue, WD. Penicillamine is effective therapy and historically has been
but they are not consistent enough to be confirmatory. The alkaline considered as first-line treatment, but it has numerous adverse
phosphatase level is often low, and the serum aminotransferase effects. Up to 20% of patients experience drug toxicity, including
levels tend to be increased less than would be expected from hypersensitivity reactions, bone marrow suppression, proteinuria,
other causes of liver necrosis. Uric acid levels are usually low autoimmune disorders, and dermatologic conditions. Importantly,
or undetectable, often because of concomitant proximal renal as many as 20% of patients with neurologic symptoms may ex-
tubular acidosis. Serum copper levels are of limited usefulness perience worsening of their symptoms during the first month
because they may be low, normal, or increased—normal serum of treatment. This deterioration is irreversible in some patients.
copper levels do not exclude WD. Therefore, trientine should be considered as initial therapy for
The initial evaluation for suspected WD should include patients with neurologic symptoms from WD.
1) determination of the serum ceruloplasmin level, 2) 24-hour Trientine was introduced as an alternative to penicillamine.
urine collection for copper quantification, and 3) slit- lamp However, because of a lower incidence of adverse effects, trientine
examination for Kayser-Fleischer rings. The serum level of should be the first choice for treatment. It is given in doses similar
ceruloplasmin is less than 20 mg/dL in 95% of patients with to those for penicillamine and also has satisfactory long-term effi-
WD. Even though the level of ceruloplasmin can be increased cacy. The cupruresis is less pronounced than with penicillamine,
nonspecifically as an acute phase reactant or as a result of es- but an initial increase is expected. Occasionally, iron deficiency
trogen administration, a level higher than 30 mg/dL essentially may develop because of sideroblastic anemia. Dosing of agents
excludes the diagnosis of WD except in rare patients who pre- and monitoring for patients with WD are outlined in Table 30.1.
sent with fulminant hepatitis. Low ceruloplasmin levels must be Response to chelator therapy is demonstrated by an acute in-
interpreted with caution because any chronic liver disease with crease in urinary copper excretion that gradually plateaus at a
synthetic dysfunction or protein-losing states may be associated lower level over 6 to 12 months. Initially, urinary copper output is
with a ceruloplasmin level that is lower than normal. Urinary often more than 2,000 µg daily, decreasing to 400 to 500 µg daily
copper excretion can be increased in other liver diseases; how- in the maintenance phase. The urinary and serum levels of copper
ever, a value less than 100 µg daily in a patient with clinical and the ceruloplasmin level should be measured and a complete
disease would be very unusual in a symptomatic patient with blood cell count should be performed weekly during the first
WD. A low rate of urinary copper excretion may indicate ac- month and then every 1 or 2 months during the first 6 months.
quired copper deficiency. This may be confusing because cases Patients whose condition is stable can then be followed annually.
of severe copper deficiency may be associated with neurologic A slit-lamp examination should be repeated annually to docu-
symptoms. The neurologic syndrome in these cases is myelop- ment the disappearance of Kayser-Fleischer rings (if present).
athy with weakness and ataxia.
In most cases, liver biopsy is necessary to confirm the diag-
Inhibition of Copper Absorption
nosis of WD, particularly in the absence of Kayser-Fleischer
rings or characteristic neurologic symptoms. Liver morpho- In the intestinal epithelium, zinc acetate induces the synthesis of
logic features are nonspecific in WD. Often, steatosis is pres metallothionein, which preferentially binds copper and prevents
ent, and glycogenated nuclei are common. The gold standard its absorption. Zinc therapy is indicated for patients who are
for confirming the diagnosis of the disease is quantitative presymptomatic or pregnant. It also may be used as maintenance
tissue copper analysis. A normal liver concentration of copper therapy for patients who present with symptomatic disease after
(<35 µg/g dry weight) excludes the diagnosis. Most patients initial chelation therapy to remove excess copper (typically after
with the disease have liver copper concentrations greater than 6-12 months). Treatment is monitored by checking urinary levels
250 µg/g dry weight, but this finding is not specific and may of zinc and copper. The urinary excretion of zinc should be at
occur in chronic cholestatic conditions or, rarely, in autoim- least 2,000 µg daily.
mune hepatitis. Unlike hereditary hemochromatosis, children For pregnant women with WD, penicillamine is probably safe,
with WD may already have marked liver fibrosis; thus, in chil- but zinc is a better choice if their condition is stable. The teratoge-
dren, liver biopsy should be strongly considered to stage the nicity of trientine is unknown, and it should not be given during
liver disease. pregnancy.
Table 30.1. Treatment of Wilson Disease

Daily dose by mouth
Agent Initial Target Monitoring Comments

Penicillamine 250-500 mg 1-2 g, divided into CBC, ceruloplasmin, and urinary and serum Administer with pyridoxine because
2-4 doses copper levels should be measured weekly penicillamine can deplete vitamin B6
during first month, then every 1 or 2 mo during Do not administer to patients with neurologic
first 6 mo; once stable, follow annually symptoms because will worsen symptoms
Slit-lamp examination to document disappearance in 20%
of K-F rings, if present
Trientine 250-500 mg 1-2 g, divided into CBC, ceruloplasmin, and urinary and serum First-line therapy for most patients
2-4 doses copper levels should be measured weekly Dosing and monitoring as with penicillamine
during first month, then every 1 or 2 mo during May cause sideroblastic anemia
first 6 mo; once stable, follow annually
Slit-lamp examination to document disappearance
of K-F rings, if present
Zinc acetate 50 mg, 3 times 50 mg, 3 times Urinary copper and zinc excretion should be Initial therapy for presymptomatic patients and
>2,000 µg daily pregnant patients
Can be used as maintenance therapy after
copper depletion with trientine or
penicillamine
Abbreviations: CBC, complete blood cell count; K-F, Kayser-Fleischer.
Liver Transplant • Diagnostic findings: 1) low serum level of ceruloplasmin

The indications for liver transplant include acute liver failure, (<20 mg/dL), 2) increased 24-hour urinary copper excretion,
end-stage liver disease unresponsive to medical therapy, and and 3) the presence of Kayser-Fleischer rings
chronic deterioration of liver function despite long- term • Gold standard confirmatory test: quantitative liver copper con-
therapy. Medical therapy is not effective in reversing fulmi- centration (typically >250 µg/g dry weight, but a similarly
high concentration may also occur in chronic cholestatic liver
nant WD; patients with fulminant disease require urgent liver
diseases)
transplant and are given high priority for donor organ alloca- ✓ Treatment of WD
tion in the US (UNOS status 1). Outcomes for liver transplant • Chelating agents: penicillamine (which can worsen the neuro
in patients with fulminant disease are good, with a 1-year sur- logic sequelae of WD) or trientine
vival rate of 73%. Among those with chronic liver failure, the • Zinc therapy to inhibit copper absorption for patients who are
1-year survival rate is about 90%. Liver transplant performed presymptomatic or pregnant or as maintenance therapy for
solely for refractory neurologic symptoms is still considered patients after 6 to 12 months of chelation therapy
experimental because of the limited experience and uncertain • Liver transplant for patients with acute liver failure or progres-
clinical improvement. sion of end-stage liver disease despite therapy
Family Screening
Hereditary Hemochromatosis
After WD has been diagnosed, family members should have
screening tests for the disease. Testing should be directed at Hereditary hemochromatosis is an inherited disorder of iron
siblings because each has about a 25% chance of having the dis metabolism characterized by the deposition of excess iron in
ease. If treatment is begun in the presymptomatic phase of the the liver, heart, joints, pancreas, skin, testes, and other organs.
disease before cirrhosis is established, disease progression can Patients with hereditary hemochromatosis may present with
be prevented. Because copper metabolism in infancy and early chronic liver disease, cardiomyopathy, or arthropathy.
childhood may simulate WD, children should not be tested be-
fore 5 years of age. Screening should include aminotransferase
and ceruloplasmin levels and a slit-lamp examination for Kayser- Inheritance and Gene Function
Fleischer rings. If the results are normal, screening should be re- Hereditary hemochromatosis is an autosomal recessive dis-
peated every 5 years until age 20. If the ceruloplasmin level is order. The gene associated with this disorder is the HFE gene
less than 20 mg/dL but there are no Kayser-Fleischer rings or (OMIM 613609) on the short arm of chromosome 6. In contrast
convincing neurologic symptoms, liver biopsy may be necessary. to the large number of alterations of the ATP7B gene for WD,
Genetic testing generally is used for screening once the pattern in the HFE gene has 2 common point variants, C282Y and H63D.
the index case is known. This may be of value if standard copper Other alterations have been described, but they probably are not
test results are equivocal. of major clinical importance. About 90% of patients with iron
✓ Wilson disease
overload consistent with hereditary hemochromatosis are homo-
• Typical age at presentation: 12 to 23 years zygous for the C282Y alteration. The HFE gene is involved in
• Characteristic laboratory findings: 1) normal or low alkaline regulating dietary iron absorption. The HFE protein binds to the
phosphatase level, 2) modestly increased aminotransferases transferrin receptor and acts as a signal when body iron stores
levels, and 3) Coombs-negative hemolytic anemia are adequate. When the HFE variant is present, iron absorption is
not downregulated from enterocytes despite adequate iron levels,

leading to iron overload.
Unlike WD, hereditary hemochromatosis is not a rare dis-
order. It is the most common single-gene, inherited disorder in
the US White population. Approximately 1 in every 200 to 300
White persons in the US is homozygous for the hemochromatosis
alteration, and at least 1 in every 10 is a heterozygous carrier.
Iron Metabolism and Pathophysiology

Iron metabolism is relatively complex. The pathophysiology of
hereditary hemochromatosis can be summarized as the failure to
downregulate dietary iron absorption in the presence of adequate
or excess body iron stores. However, not all iron overload is due
to hereditary hemochromatosis; excess iron administration, mul-
tiple blood transfusions, or hematopoietic disorders can result in
secondary iron overload states.
Dietary iron absorbed by enterocytes is transported through
the basolateral membrane into the bloodstream by the transmem-
brane transporter ferroportin. HFE and transferrin receptor 1 are
involved in signaling adequate iron stores. This, in turn, leads to
increased expression of the hepcidin protein, which inhibits iron
release from ferroportin into the bloodstream. In the presence of
the HFE variant, hepcidin is not upregulated, leading enterocytes
to detect a state of iron deficiency and continue to avidly transport
dietary iron into the bloodstream. This uninhibited iron absorp-
tion leads to iron excess and eventually end-organ toxicity.
Clinical Features
Because persons with hereditary hemochromatosis absorb only
a few more milligrams of iron each day than needed, clinical
manifestations generally do not occur until after the fifth decade
of life, when 15 to 40 g of iron have accumulated (normal body
iron stores are approximately 4 g). Among those who are homo- Figure 30.3. Hemochromatosis Arthropathy. A radiograph of the
zygous for C282Y, approximately 30% of men and 2% to 10% of hand shows cartilage loss, marginal sclerosis, and osteophyte formation
women have biochemical or clinical evidence of iron overload. in the second and third metacarpophalangeal joints (arrows) without in-
The frequency of clinical iron overload is lower among women volvement of the fourth and fifth joints. Involvement of the second and
than men most likely because of menstrual and pregnancy-related third metacarpophalangeal joints is characteristic of hemochromatosis
blood loss. Additional factors that influence disease expression arthropathy. Occasionally, calcium pyrophosphate dihydrate crystals are
present (chondrocalcinosis). (Adapted from Riely CA, Vera SR, Burrell
include age, dietary iron intake, and unknown factors, including
MI, Koff RS. The gastroenterology teaching project, unit 8: inherited
alterations in genes other than HFE. Liver disease is also affected liver disease; used with permission.)
by alcohol consumption and comorbid liver disease (eg, hepatitis
C), which accelerate hepatic fibrosis.
In the past, hereditary hemochromatosis usually was diagnosed
at an advanced stage. The classic description of hereditary he- of patients with hereditary hemochromatosis and cirrhosis,
mochromatosis as “bronze diabetes” resulted from cutaneous hepatocellular carcinoma develops and often is the cause of
hyperpigmentation, type 2 diabetes, and cirrhosis. Currently, the death. The presence of hemochromatosis imparts a roughly 200-
disease is diagnosed in most patients at an asymptomatic stage fold increased risk of liver cancer, with most cases involving
through laboratory studies. Clinical manifestations of the disease patients with cirrhosis. The increased risk of hepatocellular carci-
include fatigue, hepatomegaly, abnormal liver enzyme levels, noma does not improve after iron depletion. Patients with hered-
cirrhosis, hepatocellular carcinoma, cardiomyopathy, cardiac itary hemochromatosis–related cirrhosis should have abdominal
conduction disorders, hypothyroidism, hypogonadism, erectile ultrasonography every 6 months to screen for hepatocellular
dysfunction, and arthropathy. An example of hemochromatosis carcinoma.
arthropathy is shown in Figure 30.3. Most, if not all, clinical
manifestations are preventable if the disease is diagnosed early
Diagnosis and Evaluation
and treated appropriately. Hepatomegaly, abnormal liver test
results, skin bronzing, cardiomyopathy, and cardiac conduction Hereditary hemochromatosis is diagnosed on the basis of a
disorders may reverse after iron depletion, although most other combination of clinical, laboratory, and pathology criteria.
clinical manifestations are not reversible. Iron studies should show increased serum transferrin saturation
The development of hepatocellular carcinoma is a major (100×[serum iron concentration/ total iron-
binding capacity])
consequence of hereditary hemochromatosis. In up to one-third and an increased serum ferritin level. An increase in transferrin
saturation is the earliest laboratory abnormality in hereditary The 2 most common HFE variants are C282Y and H63D,
hemochromatosis. which account for approximately 85% of cases of hereditary he-
The serum concentration of ferritin is usually a reasonable mochromatosis. Patients homozygous for C282Y are the most
estimate of total body iron stores. However, because ferritin is likely to present with clinically evident iron overload. Patients
also an acute phase reactant, it is increased in various infectious who are compound heterozygous (C282Y/H63D) have a much
and inflammatory conditions without any iron overload. This is a lower rate of clinically evident iron overload (approximately
common pitfall in the diagnosis of hereditary hemochromatosis. 20%). Patients who are heterozygous (single copy of C282Y or
Ferritin may be increased in 30% to 50% of patients who have H63D) typically do not have iron overload, but some do have
viral hepatitis, nonalcohol-related fatty liver disease, or alcohol- slightly high (or high-normal) values on serum iron tests.
related liver disease. For these reasons, ferritin should not be used
as the initial screening test to detect hereditary hemochromatosis.
Liver Biopsy
A diagnostic algorithm for hereditary hemochromatosis is pro-
vided in Figure 30.4. Before the HFE gene test was routinely available, liver biopsy
was important in the diagnosis of hereditary hemochromatosis.
Currently, however, liver biopsy is used only to assess cases with
HFE Gene Testing diagnostic uncertainty and to assess for the presence of advanced
The HFE gene test is most useful for surveillance of adult first- fibrosis or cirrhosis. In patients with iron overload who are ho-
degree relatives of an identified proband. HFE gene testing is also mozygous for C282Y, liver biopsy is not necessary to confirm the
often useful in cases of diagnostic uncertainty, such as iron over- diagnosis. Qualitative assessments of hepatic iron may be made
load associated with hepatitis C, alcohol-related liver disease, or with an iron stain (eg, Perls Prussian blue). In hereditary hemo-
other causes of end-stage liver disease. HFE gene testing usually chromatosis, iron accumulates initially in periportal hepatocytes
is not recommended for anyone younger than 18 years. and eventually is distributed throughout the liver. This is in
Figure 30.4. Diagnostic Algorithm for Hereditary Hemochromatosis. Asterisk indicates anemias with ineffective erythropoiesis, multiple blood
transfusions, or oral or parenteral iron supplementation. AST indicates aspartate aminotransferase. (Adapted from Brandhagen DJ, Fairbanks VF, Batts
KP, Thibodeau SN. Update on hereditary hemochromatosis and the HFE gene. Mayo Clin Proc. 1999 Sep;74[9]‌:917-21; used with permission of Mayo
Foundation for Medical Education and Research.)
contrast to secondary iron overload in which iron often occurs liver biopsy is advisable to definitively assess for the presence
predominantly in Kupffer cells. In severe iron overload, this dis- of cirrhosis in patients older than 40 years who have abnormal
tinction cannot be made reliably. The histologic features of the aminotransferase concentrations or a ferritin concentration
liver in hereditary hemochromatosis and secondary iron overload greater than 1,000 µg/L.
are shown in Figure 30.5.
Quantitative measurement of liver iron is an adjunctive diag-
Secondary Iron Overload
nostic test for hereditary hemochromatosis. Liver iron stores in-
crease progressively with age, and this has led to the development Not all iron overload is due to hereditary hemochromatosis,
of the hepatic iron index, which is calculated as the hepatic iron which should be distinguished from iron overload caused by
concentration in micromoles per gram dry weight of liver divided other conditions. Secondary iron overload should be suspected
by the patient’s age in years. A hepatic iron index greater than 1.9 in patients with chronic anemia who have ineffective erythropoi-
is strongly suggestive of hereditary hemochromatosis. esis or have had multiple blood transfusions. In rare instances,
Identifying patients who have hereditary hemochromatosis– prolonged iron supplementation can produce abnormal iron test
related cirrhosis is critical because of the need to screen for results and, even more rarely, tissue iron overload.
complications of cirrhosis, including esophageal varices and the A commonly encountered cause of abnormal iron test results
increased risk for hepatocellular cancer. Age and ferritin levels is acute or chronic liver disease. Acute liver disease may be
can be used to predict which patients with hereditary hemochro- accompanied by a high ferritin level, usually with normal trans-
matosis have a minimal risk for cirrhosis. Cirrhosis is unlikely ferrin saturation. Chronic liver disease, particularly if advanced,
and liver biopsy would be unnecessary in patients who are homo- may result in abnormalities in ferritin and iron saturation that can
zygous for C282Y, with serum ferritin levels less than 1,000 µg/ mimic hereditary hemochromatosis. However, severe iron over-
L and normal aspartate aminotransferase values. Consequently, load from hereditary hemochromatosis may be indistinguishable
Figure 30.5. Iron Deposition in the Liver. A, Mild (grade 1 of 4) iron deposition in hepatocytes. B, Moderate hemosiderin deposition in precirrhotic
homozygous hemochromatosis. Zone 1 hepatocytes are predominantly involved, biliary hemosiderin is not evident, and fibrosis has not yet occurred—
all indicating relatively early precirrhotic disease (liver iron concentration, 10,307 µg/g dry weight; iron index, 3.2) (original magnification ×133). C,
Marked hemosiderosis and cirrhosis in homozygous hemochromatosis. Although most iron is in hepatocytes, some Kupffer cells (arrow) and biliary
iron (arrowheads) are also present (original magnification ×133). D, Kupffer cell hemosiderosis. The presence of hemosiderin in Kupffer cells alone
(arrows) is typical of mild transfusion hemosiderosis, is nonspecific, and should not prompt further consideration of hemochromatosis (original magni-
fication ×240). (A-D, Perls Prussian blue stain). (A, adapted from Brandhagen DJ. Liver transplantation for hereditary hemochromatosis. Liver Transpl.
2001;7[8]‌:663-72, and B-D, adapted from Baldus WP, Batts KP, Brandhagen DJ. Liver biopsy in hemochromatosis. In: Barton JC, Edwards CQ, eds.
Hemochromatosis: genetics, pathophysiology, diagnosis, and treatment. Cambridge University Press; 2000:187-99; used with permission.)
from that due to secondary causes. Patients with alcohol-related hemochromatosis undergoing liver transplant has improved in re-
steatohepatitis may present with markedly increased ferritin cent years and is now similar to that of liver transplant for other
levels. If the diagnosis is in doubt, these patients can be observed indications. The death of many liver transplant recipients who
because alcohol-related increases in ferritin will decrease re- have hereditary hemochromatosis is caused by cardiac or infec-
markably over a short period (3 months) with abstinence from tious complications.
alcohol. Patients with nonalcohol-related fatty liver disease often
present with increased liver enzyme and ferritin levels. This is ✓ Hereditary hemochromatosis—approximately 90% arise from 2
clinically relevant because it is a frequent cause for referral and sequence variants in the HFE gene, C282Y and H63D
confusion. Despite hereditary hemochromatosis being a common ✓ Typically, patients who present with hereditary hemochromatosis
are older than 50 years (men typically present at a younger age
disease, most patients with abnormal iron test results (particu-
than women)
larly isolated elevated ferritin levels) do not have the disease. ✓ Clinical manifestations of hereditary hemochromatosis
• Largely reversible conditions: hepatomegaly and fibrosis, skin
Treatment bronzing, cardiomyopathy, and cardiac conduction disorders
• Irreversible conditions: advanced cirrhosis and risk of hepato
Hemochromatosis is a simple and satisfying disease to treat, and cellular carcinoma, arthropathy, primary or secondary hypo-
treatment before the development of end-organ damage can pre- gonadism, hypothyroidism, and type 2 diabetes
vent serious morbidity and death. Treatment is iron depletion ✓ Diagnosis of hereditary hemochromatosis
by therapeutic phlebotomy, which is the preferred treatment be- • Increased ferritin level with increased transferrin saturation
cause it is simple, relatively inexpensive, and effective. Dietary (>45%)
modifications are not advised because iron depletion cannot be • Exclusion of other causes of liver disease and iron overload
• Liver biopsy for patients who have a ferritin concentration greater
achieved with dietary changes alone. Patients should be counseled
than 1,000 µg/L
to refrain from taking iron supplements, including multivitamins ✓ Goal of hereditary hemochromatosis treatment with phlebotomy—
with iron, and high-dose vitamin C supplements. Although iron maintain ferritin concentration less than 50 µg/L and hemoglobin
chelators such as the parenteral agent deferoxamine and oral agent greater than 12 to 13 g/dL
deferasirox are often administered to patients with secondary iron
overload (particularly those with hematologic disorders who may
not tolerate phlebotomy), they are associated with more adverse
effects and are much less effective than phlebotomy. Family Screening
Treatment of hereditary hemochromatosis is usually reserved Currently, experts disagree about the usefulness of screening for
for patients who have evidence of iron overload as indicated by hereditary hemochromatosis in the general population. Despite
an increase in the serum concentration of ferritin. Patients with the disease fulfilling many of the criteria of a condition appro-
HFE gene alterations without iron overload do not need phle- priate for population screening, some public health experts do not
botomy, but they should be monitored periodically. Therapeutic advocate screening. Screening for the disease in family members
phlebotomy is divided into 2 phases: 1) During the initial phase, of affected individuals is crucial because 25% of siblings and 5%
phlebotomy is performed frequently to deplete excess iron stores. of children of a proband will have the disease. HFE gene testing
2) This is followed by lifelong maintenance phlebotomy to pre- should be considered also for siblings of patients who are heter-
vent the reaccumulation of excess iron. ozygous for C282Y.
The initial phase of phlebotomy begins with removal of 500
mL of blood weekly. The hemoglobin concentration should be
measured just before each phlebotomy. Weekly phlebotomy
should continue as long as the hemoglobin concentration is higher Table 30.2. Non-
HFE Hereditary Iron Overload Disorders
than a preselected value (usually 12-13 g/dL). If the concentra-
tion is less than the preselected value, phlebotomy should not be Laboratory test
performed. Once the hemoglobin concentration remains below Disorder findings Clinical features
the preselected value for 3 consecutive weeks without phle- TFR2 hemochromatosis High transferrin Patients present at younger
botomy, the serum concentration of ferritin and transferrin sat- saturation age (30-40 y) than
uration should be determined again. Iron depletion is confirmed High ferritin level patients with HFE
if the ferritin level is not more than 50 µg/L, with a low-normal hemochromatosis
transferrin saturation. When iron depletion has been achieved, Hepatic, endocrine,
most patients require maintenance phlebotomies about every 3 and cardiovascular
to 4 months to keep the ferritin level less than 50 µg/L. Once iron involvement
HAMP or HJV alterations High transferrin Severe iron overload
is depleted, patients should have iron stores checked every 1 to
saturation phenotype
2 years to adjust the frequency of maintenance phlebotomy as High ferritin level Patients present at young
necessary. age (15-20 y)
Despite being common, hereditary hemochromatosis Cardiomyopathy
only rarely causes complications of cirrhosis and is an un- Ferroportin disease Low or normal Broad age range at
common indication for orthotopic liver transplant, accounting transferrin presentation
for less than 1% of all liver transplants performed in the US. saturation Splenic iron deposition
Patients with hepatocellular carcinoma complicating heredi- High ferritin level Liver biopsy shows iron in
tary hemochromatosis–related cirrhosis should be referred for Kupffer cells
consideration of liver transplant (the tumors must meet liver Abbreviations: HAMP, hepcidin gene (OMIM 606464); HJV, hemojuvelin gene
transplant criteria). The survival rate of patients with hereditary (OMIM 608374); TFR2, transferrin receptor 2 gene (OMIM 604720).
Table 30.3. Comparison of Hereditary Hemochromatosis, Wilson Disease, and α1-Antitrypsin Deficiency
Feature Hereditary hemochromatosis Wilson disease α1-Antitrypsin deficiency
Inheritance Autosomal recessive Autosomal recessive Autosomal codominant
Homozygote frequency 1:200 to 1:300 1:30,000 1:2,000
Heterozygote frequency 1:10 1:100 1:30
Gene HFE ATP7B NA
No. of clinically significant 2 (C282Y, H63D) >600 NA
variants
Chromosome 6 13 14
Diagnosis Transferrin saturation, ferritin level, Ceruloplasmin, slit-lamp examination α1-Antitrypsin phenotype
liver iron concentration, HFE for Kayser-Fleischer rings, urinary
gene test and liver copper quantification
Treatment Phlebotomy Penicillamine, trientine, or zinc None or orthotopic liver transplant
Abbreviation: NA, not applicable.
Non-HFE Hereditary Iron Overload Disorders Beutler E, Felitti VJ, Koziol JA, Ho NJ, Gelbart T. Penetrance of 845g-->
a (c282y) HFE hereditary haemochromatosis mutation in the USA.
With the expanding understanding of the pathogenesis of hemo- Lancet. 2002 Jan;359(9302):211–8.
chromatosis, several non-HFE forms of hereditary iron overload Ferenci P. Wilson’s disease. Clin Gastroenterol Hepatol. 2005 Aug;3(8):
disorders have been identified. These should be considered when 726–33.
iron overload is documented in the absence of a secondary cause Ferrarese A, Morelli MC, Carrai P, Milana M, Angelico M, Perricone G,
(eg, hemolysis) and HFE gene testing is negative. Patients often et al. Outcomes of liver transplant for adults with Wilson’s disease.
present at an earlier age than those with typical HFE hemochro- Liver Transpl. 2020 Apr;26(4):507–16.
matosis. The clinical features are listed in Table 30.2. Morrison ED, Brandhagen DJ, Phatak PD, Barton JC, Krawitt EL, El-
Serag HB, et al. Serum ferritin level predicts advanced hepatic fi-
brosis among US patients with phenotypic hemochromatosis. Ann
Intern Med. 2003 Apr;138(8):627–33.
Summary
Palmer WC, Vishnu P, Sanchez W, Aqel B, Riegert-Johnson D, Seaman
The features of hereditary hemochromatosis, WD, and A1ATD LAK, et al. Diagnosis and management of genetic iron overload
are summarized and compared in Table 30.3. disorders. J Gen Intern Med. 2018 Dec;33(12):2230–6.
Perlmutter DH, Brodsky JL, Balistreri WF, Trapnell BC. Molecular path-
ogenesis of alpha-1-antitrypsin deficiency-associated liver disease: a
Suggested Reading meeting review. Hepatology. 2007 May;45(5):1313–23.
Pietrangelo A. Non-HFE hemochromatosis. Hepatology. 2004 Jan;39(1):
Adams PC. Review article: The modern diagnosis and management 21–9.
of haemochromatosis. Aliment Pharmacol Ther. 2006 Jun;23(12): Pietrangelo A. Hereditary hemochromatosis: a new look at an old di-
1681–91. sease. N Engl J Med. 2004 Jun;350(23):2383–97.
Ala A, Walker AP, Ashkan K, Dooley JS, Schilsky ML. Wilson’s disease. Pietrangelo A. Hereditary hemochromatosis: pathogenesis, diagnosis,
Lancet. 2007 Feb;369(9559):397–408. and treatment. Gastroenterology. 2010 Aug;139(2):393–408.
American Thoracic Society, European Respiratory Society. American Roberts EA, Schilsky ML, American Association for Study of Liver
Thoracic Society/European Respiratory Society statement: standards Diseases. Diagnosis and treatment of Wilson disease: an update.
for the diagnosis and management of individuals with alpha- 1 Hepatology. 2008 Jun;47(6):2089–111.
antitrypsin deficiency. Am J Respir Crit Care Med. 2003 Oct;168(7): Silverman EK, Sandhaus RA. Clinical practice: alpha1-antitrypsin defi-
818–900. ciency. N Engl J Med. 2009 Jun;360(26):2749–57.
Bacon BR, Adams PC, Kowdley KV, Powell LW, Tavill AS, American Yamashita C, Adams PC. Natural history of the C282y homozygote for
Association for the Study of Liver Diseases. Diagnosis and manage- the hemochromatosis gene (HFE) with a normal serum ferritin level.
ment of hemochromatosis: 2011 practice guideline by the American Clin Gastroenterol Hepatol. 2003 Sep;1(5):388–91.
Association for the Study of Liver Diseases. Hepatology. 2011 Yu L, Ioannou GN. Survival of liver transplant recipients with hemochroma-
Jul;54(1):328–43. tosis in the United States. Gastroenterology. 2007 Aug;133(2):489–95.
31
Cholestatic Liver Diseasea

JOHN E. EATON, MD
Cholestatic liver disease in adults may or may not show evidence 5 times the upper limit of the reference ranges. Total bilirubin
of large bile duct obstruction. Drug-induced cholestasis may be levels are often normal at diagnosis but can increase in more
the most common explanation for cholestasis, which is often self- advanced stages of the disease, and serum levels of cholesterol
limiting. Primary biliary cholangitis is the most common chronic and immunoglobulin M can be abnormally high. Comorbid
cholestatic liver disease in adults, and primary sclerosing cholan-
gitis is about half as common as primary biliary cholangitis. In
contrast to primary sclerosing cholangitis, the cause of secondary Box 31.1. Differential Diagnosis for Cholestasis in
sclerosing cholangitis can often be identified. Adults Without Large-Duct Biliary Obstruction
Drug or TPN-induced cholestasis
Differential Diagnosis Primary biliary cholangitis
The differential diagnosis for cholestasis in adults without biliary Small-duct primary sclerosing cholangitis
obstruction is listed in Box 31.1; key causes of secondary sclero- Idiopathic adulthood ductopenia
sing cholangitis are outlined in Box 31.2. Intrahepatic cholestasis of pregnancy
Cystic fibrosis
Primary Biliary Cholangitis Progressive familial intrahepatic cholestasis
Diagnosis Alagille syndrome
Primary biliary cholangitis (formerly called primary biliary cir- Infiltrative disorders (eg, sarcoidosis, amyloidosis)
rhosis) has a prevalence of about 150 to 300 per million people, Nonalcoholic fatty liver diseasea
involves women in 90% of cases, and is characterized by positive Right-sided heart failure
results on the serum antimitochondrial antibody (AMA) test in Sepsis
95% of patients. These patients present with biochemical features
Paraneoplastic (Stauffer syndrome)
of cholestasis and may be asymptomatic. Fatigue is the most
common symptom. Pruritus is less common but may occur in Diabetic hepatosclerosis
30% of patients. Laboratory tests show increased serum alkaline Sickle cell intrahepatic cholestasis
phosphatase levels; aminotransferase levels are usually less than Nodular regenerative hyperplasia
Macro–alkaline phosphatase
a
The author thanks Jayant A. Talwalkar, MD, MPH, who authored pre- Abbreviation: TPN, total parental nutrition.
vious versions of this chapter. a
May present with slightly increased, isolated alkaline phosphatase levels.
Abbreviation: AMA, antimitochondrial antibody
357
cholangitis, the diagnosis can be confirmed by the presence of

Box 31.2. Differential Diagnosis for Secondary other specific autoantibodies, including Sp100 and gp210, or by
Sclerosing Cholangitis in Adults compatible histologic features on liver biopsy. A classic histo-
Mechanical logic finding in a subset of patients with primary biliary cholan-
Iatrogenic or traumatic
gitis is a florid duct lesion, which is characterized as a destructive
cholangitis with granulomatous and lymphocytic inflammation
Choledocholithiasis or hepatolithiasis
centered on the interlobular bile duct (Figure 31.1). The prog-
Chronic pancreatitis nosis and treatment of AMA-negative primary biliary cholangitis
Portal hypertensive biliopathy are the same as for AMA-positive primary biliary cholangitis.
Infectious Increases in aminotransferase levels greater than 5-fold the upper
Recurrent bacterial cholangitis limit of the reference range may indicate concurrent autoimmune
hepatitis, which is present among 5% of patients with primary
Biliary parasitic infection
biliary cholangitis.
Cryptosporidium parvum, Microsporidia,
cytomegalovirus in AIDS cholangiopathy
Ischemia Treatment
Hepatic artery occlusion Currently, the accepted standard of care is ursodeoxycholic acid,
Vascular trauma 13 to 15 mg/kg daily in divided doses, for patients with any stage of
primary biliary cholangitis who have abnormal liver test findings.
Liver transplant
Approximately 70% of patients have an adequate biochemical re-
Vasculitis sponse to ursodeoxycholic acid. Among those responders, survival
Malignancy is similar to that in the general population. The various response
Cholangiocarcinoma criteria center around decreases in the alkaline phosphatase level
Advanced gallbladder adenocarcinoma to less than 2 times the upper limit of the reference range.
Lymphoma If patients cannot tolerate ursodeoxycholic acid (a rare sit-
uation that can occur because of adverse effects related to the
Intrahepatic or biliary metastases
gastrointestinal tract), or if they have an incomplete response
Inflammatory or infiltrative to ursodeoxycholic acid after 1 year, adjunctive therapy should
Immunoglobulin G4–associated cholangitis with or be considered. Obeticholic acid is a farsenoid X receptor ago-
without concurrent autoimmune pancreatitis nist that was approved by the US Food and Drug Administration
Sarcoidosis because it decreases the alkaline phosphatase level, a surrogate
Amyloidosis marker associated with improved outcomes. However, it is un-
Eosinophilic cholangitis clear whether its use will result in improved clinical outcomes.
The use of obeticholic acid is limited by dose-dependent pruritus,
Mast cell cholangiopathy
and it is contraindicated in patients with compensated cirrhosis
Histiocytosis X and signs of portal hypertension and in patients with prior hepatic
Graft-vs-host disease decompensation.
Chronic allograft rejection There is also emerging evidence that fibrates may be used
Hepatic inflammatory pseudotumor to effectively treat primary biliary cholangitis. In particular,
bezafibrate has been shown to decrease alkaline phosphatase
Toxic
levels and improve pruritus among patients who do not have
Ketamine a response to ursodeoxycholic acid. Some data suggest that
Immunotherapy (eg, pembrolizumab, nivolumab) fenofibrate may help to achieve a biochemical response among
Intra-arterial chemotherapy (eg, fluorouracil) patients who do not have a response to ursodeoxycholic acid.
Intraductal ethanol, formaldehyde, or
hypertonic saline ✓ Primary biliary cholangitis
• Typical presentation—middle-aged woman with fatigue, pru-
Congenital ritus, and increased level of alkaline phosphatase
Biliary atresia after Kasai portoenterostomy • Positive result on serum AMA test allows diagnosis for more
Cystic fibrosis than 90% of patients
• If serum AMA test results are negative, diagnosis requires liver
Congenital biliary cysts
biopsy with compatible histology or the presence of specific
Turner syndrome autoantibodies (eg, gp210 and Sp100)
• Treatment with ursodeoxycholic acid improves survival
• Patients with inadequate response to ursodeoxycholic acid may
benefit from adjunctive therapy
autoimmune diseases are frequently present (eg, Sjögren syn-
drome, sicca syndrome, or autoimmune thyroid diseases).
The most characteristic finding is a positive result on the serum Primary Sclerosing Cholangitis
AMA test, which recognizes the lipoic acid binding site on an
enzyme in the pyruvate dehydrogenase complex. The diagnosis Diagnosis
of primary biliary cholangitis can be established in the presence Primary sclerosing cholangitis is associated with chronic inflam-
of an increased level of alkaline phosphatase with a positive mation and fibrosis of the biliary tree (intrahepatic or extrahepatic
AMA titer. Among patients with AMA-negative primary biliary or both) (Figure 31.2). It can progress to cirrhosis and is
31. Cholestatic Liver Disease 359
Figure 31.1. Histologic Features of Primary Biliary Cholangitis. Chronic nonsuppurative destructive cholangitis around the bile duct with mono
nuclear and granulomatous inflammation is consistent with a florid duct lesion.
associated with a heightened risk of hepatobiliary and colonic

malignancies. Approximately 70% of patients have inflammatory
bowel disease, which can develop at any time during the disease
(even after liver transplant). Unlike primary biliary cholangitis,
primary sclerosing cholangitis is more common in men. The typ-
ical age of onset is about 40 years.
The chief biochemical abnormality in primary sclerosing cho-
langitis is an increased level of serum alkaline phosphatase with
transaminase levels typically less than 5 times the upper limit of
the reference range (in the absence of acute biliary obstruction
or overlap with autoimmune hepatitis). However, approximately
40% to 50% of patients have a normal alkaline phosphatase level
sometime during the disease course. Hence, an abnormal alkaline
phosphatase level is not required for a diagnosis of primary scle-
rosing cholangitis. Magnetic resonance cholangiography is the
diagnostic method of choice for detection of multifocal biliary
strictures associated with large-duct primary sclerosing cholan-
gitis. Causes of secondary sclerosing cholangitis may generally
be excluded clinically. A liver biopsy is needed only if the cho-
langiogram is normal and there is concern for small-duct primary
sclerosing cholangitis or if there is a suspicion for concurrent
autoimmune hepatitis. The classic biopsy findings of periductal
fibrosis (so-called onion skin fibrosis) are not universally pres
ent (Figure 31.3). Autoantibodies such as antinuclear antibodies
or perinuclear antineutrophil cytoplasmic antibodies may be
present but are not specific or helpful in establishing the diag-
nosis. Frequently patients are asymptomatic, but they may have
manifestations of biliary strictures (jaundice, pruritus, ascending
Figure 31.2. Diagnostic Imaging Features of Primary Sclerosing cholangitis, or abdominal pain); fatigue; or signs of liver failure.
Cholangitis. Three-
dimensional magnetic resonance cholangiopan Given the prevalence of inflammatory bowel disease, typi-
creatography shows multifocal intrahepatic and extrahepatic biliary cally ulcerative colitis, all patients with a diagnosis of primary
strictures. sclerosing cholangitis should have a screening colonoscopy with
Figure 31.3. Histologic Features of Primary Sclerosing Cholangitis. Concentric rings of collagen and fibroblasts surrounding bile ducts are con-
sistent with onion skin fibrosis.
random biopsies to assess for underlying inflammatory bowel underlying anatomy or atrophic segments that should be avoided,
disease. The risk of colorectal cancer when inflammatory bowel and for helping to triage patients who may not benefit from an
disease is present is approximately 5-fold that of patients with invasive interventional endoscopic approach. Endoscopic retro-
inflammatory bowel disease alone. Patients with a concomitant grade cholangiopancreatography allows for biliary brushings for
diagnosis of inflammatory bowel disease with colonic involve- biliary cytology and fluorescence in situ hybridization analyses,
ment should have annual screening with surveillance biopsies for extrication of biliary stones, or dilation of flow-limiting strictures.
colorectal cancer screening. Biliary stenting is typically performed when balloon dilation
Primary sclerosing cholangitis is also associated with an alone does not achieve adequate decompression.
increased risk of hepatobiliary neoplasia. Cholangiocarcinoma
is the leading cause of death in this population and may occur ✓ Primary sclerosing cholangitis
in 10% to 15% of patients with primary sclerosing cholangitis. • Typical presentation—young man with inflammatory bowel
The risk of cholangiocarcinoma is highest within the first year disease
• Concomitant inflammatory bowel disease in more than 70% of
after the diagnosis of primary sclerosing cholangitis. However,
patients
cholangiocarcinoma is rare in pediatric patients or in patients who • Magnetic resonance cholangiopancreatography— diagnostic
have small-duct primary sclerosing cholangitis. In addition, gall- test of choice
bladder cancer risk is increased, and gallbladder adenocarcinoma • Concurrent inflammatory bowel disease increases risk of
may develop in approximately 2% to 4% of patients. Most experts hepatobiliary cancers (cholangiocarcinoma, gallbladder cancer,
recommend annual imaging to screen for cholangiocarcinoma and hepatocellular carcinoma) and colorectal cancer
and gallbladder cancer. Hepatocellular carcinoma occasionally
occurs with cirrhosis.
Secondary Sclerosing Cholangitis
Treatment Diagnosis
There is no approved medical therapy for primary sclerosing cho- Secondary sclerosing cholangitis is associated with chronic in-
langitis. Ursodeoxycholic acid has not been shown to be effective flammation and stricturing of the biliary tree (intrahepatic or
at decreasing the risk of death or the need for transplant. Higher extrahepatic or both) that arise as a response to an identifiable
doses of ursodeoxycholic acid (28-30 mg/kg) may be associated cause (Box 31.2). Frequently encountered benign causes of sec-
with adverse events. For patients with advanced disease, trans- ondary sclerosing cholangitis include iatrogenic or postoperative
plant has been shown to improve survival. causes (eg, hepatic artery thrombosis after liver transplant), recur-
Patients may have evidence of rapidly progressive jaundice, rent infections, and chronic obstruction due to choledocholithiasis.
they may suddenly become pruritic, or they may have fever with A disease such as sarcoidosis can cause cholestasis with or
right upper quadrant pain. Indications for an endoscopic retrograde without a large-duct biliary stricture. A biliary stricture (anasto-
cholangiopancreatography are a symptomatic biliary stricture or motic or nonanastamotic) is a common complication after liver
stricture that is concerning for underlying cholangiocarcinoma. transplant. Over time, anastomotic strictures can lead to recurrent
Magnetic resonance cholangiopancreatography before en- episodes of cholangitis, recurrent hepatolithiasis, and multifocal
doscopic intervention is often useful for detecting an under- nonanastamotic strictures. Patients with secondary sclerosing
lying malignant stricture, for informing the endoscopist of the cholangitis may present with jaundice, pruritus, or ascending
31. Cholestatic Liver Disease 361
cholangitis. Over time, cirrhosis may develop. The diagnosis can than 5% of patients with osteopenic bone disease and cholestasis.
be established with cholangiography, although additional, spe- Almost all bone disease evaluated in North American patients
cific testing may be required to identify the underlying cause. with cholestasis is due to osteoporosis, which is the result of in-
sufficient bone matrix rather than a mineralization defect as in
osteomalacia. The cause of the osteoporosis is uncertain. These
Treatment
patients lose bone at a rate of about twice that of the normal
Management involves addressing the underlying cause when fea- population. About 33% of patients with primary biliary cholan-
sible (eg, institution of antiviral therapy for AIDS cholangiopathy); gitis and about 20% of those with primary sclerosing cholan-
providing endoscopic or percutaneous therapy for flow-limiting gitis have osteopenia at the time of diagnosis, and about 10% of
biliary strictures or obstructions; and treating concurrent complica them have vertebral fractures within a few years after diagnosis.
tions (eg, ascending cholangitis). Some patients may require liver Management of the bone disease includes exercise and adequate
transplant. calcium intake with 1 to 1.5 g of elemental calcium daily in com-
bination with vitamin D supplementation if needed to correct
Management of Complications a deficiency. Postmenopausal women may have a response to
of Cholestasis hormone replacement therapy, which is usually given as patch
therapy. Treatment with bisphosphonates and newer monoclonal
Vitamin Deficiency antibodies has been shown to be effective.
Malabsorption and deficiency of fat-soluble vitamins may occur
with cholestasis, especially if cholestasis is severe and cirrhosis ✓ Complications of cholestatic liver disease
• Deficiencies of fat-soluble vitamins (vitamins A, D, E, and K)
develops. Serum levels of vitamins A, E, and D can be measured
• Hypercholesterolemia
directly, and the serum level of vitamin K can be inferred from the • Pruritus
prothrombin time. Replacement with water-soluble forms of the • Osteopenia and osteoporosis
vitamins can be offered (vitamin A, 50,000 IU twice weekly; vi-
tamin E, 200 mg twice daily; vitamin D, 50,000 IU twice weekly;
and vitamin K, 5 mg daily). Adequacy of replacement can be
reassessed by measuring levels after 6 to 12 months of therapy. Suggested Reading
Abdalian R, Heathcote EJ. Sclerosing cholangitis: a focus on secondary
Hypercholesterolemia causes. Hepatology. 2006 Nov;44(5):1063–74.
Chapman R, Fevery J, Kalloo A, Nagorney DM, Boberg KM, Shneider
Hypercholesterolemia, common in patients with cholestasis, is B, et al. Diagnosis and management of primary sclerosing cholan-
not associated with atherosclerosis. Treatment should be limited gitis. Hepatology. 2010 Feb;51(2):660–78.
to patients who have risk factors for coronary heart disease and Chen XM, LaRusso NF. Cryptosporidiosis and the pathogenesis of
who may safely begin pharmacologic therapies (eg, statins) to AIDS-cholangiopathy. Semin Liver Dis. 2002 Aug;22(3):277–89.
improve lipid profiles. Corpechot C, Carrat F, Bahr A, Chretien Y, Poupon RE, Poupon R. The
effect of ursodeoxycholic acid therapy on the natural course of pri-
mary biliary cirrhosis. Gastroenterology. 2005 Feb;128(2):297–303.
Pruritus Corpechot C, Chazouilleres O, Rousseau A, Le Gruyer A, Habersetzer F,
Mathurin P, et al. A placebo-controlled trial of bezafibrate in primary
Pruritus can be one of the most troublesome symptoms of
biliary cholangitis. N Engl J Med. 2018 Jun;378(23):2171–81.
patients with cholestasis. The severity of pruritus does not corre- Hilscher MB, Kamath PS, Eaton JE. Cholestatic liver diseases: a primer
late closely with the severity of the underlying liver disease, and for generalists and subspecialists. Mayo Clin Proc. 2020 Oct;95(10):
pruritus may resolve as the disease progresses. Ursodeoxycholic 2263–79.
acid decreases pruritus in some patients with primary biliary cho- Lammers WJ, Hirschfield GM, Corpechot C, Nevens F, Lindor KD,
langitis, but for those who remain symptomatic, antihistamines Janssen HL, et al. Development and validation of a scoring system to
(eg, diphenhydramine 25- 30 mg by mouth at bedtime) may predict outcomes of patients with primary biliary cirrhosis receiving
permit sleep, although they rarely have much effect on pruritus. ursodeoxycholic acid therapy. Gastroenterology. 2015 Dec;149(7):
Cholestyramine and other bile acid–binding resins may help re- 1804–12
lieve itching and are first-line therapy. Rifampin (150-300 mg Lewis JH. Drug- induced liver disease. Med Clin North Am. 2000
Sep;84(5):1275–311.
twice daily) has a rapid onset of action and may be useful long-
Lindor KD, Bowlus CL, Boyer J, Levy C, Mayo M. Primary biliary cho-
term, although liver toxicity may develop (<15% of patients). langitis: 2018 practice guidance from the American Association for
Sertraline (75-100 mg daily) has also been shown to improve the Study of Liver Diseases. Hepatology. 2019 Jan;69(1):394–419.
symptoms of pruritus. Naltrexone (50 mg daily) may be useful Lindor KD, Kowdley KV, Luketic VA, Harrison ME, McCashland T,
for some patients, although there is less experience with this drug Befeler AS, et al. High-dose ursodeoxycholic acid for the treatment
than with the others. UV phototherapy and the molecular ad- of primary sclerosing cholangitis. Hepatology. 2009 Sep;50(3):
sorbent recirculating system have also been shown to be effective 808–14.
for limited durations. Finally, liver transplant is available for Nevens F, Andreone P, Mazzella G, Strasser SI, Bowlus C, Invernizzi P,
patients who have severe, refractory pruritus. et al. A placebo-controlled trial of obeticholic acid in primary biliary
cholangitis. N Engl J Med. 2016 Aug 18;375(7):631–43.
Olsson R, Boberg KM, de Muckadell OS, Lindgren S, Hultcrantz R,
Bone Disease Folvik G, et al. High-dose ursodeoxycholic acid in primary sclero-
sing cholangitis: a 5-year multicenter, randomized, controlled study.
Although the insufficient delivery of bile acids to the gut lumen Gastroenterology. 2005 Nov;129(5):1464–72.
in advanced cholestasis may lead to fat-soluble vitamin defi- Poupon RE, Lindor KD, Cauch- Dudek K, Dickson ER, Poupon R,
ciency, osteomalacia due to vitamin D deficiency occurs in less Heathcote EJ. Combined analysis of randomized controlled trials of
ursodeoxycholic acid in primary biliary cirrhosis. Gastroenterology. Villa NA, Harrison ME. Management of biliary strictures after liver trans-
1997 Sep;113(3):884–90. plantation. Gastroenterol Hepatol (N Y). 2015 May;11(5):316–28.
Talwalkar JA, Angulo P, Johnson CD, Petersen BT, Lindor KD. Zein CO, Jorgensen RA, Clarke B, Wenger DE, Keach JC, Angulo P,
Cost-minimization analysis of MRC versus ERCP for the diagnosis et al. Alendronate improves bone mineral density in primary biliary
of primary sclerosing cholangitis. Hepatology. 2004 Jul;40(1): cirrhosis: a randomized placebo-controlled trial. Hepatology. 2005
39–45. Oct;42(4):762–71.
32
Drug-Induced Liver Injurya,b

OMAR Y. MOUSA, MBBS, MD
MICHAEL D. LEISE, MD
Despite increased awareness through the efforts of public and Overview of Drug Metabolism
regulatory agencies, the syndrome known as drug-induced liver
Orally administered drugs are lipid soluble, which allows
injury (DILI) is still a major public health problem in the US
them to be absorbed into cells and affect biologic processes.
and the world. Moreover, it is the single most common reason
Drug-metabolizing systems convert the parent drug into water-
for US Food and Drug Administration (FDA) regulatory actions,
soluble compounds, which are excreted into bile and urine.
including the removal of drugs from the marketplace. Although
The metabolizing systems are divided into phase 1 and phase 2
the frequency of this clinical syndrome is low within populations,
reactions. Phase 1 reactions involve the cytochrome P450 (CYP)
DILI causes a significant clinical and economic burden. This
family of enzymes (the CYP3A subfamily is the most prominent)
chapter highlights new developments in the field of idiosyncratic
and include the addition of polar groups by oxidation, reduction,
DILI and provides information about DILI from acetaminophen.
or hydrolysis. The metabolites formed by phase 1 reactions may
✓ DILI—an adverse drug reaction with presentations ranging from be toxic if not subsequently excreted or further metabolized.
asymptomatic increases in liver values to hepatocellular injury, Activity of phase 1 reactions is influenced by age, other drugs,
cholestasis, chronic hepatitis, or liver failure and toxins (Box 32.1).
✓ DILI—one of the common and most challenging disorders faced Phase 2 reactions further enhance the water solubility of a com-
by gastroenterologists and hepatologists pound and generally involve conjugation of glucuronide, sulfate,
acetate, glycine, or glutathione to a polar group. Occasionally,
phase 2 reactions may affect the parent compound directly (ie,
a
The authors thank John J. Poterucha, MD, and Jayant A. Talwalkar, MD, without a previous phase 1 reaction). Dietary factors, including
who coauthored previous versions of this chapter.
nutritional status, can alter the activity of phase 2 reactions. The
b
Portions of this chapter were adapted from Ghabril M, Chalasani N, influence of alterations in drug-metabolizing systems on DILI is
Björnsson E. Drug-induced liver injury: a clinical update. Curr Opin incompletely understood.
Gastroenterol. 2010 May;26(3):222-6 and Daly AK. Drug-induced liver
injury: past, present and future. Pharmacogenomics. 2010 May;11(5):
607–11; used with permission. Clinical Epidemiology
Abbreviations: ALP, alkaline phosphatase; ALT, alanine aminotransferase; Worldwide, the annual incidence rate of DILI is estimated to
AST, aspartate aminotransferase; CYP, cytochrome P450; DILI, drug-
be between 13.9 and 24 cases per 100,000 persons, and the
induced liver injury; DILIN, Drug-Induced Liver Injury Network; DRESS,
drug rash with eosinophilia and systemic symptoms; FDA, US Food and syndrome accounts for an estimated 3% to 9% of all adverse
Drug Administration; GWAS, genome- wide association study; HEV, drug reactions reported to health authorities. Epidemiologic
hepatitis E virus; HLA, human leukocyte antigen; Ig, immunoglobulin; data on DILI from prospective national registries have been
NAFLD, nonalcoholic fatty liver disease; NHANES, National Health published. A study from Iceland included an enumerated pop-
and Nutrition Examination Survey; NIH, National Institutes of Health; ulation and was linked to a prescription database, allowing
OR, odds ratio; ULRR, upper limit of the reference range for improved estimation of incidence. Cases of DILI were
363
✓ Amoxicillin-clavulanate—the most common cause of clinically

Box 32.1. Drugs and Conditions That Affect Activity apparent, drug-induced acute liver injury
of the Cytochrome P450 (CYP) System ✓ Most common classes of agents that cause DILI—antimicrobials,
Inhibit CYP Activity herbal and dietary supplements, and anticancer therapeutics
Cimetidine
Clarithromycin
Erythromycin Mechanisms and Classification
Fluconazole DILI is largely an unsolved problem because of our limited knowl
Itraconazole edge about the mechanisms of hepatic toxicity. Traditionally, the
Ketoconazole classification of injury patterns with DILI is based on specific
histologic features such as inflammation, cholestasis, sinusoidal
Older age
cell injury, immune- mediated damage, mitochondrial injury,
Quinidine and oxidative stress. Liver biopsy samples may show pathologic
Ritonavir features such as prominent eosinophilia, granulomas, zonal or
Induce CYP Activity massive necrosis, or cholestasis with hepatitis. The usefulness of
Carbamazepine histologic examination of the liver is limited by knowledge about
Chronic alcohol use
DILI, particularly information on the patterns of injury caused by
various agents. An overview of common histologic patterns seen
Isoniazid
with specific drugs is presented in Table 32.1.
Omeprazole DILI can be divided broadly into direct chemical toxicity and
Phenobarbital idiosyncratic hepatotoxic reactions. Direct chemical toxicity is
Phenytoin dose related; the most common example is the hepatotoxicity as-
Rifampin sociated with acetaminophen. Other examples include Amanita
mushrooms and carbon tetrachloride. Direct toxicity usually
occurs after a brief exposure. For a given drug, there is consid-
erable variability in the dose required to cause toxicity, largely
collected prospectively from 2010 through 2011. Among because of individual differences in drug metabolism. These
the 96 cases identified, the crude annual incidence was 19.1 differences can be genetic or due to exogenous effectors of drug
cases per 100,000 inhabitants (95% CI, 1.6-23.3 cases per metabolism.
100,000 inhabitants). Amoxicillin-clavulanate was the most
common drug, with an incidence of 1 in 729 users among Table 32.1. Histologic Patterns of Liver Injury and
inpatients and 1 in 2,350 among outpatients. The Regional Associated Drugs
Registry of Hepatotoxicity in Spain reported on 461 cases of
DILI identified between 1994 and 2004. In this experience, Liver injury Associated drugs
hepatocellular damage was the most common pattern observed Drug-induced Atorvastatin, halothane, hydralazine, ipilimumab,
(58%), and nearly 12% of patients with jaundice at presenta- autoimmune methyldopa, minocycline, nitrofurantoin, TNF-α
tion died or required liver transplant, compared with only 4% hepatitis antagonists, vemurafenib
of patients who did not have jaundice. The main causative Steatohepatitis Amiodarone, tamoxifen, valproic acid
medications were antibiotics (32% of cases), central nervous Steatosis Methotrexate, nucleoside reverse transcriptase
inhibitors, tetracycline, valproic acid
system drugs (17%), musculoskeletal drugs (17%), and gastro-
Cholestasis Amoxicillin-clavulanate, antifungal agents,
intestinal drugs (10%). Amoxicillin-clavulanate was again the chlorpromazine, erythromycin, histamine
most commonly implicated drug in this cohort. blockers, NSAIDs, oral contraceptives,
Among the first 300 patients enrolled in the ongoing National trimethoprim-sulfamethoxazole
Institutes of Health (NIH) Drug-Induced Liver Injury Network Granulomatous Allopurinol, amiodarone, carbamazepine,
(DILIN) prospective study, an estimated 73% of cases resulted diltiazem, hydralazine, penicillamine,
from use of a single prescription medication, 9% were attributed phenytoin, procainamide, sulfonamides
to herbal and dietary supplements, and 18% resulted from Fibrosis Methotrexate
Nodular regenerative Azathioprine, bleomycin, chlorambucil,
patients taking multiple agents. Among patients followed for at
hyperplasia cyclophosphamide, doxorubicin, interleukin 2,
least 6 months, the mortality rate was 8%, although the cause of trastuzumab
death was liver related for only 44% of patients. Among patients Sinusoidal obstruction Actinomycin, azathioprine (occasionally), cytosine
with DILI caused by a single prescription drug, the major syndrome arabinoside, dacarbazine, 5-fluorouracil,
classes of implicated agents were antimicrobials (46%), cen- oxaliplatin, plicamycin, 6-mercaptopurine
tral nervous system agents (15%), immunomodulatory agents (occasionally)
(5%), analgesics (5%), and lipid-lowering agents (3%). As in Hypersensitivity Abacavir, allopurinol, amoxicillin-clavulanate,
the Spanish and Icelandic registries, amoxicillin-clavulanate (immunoallergic) fluoroquinolones, halothane, phenytoin,
was the drug most commonly implicated. reaction sulfonamides
The Acute Liver Failure Study Group reported that aceta- Abbreviations: NSAID, nonsteroidal anti-inflammatory drug; TNF, tumor
minophen and idiosyncratic drug reactions together accounted necrosis factor.
for approximately 50% of cases of acute liver failure in the US. Adapted from Leise MD, Poterucha JJ, Talwalkar JA. Drug-induced liver
DILI is recognized as the most commonly identified cause of injury. Mayo Clin Proc. 2014 Jan;89(1):95-106. Used with permission of Mayo
acute liver failure that requires liver transplant in the US. Foundation for Medical Education and Research.
32. Drug-Induced Liver Injury 365
In contrast to the relatively predictable dose-related toxicity indicates acute disease, whereas macrovesicular steatosis or the
from acetaminophen, the more common idiosyncratic hepato- combination of both microvesicular steatosis and macrovesicular
toxic reactions appear to be related to genetic or environmental steatosis occurs with chronic exposure. Salicylate, valproate,
influences, or both, that are less well understood. They affect amiodarone, highly active antiretroviral therapy, hepatitis B an-
only susceptible individuals, have less consistent relationships tiviral therapy, and tamoxifen typically have been associated
to dose, and are more varied in their presentations. Most drug- with this form of DILI. Exposure to glucocorticoids, metho-
induced hepatotoxicity is metabolic, which involves the accumu- trexate, or diltiazem can be associated with macrovesicular
lation of toxic metabolites within hepatocytes, leading to necrosis steatosis. Amiodarone hepatoxicity is typically associated with
and inflammation. Recent investigations have identified several microvesicular steatosis, ballooning degeneration, and Mallory
categories of idiosyncratic DILI, as discussed below. bodies.
✓ DILI can be divided into 2 broad categories: direct chemical tox-

icity and idiosyncratic hepatotoxic reactions Sinusoidal Obstruction Syndrome
Sinusoidal obstruction syndrome (formerly called venoocclusive
disease) is diagnosed most often in patients who have received a
Hypersensitivity (Immunoallergic) Reaction myeloablative chemotherapeutic conditioning regimen (cyclophos-
phamide, busulfan, and melphalan) before undergoing stem cell
Liver injury from a hypersensitivity reaction usually follows 1 to 6
transplant for malignancy. This syndrome is seen also after exposure
weeks of exposure to the drug and is accompanied by rash, fever,
to 5-fluorouracil, oxaliplatin, cytosine arabinoside, actinomycin,
eosinophilia, and autoantibodies (alone or in combination) and
dacarbazine, or plicamycin and, occasionally, azathioprine, 6-
recurs rapidly with rechallenge. Hypersensitivity features are seen
mercaptopurine, or 6- thioguanine. The pyrrolizidine alkaloids
in only about 20% of all cases of idiosyncratic DILI. DILI may also
found in many plants and shrubs are well-known causes, and the
be seen in the context of stereotypical hypersensitivity reactions,
exposure is linked usually to bush tea. Other risk factors include
such as drug rash with eosinophilia and systemic symptoms
preexisting liver disease and previous radiotherapy to the abdomen.
(DRESS) syndrome, Stevens-Johnson syndrome, and toxic epi-
The diagnosis usually is based on the findings of hepatomegaly,
dermal necrolysis. Examples of drugs that can result in a hyper-
weight gain, and hyperbilirubinemia. In some cases, histologic ex-
sensitivity reaction are sulfonamides, amoxicillin- clavulanate,
amination of the liver may be required. Management is largely sup-
fluoroquinolones, phenytoin, halothane, allopurinol, and abacavir.
portive. The mortality rate is as high as 20%.
Autoimmune Reaction
Nodular Regenerative Hyperplasia
Autoimmune-mediated DILI may be caused by specific drugs,
and the immune responses mimic those typically observed Nodular regenerative hyperplasia is a rare disease that can lead
in de novo or idiopathic autoimmune hepatitis. Hydralazine, to noncirrhotic portal hypertension with possible variceal hem-
minocycline, and nitrofurantoin are drugs that are commonly as- orrhage but usually not ascites, hepatic encephalopathy, or syn-
sociated with autoimmune-mediated DILI. Infliximab, statins, thetic dysfunction. While it can be seen with hematologic and
and α-methyldopa can also lead to autoimmune-mediated DILI. rheumatologic conditions, it can also be found in association with
Although it is difficult to distinguish autoimmune-mediated DILI several medications, including azathioprine, bleomycin, chlo-
from autoimmune hepatitis on the basis of history, laboratory rambucil, cyclophosphamide, didanosine, and interleukin 2. The
findings, and histologic features, the absence of relapse after the diagnosis should be made from liver histologic findings. Nodular
withdrawal of corticosteroid therapy is highly suggestive of a regenerative hyperplasia is often overlooked since it is not easily
drug-induced autoimmune reaction. appreciated with routine hematoxylin-eosin staining and requires
a reticulin stain. The key histologic finding is small nodules
✓ Drug- induced autoimmune reaction— characterized by the ab- around the portal tract with hypertrophied hepatocytes centrally
sence of relapse after the withdrawal of corticosteroid therapy and atrophic hepatocytes peripherally.
✓ Nitrofurantoin, infliximab, and minocycline are commonly asso-
ciated with autoimmune-mediated DILI ✓ Patients with DILI may present with noncirrhotic portal hyperten-
sion secondary to nodular regenerative hyperplasia
Cholestasis
Peliosis Hepatis
Drug-induced cholestasis may occur as an acute disorder manifesting
as canalicular (bland jaundice), hepatocanalicular (cholestatic hepa- Peliosis hepatis is a rare condition that manifests with mul-
titis), or ductular (cholangiolar hepatitis) disease. Chronic cholestasis tiple, dilated, blood-
filled cavities in the liver and is associ-
often results from the vanishing bile duct syndrome. Amoxicillin- ated with the following drugs: anabolic steroids, azathioprine,
clavulanate, erythromycin, trimethoprim-sulfamethoxazole, chlor- 6-mercaptopurine, danazol, tamoxifen, hydroxyurea, and oral
promazine, antifungal agents, and oral contraceptives typically contraceptives.
produce this form of DILI. Other medications include nonsteroidal
anti-inflammatory drugs and histamine blockers.
Risk Factors
Older age is associated with DILI caused by several common
Steatosis drugs, including isoniazid, erythromycin, amoxicillin-clavulanate,
The deposition of small or large fat droplets in the liver is another and nitrofurantoin. The reason that age affects the risk of DILI
recognized form of DILI. Microvesicular steatosis generally is not clear because phase 1 and phase 2 metabolizing enzyme
activities are not altered markedly in older people. In contrast the patient has symptoms or impaired liver function. Under these
to earlier data, data from recent studies have not confirmed an circumstances potentially causative medications should be dis-
increased predisposition to DILI among women in comparison continued immediately.
with men. However, men and women might have differences in
susceptibility to particular agents that cause DILI. For example, ✓ Careful medication history is crucial in establishing the diagnosis
the majority of patients who have acute liver failure or require of DILI
liver transplant because of DILI are women. ✓ DILI can be characterized biochemically as specific patterns of
injury, such as hepatocellular, cholestatic, or mixed
Recent studies also suggest that the daily dose of a drug might
influence the development of DILI, which is in contrast to pre-
vious concepts. Among US prescription medicines, daily doses
greater than 50 mg have been associated significantly with liver Diagnosis
failure, liver transplant, and death from DILI. In the Swedish There is no specific test for DILI. The maxim that “almost any
and Spanish registries, 77% of the DILI cases were seen with drug can do almost anything” is important to consider when
oral medication doses of 50 mg or more. Lipophilicity has re- evaluating patients who have abnormal liver test results. Although
cently been shown to be an important medication risk factor. the time between the initiation of medication use and the onset
Although not an independent risk factor, it has synergism with of hepatotoxicity varies, most cases of DILI occur within a year
increased medication dose: high drug lipophilicity (logP ≥3) after treatment is started with the drug. DILI should be suspected
and high medication dosage (>100 mg daily) increase the risk when liver injury occurs soon (within 4 weeks) after the initiation
of DILI by as much as 14 times. Drugs with hepatic metabo- of treatment with an agent or after an increase in the dose of an
lism and hepatobiliary excretion are also associated with a higher agent that had been administered previously.
risk of serious DILI. The role of alcohol in idiosyncratic DILI is Generally, other causes of liver disease must be excluded be-
debated; however, chronic alcohol consumption upregulates sev- fore the diagnosis of DILI can be made. Screening is required for
eral CYP system enzymes, which leads to increased metabolism hepatitis (hepatitis A, B, C, and E), alcoholic or autoimmune hep-
of different medications to potentially toxic metabolites. The in- atitis, and hemodynamic derangement. Although infections are
fluence of underlying chronic liver disease as a risk factor for less common, testing to exclude cytomegalovirus and Epstein-Barr
DILI is not fully understood. Clearly, patients with underlying virus infections is helpful. The possibility of hepatitis E involve-
liver disease have a higher risk for adverse outcomes than those ment in suspected DILI cases was recently evaluated. Hepatitis E
without liver disease. virus (HEV) immunoglobulin (Ig) G serologies were positive in
There is growing evidence that obesity and nonalcoholic fatty 16% of patients (50 of 318) in the NIH DILIN series, with 3%
liver disease (NAFLD) can increase the risk of DILI, at least with testing positive for HEV IgM, which suggests acute HEV infection.
some drugs, either by aggravating NAFLD (eg, methotrexate Of the participants in a National Health and Nutrition Examination
and tamoxifen) or by causing acute hepatitis (eg, acetamino- Survey (NHANES) study (N=18,695), 21% were HEV seroposi-
phen, halogenated anesthetic halothane, and isoflurane). Patients tive, suggesting that HEV should no longer be considered a disease
with a history of DILI have a higher risk of DILI from other found only in resource-limited countries. If a patient is suspected
medications. Other risk factors include malnutrition, tobacco use, of having DILI with a hepatocellular pattern, HEV serology should
and polypharmacy. The understanding of genetic risk factors for be checked. Also, biliary abnormalities, through obstruction or in-
DILI is still emerging. fection, can injure the liver, as in cholangitis. If the liver injury
pattern is cholestatic, the biliary tree should be imaged, initially
Clinical Presentation with ultrasonography and then with computed tomography or
magnetic resonance imaging (Figure 32.1). Also, resolution of the
The clinical presentation of patients with DILI varies with the
injury after withdrawal of the drug (“dechallenge”) is helpful in
severity of injury to the liver. Patients with mild DILI may have
confirming the diagnosis of DILI, although the timing of improve-
an increase in the level of aspartate aminotransferase (AST), ala-
ment after the withdrawal varies.
nine aminotransferase (ALT), or alkaline phosphatase (ALP) (or
DILI can be characterized biochemically as specific patterns
a combination of these) and normal levels of total bilirubin and
of injury, such as hepatocellular, cholestatic, or mixed (Box 32.2),
have no symptoms or nonspecific symptoms such as fatigue and
with the use of the R ratio, defined by the following equation:
nausea. Moderate to severe DILI is accompanied often by ab-
dominal pain, jaundice, and pruritus. Rash, fever, facial edema,
ALT (Reported as Multiple of ULRR)
and lymphadenopathy, in combination with eosinophilia or atyp- R=
ical lymphocytosis, may be present with hypersensitivity-type ALP (Reported as Multipple of ULRR)
reactions. Coagulopathy, kidney dysfunction, and mental status
changes, when present, are seen typically when patients have ful- The liver injury pattern is hepatocellular when, at presenta-
minant DILI. tion, R exceeds 5, cholestatic when R is less than 2, and mixed
Many drugs cause mild, clinically insignificant, and transient when R is between 2 and 5. An important issue in calculating the
increases in liver enzyme levels within a few months. These R ratio is which values to use during the course of illness. For ex-
increased levels usually indicate an adaptive response to the drug ample, in the NIH DILIN study, R was calculated for 192 patients
and do not necessitate withdrawal of treatment with the agent. in whom DILI was thought to be due to a single agent. When
For example, isoniazid increases the ALT level more than 3 times R was calculated from the values obtained initially in the study,
the upper limit of the reference range (ULRR) in 15% of patients, 57% of patients had the hepatocellular pattern of injury, 21%
but the enzyme levels usually normalize despite continued the mixed pattern, and 22% the cholestatic pattern. However,
treatment. Generally, clinically significant DILI may be present when R was calculated from the values at the time of the peak
when liver enzyme levels increase more than 3 to 5 times the serum levels of bilirubin, 45% of patients had the hepatocellular
ULRR, when the bilirubin level is 2.5 mg/dL or more, or when pattern, 37% the cholestatic pattern, and 17% the mixed pattern.
Figure 32.1. Evaluation for Potential Drug-Induced Liver Injury. Evaluation for acute disease should include testing for 1) hepatitis A immunoglobulin (Ig) M antibody; 2) hepatitis B surface an-
tigen and hepatitis B core antibody IgM; 3) hepatitis C antibody (and subsequent hepatitis C virus RNA testing if antibody result is positive); 4) hepatitis E IgM antibody; 5) cytomegalovirus (CMV) (IgM
antibody or polymerase chain reaction or both); 6) Epstein-Barr virus (EBV) (heterophile antibody or EBV-specific antibody); 7) autoimmune hepatitis (AIH) (anti–smooth muscle antibody, antinuclear
antibody, and serum IgG level—there is no specific blood test for diagnosis); and 8) Wilson disease (ceruloplasmin, and consider ophthalmologic examination and 24-hour urine copper test—there is no
specific blood or urine test for diagnosis). Evaluation for chronic disease should include testing for 1) nonalcoholic fatty liver disease (NAFLD) with a combination of historic and imaging features with
or without histology (there is no specific blood test for diagnosis); 2) α1-antitrypsin (AAT) deficiency (AAT phenotype); 3) hemochromatosis (transferrin saturation and ferritin level); and 4) celiac disease
(tissue transglutaminase IgA). Evaluation for miscellaneous diseases should include testing for 1) biliary obstruction (ultrasonography or magnetic resonance cholangiopancreatography); 2) ischemic hepa-
titis (clinical diagnosis); 3) Budd-Chiari syndrome (ultrasonography with Doppler studies of hepatic veins); 4) total parental nutrition (TPN) (clinical diagnosis with or without histology); and 5) congestive
hepatopathy (transthoracic echocardiography). (Adapted from Leise MD, Poterucha JJ, Talwalkar JA. Drug-induced liver injury. Mayo Clin Proc. 2014 Jan;89[1]‌:95-106. Used with permission of Mayo
Foundation for Medical Education and Research.)
Box 32.2. Biochemical Patterns of Liver Injury With Certain Drugs

Hepatocellular (increased ALT) Cholestatic (increased ALP) Mixed (increased ALP and ALT)
Acarbose Amoxicillin-clavulanate Amitriptyline
Acetaminophen Anabolic steroids Azathioprine
Allopurinol Chlorpromazine Captopril
Amiodarone Clopidogrel Carbamazepine
Baclofen Erythromycins Clindamycin
Bupropion Estrogens Cyproheptadine
Fluoxetine Fluconazole Enalapril
HAART drugs Histamine blockers Flutamide
Isoniazid Irbesartan Nitrofurantoin
Ketoconazole Mirtazapine Phenobarbital
Lisinopril NSAIDs Phenytoin
Losartan Oral contraceptives Sulfonamides
Methotrexate Phenothiazines Trazodone
NSAIDs Phenytoin Trimethoprim-sulfamethoxazole
Omeprazole Terbinafine Verapamil
Paroxetine Tricyclic antidepressants
Pyrazinamide
Rifampin
Risperidone
Sertraline
Statins
Tetracyclines
Trazodone
Trovafloxacin
Valproic acid
Abbreviations: ALP, alkaline phosphatase; ALT, alanine aminotransferase; HAART, highly active antiretroviral therapy; NSAID,
nonsteroidal anti-inflammatory drug.
Adapted from Navarro VJ, Senior JR. Drug-related hepatotoxicity. N Engl J Med. 2006 Feb;354(7):731-9; used with permission.
Consequently, during DILI, a shift occurs in the ALP levels in re- further study. Protein adducts have also been investigated, and
lation to the ALT levels, and the later in the course of disease that acetaminophen- cysteine adducts were found in 18% of 110
values are obtained for calculating R, the more likely the patient patients with indeterminate cases in the US Acute Liver Failure
is to have a cholestatic pattern of injury. Study Group series as compared with 95% of the 199 patients
Ultimately, the level of certainty for making a diagnosis of with established acetaminophen-related acute liver failure. A re-
DILI is related to the clinical history, chronology of exposure cent proteomic analysis suggested that apolipoprotein E may be
and injury, exclusion of competing causes, and previous knowl helpful in the diagnosis of DILI, but that will require further study.
edge of DILI with a specific agent through clinical experience
and published data. Several causality assessment systems have
Histologic Patterns
been developed to identify the likelihood of suspected DILI and
an implicated agent in research settings. Recent studies have No unique histologic patterns unequivocally confirm the diag-
shown that the results from these assessment systems are not well nosis of DILI. Notably, the results of histologic examination of the
reproduced among multiple users, thus limiting their usefulness liver may vary with the timing of biopsy because hepatocellular
in research and clinical settings. More precise algorithms and injury is more prominent in the initial few weeks of injury;
ones that are easier to use in clinical practice are being developed. cholestatic features, however, are more prominent later in the
Recent progress has been made related to biomarkers for DILI. course of disease. The 2 main categories of histologic change that
MicroRNAs produced by the liver were evaluated in patients with can be observed are 1) acute and chronic hepatitis and 2) acute
acetaminophen liver injury or nonacetaminophen liver injury and and chronic cholestasis/mixed hepatocellular-cholestatic injury.
in healthy controls. MicroRNA 122 was significantly elevated in
patients with acetaminophen or nonacetaminophen liver injury
Acute and Chronic Hepatitis
compared with controls. Day 1 microRNA 122 levels correlated
with the peak ALT level and were 2- fold higher in patients In the acute and chronic hepatitis pattern, the dominant feature
meeting King’s College criteria, but these relationships were not is expansion of the portal area by a mononuclear infiltrate in the
statistically significant. The clinical utility of microRNA requires presence of interface hepatitis. Also, involvement of bile ducts
by inflammation or reactive changes may be seen. The paren- hospitalized and their condition monitored. The King’s College
chyma has scattered foci of inflammation and usually apoptotic criteria for liver transplant are listed in Box 23.2 in Chapter 23.
hepatocytes. At the severe end of liver injury, lobular disarray, When N-acetylcysteine is administered soon after acetamino-
areas of confluent necrosis, and central venulitis without true phen has been ingested, it acts by enhancing the conjugation and,
venoocclusive changes may be observed. Microgranulomas are thus, the water solubility and excretion of N-acetyl-p-quinone
common in cases of DILI due to allopurinol and phenytoin. Fibrin imine. When administered later, after liver injury has devel-
ring granulomas have been described in allopurinol-related DILI, oped, N-acetylcysteine acts by antioxidant and anti-inflammatory
but this is a nonspecific finding that can be seen in Q fever, hepa- mechanisms that are not well understood. N-acetylcysteine also
titis A, leishmaniasis, and Hodgkin lymphoma. may enhance liver perfusion through inotropic and vasodilatory
effects. Although the efficacy of N-acetylcysteine diminishes
when it is given more than 8 hours after acetaminophen has been
Acute and Chronic Cholestasis/Mixed
ingested, it nonetheless should be administered up to 24 hours
Hepatocellular-Cholestatic Injury
after ingestion because of its putative hepatoprotective effects.
The acute or intrahepatic cholestatic pattern is defined as
hepatocellular or canalicular bile stasis (or both) in the ab- ✓ Acetaminophen hepatotoxicity is characterized by very high
sence of marked inflammation. If intrahepatic cholestasis is as- levels of aminotransferases (often >5,000 U/L)
sociated with one of the necroinflammatory patterns described ✓ Recommended treatment of acetaminophen hepatotoxicity:
for hepatocellular injury, the pattern is categorized as mixed N-acetylcysteine
hepatocellular-cholestatic injury or cholestatic hepatitis. Bile
duct injury is usually present, although pronounced duct loss
suggests a chronic disorder such as primary biliary cholangitis, Antibiotics
primary sclerosing cholangitis, or vanishing bile duct syndrome.
The drug class that most commonly causes nonfulminant liver in-
The combination of cholestasis with inflammation and hepatic
jury is antibiotics. Amoxicillin-clavulanate is the most frequently
injury is a common histologic pattern of injury in DILI.
reported antibiotic that causes hepatotoxicity. Liver injury usually
manifests within 1 to 4 weeks after treatment with the drug has
Liver Biopsy been stopped, but it can occur even later. The clinical presentation
of patients with DILI can be either hepatocellular or cholestatic.
Liver biopsy is not mandatory in the evaluation of DILI. However,
Similar to other forms of drug-induced cholestatic liver injury,
the findings can be helpful for confirming a clinical suspicion of
the cholestasis due to amoxicillin-clavulanate may take weeks
DILI, assessing disease severity, and excluding other competing
or months to resolve. Other classic antibiotics associated with
causes of liver injury. Biopsy should be considered if autoim-
DILI are nitrofurantoin, minocycline, isoniazid, trimethoprim-
mune hepatitis remains a possible cause and if immunosuppres-
sulfamethoxazole, erythromycin, and the fluoroquinolones.
sive therapy is considered. Biopsy may be considered if liver
Telithromycin, a ketolide antibiotic, has been reported to cause
biochemistry results or liver function are worsening even though
severe hepatotoxicity, including the development of ascites. In
use of the suspected offending agent was stopped, or if continued
2007, the FDA required a label change and a boxed warning
use of the agent or reexposure to it is expected. In addition, a
about hepatotoxicity.
reasonable consideration would be a biopsy at 60 days for unre-
The NIH DILIN series has also reported on 12 patients with
solved acute hepatocellular DILI (if the peak ALT level has not
fluoroquinolone-related DILI, of which 7 had features of hyper-
decreased by >50%) and 180 days for cholestatic DILI (if the
sensitivity. The biochemical pattern of liver injury was evenly
peak ALP level has not decreased by >50%) despite stopping the
split between hepatocellular, mixed, and cholestatic types. The
suspected offending agent. Biopsy may also be considered in the
median latency was 2.5 days. Serious outcomes occurred: 3
evaluation of chronic DILI if abnormalities in liver biochemistry
patients had hepatic or other organ failure, 1 patient required liver
persist beyond 180 days.
transplant for vanishing bile duct syndrome, and another died of
acute liver failure. Antifungal agents such as ketoconazole can
Examples of Drugs Associated With DILI lead to cholestasis as well.
Acetaminophen
The most common cause of acute liver failure in the US and Antiretroviral Agents
Europe is acetaminophen toxicity. The metabolism of acetamino- Drugs for HIV cause hepatotoxicity in 2% to 18% of patients.
phen is shown in Figure 32.2. Decreases in glutathione in patients Most episodes of DILI are asymptomatic, and in most cases,
with chronic liver disease predispose the patients to production of increases in ALT levels resolve spontaneously.
the toxic metabolite. Also, patients with chronic excessive intake Of the protease inhibitors, ritonavir (especially at high doses)
of alcohol produce more of the toxic intermediate because of the carries the highest risk of liver toxicity, with an incidence of 3%
induction of CYP2E1 activity. to 9%. The newer protease inhibitor tipranavir has been associ-
Acetaminophen hepatotoxicity is characterized by very high ated with severe hepatotoxicity, especially when used in combi-
levels of aminotransferases (often >5,000 U/L). Kidney failure nation with ritonavir and particularly in patients with hepatitis
is also common. The degree of increase in the AST level at the B or C.
time of presentation after an acetaminophen overdose is helpful Newer nucleoside reverse transcriptase inhibitors, such as
in predicting hepatotoxicity. Hepatotoxicity rarely develops emtricitabine, abacavir, and tenofovir, are associated with a
in patients with AST levels less than 50 U/L at presentation, low incidence of increased ALT levels. The major toxic effect
whereas 16% of those with AST levels more than 1,000 U/L at of nucleoside reverse transcriptase inhibitors (especially didan-
presentation die or need liver transplant. Patients with acetamin- osine and stavudine) is lactic acidosis due to mitochondrial tox-
ophen hepatotoxicity and poor prognostic markers should be icity, which generally occurs after several weeks or months of
Figure 32.2. Metabolism of Acetaminophen (APAP). Most APAP is conjugated to either glucuronide or sulfate. The portion that is oxidized to N-
acetyl-p-benzoquinone imine (NAPQI) is further detoxified by glutathione (GSH) transferase. If this system is overwhelmed, NAPQI binds to cellular
targets, leading to hepatocellular necrosis. CYP indicates cytochrome P450. (Adapted from Zimmerman HJ. Acetaminophen hepatotoxicity. Clin Liver
Dis. 1998 Aug;2[3]‌:523-41; used with permission.)
treatment. Histologic examination of the liver usually shows stea- documented reports of severe liver injury, transplant, and death
tosis, and the mortality rate is high. Among patients with hepatitis associated with these compounds. Hydroxycut products were
C, the administration of ribavirin to those also receiving didano- recalled, and new formulations were released.
sine or stavudine has been associated with mitochondrial toxicity. According to the NIH DILIN prospective study, herbal and
A hypersensitivity DILI reaction due to the nonnucleoside re- dietary supplements were implicated in approximately 10%
verse transcriptase inhibitor nevirapine occurs in 2.3% of patients of consecutively enrolled cases of DILI. Furthermore, in the
and has also been seen with abacavir and efavirenz. This form of Spanish registry, 2% of cases of DILI were attributed to herbal
liver injury tends to develop within a few weeks after the start remedies or dietary supplements. In Asian countries, the propor-
of therapy. A different pattern of drug injury has emerged with tion of DILI caused by herbal supplements can be as high as 19%
the use of nevirapine: Liver enzyme levels begin to increase after to 63%.
more than 16 weeks of therapy, consistent with direct or idiosyn- Herbal and dietary supplements should be considered in the
cratic host-mediated liver injury. Patients who have chronic viral differential diagnosis of liver injury. Many patients do not con-
hepatitis are likely at increased risk for toxicity with nevirapine sider over-the-counter, nutritional, or herbal supplements as med-
therapy. In a large group of 8,851 patients studied by the AIDS icine; thus, these agents may not be included when patients are
Clinical Trials Group, baseline elevations of aminotransferases, asked about medicines taken before the episode of liver injury.
hepatitis C, and regimens containing didanosine or nevirapine Careful, repeated, and directed questioning is required.
were associated with severe hepatoxicity.
Lipid-Lowering Agents
Herbal and Dietary Supplements Because of the frequency with which statins are prescribed, there
Herbal and dietary supplements are commonly used in the US has been much interest in the potential liver toxicity of these
and throughout the world. The clinical patterns of presentation agents. Determining whether patients receiving statins have DILI
and severity of hepatotoxicity associated with these supplements is difficult because mild increases in liver enzyme levels are
can be highly variable, even for the same product. Box 32.3 common within 1 month after the initiation of statin therapy, but
lists some of the most common herbal and dietary supplements the levels nearly always improve despite continued administra-
associated with DILI. The FDA assigned warnings to sev- tion of these agents. Furthermore, mildly fluctuating liver enzyme
eral Hydroxycut (Iovate Health Sciences, Inc) and Herbalife levels occur also in hyperlipidemic patients not receiving statin
(Herbalife International of America, Inc) products on the basis of therapy. The presence of nonalcoholic fatty liver disease in many
Box 32.3. Selected Herbal and Dietary Supplements Associated With Hepatoxicity
Aloe vera Hydroxycut productsb (first-generation formulation
Atractylis gummifera production was halted in 2009)
Black cohosh Jin bu huan (Lycopodium serratum)
Callilepsis laureola (impila) Kava (Piper methysticum)
Camphor oil Ma huang (Ephedra sinica)
Cascara (cascara sagrada) Mistletoe (Viscum album)
Centella asiaticus (gotu kola) Noni juice (Morinda citrifolia)
Chaparral (Larrea tridentata) Pennyroyal (squawmint oil)
Dai-saiko-to (Sho-saiko-to, TJ-19, Da-Chai-Hu-Tang, Pyrrolizidine alkaloids (Crotalaria, Heliotropium,
Xiao-Chai-Hu-Tang) Senecio, Symphytum [comfrey])
Geniposide (Gardenia jasminoides) Saw palmetto (Serenoa repens)
Germander (Teucrium chamaedrys and other Senna (Cassia angustifolia and Cassia acutifolia)
Teucrium species) Skullcap (Scutellaria)
Greater celandine (Chelidonium majus) Valerian (Valeriana officinalis)
Green tea (Camellia sinensis)
Herbalife productsa
a
Herbalife International of America, Inc.
b
Iovate Health Sciences, Inc.
patients who are candidates for statin therapy further confounds Tumor Necrosis Factor α Antagonists
the issue, although it has been well demonstrated that statin drugs
are safe for patients with nonalcoholic fatty liver disease. In the NIH DILIN study, 6 patients who had DILI from tumor
Serious DILI from statin agents is rare. The risk of acute necrosis factor antagonists were evaluated with 28 other cases
liver failure associated with lovastatin, the first of the statins to from the DILI literature. All reported cases were caused by
be approved for treatment of hypercholesterolemia, is about 1 infliximab (n= 26), adalimumab (n= 4), and etanercept (n= 4).
in 1 million patient-treatment years. From 1990 to 2002, only 3 Interestingly, 67% of patients had positive autoantibodies, and
of more than 51,000 liver transplants in the US were performed for 15 of 17 patients who underwent liver biopsy, the histologic
for presumed statin-induced liver injury. In a study from Sweden findings included autoimmune features. The median latency was
(1998-2010), 73 cases of DILI from statins were identified; 19% 13 weeks, but patients with autoimmune features tended to pre-
were considered probable, and 10% highly probable. One patient sent later than those without. Most cases of DILI were either
required liver transplant, and 2 patients died. The median latency mild or moderate; 1 patient with preexisting cirrhosis required
was 3 months. Patients taking atorvastatin were more likely to liver transplant.
present with a cholestatic or mixed profile (57%) compared with Vedolizumab has been linked to a low rate of increased liver
patients taking simvastatin (25%). Although atorvastatin and enzyme levels during therapy, but it has not been linked to cases
simvastatin were the most frequent culprits responsible for DILI, of idiosyncratic clinically apparent liver injury with jaundice.
patients taking fluvastatin had the highest incidence of DILI Immunotherapy with immune checkpoint inhibition is a re-
compared with patients taking any other statin. The estimated in- cent advancement in the management of various solid tumors.
cidence of DILI from statins was estimated to be 1.6 per 100,000 Checkpoint inhibitors have been shown to initiate an antitumor
person-years. immune response directed against melanoma. Pembrolizumab
The FDA labeling for statins has changed. Patients should and nivolumab are antibodies directed against programmed cell
have baseline liver tests before treatment is initiated. Routine death receptor 1, and ipilimumab is an antibody directed against
posttreatment monitoring is not recommended, although the cytotoxic T-lymphocyte antigen-4 receptor on T lymphocytes.
symptoms, such as jaundice, that suggest liver disease should be They can cause various autoimmune adverse effects, including
investigated with liver tests. Statins rarely have been associated immune-mediated hepatitis. Increased levels of ALT and AST
with the development of autoimmune hepatitis, although the as- (with either value >3 up to 5 times the ULRR), ALP, and total
sociation may be only coincidental. bilirubin (>1.5 up to 3 times the ULRR) have been reported, most
Ezetimibe, which blocks the intestinal absorption of choles- commonly 8 to 12 weeks after initiating treatment.
terol, has been associated with increased liver enzyme levels and,
when administered in combination with statins, may rarely cause Treatment
clinically significant hepatoxicity. Sustained-release niacin also
may produce symptomatic hepatotoxicity. For most patients with DILI, treatment is based on withdrawal
of the agent and general support (Figure 32.1). For acetamino-
✓ Slight increases in transaminase levels after treatment with statins phen toxicity, N-acetylcysteine should be given. Carnitine may
are expected as part of an adaptive response and do not necessitate be helpful for valproate-induced microvesicular steatosis. Drug-
treatment withdrawal induced autoimmune hepatitis that does not improve spontane-
ously can be treated with corticosteroids.
The US Acute Liver Failure Study Group reported the results a small proportion of patients may have chronically increased
of a randomized controlled trial examining intravenous N- serum levels of liver enzymes that may signify chronicity. A re-
acetylcysteine for the treatment of acute liver failure from causes cent follow-up study of DILI patients from Sweden (mean dura-
other than acetaminophen. In this prospective, double-blind trial, tion of follow-up, 10 years) concluded that the development of
patients with acute liver failure (nonacetaminophen) were ran- clinically important liver disease after severe DILI was highly un-
domly assigned to receive N-acetylcysteine or placebo infusion common. A prospective follow-up of DILI patients in the Spanish
for 72 hours. Patients with acute liver failure caused by DILI (n= hepatotoxicity registry showed a 5% incidence of chronic DILI;
45) represented the single largest group among the 173 patients. in comparison, 14% of patients in the NIH DILIN study had per-
Although the overall survival at 3 weeks was not significantly sistent laboratory test result abnormalities. The most recent data
different between the groups, transplant-free survival was sig- from Iceland showed chronicity in 7% of patients. Further study
nificantly better for patients in the N-acetylcysteine group (40% is needed to determine the frequency and impact of chronic DILI.
vs 27%, P=.43). The benefits of N-acetylcysteine were seen pri-
marily in patients with early-stage disease and coma grade I or ✓ Without liver transplant, acute liver failure due to idiosyncratic
II (52% vs 30% transplant-free survival) but not in those with drug injury carries a high mortality rate (up to 80%)
advanced coma grade (III or IV) at randomization. When the ✓ If encephalopathy or coagulopathy develops in patients who have
hepatocellular DILI and jaundice, they should be referred to a
overall and transplant- free survival of the 4 largest etiologic
liver transplant center
groups was considered, patients with DILI and hepatitis B virus
infection showed improved outcome compared with patients in
the autoimmune hepatitis indeterminate groups. For the DILI
patients, the transplant-free survival was 58% for those receiving Pharmacogenetics
N-acetylcysteine and 27% for those receiving placebo. The study There is considerable interest in identifying the genes that con-
results suggest that therapy with intravenous N-acetylcysteine tribute to DILI. Before the year 2000, little information was
should be considered for patients with acute liver failure due to available on genetic susceptibility to DILI. However, both
idiosyncratic DILI. genome-wide association studies (GWASs) and candidate gene
Compared with hepatocellular drug injury, cholestatic liver in- studies have confirmed an important role for human leukocyte an-
jury is less likely to be serious but more likely to be prolonged. tigen (HLA) class I and class II genes in some but not all forms of
Ursodiol has been used in cases of drug-induced cholestasis, with DILI. An identified association between DILI due to flucloxacillin
a prolonged recovery phase. Responses have been reported, but and the HLA-B*5701 allele is the strongest reported association
the lack of controlled data makes it difficult to draw conclusions between any gene and DILI (odds ratio [OR], 80). The HLA-
about the efficacy of ursodiol. B*5701 allele is also associated with the thrombin inhibitor
Management of checkpoint inhibitor– related liver injury ximelagatran (OR, 45) and lapatinib-related DILI. The second
should follow the American Society of Clinical Oncology replicated HLA association is between amoxicillin-clavulanate–
guidelines. For asymptomatic patients with an ALT or AST level related DILI and the HLA class II allele DRB1*1501. The same
that is abnormal but less than 3 times the ULRR or an abnormal risk allele is associated with DILI due to lumiracoxib. Also, ev-
bilirubin level less than 1.5 times the ULRR, the checkpoint in- idence for the association between a polymorphism in the gene
hibitor can be continued with biweekly laboratory monitoring. encoding N-acetyltransferase 2 (NAT2), an enzyme important in
For asymptomatic patients with persistently increased AST or isoniazid metabolism, and susceptibility to DILI has been con-
ALT (>3 up to 5 times the ULRR) or increased total bilirubin firmed. Persons who have NAT2 variants associated with slow
levels (>1.5 to ≤3 times the ULRR) or both, the checkpoint in- acetylation appear to have an increased risk of isoniazid-related
hibitor should be withheld and prednisone should be initiated at a DILI. Common variants in the SLCO1B1 gene were found to be
dose of 0.5 to 1 mg/kg daily. For patients with symptoms, fibrosis strongly associated with an increased risk of statin-induced my-
detected by biopsy, cirrhosis, or high levels of AST or ALT (>5 opathy. This demonstrated that GWASs can successfully identify
times the ULRR) or bilirubin (>3 times the ULRR), the check- genetic risk factors for adverse drug reactions.
point inhibitor should be permanently discontinued and intrave- In recent studies, HLA-A*33:01 was associated with DILI due
nous methylprednisone should be initiated at 1 to 2 mg/kg daily. to ticlopidine (OR, 163.1), methyldopa (OR, 97.8), fenofibrate
(OR, 58.7), terbinafine (OR, 40.5), enalapril (OR, 34.8), sertraline
Prognosis (OR, 29), and erythromycin (OR 10.2) in GWASs of persons of
European descent. HLA-B*35:02 carriers were found to have an
The prognosis for patients with DILI varies. According to the Hy increased risk for minocycline-induced DILI (OR, 29.6). ERN1
rule (named after the hepatologist Hyman Zimmerman), patients was associated with efavirenz- related DILI (OR, 18.2), and
with jaundice due to drug-induced hepatocellular injury have a DRB1*16:01-DQB1*05:02 was associated with the nonopioid
10% mortality rate without transplant even if treatment with the analgesic flupirtine (OR, 18.7). Genetic polymorphisms associ-
drug is discontinued promptly. This rule has been confirmed by ated with statin-related DILI were found on chromosome 18.
recent studies from Spain, Sweden, and the US that reported mor- However, not all genetic effects relevant to DILI will neces-
tality rates between 9% and 12% for patients with hepatocellular sarily be of the magnitude identified in GWASs, and larger studies
jaundice. Patients with acute liver failure due to idiosyncratic may be needed to detect genes with smaller effects. Emerging
drug injury have an 80% mortality rate without transplant. Thus, techniques, such as whole-genome sequencing, will be needed
patients who have hepatocellular DILI and jaundice in whom en- for further progress in this area of study.
cephalopathy or coagulopathy develops should be referred for
consideration of liver transplant.
Whether chronic DILI will develop after a patient recovers Suggested Reading
from an acute injury is not clear. Most patients with DILI who Bell LN, Chalasani N. Epidemiology of idiosyncratic drug-induced liver
survive have complete biochemical and histologic recovery. Yet, injury. Semin Liver Dis. 2009 Nov;29(4):337–47.
Bjornsson E, Talwalkar J, Treeprasertsuk S, Kamath PS, Takahashi N, Kaliyaperumal K, Grove JI, Delahay RM, Griffiths WJH, Duckworth
Sanderson S, et al. Drug-induced autoimmune hepatitis: Clinical A, Aithal GP. Pharmacogenomics of drug- induced liver injury
characteristics and prognosis. Hepatology. 2010 Jun;51(6):2040–8. (DILI): Molecular biology to clinical applications. J Hepatol. 2018
Bjornsson ES, Bergmann OM, Bjornsson HK, Kvaran RB, Olafsson S. Oct;69(4):948–57.
Incidence, presentation, and outcomes in patients with drug-induced Kleiner DE. The pathology of drug-induced liver injury. Semin Liver
liver injury in the general population of iceland. Gastroenterology. Dis. 2009 Nov;29(4):364–72.
2013 Jun;144(7):1419–25, 25 e1–3; quiz e19–20. Kullak-Ublick GA, Andrade RJ, Merz M, End P, Benesic A, Gerbes AL,
Chalasani N, Bjornsson E. Risk factors for idiosyncratic drug-induced et al. Drug-induced liver injury: Recent advances in diagnosis and
liver injury. Gastroenterology. 2010 Jun;138(7):2246–59. risk assessment. Gut. 2017 Jun;66(6):1154–64.
Chalasani N, Fontana RJ, Bonkovsky HL, Watkins PB, Davern T, Larson AM, Polson J, Fontana RJ, Davern TJ, Lalani E, Hynan LS, et al.
Serrano J, et al. Causes, clinical features, and outcomes from a pro- Acetaminophen-induced acute liver failure: Results of a united states
spective study of drug-induced liver injury in the United States. multicenter, prospective study. Hepatology. 2005 Dec;42(6):1364–72.
Gastroenterology. 2008 Dec;135(6):1924–34, 34 e1–4. Leise MD, Poterucha JJ, Talwalkar JA. Drug-induced liver injury. Mayo
Chalasani NP, Hayashi PH, Bonkovsky HL, Navarro VJ, Lee WM, Clin Proc. 2014 Jan;89(1):95–106.
Fontana RJ, et al. ACG clinical guideline: the diagnosis and manage- Navarro VJ, Senior JR. Drug-related hepatotoxicity. N Engl J Med. 2006
ment of idiosyncratic drug-induced liver injury. Am J Gastroenterol. Feb 16;354(7):731–9.
2014 Jul;109(7):950–66; quiz 67. Nicoletti P, Aithal GP, Bjornsson ES, Andrade RJ, Sawle A, Arrese M,
Chalasani NP, Maddur H, Russo MW, Wong RJ, Reddy KR, Practice et al. Association of liver injury from specific drugs, or groups of
Parameters Committee of the American College of Gastroenterology. drugs, with polymorphisms in HLA and other genes in a genome-
ACG clinical guideline: diagnosis and management of idiosyn- wide association study. Gastroenterology. 2017 Apr;152(5):1078–89.
cratic drug-induced liver injury. Am J Gastroenterol. 2021 May Search Collaborative Group, Link E, Parish S, Armitage J, Bowman L,
1;116(5):878–98. Heath S, et al. SLCO1B1 variants and statin-induced myopathy: a
Daly AK. Drug- induced liver injury: Past, present and future. genomewide study. N Engl J Med. 2008 Aug 21;359(8):789–99.
Pharmacogenomics. 2010 May;11(5):607–11. Urban TJ, Nicoletti P, Chalasani N, Serrano J, Stolz A, Daly AK, et al.
Jones M, Nunez M. Liver toxicity of antiretroviral drugs. Semin Liver Minocycline hepatotoxicity: Clinical characterization and identification
Dis. 2012 May;32(2):167–76. of HLA-B *35:02 as a risk factor. J Hepatol. 2017 Jul;67(1):137–44.
33
Autoimmune Hepatitis
JOHN E. EATON, MDa
Epidemiology late-onset, mild disease; and South American patients are more
commonly young children with severe disease.
Autoimmune hepatitis is a chronic inflammatory disorder of
the liver that is associated with formation of autoantibodies,
hypergammaglobulinemia, plasma cell infiltrate, and interface Etiology
hepatitis seen on histologic examination. Autoimmune hepatitis The cause of autoimmune hepatitis is unknown, and the vast ma-
affects patients of all ages and both sexes but occurs more com- jority of cases are not preceded by an inciting exposure. However,
monly in women (female to male ratio, 3.6:1). The global annual several potential triggers of the disease have been suggested, such
incidence of autoimmune hepatitis ranges from 0.7 to 2 cases as hepatitis A, hepatitis B, hepatitis C, Epstein-Barr, herpes sim-
per 100,000 persons. Among White people of northern European plex, and measles viruses. Medications can cause drug-induced
ancestry, the mean annual incidence of autoimmune hepatitis is autoimmune hepatitis. Key examples include immunotherapy (eg,
1.9 per 100,000, and the point prevalence is 16.9 per 100,000. The pembrolizumab), antimicrobials (eg, minocycline, nitrofuran-
annual incidence of autoimmune hepatitis in children is 0.4 cases toin, moxifloxacin, and isoniazid), antihypertensive medications
per 100,000 persons with a prevalence of 3 cases per 100,000 (eg, hydralazine and α-methyldopa), complementary and alter-
persons. Autoimmune hepatitis occurs in 100,000 to 200,000 per- native medications or supplements (eg, black cohosh, khat, and
sons in the US annually and accounts for approximately 6% of Chinese herbal teas), and others (eg, diclofenac, propylthiouracil,
liver transplants performed in the US. atorvastatin, infliximab, and adalimumab). Hepatitis A virus in-
Originally described from White patients of northern European fection (and hepatitis A vaccine) and minocycline have been
ancestry and North Americans, autoimmune hepatitis is now implicated most often worldwide. In 1 series, drug-induced auto-
recognized to occur worldwide. Ethnic background may affect immune hepatitis accounted for 9% of all autoimmune hepatitis
the clinical presentation: African American patients have a cases; nitrofurantoin and minocycline were the leading culprits.
higher frequency of cirrhosis at presentation than White North Distinguishing drug- induced autoimmune hepatitis from
Americans; Alaskan natives have a higher occurrence of acute ic- classic autoimmune hepatitis can be challenging. However, sev-
teric disease than nonnative patients; Asian patients tend to have eral key features can assist clinicians: 1) Drug-induced autoim-
mune hepatitis has a temporal relationship with the offending
agent. 2) The presence of cirrhosis in patients with drug-induced
a
The author thanks Albert J. Czaja, MD, who authored previous versions autoimmune hepatitis is rare. Otherwise, histologic features can
of this chapter. look similar. 3) Cessation of the offending agent and short-term
Abbreviations: ALT, alanine aminotransferase; ANA, antinuclear an- use of prednisone is sufficient to treat drug-induced autoimmune
tibody; anti-LKM1, antibody to liver-kidney microsome type 1; Ig, hepatitis. 4) Drug-induced autoimmune hepatitis is characterized
immunoglobulin; PBC, primary biliary cholangitis; PSC, primary scle- by a low rate of relapse and better outcomes when compared
rosing cholangitis; SMA, smooth muscle antibody; TPMT, thiopurine to classic autoimmune hepatitis. 5) Up to a quarter of patients
methyltransferase with drug-induced autoimmune hepatitis may have a concurrent
375
fever, rash, and eosinophilia, which is rare in classic autoimmune common concurrent immune diseases. Autoimmune hepatitis is
hepatitis. present in 15% of patients with autoimmune polyendocrinopathy-
candidiasis-ectodermal dystrophy.
A subset of patients with autoimmune hepatitis may also have
Presentation
primary sclerosing cholangitis (PSC) or primary biliary cholangitis
Autoimmune hepatitis is characterized by a phenotypic spectrum. (PBC). Of the patients who have autoimmune hepatitis and ulcer-
Most patients with autoimmune hepatitis have normal findings on ative colitis, 41% have PSC. In children, this has historically been
physical examination despite having severe inflammatory activity referred to as autoimmune sclerosing cholangitis. Approximately
(Table 33.1). Women constitute at least 70% of cases, and 50% 5% of patients with PSC and PBC have an overlap syndrome with
are younger than 40 years (Table 33.1). Onset is usually between concurrent autoimmune hepatitis. An overlap syndrome should be
the third and fifth decades but can occur at any age. Children are considered if patients have pronounced cholestasis on presenta-
less likely to have sustained remission and are more likely to have tion or a persistently increased level of alkaline phosphatase after
disease relapse after treatment withdrawal, particularly if they the aminotransferase levels have improved with therapy directed
have antibodies to liver-kidney microsome type 1 (anti-LKM1). to autoimmune hepatitis. The diagnosis of concurrent PSC can be
There are 2 subtypes of autoimmune hepatitis (Table 33.2). established when multifocal biliary strictures are seen on mag-
Type 2 occurs in children, is rarely associated with remission netic resonance cholangiography or when characteristic histo-
after drug withdrawal, and has varied disease associations and logic features are found on liver biopsy. Concurrent PBC can be
autoantibodies when compared to type 1 autoimmune hepatitis. diagnosed when the serum alkaline phosphatase level is increased
Nearly 30% of patients may present with asymptomatic with either positive results for antimitochondrial antibodies or
increases in liver test results. Of those asymptomatic patients, compatible histologic changes.
25% have inactive autoimmune hepatitis with advanced fibrosis
when their diagnosis is established. Nonspecific symptoms such
Diagnosis
as fatigue, arthralgias, and malaise are common. Jaundice, pru-
ritus, and manifestations of portal hypertension can be present in There is no specific diagnostic biomarker for autoimmune hep-
severe or advanced disease. Approximately 30% of patients have atitis. Instead, the diagnosis of autoimmune hepatitis can be es-
cirrhosis at presentation. Although many patients have a long his- tablished with compatible histologic features along with typical
tory of increased liver test results, 25% to 75% of patients have laboratory and clinical features after excluding other causes of
an acute presentation with variable severity. At their initial pre- liver disease such as viral hepatitis and drug-induced liver in-
sentation, less than 6% of patients have acute severe autoimmune jury. Diagnostic scoring systems have been created, such as the
hepatitis with jaundice and coagulopathy or, more rarely, acute simplified scoring system shown in Table 33.3. However, their use
liver failure. has been limited by a lack of prospective validation and uncertain
accuracy with severe presentations of autoimmune hepatitis and
by situations when concurrent PSC, PBC, or nonalcoholic fatty
Concurrent Immune-Mediated Diseases
liver disease is present and testing involves autoantibody quan-
Concurrent immune-mediated diseases are present in 30% to 48% tification with indirect immunofluorescence titers rather than
of patients with autoimmune hepatitis (Box 33.1). Autoimmune enzyme- linked immunoassay units. Clinicians should always
thyroid disease, synovitis, and ulcerative colitis are the most reconsider a previous diagnosis of autoimmune hepatitis when
patients do not have an expected response to medical therapy.
Table 33.1. Typical Features of Autoimmune Hepatitis
Laboratory Features
Feature Patients, %
In patients with active autoimmune hepatitis, abnormalities in
Clinical features
serum aminotransferase levels are essential for the diagnosis
Female sex 70
Age <40 y 50
(Table 33.1). The serum aminotransferase levels at presenta-
Acute onset 25-75 tion are often 500 U/L or less but occasionally exceed 1,000 U/
Asymptomatic 25-34 L in a severe presentation. Increased levels of serum alkaline
Common symptoms
phosphatase occur in 81% of patients, but the values are typi-
Fatigue 85 cally less than 2-fold the upper limit of the reference range. Mild
Arthralgia 30 hyperbilirubinemia is present in 83% of patients with severe in-
Myalgia 30 flammatory activity. The serum γ-globulin level is often increased
Development after asymptomatic presentation 26-70 and is usually a polyclonal increase that involves serum immuno-
Frequent physical examination findings globulin (Ig) G.
Normal 80 Antinuclear antibody (ANA), smooth muscle antibody
Hepatomegaly 20
(SMA), and anti- LKM1 are often increased in autoimmune
Typical laboratory abnormalities hepatitis. Among adults with autoimmune hepatitis, ANA is
Increased serum levels of AST and ALT 100 detected in 80% and SMA is detected in 63%. However, anti-
Increased serum levels of γ-globulin and IgG 90
LKM1 is seen in only 3% of adults but is more common in chil-
Mild hyperbilirubinemia (bilirubin <3 mg/dL) 83
Serum ALP increased <2-fold ULRR 67
dren and is associated with type 2 autoimmune hepatitis (Table
ANA, SMA, or anti-LKM1 present 80 33.2). Autoantibodies such as ANA and SMA are frequently
seen in other conditions such as nonalcoholic fatty liver disease.
Abbreviations: ALP, alkaline phosphatase; ALT, alanine aminotransferase; ANA, Moreover, anti-LKM1 is found in as many as 10% of European
antinuclear antibody; anti-LKM1, antibody to liver-kidney microsome type 1; patients with chronic hepatitis C. Hence, the presence of these
AST, aspartate aminotransferase; IgG, immunoglobulin G; SMA, smooth muscle
antibody; ULRR, upper limit of the reference range. autoantibodies is not pathognomonic, and ANA or SMA titers
33. Autoimmune Hepatitis 377
Table 33.2. Comparison of Types 1 and 2 Autoimmune Hepatitis

Autoimmune Hepatitis
Feature Type 1 Type 2

Characteristic autoantibodies ANA, SMA Anti-LKM1
Associated autoantibodies pANCA Anti-LC1
Anti-SLA Anti-ASGPR
Anti-actin Anti–parietal cell
Anti-ASGPR
Age at onset Any age Mainly pediatric (2-14 y)
Common concurrent immune Autoimmune thyroiditis Vitiligo
diseases Synovitis Type 1 diabetes
Ulcerative colitis Autoimmune thyroiditis
Overlap syndrome with PSC Varies (6%-11%); more common in children Rare
Overlap syndrome with PBC Varies (7%-11%); seen in adults Not reported
Cirrhosis at time of diagnosis Approximately 30% Rare
Implicated genetic factors DRB1*0301 (northern Europe) DQB1*02
DRB1*0401 (northern Europe) DRB1*03 (anti-LKM1)
DRB1*1501 (protective) DRB1*07 (anti-LC1)
DRB1*1301 (South America)
Autoantigen Uncertain CYP2D6
Remission after drug withdrawal Possible in select cases Rare
Abbreviations: ANA, antinuclear antibody; anti-ASGPR, antibody to asialoglycoprotein receptor; anti-LC1, antibody to
liver cytosol type 1; anti-LKM1, antibody to liver-kidney microsome type 1; anti-SLA, antibody to soluble liver antigen;
CYP2D6, cytochrome P450 2D6; pANCA, perinuclear antineutrophil cytoplasmic antibody; PBC, primary biliary
cholangitis; PSC, primary sclerosing cholangitis; SMA, smooth muscle antibody.
Adapted from Czaja AJ. Autoimmune liver disease. In: Zakim D, Boyer TD, editors. Hepatology: a textbook of liver disease.
Vol 2. 4th ed. Philadelphia (PA): Saunders; c2003. p. 1163-202; used with permission.
do not have prognostic significance. They may be absent in ap- therapy. When therapy is successful, improvement can be ex-
proximately 20% of patients with autoimmune hepatitis (ie, sero- pected in transaminase values, histologic findings, and survival.
negative autoimmune hepatitis). Therefore, low or undetectable Autoimmune hepatitis can be treated effectively with im-
titers should not dissuade a clinician from the diagnosis if other munosuppression with glucocorticoids alone or at a lower dose
features implicate the disorder. in combination with azathioprine. Treatment induces clinical,
Several other autoantibodies are used less frequently in clin- laboratory, and histologic remission in 65% of patients within
ical practice. Atypical perinuclear antineutrophil cytoplasmic 18 months and in 80% within 3 years (Figure 33.3). Medical
antibodies are often seen in type 1 autoimmune hepatitis but have therapy also enhances survival expectations. For example, the
limited specificity. Conversely, antibodies to soluble liver an- life expectancy of successfully treated patients exceeds 80% after
tigen have high specificity for type 1 autoimmune hepatitis but 20 years of observation and is akin to that of the general popula-
poor sensitivity. Additional autoantibodies that can be present are tion. Improvement in hepatic fibrosis occurs in conjunction with
shown in Table 33.2. decreases in liver inflammation, and corticosteroids suppress in-
flammatory activity.
Patients who have autoimmune hepatitis with active disease
Histologic Features are candidates for therapy. Dosages for adults are prednisone
A liver biopsy that shows compatible histologic features is essen- alone at 40 to 60 mg daily (prednisolone is frequently used in
tial. Interface hepatitis is the histologic hallmark of autoimmune Europe) or at 20 to 40 mg daily in combination with azathioprine
hepatitis (Figure 33.1). Plasma cell infiltration of the hepatic pa- (50-150 mg daily in the US; 1-2 mg/kg daily in many European
renchyma or portal tracts (or both) is apparent in 66% of tissue centers). For most patients, combination therapy is preferred
specimens, but its presence is neither specific nor required for because it is associated with fewer corticosteroid- related ad-
the diagnosis (Figure 33.2). A lobular, or panacinar, hepatitis fre- verse effects. However, azathioprine is not recommended in the
quently accompanies interface hepatitis, and a centrilobular (zone following situations: 1) when patients have complete deficiency
3) necrosis has also been described. Successive examinations of of thiopurine methyltransferase (TPMT); 2) when oral or intrave-
liver tissue have shown transition of the centrilobular (zone 3) ne- nous corticosteroid monotherapy is used in the initial treatment
crosis to interface hepatitis, and it may be an early form of the of hospitalized patients who have acute severe autoimmune hep-
disease. Emperipolesis can be present in 65% of specimens; hepatitis; 3) when patients have drug-induced autoimmune hepatitis,
atocyte rosettes in 33%. While these histologic features are typ- where treatment with prednisone for less than 6 months is gen-
ical for autoimmune hepatitis, they are not pathognomonic and erally sufficient; 4) when patients have decompensated cirrhosis;
can be seen in other conditions. and 5) when patients have active malignancy (eg, lymphoma) that
could be exacerbated by azathioprine.
In many centers, the introduction of azathioprine is delayed
Treatment for 2 weeks after initiation of corticosteroids. This delay is used
Therapy for autoimmune hepatitis involves immunosuppression to confirm a response to corticosteroids, to verify TPMT status,
to achieve remission and subsequent long- term maintenance and to decrease the rare likelihood of azathioprine-associated
Table 33.3. Diagnostic Criteria for Autoimmune

Box 33.1. Key Immune-Mediated Diseases Associated Hepatitis (AIH)
With Autoimmune Hepatitis
Variable Pointsa
Autoimmune thyroiditisa
ANA or SMA ≥1:40 1
Celiac disease
ANA or SMA ≥1:80 or 2b
Coombs-positive hemolytic anemia Anti-LKM1 ≥1:40 or
Cryoglobulinemia Anti-SLA positive
IgG >1×ULRR 1
Dermatitis herpetiformis
IgG >1.10×ULRR 2
Erythema nodosum Histology compatible with AIH 1
Fibrosing alveolitis Histology typical of AIH 2
Focal myositis Absence of viral hepatitis 2
Gingivitis Abbreviations: ANA, antinuclear antibody; anti-LKM1, antibody to liver-

Glomerulonephritis kidney microsome type 1; anti-SLA, antibody to soluble liver antigen; IgG,
immunoglobulin G; SMA, smooth muscle antibody; ULRR, upper limit of the
Graves diseasea reference range.
Idiopathic thrombocytopenic purpura a
Score ≥6 points =probable AIH (sensitivity, 88%; specificity, 97%). Score ≥7
Intestinal villous atrophy points =definite AIH (sensitivity, 81%; specificity, 99%).
Iritis b
Maximum of 2 points for all autoantibodies.
Lichen planus Data from Hennes EM, Zeniya M, Czaja AJ, Pares A, Dalekos GN, Krawitt
Myasthenia gravis EL, et al; International Autoimmune Hepatitis Group. Simplified criteria for the
diagnosis of autoimmune hepatitis. Hepatology. 2008 Jul;48(1):169-76.
Neutropenia
Pericarditis
Peripheral neuropathy Alternatively, other smaller studies have suggested that patients
Pernicious anemia treated with budesonide are more likely to have an incomplete
Primary biliary cholangitis response, which suggests that prednisone is a more potent agent
for induction of remission. Hence, there is limited quality of
Primary sclerosing cholangitis
evidence to suggest that either is superior for inducing remis-
Pyoderma gangrenosum sion. For patients with more mild disease and those at risk for
Rheumatoid arthritisa corticosteroid-
related adverse effects, budesonide may be a
Sjögren syndrome pragmatic option. Budesonide has a 90% first-pass effect on the
Synovitisa liver and should not be used in patients who have cirrhosis or
portosystemic shunting. Moreover, it has not been studied in
Systemic lupus erythematosus
patients with severe disease and should be avoided in those with
Type 1 diabetes acute severe autoimmune hepatitis.
Ulcerative colitisa
Vitiligoa
a
Most common associations.
Adapted from Czaja AJ. Autoimmune liver disease. In: Zakim D,
Boyer TD, editors. Hepatology: a textbook of liver disease. Vol 2.
4th ed. Philadelphia (PA): Saunders; c2003. p. 1163-202; used with
permission.
liver injury as a confounding factor in the determination of

whether there is biochemical improvement with corticosteroids.
For most outpatients without severe disease, laboratory values are
typically checked every 2 to 4 weeks. After biochemical remis-
sion is achieved, a response-guided approach to corticosteroid
tapering is recommended, where the prednisone dosage is gradu-
ally decreased to 5 to 10 mg daily (or budesonide to 3 mg daily)
over the next 6 months. Thereafter, patients with biochemical re-
mission are candidates for a trial of withdrawal of corticosteroids
Figure 33.1. Interface Hepatitis. The limiting plate of the portal
and continuation of azathioprine monotherapy long- term for
tract is disrupted by an inflammatory infiltrate that extends into the ac-
maintenance of remission. inus. Interface hepatitis is a requisite for the diagnosis of autoimmune
Budesonide has been used to avoid the short-and long-term hepatitis, but it is not specific for the diagnosis (hematoxylin-eosin, orig-
adverse effects associated with prednisone. In a randomized inal magnification ×200). (Adapted from Czaja AJ. Current concepts in
controlled trial, budesonide was more likely to be associ- autoimmune hepatitis. Ann Hepatol. 2005 Jan-Mar;4[1]‌:6-24; used with
ated with biochemical remission compared to prednisone. permission.)
33. Autoimmune Hepatitis 379
Patients with overlap syndromes should receive the standard

medical therapy for autoimmune hepatitis along with the typical
treatment and management of PBC or PSC.
Relapse
Relapse connotes the exacerbation of disease activity after with-
drawal of drug therapy. It is characterized by an increase in serum
levels of liver enzymes (ALT or AST) and reappearance of char-
acteristic hepatic inflammation (although biopsy is not often re-
quired in this situation). Normalization of the serum levels of
aminotransferases and IgG in conjunction with histologic reso-
lution decreases the relative risk of relapse after drug withdrawal
by 3-to 11-fold. However, it is noteworthy that among non–drug-
induced autoimmune hepatitis cases, only a minority of patients
have disease that stays in remission without maintenance therapy.
For example, among 131 patients with autoimmune hepatitis who
had clinical and biochemical remission for 2 years, nearly 90%
Figure 33.2. Plasma Cell Infiltration of the Hepatic Parenchyma.
had a relapse within 5 years after withdrawal of immunosuppres-
Plasma cells (arrow) are characterized by a cytoplasmic halo adjacent
to a deeply basophilic nucleus. Plasma cells typically are abundant at sion. In a smaller study with 28 patients who had prolonged bio-
the interface and throughout the acinus, but their presence does not chemical remission, 46% had a relapse within 2 years of stopping
have diagnostic specificity (hematoxylin-eosin, original magnification immunosuppression. Hence, relapse is common and long-term
×400). (Adapted from Czaja AJ. Current concepts in autoimmune hepa- monitoring is required. Moreover, multiple relapses can be as-
titis. Ann Hepatol. 2005 Jan-Mar;4[1]‌:6-24; used with permission.) sociated with progression to cirrhosis and shorter transplant-free
survival.
The initial step in treating relapse is reinstitution of the original
Patients with normalization of alanine aminotransferase (ALT) corticosteroid. The second step is reintroduction of azathioprine
levels at 6 months after diagnosis have improved outcomes. as the dose of prednisone is gradually decreased and then stopped.
Histologic improvement lags behind clinical and laboratory In more than 80% of patients treated in this fashion the disease
resolution by 3 to 8 months (Figure 33.3). A decrease in liver remains in clinical and laboratory remission for 10 years.
stiffness, measured by elastography, is associated with biochem-
ical remission, fibrosis regression, and an enhanced prognosis.
Examination of a liver biopsy specimen before initial withdrawal Suboptimal Response and Treatment Failure
of drug therapy is the only method for confirming histologic res- Incomplete resolution of inflammation with therapy (according to
olution, but biopsy is infrequently performed in clinical prac- biochemical markers and histologic findings) is considered a sub-
tice. Before withdrawal of drug therapy is considered, treatment optimal response, which occurs in 13% of patients. A lack of a bi-
should be continued for at least 2 years after normalization of ochemical response to prednisone should prompt considerations
transaminase and IgG levels and clinical remission. of alternative diagnoses. Approximately 9% of patients have a
deterioration in their condition despite their adherence to the drug
regimen (ie, treatment failure). The use of a high dose of predni-
sone (60 mg daily) or prednisone at a lower dose (30 mg daily)
in conjunction with a high dose of azathioprine (150 mg daily) is
the regimen for treatment failure that induces laboratory remis-
sion in 75% of patients within 2 years. Intolerable adverse effects
(ie, drug toxicity) develop in 13% of patients, who stop taking the
medication prematurely.
Data supporting second-and third-line treatment options (after
exclusion of azathioprine and corticosteroids) are largely from un-
controlled and retrospective studies. Mycophenolate mofetil is the
most widely studied second-line agent, which can be used instead
of azathioprine. Response rates to mycophenolate mofetil appear to
be higher among patients who have an intolerance to azathioprine
rather than an incomplete response. Use of mycophenolate mofetil
should be avoided during pregnancy. Calcineurin inhibitors such
as tacrolimus have also been examined. For example, in an inter-
national multicenter retrospective study, 57% of patients who had
Figure 33.3. Frequencies of Clinical, Biochemical, and Histologic an inadequate response to standard therapy had a complete bio-
Remission During Conventional Corticosteroid Treatment of chemical response 6 months after initiation of tacrolimus. Small
Autoimmune Hepatitis. Histologic improvement lags clinical and case series and anecdotal reports from specialized centers have
biochemical improvement by 3 to 8 months. (Data from Czaja AJ. also reported the successful use of rituximab and mammalian
Treatment strategies in autoimmune hepatitis. Clin Liver Dis. 2002 target of rapamycin inhibitors (eg, sirolimus and everolimus) in
Aug;6[3]‌:799-824.) patients who have had difficulty with other therapies.
Liver Transplant Suggested Reading

Autoimmune hepatitis accounts for 5% of all liver transplants Czaja AJ. Overlap syndromes. Clin Liver Dis (Hoboken). 2014 Jan;3(1):
in the US. Liver transplant is effective in the treatment of 2–5.
patients who have acute liver failure, severe acute hepatitis that Efe C, Hagstrom H, Ytting H, Bhanji RA, Muller NF, Wang Q,
is unresponsive to conventional therapies, or cirrhosis-related et al. Efficacy and safety of mycophenolate mofetil and tacrolimus
as second-line therapy for patients with autoimmune hepatitis. Clin
complications. The 5-year survival rate of patient and graft ranges
Gastroenterol Hepatol. 2017 Dec;15(12):1950–6.
from 83% to 92%. Autoimmune hepatitis recurs in approximately Kalra A, Burton JR, Jr., Forman LM. Pro: Steroids can be withdrawn
one-third of patients after 5 years. Rejection occurs more fre- after transplant in recipients with autoimmune hepatitis. Liver
quently in patients who underwent liver transplant for autoim- Transpl. 2018 Aug;24(8):1109–12.
mune hepatitis compared to other indications. In some studies, Mack CL,Adams D,Assis DN, Kerkar N, Manns MP, Mayo MJ, et al. Diagnosis
long-term use of prednisone (5-10 mg daily) in addition to the and management of autoimmune hepatitis in adults and children: 2019
standard immunosuppression regimen (typically a calcineurin practice guidance and guidelines from the American Association for the
inhibitor) has decreased the risk of recurrent autoimmune hepa- Study of Liver Diseases. Hepatology. 2020 Aug;72(2):671–722.
titis without increasing the risk of infections or osteoporosis. In Theocharidou E, Heneghan MA. Con: Steroids should not be withdrawn
contrast, other studies have shown that corticosteroid withdrawal in transplant recipients with autoimmune hepatitis. Liver Transpl.
2018 Aug;24(8):1113–8.
is not associated with disease recurrence, episodes of rejection,
Trivedi PJ, Hubscher SG, Heneghan M, Gleeson D, Hirschfield GM. Grand
or shortened survival of patient or graft. Hence, management of round: Autoimmune hepatitis. J Hepatol. 2019 Apr;70(4):773–84.
immunosuppression should be individualized. Autoimmune hep- van Gerven NM, Verwer BJ, Witte BI, van Hoek B, Coenraad MJ, van
atitis can develop in 2.5% to 3.4% of allografts of children and Erpecum KJ, et al. Relapse is almost universal after withdrawal of im-
adults who received liver transplants for liver diseases other than munosuppressive medication in patients with autoimmune hepatitis
autoimmune hepatitis. in remission. J Hepatol. 2013 Jan;58(1):141–7.
34
Nonalcoholic Fatty Liver Diseasea

GOPANANDAN PARTHASARATHY, MBBS
HARMEET MALHI, MBBS
Nonalcoholic fatty liver disease (NAFLD) refers to a spectrum Hepatic steatosis may be categorized as primary or secondary,
of disorders defined by accumulation of fat in hepatocytes and depending on the underlying pathogenesis (Table 34.1). Primary
includes isolated hepatic steatosis, also known as nonalcoholic steatosis, the more common type, is associated with insulin-
fatty liver (NAFL), and nonalcoholic steatohepatitis (NASH), resistant states, such as obesity, type 2 diabetes, and dyslipidemia.
which is characterized by the presence of inflammation and hep- Other conditions associated with insulin resistance, such as poly
atocyte injury (including ballooning), with or without fibrosis. cystic ovarian syndrome and hypopituitarism, have also been
NAFLD is the most common chronic liver disease in the Western described in association with NAFLD; however, the exact preva-
world, affecting a quarter of the population. NAFL, defined by lence and significance of NAFLD in these conditions is not clear.
steatosis without inflammation, is generally benign, whereas The differentiation of primary steatosis from secondary types is
NASH may progress to cirrhosis, liver failure, and hepatocellular important because the treatments and prognoses are different.
carcinoma. Hence, distinguishing between NAFL and NASH has
important prognostic and management implications. Recently, Table 34.1. Causes of Hepatic Steatosis
to improve the nomenclature, experts have proposed the use of
the term metabolic dysfunction– associated fatty liver disease Type of cause Characteristics
(MAFLD). This terminology better captures the underlying Primary Obesity, glucose intolerance, type 2 diabetes,
obesity-associated or obesity-independent metabolic dysfunction, hypertriglyceridemia, low HDL cholesterol,
which is often a prerequisite for the development of hepatic stea- hypertension
tosis. However, neither term, NAFLD or MAFLD, captures the het- Nutritional Protein-calorie malnutrition, rapid weight loss,
erogeneous pathogenesis and progression; ideally terms related to gastrointestinal bypass surgery, total parental
molecular phenotypes will replace them in the future. This chapter nutrition
uses the existing nomenclature: NAFLD, NAFL, and NASH. Pharmacologic Glucocorticoids, estrogens, tamoxifen, amiodarone,
methotrexate, diltiazem, zidovudine, valproate,
aspirin, tetracycline, cocaine
Metabolic Lipodystrophy, hypopituitarism, dysbetalipoproteinemia,
Weber-Christian disease
a
The authors thank Kymberly D. Watt, MD, who authored previous Toxic Poisoning from Amanita phalloides (a mushroom),
versions of this chapter. phosphorus, petrochemicals, Bacillus cereus toxin
Abbreviations: ALT, alanine aminotransferase; AST, aspartate amino Infectious HIV, hepatitis C, small-bowel diverticulosis with
transferase; BMI, body mass index; CT, computed tomography; FXR, bacterial overgrowth
farnesoid X receptor; GLP-1, glucagon-like peptide-1; HCC, hepato
cellular carcinoma; MAFLD, metabolic dysfunction–associated fatty Abbreviation: HDL, high-density lipoprotein.
liver disease; MR, magnetic resonance; MRI, magnetic resonance im- Adapted from Aithal GP, Das A, Chowdhury A. Epidemiology of nonalcoholic
aging; NAFL, nonalcoholic fatty liver; NAFLD, nonalcoholic fatty fatty liver disease (NAFLD). In: Talley NJ, Locke GR, Moayyedi P, West J, Ford
liver disease; NASH, nonalcoholic steatohepatitis; PPAR, peroxisome AC, Saito YA, eds. GI epidemiology: diseases and clinical methodology. 2nd ed.
proliferator-activated receptor; ULRR, upper limit of the reference range John Wiley & Sons; 2014:357-72; used with permission.
381
✓ Nonalcoholic steatohepatitis (NASH)—hepatic steatosis with ev- development of NAFLD (eg, lipotoxicity, bile acid metabolism,
idence of inflammation and hepatocyte injury, such as ballooning, genetic polymorphisms, and intestinal dysbiosis).
with or without fibrosis Hepatic steatosis, the hallmark feature of NAFLD, is the net
✓ Nonalcoholic fatty liver disease (NAFLD)—spectrum of disorders result of altered lipid homeostasis in the liver. Insulin resistance
ranging from isolated accumulation of fat in the liver (nonalcoholic is pathogenically linked to hepatic steatosis. Increased adipose
fatty liver [NAFL]) to NASH and NASH cirrhosis tissue lipolysis in insulin-resistant states results in the delivery of
✓ Metabolic dysfunction–associated fatty liver disease (MAFLD)— excess free fatty acids to the liver. These free fatty acids provide
hepatic steatosis in the presence of obesity, type 2 diabetes, or meta- substrate for triglyceride accumulation. In addition, contributors
bolic dysfunction
to steatosis include increased de novo lipogenesis in the liver,
which persists in selective insulin resistance in the liver, and
increased diet-derived fatty acids. Several additional mechanistic
Epidemiology processes are recognized as contributors or modifiers of steatosis.
These include bile acid metabolism, intestinal dysbiosis, defects
NAFLD has reached epidemic proportions in many countries, as
in lipidation or secretion of very low-density lipoprotein, and ge-
shown by several population-based studies. In the US, an estimated
netic variations.
30% to 40% of the adult population (75 million to 100 million
Bile acid metabolism is predominantly regulated through the
persons) has NAFLD. The prevalence of NAFLD in the general
nuclear hormone receptor farnesoid X receptor (FXR), which is
population in the US is almost 14-fold higher than the prevalence
found in the hepatocyte. Activation of the FXR decreases lipo-
of hepatitis C, which affects about 4 million people. It also is al-
genesis and increases fatty acid oxidation. The bile acid metabo-
most 3-fold higher than alcohol-associated liver disease. Although
lism pathway has been a key target in clinical trial development.
the majority of patients with NAFLD have NAFL, an estimated
Several other nuclear hormone receptors have also been associ-
15 million to 20 million have NASH, and in approximately 10% to
ated with NAFLD, and studies are ongoing.
30% of those patients, NASH progresses to cirrhosis (Table 34.2).
Research into the genetics behind the pathogenesis has
NAFLD is more prevalent in men than in women, especially
been prompted by differences in the prevalence of NAFLD
premenopausal women (men, 31%; premenopausal women,
among ethnic groups and clustering in families and in twin
16%), and prevalence is higher among Hispanic patients (45%)
cohorts. The protein PNPLA3 (also called adiponutrin) is im-
compared to White patients who are not Hispanic (33%) and
portant in lipid metabolism, and patients who have the I148M
African American patients (24%).
variant of PNPLA3 (OMIM 609567) have a greater risk for
✓ An estimated one-third of adults in the US have NAFLD; about increased incidence and severity of disease. TM6SF2 (OMIM
5% have NASH, and advanced fibrosis may develop in a third 606563) is a risk allele associated with dyslipidemia and he-
of them patic steatosis. A variant in MBOAT7 (OMIM 606048) is asso-
✓ Prevalence of NAFLD is greater in men, Hispanic persons, and ciated with NAFLD. Conversely, a recently recognized variant
patients with obesity or type 2 diabetes in HSD17B13 (OMIM 612127) decreases the risk of NAFLD
development.
Sophisticated sequencing of the gut microbiome has shown
that patients with NAFLD have lower gut microbial diversity (ie,
Pathogenesis dysbiosis) compared with healthy persons. Separate studies have
The pathogenesis of NAFLD is complex and includes contributions shown that differences in the gut microbiome are correlated with
from many genetic, environmental, and lifestyle factors. Since the the presence of obesity and the degree of fibrosis. This dysbiosis
recognition of the initial “2-hit pathogenesis” in the late 1980s, is thought to alter the function of the intestinal barrier and allow
several additional factors have been identified that contribute to the for the translocation of more bacterial components and microbial
Table 34.2. Definitions of Liver Diseases

Term Definition Prevalence Prognosis
NAFLD Spectrum of fatty liver disease without Estimated 25%-52% of global
excessive alcohol consumption population
Estimated 30%-40% of US
population
NAFL Liver fat ≥5% (hepatic steatosis) without >80% of patients with NAFLD Minimal risk for progression to cirrhosis
evidence of hepatocellular injury
(hepatocyte ballooning) or fibrosis
NASH Liver fat ≥5% (hepatic steatosis) and ≤20% of patients with NAFLD; 10%-30% of patients have progression to
inflammation estimated 1.5%-6.45% of cirrhosis over 15 y
and hepatocellular injury with ballooning general population
with or without fibrosis
NASH cirrhosis Presence of cirrhosis with current or past 10%-30% of patients with NASH About 31% of patients have decompensation
histologic evidence of steatosis over 8 y; in about 7%, hepatocellular
carcinoma develops over 6.5 y
Cryptogenic Presence of cirrhosis without a specific
cirrhosis cause; often with similar risk factors
as for NAFLD
Abbreviations: NAFL, nonalcoholic fatty liver; NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis.
34. Nonalcoholic Fatty Liver Disease 383
metabolites, including short- chain fatty acids and bile acids, Table 34.3. Principal Clinical, Laboratory, Histologic, and
which contributes to hepatic steatosis and inflammation. Diagnostic Characteristics of Patients With Nonalcoholic Fatty
In addition to hepatic steatosis, the pathogenesis of NASH Liver Disease (NAFLD)
is characterized by hepatocyte injury, inflammation, and fi-
Type of feature Characteristics
brosis. The accumulation of toxic lipids, a process referred to as
lipotoxicity, results in direct injury and cell death of hepatocytes. Clinical Usually asymptomatic; sometimes mild right upper
Danger signals released from hepatocytes, translocation of micro- quadrant discomfort, hepatomegaly, acanthosis
bial products from the intestine, and direct effects of lipids on the nigricans, or “cryptogenic” cirrhosis
innate immune system contribute to the sterile inflammatory re- Often associated with features of metabolic
syndrome: type 2 diabetes, obesity, dyslipidemia
sponse that occurs in the liver in NASH. Hepatocyte ballooning, a
(hypertriglyceridemia, low HDL cholesterol,
key feature of NASH and a component of the histologic NAFLD hypobetalipoproteinemia), and cardiovascular
activity score, refers to enlarged hepatocytes with accumulation disease
of fat droplets, loss of keratin 8 and 18 staining, and the presence Biochemical Increased AST and ALT levels (usually <5-fold
of Mallory-Denk bodies. Ballooned hepatocytes are thought to be ULRR)
bioactive and secrete inflammatory mediators, which also con- Increased levels of alkaline phosphatase and
tribute to the inflammatory response in NASH. Fibrosis occurs in γ-glutamyltransferase (usually <3-fold ULRR)
response to ongoing hepatocyte injury and inflammation. AST:ALT ratio <1:1
Hyperinsulinemia and insulin resistance
✓ Steatosis results from increased free fatty acid delivery from the Dyslipidemia and increased ferritin level
gut and adipose tissue lipolysis and from increased de novo syn- Histologic Steatosis (fatty infiltration >5% hepatocytes)
thesis of free fatty acid in the liver; the result is hepatocyte injury Necroinflammation (lobular or portal inflammation,
and death, which perpetuates inflammation and fibrosis Mallory-Denk bodies, ballooning)
✓ Genetic variants and risk of NAFLD Fibrosis (perisinusoidal, perivenular, bridging,
• Increased risk of NAFLD: variants in PNPLA3, TM6FSF2, cirrhosis)
and MBOAT7 Imaging Imaging indicative of fatty infiltration of the liver
• Decreased risk of NAFLD: variants in HSD17B13 (ultrasonography, computed tomography,
✓ Histologic features of NASH are assessed with the NAFLD activity magnetic resonance imaging, magnetic
score, which includes severity of steatosis, lobular inflammation, resonance spectroscopy)
and hepatocyte ballooning Exclusion of other Alcohol intake <140 g weekly for women and
causes (alcohol use, <210 g weekly for men
secondary causes) Absence of liver disease of viral, autoimmune, or
genetic origin
Clinical Manifestations
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase;
The clinical, laboratory, histologic, and diagnostic features of HDL, high-density lipoprotein; ULRR, upper limit of the reference range.
NAFLD are listed in Table 34.3. The majority of patients are Adapted from Moscatiello S, Manini R, Marchesini G. Diabetes and liver
asymptomatic, but they may complain of fatigue or malaise and a disease: an ominous association. Nutr Metab Cardiovasc Dis. 2007 Jan;17(1):63-
sensation of fullness or discomfort in the right upper abdomen. In 70; used with permission.
children and adolescents, hepatomegaly and acanthosis nigricans
are common physical findings, but stigmata of chronic liver dis
ease, which would suggest cirrhosis, are uncommon. observed to resolve over time in patients with NASH-related
The most common clinical scenario leading to the diagnosis of cirrhosis, potentially masking the diagnosis. Not infrequently,
NAFLD is an asymptomatic increase in alanine aminotransferase NAFL occurs in patients who received a liver transplant for cryp-
(ALT) and aspartate aminotransferase (AST) not due to viral togenic cirrhosis, suggesting that NASH is the cause of what was
hepatitis, autoimmune processes, iron overload, or alcohol use. previously thought to be cryptogenic cirrhosis. Rarely, NASH
Aminotransferase levels can be increased in up to 50% to 90% could be a consideration for patients who have subacute liver
of hospitalized patients who have NASH but are less commonly failure because they may have a background of asymptomatic
increased in patients in the general population who have NAFLD. NASH and an unknown stimulus that precipitates liver failure (in
The increase is usually mild (1-4 times the upper limit of the ref- an already metabolically stressed liver). The clinical spectrum of
erence range [ULRR]) with the AST:ALT ratio less than 1:1. This NAFLD is summarized in Table 34.2.
ratio increases as fibrosis advances but is almost never greater
✓ Most patients with NAFLD and NASH are asymptomatic and have
than 2. Fatty infiltration of the liver is detected with ultrasonog-
an incidental finding of fatty liver on imaging or slightly increased
raphy or computed tomography (CT) (as described below) and levels of serum alanine aminotransferase (ALT)
often is an incidental finding, prompting further investigation or ✓ Cardiovascular disease—the leading cause of death among patients
referrals. with NAFLD
Because a patient with NAFLD is commonly asymptomatic,
fibrosis can progress silently over many years, and the patient
may then present with cirrhosis, termed NASH cirrhosis. With
Comorbidities Associated With NAFLD
its asymptomatic nature, NASH is a leading cause of “crypto-
genic” cirrhosis. In support of this, the prevalence of metabolic The comorbidities most commonly associated with NAFLD are the
risk factors such as type 2 diabetes and obesity is similar among components of metabolic syndrome. The most commonly used defi-
patients with cryptogenic cirrhosis and NAFLD but is less fre- nition is from the 2005 recommendations of the National Cholesterol
quent among patients with cirrhosis of other causes, suggesting Education Program (Adult Treatment Panel III) (Table 34.4). An as-
that NASH may account for a substantial proportion of cases sociated condition not included in this definition is obstructive sleep
of cryptogenic cirrhosis. Histologic hepatic steatosis has been apnea. Of patients with NAFLD, 50% to 90% have obesity (body
Table 34.4. National Cholesterol Education Program (Adult patients undergoing coronary angiography, whether they do or
Treatment Panel III) Criteria for Metabolic Syndrome do not have diabetes, ultrasonographically confirmed presence
of NAFLD is the strongest predictor of positive results on angi-
Criteriona Definition
ography (even stronger than diabetes or smoking). Patients with
Impaired glucose tolerance Fasting plasma glucose ≥100 mg/dL carotid artery disease seen on imaging were more likely to have
Abdominal obesityb Waist circumference >102 cm for men not only increased steatosis but also more necroinflammation and
and >88 cm for women fibrosis, as confirmed with liver biopsy specimens.
Hypertriglyceridemia ≥150 mg/dL or drug treatment for high
NAFLD is associated with an increased risk of incident
triglyceride level
Low levels of HDL <40 mg/dL in men, <50 mg/dL in women, cancers, including hepatocellular carcinoma (with or without
or drug treatment for low HDL cirrhosis), colon cancer, and history of colon polyps on prior
High blood pressure ≥130/85 mm Hg or drug treatment for colonoscopy.
hypertension
Abbreviation: HDL, high-density lipoprotein. Biochemical Features

a
Patient must meet 3 or more of these criteria. The level of serum liver enzymes (ALT or AST or both) may
b
The International Diabetes Federation uses the same criteria but defines the
be increased. The increase is usually less than 5-fold the ULRR.
waist circumference criteria by ethnicity: South Asian, Chinese, and South or Aminotransferase levels in patients with NAFLD fluctuate; with
Central American, 90 cm for men and 80 cm for women; Japanese, 85 cm for any 1 measurement, 70% to 80% of patients have levels less than
men and 90 cm for women; and all others, 94 cm for men and 80 cm for women. the ULRR, but with repeated measurements, increased levels are
Adapted from National Cholesterol Education Program (NCEP) Expert Panel on detected in most patients with NAFLD. However, the finding
Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Third of transaminase levels less than the ULRR does not exclude
Report of the National Cholesterol Education Program (NCEP) Expert Panel on NAFLD because disease along the entire histologic spectrum can
Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult still be present with those values. Alkaline phosphatase and γ-
Treatment Panel III) final report. Circulation. 2002 Dec 17;106(25):3143-421;
used with permission. glutamyltransferase levels may be increased modestly (generally
<3-fold the ULRR) in one-third of patients; rarely, the level of
either or both enzymes has been reported to be increased without
an increase in aminotransferase levels. Hyperbilirubinemia, low
mass index [BMI] ≥30 [calculated as weight in kilograms divided
albumin levels, or an increase in the international normalized
by height in meters squared]), 55% to 65% have dyslipidemia, and
ratio usually indicates advanced liver disease and cirrhosis.
60% to 70% have hypertension. Type 2 diabetes is present in 30% to
Serum iron test results are commonly abnormal. Ferritin levels
60% of patients with NAFLD, and, if tested, up to 50% of patients
are increased in up to 50% of patients, and transferrin saturation
with nondiabetic NAFLD may have insulin resistance. Conversely,
is increased in up to 10%. These findings may lead to confusion
up to 70% of patients with type 2 diabetes have ultrasonographic
about a diagnosis of hemochromatosis. The presence of hetero-
evidence of NAFLD (86% have normal levels of liver enzymes).
zygous HFE gene variants does not appear to be associated with
A separate study showed that 87% of patients with type 2 diabetes
hepatic iron loading or liver fibrosis. Testing for antinuclear anti-
and fatty infiltration who underwent biopsy had histologic con-
body or anti–smooth muscle antibody (or both) is recommended
firmation of NAFLD. Almost 50% of patients with NAFLD have
for screening for autoimmune hepatitis in patients with chron-
metabolic syndrome (ie, ≥3 features of the syndrome). Also, about
ically increased enzyme levels. Although serum autoantibodies
75% of lean patients (BMI <25) with NAFLD have at least 1 feature
are present in 23% to 36% of patients with NAFLD, liver biopsy
of metabolic syndrome. More than 80% of patients with metabolic
features help to exclude the diagnosis of autoimmune hepatitis in
syndrome have steatosis on ultrasonography.
most patients with NAFLD who have a positive test for antinu-
Most patients with NAFLD who have a BMI of 30 or more also
clear antibody or anti–smooth muscle antibody (or both).
meet the criteria for central obesity, as defined by waist circumfer-
ence (Table 34.4). The presence and severity of NAFLD correlate
more strongly with central obesity than with BMI, which emphasizes Imaging Features
the importance of visceral adiposity in steatosis development. BMI Ultrasonography, CT, and magnetic resonance imaging (MRI)
is not an accurate measure of visceral obesity; some patients with can be used to noninvasively diagnose fatty infiltration of the
NAFLD have a BMI less than 30 and still have central obesity. liver. Hepatic steatosis causes increased echogenicity on ultra-
The degree of obesity can be difficult to quantify in patients sonography, which can be compared with the lower echogenicity
with liver disease. BMI can be affected also by the fluid volume of the spleen or kidney cortex (Figure 34.1). The use of ultra-
status of a patient with cirrhosis where the presence of ascites and sonography for detecting hepatic steatosis (≥30% of hepatocytes
edema must be accounted for clinically in the weight used for cal- must be steatotic) has a sensitivity of 80% to 94% and a speci-
culation. Although waist circumference is a better measure than ficity of 88% to 95%. If patients have morbid obesity, the sensi-
BMI in patients without cirrhosis, it is of limited value in patients tivity decreases to 49% and the specificity decreases to 75%. If
with ascites. detected with ultrasonography, fatty infiltration is highly likely to
NAFLD is not only intricately tied to metabolic syndrome but be present, but if fatty infiltration is not detected with ultrasonog-
also to overt cardiovascular disease (and vice versa), which is the raphy, the diagnosis should not be ruled out.
leading cause of death among patients with NAFLD. NAFLD has On noncontrast CT images, hepatic steatosis has a low atten-
been linked to increased cardiovascular disease that is independent uation and appears darker than the spleen (Figure 34.2). The sen-
of metabolic syndrome in populations of patients without obesity sitivity of CT for detection of hepatic steatosis of more than 33%
and without type 2 diabetes. Among patients who have diabetes, is as high as 93%, with a positive predictive value of 76%. Both
those who have NAFLD have higher prevalence rates of cardi- phase-contrast MRI techniques and magnetic resonance (MR)
ovascular disease than those who do not have NAFLD. Among spectroscopy are reliable for detecting steatosis and offer good
Figure 34.1. Ultrasonographic Findings in Hepatic Steatosis. A,

Normal liver has distinctive vascular features. B, Liver with fatty infil-
tration has a diffuse bright echotexture and blurring of hepatic vessels.
correlation with the volume of liver fat. A liver fat content of

more than 5% apparent on MR spectroscopy indicates steatosis.
MRI-derived proton density fat fraction allows for fat mapping Figure 34.2. Features of Hepatic Steatosis Visualized With
of the entire liver with results closely correlated to those of liver Computed Tomography. A, Normal liver has no attenuation of the
signal compared with the spleen. B, Liver with fatty infiltration has an
biopsies. Studies have shown superiority to biopsy, which is
attenuated signal compared with the spleen.
subject to heterogeneity of the tissue, in evaluating liver fat con-
tent. Routine application of MRI is limited by cost and lack of
availability. hepatocytes, forming a lesion termed satellitosis, which is more
commonly seen in alcohol-related hepatitis. Portal inflammation
is also seen but is generally mild and lymphocyte predominant.
Histologic Features
Severe portal inflammation should prompt a search for concomi-
Histologically, NAFLD is indistinguishable from liver damage that tant liver disease, including hepatitis C and autoimmune hepatitis.
results from alcohol-induced liver injury. Liver biopsy features in- Ballooned hepatocytes are characterized by ubiquitination and
clude steatosis, mixed inflammatory cell infiltration, hepatocyte subsequent destruction of keratin cytoskeleton (forming keratin-
ballooning and necrosis, glycogenated nuclei, Mallory- Denk empty cells), the accumulation of fat droplets, and Mallory-Denk
bodies, and fibrosis. The presence of steatosis alone or in com- bodies. These hepatocytes are typically noted in zone 3 and are
bination with the other features accounts for the wide spectrum 2 to 3 times larger than surrounding steatotic hepatocytes. In
of NAFLD (Figure 34.3). Steatosis is present predominantly as about half the adult patients who have NAFLD, Mallory-Denk
macrovesicular fat, although some hepatocytes may show an ad- bodies are found in ballooned hepatocytes in zone 3, but they are
mixture with microvesicular steatosis. Fatty infiltration that is neither unique nor specific for NAFLD. The pattern of fibrosis
mild is concentrated typically in acinar zone 3; moderate to severe is a characteristic feature of NAFLD. Collagen is laid down
fatty infiltration shows a more diffuse distribution. Inflammation first in the pericellular space around the central vein and in the
in NASH is predominantly lobular and consists of mixed inflam- perisinusoidal region in zone 3. In some areas, the collagen fibers
matory cell infiltrates (neutrophils, lymphocytes, eosinophils, and invest single cells with a pattern referred to as chicken-wire fi-
infiltrating macrophages). Neutrophils can surround ballooned brosis, as described in alcohol-induced liver damage. This pattern
Figure 34.3. Liver Biopsy Specimens. A, Bland steatosis. Steatosis is present predominantly as macrovesicular fat, although some hepatocytes
may show an admixture with microvesicular steatosis (hematoxylin-eosin, original magnification ×100). B, Nonalcoholic steatohepatitis with stea-
tosis, inflammatory infiltrate, Mallory-Denk bodies, and hepatocyte ballooning (hematoxylin-eosin, original magnification ×100). C, Pericellular and
perisinusoidal fibrosis in zone 3 (Masson trichrome, original magnification ×400). D, Cirrhotic stage of nonalcoholic fatty liver disease (Masson tri-
chrome, original magnification ×100).
of fibrosis helps to distinguish NAFLD and alcohol-related liver liver biopsy or imaging tests and the appropriate exclusion of
disease from other forms of liver disease in which fibrosis shows other causes (Table 34.3). Alcohol should be excluded as the
an initial portal distribution (Figure 34.3). cause of fatty liver. Fatty liver can be induced with a minimal
Portal tracts are relatively spared from inflammation, although amount of alcohol—20 g daily (1-2 standard drinks) for women
children with NAFLD may show a predominance of portal-based and 30 g daily (2-3 standard drinks) for men—and these limits
injury instead of a lobular pericentral injury. Mallory- Denk are commonly used to distinguish between alcohol-related fatty
bodies are notably sparse or absent in children with NAFLD. In liver and NAFL. Secondary causes of steatosis (Table 34.1)
some patients with cirrhotic-stage NAFLD, the features of stea- should be excluded because steatosis associated with these
tosis and necroinflammatory activity may no longer be present. conditions has a different course and treatment.
Although liver biopsy is the gold standard for diagnosing NASH For patients with persistently increased serum levels of
and staging fibrosis, sampling variability may underestimate the liver enzymes, other causes of steatosis and other common
severity of liver injury in up to 30% of patients. causes of liver disease should be excluded by clinical re-
view and laboratory testing. With the increasing prevalence
✓ Liver biopsy is the gold standard for diagnosis of NASH, and a of NAFLD, more patients may have a second cause of liver
careful evaluation of the patient’s history is crucial to look for disease superimposed on a background of steatosis. Thus, it
secondary causes of steatohepatitis, especially alcohol intake is essential to exclude viral hepatitis, drug-induced liver dis
ease, celiac disease, autoimmune disease, vascular disease,
and metabolic diseases such as α1-antitrypsin deficiency. In a
young person, Wilson disease can manifest with steatohepatitis
Diagnosis findings on biopsy, requiring hepatic copper quantification,
The gold standard for diagnosing NAFLD is clinicopathologic slit-lamp examination, and 24-hour urine studies to rule it
correlation, which is based on the confirmation of steatosis by out. The need for a liver biopsy to establish the diagnosis of
NAFLD should be determined on an individual basis. Liver ✓ Advanced fibrosis—the most important predictor of liver-related
biopsy may be useful for diagnosing NAFLD when a poten- death
tial differential diagnosis is suggested by clinical, serologic, ✓ Diagnosis of liver fibrosis—noninvasive modalities such as scores
or biochemical testing. These situations include the presence based on blood tests (eg, FIB-4) or imaging (eg, vibration-controlled
of autoantibodies or increased iron index results, a history of transient elastography or magnetic resonance elastography) can
recent medication change, or the absence of detectable hepatic be used
steatosis on cross-sectional imaging. Also, the persistence of
increased levels of aminotransferases after 3 to 6 months of
lifestyle intervention with appropriate weight loss and control Prognosis
of lipid and glucose levels may suggest another diagnosis and
dictate the need for liver biopsy. Knowledge of the histologic subtype of NAFLD (NAFL vs
NASH) and the stage of fibrosis is useful in determining prog-
nosis and may alter clinical management. The natural history
Staging of uncomplicated hepatic steatosis is relatively benign; follow-
Liver biopsy is the gold standard investigation that can be up of 342 patients for over 15 years showed progression to cir-
used to help differentiate NASH from NAFL and to stage the rhosis and liver-related mortality in less than 1% of patients.
extent of fibrosis. Standard imaging studies such as ultraso- In contrast, NASH may progress to cirrhosis in up to 11% of
nography, CT, and MRI cannot be used to distinguish between patients, and about 7% of patients with NASH die of liver-related
steatosis and NASH nor to stage the degree of hepatic fibrosis. complications within 15 years after diagnosis. Therefore, the di-
Elastography with either ultrasound-based shear waves (transient agnosis of NASH, particularly when associated with any fibrosis,
elastography) or MR-based technology (MR elastography) can may prompt a more aggressive therapeutic approach toward met-
be used to estimate liver stiffness as a noninvasive surrogate for abolic risk factors and participation of patients in clinical trials
fibrosis. Obesity and abdominal wall thickness can limit the ef- with novel agents, if available. The presence of advanced fibrosis
fectiveness of ultrasound-based elastography because the depth or cirrhosis should initiate screening for hepatocellular carci-
of penetration is limited, but they do not seem to have a major noma and esophageal varices, with closer monitoring for disease-
effect on MR-based elastography. Vibration-controlled transient related complications.
elastography is more sensitive for distinguishing between mild
and advanced fibrosis (and results have a good correlation with Prevention
histologic findings) than for distinguishing between mild and
moderate fibrosis. The sensitivity of MR elastography is better No studies have been aimed at preventing the development of
than that of transient elastography, but cost and availability limit NAFLD. Achieving and maintaining appropriate weight con-
its widespread use. trol would be expected to prevent the development of metabolic
The potential benefits of liver biopsy must be weighed syndrome, and thus NAFLD, in many people. The treatment of
against the small risk of complications, including pain, bleeding, established glucose and lipid abnormalities may decrease the
and, rarely, death. Several clinical and laboratory features are likelihood of NAFLD or NASH, but no data exist that specifi-
recognized in association with NASH or advanced fibrosis (or cally validate this. However, data from the Diabetes Prevention
both) in patients with NAFLD, including older age, presence of Program in the US showed that both lifestyle intervention and
type 2 diabetes, higher BMI, higher AST:ALT ratio, low albumin the insulin-sensitizing drug metformin significantly decreased
level, and low platelet count. Several calculators incorporate the development of metabolic syndrome, which, intuitively, may
those features and provide an estimate of the risk of advanced prevent the development of NAFLD.
fibrosis; they include the fibrosis-4 index for liver disease, the
AST to Platelet Ratio Index, and the NAFLD fibrosis score. Treatment
Among these, the NAFLD fibrosis score has the best validation
Weight Loss
for predicting liver-related outcomes.
Advanced fibrosis in patients with NAFLD has been associ- Weight loss, particularly if gradual, may lead to improvement
ated with levels of serum markers of fibrogenesis, including hyal in the histologic features of the liver in NAFLD. Rapid weight
uronic acid, propeptide of type III collagen, and tissue inhibitor loss or very low-calorie diets may cause worsening of the his-
of matrix metalloproteinase 1. These serum markers have been tologic features and, thus, should be avoided. Weight loss of as
combined in the Enhanced Liver Fibrosis score, which is a nu- little as 5% of the baseline weight has been shown to improve
merical value that is used to predict the presence and severity of or normalize ALT levels in NASH, and a 7% to 10% decrease
liver fibrosis in NAFLD. Similarly, the FibroTest (BioPredictive; in weight produced histologic improvement at 1 year. Studies
FibroSURE in the US [LabCorp]), which has been studied ex- have shown that a rigorous lifestyle modification program is
tensively for viral hepatitis to predict the severity of fibrosis, necessary for patients to achieve successful weight loss. These
has been evaluated for NAFLD. A combination of several other modifications include the following: 1) dietary restrictions,
markers is used in the SteatoTest (BioPredictive). In addition, depending on the baseline weight (1,000-1,200 kcal daily if the
caspase-3–generated cytokeratin-18 fragments, a marker of ap- baseline weight is ≤91 kg, or 1,200-1,500 kcal daily if the base-
optosis measured in plasma, showed initial promise for distin- line weight is >91 kg), and a daily goal for grams of fat of 25%
guishing between simple steatosis and NASH that could not be of caloric requirements; 2) physical activity (goal of 10,000 steps
confirmed in large meta-analyses. Other noninvasive test results daily and 200 minutes weekly of moderate-intensity activity);
have been studied, but overall, additional validation is required and 3) weekly group sessions for behavioral modifications. With
before the markers can be used routinely in clinical practice. (For rigorous programs, which usually are accomplished through the
a summary of these tests, see the article by Anstee et al in the work of a multidisciplinary team, successful weight loss and his-
Suggested Reading list.) tologic improvement are possible.
syndrome measures and improvement in or resolution of steatosis.

Box 34.1. Therapeutic Interventions for Nonalcoholic The severity of inflammation and fibrosis seen in liver biopsy
Fatty Liver Disease specimens often improves 5 years after bariatric surgery, but both
Sufficient evidence of benefit inflammation and fibrosis worsen in some patients. For medically
Weight loss of 7%-10% of body weight
complicated obesity, bariatric surgery should be considered.
In addition to weight loss, treatment of patients with NAFLD
Nonsurgical—caloric restriction, 10,000 steps daily,
should include management of cardiovascular comorbidities and
and 200 min weekly of moderate-intensity exercise
obstructive sleep apnea and age-appropriate cancer screening. 3-
Surgical—bariatric surgery Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors are
Vitamin E safe to use in patients with NAFLD. Patients with comorbid dia-
Pioglitazone betes may benefit from glucagon-like peptide-1 (GLP-1) agonist
Insufficient evidence but possible benefit therapy for glycemic control, reduction in liver fat, and histologic
Rosiglitazone
improvement in NASH.
Metformin ✓ First-line management of NAFLD—lifestyle interventions that
Statins include dietary restriction and regular physical activity with or
Fish oil without weight loss
✓ Bariatric surgery improves all histologic features of NASH and
Angiotensin-converting enzyme inhibitors liver fibrosis
Angiotensin II receptor blockers
Pentoxifylline
Coffee (regular, not espresso) Nonpharmacologic Treatment
Milk thistle Caffeine from regular coffee (not espresso) has been associ-
Probiotics with or without prebiotics ated with reduced fibrosis progression in patients with estab-
Ongoing select clinical drug trials lished NASH. Two studies confirmed that more than 2 cups
Obeticholic acid of coffee daily potentially affected disease progression fa-
Tropifexor vorably. In a meta-analysis of 8 randomized controlled trials
evaluating silymarin, an active ingredient extracted from the
Lanifibranor
seeds of milk thistle, AST and ALT levels improved in the
Semaglutide treatment groups compared to control groups and compared
Aramchol to other interventions, which included simvastatin, vitamin E,
NGM282 (engineered human hormone FGF19) pioglitazone, and gankangyin.
Pegbelfermin (pegylated recombinant analogue Results were also favorable from the use of probiotics with or
of human FGF21) without prebiotics in 3 small, randomized studies. Thus far, their
Resmetirom (MGL-3196; oral selective THR-β agonist)
use has been associated with lower values for liver enzymes, but
histologic effects are not known. Studies are ongoing in the use of
No benefit
nutraceuticals and in targeting the microbiome as its contribution
Ursodiol in the development of NAFLD is better understood.
Betaine
Abbreviations: FGF, fibroblast growth factor; THR, thyroid hormone

Pharmacologic Treatment
receptor. Achieving and maintaining appropriate weight control is diffi-
cult for most patients who have obesity. The use of medications
to directly decrease the severity of liver damage independently of
weight loss is an attractive alternative. Medical management of
Weight loss agents such as orlistat and sibutramine produce metabolic syndrome is important, but pharmacologic therapy also
only modest weight loss (generally 3-5 kg more than placebo) at may benefit patients who do not have metabolic syndrome (Box
the expense of adverse effects. Orlistat can cause diarrhea, gas- 34.1). Until recently, the results of only pilot studies suggested
trointestinal pain, and vitamin deficiencies, and sibutramine can that insulin-sensitizer medications, antioxidants, lipid-lowering
cause hypertension and drug interactions. Rimonabant (a cannab- medications, and some hepatoprotective medications may be of
inoid type-1 receptor antagonist) produced clinically meaningful potential benefit. Most of these studies were uncontrolled, open-
weight loss and improvement in metabolic syndrome measures, label studies that lasted 1 year or less, and only a few evaluated
but it has been withdrawn from the market because of its psy- the effect of treatment on the histologic features of the liver. More
chiatric adverse effects. Newer agents recently approved by the data from phase 2 and phase 3 clinical trials are available now for
US Food and Drug Administration for weight loss (phentermine- several classes of agents, including oral hypoglycemics, vitamin
topiramate and lorcaserin) have not been studied for NAFLD. E, GLP-1 agonists, and nuclear receptor agonists.
Bariatric surgery has become one of the most common sur- A collaboration of investigators, the NASH Clinical Research
gical procedures performed in the US. Several surgical procedures Network, has found histologic benefit with vitamin E therapy (800
are available to decrease the size of the gastric reservoir (restric- IU daily) or pioglitazone therapy (30 mg once daily) over pla-
tive procedures) and to decrease intestinal absorption of nutrients cebo for patients who have NASH but not diabetes. This study,
(malabsorptive procedures). Because weight loss after these with approximately 80 patients in each treatment group followed
procedures can be extreme and rapid, careful monitoring is re- for more than 2 years, showed improvement in the serum levels of
quired. Several studies have shown improvement in metabolic aminotransferases and biopsy evidence of improved steatosis and
inflammation scores in both treatment groups compared with pla- Hepatocellular Carcinoma Screening
cebo. Improvement in the vitamin E group showed greater statistical
NAFLD is an important contributor to the burden of HCC glob-
significance, but fibrosis scores did not improve in any treatment
ally and the third most common cause of HCC in the US. In
group. Although improvement in aminotransferase levels and bi-
observational studies, the reported annual incidence of HCC
opsy findings was greater in the treatment groups, only 36% to 47%
ranges from 0.5% to 2.4%. Most HCC arises secondary to NASH
of the patients had histologic resolution of definite NASH. More
cirrhosis, and routine screening for HCC is recommended for
importantly, 30% of patients in the placebo group had elements of
patients with NASH cirrhosis. The small reported increase in
histologic improvement and 21% had histologic resolution of def-
HCC risk in patients with noncirrhotic NAFLD does not meet
inite NASH, as seen in biopsy specimens. The beneficial effects of
the threshold to justify population-based screening, although
vitamin E and pioglitazone in NASH should be weighed against
advanced fibrosis can increase patients’ risk for HCC.
the risk of serious adverse events, such as increased mortality or
increased risk of prostate cancer associated with vitamin E at a
daily dose of 400 IU or more, and weight gain, bone fractures, heart
failure, and bladder cancer associated with pioglitazone. Suggested Reading
Several drugs are currently undergoing clinical trial testing for Adams LA, Lymp JF, St Sauver J, Sanderson SO, Lindor KD,
efficacy in NAFLD. Obeticholic acid, an FXR agonist administered Feldstein A, et al. The natural history of nonalcoholic fatty liver
at 25 mg daily, has been shown in trials to improve liver histology, disease: A population-based cohort study. Gastroenterology. 2005
including steatosis, inflammation, and fibrosis, and to improve Jul;129(1):113–21.
NAFLD activity scores without worsening fibrosis. This effect Angulo P, Hui JM, Marchesini G, Bugianesi E, George J, Farrell
size was similar to that achieved with vitamin E. Adverse effects GC, et al. The NAFLD fibrosis score: A noninvasive system that
identifies liver fibrosis in patients with NAFLD. Hepatology. 2007
of this medication include pruritus, which is dose dependent, and
Apr;45(4):846–54.
dyslipidemia, which can be treated with statins. Anstee QM, Lawitz EJ, Alkhouri N, Wong VW, Romero-Gomez M,
In recent years, several lead agents did not meet predetermined Okanoue T, et al. Noninvasive tests accurately identify advanced
primary end points in phase 3 clinical trials. These include fibrosis due to NASH: Baseline data from the STELLAR trials.
elafibranor, a dual agonist of peroxisome proliferator-activated re- Hepatology. 2019 Nov;70(5):1521–30.
ceptor (PPAR)-α and PPAR-δ; selonsertib, an inhibitor of apoptosis Chalasani N, Younossi Z, Lavine JE, Charlton M, Cusi K, Rinella M,
signal-regulating kinase 1; simtuzumab, an anti–lysyl oxidase-like et al. The diagnosis and management of nonalcoholic fatty liver
2 monoclonal antibody; and emricasan, a pan-caspase inhibitor. disease: Practice guidance from the American Association for the
Despite these setbacks, the drug pipeline for NASH is robust with Study of Liver Diseases. Hepatology. 2018 Jan;67(1):328–57.
several agents in phase 2 or phase 3 clinical trials. Some of the Cotter TG, Rinella M. Nonalcoholic fatty liver disease 2020: The state of
the disease. Gastroenterology. 2020 May;158(7):1851–64.
mechanisms include FXR agonists, pan-PPAR agonists, fibroblast
Ekstedt M, Franzen LE, Mathiesen UL, Thorelius L, Holmqvist M,
growth factor analogues, GLP-1 agonists, inhibitors of fatty acid Bodemar G, et al. Long-term follow-up of patients with NAFLD and
synthesis, and thyroid receptor-β agonists. Trial designs incorpo- elevated liver enzymes. Hepatology. 2006 Oct;44(4):865–73.
rate both single agents and combinations of agents. The heteroge- Eslam M, Sanyal AJ, George J, International Consensus P.
neity in drug mechanisms of action that may be effective in NASH MAFLD: A consensus-driven proposed nomenclature for metabolic
underscores the heterogeneity in the pathogenesis. associated fatty liver disease. Gastroenterology. 2020 May;158(7):
A meta-analysis of all NASH placebo-controlled trials reported 1999–2014.
that up to 30% of patients receiving placebo may have had modest Friedman SL, Neuschwander-Tetri BA, Rinella M, Sanyal AJ. Mechanisms
histologic improvement. Previously, it was determined that up to of NAFLD development and therapeutic strategies. Nat Med. 2018
20% to 30% of liver biopsy specimens may be understaged by sam- Jul;24(7):908–22.
Kang JH, Cho KI, Kim SM, Lee JY, Kim JJ, Goo JJ, et al. Relationship
pling error. Thus, it cannot be overstated that NASH studies need to
between nonalcoholic fatty liver disease and carotid artery atheroscle-
be placebo-controlled to assess the true benefit of any agent studied. rosis beyond metabolic disorders in non-diabetic patients. J Cardiovasc
For patients with cirrhotic-stage NAFLD and decompensated Ultrasound. 2012 Sep;20(3):126–33.
disease, liver transplant is a potentially life-extending therapeutic Lassailly G, Caiazzo R, Buob D, Pigeyre M, Verkindt H, Labreuche
alternative. However, some patients with cirrhotic-stage NAFLD J, et al. Bariatric surgery reduces features of nonalcoholic
have comorbid conditions, including type 2 diabetes, cardio- steatohepatitis in morbidly obese patients. Gastroenterology. 2015
vascular disease, hepatocellular carcinoma (HCC), and other Aug;149(2):379–88.
cancers, that may limit their candidacy for liver transplant. Newsome PN, Buchholtz K, Cusi K, Linder M, Okanoue T, Ratziu
V, et al. A placebo-controlled trial of subcutaneous semaglutide
✓ Therapy for NASH in nonalcoholic steatohepatitis. N Engl J Med. 2021 Mar
• No US Food and Drug Administration–approved pharmacothe 25;384(12):1113–24.
rapies Sanyal AJ, Chalasani N, Kowdley KV, McCullough A, Diehl AM, Bass
• Oral vitamin E can be used in patients without type 2 diabetes NM, et al. Pioglitazone, vitamin e, or placebo for nonalcoholic
who have biopsy-proven NASH steatohepatitis. N Engl J Med. 2010 May 6;362(18):1675–85.
• Pioglitazone (PPAR-γ agonist) or liraglutide (GLP-1 agonist) Sanyal AJ, Van Natta ML, Clark J, Neuschwander- Tetri BA, Diehl
can be considered for patients with type 2 diabetes who have A, Dasarathy S, et al. Prospective study of outcomes in adults
biopsy-proven NASH with nonalcoholic fatty liver disease. N Engl J Med. 2021 Oct
✓ For any patient with NAFLD, statins are safe to use, and intake 21;385(17):1559–69.
of regular coffee (not espresso) may have a favorable effect on Welsh JA, Karpen S, Vos MB. Increasing prevalence of nonalcoholic
disease progression fatty liver disease among United States adolescents, 1988-1994 to
2007-2010. J Pediatr. 2013 Mar;162(3):496–500.
35
Liver Disease in Pregnancya,b

PROWPANGA UDOMPAP, MD
ALINA M. ALLEN, MD
Because most pregnant women are young and healthy, liver with a clinical significance that varies from self-limiting to rap-
disease is uncommon in this population. Also, the presence of idly fatal.
liver disease must not be confused with some of the physiologic For diagnostic purposes, it is useful to divide liver diseases
changes of pregnancy that mimic features commonly associated in pregnant women into 3 main categories (Box 35.1): 1) liver
with liver dysfunction (Table 35.1). Examples of physiologic diseases unique to pregnancy, 2) preexisting liver disease before
changes include spider angioma and palmar erythema, which may pregnancy, and 3) coincidental liver diseases that are discovered
occur in half the pregnant women because of the hyperestrogenic during pregnancy.
state, increased serum alkaline phosphatase level from placental Within the framework of these 3 categories, the gestational
production, and decreased albumin and hemoglobin levels with age is used as a guide in the differential diagnosis of liver dis
volume expansion. Increased bilirubin and transaminase levels, ease in pregnancy. Coincidental liver disease and preexisting
hepatomegaly, splenomegaly, liver tenderness, and bruits do not liver diseases can occur at any point in pregnancy. However, the
occur in normal pregnancy, and the clinical finding of jaundice is liver diseases unique to pregnancy are related to gestational age
always abnormal. Abnormal liver test results occur in about 3% (Figure 35.1). Liver enzyme levels are variable in all diseases and
to 5% of pregnant women, and jaundice occurs in about 0.1%,
Table 35.1. Physiologic Changes in Liver-Related

Laboratory Test Results During Pregnancy
a
Portions of this chapter were adapted from Shams M. Update in liver
diseases with pregnancy. J Gastroenterol Hepatol Res. 2013 2(2):391-8; Test Change
used under Creative Commons Attribution License (https://creative Bilirubin Unchanged
commons.org/licenses/by/3.0/) AST and ALT Unchanged
b
The authors thank J. Eileen Hay, MB, ChB, who authored the previous Alkaline phosphatase Increased
version of this chapter. Prothrombin time Unchanged
Fibrinogen Increased
Abbreviations: AFLP, acute fatty liver of pregnancy; ALT, alanine
Globulin
aminotransferase; AST, aspartate aminotransferase; CMV, cytomega-
α-Globulin Increased
lovirus; DAA, direct-acting antiviral; DIC, disseminated intravascular
β-Globulin Increased
coagulation; DILI, drug-induced liver injury; EBV, Epstein-Barr virus;
γ-Globulin Unchanged
HBeAg, hepatitis B e antigen; HBIG, hepatitis B immunoglobulin; HBV,
Alpha fetoprotein Increased
hepatitis B virus; HCV, hepatitis C virus; HELLP, hemolysis, elevated
Leukocytes Increased
liver enzymes, and low platelet count; HG, hyperemesis gravidarum; Ceruloplasmin Increased
HSV, herpes simplex virus; ICP, intrahepatic cholestasis of pregnancy; Cholesterol Increased
LCHAD, long-chain 3-hydroxyacyl–coenzyme A dehydrogenase; LDH, Triglyceride Increased
lactate dehydrogenase; MELD, Model for End- stage Liver Disease;
UDCA, ursodeoxycholic acid; ULRR, upper limit of the reference range Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase.
391
between 4 and 10 weeks of gestation. This condition usually

Box 35.1. Liver Diseases Occurring During Pregnancy resolves by the 20th week of gestation, although up to 20% of
Diseases unique to pregnancy pregnant women can have symptoms throughout the pregnancy.
The diagnosis of HG is made on clinical grounds prima-
Hyperemesis gravidarum
rily. According to the UK Royal College of Obstetricians and
ICP Gynaecologists guidelines, the diagnosis should be based on the
Preeclamptic liver dysfunction triad of weight loss of at least 5%, electrolyte imbalance, and
HELLP syndrome dehydration. Increased transaminase values are present in ap-
Acute fatty liver of pregnancy proximately 50% of patients, yet the degree of transaminase
Preexisting diseases abnormalities is not diagnostic for this condition and can be
as high as 20-fold above the upper limit of the reference range
Viral hepatitis
(ULRR). If transaminase levels are high, serologic testing for
Autoimmune liver disease viral hepatitis should be performed. Rarely a patient requires
Primary biliary cholangitis a liver biopsy to exclude more severe disease; the histologic
Primary sclerosing cholangitis appearance of the liver is generally normal but may show ne-
Wilson disease crosis, steatosis, and bile plugs. Despite high transaminase levels,
no inflammation or notable necrosis is observed.
Cirrhosis from any cause
Coincidental diseases
Viral hepatitis Management
Gallstone-related disease Supportive and symptomatic management is a mainstay of
DILI therapy for this condition. Pyridoxine or alternative medicine (eg,
acupressure, ginger capsule, antihistamine, antiemetics, and do-
Budd-Chiari syndrome
pamine agonists) can be used for nausea control. Hospitalization
Abbreviations: DILI, drug-induced liver injury; HELLP, hemolysis, might be necessary for treatment with intravenous hydration,
elevated liver enzymes, and low platelet count; ICP, intrahepatic thiamine, corticosteroids, or, in severe cases, total parenteral
cholestasis of pregnancy. nutrition. Thiamine should be given to all women admitted
with prolonged vomiting. Referral to a psychiatrist could be
considered for mental health support because of a high rate of
suicidal ideation.
are generally not helpful in identifying the cause. The details of
each liver disease in pregnancy are discussed below. Medications Prognosis and Complications
commonly used for liver diseases are listed in Table 35.2.
HG contributes to maternal morbidity mainly through the
consequences of electrolyte abnormality (eg, arrhythmia from
Liver Diseases Unique to Pregnancy hypokalemia and encephalopathy). In addition, Wernicke en-
Five diseases unique to pregnancy primarily or secondarily affect cephalopathy can result from thiamine deficiency. HG can also
the liver. Each has characteristic clinical features and timing of heighten the suicidal ideation.
onset in relation to pregnancy: hyperemesis gravidarum (HG); For infants, HG is not associated with adverse prenatal or fetal
intrahepatic cholestasis of pregnancy (ICP); acute fatty liver of outcomes. However, it could lead to low gestational weight gain,
pregnancy (AFLP); preeclampsia; and hemolysis, elevated liver which is associated with low birth weight and premature delivery.
enzymes, and low platelet count (HELLP) syndrome. In addition, the recurrence rate is high (approximately 64% in
subsequent pregnancies).
Hyperemesis Gravidarum
Intrahepatic Cholestasis of Pregnancy
About half of pregnant women have mild nausea and vomiting,
which is transient and does not cause weight loss. However, HG ICP is characterized by severe pruritus, mild jaundice, and
is defined as excessive intractable nausea and vomiting in the first cholestasis in the second half of pregnancy, and it disappears after
trimester or the first part of the second trimester that result in de- delivery. However, these features typically recur in subsequent
hydration and weight loss. pregnancies. ICP is second only to viral hepatitis as a cause of
jaundice in pregnant women.
Pathogenesis
Pathogenesis
The etiology of HG is multifactorial. It occurs more commonly
in parous sisters. It is also associated with a molar pregnancy, The pathogenesis of ICP is thought to be related to impaired se-
a multiple pregnancy, hyperthyroidism, and hypoadrenalism. An cretion and transport of bile acids into biliary canaliculi when
animal study showed that the genes GDF15 (OMIM 605312) and estrogen and progesterone levels are high, as evidenced by the
GFRAL (OMIM 617837) contribute to HG. temporal relationship to hormone levels in late pregnancy and
by the fact that estrogens may cause cholestasis in nonpregnant
women who have ICP when they are pregnant. These and other
Clinical Features and Diagnosis observations suggest that ICP is due to a genetically abnormal
Patients with HG typically present with persistent vomiting for or exaggerated metabolic response by the liver to the physio-
more than 1 week during the first or second trimesters, usually logic increase in estrogens during pregnancy. Impaired sulfation
35. Liver Disease in Pregnancy 393
Figure 35.1. Liver Diseases Occurring During the Trimesters of Pregnancy. AFLP indicates acute fatty liver of pregnancy; HELLP, hemolysis,
elevated liver enzymes, and low platelet count.
(an important detoxification pathway) has been identified in marker of ICP is a serum level of bile acid, which is always
some patients with ICP. Abnormalities in progesterone metabo- increased in this condition (eg, 100 times above the ULRR) and
lism may occur from genetic or exogenous causes. Exogenous may correlate with fetal risk. A liver biopsy is needed only if a
progesterone therapy administered in the third trimester of more serious liver disease is strongly suspected clinically. In ICP,
pregnancy increases the serum levels of bile acid and alanine the appearance of the liver is nearly normal, with mild cholestasis
aminotransferase (ALT). Progesterone given to prevent prema- and minimal or no hepatocellular necrosis.
ture delivery can precipitate ICP in some women. Also, the clear
seasonal variability of ICP suggests that the disease is modified
Management
by exogenous factors. Dietary factors, such as selenium defi-
ciency, have been implicated in some studies from Chile. Management strategies center around controlling maternal pru-
Genetic predisposition is probably important because ICP ritus and decreasing the bile acid levels to improve the pregnancy
occurs more frequently in some ethnic groups (eg, the Mapuche outcome. Ursodeoxycholic acid (UDCA) is the most commonly
population of the Andean nations and Hispanics). Variants used agent for the treatment of ICP. Therapy with UDCA (10-20
of ABCB4 (MDR3) (OMIM 171060), the transporter for mg/kg daily; 500-2,000 mg daily) decreases the levels of liver
phospholipids across the canalicular membrane, and ABCB11 enzymes and bile acid and improves pruritus, although not all
(BSEP) (OMIM 603201) have been shown to be associated with pregnant women have remarkable improvement with UDCA.
ICP. Variants of other genes (eg, ATP8B1 [OMIM 602397], FXR UDCA has no adverse maternal or fetal effects. Other agents
[OMIM 603826], and TJP2 [OMIM 607709]) have also been re- that can control pruritus include rifampicin (US Food and Drug
ported to be associated with ICP. Administration pregnancy category C) and topical emollients.
Plasma exchange is reserved for severe cases when other options
have been exhausted.
Clinical Features and Diagnosis
Elective early delivery can be considered. The decision can be
ICP should be a strong consideration if pruritus begins at 25 to based on the bile acid levels: Delivery should be considered at 37
32 weeks of gestation without other signs of liver disease. This weeks if the bile acid level is greater than 40 µmol/L; otherwise,
is especially true if pruritus occurred in other pregnancies and delivery should be considered at 39 weeks.
then resolved immediately after delivery. In the first pregnancy,
diagnosis is generally made on clinical grounds alone and can be
confirmed with the rapid postpartum disappearance of pruritus. Prognosis and Complications
Serum bile acid concentration can be used to help diagnose ICP. Pruritus and liver dysfunction resolve immediately after de-
The pruritus affects all parts of the body, worsens at night, livery without maternal mortality, although some data show
and may be so severe that the patient has suicidal ideation. that ICP may lead to increased risk for future development of
Excoriations are usually obvious, and occasionally cholestasis hepatobiliary diseases and liver cancer. In addition, after ICP has
is complicated by diarrhea or steatorrhea. Jaundice occurs but is occurred, the recurrence rate is remarkably high (63%-90% in
less common and usually occurs after the onset of pruritus by 2 to subsequent pregnancies).
4 weeks. Jaundice without pruritus is rare. Biliary tract obstruc- Fetal complications in ICP include placental insufficiency,
tion must be excluded first. After biliary obstruction is excluded, premature labor, asphyxia, and sudden fetal death, which most
ICP is confirmed if the bile acid level is high. likely result from the increased fetal levels of bile acid due to
Variable levels of transaminases occur in ICP (from 10-to 20- increased maternal levels of bile acid and the immaturity of the
fold increases). The concentration of bilirubin usually increases fetal bile acid transport system across the placental membranes,
by less than 5 mg/dL. The serum level of alkaline phosphatase which may all contribute to increased fetal levels of bile acid
is less helpful during pregnancy. The most specific and sensitive in ICP. Fetal monitoring for chronic placental insufficiency is
Section VI. Liver
Table 35.2. Commonly Used Medications for Liver-Related Conditions and Their Compatibility With Pregnancy and Lactation
Medication FDA category Pregnancy Lactation
Anti-copper agents
d-penicillamine D May continue with dose adjustments during Compatible but limited data
pregnancy
Trientine C Compatible with dose adjustments during Compatible but limited data
pregnancy
Zinc C Compatible Compatible
Antivirals
DAAs Ledipasvir-sofosbuvir: B Not recommended (no data) Not recommended (no data)
Glecaprevir-pibrentasvir and
sofosbuvir-velpatasvir: not
assigned
Entecavir C Not recommended Not recommended
Lamivudine C Compatible on the basis of HIV data Compatible on the basis of HIV data
Pegylated interferon alfa C Use if potential benefit outweighs potential Use if potential benefit outweighs
risk potential risk
Ribavirin X Avoid Avoid
Telbivudine B Compatible Compatible
Tenofovir Tenofovir disoproxil Compatible Compatible
fumarate: B
Tenofovir alafenamide:
not assigned
Antihistamines
Chlorpheniramine B Compatible Compatible (lowest dose possible)
Diphenhydramine B Compatible Compatible (lowest dose possible)
Hydroxyzine C Compatible Compatible (lowest dose possible)
Antimicrobials
Acyclovir B Compatible Compatible
Cephalosporins (eg, B Compatible Compatible
cefotaxime, ceftriaxone)
Fluoroquinolones C Not recommended (toxic effects on cartilage Compatible, but need close
development in animal studies; arthralgias monitoring of infant GI infections
and tendonitis in adolescents) (Clostridioides difficile, Candida)
Rifampin C Compatible Compatible
Rifaximin C Not recommended (no data) Not recommended (no data)
β-Blockers
Carvedilol C Not recommended (no data) Not recommended (no data)
Nadolol C Compatible (but propranolol is preferred for Compatible (but propranolol is
its shorter half-life) preferred for its shorter half-life)
Propranolol C Compatible (some risks of intrauterine growth Compatible
restriction, neonatal respiratory depression,
and infant hypoglycemia)
Bile acid–related
Cholestyramine C Compatible Compatible
UDCA B Compatible Compatible
Vasoactive
Octreotide B Appropriate when benefits outweigh the risk Appropriate when benefits outweigh
(eg, acute variceal bleeding); otherwise, the risk (eg, acute variceal bleeding);
data are limited otherwise, data are limited
Diuretics
Furosemide C Use lowest effective dose; risk of decreasing Use lowest effective dose; may
uteroplacental circulation suppress lactation
Spironolactone C Not recommended Compatible
Immunosuppressives
Azathioprine D Compatible (benefits of controlling the Compatible
disease, especially autoimmune hepatitis,
outweigh the risks of the disease flare)
Cyclosporine C Compatible Compatible
Methylprednisolone C Can be used if benefits outweigh the risk Can be used if benefits outweigh the
risk
Mycophenolate mofetil D Avoid Not recommended (limited data)
Prednisone B Compatible Compatible
Tacrolimus C Compatible Compatible
Laxatives
Lactulose B Compatible Compatible
Abbreviations: DAA, direct-acting antiviral; FDA, US Food and Drug Administration; GI, gastrointestinal tract; UDCA, ursodeoxycholic acid.
essential but does not prevent adverse outcomes. Acute anoxic in- Prognosis and Complications
jury can be prevented only by delivery as soon as the fetus is ma- The major causes of maternal morbidity and death are hem-
ture. A bile acid level greater than 40 µmol/L at any time during orrhage, liver failure, and acute kidney injury. The maternal
pregnancy is usually associated with worse fetal outcomes. mortality rate has decreased considerably over the past sev-
eral decades. It is best predicted by the Model for End-stage
Acute Fatty Liver of Pregnancy Liver Disease (MELD) score. However, the long-term maternal
consequences of AFLP remain unclear. Women with a history of
AFLP is a rare catastrophic illness that occurs almost exclu-
AFLP should be closely monitored in a subsequent pregnancy
sively in the third trimester. The incidence of AFLP is approx-
because of the risk of recurrence, particularly among women
imately 1 in 10,000 to 1 in 20,000 deliveries. AFLP occurs with
who are heterozygous for genetic variants involved in LCHAD
microvesicular fatty infiltration of the liver that results in enceph-
deficiency.
alopathy and liver failure. Although the pathogenesis of AFLP is
Fetal and neonatal deaths are related to maternal decompensa-
different from that of preeclampsia and HELLP syndrome, pre
tion or preterm birth (or both). Infants are at risk for hypoketotic
eclampsia can be present in about 50% of the patients, making the
hypoglycemia, neuromyopathy, and sudden death, and they
diagnosis of AFLP particularly challenging.
should be evaluated for fatty acid oxidation disorders. If results
are positive, the parents should also be tested, and genetic coun-
Pathogenesis seling should be pursued. No long- term consequence is ex-
The pathogenesis of AFLP involves abnormalities in mitochon- pected in persons who do not have defects in fatty acid oxidation
drial fatty acid oxidation. Autosomally inherited genetic variations disorders.
affect the enzyme long-chain 3-hydroxyacyl–coenzyme A dehy-
drogenase (LCHAD) (eg, G1528C), resulting in LCHAD defi- Preeclamptic Liver Dysfunction and HELLP
ciency, and are associated with AFLP. AFLP tends to occur among Syndrome
persons who have the heterozygous LCHAD-related variants and
whose babies may or may not have homozygous LCHAD-related Preeclampsia is the triad of hypertension, edema, and protein-
variants. It has been speculated that maternal heterozygosity for uria from the third trimester of pregnancy through the first several
LCHAD deficiency decreases the maternal capacity to oxidize weeks post partum. The prevalence varies from 3% to 10% of
long-chain fatty acids in the liver and the placenta. pregnancies. Liver involvement occurs in approximately 10% to
20% of patients with preeclampsia. Preeclamptic liver dysfunc-
tion and HELLP syndrome are the most common causes of ab-
Clinical Features and Diagnosis normal liver test results in pregnancy, and both conditions are
Unlike patients with HELLP syndrome, 50% of patients with within the spectrum of preeclampsia.
AFLP are nulliparous. Patients usually present with nonspe-
cific symptoms (eg, vomiting, abdominal pain, polydipsia and
Pathogenesis
polyuria, and jaundice). Laboratory results may show increased
levels of transaminases and bilirubin (usually up to 5 mg/dL), The pathophysiology of preeclampsia appears to involve
leukocytosis, thrombocytopenia, and acute kidney injury. These placental hypoperfusion (from shallow placental implan-
signs and symptoms can be seen in patients with preeclampsia tation), which affects the remodeling of spiral arteries and
or HELLP syndrome. However, several other features that are leads to hypoperfusion and increased placental oxidative stress.
highly suggestive of AFLP include encephalopathy, hypogly- The result is systemic vasoconstriction and endothelial dys-
cemia, coagulopathy, increased urate level, ascites or bright liver function, which cause fibrin thrombi deposition and ischemic
on ultrasonography, and microvesicular steatosis on liver biopsy necrosis.
(but liver biopsy is not required for the diagnosis). At least 6 of
the features mentioned above, in the absence of another explana- Clinical Features
tion, support the diagnosis of AFLP (according to the Swansea
criteria). In addition, liver test abnormalities are common in Patients with preeclampsia tend to present with nonspecific
AFLP. Therefore, patients should undergo testing for other causes symptoms, such as headache, nausea and vomiting, flulike illness,
of acute liver injury unrelated to pregnancy (eg, viral hepatitis and abdominal pain. Jaundice is uncommon (≤5% of patients).
and drug-induced liver injury). Aspartate aminotransferase (AST) and ALT can be mildly ele-
vated or extremely high (>1,000 U/L). Total bilirubin is usually
less than 5 mg/dL. Disseminated intravascular coagulation (DIC)
Management is uncommon in patients who have preeclampsia or eclampsia
AFLP is an obstetric emergency. Early recognition of AFLP, alone, but it occurs more frequently in patients with HELLP.
with immediate delivery of the newborn and intensive sup- Liver biopsy is not required for the diagnosis, but, if performed,
portive care, is essential for the survival of both the mother and it would be expected to show periportal hemorrhage and fibrin
the newborn. Recovery before delivery has not been reported. deposition.
Transaminase levels and encephalopathy usually start to im- Hepatic infarction or hematoma can occur and should be
prove by 2 to 3 days after delivery. However, full recovery can suspected in patients with severe abdominal pain in the right upper
take months. Patients should be transferred to a liver transplant quadrant or sudden increases in transaminase levels. Imaging
center for consideration of liver transplant if they are critically ill should be performed. Liver rupture, a rare but life-threatening
at presentation, if they have complications (eg, encephalopathy, condition, usually is preceded by an intraparenchymal hemor-
hypoglycemia, coagulopathy, or bleeding), or if their clinical rhage that progresses to a contained subcapsular hematoma and
condition deteriorates despite emergency delivery. then intraperitoneal rupture.
Criteria for Diagnosis an increased lifetime risk of cardiovascular disease, including

Preeclamptic liver dysfunction is diagnosed when the criteria major adverse cardiovascular events and stroke.
for preeclampsia are fulfilled (hypertension with systolic blood
pressure ≥140 mm Hg or diastolic blood pressure ≥90 mm Hg; Preexisting Liver Disease
edema; and proteinuria after gestational age of 20 weeks or Before Pregnancy
within the first several weeks post partum) and the patient has
Chronic Hepatitis B
increased levels of liver enzymes or bilirubin.
The degree of increase in the level of liver enzymes or bilirubin Pregnancy does not increase the maternal risk of complications
does not help distinguish between preeclamptic liver dysfunction from hepatitis B if the infection is well controlled. Transmission
and HELLP syndrome because the ranges are wide, and there of hepatitis B virus (HBV) is not transplacental but occurs at de-
are no specific cutoffs. The Tennessee Classification System for livery. The risk of maternal-fetal transmission is approximately
the diagnosis of HELLP syndrome uses the following criteria: 1) 90% if the mother tests positive for hepatitis B e antigen (HBeAg)
lactate dehydrogenase (LDH) 600 IU/L or greater; 2) AST 70 U/ and 10% to 40% if the mother tests negative. Whether the mother
L or greater; and 3) platelets 100×109/L or less. Patients could be tests positive or negative for HBeAg, immunoprophylaxis with
considered to have partial HELLP if they have 1) LDH 600 IU/L hepatitis B immunoglobulin at birth for the baby decreases the
or greater; 2) AST 40 U/L or greater; and 3) platelets 150×109/L risk of maternal-fetal transmission to approximately 26%, and
or less. Prothrombin time, activated partial thromboplastin time, hepatitis B vaccination as well as hepatitis B immunoglobulin
and fibrinogen levels are usually normal, but DIC may occur even (HBIG) at birth could decrease the risk further to as low as 3%.
with these normal values. If patients meet the criteria for HELLP The risk for vertical transmission varies with the level of HBV
syndrome, liver imaging is indicated to screen for liver rupture, DNA. If the maternal HBV DNA level is greater than 106 copies/
subcapsular hematomas, intraparenchymal hemorrhage, or liver mL (>200,000 IU/mL), antiviral therapy should be initiated be-
necrosis. These abnormalities may be consistent with the platelet cause the risk of vertical transmission will remain high despite
count but not with abnormal liver values. the use of immunoprophylaxis. In addition, antiviral treatment
should be started in patients with liver injury, including advanced
fibrosis or cirrhosis, despite the lower level of HBV DNA.
Management
Antiviral treatment (eg, tenofovir, telbivudine, or lamivudine)
The recommended preventive approach is to start low-dose as- should be started in the third trimester or by approximately 28
pirin (81 mg) at a gestational age of approximately 12 to 16 weeks weeks of gestation, and consideration should be given to stopping
and continue until delivery. However, once preeclampsia occurs, therapy 3 months after delivery if patients do not have cirrhosis,
the mainstay management is blood pressure control, seizure pre- with close monitoring for flare (Figure 35.2). The data on mode
vention, DIC treatment if indicated, and prompt delivery if the of delivery are limited. The benefits of cesarean delivery for
patient meets the criteria for severe preeclampsia or HELLP. If decreasing vertical transmission are controversial. All infants
hepatic infarction or hematoma occurs, it is managed conserva- require the HBV vaccination series and HBIG within 12 hours
tively in hemodynamically stable patients, but all patients need of birth. Breastfeeding is not contraindicated for mothers with
close hemodynamic monitoring in an intensive care unit. If liver chronic hepatitis B.
necrosis or hepatic rupture eventually leads to liver failure, liver
transplant should be considered.
In most patients, HELLP syndrome resolves rapidly after de- Chronic Hepatitis C
livery. The platelet count usually normalizes within 5 days. If In a woman who has chronic hepatitis C and is pregnant, liver
improvement is not apparent within 72 hours after delivery, plas- enzyme levels may decrease during pregnancy, while hepatitis
mapheresis could be considered, particularly if the patient’s con- C virus (HCV) RNA levels may increase. The risk of vertical
dition worsens. transmission is approximately 5%, but the risk increases to 10%
to 15% for mothers who have HIV coinfection or who are active
Prognosis and Complications intravenous drug users. Recent data showed that no vertical trans-
mission occurred in patients with HCV RNA less than 3.5 log10
Preeclampsia leads to high rates of maternal and fetal IU/mL, while the odds of vertical transmission increased at least
complications. Serious maternal complications are common 3-fold in those with HCV RNA of 6 log10 IU/mL or more. In
in HELLP syndrome, including DIC, abruptio placentae, addition, HCV viremia was associated with adverse pregnancy
acute kidney failure, pulmonary edema, and liver failure. Fetal outcomes (eg, preterm delivery, ICP, and postpartum hemor-
complications include preterm delivery and fetal loss. However, rhage). Treatment of hepatitis C with direct- acting antivirals
once delivered, most babies do well. (DAAs) is recommended before or after pregnancy. Breastfeeding
Survival depends on rapid and aggressive medical manage- is not contraindicated for mothers with chronic hepatitis C.
ment and immediate surgery, although the best surgical man-
agement is still debated. Preoperatively, aggressive supportive
management is essential for hypovolemia, thrombocytopenia, Autoimmune Hepatitis
and coagulopathy. Maternal mortality from liver rupture is high Autoimmune liver disease can flare during or after pregnancy be-
(50%), and perinatal mortality rates are 10% to 60%, mostly from cause of changes in the activity of the immune system. Therefore,
placental rupture, intrauterine asphyxia, or prematurity. Recurrent pregnant women must continue therapy to maintain remission.
preeclampsia is common, particularly in patients with early-onset Azathioprine therapy in pregnancy has not been associated with
preeclampsia. The risks of preterm delivery, intrauterine growth increased fetal risk, and patients should continue treatment
retardation, and abruptio placentae are also heightened in subse- to maintain remission. Mycophenolate mofetil, however, is
quent pregnancies. In addition, women with preeclampsia have contraindicated during pregnancy because it has teratogenic
Figure 35.2. Management of Hepatitis B in a Pregnant Woman. For patients without cirrhosis, testing should include tests for hepatitis B e an-
tigen, hepatitis B e antibody, hepatitis B virus (HBV) DNA, and alanine aminotransferase at baseline and at 28 weeks. HBsAg+indicates positive results
for hepatitis B surface antigen. (Data from Ayoub WS, Cohen E. Hepatitis B management in the pregnant patient: an update. J Clin Transl Hepatol.
2016 Sep;4[3]:241-7.)
effects, so the therapy should be switched to other agents before a the mainstay. It is safe and should be continued throughout the
patient is pregnant. The best pregnancy outcomes are associated pregnancy.
with autoimmune hepatitis that has been adequately controlled
for at least 12 months.
Other Liver Diseases
Patients with Dubin- Johnson syndrome or benign recurrent
Wilson Disease intrahepatic cholestasis may become more jaundiced during preg-
Patients with Wilson disease must receive adequate treatment nancy, especially in the second and third trimesters. It is still cru-
before pregnancy and continue receiving therapy throughout cial to rule out other possible causes when jaundice occurs. Also,
pregnancy. Cessation of treatment during pregnancy can lead to symptomatic therapy for pruritus should be provided. Gilbert
fulminant Wilson disease and acute liver failure. Although data syndrome and Rotor syndrome are unaffected by pregnancy.
showed teratogenic effects in animal studies, d-penicillamine
and trientine are safe in clinical practice. The dosages of both
Pregnancy and Cirrhosis
medications should be decreased by 25% to 50% (750-1,000 mg
daily of d-penicillamine or trientine during the first and second Successful pregnancies are possible in patients with well-
trimesters; 500 mg daily during the third trimester). Patients compensated cirrhosis. Most patients with advanced cirrhosis
should not breastfeed while they are receiving d-penicillamine. are amenorrheic and infertile because of hypothalamopituitary
dysfunction, but if pregnancy does occur, the risk of maternal
and fetal problems can be expected to increase. Plasma volume
Cholestatic Liver Disease expansion and increased intra-abdominal pressure can lead to
Pregnant women with a history of primary biliary cholangitis increased portal pressure and, therefore, to a heightened risk of
or primary sclerosing cholangitis generally do well throughout variceal bleeding during pregnancy. MELD scores greater than
pregnancy. They may have a worsening of pruritus, jaundice, and 10 also predict hepatic decompensation during pregnancy.
cholangitis because of gallstones or biliary strictures. Preterm All pregnant patients with cirrhosis should undergo upper en-
delivery and ICP that occurred in a cohort study seemed to be doscopy for esophageal variceal screening and treatment as indi-
associated with peak maternal bile acid level. UDCA therapy is cated. Abdominal ultrasonography should be used to screen for
splenic artery aneurysm, which could be fatal if it ruptured. Acute
variceal bleeding is managed endoscopically in the same way as should not be used. Other details of chronic hepatitis B and hep-
for nonpregnant patients, although vasoconstrictive medications atitis C infection are discussed above.
may induce uterine contraction, decrease uterine blood flow, and
lead to placental abruption and spontaneous abortion. Therefore,
those medications should be avoided. Octreotide, however, can Nonhepatotropic Viruses
be used. Ascites and hepatic encephalopathy are treated similarly The 3 nonhepatotropic viruses most likely to affect pregnancy
as in nonpregnant patients, except that the use of spironolactone, are herpes simplex virus (HSV), Epstein-Barr virus (EBV), and
rifaximin, and prophylactic antibiotics should be avoided. cytomegalovirus (CMV).
Vaginal deliveries with an assisted, short second stage are Herpes simplex hepatitis is a rare condition; however, it must
preferable because abdominal surgeries should be avoided. be diagnosed because it can lead to liver failure and death. In
However, for patients who are known to have large varices, pregnant women, it typically occurs as a primary infection in
cesarean delivery is recommended to avoid labor and, thus, to the third trimester and has systemic features with a prodrome of
prevent an increase in portal pressure and in the risk of variceal fever, diffuse vesicular rash, leukopenia, vulvar or oropharyn-
bleeding. The risk of postpartum hemorrhage and bacterial in- geal vesicular lesions, and coagulopathy. These patients usu-
fection is decreased when the patient receives therapy to correct ally do not have icterus even if they have liver failure. Serology
coagulopathy and antibiotic prophylaxis. testing, HSV polymerase chain reaction, or liver biopsy may
be necessary to diagnose herpes simplex hepatitis. All patients
Pregnancy in the Liver Transplant Recipient with herpes simplex hepatitis should be treated with intravenous
acyclovir.
A pregnant liver transplant recipient requires specialized care. For patients with EBV or CMV infection, serologic testing for
With the success of liver transplant, more liver transplant the viruses should be performed for pregnant patients who have
recipients are becoming pregnant, and a carefully planned preg- acute jaundice, and serologic testing should also be performed
nancy in a clinically stable, healthy patient at least 1 or 2 years for hepatitis A, B, and C. Congenital fetal malformations tend to
after orthotopic liver transplant can have excellent outcomes for occur only with early CMV infection.
the fetus, mother, and graft. However, the pregnancy still has a
high risk of increased fetal prematurity and dysmaturity. Also,
the allograft has some risk from acute cellular rejection or re- Gallstones and Biliary Disease
current viral hepatitis. Consequently, immunosuppression must
Increased lithogenicity of bile and biliary stasis during preg-
be monitored closely and the calcineurin inhibitor doses must
nancy predispose pregnant women to enhanced formation of
be adjusted as needed for increased blood volume in the second
biliary sludge and stones. Despite their prevalence, sympto-
half of pregnancy. Mycophenolate mofetil should never be used
matic gallstones occur in only 0.1% to 0.3% of pregnancies, and
in women contemplating pregnancy or who are pregnant. Liver
symptoms usually develop after multiple pregnancies rather than
biochemistry values must be monitored regularly, and all liver
during gestation. The common clinical presentations are biliary
abnormalities must be investigated.
colic and gallstone pancreatitis; less commonly, acute cholecys-
titis occurs. Clinical features of biliary disease and pancreatitis
Coincidental Liver Diseases Discovered are the same as in nonpregnant patients. The diseases can also
During Pregnancy occur at any time during gestation, and they may recur during
Viral Hepatitis pregnancy.
Intractable biliary colic, severe acute cholecystitis not
Hepatotropic Viruses responding to conservative measures, and acute gallstone pan-
Hepatitis A, B, and C occur with the same frequency in pregnant creatitis are indications for immediate cholecystectomy despite
and nonpregnant populations and during each trimester of preg- the patient’s pregnant state. For acute biliary colic or acute cho-
nancy. Hepatitis D is rare. Hepatitis E is rare in the US, but it is en- lecystitis, conservative therapy (bed rest, intravenous fluids, and
demic in large areas of Asia, Africa, and Central America, where, antibiotics) is instituted initially and successfully in more than
in the third trimester of pregnancy, the infection can become ful- 80% of patients with no fetal or maternal mortality. However,
minant and carry a high mortality rate. The serologic course of because symptoms recur during pregnancy in about 50% of
acute hepatitis in pregnant women is the same as in nonpregnant patients, cholecystectomy is indicated for all patients with
patients with the exception of hepatitis E as mentioned above. In symptoms in the second trimester. For these patients, the op-
general, viral hepatitis does not adversely affect pregnancy. For eration has minimal morbidity and mortality. Indeed, patients
patients who have acute viral hepatitis, management is primarily who undergo cholecystectomy have better pregnancy outcomes
supportive care. Acute or chronic hepatitis is not an indication for than those treated medically. Surgery is avoided in the first 10
termination of pregnancy. In addition, viral hepatitis itself is not weeks of pregnancy because of the risk of abortion with anes-
an indication for cesarean delivery, and breastfeeding should not thesia and the potential teratogenic effect from carbon dioxide.
be discouraged. In the third trimester, the uterus may impinge into the surgical
Vertical transmission of hepatitis A and D is rare. In the third field, and the risk of premature labor is increased. Laparoscopic
trimester, newborns of mothers with hepatitis A should be given cholecystectomy with precautions for the pregnant state is now
passive immunoprophylaxis with immunoglobulin within 48 the standard of care for these patients. If choledocholithiasis is
hours after birth. The benefits of immunoglobulin for babies of suspected, endoscopic retrograde cholangiopancreatography can
mothers who are seropositive for HCV are unknown, and there be performed safely in pregnant women. Radiation exposure
is no effective therapy for preventing transmission of HCV. The with fluoroscopy is well below the fetal safety level. Midazolam,
use of DAAs in pregnancy has not been studied well, and DAAs meperidine, and glucagon can be given safely.
Budd-Chiari Syndrome Kamath P, Kamath A, Ullal SD. Liver injury associated with drug intake
during pregnancy. World J Hepatol. 2021 Jul 27;13(7):747–62.
Budd-Chiari syndrome is rare, and when it occurs in pregnancy, Kushner T, Djerboua M, Biondi MJ, Feld JJ, Terrault N, Flemming
it is usually in the postpartum period. It has been associated with JA. Influence of hepatitis C viral parameters on pregnancy
antiphospholipid syndrome, thrombotic thrombocytopenic pur- complications and risk of mother-to-child transmission. J Hepatol.
pura, preeclampsia, and septic abortion. 2022 Nov;77(5):1256–64.
Lao TT. Drug-induced liver injury in pregnancy. Best Pract Res Clin
Obstet Gynaecol. 2020 Oct;68:32–43.
Bacterial Infection in Pregnancy Murali AR, Devarbhavi H, Venkatachala PR, Singh R, Sheth KA. Factors
Sepsis associated with pyelonephritis or abortion can cause that predict 1-month mortality in patients with pregnancy-specific
jaundice in early pregnancy. Severe gram-negative sepsis with liver disease. Clin Gastroenterol Hepatol. 2014 Jan;12(1):109–13.
jaundice has been described for patients in the third trimester. Nana M, Tydeman F, Bevan G, Boulding H, Kavanagh K, Dean C, et
al. Hyperemesis gravidarum is associated with increased rates of
Listeriosis is an uncommon infection, but 43% of cases occur
termination of pregnancy and suicidal ideation: Results from a
during pregnancy. Listeriosis occasionally affects the liver. survey completed by >5000 participants. Am J Obstet Gynecol. 2021
Maternal symptoms are generally mild, but fetal infection is a Jun;224(6):629–31.
serious condition that causes preterm birth, abortion, or death. In Pan YC, Jia ZF, Wang YQ, Yang N, Liu JX, Zhai XJ, et al. The role of
a murine model, listeriosis led to severe necrotizing hemorrhagic caesarean section and nonbreastfeeding in preventing mother-to-child
hepatitis and abortion. transmission of hepatitis B virus in HBsAg- and HBeAg- positive
mothers: results from a prospective cohort study and a meta-analysis.
J Viral Hepat. 2020 Oct;27(10):1032–43.
Drug-Induced Liver Injury
Rahim MN, Pirani T, Williamson C, Heneghan MA. Management of
Drug-induced liver injury (DILI) should be in the differential di- pregnancy in women with cirrhosis. United European Gastroenterol
agnosis for pregnant women with hepatitis. DILI is a diagnosis J. 2021 Feb;9(1):110–9.
of exclusion in both pregnant and nonpregnant women. The Royal College of Obstetricians & Gynaecologists. The management of
hepatotoxicity is usually of the idiosyncratic form and usually nausea and vomiting of pregnancy and hyperemesis gravidarum.
Green-top guideline no 69. 2016:27.
resolves spontaneously. Common medications causing DILI in
Shames BD, Fernandez LA, Sollinger HW, Chin LT, D’Alessandro AM,
pregnant women include antihypertensives (eg, α-methyldopa), Knechtle SJ, et al. Liver transplantation for HELLP syndrome. Liver
antithyroid medication (eg, propylthiouracil), antiretrovirals (eg, Transpl. 2005 Feb;11(2):224–8.
nevirapine), antituberculosis medications, and antibiotics. Terrault NA, Williamson C. Pregnancy- associated liver diseases.
Gastroenterology. 2022 Jul;163(1):97–117.
Wang J, Zhu Q, Zhang X. Effect of delivery mode on maternal-infant
Suggested Reading
transmission of hepatitis b virus by immunoprophylaxis. Chin Med J
Abram M, Schluter D, Vuckovic D, Waber B, Doric M, Deckert M. (Engl). 2002 Oct;115(10):1510–2.
Effects of pregnancy- associated listeria monocytogenes infec- Wang Z, Tao X, Liu S, Zhao Y, Yang X. An update review on listeria in-
tion: necrotizing hepatitis due to impaired maternal immune re- fection in pregnancy. Infect Drug Resist. 2021 14:1967–78.
sponse and significantly increased abortion rate. Virchows Arch. 2002 Webb GJ, Elsharkawy AM, Hirschfield GM. The etiology of intrahepatic
Oct;441(4):368–79. cholestasis of pregnancy: towards solving a monkey puzzle. Am J
Ayoub WS, Cohen E. Hepatitis B management in the pregnant patient: an Gastroenterol. 2014 Jan;109(1):85–8.
update. J Clin Transl Hepatol. 2016 Sep 28;4(3):241–7. Westbrook RH, Yeoman AD, O’Grady JG, Harrison PM, Devlin J,
Bradke D, Tran A, Ambarus T, Nazir M, Markowski M, Juusela A. Grade Heneghan MA. Model for end- stage liver disease score predicts
III subcapsular liver hematoma secondary to HELLP syndrome: a outcome in cirrhotic patients during pregnancy. Clin Gastroenterol
case report of conservative management. Case Rep Womens Health. Hepatol. 2011 Aug;9(8):694–9.
2020 Jan;25:e00169. Wikstrom Shemer E, Marschall HU, Ludvigsson JF, Stephansson O.
Brown MC, Best KE, Pearce MS, Waugh J, Robson SC, Bell R. Intrahepatic cholestasis of pregnancy and associated adverse preg-
Cardiovascular disease risk in women with pre-eclampsia: system- nancy and fetal outcomes: a 12-year population-based cohort study.
atic review and meta-analysis. Eur J Epidemiol. 2013 Jan;28(1):1–19. BJOG. 2013 May;120(6):717–23.
Cauldwell M, Mackie FL, Steer PJ, Henehghan MA, Baalman JH, Wikstrom Shemer EA, Stephansson O, Thuresson M, Thorsell M,
Brennand J, et al. Pregnancy outcomes in women with primary biliary Ludvigsson JF, Marschall HU. Intrahepatic cholestasis of preg-
cholangitis and primary sclerosing cholangitis: a retrospective cohort nancy and cancer, immune-mediated and cardiovascular diseases: a
study. BJOG. 2020 Jun;127(7):876–84. population-based cohort study. J Hepatol. 2015 Aug;63(2):456–61.
Chang MS, Gavini S, Andrade PC, McNabb-Baltar J. Caesarean section Yang J, Zeng XM, Men YL, Zhao LS. Elective caesarean section versus
to prevent transmission of hepatitis b: a meta- analysis. Can J vaginal delivery for preventing mother to child transmission of hepa-
Gastroenterol Hepatol. 2014 Sep;28(8):439–44. titis B virus: a systematic review. Virol J. 2008 Aug 28;5:100.
36
Liver Transplantationa
OMAR Y. MOUSA, MBBS, MD
SUMERA I. ILYAS, MBBS
Liver transplant (LT) is highly effective for patients with liver to chronic hepatitis C infection. Since 2016, however, alcohol-
failure to restore normal health and a normal lifestyle. Patient associated liver disease (ALD) and nonalcoholic steatohepatitis
survival after LT is excellent, reaching 90% at 1 year and 77% have been the leading indications for patients being added to the
at 5 years in the US according to the Scientific Registry of LT waiting list (both diagnoses accounted for over half the patients
Transplant Recipients. The 5-year survival rate for living-donor
LT (LDLT) recipients for 2008-2011 was 81.2%. Timely evalu-
ation for transplant and optimization of pretransplant care is es-
Box 36.1. Indications for Liver Transplant
sential for the potential liver recipient. However, the demand for
donor organs greatly exceeds supply. In 2019 in the US, 8,345 Cirrhosis of any cause
liver transplants were performed for patients 18 years or older, Cirrhotic complications
442 (5.3%) of whom underwent LDLT. At the end of 2019, the Hepatocellular carcinoma
liver transplant waiting list had 12,562 patients. Patient selection Hepatopulmonary syndrome
and organ allocation are the 2 main problems. Portopulmonary hypertension
✓ Liver transplant is highly effective in restoring patients’ health Acute liver failure
and lifestyle and in extending their lifespan Fulminant Wilson disease
Primary nonfunction or early hepatic artery throm-
bosis of hepatic allograft
Indications for LT Metabolic diseases
Decompensated cirrhosis is the most common indication for LT Hereditary hemochromatosis
(about 70% of cases) (Box 36.1). Until 2015, the most common α1-Antitrypsin deficiency
underlying liver disease that led to LT in the US was cirrhosis due Primary hyperoxaluria
Familial amyloidosis
Cystic fibrosis
a
The authors thank J. Eileen Hay, MB, ChB, who authored the previous
Glycogen storage disease
version of this chapter.
Perihilar cholangiocarcinoma
Abbreviations: ALD, alcohol- associated liver disease; DAA, direct-
acting antiviral; DCD, donation after cardiac death; HCC, hepatocellular Severe alcoholic hepatitis not responding to medical
carcinoma; INR, international normalized ratio; LDLT, living- donor therapya
liver transplant; LT, liver transplant; MELD, Model for End-stage Liver
Disease; MELD-Na, Model for End-stage Liver Disease incorporating a
Liver transplant may be considered for carefully selected patients who
sodium level; mTOR, mammalian target of rapamycin; OPTN, Organ have favorable psychosocial profiles.
Procurement and Transplantation Network
401
added to the waiting list). The complications of cirrhosis that are ✓ Alcohol-associated liver disease and nonalcoholic steatohepatitis
accepted indications for LT are hepatocellular carcinoma (HCC), are the leading indications for patients being added to the waiting
hepatopulmonary syndrome, and portopulmonary hypertension. In list for LT
addition, unresectable perihilar cholangiocarcinoma with a mass no ✓ Patients are eligible for LT if they have hepatocellular carcinoma
larger than 3 cm in radial diameter is an accepted indication for that meets the OPTN T2 criteria (also known as the Milan criteria),
LT after neoadjuvant radiotherapy and chemotherapy. LT may be cirrhosis, and an alpha fetoprotein level less than 1,000 ng/mL
considered for carefully selected patients who have favorable psy- ✓ Some patients do not qualify for LT because they have absolute or
chosocial profiles and no response to medical therapy for severe relative contraindications, which are listed in Box 36.3
alcoholic hepatitis (Model for End-stage Liver Disease [MELD]
incorporating sodium level [MELD-Na] score >20). A favorable
psychosocial profile includes 1) first presentation with decompen- Allocation of Organs
sated ALD; 2) absence of severe, uncontrolled medical or psychi-
atric comorbidities; 3) lack of repeated, unsuccessful attempts at In February 2002, the allocation system for deceased donor livers
rehabilitation; 4) lack of other substance use or dependency; 5) ac- in the US was changed to a system based on short-term mortality;
ceptance of ALD diagnosis with insight; 6) commitment of the pa- that is, an organ is allocated to the patient most likely to die in
tient to lifelong sobriety; and 7) the presence of close, supportive the next 3 months (Table 36.1). The most urgent indication for
family members or caregivers who will assist the patient with ab- LT is acute liver failure, and these patients are given the highest
stinence goals. priority for urgent organ allocation (status 1A). Unlike patients
The Organ Procurement and Transplantation Network (OPTN) with status 1A, who should be assigned an organ quickly after
T2 criteria (also known as the Milan criteria) (Box 36.2) are used to activation, patients with chronic liver disease generally have a
select tumors suitable for LT (ie, those likely to be cured by LT): The 2-step process: listing for LT and allocation of a donor organ.
patient should have 1 tumor with a diameter of at least 2 cm and no If otherwise suitable to be a transplant recipient, a patient with
larger than 5 cm or 2 or 3 tumors with diameters of at least 1 cm and cirrhosis will be registered with the United Network for Organ
no larger than 3 cm without vascular invasion or extrahepatic spread. Sharing on the liver transplant waiting list; however, organ al-
About 5% of all LTs in the US are performed for acute med- location is prioritized for patients listed within each ABO blood
ical emergencies: acute liver failure, fulminant Wilson disease, or group, according to their expected 3-month mortality, as defined
early failure of a liver allograft (primary nonfunction or hepatic by the MELD scoring system. In January 2016, the updated
artery thrombosis within the first postoperative week). Acute liver OPTN Policy 9.1 (MELD Score) incorporated the serum sodium
failure is an uncommon condition, with only about 2,500 cases level into calculation of the MELD score. Hyponatremia is a
annually in the US. The most frequent causes are acetaminophen common problem in patients with cirrhosis, and the severity of
hepatotoxicity (nearly 50% of all cases), indeterminate causes hyponatremia is a marker of the severity of cirrhosis.
(20%), and idiosyncratic drug reactions (14%). Other recognized The MELD-Na score is based on serum levels of creatinine,
indications for LT in adults are primary hyperoxaluria, familial bilirubin, and sodium and the international normalized ratio
amyloid polyneuropathy, cystic fibrosis, and metabolic diseases (INR). It is calculated according to the following formula:
in which the metabolic defect is in the liver. For children, sev-
eral other metabolic diseases are indications for LT. Controversy MELD-Na Score = MELD + 1.32 × (137 − Na )
continues to surround several proposed indications for LT, in- − [0.033 × MELD × (137 − Na )]
cluding metastatic neuroendocrine tumors, metastatic colorectal
cancer, and polycystic liver disease. Occasionally, in some re- The 4 variables (serum levels of creatinine, bilirubin, and so-
gions of the US, LT is performed for these indications. dium and the INR) are entered into a computer program, and the
Despite the success of LT, the procedure has some abso- MELD-Na score is calculated (https://optn.transplant.hrsa.gov/
lute and relative contraindications (Box 36.3). The relative resources/allocation-calculators/meld-calculator/). For patients
contraindications do not necessarily preclude transplant depending with MELD scores higher than 40, the expected 3-month mor-
on the transplant center, but several relative contraindications in tality rate is 80% without LT; for patients with scores of 20 to 29,
aggregate may result in a patient being ineligible for transplant. the rate is 20% to 25%; and for patients with scores less than 10,
there is no excess short-term mortality. In 2021, MELD 3.0 was
✓ Hepatic decompensation—development of life-threatening compli proposed. To the MELD-Na variables, MELD 3.0 added serum
cations, including hepatic encephalopathy, ascites, spontaneous bac- albumin level and female sex (women received an additional
terial peritonitis, esophageal variceal hemorrhage, hepatocellular
1.3 points) and updated creatinine cutoffs. MELD 3.0 resulted
carcinoma, hepatopulmonary syndrome, and hepatorenal syndrome

in fewer deaths of patients on the waiting list, but the OPTN
continues to use the MELD-Na score.
HCC is an accepted indication for LT even though mortality
Box 36.2. Organ Procurement and Transplantation is not reflected by the MELD score. In the US, patients with
Network (OPTN) T2 Criteria (Milan Criteria) HCC within the Milan criteria and an alpha fetoprotein level
Patient with cirrhosis or hepatocellular carcinoma is less than 1,000 ng/mL are eligible for the standardized MELD
a suitable candidate for transplant score exception based on the median MELD at transplant score
Patient has a single tumor with a diameter of 2-5 cm 6 months after being listed as an acceptable candidate. If the HCC
burden extends beyond the Milan criteria, the patient needs to
Patient has 2 or 3 tumors that each have a diameter
of 1-3 cm
meet the criteria of the OPTN downstaging protocol to be eli-
gible for a MELD exception score. In this situation, HCC should
Patient has no extrahepatic involvement
be downstaged to and maintained within the Milan criteria with
Patient has no major vessel involvement a treatment modality such as locoregional therapy, and the pa-
tient must have an alpha fetoprotein level less than 1,000 ng/mL.
36. Liver Transplantation 403
Table 36.1. Allocation of Deceased Donor Organs for Adult In addition, adult patients with any of the following diagnoses
Candidates are eligible for the standardized MELD score exception based on
the median MELD at transplant policy: hepatopulmonary syn-
Allocation status Disease category
drome, primary hyperoxaluria, familial amyloidosis, perihilar
Status 1A Acute liver failure in ICU, no preexisting liver disease, cholangiocarcinoma, cystic fibrosis, and portopulmonary hyper-
hepatic encephalopathy within 56 d of onset, tension. For all these MELD exceptions, there are strict inclusion
and 1 of the following: ventilator dependency, and exclusion criteria (https://unos.org/).
receiving hemodialysis or continuous venovenous The only ways for patients to be guaranteed consideration for
hemofiltration, or INR >2.0
allocation of a deceased donor organ are to have status 1A, have a
Acute decompensated Wilson disease
Anhepatic
calculated MELD-Na score, or have an assigned MELD score (ie,
Primary nonfunction of allograft within 7 d of standardized MELD exceptions). For controversial indications
transplant for LT or for patients who are more symptomatic than suggested
Hepatic artery thrombosis within 7 d of transplant by their MELD score, transplant programs may appeal to the na-
MELD-Na score, Cirrhosis from any cause tional review board to be given an assigned MELD score.
calculated
MELD-Na score Hepatocellular carcinoma ✓ Each liver transplant candidate is assigned a score that reflects the
exceptions Perihilar cholangiocarcinoma probability of death within a 3-month period as determined with
Hepatopulmonary syndrome the calculated MELD score
Portopulmonary hypertension ✓ A candidate can also be assigned a priority status if the candidate
Primary hyperoxaluria meets the requirements for that status
Familial amyloid polyneuropathy
Cystic fibrosis
Metabolic disease (urea cycle disorder or organic
acidemia) Immunosuppression
Hepatic artery thrombosis (within 14 d of transplant
but does not meet criteria for status 1A) Five main groups of immunosuppressive medications are used
Appeal to regional review boarda in LT (Table 36.2). Each immunosuppressive drug has its
own site of action and adverse effects. The risk of rejection is
Abbreviations: ICU, intensive care unit; INR, international normalized ratio; highest in the first weeks after LT, when immunosuppression is
MELD-Na, Model for End-stage Liver Disease incorporating sodium level.
at its highest level. Tacrolimus has replaced cyclosporine as the
a
Any transplant program can appeal to the regional review board for an assigned calcineurin inhibitor of choice in most liver transplant programs.
MELD-Na score for any patient to allow the patient to receive an organ. Frequently, corticosteroids with or without mycophenolate
mofetil are administered in the first postoperative weeks.
Immunosuppression is tapered by 4 months, often to tacrolimus
Box 36.3. Contraindications to Liver Transplant monotherapy, with lower serum levels. Long-term calcineurin
Absolute contraindications inhibitor monotherapy is ideal, but if nephrotoxicity develops
in response to the treatment, a low dose of calcineurin inhibitor
Extrahepatic malignancy unless tumor-free for ≥2 y
and low probability of recurrence and mycophenolate mofetil or a mammalian target of rapamycin
(mTOR) inhibitor may be used. Overall, the trend now is to tailor
Untreated alcoholism
immunosuppression to each patient, depending on the time from
Uncontrolled sepsis LT, rejection history, and adverse effects from individual drugs.
Severe multiorgan failure Newer agents are being sought to avoid kidney and metabolic
Severe psychologic disease likely to affect dysfunction.
adherence to therapy
Severe pulmonary hypertension ✓ Risk of rejection is highest in the first weeks after LT, when immu-
nosuppression is at its highest level
Advanced cardiopulmonary disease ✓ Calcineurin inhibitors (tacrolimus and cyclosporine) can lead to
AIDS nephrotoxicity and neurotoxicity
Hepatocellular carcinoma or perihilar ✓ mTOR inhibitors (sirolimus and everolimus) can lead to cytopenias,
cholangiocarcinoma with metastasis hepatic artery thrombosis, and poor wound healing
Fulminant liver failure with sustained ICP >50 mm Hg
or CPP <40 mm Hg
Relative contraindications Complications After LT
General debility
Primary Nonfunction of the
Persistent nonadherence to therapy Liver Allograft
Social isolation
The worst early complication is primary nonfunction of the allo-
Advanced age graft. This starts immediately with the appearance of clear bile or
Extensive, previous abdominal surgery no output of bile, high aminotransferase levels, and an increase
Extensive portal or mesenteric thrombosis in bilirubin concentration. The main identified risk factor is high
fat content of the allograft. Grafts may be biopsied to assess
Abbreviations: CPP, cerebral perfusion pressure; ICP, intracranial this before implantation. No therapy is available for primary
pressure. nonfunction, and the patient’s status needs to be reactivated as
status 1A for the patient to receive a second graft.
Table 36.2. Immunosuppressive Drugs and Their Adverse Effects

Drug class Drug Adverse effects
Corticosteroids a
Methylprednisolone Hypertension, type 2 diabetes, neurotoxicity, hyperlipidemia, bone loss, myopathy
Prednisone
Purine antagonists Azathioprine Cytopenias
Mycophenolate mofetil Adverse effects in the gastrointestinal tract (mycophenolate mofetil only)
Calcineurin inhibitorsa,b Tacrolimus Nephrotoxicity, hypertension, type 2 diabetes, neurotoxicity (headache, tremors,
Cyclosporine seizures, posterior reversible encephalopathy syndrome), hair loss (tacrolimus), hair
gain (cyclosporine)
mTOR inhibitors Sirolimus (rapamycin) Cytopenias, hypertriglyceridemia, poor wound healing, hepatic artery thrombosis, oral
Everolimus and gastrointestinal tract ulcers, edema, proteinuria
Antibody therapy Antithymocyte globulin Profound immunosuppression, opportunistic infections
(intravenous)a (thymoglobulin)
Basiliximab
Abbreviation: mTOR, mammalian target of rapamycin.

a
Used for treatment and prevention of rejection (others used only for prevention).
b
Interactions can occur with drugs that affect the cytochrome P450 enzyme system: Drugs inhibiting the cytochrome P450 system (eg, fluconazole) increase the levels of
calcineurin inhibitors, and drugs stimulating the cytochrome P450 system (eg, phenytoin) decrease calcineurin inhibitor levels and thus increase the risk of rejection.
Hepatic Artery Thrombosis Biliary Strictures

Another dreaded early complication of LT is hepatic artery throm- The biliary anastomosis, either duct-to-duct or biliary-enteric
bosis. This is most common in children, size-mismatched grafts, anastomosis, is the most common site of biliary strictures, which
and LDLT. It usually occurs in the first week after LT, but it can usually form in the first month. Most strictures respond to endo-
develop later. The clinical manifestations may be subtle, and scopic dilatation, with or without stents, but occasionally surgical
patients may be asymptomatic or have mild fever or increased revision of the anastomosis is needed.
aminotransferase levels. In the majority of adults with hepatic Nonanastomotic or ischemic-type biliary strictures may form
artery thrombosis, the grafts fail because of hepatic necrosis or at any time, but the median time is about the eleventh postopera-
ischemic cholangiopathy. When hepatic artery thrombosis occurs tive week. The most commonly identified cause is hepatic artery
in the first 7 days after LT and there is evidence of severe graft thrombosis, either early or late. Other associations are with ABO
dysfunction, the patient will be listed for retransplant as status incompatibility, long warm (>90 minutes) or cold (>12 hours)
1A. If graft dysfunction is not severe or hepatic artery thrombosis ischemia time, and graft donation after cardiac death (DCD).
occurs 7 to 14 days after transplant, the patient can be listed with Some of these strictures can be managed with endoscopic or
a MELD exception score of 40. percutaneous biliary stenting, although ischemic- type biliary
stricturing leads to death or a need for retransplant in about 50%
of patients.
Cellular Rejection
Acute cellular rejection occurs in up to 50% of liver recipients
and usually is associated with mild to moderate biochemical Infections
abnormalities and, occasionally, fever. Although the diagnosis A systemic fungal, viral, or bacterial infection develops in
can be suspected by the timing in the early weeks after LT, de- 1 in 5 LT recipients during the first postoperative month.
finitive diagnosis requires histologic examination of the liver Cytomegalovirus infection is the most common viral infection.
and the following findings: 1) portal infiltrates with activated Its incidence peaks in the first 3 to 5 postoperative weeks, and it
lymphocytes and some eosinophils, 2) lymphocytic cholangitis, is rare after the first year. Its presence is suggested by fever and
and 3) venous endotheliitis. Ninety percent of cases of rejec- leukopenia. Treatment is with intravenous ganciclovir or oral
tion occur in the first 2 postoperative months. Most rejections valganciclovir. Candida infection is the most common fungal
are treated with intravenous corticosteroids, and 85% of patients infection, although opportunistic infections can also be seen
with rejection have a response to corticosteroids. Of the patients with Aspergillus, Nocardia, Cryptococcus, and Pneumocystis.
with corticosteroid-resistant rejection, 90% respond to intrave- Many transplant programs provide prophylaxis for Pneumocystis
nous antibody therapy with antithymocyte globulin. Acute cel- in the early postoperative months when immunosuppression is
lular rejection soon after LT generally has no effect on long-term at its highest level.
graft outcome, except for patients with hepatitis C, and very few
grafts are lost to chronic rejection.
Late Complications
✓ Acute cellular rejection is associated with mild to moderate bio-
The main late complications after LT are recurrent disease,
chemical abnormalities and, occasionally, fever
✓ Definitive diagnosis of acute cellular rejection requires a liver bi- complications of immunosuppression, and de novo malignancies.
opsy that shows: 1) portal infiltrates with activated lymphocytes When late allograft dysfunction occurs in a patient who is
and some eosinophils, 2) lymphocytic cholangitis, and 3) venous well and receiving stable, therapeutic immunosuppression, re-
endotheliitis current disease is the most likely diagnosis. The diagnosis is his-
tologic, and liver biopsy is needed. The incidence and potential
36. Liver Transplantation 405
severity of recurrent disease in an allograft is greatest with Increasingly, data show notable mortality at 5 to 10 years after
hepatitis C. In the past, treatment of recurrent hepatitis C with LT from upper aerodigestive cancers in recipients who continue
peginterferon and ribavirin resulted in a sustained virologic re- to smoke and drink.
sponse in about 30% of patients. Since 2014, introduction of
interferon-free regimens with direct- acting antiviral (DAA)
Expansion of the Donor Pool
regimens provided LT recipients with efficacious hepatitis C
treatment and sustained virologic response rates of up to 83% Adult-to-adult LDLT uses the right, and less frequently the left,
to 100%. The safety profile of these agents is favorable. The lobe of the donor for implant into the recipient. For pediatric
DAA regimen for LT recipients—regardless of the hepatitis C recipients, the left lobe may be used, depending on size. The
genotype, the recipient being treatment naïve or experienced major advantages of LDLT over deceased donor transplant are
with peginterferon and ribavirin, or the presence or absence of availability of the organ and expansion of the donor pool. LDLT
cirrhosis— includes the following for 12 weeks: glecaprevir- is associated with more vascular and biliary complications but
pibrentasvir or sofosbuvir- velpatasvir. Ledipasvir- sofosbuvir not less rejection. The donor morbidity rate is 8% to 26%, and
can be used for 12 weeks in patients with hepatitis C genotypes the mortality rate is 0.3%. In addition, expanding the donor pool
1, 4, 5, or 6. Patients with decompensated cirrhosis require can be achieved by using grafts from older donors (higher rate
treatment with ledipasvir-sofosbuvir and a low initial dose of of primary nonfunction); split livers (higher complication rate,
ribavirin (genotypes 1, 4, 5, or 6) or sofosbuvir-velpatasvir and labor-intensive procedure, and disadvantage for the primary re-
a low initial dose of ribavirin (all genotypes) for 12 to 24 weeks. cipient); marginal donors (eg, fatty liver with an increased risk
DAA-experienced patients with genotype 1 to 6 infection in the of primary nonfunction); DCD graft (increased risk of biliary
allograft with or without compensated cirrhosis can be treated complications; 5-year graft survival among adult deceased donor
with sofosbuvir-velpatasvir-voxilaprevir for 12 weeks (https:// liver transplant recipients, 73%); and high-risk donors (high-risk
www.hcvguidelines.org/). Recurrent hepatitis B is prevented in lifestyle or medical history).
more than 90% of patients with hepatitis B immunoglobulin and
antiviral therapy. Other liver diseases, including primary biliary
Suggested Reading
cholangitis and primary sclerosing cholangitis, autoimmune
hepatitis, nonalcoholic fatty liver disease, and HCC, may also Burra P, Freeman R. Trends in liver transplantation 2011. J Hepatol. 2012
recur. The incidence of immune-mediated liver disease recur- 56 Suppl 1:S101–11.
rence is 10% to 20%. Burton JR, Jr, Everson GT. Management of the transplant recipient with
chronic hepatitis C. Clin Liver Dis. 2013 Feb;17(1):73–91.
Most LT recipients have normal cardiac function, but in-
Cholankeril G, Ahmed A. Alcoholic liver disease replaces hepatitis C
creasingly patients who are obese or have type 2 diabetes or virus infection as the leading indication for liver transplantation in the
hypertension are undergoing LT. In addition, even in those with United States. Clin Gastroenterol Hepatol. 2018 Aug;16(8):1356–8.
no risk factors for coronary artery disease before LT, treatment Crabb DW, Im GY, Szabo G, Mellinger JL, Lucey MR. Diagnosis and
with immunosuppressive drugs may lead to hypertension, type treatment of alcohol-associated liver diseases: 2019 practice guidance
2 diabetes, kidney failure, dyslipidemia, and obesity in a high from the American Association for the Study of Liver Diseases.
percentage of patients. This predisposes many LT recipients to Hepatology. 2020 Jan;71(1):306–33.
a high risk for cardiovascular disease, with cyclosporine having Kwong AJ, Kim WR, Lake JR, Smith JM, Schladt DP, Skeans MA, et al.
more metabolic effects than tacrolimus. LT recipients must re- OPTN/SRTR 2019 annual data report: liver. Am J Transplant. 2021
ceive adequate screening and therapy for these risk factors. Feb;21 Suppl 2:208–315.
Limaye AR, Firpi RJ. Management of recurrent hepatitis C infection
LT recipients have multiple potential risk factors for cancer:
after liver transplantation. Clin Liver Dis. 2011 Nov;15(4):845–58.
immunosuppression, viruses (hepatitis C virus, hepatitis B virus, Lucey MR, Terrault N, Ojo L, Hay JE, Neuberger J, Blumberg E, et al.
human papillomavirus, human herpesvirus 6, Epstein-Barr virus), Long-term management of the successful adult liver transplant: 2012
alcohol use, and smoking. Furthermore, many recipients are practice guideline by the American Association for the Study of Liver
older than 60 years at the time of LT and, thus, have the increased Diseases and the American Society of Transplantation. Liver Transpl.
cancer risk of aging. The effect of immunosuppression probably 2013 Jan;19(1):3–26.
is related to the degree of immunosuppression rather than to in- Marrero JA, Kulik LM, Sirlin CB, Zhu AX, Finn RS, Abecassis MM,
dividual agents. Depending on the series, the reported overall et al. Diagnosis, staging, and management of hepatocellular carci-
incidence of cancer varies from 2.9% to 14%; the reported noma: 2018 practice guidance by the American Association for the
cancer-related mortality rate is 0.6% to 8%. Malignancies are an Study of Liver Diseases. Hepatology. 2018 Aug;68(2):723–50.
Tan HH, Martin P. Care of the liver transplant candidate. Clin Liver Dis.
important cause of long-term mortality.
2011 Nov;15(4):779–806.
Malignancies that occur frequently in LT recipients are Weber ML, Ibrahim HN, Lake JR. Renal dysfunction in liver trans-
skin cancers and posttransplant lymphoproliferative disease in plant recipients: evaluation of the critical issues. Liver Transpl. 2012
addition to cervical, vulvar, and anal squamous cancers. The in- Nov;18(11):1290–301.
cidence of colorectal cancer is increased only for recipients with Wiesner RH, Fung JJ. Present state of immunosuppressive therapy in
primary sclerosing cholangitis, likely related to ulcerative colitis. liver transplant recipients. Liver Transpl. 2011 Nov;17 Suppl 3:S1–9.
Questions IBD, inflammatory bowel disease

Ig, immunoglobulin
Abbreviations used: INR, international normalized ratio
AFP, alpha fetoprotein LDL, low-density lipoprotein
ALP, alkaline phosphatase MCV, mean corpuscular volume
ALT, alanine aminotransferase MELD, Model for End-stage Liver Disease
AMA, antimitochondrial antibody MRCP, magnetic resonance cholangiopancreatography
ANA, antinuclear antibody MRI, magnetic resonance imaging
anti-HAV, antibody to hepatitis A virus NAFLD, nonalcoholic fatty liver disease
anti-HBc, antibody to hepatitis B core antigen NASH, nonalcoholic steatohepatitis
anti-HBs, antibody to hepatitis B surface antigen NSBB, nonselective β-blocker
anti-HCV, antibody to hepatitis C virus PBC, primary biliary cholangitis
anti-LKM, antibody to liver-kidney microsome type 1 PMN, polymorphonuclear neutrophil
ASMA, anti–smooth muscle antibody PSC, primary sclerosing cholangitis
AST, aspartate aminotransferase SMA, smooth muscle antibody
BCLC, Barcelona Clinic Liver Cancer TIPS, transjugular intrahepatic portosystemic shunt
BCS, Budd-Chiari syndrome WBC, white blood cell count
BMI, body mass index
CBC, complete blood cell count
CT, computed tomography Multiple Choice (choose the best answer)
DAA, direct-acting antiviral VI.1. A 20-year-old man is referred with abnormally high liver test
DILI, drug-induced liver injury results. He felt well until 2 weeks ago when he noted fatigue
EGD, esophagogastroduodenoscopy and sore throat. His primary care provider cultured his throat;
ERCP, endoscopic retrograde cholangiopancreatography results were negative. The symptoms continued, and jaundice
FISH, fluorescence in situ hybridization developed. The patient has no prior history of liver disease.
GAVE, gastric antral vascular ectasia He drinks 3 or 4 alcoholic beverages weekly. Medications in-
HAV, hepatitis A virus clude minocycline for 2 months for acne and acetaminophen 2
HBsAg, hepatitis B surface antigen g daily for the past 2 weeks. Physical examination findings are
HBV, hepatitis B virus notable for a relatively well-appearing man in no distress. His
HCC, hepatocellular carcinoma temperature is 38.2 °C. He has mild scleral icterus, enlarged
HCV, hepatitis C virus and soft cervical lymph nodes, and mild splenomegaly. Notable
HE, hepatic encephalopathy laboratory test results are shown below:
407
Component Result Component Result

Hemoglobin, g/dL 14 Hemoglobin, mg/dL 14.2
WBC count, /µL 3,300 Platelet count, ×103/µL 160
Neutrophils, % 20 Total bilirubin, mg/dL 1.0
Lymphocytes, % 60 Direct bilirubin, mg/dL 0.3
Monocytes, % 20 ALP, U/L 343
Platelet count, ×103/µL 130 AST, U/L 64
ALP, U/L 100 ALT, U/L 79
AST, U/L 202
ALT, U/L 217
Total bilirubin, mg/dL 3.4
Ultrasonography of the liver shows mild hepatosplenomegaly
Direct bilirubin, mg/dL 2.1 and slightly enlarged abdominal lymph nodes. Chest radiog-
ANA, U 1.4 raphy shows mild hilar adenopathy and changes consistent
Smooth muscle antibody Negative with interstitial lung disease. Which of the following is the
Gammaglobulin, g/dL 1.2 most likely diagnosis?
Hepatitis B surface antigen Negative a. Amyloidosis
Hepatitis B core antibody Negative
b. Sarcoidosis
Hepatitis C antibody Negative
c. PSC
Hepatitis A antibody Negative
d. PBC
e. Celiac disease
Which of the following is the most likely diagnosis?
VI.4. You are asked to evaluate a 53-year-old man who has high liver
a. Minocycline-induced liver disease test results. He was admitted 4 days ago when he was found on
b. Wilson disease his apartment floor. Initial examination findings were notable
c. Lymphoma for a tongue laceration, so it was thought that he might have
d. Infectious mononucleosis had a seizure. Blood work on admission was notable for the
e. Acetaminophen hepatotoxicity following: AST 4,120 U/L, ALT 714 U/L, and normal levels of
VI.2. A 63-year-old woman presents with a 4-hour history of ab- ALP and bilirubin. An acetaminophen level was undetected.
dominal pain, fever, and nausea. She has no prior history Results from yesterday were AST 1,024 U/L and ALT 434 U/L.
of liver disease. Physical examination findings are notable The patient has a history of heavy alcohol use. He does not use
for blood pressure 110/60 mm Hg, heart rate 104 beats/min, medications. Examination findings are notable for obesity with
and temperature 38.7 °C. She has jaundice and mild epigas- a normal liver and spleen. Which of the following is the most
tric tenderness. Notable laboratory test results are shown likely diagnosis?
below: a. Muscle injury
b. Alcoholic hepatitis
c. Acute viral hepatitis
Component Result d. Acetaminophen hepatotoxicity
WBC count, /µL 18,000 e. Hepatic ischemia
Polymorphonuclear cells, % 80 VI.5. Which of the following agents can be used to treat HCV geno-
Band cells, % 10 type 1a in a patient with decompensated cirrhosis?
ALP, U/L 150
AST, U/L 745 a. Grazoprevir-elbasvir
ALT, U/L 650 b. Glecaprevir-pibrentasvir
Total bilirubin, mg/dL 5.0 c. Sofosbuvir-velpatasvir-voxilaprevir
Amylase, U/L 270 d. Sofosbuvir-ledipasvir
VI.6. A 23-year-old woman presents with jaundice that she noticed
Ultrasonography shows gallbladder stones, no bile duct dil- 1 week ago. The transplant service is aware of her admission.
atation, and a pancreas that appears normal. The patient is On examination she is oriented, and she has jaundice but no
prescribed antibiotics. Blood cultures 12 hours later are pos- asterixis. Laboratory test results are shown below:
itive for Escherichia coli. Which of the following would you
advise next?
Component Result
a. Endoscopic ultrasonography
b. MRCP ALT, U/L 1,648
c. ERCP Total bilirubin, mg/dL 5.5
d. Laparoscopic cholecystectomy Direct bilirubin, mg/dL 3.4
e. Doppler ultrasonography of the hepatic vasculature INR 1.2
HBsAg Positive
VI.3. A 39- year-
old asymptomatic man presents with a high IgM anti-HBc Positive
ALP level that was initially discovered when he had blood HBV DNA, IU/mL 35,000
tests done to assess symptoms that turned out to be due to Anti-HCV Negative
a COVID-19 infection. The ALP level has been persistently Anti-HAV Negative
high for a year. He drinks 1 or 2 alcoholic beverages weekly.
He has no family history of liver disease. Physical exami-
Which of the following should you advise now?
nation findings are unremarkable. Notable laboratory test
results are shown below: a. Urgent liver transplant
b. Peginterferon and entecavir abdominal ultrasonography, a large 15-cm cyst is in the cen-
c. Entecavir tral right lobe of the liver. The bile ducts are compressed cen-
d. N-acetylcysteine trally in the liver with bilateral peripheral biliary dilatation.
e. Serial monitoring The cyst appears to compress the intrahepatic inferior vena
cava. The cyst wall shows no nodularity or increased vascu-
VI.7. A 58-year-old man, a former user of intravenous drugs, is
larity on Doppler evaluation. Echogenic densities in the cyst
evaluated for treatment of infection with HCV genotype 1
suggest prior hemorrhage. The ultrasonographic findings
with stage 2 fibrosis. Baseline laboratory tests include normal
are confirmed on multiphasic contrast MRI. After the cyst
results for the following: CBC, creatinine, total bilirubin,
was aspirated and sclerosis was performed with 3% sodium
ALP, and albumin. Other results are ALT 64 U/L, AST 54 U/L,
tetradecyl sulfate, the symptoms resolved. However, the ab-
HIV negative, HBsAg positive, and HBV DNA less than 20 IU/
dominal pain returned after 2 months and ultrasonography
mL. He is not taking any medications. He begins treatment
showed reaccumulation of the cyst fluid with no evidence of
with an interferon-free DAA regimen. At week 4, he presents
increased nodularity or vascularity of the cyst wall. What is
to the clinic and says that his eyes are yellow. Which of the
the best next step in management?
following should be evaluated next?
a. A second cyst aspiration and sclerosis with 3% sodium
a. HAV RNA
tetradecyl sulfate
b. HBV DNA
b. Laparoscopic decompression and unroofing of the cyst
c. HCV RNA
c. Initiation of diuretic therapy
d. Lactate
d. Evaluation for liver transplant
e. Smooth muscle antibody
VI.12. A 44-year-old man with ulcerative colitis has an increased
VI.8. Which antiviral regimen is contraindicated in patients re-
ALP level during a follow-up evaluation for ulcerative co-
ceiving amiodarone?
litis. MRI with MRCP suggests that he has cirrhotic-stage
a. Glecaprevir-pibrentasvir PSC with a dominant stricture in the left hepatic duct.
b. Entecavir MRI does not show a definite enhancing mass. The car-
c. Tenofovir bohydrate antigen 19-9 value is high (150 U/mL). ERCP
d. Sofosbuvir-ledipasvir evaluation with brushings and biopsies provides cytologic
confirmation of malignancy, and pancreatobiliary FISH
VI.9. A 55-year-old woman with type 2 diabetes has abdominal
shows polysomy. Transpapillary forceps biopsy findings are
pain. On abdominal ultrasonography that was performed to
negative. Endoscopic ultrasonography shows no evidence
rule out cholecystitis, the gallbladder appears normal, but
of lymph node metastasis. What is the best next step in
an indeterminate 5-cm mass is apparent in the right lobe of
management?
the liver. No previous imaging studies of the liver have been
performed. Multiphasic MRI is performed with gadoxetate a. Surgical resection for cure
as a contrast agent to characterize the mass. The MRI shows b. Referral for evaluation for liver transplant
rapid homogeneous enhancement of the mass with a prompt c. Radiofrequency ablation of the area of the dominant stricture
return to isointensity with the surrounding liver in the portal d. Photodynamic therapy
venous phase. The mass retains contrast material in the bil-
VI.13. A 73-year-old woman who has cirrhosis secondary to NAFLD
iary phase of the study. What is the most likely diagnosis?
received a diagnosis of BCLC stage C multifocal advanced
a. Hepatic adenoma HCC. EGD showed large varices with red wale signs, which
b. Hepatic hemangioma were banded until all varices had been successfully treated.
c. Focal nodular hyperplasia She has Child-Pugh class A cirrhosis. The serum AFP value
d. Intrahepatic cholangiocarcinoma was 1,500 ng/mL, and she is not a candidate for surgical re-
section. Her performance status at the time of diagnosis was
VI.10. A 36-year-old man who was born in South Korea and was
0. She had 1 session of transarterial chemoembolization
adopted to live in the US at the age of 5 years had a positive
without evidence of benefit, and the AFP value increased to
test result for HBsAg at the time of adoption. His hepatitis B
2,500 ng/mL 3 months after chemoembolization. What is the
status has been monitored periodically. Results are now neg-
ative for hepatitis B e antigen and positive for hepatitis B e
antibody. His baseline ALT level ranges from 20 to 28 U/L. a. Atezolizumab in combination with bevacizumab
The hepatitis B virus DNA level is 1,000 IU/mL. He has no b. Sorafenib
known family history of HCC. Laboratory tests show no ev- c. Best supportive care
idence of cirrhosis or complications of chronic liver disease. d. Ramucirumab
Transient elastography shows no increase in liver stiffness.
VI.14. A 39-year-old woman who has a history of obesity (treated
On physical examination he has no evidence of cirrhosis or
with Roux-en-Y gastric bypass), hypertension, and hyper-
chronic liver disease. At what age should surveillance begin
lipidemia is referred for evaluation of abnormal liver bio-
for liver cancer?
chemistry results. She drinks 2 glasses of wine each evening.
a. 20 years Laboratory test results are shown below:
b. 30 years
c. 40 years
d. 50 years Component Result
VI.11. A 55-year-old woman presents with a 3-month history of pro- ALT, U/L 75
gressive right upper quadrant abdominal pain, jaundice, and AST, U/L 144
ALP, U/L 125
bilateral leg swelling. She slipped and fell on her side during
Bilirubin, mg/dL 0.7
the winter and has had progressively worse abdominal pain
INR 1.1
since then. About a week ago her daughter noticed that she ANA, U Negative
appeared to have a yellow tint to her skin. Two days ago, the SMA Negative
patient noticed increased puffiness of her feet and ankles. On HBV and HCV antibodies Negative
Her BMI is 33. Ultrasonography of the liver shows fatty infil- c. Begin diuretic therapy with furosemide and spironolactone
tration. What should be your initial management approach? d. Refer for an urgent TIPS
e. Refer for urgent liver transplant
a. Recommend that she lose 7% to 10% of her body weight
b. Recommend that she abstain from drinking alcohol VI.19. A 64-year-old man presents to the emergency department
c. Begin treatment with ursodiol (13-15 mg/kg daily) with hematemesis that began this morning. He has no known
d. Refer her for evaluation for liver transplant history of chronic liver disease. His past medical history is
notable for controlled hypertension, hyperlipidemia, and
VI.15. A 32-year-old man who had been well now has fatigue, jaun-
a previous episode of severe gallstone pancreatitis. After he
dice, and dark urine. He typically drinks 6 cans of beer daily.
receives fluid resuscitation, his condition is stabilized. On
He has been drinking more heavily recently while he is unem-
upper endoscopy, esophageal varices are not seen, but there
ployed. Examination findings are as follows: blood pressure
are large gastric fundic varices with red signs, and there is
130/86 mm Hg, heart rate 102 beats/min, temperature 38.5
altered blood in the stomach. What is the most appropriate
°C, scleral icterus, hepatomegaly with an abdominal bruit,
next step?
and no splenomegaly. Laboratory test results include the
following: WBC count 20×109/L, platelet count 232×109/L, a. Therapy with propranolol
and albumin 4.5 g/dL. Which of the following is the most b. CT of the abdomen with an intravenous contrast agent
likely cause of the bruit? c. Endoscopic band ligation of the gastric varices
d. TIPS
a. Splenorenal shunting
e. Referral for liver transplant
b. Dilation of the hepatic artery
c. HCC VI.20. A 48-year-old woman underwent a liver biopsy during evalu-
d. Cruveilhier-Baumgarten murmur ation of abnormal liver test results 1 week ago. Liver biopsy
showed mild autoimmune hepatitis with minimal hepatic fi-
VI.16. A 45-year-old woman drinks 2 alcoholic beverages daily. She
brosis. This morning she had sudden onset of abdominal pain
decreased her consumption when she recently received a diag-
and distention, with light-headedness and diaphoresis; subse-
nosis of COVID-19–related pneumonia. She was treated ini-
quently she had a large bowel movement with melenic stool.
tially with azithromycin and later with COVID-19 monoclonal
Which of the following is the most likely cause of the patient’s
antibody therapy. She recently completed a 10-day quaran-
clinical presentation?
tine period. On follow-up evaluation with her primary care
physician, test results included the following: AST 1,000 U/L, a. Hepatic vein thrombosis
ALT 1,100 U/L, CBC normal, total bilirubin 0.5 mg/dL, and b. Portal vein thrombosis
INR 1.0. She does not take herbal supplements, but she took c. Hepatic artery thrombosis
over-the-counter cold medications while she was ill. What is d. Hepatic artery aneurysm
the most likely cause of the increased liver test results? e. Hepatic artery–portal vein fistula
a. COVID-19–related hepatitis VI.21. A 29-year-old woman is brought to the emergency depart-
b. Drug-induced autoimmune-like hepatitis ment by ambulance after being found unresponsive. She has
c. Acetaminophen hepatotoxicity a history of polysubstance use with multiple hospitalizations
d. Severe alcohol-related hepatitis for intoxication. After fluid resuscitation she is alert but
disoriented. Physical examination findings are notable for
VI.17. A 62-year-old man with alcohol-related cirrhosis is being
signs of injection drug use. Laboratory test results are no-
evaluated for liver transplant. His blood type is B, and his
table for markedly increased aminotransferase levels (AST
MELD score with determination of sodium is 25. His cir-
8,500 U/L; ALT 9,700 U/L). After she is admitted to the
rhosis is complicated by ascites that requires diuretic
hospital, her condition improves. The next day, her liver
therapy, mild hepatic encephalopathy that requires lactulose,
enzyme values have improved (AST 3,000 U/L; ALT 4,500
and small, nonbleeding esophageal varices. He has abstained
U/L). Urine drug screening is positive for alcohol and meth-
from drinking alcohol for 1 year, he has completed primary
amphetamine. She feels better and is requesting to leave
addiction treatment, and he attends Alcoholics Anonymous
the hospital. What is the most likely cause of her abnormal
meetings regularly. On the 6-minute walk test, he had a total
liver tests?
of 200 m, which was limited by knee pain due to severe osteo-
arthritis. What is the best management for his knee pain? a. Alcohol-associated hepatitis
b. Ischemic hepatopathy
a. Acetaminophen 500 mg 4 times daily
c. Acute hepatitis A
b. Ibuprofen 400 mg 4 times daily
d. Acute hepatitis B
c. Oxycodone 10 mg 4 times daily
e. Acute hepatitis C
d. Knee replacement surgery
VI.22. A 52-year-old woman is referred for evaluation of high liver
VI.18. A 32- year-
old woman presents to the emergency depart-
test values. She has obesity (BMI 36) and type 2 diabetes. She
ment with sudden onset of abdominal pain and distention.
consumes 2 or 3 alcoholic beverages a week. Laboratory test
Previously, she had been healthy, and her only medication is
results are shown below:
an oral contraceptive. She smokes 1 pack of cigarettes daily.
On examination she has tender hepatomegaly with moderate
ascites. Laboratory studies are notable for the following: INR Component Result
1.8, AST 780 U/L, ALT 890 U/L, and total bilirubin 5.6 mg/dL.
The hepatic veins are not apparent on ultrasonography of Hemoglobin, g/dL 11.2
the abdomen. The patient is hospitalized, and therapy is MCV, fL 92.3
started with unfractionated heparin. The next morning, she Platelet count, ×109/L 187
is disoriented and somnolent, and she has asterixis. What is ALT, U/L 62
the most appropriate next step? AST, U/L 53
ALP, U/L 117
a. Continue therapy with intravenous unfractionated heparin INR 1.0
b. Switch therapy to subcutaneous low-molecular-weight heparin
Liver stiffness is 15 kPa on transient elastography, and he- spironolactone, lactulose, nadolol, and zinc. Laboratory test
patic steatosis is apparent on ultrasonography. What should results are shown below:
you advise for variceal screening?
a. Perform CT of the abdomen and pelvis with an intravenous Component Result
contrast agent
b. Proceed with EGD now Hemoglobin, g/dL 8.0
c. Monitor platelet count and transient elastography annually WBC count, ×109/L 4.5
d. Start primary prophylaxis with NSBB therapy Platelet count, ×109/L 70
Albumin, g/dL 2.5
VI.23. A 63-year-old woman presents for evaluation of compensated Total bilirubin, mg/dL 2.0
cirrhosis secondary to NASH. Her medical history is signifi- INR 1.7
cant for hypertension, type 2 diabetes, hyperlipidemia, and Creatinine, mg/dL 0.8
obesity (BMI 33). Laboratory test results are shown below:
On paracentesis, the WBC count is 700 cells/µL, with 40%
Component Result PMNs. What is the best next step in management?
Platelet count, ×10 /L

9
130 a. Discontinue nadolol
AST, U/L 52 b. Perform EGD to evaluate for recurrent bleeding in the gastro-
ALT, U/L 58 intestinal tract
INR 1.3 c. Start rifaximin 550 mg orally every 12 hours
Total bilirubin, mg/dL 1.9 d. Start cefotaxime 2 g intravenously every 8 hours
VI.27. A 62-year-old woman with cirrhosis secondary to primary
Ultrasonography shows hepatic steatosis, and EGD findings biliary cholangitis reports ongoing abdominal distention.
are normal. Which of the following should you recommend to For 5 months she has had ascites, which was previously
screen for varices? drained, and she does not have a history of gastrointes-
tinal tract bleeding or HE. She reports that her ascites has
a. Repeat EGD in 3 years improved only partially with diuretics that her primary care
b. Repeat EGD in 2 years doctor prescribed 3 months ago. Her medications include
c. Start NSBB therapy to prevent development of varices furosemide 80 mg daily and spironolactone 200 mg daily.
d. Recommend annual transient elastography and follow- up On examination, she has no jaundice or asterixis. She has
EGD if liver stiffness exceeds 20 kPa bulging flanks, shifting dullness, and peripheral edema but
VI.24. A 42-year-old man with cirrhosis due to alcohol use presents with no fluid wave or tense ascites. Laboratory test results in-
hematemesis. He has hypotension (blood pressure 83/56 mm Hg) clude the following: creatinine 0.8 mg/dL, sodium 132 mmol/
and a heart rate of 112 beats/min. Laboratory test results include L, and potassium 5.1 mmol/L. What is the best next step in
the following: hemoglobin 7.2 g/dL, platelet count 59×109/L, INR management?
1.9, and total bilirubin 3.1 mg/dL. He is intubated and admitted a. Refer the patient to a dietitian
to the intensive care unit. Which of the following is the best next b. Increase furosemide to 120 mg daily
step in management of this patient’s bleeding? c. Refer the patient to a tertiary center to consider TIPS
a. Transfusion of packed red blood cells d. Perform large-volume paracentesis
b. Urgent TIPS VI.28. A 74-year-old man presents with new-onset ascites. He has not
c. Fresh frozen plasma and then EGD received regular care from a medical professional throughout
d. Proton pump inhibitor, octreotide, and antibiotics his adult life, and he has a history of untreated hypertension
VI.25. A 68-year-old woman with cirrhosis due to α1-antitrypsin de- and obstructive sleep apnea. The serum albumin level is 3 g/dL.
ficiency presents for evaluation of anemia. Laboratory test Ascitic fluid analysis shows the following: albumin 1.4 g/dL,
results are shown below: total protein 2.8 g/dL, and WBC count 200 cells/µL with 40%
PMNs. What is the best next step in his management?
Component Result a. Initiate therapy with furosemide and spironolactone

b. Order a transthoracic echocardiographic examination
Hemoglobin, g/dL 7.1 c. Start cefotaxime 2 g intravenously every 8 hours
MCV, fL 77.7 d. Order an upper endoscopic examination for variceal screening
Platelet count, ×109/L 67
INR 1.4 VI.29. A 66-year-old woman has alcohol-associated cirrhosis with
Total bilirubin, mg/dL 1.8 diuretic-responsive ascites. She presents to the emergency
Creatinine, mg/dL 1.1 department feeling dehydrated. Her medications include
levothyroxine 88 µg daily, furosemide 100 mg daily, and spi-
ronolactone 40 mg daily. Her heart rate is 78 beats/min, and
On EGD, antral red spots in a linear pattern suggest GAVE. her blood pressure is 105/50 mm Hg. Laboratory test results
Which of the following should you recommend to stop the are shown below:
bleeding?
a. TIPS Component Result
b. NSBB
Hemoglobin, g/dL 9.2
c. Surgical portosystemic shunt
WBC count, ×109/L 4.8
d. Argon plasma coagulation
Platelet count, ×109/L 88
VI.26. A 52-year-old man with alcohol-related cirrhosis presents Albumin, g/dL 2.5
to the emergency department with confusion. He has a his- Total bilirubin, mg/dL 2.0
tory of esophageal variceal hemorrhage, ascites, and a prior INR 1.3
episode of overt HE. His medications include furosemide, Creatinine, mg/dL 1.9
The creatinine value (1.9 mg/dL) was increased from 0.6 consume alcohol. He is an avid runner and has been training
mg/dL 1 week ago. On diagnostic paracentesis, the WBC for a marathon without any cardiopulmonary symptoms.
count is 100 cells/µL with 10% PMNs. Urinalysis shows no Laboratory tests are notable for normal CBC results and
proteinuria or other abnormality. What is the best next step normal levels of bilirubin and albumin; increased values for
in management? AST (204 U/L), ALT (284 U/L), and transferrin saturation
(64%); and a ferritin level of 692 µg/L. HFE gene testing
a. Fluid resuscitation with normal saline (0.9% sodium chlo-
confirms 2 copies of the C282Y alteration. What should you
ride) 1 L intravenously
advise next?
b. Midodrine and octreotide
c. Urgent evaluation for liver transplant a. Begin therapeutic phlebotomy weekly
d. Administration of 25% albumin 1 g/kg intravenously daily b. Begin therapeutic phlebotomy every 3 months
and discontinuation of diuretics c. Advise the patient to follow a strict low-iron diet
d. Initiate treatment with deferasirox
VI.30. A 63-year-old woman is referred for further evaluation of
e. Initiate treatment with trientene
high liver enzyme values, which were identified during rou-
tine health screening. Laboratory test results include the VI.33. A 21-year-old man is being evaluated for recently diagnosed
following: CBC normal, total and direct bilirubin levels cardiomyopathy. Liver test results were high (AST 185 U/L
normal, AST 103 U/L, ALT 49 U/L, and ALP 112 U/L. Her and ALT 215 U/L). Results of serologic evaluation show the
medical history is notable for hypothyroidism, hypertension, following: normal CBC and normal levels of bilirubin, al-
and obstructive sleep apnea. She does not have a family his- bumin, and ceruloplasmin level; and elevated results of iron
tory of liver disease or iron storage disorders. She consumes tests (transferrin saturation 75% and ferritin 893 µg/ L).
approximately 2 or 3 alcoholic beverages daily on most days. What is the most likely diagnosis?
On physical examination she has central obesity without stig-
a. Acute viral hepatitis
mata of chronic liver disease. Additional laboratory studies
b. Wilson disease
include negative results for hepatitis B and hepatitis C
c. Hereditary hemochromatosis (HFE alteration)
serologies, normal α1-antitrypsin genotype, transferrin satu-
d. Juvenile hemochromatosis (HJV alteration)
ration 39%, and serum ferritin 480 µg/L. What is the most
e. Ferroportin disease
likely diagnosis?
VI.34. A 55-year-old man presents with high levels of liver enzymes
a. Hereditary hemochromatosis
(ALT 68 U/L, AST 97 U/L, ALP 165 U/L, and total bilirubin
b. NAFLD
0.8 mg/dL). His BMI is 31, and during the past 10 years he
c. Alcohol-related liver disease
has been drinking 2 or 3 beers daily. Results from the other
d. Wilson disease
laboratory investigations are unremarkable, except for the
e. Ferroportin disease
iron studies (iron 250 µg/dL, ferritin 988 µg/L, and trans-
VI.31. A 19-year-old college student is brought to the emergency de- ferrin saturation 95%). Ultrasonography shows hepato-
partment by his roommate because of jaundice and altered megaly and normal spleen size. What is the best next step in
mental status. He had been feeling unwell with nonspecific management?
symptoms for the past 3 or 4 days. He has no previous med-
a. Liver biopsy for iron quantification
ical history. He typically consumes 2 or 3 beers on weekend
b. MRI with elastography for measurement of hepatic iron
nights but has not had anything to drink since he began
concentration
feeling unwell. The patient has not used recreational drugs,
c. HFE genetic testing
but he does have a new sexual partner. He has not traveled
d. Counseling for 10% weight loss and alcohol abstinence
outside the state this semester. On examination, he is drowsy
and difficult to arouse, he has intense jaundice, and he has VI.35. You are examining a 16- year-
old adolescent boy, who is
asterixis. He does not have palpable ascites. Notable labora- accompanied by his parents, for right upper quadrant pain.
tory test results are shown below: An incidental finding is increased values for liver enzymes.
The ceruloplasmin level is 20 mg/ dL, and the 24- hour
urine copper level is 120 µg. What is the best next step in
Component Result
management?
a. Ophthalmologic referral for assessment for Kayser-Fleischer
INR 2.8
rings
Direct bilirubin, mg/dL 4.5 b. Liver biopsy for copper quantification
AST, U/L 109 c. Testing for serum copper level
ALT, U/L 128 d. Genetic testing for ATP7B variants
ALP, U/L 75 VI.36. You have made a definitive diagnosis of Wilson disease in a
patient and want to start treatment. What are the potential
Results of abdominal ultrasonography and additional complications from treatment?
serologies, including laboratory tests for viral hepatitis, are a. Acute liver failure
pending. What is the most likely diagnosis? b. New-onset extrapyramidal symptoms
a. Acute BCS c. Sideroblastic anemia
b. Acute hepatitis A d. Myelopathy with weakness and ataxia
c. Acute hepatitis B VI.37. A patient with increased liver enzyme levels has been re-
d. Wilson disease ferred to you for evaluation. The laboratory test results in-
e. Alcohol-related hepatitis clude the following: ALT 68 U/L, AST 78 U/L, ALP 115 U/L,
VI.32. A 54-year-old man presents for evaluation because his older and total bilirubin 0.7 mg/dL. The other results are un-
brother recently received a diagnosis of cirrhosis secondary to remarkable. You perform a complete evaluation for causes
hemochromatosis. The patient has no symptoms and does not of chronic liver disease. The α1- antitrypsin level is low
(75 mg/dL). What is the most likely diagnosis and the best 10-day course of amoxicillin-clavulanate, and her symptoms
next step in management? improved. However, jaundice, generalized itching, low-grade
fever, fatigue, and nausea developed over the past 2 days. She
a. Pi*ZZ phenotype; liver biopsy to assess for globules with pe-
does not have abdominal pain or confusion. Laboratory tests
riodic acid-Schiff–diastase staining and for staging of fibrosis
show abnormal values for ALP (650 U/L) and total bilirubin
b. Pi*ZZ phenotype; pulmonary function tests to assess for
(10 mg/dL) and normal values for AST, ALT, albumin, INR,
emphysema
and the CBC. Results were negative for ANA, AMA, and
c. Pi*MZ phenotype; noninvasive testing for fibrosis
ASMA. Viral hepatitis serology results were unremarkable.
d. Pi*MZ phenotype; screening ultrasonography for HCC
VI.38. A 52-year-old woman presents with pruritus and fatigue.
a. Initiate a short course of prednisone 40 mg daily with taper
She is otherwise healthy and does not use medications or
dosing
supplements. Liver test results are as follows: ALT 134 U/L,
b. Proceed with a liver biopsy
AST 72 U/L, ALP 653 U/L, and total bilirubin 1.1 mg/dL.
c. Proceed with evaluation for liver transplant
Abdominal ultrasonographic findings are normal. What is
d. Provide conservative management with close monitoring of
her liver profile
a. ERCP
VI.43. A 62-year-old woman has a known history of hypertension,
b. AMA testing
type 2 diabetes, obesity, and recurrent urinary tract infections
c. Liver biopsy
requiring several courses of antibiotics over the past year. She
d. MRCP
presented to her primary care physician with dysuria and
VI.39. A 22-year-old man recently received a diagnosis of PSC. He is lower abdominal discomfort for 3 days. Urinalysis confirmed
asymptomatic and has 1 formed, nonbloody bowel movement a urinary tract infection, and she was prescribed nitrofuran-
daily. Laboratory test results are shown below: toin 100 mg twice daily for 7 days. She also took acetamin-
ophen 325 mg twice daily as needed. She continued to take
metformin and amlodipine as her regular home medications.
Component Result
A few weeks later, she presents with fatigue, jaundice, and
ALT, U/L 155 nausea. Blood work results include serum ALT, 1,250 U/L;
AST, U/L 172 ALP, 142 U/L; and total bilirubin, 3.3 mg/dL. ANA is present
ALP, U/L 1,053 (1:160), and globulin levels are mildly elevated. Viral hepa-
Total bilirubin, mg/dL 0.8 titis serology results are unremarkable. What is the best next
INR 1.1 step in management?
WBC count, ×109/L 4.5 a. Recommend a liver biopsy
Platelet count, ×109/L 356 b. Initiate prednisone 40 mg daily
c. Stop nitrofurantoin
d. Recommend abdominal Doppler ultrasonography
MRCP shows multifocal biliary strictures involving the
intrahepatic ducts. What is the best next step? VI.44. A 50-year-old man presents with a known history of coronary
artery disease, hypertension, type 2 diabetes, and hyperlip-
a. Refer for liver transplant evaluation idemia. He takes lisinopril, metoprolol, and metformin. He
b. Start therapy with ursodeoxycholic acid (28-30 mg/kg in di- began taking atorvastatin 1 month earlier. He has adhered to
vided doses) his medical therapy, and he does not have any new symptoms.
c. Perform abdominal ultrasonography He drinks alcohol 4 times a week. At an annual evaluation,
d. Perform colonoscopy with random biopsies he had increased values for AST (70 U/L) and ALT (74 U/L).
VI.40. A 67-year-old woman with PBC was recently referred to your Otherwise, results were unremarkable for ALP, total bili-
clinic. Three months ago, she tripped on carpet in her home, rubin, a CBC, and a kidney profile. Abdominal ultrasonog-
fell, and fractured her right hip. She underwent an uncom- raphy showed a hyperechoic liver consistent with fatty liver
plicated right hip replacement. What is the best next step in but otherwise no liver masses or biliary ductal dilatation.
management? What is the best next step in management?
a. Start supplementation with calcium (1,500 mg daily) and vi- a. Withhold atorvastatin and monitor the liver enzymes
tamin D (800 IU daily) b. Stop alcohol consumption and recommend liver biopsy to
b. Check ionized calcium levels confirm the diagnosis of steatohepatitis
c. Begin therapy with a bisphosphonate c. Continue atorvastatin
d. Perform bone densitometry d. Recommend magnetic resonance elastography to assess the
stage of fibrosis
VI.41. You are evaluating a 32-year-old man with asymptomatic
cholestasis and a history of ulcerative colitis. Liver test VI.45. A 40-year-old man presents to the emergency department
results are as follows: ALT 52 U/L, AST 47 U/L, ALP 563 U/L, of a community hospital with abdominal pain, nausea, and
and total bilirubin 1.0 mg/dL. AMA test results are nega- vomiting. A year ago, he had acute cholecystitis, for which
tive and MRCP findings are normal. What is the most likely he underwent laparoscopic cholecystectomy; however, he
diagnosis? states that his current symptoms are different. Earlier this
week, he had flulike symptoms and myalgia. He has been
a. HIV-related cholangiopathy taking 2 extra-strength acetaminophen tablets 3 or 4 times
b. Large-duct PSC daily to help him finish an important project he is working
c. Small-duct PSC on. The last dose of acetaminophen was before his presen-
d. PBC tation to the emergency department. He also states that he
VI.42. A 28- year-
old woman has a known history of seasonal has been drinking a couple beers each night to help with his
allergies. She received a diagnosis of peritonsillar abscess stressful job. On physical examination, he appears ill but is
1 month ago when she presented to the primary care clinic awake and alert. Blood work results at presentation showed
with acute cough, fever, and severe sore throat. She received a an unremarkable CBC but increases in AST (3,500 U/L), ALT
(2,500 U/L), INR (3.5), and total bilirubin (2.2 mg/dL). The a. Avoid use of minocycline in the future, and start prednisone
creatinine level is 2 mg/dL. Results for the acetaminophen therapy with subsequent taper
level and viral hepatitis serology are pending. Findings from b. Start therapy with prednisone and azathioprine
abdominal ultrasonography are unremarkable. What is the c. Refer the patient for liver transplant evaluation
best next step in management? d. Assess AMA
a. Wait for the acetaminophen level results before considering VI.48. A 28-year-old woman presents with fatigue, scleral icterus,
intravenous N-acetylcysteine and mild constant discomfort in the right upper quadrant
b. Administer penicillin G of her abdomen. The symptoms began 6 months earlier. At
c. Recommend intravenous corticosteroids for 7 days that time ALT was 500 U/L, ALP was 125 U/L, and total bil-
d. Administer activated charcoal and intravenous N-acetylcysteine, irubin was 3.1 mg/dL. No additional testing was performed
and monitor the patient in the hospital at that time. One year earlier she recalled being told that her
aminotransferase levels were high, but they had been normal
VI.46. A 55-year-old man with a past medical history of type 2
on routine testing when she was 25 years old. Five years ago,
diabetes and hypertension presents for evaluation of
when she received a diagnosis of hypothyroidism and celiac
increased liver enzyme levels detected during a routine an-
sprue, she began therapy with levothyroxine; since then, she
nual visit. He does not consume alcohol. His medications
has adhered to a gluten-free diet. She does not use alcohol,
include lisinopril and metformin. On physical examination,
supplements, or other medications. On examination she has
his blood pressure is 132/89 mm Hg, and he appears well.
scleral icterus and jaundice. Current laboratory test results
His BMI is 36. He has obesity, but abdominal examination
are shown below:
findings are otherwise normal. Laboratory test results are
shown below:
Component Result
Component Result ALT, U/L 567
AST, U/L 450
ALT, U/L 55 ALP, U/L 189
AST, U/L 40 Total bilirubin, mg/dL 4.5
ALP, U/L 90 Direct bilirubin, mg/dL 4.0
Total bilirubin, mg/dL 1.0 INR 1.2
Hemoglobin A1c,% 8.5 Albumin, g/dL 3.6
Lipid profile Normal Ferritin, µg/L 300
Hepatitis A and C serology Negative Transferrin saturation, % 22
Hepatitis B core and surface antibodies Positive IgG, mg/dL 7,620
Hepatitis B surface antigen Negative
Serum IgG Normal
ANA 1:160 Results for the following are normal or negative: thyro-
tropin, hepatitis B surface antigen, hepatitis C antibody,
ANA, SMA, AMA, ceruloplasmin, tissue transglutaminase
Ultrasonography of the liver showed increased echogenicity
IgA, serum IgA, and α1-antitrypsin. Abdominal ultrasonog-
consistent with hepatic steatosis. What is the most likely
raphy shows nonspecific coarsening of the liver parenchyma
diagnosis?
without ductal dilation or splenomegaly. A liver biopsy shows
a. Chronic hepatitis B moderate inflammation with a lymphoplasmacytic infiltrate
b. NAFLD and interface hepatitis with stage 3 fibrosis. What is the most
c. Autoimmune hepatitis likely cause of the increased liver test values?
d. PBC
a. Celiac sprue
VI.47. A 19- year-old woman presents with recent- onset fatigue b. Hemochromatosis
and scleral icterus. She has a history of acne and recently c. Drug-induced liver injury
completed a course of minocycline 2 weeks before the onset d. Autoimmune hepatitis
of symptoms. On examination she has scleral icterus and
VI.49. A 48-year-old woman presents to your office for routine
jaundice without other abnormal findings. Laboratory tests 6
follow-up and reports no problems. She received a diagnosis
months ago showed normal liver values. Current laboratory
of autoimmune hepatitis 7 months ago when she presented
test results are shown below:
with jaundice. Test results at that time showed the following:
Component Result
Component Result
Direct bilirubin, mg/dL 5.0 Total bilirubin, mg/dL 8.5
ALT, U/L 624 ALT, U/L 1,005
AST, U/L 510 AST, U/L 905
ALP, U/L 180 ALP, U/L 200
IgG, mg/dL 1,400 ANA 1:1,280
INR 1.2 SMA 1:320
Epstein-Barr virus Negative IgG, mg/dL 7,620
Hepatitis A, B, and C Negative
ASMA, ANA, and anti-LKM Normal Results from laboratory investigations for other causes of
chronic liver disease were unremarkable. At that time, she did
Abdominal ultrasonographic findings are normal. Liver not use medications or supplements, and a liver biopsy showed
biopsy shows mild interface hepatitis and plasma cell infil- severe inflammation with lymphoplasmacytic infiltrate, areas
tration of the hepatic parenchyma. There is no evidence of of necrosis, and interface activity. Bridging fibrosis was also
fibrosis. What is the best next step? present. Prednisone therapy was initiated, and the laboratory
test results improved. Azathioprine was added several weeks what treatments are available for her condition. Which of the
later, and the prednisone dose was slowly tapered as the liver following statements is true?
test results improved. Three months ago, the liver test results
a. Initiation of statin therapy is safe despite the increased liver
were normal, and prednisone was decreased to 10 mg daily.
test values
Now she takes azathioprine 50 mg daily and prednisone 5 mg
b. Alcohol cessation counseling should be considered
daily. Results of the physical examination, CBC, and blood
c. Prophylactic use of metformin is beneficial for NASH
glucose and liver tests are normal. What is the best next step?
d. A ketogenic diet is recommended for NASH
a. Stop prednisone therapy and continue use of azathioprine 50
VI.53. In which of the following genes are variants protective against
mg daily
the development of advanced fibrosis in NAFLD?
b. Discontinue use of azathioprine but continue prednisone
therapy a. PNPLA3
c. Start mycophenolate mofetil therapy (1,000 mg twice daily) b. MBOAT7
and discontinue use of azathioprine and prednisone c. TM6SF2
d. Discontinue use of azathioprine and prednisone and monitor d. HSD17B13
laboratory results for relapse
VI.54. A 25- year-
old woman who is pregnant for the first time
VI.50. A 50-year-old man is referred to you for evaluation of un- presents during the 35th week of gestation with abdominal
explained elevated liver enzymes for the past 6 months. pain, nausea, and vomiting for 2 days. Her blood pressure is
Laboratory test results are shown below: 140/90 mm Hg. She is somnolent; she does not have jaundice.
Pertinent laboratory test results are shown below:
Component Result
Component Result
AST, U/L 70
ALT, U/L 84 Hemoglobin, g/dL 11.3
ALP, U/L 90 Platelet count, ×109/L 140
Total bilirubin, mg/dL 0.9 AST, U/L 180
Serum albumin, g/dL 4.0 ALT, U/L 238
CBC Normal Bilirubin, mg/dL 0.9
Hepatitis B surface antigen Negative INR 2.0
Hepatitis B surface antibody Positive Creatinine, mg/dL 1.5
Hepatitis B core antibody, total Negative Lactate dehydrogenase, U/L 250
Hepatitis C antibody Negative Glucose, mg/dL 55
ANA 1:40
ASMA Negative
AMA Negative What is the best next step for management?
Iron studies Normal a. Test for viral hepatitis
α1-Antitrypsin phenotype MM b. Continue to monitor with liver tests and other laboratory tests
c. Control the patient’s blood pressure
Ultrasonography of the liver shows an enlarged, echogenic d. Proceed with a prompt delivery
liver with patent portal and hepatic veins and no radio- VI.55. A 30-year-old pregnant woman with a gestational age of 14
graphic signs of portal hypertension or cirrhosis. Physical ex- weeks presents to the emergency department with a new
amination findings are notable for central obesity (BMI, 39) onset of right upper quadrant abdominal pain for the past
in a man who appears well otherwise. His past medical his- 2 hours. The pain started approximately 1 hour after her
tory includes diagnoses of type 2 diabetes, hypertension, and dinner. Laboratory results are unremarkable except for ALT
obstructive sleep apnea. His medications include metformin of 78 U/L. Abdominal ultrasonography shows cholelithiasis
and hydrochlorothiazide. He has not used any alcohol since without biliary duct dilatation. The pain subsided in the
his 20s. What is the best next step in management? emergency department during evaluation. What is the best
a. Prescribe prednisone for autoimmune hepatitis next step for management?
b. Perform EGD to look for varices a. Proceed with cholecystectomy
c. Perform liver biopsy b. Conservative management
d. Reassure the patient and repeat the tests in 4 weeks c. Proceed with MRCP to rule out biliary obstruction given the
VI.51. A 60-year-old man with obesity and type 2 diabetes receives abnormal value for ALT
a diagnosis of NASH with stage F3 fibrosis according to liver d. Proceed with ERCP
biopsy results. What is the most common cause of death VI.56. A 28-year-old woman was found to have hepatitis B infection
among patients with NASH? about 1 year ago. She does not have cirrhosis and has not
a. Liver cancer received any antiviral treatment. She is pregnant with a ges-
b. Other malignancies tational age of 14 weeks. She was referred from her primary
c. Cardiovascular disease care provider to you for advice. Her mother and her other
d. Infection 2 siblings also have chronic hepatitis B. She feels well. She
is aware that her newborn child should receive both HBV
VI.52. A 60-year-old woman underwent a liver biopsy for persistent, vaccine and hepatitis B immunoglobulin. Her laboratory test
slightly increased liver test values. Biopsy findings showed results include a platelet count of 300×109/L and ALT of 12 U/
histologic features typical of NASH with stage 1 fibrosis. Her L. Results are positive for hepatitis B surface antigen, hepa-
past medical history is notable for obesity (BMI, 32), hyper- titis B core antibody, and hepatitis B e antigen. The level of
tension, and hyperlipidemia (LDL cholesterol, 90 mg/dL). HBV DNA is 106 IU/mL. What should you advise this patient?
Her hemoglobin A1c is 5.9%, and she drinks 2 or 3 glasses of
wine weekly. In addition to adopting lifestyle interventions a. Start lamivudine now
to achieve a weight loss of 5% to 10%, she wants to know b. Start tenofovir now
c. Repeat the tests for HBV DNA and ALT in 3 months and de- a. Liver biopsy
cide whether antiviral treatment is indicated at that time b. Doppler ultrasonography of the abdomen
d. No further testing is indicated until after pregnancy c. CT of the head
d. Withhold tacrolimus therapy
VI.57. A 26-year-old woman with a history of autoimmune hepa-
titis has just found out that she is pregnant. Her gestational VI.61. A 54-year-old man underwent deceased-donor liver trans-
age is approximately 8 weeks. She does not have cirrhosis, plant for cirrhosis secondary to chronic hepatitis C. He re-
and her autoimmune hepatitis has been in remission during ceived chronic hepatitis C therapy before liver transplant and
the past year. Her current treatment is monotherapy with had a sustained virologic response. He was discharged home
azathioprine 150 mg once daily. She feels well. Laboratory within a week with no immediate complications. He presents
test results include AST 15 U/L and ALT 20 U/L. She presents to the liver transplant clinic 4 weeks after liver transplant. His
to your clinic to discuss medication management during her CBC results are similar to previous results. Liver test results,
pregnancy. What should you advise this patient? which are increased compared to results from 1 week before,
are as follows: total bilirubin, 2.2 mg/dL; ALT, 195 U/L; AST,
a. Continue therapy with azathioprine
210 U/L; and ALP, 305 U/L. Findings from Doppler ultra-
b. Change the therapy from azathioprine to prednisone, and plan
sonography of the liver were unremarkable except for mild
to continue use of prednisone throughout the pregnancy
steatosis. The patient describes adherence to the tacrolimus
c. Stop the azathioprine therapy, and do not use any medication
regimen, and his current tacrolimus trough level is 3.0 ng/
during the pregnancy because autoimmune diseases tend to
mL. What is the most likely diagnosis?
become less active during pregnancy
d. Stop the azathioprine therapy and restart it during the second a. Recurrent hepatitis C infection
trimester b. Acute cellular rejection
c. Hepatic artery thrombosis
VI.58. A 66-year-old man has a known history of chronic hepatitis C
d. Cytomegalovirus infection
cirrhosis. When he received direct-acting antiviral therapy for
chronic hepatitis C infection, genotype 1, he had a sustained
virologic response. He is asymptomatic and has no ascites, Answers
encephalopathy, or evidence of bleeding in the gastrointes-
tinal tract. He is presenting for routine follow-up for HCC VI.1. Answer d.
screening. His MELD score is 10. Recent upper endoscopy The patient presents with increased liver test results and symptoms
showed grade 2 esophageal varices. The alpha fetoprotein compatible with a recent viral infection. The symptoms and
level is 320 ng/mL. Ultrasonography of the abdomen shows lymphocytosis would be compatible with infectious mononu-
a liver mass. CT of the abdomen provided confirmation of a cleosis, most likely due to Epstein-Barr virus. Minocycline can
4-cm mass in the right hepatic lobe. The mass shows arterial cause a drug-induced liver injury that mimics autoimmune hep-
enhancement with portal venous washout. Hepatic vessels are atitis, but that would be less likely than an infection to explain
patent without thrombosis. CT of the chest and a bone scan the sore throat, fever, and enlarged lymph nodes. Wilson disease
show no evidence of metastatic disease. What is the best next
should always be considered when a patient presents with acute
step in management?
liver disease, but that would not explain the symptoms, which
a. Biopsy of the lesion under ultrasonographic guidance to con- suggest infection. Lymphoma can result in fever and abnormal
firm the diagnosis liver test results but would be less likely than infectious mon-
b. Administration of sorafenib 400 mg orally twice daily onucleosis for explaining an acute syndrome that includes sore
c. Evaluation for liver transplant
throat. Acetaminophen hepatic toxicity produces much higher
d. Interventional radiology consultation for transarterial emboli-
zation of the tumor before surgical consultation for resection liver enzyme levels than present in this patient. In addition, 2 g of
acetaminophen daily is unlikely to cause liver injury.
VI.59. A 62-year-old woman with a known history of PBC presents
to the general hepatology clinic for a scheduled follow-up. Her VI.2. Answer c.
liver biopsy 2 years ago showed cirrhosis. She has not had he- Acute biliary obstruction, usually from a stone, can produce mark-
patic encephalopathy, variceal bleeding, or ascites. Her main edly increased levels of aminotransferases, and the clinical pre-
symptoms are fatigue, pruritus, and leg edema. Her current
sentation, gallbladder stones, and positive blood cultures would
MELD score is 17. What is the best next step in management?
be compatible with acute cholangitis. According to guidelines,
a. Recommend ultrasonography of the abdomen every 6 months the patient should undergo ERCP directly. Both endoscopic ultra-
for HCC screening because she has PBC sonography and MRCP are reasonable options, but when clinical
b. Recommend an annual bone density scan suspicion is high, as in this case, it is best to proceed directly
c. Postpone liver transplant evaluation until her MELD score is
with ERCP. Laparoscopic cholecystectomy should be considered
greater than 20
d. Proceed with liver transplant evaluation after her episode of acute cholangitis resolves. In the absence of
clinical features suggestive of portal hypertension, Doppler ul-
VI.60. A 70-year-old man underwent deceased-donor liver trans- trasonography of the hepatic vasculature would be unnecessary.
plant 1 year ago for NASH. He has been receiving immuno-
suppressive therapy with tacrolimus. Odynophagia developed VI.3. Answer b.
recently, and upper endoscopy showed candidal esopha- This asymptomatic patient has a cholestatic liver disease and ev-
gitis, for which he was prescribed fluconazole. He called idence of lymphadenopathy with interstitial lung disease. This
the transplant clinic this morning and reported an acute, constellation of findings suggests sarcoidosis. Amyloidosis
worsening headache and vomiting but no light-headedness
can present as intrahepatic cholestasis, but patients usually are
or presyncope. On presentation the physical examination
findings were remarkable for new tremors in both hands, and more ill with abnormalities of the CBC. PSC would be a consid-
he appeared anxious. Results from liver profile testing were eration if the patient had a history of ulcerative colitis. PBC is
unremarkable, but the creatinine level increased to 2.0 mg/dL more common in women than in men. Celiac disease should be
from 1.2 mg/dL 1 month before. Results for tacrolimus trough excluded in patients with chronic liver disease but would be un-
level are pending. What is the best next step in management? likely to explain the pulmonary findings.
VI.4. Answer a. venous phase are most likely either a focal nodular hyperplasia
The marked AST out of proportion to the ALT is suggestive or a hepatic adenoma. Because they contain biliary elements,
of muscle injury. Severe muscle injury, as can occur with focal nodular hyperplasias retain contrast material in the biliary
polymyositis or rhabdomyolysis, may produce enough muscle in- phase of MRI with gadoxetate. Because hepatic adenomas con-
jury to cause an increase in ALT. ALT has a longer half-life than sist of sheets of hepatocytes with naked arteries but no biliary
AST; therefore, improvements occur less rapidly than for AST. elements, they do not retain contrast material in the biliary phase
Liver disease associated with alcohol produces an increased AST of multiphasic imaging. Hepatic hemangiomas show peripheral
to ALT ratio, but the AST is rarely over 400 U/L and would cer- nodular enhancement of the mass that fills in during the portal
tainly not be increased to this extent. Acute viral hepatitis would venous and delayed phases of the imaging study. Intrahepatic
produce an ALT that is generally the same or slightly higher than cholangiocarcinomas show moderate enhancement in the arterial
the AST. Acetaminophen hepatic toxicity and hepatic ischemia phase that increases progressively during the portal venous and
produce markedly increased levels of aminotransferases, but the delayed phases of imaging.
ALT is elevated to a similar range as the AST.
VI.10. Answer c.
VI.5. Answer d. The recommended age for starting surveillance for HCC in per-
Grazoprevir, glecaprevir, and voxilaprevir are all NS3/4A pro- sons with chronic hepatitis B without cirrhosis depends on the
tease inhibitors, which are contraindicated in patients with de- person’s region of birth and sex. For Asian men, the recommended
compensated cirrhosis because of the risk of worsening hepatic age for initiation of surveillance is 40 years. For persons (male or
decompensation. Sofosbuvir and the NS5A inhibitors (including female) born in Africa, 20 years is the recommended age for sur-
ledipasvir) are safe to use in patients with decompensated cir- veillance initiation, and for women born in Asia, 50 years is the
rhosis, although they are most often used in patients who have recommended age. Age 30 years is not a recommended age for
MELD scores of 20 or less. surveillance initiation for any group of persons.
VI.6. Answer e. VI.11. Answer b.
The positive findings for HBsAg and IgM anti-HBc are consistent Laparoscopic decompression and unroofing or fenestration of
with acute hepatitis B infection. This patient has acute liver injury a cyst wall is usually definitive therapy for a large or recurrent
but not acute liver failure given the absence of hepatic encepha- simple cyst. A second cyst aspiration and sclerosis is less likely to
lopathy and coagulopathy. Therefore, neither liver transplant nor succeed as the sclerosant causes thickening of the cyst walls, and
N-acetylcysteine is appropriate. Treatment of hepatitis B is not in- it becomes more difficult to completely empty and collapse the
dicated given that more than 95% of adults with acute hepatitis B cyst. Diuretic therapy typically has no effect on the cyst volume.
recover spontaneously and do not require specific treatment. Oral Liver transplant may be required for patients with progressive
antiviral drugs are recommended (in addition to urgent listing for adult polycystic liver disease whose functional status is severely
liver transplant) for patients who have acute HBV infection with compromised, but it typically is not indicated for a patient with a
acute liver failure or severe, protracted (>4 weeks) symptoms. recurrent simple cyst.
VI.7. Answer b. VI.12. Answer b.
This patient has evidence of chronic hepatitis B with a posi- This patient has cirrhotic-stage PSC. The evidence of malig-
tive surface antigen. Hepatitis B has been reported to reactivate nancy is conclusive from positive results on cytology, and FISH
during treatment of hepatitis C with DAA therapy. Although 29 shows polysomy. Liver transplant after combined chemoradiation
cases of HBV reactivation, including 2 patients who died and 1 therapy (the protocol at Mayo Clinic) would offer the best chance
patient who required liver transplant, were initially reported to of long-term survival. Surgical resection is generally not advised
the US Food and Drug Administration, this is not unique to a for patients with cirrhotic-stage PSC because of the likelihood
particular DAA regimen and occurs at 4 to 8 weeks. Most of the of liver decompensation after surgery. Radiofrequency ablation
patients had positive results for HBsAg and a low level of HBV is considered palliative therapy for patients who have inoperable
DNA. One patient had an isolated anti-HBc. The recommenda- biliary tract cancer. Similarly, photodynamic therapy is used as a
tion is to test for HBsAg, anti-HBs, and anti-HBc at baseline palliative treatment.
and to check HBV DNA in patients who have positive results
for HBsAg. Hepatitis B treatment or vaccination should be de- VI.13. Answer a.
termined according to standard guidelines. HBV DNA should be Patients who have advanced BCLC stage C HCC and are not at
monitored about every 4 weeks if results are positive for HBV risk for variceal bleeding are candidates for first-line systemic
DNA at baseline. Antiviral treatment should be initiated if the therapy with atezolizumab and bevacizumab. Sorafenib is a rea-
HBV DNA level increases more than 10 times or exceeds 1,000 sonable choice for first-line treatment of patients who are not
IU/mL in a patient who has undetectable or unquantifiable levels candidates for treatment with atezolizumab and bevacizumab or
of HBV DNA before DAA treatment. with the alternative first-line treatment of durvalumab in combi-
nation with tremelimumab. Best supportive care is not appropriate
VI.8. Answer d. for this patient who still has several treatment options available.
The interaction between amiodarone and sofosbuvir-containing Ramucirumab is approved for second-line treatment of patients
regimens can result in serious bradycardia requiring a pacemaker whose condition has progressed after use of first-line sorafenib
or in death. Amiodarone therapy is an absolute contraindication and whose AFP level is 400 ng/mL or more.
for the use of sofosbuvir-containing regimens.
VI.14. Answer b.
VI.9. Answer c. This patient has alcohol-related steatohepatitis. Risk factors in-
Masses that show rapid arterial phase enhancement and a re- clude female sex and a history of weight loss surgery. In this sce-
turn to the isointensity of the surrounding liver in the portal nario, considerable liver injury can occur at a lower threshold of
alcohol intake, so she should abstain from drinking alcohol. The is a risk factor for splenic vein thrombosis, which can lead to
high AST:ALT ratio supports the diagnosis. Weight loss would be sinistral portal hypertension. CT with a contrast agent would be
reasonable but is not the best answer among the choices provided. the next step to assess for splenic vein thrombosis. For patients
None of the information about this patient suggests that she has with gastric varices due to splenic vein thrombosis, splenectomy
cholestatic liver disease or a need for ursodiol. Her liver synthetic can be curative. Nonselective β-blockers such as propranolol are
function is preserved, so evaluation for transplant is not needed. used for prophylaxis against bleeding in patients with portal hy-
pertension but not for an acute situation. Gastric fundic varices
VI.15. Answer b. are typically not amenable to endoscopic band ligation. TIPS is
This patient has severe alcohol-related hepatitis without cirrhosis. the treatment of choice for bleeding gastric fundic varices from
Patients with alcohol-related hepatitis can have a profound he- cirrhosis. Liver transplant is not indicated for patients with sinis-
patic bruit related to dilation of the hepatic artery. The other antral portal hypertension.
swer choices are also causes of hepatic bruits, but they are less
likely in this patient. Splenorenal shunting is unlikely without VI.20. Answer e.
splenomegaly. HCC is unlikely in the absence of cirrhosis. This patient had delayed gastrointestinal bleeding after a liver
A Cruveilhier-Baumgarten murmur is caused by recanalization biopsy. The most likely cause is an iatrogenic fistula between
of the umbilical vein in a person with chronic portal hyperten- a branch of the hepatic artery and a branch of the portal vein.
sion, which this patient does not have. Rupture of the hepatic artery branch leads to an acute increase
in portal pressure with ascites and gastrointestinal tract bleeding.
VI.16. Answer c. Although both hepatic vein thrombosis (as in BCS) and portal
This is an example of therapeutic misadventure, in which a reg- vein thrombosis could occur acutely, the recent liver biopsy
ular user of alcohol has an intercurrent illness, stops drinking, makes the fistula more likely. The patient does not have risk
and begins taking over-the-counter medications containing ace- factors for hepatic artery thrombosis. Patients with hepatic artery
taminophen. Chronic alcohol exposure induces the cytochrome aneurysms are typically asymptomatic until the aneurysms rup-
P450 2E1 isozyme system that also metabolizes acetaminophen ture, but then hemoperitoneum and hemorrhagic shock would be
to acetaldehyde, allowing for acetaminophen hepatotoxicity to the presenting signs.
occur at lower doses. Ironically, stopping alcohol use accentuates
this problem. Even moderate doses of acetaminophen can cause VI.21. Answer b.
hepatotoxicity in this scenario. COVID-19–related hepatitis is The pattern of extremely high liver test results (several thou-
possible, but the transaminase values are increased out of pro- sand units per liter) with rapid improvement after supportive care
portion. Azithromycin is not a typical cause of drug-induced suggests ischemic hepatopathy. The most likely cause in this pa-
autoimmune- like hepatitis, and this entity also rarely causes tient is global hypotension and vasoconstriction from metham-
transaminase values to increase to more than 1,000 U/L. Severe phetamine intoxication. The laboratory pattern does not suggest
alcohol-related hepatitis is unlikely with this quantity of alcohol alcohol-associated hepatitis (in which aminotransferase levels are
consumption, and other features of alcohol-related hepatitis are typically 200-300 U/L). Although the patient has risk factors for
not present. acute viral hepatitis, a rapid improvement in the liver tests would
not be expected.
VI.17. Answer a.
Although acetaminophen can be hepatotoxic, acetaminophen is VI.22. Answer c.
the analgesic of choice for patients with cirrhosis. This is true This patient is presenting for evaluation of increased amino
even in alcohol-related cirrhosis as long as the patient is not cur- transferase values. She does not have thrombocytopenia (platelet
rently drinking alcohol. The total cumulative daily dose of ace- count >150×109/L), and transient elastography does not suggest
taminophen should remain less than 2,000 mg. Nonsteroidal that she has clinically significant portal hypertension (liver stiffness
anti-inflammatory drugs such as ibuprofen can precipitate gas- <20 kPa). Therefore, according to the American Association for the
trointestinal bleeding and hepatorenal syndrome in people with Study of Liver Diseases guidelines, she has a low risk for large
cirrhosis. Opiates such as oxycodone can precipitate or worsen he- esophageal varices, and screening endoscopy can be deferred.
patic encephalopathy. Elective surgery would be contraindicated Transient elastography and platelet count should be repeated annu-
because of the high risk of hepatic decompensation with general ally. Although portosystemic collaterals can be incidentally noted
anesthesia. on cross-sectional imaging, CT scans are not recommended to
screen for varices. NSBBs have been shown to reduce the risk of
VI.18. Answer e. first decompensation in patients with clinically significant portal
This woman has BCS and acute (fulminant) liver failure hypertension; however, this patient does not have features that
characterized by the acute onset of jaundice, coagulopathy, and suggest clinically significant portal hypertension.
hepatic encephalopathy. For a patient with acute liver failure, the
most appropriate next step is referral for urgent liver transplant. VI.23. Answer b.
Although anticoagulation is critical in the management of BCS, Continued screening for varices is indicated in 2 years. The
this patient’s condition has progressed despite anticoagulation presumed cause of the cirrhosis is NASH, and this patient has
therapy. TIPS can be used in patients who have BCS that is not obesity with features of the metabolic syndrome. For patients
responsive to anticoagulation, but it is not the best treatment if a who have compensated cirrhosis and quiescent injury, such as
patient has acute liver failure. hepatitis C infection that has been eradicated, the screening in-
terval can be decreased to every 3 years. Studies suggest that
VI.19. Answer b. NSBBs are not effective in preventing the development of var-
This patient had an episode of upper gastrointestinal bleeding ices; therefore, initiation of NSBB therapy is not warranted. This
from isolated gastric varices, but he did not have a history of cir- patient has thrombocytopenia, so continued endoscopic surveil-
rhosis or chronic liver disease. The prior episode of pancreatitis lance for varices is indicated.
VI.24. Answer d. to rule out a cardiac cause, which could include constrictive
This patient’s presentation is concerning for variceal bleeding. pericarditis or right-sided heart failure. Doppler abdominal ul-
In patients with suspected variceal bleeding, after intubation trasonography would also be a reasonable option to rule out
and establishment of intravenous access, hemodynamic resus- BCS, although a cardiac cause appears more likely given his
citation is warranted. Guidelines recommend a conservative history. Furosemide and spironolactone could be considered to
transfusion strategy with a hemoglobin goal of 7 g/dL to pre- help manage the ascites, but the underlying diagnosis should
vent portal pressure increases associated with excessive volume be clarified first. The patient does not have spontaneous bac-
resuscitation. Studies have not shown benefit after transfusion terial peritonitis, so he does not require antibiotics. Upper en-
of clotting factors; thus, fresh frozen plasma transfusion is not doscopy is recommended for variceal screening if patients have
warranted. Therapy with an intravenous proton pump inhibitor cirrhosis when the first decompensating event occurs, but it is
and octreotide should be started without delay. Antibiotics are not clear that this patient has cirrhosis.
also warranted to prevent sepsis and have been shown to decrease
mortality associated with variceal bleeding. EGD for band liga- VI.29. Answer d.
tion is recommended within 12 hours of admission and after the This patient has acute kidney injury and cirrhosis with ascites.
patient is hemodynamically stable. Before a diagnosis of hepatorenal syndrome–acute kidney injury
is made, she must first have no improvement in kidney function
VI.25. Answer d. after 2 days of diuretic withdrawal and plasma volume expan-
This patient presents with microcytic anemia due to gastroin- sion with 25% albumin. In patients with cirrhosis, normal saline
testinal blood loss. EGD shows GAVE. In contrast to portal should generally be avoided, and albumin is the preferred volume
hypertensive gastropathy, GAVE does not typically respond to expander. She does not have a confirmed diagnosis of hepatorenal
portosystemic shunts, regardless of whether they are done sur- syndrome, so midodrine and octreotide and urgent evaluation for
gically or as a TIPS. NSBBs have also not shown efficacy in re- liver transplant are not yet necessary.
ducing blood loss due to GAVE. Thermoablation therapies such
as argon plasma coagulation can decrease bleeding and are often VI.30. Answer c.
first-line therapy in the management of GAVE. This patient has an isolated increase in the serum ferritin level.
This is a common clinical pitfall, which can lead to confusion.
VI.26. Answer d. This patient’s alcohol consumption is above the threshold for
This patient has spontaneous bacterial peritonitis, and antibiotic causing liver injury in a woman (ie, >1 standard alcoholic bev-
therapy with cefotaxime must begin immediately to reduce mor- erage daily), and she has laboratory evidence of alcohol-related
tality. Nadolol does not need to be discontinued in patients with liver disease (AST-ALT ratio 2:1). Hemochromatosis is unlikely
spontaneous bacterial peritonitis unless the sodium level is less because the transferrin saturation is not increased. NAFLD is less
than 130 mmol/L, systolic blood pressure is less than 90 mm Hg, likely because of the pattern of alcohol use. Patients with Wilson
or acute kidney injury develops; however, the maximum dose disease can present with various laboratory findings, but they
should be 80 mg daily in patients with ascites. Gastrointestinal would be unlikely to present initially in their 60s. Ferroportin dis
tract bleeding can precipitate HE, but there is no indication that this ease is a non-HFE iron overload state in persons with increased
patient has been overtly bleeding, and he has a clear diagnosis of ferritin levels; however, the clinical pattern makes alcohol-related
infection that merits expedited treatment. This patient’s lactulose liver disease more likely.
dose could be increased if the current dose is inadequate, and initi-
ation of rifaximin could be considered to prevent further recurrent VI.31. Answer d.
HE, but the primary management of HE in this patient would be This patient has acute liver failure with sudden onset of jaundice,
to treat the precipitating cause (spontaneous bacterial peritonitis). coagulopathy, and hepatic encephalopathy. For a patient in this age
group, fulminant Wilson disease (Wilsonian crisis) is an important
VI.27. Answer a. diagnostic consideration. Although the patient has a new sexual
This patient has moderate ascites despite diuretic therapy. Most partner, it is unclear whether there are other risk factors for viral hep-
patients with ascites can achieve good control with sodium re- atitis. Patients with acute BCS can present with acute liver failure but
striction and diuretics alone. Before increased diuretic dosages will often present with ascites. The presence of hemolytic anemia
are considered, she should be assessed by a dietitian to ensure (low hemoglobin), unconjugated (indirect) hyperbilirubinemia, and
that she is adhering to a strict, low-sodium diet (<2,000 mg a low ALP level make Wilson disease the most likely diagnosis.
daily). If ascites persists despite adherence to a sodium-restricted
diet, it would be reasonable to increase the furosemide dose to VI.32. Answer a.
120 mg and the spironolactone dose to 300 mg while monitoring This patient has hereditary hemochromatosis with biochemical
her electrolytes and kidney function. TIPS could be considered if evidence of iron overload. The mainstay of treatment is phle-
she had clearly defined refractory ascites and a low MELD score. botomy, which is typically recommended at an initial frequency
Large-volume paracentesis should not be necessary because she of every 1 to 2 weeks until iron stores are depleted. Patients are
does not have tense ascites; however, a diagnostic paracentesis then treated with maintenance phlebotomy approximately every
would be recommended if it was not done when ascites was 3 months. Dietary restriction is insufficient to treat this patient’s
diagnosed. iron overload. Chelation therapy, such as with deferasirox, is
more commonly used with secondary iron overload (eg, for
VI.28. Answer b. patients who have hematopoietic disorders). Trientene is a chela-
This patient appears to have postsinusoidal portal hyperten- tion agent used to treat Wilson disease.
sion related to a hepatic venous outflow obstruction as indi-
cated by the high serum-ascites albumin gradient (≥1.1) and the VI.33. Answer d.
high ascitic fluid protein level (≥2.5 g/dL). The best next step This patient has clinical and biochemical evidence of severe iron
would be an investigation with transthoracic echocardiography overload at a young age, which would be unusual for typical
(HFE) hemochromatosis. This clinical presentation (early onset, VI.39. Answer d.

severe iron overload, and cardiomyopathy) is more characteristic This patient with newly diagnosed PSC should undergo colonos-
of disease caused by HJV alteration. Patients with ferroportin copy, regardless of his symptoms, because of the high prevalence
disease typically have splenic iron deposition and high ferritin of IBD in patients with PSC. Patients with PSC and IBD have an
levels but normal transferrin saturation. Wilson disease can occur increased risk for colorectal neoplasia and require colonoscopies
in patients in this age group, and atypical viruses can cause car- with surveillance biopsies annually. The patient has no clear
diomyopathy, but the clinical and laboratory features are not con- indications for liver transplant. High doses of ursodeoxycholic
sistent with these diagnoses. acid have been shown to be harmful. Abdominal ultrasonography
would not be indicated because recent MRCP findings supported
VI.34. Answer c. the diagnosis of PSC.
This patient may have hereditary hemochromatosis, but con-
firmatory testing is required as other conditions (eg, NASH VI.40. Answer d.
and alcohol-related steatohepatitis) may also cause increased Patients with PBC, particularly postmenopausal women, are at
values for iron indices. Additional testing would include viral risk for osteoporosis. Bone densitometry should be performed
hepatitis serologies. Liver biopsy is generally not required for to assess for osteopenia or osteoporosis. Calcium supplementa-
diagnostic purposes unless hereditary hemochromatosis is a tion is recommended if dietary consumption of calcium is inad-
strong possibility and genetic testing is negative or advanced equate. Likewise, vitamin D supplementation is recommended,
fibrosis or cirrhosis is a concern (eg, ferritin level >1,000 µg/L particularly if vitamin D levels are low. There is no reason to
or aminotransferase levels are high or both). Similarly, there check ionized calcium levels, and there is no reason to start a
is no need to use MRI with elastography to measure hepatic bisphosphonate without evidence of bone disease.
iron concentration for the diagnosis of hereditary hemochroma-
VI.41. Answer c.
tosis unless cirrhosis is a concern. Counseling for weight loss
This patient has cholestasis and a history of IBD, but AMA test
and alcohol abstinence is indicated but would not be the best
results are negative and imaging findings are normal. Therefore,
next step.
the most likely diagnosis is small-duct PSC, but a biopsy would
VI.35. Answer a. be required to confirm the diagnosis. In the era of highly active
A definitive diagnosis of Wilson disease can be made if the pa- antiretroviral therapy, HIV-related cholangiopathy is quite rare
tient has a markedly low ceruloplasmin level, a high 24-hour and manifests with large- duct abnormalities. With large- duct
urine copper level, and Kayser- Fleischer rings. Liver biopsy PSC, imaging findings would be abnormal. In a young man who
would be performed if the patient did not have evidence of has a history of IBD, AMA-negative PBC is less likely.
Kayser-Fleischer rings or if the ceruloplasmin and 24-hour urine VI.42. Answer d.
copper results were conflicting. Testing for serum copper levels Amoxicillin-clavulanate is the most common cause of clinically
and ATP7B variants would not be helpful. apparent acute DILI in the US and Europe. The onset of injury
VI.36. Answer c. is typically a few days to 8 weeks after initiation of therapy,
Trientene may be associated with sideroblastic anemia. Acute and a patient may present with liver injury days or weeks after
liver failure occurs as a result of a fulminant presentation of cessation of therapy. Patients commonly present with fatigue,
Wilson disease rather than the treatment itself. The only therapy low-grade fever, nausea, abdominal pain, jaundice, and pruritus.
for fulminant Wilson disease is liver transplant. Penicillamine The pattern of injury is typically cholestatic, but some patients
can worsen the neurologic symptoms of Wilson disease if they may present with liver biochemistry results that suggest a mixed
are preexisting. Myelopathy is associated with copper deficiency or hepatocellular pattern. As in other forms of cholestatic DILI,
rather than with Wilson disease or its treatment. the cholestasis due to amoxicillin-clavulanate may take weeks or
months to resolve. Conservative management is recommended at
VI.37. Answer b. this time. Amoxicillin-clavulanate does not lead to autoimmune-
With the low α1-antitrypsin level, this patient most likely has the mediated DILI; therefore, initiating prednisone or proceeding
PI*ZZ phenotype. The patient is at risk for emphysema and should with a liver biopsy would not be indicated. The patient does
undergo baseline chest radiography and pulmonary function not have evidence of liver failure (ie, hepatic encephalopathy or
testing. Liver biopsy can be nondiagnostic because globules coagulopathy) and therefore does not require evaluation for liver
that stain with periodic acid-Schiff–diastase can be present transplant.
throughout the liver, so liver biopsy would not be necessary
to confirm the diagnosis for this patient. Noninvasive fibrosis VI.43. Answer c.
assessment is useful if patients have α1-antitrypsin deficiency, Autoimmune-mediated DILI may be caused by specific drugs,
and screening for HCC is useful if patients have α1-antitrypsin and the immune responses mimic those typically observed in
deficiency and cirrhosis; however, this patient has a low level de novo or idiopathic autoimmune hepatitis. Nitrofurantoin
of α1-antitrypsin, so the Pi*MZ phenotype is unlikely. is commonly associated with autoimmune-like DILI. Other
medications include hydralazine, minocycline, diclofenac,
VI.38. Answer b. and anti–tumor necrosis factor agents. Although it is difficult
The most likely diagnosis is PBC in this patient, a middle-aged to distinguish autoimmune-like DILI from autoimmune hep-
woman presenting with pruritus and cholestasis. Given the clin- atitis on the basis of history, laboratory findings, and histo-
ical presentation and normal findings on ultrasonography, the like- logic features, the absence of relapse after the withdrawal of
lihood of a large bile duct obstruction is low. Therefore, neither corticosteroid therapy is highly suggestive of a drug-induced
MRCP or ERCP would be an appropriate next step. Moreover, autoimmune-like reaction. The clinical pattern is more similar
ERCP is invasive. Liver biopsy would not be indicated until a to chronic hepatitis, and recovery may be delayed. The best
complete serologic and imaging evaluation has been performed. next step for this patient is discontinuation of the suspected
offending agent. Autoantibodies (including ANA or ASMA) with autoimmune hepatitis have a positive ANA titer. While au-
may persist after withdrawal of nitrofurantoin. Drug-induced toimmune hepatitis can occur in men, the prevalence is higher
autoimmune hepatitis that does not improve spontaneously can in women, and comorbid autoimmune conditions are frequently
be treated with corticosteroids. Ultrasonography and liver bi- present. PBC is a rare cholestatic liver disease characterized by
opsy would be useful if the patient did not improve upon with- increases in ALP values and positive results for AMA, and more
drawal of nitrofurantoin and initiation of prednisone. than 90% of affected patients are women.
VI.44. Answer c. VI.47. Answer a.

Because of the frequency with which statins are prescribed, there This patient has drug-induced autoimmune hepatitis related to
has been much interest in the potential liver toxicity of these minocycline. Drug-induced autoimmune hepatitis accounts for
agents. Determining whether patients receiving statins have about 9% of autoimmune hepatitis cases and can resemble classic
DILI is difficult because mild increases in liver enzyme levels autoimmune hepatitis both biochemically and histologically.
are common within 1 month after the initiation of statin therapy, However, cirrhosis is rarely present in drug- induced auto-
but the levels nearly always decrease despite continued admin- immune hepatitis, which should respond to discontinuation
istration of the agents. The increased levels usually result from of the offending agent and a limited duration for the use of
an adaptive response to the drug and do not necessitate with- glucocorticoids (<6 months) without azathioprine. Recurrent
drawal of treatment. Patients should have baseline liver tests be- increases in liver test results after cessation of corticosteroids is
fore treatment is initiated. Routine posttreatment monitoring is unusual for drug-induced autoimmune hepatitis and may suggest
not recommended, although signs and symptoms that suggest classic autoimmune hepatitis. The patient has no indication for
liver injury or disease (eg, jaundice) should be investigated with liver transplant at this time. PBC is a chronic cholestatic liver
liver tests. Serious DILI from statins is rare. Patients taking disease characterized by positive AMA titers. This patient has a
atorvastatin are more likely to present with a cholestatic or mixed hepatocellular-predominant injury pattern that was acute in onset
profile (57%) compared with patients taking simvastatin (25%). and liver biopsy findings that were not consistent with PBC.
Statins rarely have been associated with the development of
autoimmune-like hepatitis, although the association may be only VI.48. Answer d.
coincidental. It would be premature to consider a liver biopsy or This clinical presentation is typical for seronegative autoimmune
magnetic resonance elastography at this time. hepatitis in a young woman with comorbid immune-mediated
disease. She has chronic hepatocellular-predominant injury. The
VI.45. Answer d. biopsy shows typical features of autoimmune hepatitis with ad-
Acetaminophen hepatotoxicity is characterized by very high vanced fibrosis. Other causes of liver disease have been excluded,
levels of aminotransferases (often >5,000 U/L). Of the patients so autoimmune hepatitis is the most likely cause. Approximately
who have AST levels greater than 1,000 U/L at presentation, 20% of patients may have seronegative autoimmune hepatitis
16% will die or require liver transplant. Patients with aceta- without increased titers of ANA or SMA. Initiation of predni-
minophen hepatotoxicity and poor prognostic markers should sone therapy should result in improvement in her liver test results
be hospitalized and their condition monitored. N-acetylcysteine within several weeks. If the expected response to medical therapy
enhances the conjugation and excretion of N-acetyl-p-quinone does not occur, the diagnosis should be reconsidered. Celiac
imine, and when administered after liver injury has developed, sprue can lead to mild aminotransferase elevations with nonspe-
N-acetylcysteine acts by antioxidant and anti- inflammatory cific histologic features, which can improve with gluten avoid-
mechanisms. It may enhance liver perfusion through inotropic and ance. Although ferritin was slightly increased (most likely from
vasodilatory effects. Although the efficacy of N-acetylcysteine underlying inflammation), the normal result for transferrin satu-
diminishes when it is given more than 8 hours after acetamin- ration, the biopsy findings, and her clinical presentation would
ophen ingestion, it nonetheless should be administered up to 24 not be consistent with hemochromatosis. Drug-induced liver in-
hours after ingestion because of its putative hepatoprotective jury is less likely given the lack of temporal relationship between
effects. To maximize the potential benefit of N-acetylcysteine, it the increase in liver test results and the use of a medication. Drug-
should be used to treat any patient who has high serum transami- induced liver injury from levothyroxine, a frequently prescribed
nase concentrations and a history consistent with acetaminophen medicine, would be unusual. Moreover, advanced fibrosis in
exposure regardless of the serum acetaminophen concentration. drug-induced autoimmune hepatitis is uncommon.
Treatment with activated charcoal is recommended as well for
all patients who present within 4 hours of a known or suspected VI.49. Answer a.
acetaminophen ingestion unless there are contraindications to its The patient presented with acute autoimmune hepatitis and has
administration. This patient does not need penicillin G, which is features of advanced fibrosis. With the disease in biochemical
used to treat poisoning from the mushroom Amanita phalloides. remission with prednisone and azathioprine, she has had per-
He does not have alcoholic hepatitis, and corticosteroids are not sistently normal liver test results while taking low doses of pred-
indicated at this time. nisone and azathioprine. For most patients the recommended
strategy is to withdraw the corticosteroid, thereby decreasing its
VI.46. Answer b. adverse effects, while remission is maintained with azathioprine.
NAFLD is common and is the most likely diagnosis given this Mycophenolate mofetil is a second-line agent that can be used
patient’s metabolic risk factors and the imaging finding con- instead of azathioprine if a patient has a drug intolerance or an
sistent with steatosis. Up to one-third of patients with NAFLD incomplete response to standard therapy. Discontinuing therapy
have slight increases in ANA, but titers greater than 1:320 are completely would not be recommended. After liver test results
rare. With the negative result for hepatitis B surface antigen, become normal, histologic remission may take months to occur.
chronic hepatitis B is unlikely. In contrast to NAFLD, autoim- The recommendation is to treat and maintain remission for at least
mune hepatitis is uncommon. Approximately 80% of patients 2 years before withdrawal of immunosuppression is considered
for select patients. Even when patients have had biochemical re- VI.55. Answer b.
mission for 2 years, relapse after stopping immunosuppression is This patient’s presentation is most consistent with biliary colic.
common. This patient already has advanced fibrosis and would Gallstones are common in pregnancy. The first episode of biliary
be at higher risk for complications of repeated disease flares and colic can be managed conservatively and successfully in most
uncontrolled disease activity. patients. If patients have recurrent biliary colic, laparoscopic cho-
lecystectomy should be considered in the second trimester. ERCP
VI.50. Answer c. can be safely performed during pregnancy if indicated (eg, con-
This patient has metabolic syndrome and the evaluation has been cern for choledocholithiasis) with limited fluoroscopic exposure
negative for other causes of increased liver values. A low-positive and fetal shielding. Nothing in this patient’s history or laboratory
ANA test result is common in patients with NAFLD and does findings suggests choledocholithiasis or biliary obstruction.
not have diagnostic significance. With normal findings on ultra-
sonography and the CBC, the likelihood of advanced fibrosis is VI.56. Answer c.
low, so EGD is not indicated at this time. A liver biopsy would The level of HBV DNA should be checked at baseline and at
help confirm the diagnosis of NASH, assess for fibrosis, and jus- approximately 28 weeks of gestation. If the HBV DNA level
tify the use of pharmacotherapy for NASH and type 2 diabetes. at 28 weeks of gestation is greater than 200,000 IU/mL (>106
Given the persistent increases in the liver test results, subsequent copies/mL), antiviral treatment with category B medications (eg,
testing would not be appropriate at this time. tenofovir) should be initiated at 28 to 30 weeks of pregnancy and
continued until delivery. All babies should receive hepatitis B
VI.51. Answer c. vaccination and hepatitis B immunoglobulin at birth. There is no
NAFLD is a well-established risk factor for NASH and progres- contraindication for vaginal delivery or breastfeeding.
sion to cirrhosis. Risk of liver-related death is greater for patients
with NASH than isolated steatosis, and the most common causes VI.57. Answer a.
of death are cardiovascular disease (15.5%), nonliver cancer Patients who have autoimmune hepatitis that has been adequately
(5.6%), and liver cancer (2.8%). Among patients with NASH, the controlled for at least a year before conception can expect to have
stage of fibrosis is the most important predictor of death. desirable outcomes and a successful pregnancy. The treatment
of autoimmune hepatitis should be continued without cessation
VI.52. Answer a. or interruption during the pregnancy to avoid flares. The use of
Patients with NASH have an increased risk of cardiovas- azathioprine is safe and should be continued, but mycophenolate
cular events; thus, optimal management of cardiovascular risk mofetil is contraindicated during pregnancy. Patients of child-
with lipid-lowering treatment if indicated, is appropriate. This bearing age who are receiving mycophenolate mofetil should have
patient’s high score for atherosclerotic cardiovascular disease risk a preconception discussion with their clinician, and mycophenolate
and high LDL cholesterol level justify the use of statin therapy. mofetil should be changed to an alternative therapy. Treatment of
Statins are safe to use in patients with NAFLD, NASH, and flares in pregnant patients is the same as in nonpregnant patients.
compensated NASH-related cirrhosis. Although statins are not
indicated for treatment of NASH, several studies have suggested VI.58. Answer c.
a hepatoprotective effect from statins. The patient’s low alcohol For patients who have hepatocellular carcinoma and cirrhosis,
intake does not justify therapy for cessation. Although no data transplant is an effective option because it addresses both the ne-
suggest benefit, limited data do suggest that a low amount of al- oplasm and the underlying liver disease. In the past, outcomes
cohol (average of <2 drinks daily for a man and <1 drink daily for were poor with transplant for hepatocellular carcinoma. However,
a woman) is associated with increased risk of NASH progression. with advances in patient selection and use of the Milan criteria (1
Although prophylactic use of metformin may be considered for tumor ≤5 cm or 2 or 3 tumors ≤3 cm, without vascular invasion or
patients with prediabetes, it is not recommended for management extrahepatic spread), the 5-year survival rate is 70% to 80% and
of NASH. Weight loss of even 5% to 10% of body weight is the the recurrence rate is less than 15%. A patient with hepatocellular
cornerstone of NASH therapy and is associated with improve- carcinoma within the Milan criteria is assigned a MELD score
ment in all histologic features of NASH. A Mediterranean diet to allow orthotopic liver transplant in 3 to 12 months (called a
is recommended for patients who have NASH and metabolic MELD exception). Biopsy of the lesion is not recommended be-
syndrome. cause arterial enhancement with portal venous washout on CT
is diagnostic for HCC. Chemotherapy is indicated for advanced,
VI.53. Answer d. unresectable HCC. Transarterial embolization is not indicated
Published genome-wide and exome-wide association studies have before completion of a liver transplant evaluation for poten-
led to the identification of loci in PNPLA3, TM6SF2, HSD17B13, tial listing on the liver transplant waiting list. Liver resection is
MBOAT7, and MTARC1 that are associated with NASH, progres- the preferred treatment of hepatocellular carcinoma in patients
sion of fibrosis, and hepatocellular carcinoma in patients with without cirrhosis and in those with cirrhosis who have well-
NAFLD. Of these, a variant in HSD17B13 is associated with a preserved liver function and little or no portal hypertension.
decreased risk of progression from NAFL to NASH and chronic
liver disease; the others are associated with an increased risk of VI.59. Answer d.
disease progression. Patients with cirrhosis are typically candidates for liver trans-
plant when their biologic MELD score is 15 or more. This is im-
VI.54. Answer d. portant because for patients with a MELD score less than 15, the
This patient has abdominal pain, nausea, vomiting, increased 3-month mortality after transplant exceeds the 3-month mortality
transaminase levels, impaired kidney function, coagulopathy, and without a transplant. However, some patients may be candidates
hypoglycemia. She most likely has acute fatty liver of pregnancy, for liver transplant evaluation when they have Child-Pugh class
with more than 6 features of the Swansea criteria, and prompt de- B cirrhosis with portal hypertension despite having a low MELD
livery is the best management option. score. This permits the patient to meet the transplant team before the
development of end-stage liver disease and its complications (eg, VI.61. Answer b.
hepatic encephalopathy). It ensures adequate time for the patient to Acute cellular rejection occurs in up to 50% of liver recipients
complete the pretransplant evaluation and the necessary education. and usually is associated with mild to moderate biochemical
Patients may also qualify for liver transplant if they have a com- abnormalities (mixed hepatocellular- cholestatic pattern) and,
plication or condition that qualifies for standard MELD exception occasionally, fever. The tacrolimus level is low for 4 weeks
points. Ultrasonographic screening for hepatocellular cancer should after transplant. Although the diagnosis can be suspected
be performed every 6 months in patients with cirrhosis and in men by the timing in the early weeks after liver transplant, defini-
with PBC. Bone mineral density should be assessed every 2 years, tive diagnosis requires histologic examination of the liver,
depending on baseline density and severity of cholestasis. and the following findings: 1) portal infiltrates with activated
lymphocytes and some eosinophils, 2) lymphocytic cholangitis,
VI.60. Answer d. and 3) venous endotheliitis. Most cases of rejection (90%) occur
Clinicians should be aware of drug interactions with drugs in the first 2 months postoperatively. Acute cellular rejection
affecting cytochrome P450 enzymes. Drugs that inhibit the cy- soon after liver transplant generally has no effect on long-term
tochrome P450 system (eg, fluconazole for candidal esopha- graft outcome, except for patients with hepatitis C, and very few
gitis) increase the levels of calcineurin inhibitors, and drugs grafts are lost to chronic rejection. The patient had a sustained
that stimulate the cytochrome P450 system (eg, phenytoin) de- virologic response before transplant, and recurrent hepatitis C
crease calcineurin inhibitor levels and thus increase the risk of would be unlikely. Although hepatic artery thrombosis usually
rejection. The patient likely had a drug-drug interaction between occurs in the first week after orthotopic liver transplant, it can
tacrolimus and fluconazole, which was recently prescribed for develop later, but that would be unlikely in this patient given the
candidal esophagitis. Tacrolimus should be withheld while the normal findings from Doppler ultrasonography of the allograft.
tacrolimus level results are pending. Classic adverse effects of Cytomegalovirus infection is the most common viral infection.
increased tacrolimus levels include nephrotoxicity and neurotox- Its incidence peaks in the first 3 to 5 postoperative weeks, and
icity. At this time a liver biopsy would not be useful, and findings it is rare after the first year. Its presence is suggested by fever,
from Doppler ultrasonography of the liver would most likely be malaise, and leukopenia, and patients tend to appear sicker than
unremarkable. CT of the head would be reasonable because of the patient described above. Cytomegalovirus infection is less
the acute headache, but both medications should be withheld first. common than acute cellular rejection.
VII
Pancreas and Biliary Tree

37
Acute Pancreatitisa
DANIEL B. MASELLI, MD
VINAY CHANDRASEKHARA, MD
Acute pancreatitis is an inflammatory condition characterized 20% of cases, severe acute pancreatitis develops, leading in the
by severe abdominal pain and both locoregional and systemic early phase to the systemic inflammatory response syndrome
inflammatory complications. More than 200,000 new cases of (SIRS), organ failure (hypotension, kidney failure, and acute res-
acute pancreatitis occur in the US each year, and the incidence piratory distress syndrome), and pancreatic necrosis.
is increasing. The disease is severe in 20% of patients with acute
pancreatitis, and approximately 5% of all patients with pancre-
Clinical Presentation and Diagnosis
atitis die of the disease. Hence, key management principles in-
clude prompt diagnosis, triage of patients with severe pancreatitis The clinical presentation of patients with acute pancreatitis
to aggressive care, and identification of the underlying cause to ranges from mild, nonspecific epigastric pain to catastrophic, un-
prevent recurrence. Necrotizing pancreatitis accounts for most of stable acute medical illness. Typically, the pain of acute pancre-
the morbidity and nearly all the mortality associated with acute atitis is located in the epigastrium and, in approximately half the
pancreatitis. patients, radiates into the back. The onset of pain is usually swift,
reaching maximum intensity within an hour. Pain is frequently
unbearable and generally persists without episodic improvement
Pathophysiology for at least 24 hours in the absence of intervention. Pain often is
The pathophysiology of acute pancreatitis begins with inappro- accompanied by nausea and vomiting. In severe episodes of acute
priate activation of trypsin within the acinar cell. Activated intra- pancreatitis, SIRS dominates and patients appear systemically ill,
cellular trypsin, in turn, activates a cascade of digestive enzymes with fever, tachycardia, tachypnea, and hypotension.
that leads to autodigestion and cellular injury. Acinar cell in- It is now understood that there are 2 overlapping phases of
jury leads to inflammation by recruitment of inflammatory cells acute pancreatitis. The early phase, characteristically lasting 1
through cytokines and other mediators. In 80% of cases, acute to 2 weeks, manifests as cytokine-mediated systemic inflamma-
pancreatitis is mild and self-limited, with little or no long-term tion as a host response to pancreatic injury. The late phase is
sequelae to the pancreatic parenchyma or systemic toxicity. In typified by 1 or more of the following (described later in this
chapter): persistence of systemic inflammation, diminished
immune function, and the evolution of local complications.
a
The authors thank Bret T. Petersen, MD, and Randall K. Pearson, MD, Consequently, most of the morbidity and mortality that occur
who authored previous versions of this chapter. early in the course of severe acute pancreatitis is due to systemic
Abbreviations: APACHE, Acute Physiology and Chronic Health toxicity and organ failure secondary to SIRS, whereas late mor-
Evaluation; CT, computed tomography; ERCP, endoscopic retrograde tality (ie, beyond 10-14 days) is typically related to pancreatic
cholangiopancreatography; EUS, endoscopic ultrasonography; ICU, necrosis and infection.
intensive care unit; MRI, magnetic resonance imaging; SIRS, systemic The differential diagnosis of acute pancreatitis is broad and
inflammatory response syndrome; ULRR, upper limit of the reference includes most of the important causes of abdominal pain, in-
range; WON, walled-off necrosis cluding mesenteric ischemia and infarction, perforated peptic
427
428 Section VII. Pancreas and Biliary Tree
ulcer, symptomatic cholelithiasis, dissecting aortic aneurysm, in-

testinal obstruction, and inferior wall myocardial infarction. Box 37.1. Differential Diagnosis of High Levels of
By consensus, the diagnosis of acute pancreatitis requires 2 of Pancreatic Enzymes
the following 3 findings: Amylase: cleared by reticuloendothelial system
1. Abdominal pain features consistent with acute pancreatitis excretion and kidney filtration
2. Serum level of amylase or lipase >3 times the upper limit of the ref- • Pancreatic inflammation (acute and chronic
erence range (ULRR) pancreatitis) or trauma; ERCP
3. Findings of acute pancreatitis seen on cross-sectional imaging with
• Salivary inflammation, obstruction, or trauma
computed tomography (CT), ultrasonography, or magnetic reso-
nance imaging (MRI) • GI inflammation, obstruction, perforation, or
ischemia
These criteria indicate that the diagnosis of acute pancrea-
• Ovarian disease or cysts; ectopic pregnancy
titis can be based on classic pain symptoms and diagnostic levels
of amylase and lipase, obviating the need for imaging in many • Cancer of the ovary, prostate, lung, breast, or
thymus; multiple myeloma; pheochromocytoma
cases. If the serum levels of amylase or lipase are only modestly
elevated (<3 times the ULRR), the lack of specificity dictates the • Macroamylasemia: rarely associated with ce
need for imaging, most commonly CT, to establish the diagnosis. liac disease, ulcerative colitis, rheumatoid ar
thritis, lymphoma, HIV infection, or monoclonal
The definition also provides means to diagnose acute pancrea-
gammopathy
titis when a patient cannot give a clinical history because of al-
tered mental status or the severity of the acute presentation. When • Other causes, including kidney failure, burns,
acidosis, anorexia nervosa, bulimia, cerebral
performed more than 48 hours after presentation, CT with con-
trauma, and drugs
trast enhancement also provides important prognostic informa-
tion, as discussed below. Lipase: kidney filtration and tubular resorption
Both amylase and lipase levels are usually increased during (increased half-life)
the acute phase of pancreatitis. Amylase elevations are more than • Pancreatic inflammation (acute and chronic
90% sensitive for acute pancreatitis, and 3-fold elevations are pancreatitis), trauma, or tumors
more than 90% specific (but with lower sensitivity). The serum • GI: acute cholecystitis, bowel obstruction or in
lipase level generally is preferred to the serum amylase level be- farction, duodenal ulcer, or celiac disease
cause lipase is more specific to the pancreas. Therefore, increased
lipase levels tend to reflect pancreatic pathology for a longer in- Abbreviations: ERCP, endoscopic retrograde cholangiopancreatography;
terval compared with amylase levels, which become lost in the GI, gastrointestinal tract.
noise of normal basal amylase from multiple sources. Amylase
and lipase levels can be abnormally high from bowel ischemia,
obstruction, or perforation leading to enteric leakage and systemic gallstones and, thus, adds clinical information about the under-
absorption of intraluminal pancreatic enzymes. The amylase level lying cause of the pancreatitis and should be used for patients
is also increased nonspecifically in various nongastrointestinal with an intact gallbladder.
conditions (Box 37.1), including macroamylasemia, diseases of
the parotid glands, and some carcinomas.
Etiology
Macroamylasemia is a benign condition that may cause
confusion when present with other causes of abdominal pain. Once a diagnosis of acute pancreatitis is established, characteri-
Macroamylase is a macromolecular aggregation of amylase zation of the underlying cause is critical for prevention of future
molecules that are poorly excreted by the kidney, yielding chron- episodes (Box 37.2). Gallstones are the most common cause of
ically fluctuating increases in serum amylase, which are gener- acute pancreatitis in middle and upper socioeconomic groups in
ally less than twice the ULRR. Infrequent disease associations the US. Gallstones cause acute pancreatitis by mechanical ob-
have been reported. The diagnosis of macroamylasemia may be struction of the common channel shared by the bile duct and pan-
suggested by a low ratio of amylase to creatinine clearance and is creatic duct, with increased intraductal pressure in the pancreas
easily established by immunologic assay. and possibly pancreatic reflux of bile acids in some cases. When
Importantly, the degree of increase of either lipase or amylase they present with acute pancreatitis, patients often have a history
beyond diagnostic criteria for acute pancreatitis is not predictive of of biliary-type pain, ultrasonographic evidence of cholelithiasis,
disease severity. After the diagnosis of acute pancreatitis has been and abnormal liver test results.
made, serial measurements of lipase and amylase levels have no Alcohol, which induces a direct toxic injury to the pancreas,
prognostic value in guiding management and should be avoided. is the predominant cause of acute pancreatitis in resource-limited
Resolution of high enzyme levels may lag clinical improvement, populations in the US. Development of acute pancreatitis from
and thus reassessment of enzyme levels has a diminishingly lim- alcohol typically requires prolonged consumption of a consider-
ited role in acute pancreatitis, although reassessment may be useful able amount of alcohol (usually >50 g daily), but acute pancre-
in selected patients when clinical relapse is suspected. atitis develops in less than 5% of those who drink this heavily.
Plain abdominal radiographs are frequently normal at presen- An important metabolic cause of acute pancreatitis is hyper
tation with acute pancreatitis, but they are useful in excluding triglyceridemia; a threshold triglyceride level of 1,000 mg/dL has
bowel perforation. A nonspecific ileus may be present along with been established as being causative, although lower levels, espe-
a focally dilated small-bowel loop, the so-called sentinel loop. cially in combination with other pancreatic insults, are now thought
Abdominal ultrasonography is frequently nondiagnostic in to precipitate acute pancreatitis. Severity corresponds to the degree
acute pancreatitis because overlying bowel gas may obscure the of increase in the triglyceride level. Hypertriglyceridemia can
pancreas. However, ultrasonography is sensitive for detecting arise from inherited disorders of lipoprotein metabolism or from
37. Acute Pancreatitis 429
Box 37.2. Etiology of Acute Pancreatitis Box 37.3. Drugs Reliably Associated With Acute
• Mechanical: gallstones, biliary sludge, ascariasis, Pancreatitisa
periampullary diverticulum, pancreatic or periam • Antimicrobials: erythromycin, clarithromycin, iso
pullary cancer, ampullary or papillary stenosis, duo niazid, metronidazole, nitrofurantoin, ceftriaxone,
denal stricture or obstruction trimethoprim-sulfamethoxazole, pentamidine, am
• Toxic: ethanol, methanol, scorpion venom, organo picillin, rifampin, tetracycline
phosphate poisoning • HIV agents: didanosine, nelfinavir
• Metabolic: hypertriglyceridemia, hypercalcemia • Diuretics: furosemide, chlorothiazide, hydro-
• Drugs: numerous (see Box 37.3) chlorothiazide
• Infection • GI agents: omeprazole, cimetidine, ranitidine, sul-
fasalazine, hydrocortisone, lamivudine, interferon,
Viruses: mumps, coxsackievirus, hepatitis B virus, cy
ribavirin, octreotide
tomegalovirus, varicella-zoster virus, herpes sim
plex virus, HIV • Cardiac agents: procainamide, α-methyldopa,
captopril, enalapril, lisinopril, amiodarone, losartan
Bacteria: Mycoplasma, Legionella, Leptospira,
Salmonella • Immunosuppressives or chemotherapeutics: aza
thioprine, 6-mercaptopurine, l-asparaginase, cy
Fungi: Aspergillus
tosine arabinoside, dexamethasone, ifosfamide,
Parasites: Toxoplasma, Cryptosporidium, Ascaris paclitaxel, tacrolimus, cyclosporine
• Trauma: post-ERCP, blunt or penetrating abdominal • Neuropsychiatric agents: valproic acid, clozapine,
injury, iatrogenic injury, surgery carbamazepine, risperidone, sertraline
• Congenital or anatomical: choledochocele, pan • Other common drugs: bezafibrate, carbimazole,
creas divisum codeine, pravastatin, simvastatin, all-trans retinoic
• Vascular: ischemia, atheroembolism, vasculitis acid, acetaminophen, estrogens, alendronate, in
(polyarteritis nodosa, systemic lupus erythematosus) domethacin, metformin, naproxen, diclofenac,
• Genetic: CFTR and other genetic alterations sulindac, orlistat, danazol, ergotamine, propofol
• Miscellaneous: pregnancy, kidney transplant, α1-

Abbreviation: GI, gastrointestinal tract.
antitrypsin deficiency, sphincter of Oddi dysfunc
tion (possibly) a
Boldface type indicates medications that have strong associations.
• Idiopathic
Abbreviation: ERCP, endoscopic retrograde cholangiopancreatography.

pancreatitis, and evaluation for sphincter of Oddi dysfunction);
and 3) procedure-related factors (eg, difficult cannulation, pan-
creatic duct injection, and pancreatic sphincterotomy). Pancreatic
changes in lipid homeostasis, such as those that occur in obesity, stent placement and periprocedural rectal administration of
type 2 diabetes, hypothyroidism, or pregnancy or with the use of nonsteroidal anti-inflammatory drugs are reasonably effective for
certain medications (eg, tamoxifen or estrogen). Distinct clinical prevention of post-ERCP pancreatitis.
features include eruptive xanthomas, hepatosplenomegaly from Genetic causes are increasingly recognized as etiologic factors
fatty infiltration, and lipemia retinalis. in acute pancreatitis. Loss of the PRSS1 gene (OMIM 276000) or
Medications are implicated in 0.1% to 2% of cases of acute gain-of-function alterations in the CFTR (OMIM 602421) and
pancreatitis (Box 37.3), although the range may be as high as SPINK1 (OMIM 167790) genes are notable examples. Other
5% to 10%. Less than half the cases of drug-induced pancreatitis causes of acute pancreatitis include hypercalcemia, trauma, post-
are recognized by clinicians because there are no unique clin- operative state, and infections by various agents.
ical features, and most cases are mild. Historically, case reports About 15% to 20% of acute pancreatitis cases are classified as
and small series have enabled drugs to be classified as definite, idiopathic because no cause is found even after extensive testing.
probable, or possible causes of acute pancreatitis. An impor- Several clues to the cause should be kept in mind (Box 37.4).
tant diagnostic clue is the rapid onset of acute pancreatitis after Most useful is early characterization of the serum transaminase
rechallenging with the offending medication. Medications asso- levels, since they are often increased transiently in biliary pancre-
ciated with pancreatitis are classified into 5 risk classes according atitis, reflecting liver injury associated with the obstruction of the
to the strength of the supporting literature, temporal relationships bile duct. In patients with pancreatitis, an increase in the alanine
between drug use and onset of pancreatitis, and reaction with aminotransferase level greater than 3-fold has a positive predic-
rechallenge. Patients at heightened risk for drug-induced pancre- tive value greater than 90% for a biliary source and a sensitivity
atitis include pediatric and elderly patients, female patients, and of about 50%.
those with inflammatory bowel disease or HIV infection. If the cause of acute pancreatitis is unclear, the diagnostic
Pancreatitis occurs as an adverse event of endoscopic ret- approach should include investigations for neoplasm (eg,
rograde cholangiopancreatography (ERCP) in 3% to 10% of intraductal papillary mucinous neoplasm of the main duct, neuro-
patients undergoing ERCP. In up to 90% of patients, the severity endocrine tumor, or pancreatic ductal adenocarcinoma). Dedicated
of post-ERCP is mild or moderate. Risk factors for post-ERCP pancreatic imaging with CT, MRI, or endoscopic ultrasonography
pancreatitis include 1) operator- related factors (eg, relatively (EUS) should be performed if patients are older than 40 years or
less experience); 2) patient-related factors (eg, younger age, fe- have unintentional weight loss, new-onset type 2 diabetes, or a
male sex, recurrent pancreatitis, previous episode of post-ERCP family history of pancreatitis, particularly in a first-degree relative.
Box 37.4. Etiologic Clues in Acute Pancreatitis (AP) Box 37.5. Ranson Criteria for Assessing the Severity
• Early transaminase elevations (>3 times ULRR) are of Acute Pancreatitis
the best laboratory indicators of biliary AP. Measured at admission
• Normal gallbladder ultrasonographic findings do Age >55 y
not exclude biliary AP.
Leukocytes >16.0×109/L
• Finding gallbladder sludge at presentation is
Blood glucose >200 mg/dL
equivalent to finding gallstones; subsequent devel
opment of sludge is common in patients who are Serum lactate dehydrogenase >350 U/L
fasting or ill. Serum aspartate aminotransferase >250 U/L
• In hypertriglyceridemic AP (usually triglycerides Measured during initial 48 h
>1,000 mg/dL), amylase levels may be artificially
Hematocrit decreases >10%
normal.
Serum urea nitrogen increases >5 mg/dL
• Triglyceride values decrease rapidly when a pa
tient is taking nothing by mouth. Levels should be Serum calcium <8 mg/dL
checked soon after diagnosis, and, if normal, they Arterial Pao2 <60 mm Hg
should be rechecked again after resolution of AP. Base deficit >4 mEq/L
• Serum calcium level may normalize in severe AP, Fluid sequestration >6 L
and it should be rechecked after resolution if a
cause is not identified.
Adapted from Banks PA. Practice guidelines in acute pancreatitis. Am
• Cancer should be considered in patients older J Gastroenterol. 1997 Mar;92(3):377-86; used with permission.
than 50 years; cancer causes 2% of AP, and up
to 5% of patients with pancreatic cancer present
with AP.
• Genetic causes should be considered if a patient are measured between admission and 48 hours later (Box 37.5).
is young and AP is idiopathic or recurrent. The number of Ranson criteria correlates with the incidence of
systemic complications and the presence of pancreatic necrosis.
Abbreviation: ULRR, upper limit of the reference range. The main disadvantage of the Ranson criteria is that they may not
be evaluated until 48 hours after admission.
The Acute Physiology and Chronic Health Evaluation
(APACHE) II scoring system is based on 12 physiologic variables,
Severity Stratification patient age, and previous history of severe organ system insuf-
After acute pancreatitis has been diagnosed, patients most ficiency or immunocompromised state (Table 37.1). It allows
likely to have severe disease should be identified promptly for stratification of the severity of illness on admission and may be
early triage to aggressive monitoring and supportive care. Most recalculated daily. Although the APACHE II scoring system has
patients (approximately 80%) have interstitial or edematous the advantage of being completed at the initial presentation and
pancreatitis with a mild self-limited course and very low mor- being repeated daily, it is cumbersome to use.
tality. In 20% of patients the disease is moderate to severe with To simplify prognostication, clinical investigators have sought
considerable local morbidity and a mortality rate of about 20%. a single biochemical marker for severity. The acute-phase reac-
Most patients with severe disease have necrotizing pancreatitis. tant C-reactive protein level has been used to predict severity, but
Several severity-of-illness scoring systems have been devised it generally must increase to more than 150 mg/L over 36 to 72
to identify patients at risk for complications; some systems are hours after admission before it is useful. Other simple markers
remarkably simple, while others are more complex or require have included serum glucose and creatinine, but all have poor
serial investigations over 48 hours. Owing to the cumbersome specificity.
nature of many of the scoring systems, the revised Atlanta Hemoconcentration due to extravasation of fluid into third
classification has been adopted by many centers to provide spaces, reflected by an increase in the serum hematocrit, has been
a simplified schema of degree of illness in acute pancreatitis proposed as a simple reliable predictor of necrotizing pancrea-
(discussed below). titis. This is particularly true if the hematocrit does not decrease
after 24 hours, which likely reflects inadequate volume resusci-
tation. According to other reports, hemoconcentration, although
Patient Characteristics
quite sensitive, is nonspecific in that it overpredicts severity. This
Risk factors for a severe course can be understood as 1) patient is the problem with most of the single biochemical markers de-
characteristics (age >55 years, body mass index >30, and altered termined on admission.
mental status); 2) the presence of SIRS; 3) abnormal laboratory The harmless acute pancreatitis score is designed to identify
values (serum urea nitrogen >20 mg/ dL, hematocrit >44%); patients who will have a mild, self-limited course rather than se-
and 4) abnormal imaging findings (pleural effusion, pulmonary vere disease. Its 3 components, which can be measured within 30
infiltrates, and peripancreatic collections). Organ failure at ad- minutes, include 1) an absence of rebound tenderness on phys-
mission, particularly kidney or pulmonary, is an especially fore- ical examination, 2) a normal hematocrit, and 3) a normal serum
boding feature of severe acute pancreatitis. Patients with these creatinine level. The presence of all 3 components was found to
findings require close observation and often warrant admission to predict a mild course with 96% specificity and a 98% positive
an intensive care unit (ICU). predictive value. This has been validated in several European
The Ranson criteria consist of 11 clinical signs with prog- studies and may guide clinicians in at least identifying patients
nostic significance: 5 criteria are measured at admission, and 6 who do not need aggressive early management.
Table 37.1. Acute Physiology and Chronic Health Evaluation (APACHE) II Scoring Systema,b
Physiology points
Variable 4 3 2 1 0 1 2 3 4
Rectal temperature, °C ≥41.0 39.0-40.9 NA 38.5-38.9 36.0-38.4 34.0-35.9 32.0-33.9 30.0-31.9 ≤29.9
Mean blood pressure, mm Hg ≥160 130-159 110-129 NA 70-109 NA 50-69 NA ≤49
Heart rate, beats/min ≥180 140-179 110-139 NA 70-109 NA 55-69 40-54 ≤39
Respiratory rate, breaths/min ≥50 35-49 NA 25-34 12-24 10-11 6-9 NA ≤5
Oxygenation, kPac
Fio2 ≥50% Aado2 66.5 46.6-66.4 26.6-46.4 NA <26.6 NA NA NA NA
Fio2 >50% Pao2 NA NA NA NA >9.3 8.1-9.3 NA 7.3-8.0 <7.3
Arterial pH ≥7.70 7.60-7.69 NA 7.50-7.59 7.33-7.49 NA 7.25-7.32 7.15-7.24 <7.15
Serum sodium, mmol/L ≥180 160-179 155-159 150-154 130-149 NA 120-129 111-119 ≤110
Serum potassium, mmol/L ≥7.0 NA 6.0-6.9 NA 5.5-5.9 3.5-5.4 3.0-3.4 2.5-2.9 <2.5
Serum creatinine, mg/dL ≥3.5 2.0-3.4 1.5-1.9 NA 0.6-1.4 NA <0.6 NA NA
Packed cell volume, % ≥60 NA 50-59.9 46-49.9 30-45.9 NA 20-29.9 NA <20
White blood cell count, ×109/L ≥40.0 NA 20.0-39.9 15.0-19.9 3.0-14.9 NA 1.0-2.9 NA <1.0
Abbreviations: Aado2, alveolar-arterial oxygen difference; Fio2, fraction of inspired oxygen; NA, not applicable.
a
APACHE II score =acute physiology score +age points +chronic health points.
b
Other points are determined as follows:
• Glasgow Coma Scale: score is subtracted from 15 to obtain points.
• Age: <45 y =0 points; 45-54 y =2 points; 55-64 y =3 points; 65-75 y =5 points; >75 y =6 points.
• Chronic health points (must be present before hospital admission): 5 points are added for an emergency surgical or nonsurgical patient, and 2 points are added for
an elective surgical patient who has chronic liver disease with hypertension or previous liver failure, encephalopathy, or coma; chronic heart failure (New York Heart
Association class IV); chronic respiratory disease with severe exercise limitation, secondary polycythemia, or pulmonary hypertension; dialysis-dependent kidney
disease; or immunosuppression (eg, radiotherapy, chemotherapy, recent or long-term therapy with high-dose corticosteroid therapy, leukemia, AIDS).
c
If Fio2 ≥50%, the alveolar-arterial gradient is assigned points. If Fio2 <50%, partial pressure of oxygen is assigned points.
Adapted from Banks PA. Practice guidelines in acute pancreatitis. Am J Gastroenterol. 1997 Mar;92(3):377-86; used with permission.
Revised Atlanta Classification mature (ie, organized) fluid collections, which can cause pain,
nausea, and luminal or biliary obstruction.
Adopted in 2012, the revised Atlanta classification is the most
Four distinct subtypes of these local complications may arise
widely used clinical system for characterizing acute pancreatitis.
from acute pancreatitis. They are based primarily on the presence
It is principally helpful in 3 ways: phenotyping acute pancreatitis,
or absence of necrosis and whether they have matured into de-
describing severity of acute pancreatitis, and describing local
fined collections (Table 37.3). Interstitial edematous pancre-
complications of acute pancreatitis.
atitis can have peripancreatic fluid collections that mature into
Acute pancreatitis is divided into 2 phenotypes according to
encapsulated collections called pseudocysts, which contain ho-
imaging findings: 1) interstitial edematous pancreatitis, which
mogeneous fluid. Conversely, necrotizing pancreatitis may have
has uniform enhancement of the gland on contrast-enhanced im-
pancreatic or peripancreatic acute necrotic collections that ma-
aging, and 2) necrotizing pancreatitis, which is seen in about 5%
ture into defined, encapsulated collections called walled-off ne-
to 10% of patients with acute pancreatitis and is identified by
crosis (WON), which contain both fluid and debris. Maturation
unenhanced (ie, necrotic) pancreatic parenchyma on contrasted-
in either presentation typically occurs over a 4-week period after
enhanced imaging. Necrosis may involve the pancreatic tissue or
disease onset. WON is often associated with signs of persistent
the peripancreatic tissue (or both); the presence of either implies
systemic inflammation. Importantly, none of these terms implies
necrotizing pancreatitis. Notably, this impaired enhancement
infection, and any sterile mature or immature fluid collection can
may take several days to be appreciated, so lack of necrosis on
be secondarily infected, although infection is far more frequently
presentation should not obviate the need for reappraisal with sub-
sequent imaging if the patient’s condition does not improve with
appropriate care. Table 37.3. Summary of Revised Atlanta Criteria
The revised Atlanta classification describes illness severity for Pancreatic Collections
as mild, moderately severe, or severe depending on the presence
or absence of organ failure or local complications (Table 37.2). Time after disease onset, wk
Type of
Organ failure typically refers to respiratory, cardiovascular, and pancreatitis ≤4 >4
kidney function and can be identified with the modified Marshall
scoring system. Local complications manifest as immature or Interstitial Acute peripancreatic fluid Pseudocyst
edematous collection Homogenous, without
Homogeneous nonliquid content
Confined by normal Well-circumscribed,
Table 37.2. Summary of Revised Atlanta Criteria fascial planes well-defined
for Severity of Acute Pancreatitis Adjacent to pancreas
Necrotizing Acute necrotic collection Walled-off necrosis
Severity of acute pancreatitis Heterogeneous (liquid and Heterogeneous (liquid and
nonliquid component) nonliquid component)
Feature Mild Moderately severe Severe
No definable capsule Well-defined capsule
Organ failure Absent Transient (<48 h) Persistent (>48 h) Intrapancreatic and/or Intrapancreatic and/or
Local complications Absent May be present Often present extrapancreatic extrapancreatic
encountered in necrotic collections. Infection of a fluid collection

often has internal gas, although this feature does not reliably dif-
ferentiate infected collections from WON.
Abdominal Imaging Studies

Disruption of pancreatic perfusion causes pancreatic necrosis and
is detectable when an intravenous contrast agent is given during
CT imaging (Figures 37.1, 37.2, and 37.3). The Balthazar score
is a CT classification system for estimating the severity of acute
pancreatitis according to the proportion of pancreas that is not
perfused (reflecting necrosis) and the number of fluid collections.
High mortality can be expected if the Balthazar CT severity index
is 7 or more. Patients with acute pancreatitis who have normal CT
findings have a good prognosis. The correlation is good between
the lack of enhancement of more than 30% of the pancreas on
contrast-enhanced CT and the finding of pancreatic necrosis at
surgery or autopsy. As the degree of necrosis increases, morbidity
and mortality also increase.
Features of poor perfusion are often lacking in the first 48 to 72
hours after the onset of acute pancreatitis. Hence, CT performed
early in the course of disease may be falsely reassuring when
necrosis is not identified. In definite cases of acute pancrea-
titis, contrast-enhanced CT can be deferred for 2 to 3 days and
then—only if the patient’s clinical condition is deteriorating or
not responding to supportive care—performed to confirm the
presence of necrosis and guide appropriate therapy. MRI has
been compared prospectively with CT in the context of severe
pancreatitis and found to be reliable for staging severity, to have
predictive value for the prognosis of the disease, and to have
fewer contraindications than CT. It may also detect disruption of
the pancreatic duct, which can occur early in the course of acute
pancreatitis.
Treatment
Keys to management of all cases of acute pancreatitis are 1) early
estimation of severity (as outlined above), 2) aggressive initial
fluid administration, 3) antiemetics and analgesia, and 4) elucida- Figure 37.2. Acute Necrotizing Pancreatitis. A, The patient had
tion and treatment of the underlying cause. severe biliary pancreatitis. The density of the necrotic portion of the
pancreas (short arrows) is less than that of the normal enhancement in
the tail (long arrow). B, Note the necrosis in the body (arrow) and the
peripancreatic edema (asterisks). The pancreatic head is well perfused.
In the absence of heart failure or chronic oliguria, lactated Ringer

solution or normal saline should be administered intravenously at
a rate of at least 200 to 300 mL hourly and titrated according to
urine output (goal >1.5-3 mL/kg/h) and change in the serum urea
nitrogen or creatinine level. In patients with severe volume deple-
tion, an intravenous fluid bolus of 10 to 20 mL/kg over 1 to 2 hours
may be required before continuous intravenous infusion. Lactated
Ringer solution, with its calcium content, should not be used in
patients with acute pancreatitis because of possible hypercalcemia.
After the hematocrit decreases, the adequacy of fluid resuscitation
must be monitored carefully at 12 and 24 hours, with more frequent
serial checking of vital signs and measurement of urinary output.
Serum levels of electrolytes, calcium, magnesium, and glucose
and oxygenation should be monitored and supported or corrected
as indicated. These issues may require admission to an ICU. To
Figure 37.1. Normal Pancreas. Contrast-enhanced computed to- prevent volume overload and abdominal compartment syndrome,
mography shows the pancreas (P) with a uniform enhancement interme- aggressive fluid resuscitation should be limited to the first 24 to 48
diate between that of the liver (L) and the spleen (S). hours after the onset of acute pancreatitis (not hospital admission).
(according to the hematocrit) that did not decrease with fluid

resuscitation in 24 hours, underscoring the importance of suffi-
cient volume resuscitation early in the disease course. Although
our understanding of optimal fluid selection for treatment has
considerable gaps, hydration with lactated Ringer solution,
compared with normal saline, has been associated with less
inflammation (as measured with C-reactive protein), shorter
length of hospital stay, and fewer ICU admissions. Thus, in
many centers lactated Ringer solution is the fluid of choice for
patients with acute pancreatitis without contraindications to its
use. Analgesia requires narcotic-strength agents (typically fen-
tanyl or morphine) administered as patient-controlled analgesia.
Although in animal experiments, morphine has caused spasm
of the sphincter of Oddi, there is no definite evidence that mor-
phine worsens the disease in humans.
Interstitial edematous pancreatitis can be managed with
supportive care in a general hospital ward without the need for
monitoring in an ICU. Generally, nasogastric tubes are not in-
dicated because they do not improve disease outcome and they
increase patient discomfort. However, nasogastric tubes may
decrease symptoms in patients with extreme nausea, vomiting,
and ileus. Empirical use of antibiotics should be avoided in
patients with interstitial pancreatitis because these agents do
not alter the outcome. Nutritional support (discussed below) is
indicated only if the patient is expected to receive nothing by
mouth for 1 or more weeks. For mild interstitial pancreatitis,
recent studies have shown that early oral feeding, as tolerated,
is safe.
Specific therapy for identified causes of acute pancre-
atitis should be instituted early to prevent recurrence of
acute episodes. This includes discontinuation of suspected
medications that might have induced pancreatitis, initiation of
therapy for hypertriglyceridemia, and performance of chole-
cystectomy for suspected biliary pancreatitis. Cholecystectomy
should be performed during the index hospital admission to pre-
vent early recurrence of acute pancreatitis—and other gallstone-
related complications—among patients who delay their return
or do not return for follow-up. If the patient is a poor surgical
Figure 37.3. Walled-off Pancreatic Necrosis. A, Computed tomo- candidate because of severe coexisting medical illness, ERCP
graphic scan from the same patient as in Figure 37.2 shows that, 6 weeks with biliary sphincterotomy may be a good alternative to cho-
later, most of the peripancreatic edema has resolved. The necrosis and lecystectomy, especially if ultrasonography shows only sludge
fluid collection are well contained in the lesser sac, with a discrete wall or small stones.
or rind (arrows). The scan does not show the necrotic debris contained If biliary stone disease, hyperlipidemia, and medications are
within the fluid collection (broken circle indicates area void of material).
excluded as causes, abdominal CT should be performed to ex-
B, Magnetic resonance imaging of the same collection shows clear ev-
idence of solid debris (arrow) within the fluid collection, a result of ne- clude anatomical causes of pancreatic ductal obstruction, such as
crosis of the pancreatic body. a pancreatic or ampullary mass lesion or intraductal papillary mu-
cinous neoplasm, especially in patients older than 40 years. For
elderly patients with negative CT findings, consideration should
The need for early and adequate fluid resuscitation in patients be given to performing EUS or MR cholangiopancreatography
with acute pancreatitis cannot be overstated. Aggressive intra- after the acute changes have resolved.
venous fluid replacement counteracts intravascular volume de- Severe acute pancreatitis, with or without pancreatic ne-
pletion caused by third space losses, vomiting, fever, and the crosis, requires aggressive medical management, with greater
vascular permeability related to SIRS. Intravascular volume de- emphasis on fluid supplementation and the prevention and early
pletion causes hemoconcentration, low urine output, azotemia, diagnosis of infection. In recent years, the management of severe
tachycardia, and hypotension, thus compromising the blood acute pancreatitis has shifted from early surgical débridement
supply of the pancreas, which contributes to the development of (necrosectomy) to intensive medical care.
pancreatic necrosis with its attendant complications. Evidence Early mortality during the first 1 to 2 weeks of acute pancrea-
from experimental models and from large clinical databases titis is primarily due to multisystem organ failure resulting from
supports the concept that early aggressive fluid resuscitation SIRS. Systemic complications include adult respiratory distress
minimizes or aborts pancreatic necrosis and improves survival. syndrome, acute kidney failure, shock, coagulopathy, hypergly-
In a retrospective comparative study of 39 patients with acute cemia, and hypocalcemia. These complications are managed
pancreatitis of various severities, pancreatic necrosis devel- with endotracheal intubation, aggressive fluid resuscitation, fresh
oped in all patients who had evidence of hemoconcentration frozen plasma, insulin, and calcium as needed.
Nutritional Support necrosis is rare during the first week of acute pancreatitis, a pe-
riod characterized by overactivation of the immune system, and is
Nutritional support is often indicated to meet increased metabolic
more often recognized by the third or fourth week. Nevertheless,
demands and to rest the pancreas during the prolonged fasting state
without intervention, the mortality rate for patients with infected
of acute pancreatitis. Multiple randomized prospective studies of
acute necrotizing pancreatitis is nearly 100%; thus, early em-
severe acute pancreatitis have compared total parenteral nutrition
pirical use of antibiotics is warranted while the infection is
with enteral feeding through a nasoenteric feeding tube placed
investigated. Predisposing factors for the development of infec-
under endoscopic or radiographic guidance. Enteral feeding
tion include necrosis (90% of infections in acute pancreatitis
yields significantly fewer total and infectious complications, a
occur in the presence of necrosis) and an increased number of
3-fold decrease in the cost of nutritional support, and improve-
fluid collections. The bacteriologic status of the pancreas can be
ment in the acute-phase response and disease severity scores,
determined with CT-guided fine-needle aspiration of pancreatic
compared with parenteral (intravenous) nutrition. Enteral nutri-
and peripancreatic tissue or fluid. This aspiration method is safe,
tion helps preserve the mucosal barrier of the gut and reduces
accurate (96% sensitivity and 99% specificity), and recommended
translocation of bacteria from the gut, thus decreasing the rate of
for patients with acute necrotizing pancreatitis whose clinical
infected necrosis. A recent meta-analysis of nutritional therapy
condition deteriorates or does not improve despite aggressive sup-
for patients with acute pancreatitis reported that, compared with
portive care. Ultrasonographically guided aspiration may have
parenteral nutrition, enteral nutrition was associated with a signif-
lower sensitivity and specificity, but it can be performed at the
icantly lower incidence of infections, fewer surgical interventions
bedside. If CT-guided sampling documents the presence of gram-
to control pancreatitis, and a decrease in mortality. Enteral nutri-
negative organisms, appropriate choices for antibiotics include a
tion should be considered the standard of care for patients with
carbapenem, a fluoroquinolone with metronidazole, or a third-
severe acute pancreatitis.
generation cephalosporin with metronidazole. If Gram stains
For patients who have mild disease (ie, no organ failure or
show gram-positive organisms, the addition of vancomycin is
necrosis) and no symptoms of nausea or vomiting, and for whom
appropriate. In all cases, antibiotic coverage can be narrowed or
ileus is not a concern, oral feeding can be initiated within 24
expanded once the identity and sensitivities of the organism are
hours and advanced as tolerated. For patients who have more se-
known. An evolving understanding implicates fungal organisms
vere disease (ie, with failure of 1 or more organs or the presence
as also having a pivotal role in infected pancreatic necrosis.
of necrosis), emphasis should still be placed on aggressive, early
nutritional support to reduce the risk of further organ failure, in-
fection, and need for operative intervention. Therapy for Pancreatic Fluid Collections
For patients who have moderately severe or severe pancreatitis As mature, encapsulated collections, pancreatic pseudocysts and
who cannot tolerate oral feeding, enteral tube feeding should be WON can be targeted through endoscopic, percutaneous radio-
considered by days 3 to 5. Ideally, enteral nutrition is delivered logic, or surgical means. In addition to their inherent risks, any
to the jejunum or at least to the postpyloric gut. Placement of the such procedure threatens infection of a sterile fluid collection;
feeding tube into the jejunum theoretically decreases stimulation thus, intervention on fluid collections should be pursued only if
of the inflamed pancreas, but radiologic or endoscopic guidance they are causing symptoms (eg, pain, nausea, or anorexia), causing
adds expense and is not readily available in all facilities. From luminal or biliary obstruction, contributing to SIRS (as is often
studies with contradictory results, nasogastric feeding may or the case with WON), or becoming infected. Ideally, interventions
may not be as safe and beneficial as nasojejunal feeding, but this should be delayed until fluid collections have become organ-
issue requires further study. Enteral feeding with a high-protein, ized, a process that typically takes 4 weeks. Pseudocysts may re-
low-fat, semielemental formula should be initiated even in se- quire only simple drainage, whereas WON with a considerable
vere cases unless the patient has bowel obstruction. If this en- amount of solid necrotic material is likely to require mechanical
teral feeding does not help, a transition to total parental nutrition débridement (ie, necrosectomy), often necessitating multiple
should be initiated promptly. procedures over time. Minimally invasive endoscopic drainage
is now the first-line therapy for symptomatic pseudocysts and
Prophylactic Antibiotics WON at many centers. Asymptomatic and sterile pancreatic fluid
collections can be managed through observation and serial im-
Prophylactic antibiotics are not recommended in patients with aging alone.
acute pancreatitis, regardless of severity or presence of necrosis.
Clinically, patients with severe pancreatitis often have features
of sepsis, including fever, leukocytosis, and organ failure in the Role of ERCP
first 7 to 10 days, which may be clinically difficult to distinguish Early ERCP with biliary sphincterotomy improves outcomes
from infection. Furthermore, patients may have extrapancreatic among patients who have severe gallstone pancreatitis with as-
infections (eg, pneumonia or bacteremia). Therefore, patients sociated cholangitis. Studies that exclude patients with biliary
who are thought to have an infection may begin appropriate obstruction have shown limited or no benefit from early ERCP
antimicrobial therapy; however, if the evaluation and blood in patients predicted to have severe acute pancreatitis. Hence,
cultures are negative for infection, antibiotic therapy should be improved outcome after ERCP and sphincterotomy in gallstone
discontinued. pancreatitis appears to be the result of reduced biliary sepsis
rather than improvement in pancreatitis. Ideally, when performed
Detection of Pancreatic Infection for concomitant cholangitis, ERCP should be undertaken in the
first 24 to 48 hours, since later cholestasis often reflects pancre-
Sterile or infected acute necrotizing pancreatitis can be difficult atic edema rather than stone obstruction and biliary infection;
to distinguish clinically because either may produce fever, leu- moreover, associated duodenal edema compromises the success
kocytosis, and severe abdominal pain. Infection of pancreatic of ERCP after this interval.
Additional Complications higher if infected necrosis occurs. Patients with sterile necrosis
and severe disease accompanied by multisystem organ failure,
Disconnected pancreatic duct syndrome is characterized by com-
shock, or kidney insufficiency have a significantly higher mor-
plete discontinuity of the pancreatic duct that occurs in up to 30%
tality rate.
of persons with necrotizing pancreatitis. It typically results from
The long-term clinical endocrine and exocrine consequences
inflammation and swelling in the pancreatic neck, which leads to
of acute necrotizing pancreatitis appear to depend on several
failure of the viable distal pancreas to drain through the proximal
factors: the severity of necrosis, the cause of pancreatitis (alco-
pancreas into the duodenum. This causes pancreatic secretions to
holic or nonalcoholic), the continued use of alcohol, and the de-
leak into the retroperitoneum, where they may eventually coalesce
gree of pancreatic débridement. Sophisticated exocrine function
into a pseudocyst or WON. CT or MRI findings may suggest the
studies have shown persistent subclinical exocrine insufficiency
presence of a disconnected pancreatic duct, but confirmation may
in many patients up to 2 years after severe acute pancreatitis.
require pancreatography to show extravasation of contrast mate-
Treatment with pancreatic enzymes should be restricted to
rial injected into the main pancreatic duct, most often with ERCP
patients with symptoms of steatorrhea and weight loss due to fat
or EUS. Management of disconnected pancreatic duct syndrome
malabsorption. Although subtle glucose intolerance is frequent,
may require surgical resection of the disconnected but functional
overt type 2 diabetes is uncommon.
upstream portion of the gland (distal pancreatectomy) or surgical
cyst enterostomy for prolonged diversion of leaking pancreatic
juice. In some cases, a chronic fistula can be maintained to the Suggested Reading
stomach or the duodenum by endoscopic long-term placement of Abu Dayyeh BK, Topazian M. Endoscopic management of pancreatic
transmural stents. A disrupted pancreatic duct leads to a similar necrosis. Am J Gastroenterol. 2018 Sep;113(9):1269–73.
clinical presentation from lack of duct continuity without a com- ASGE Standards of Practice Committee, Chandrasekhara V, Khashab
plete disconnected segment. Continuity may be reestablished by MA, Muthusamy VR, Acosta RD, Agrawal D, et al. Adverse events
endoscopic stent placement through the papilla and across the associated with ERCP. Gastrointest Endosc. 2017 Jan;85(1):32–47.
disrupted duct segment; endoscopic management becomes con- Crockett SD, Wani S, Gardner TB, Falck- Ytter Y, Barkun AN,
siderably more challenging if the disruption is closer to the tail. American Gastroenterological Association Institute Clinical
Beyond local duct and parenchymal pancreatic phenomena, Guidelines Committee. American Gastroenterological Association
Institute guideline on initial management of acute pancreatitis.
vascular complications can occur in patients who have acute pan-
Gastroenterology. 2018 Mar;154(4):1096–101.
creatitis; these include splanchnic vein thrombosis and splanchnic Forsmark CE, Vege SS, Wilcox CM. Acute pancreatitis. N Engl J Med.
artery pseudoaneurysm. Treatment of splanchnic vein throm- 2016 Nov;375(20):1972–81.
bosis focuses on managing the underlying pancreatitis. While the Lee A, Ko C, Buitrago C, Hiramoto B, Hilson L, Buxbaum J, et al.
majority of splanchnic vein thromboses resolve spontaneously, Lactated ringers vs normal saline resuscitation for mild acute pancre-
anticoagulation is needed if the clot extends into the portal or atitis: a randomized trial. Gastroenterology. 2021 Feb;160(3):955–7.
superior mesenteric vein, as this could lead to hepatic or enteric Sandrasegaran K, Heller MT, Panda A, Shetty A, Menias CO. MRI in
ischemia. Pseudoaneurysm develops in approximately 10% of acute pancreatitis. Abdom Radiol (NY). 2020 May;45(5):1232–42.
patients with a pancreatic fluid collection, typically occurring Schepers NJ, Hallensleben NDL, Besselink MG, Anten MGF,
in the wake of inflammation and erosion of the gastroduodenal Bollen TL, da Costa DW, et al. Urgent endoscopic retrograde
cholangiopancreatography with sphincterotomy versus conser-
or splenic arteries. Pseudoaneurysm can manifest as bleeding—
vative treatment in predicted severe acute gallstone pancreatitis
which may be catastrophic—into the gastrointestinal tract or into (APEC): a multicentre randomised controlled trial. Lancet. 2020 Jul
a pancreatic fluid collection. Evaluation for pseudoaneurysm 18;396(10245):167–76.
and treatment with interventional radiology-based embolization Tenner S, Baillie J, DeWitt J, Vege SS, American College of
therapies is critical before the use of endoscopic therapy for pan- Gastroenterology. American College of Gastroenterology guide-
creatic fluid collections. line: management of acute pancreatitis. Am J Gastroenterol. 2013
Sep;108(9):1400–15; 16.
Vaughn VM, Shuster D, Rogers MAM, Mann J, Conte ML, Saint S, et al.
Prognosis Early versus delayed feeding in patients with acute pancreatitis: a
The overall mortality rate for patients with severe acute pancrea- systematic review. Ann Intern Med. 2017 Jun 20;166(12):883–92.
titis has decreased to approximately 15% as a result of improved Vege SS, DiMagno MJ, Forsmark CE, Martel M, Barkun AN. Initial med-
ical treatment of acute pancreatitis: American Gastroenterological
ICU therapies, antibiotics, and deferral of surgery. Early deaths
Association Institute technical review. Gastroenterology. 2018
(1-2 weeks after the onset of pancreatitis; approximately 50% of Mar;154(4):1103–39.
all deaths) are primarily due to multisystem organ failure, and Wan J, He W, Zhu Y, Zhu Y, Zeng H, Liu P, et al. Stratified analysis
late deaths result from local or systemic infections. The overall and clinical significance of elevated serum triglyceride levels in early
mortality rate for patients with sterile acute necrotizing pancrea- acute pancreatitis: a retrospective study. Lipids Health Dis. 2017
titis is approximately 10%. The mortality rate is at least 3 times Jun;16(1):124.
38
Chronic Pancreatitisa
LAURENS P. JANSSENS, MD
SHOUNAK MAJUMDER, MD
Chronic pancreatitis is an inflammatory condition of the pancreas involving the obstructed part of the gland. Obstructive pancre-
characterized by progressive fibrosis that leads to irreversible de- atitis commonly occurs distally to pancreatic tumors (ductal
struction of exocrine and endocrine tissue, resulting eventually in adenocarcinoma and intraductal papillary mucinous tumor),
exocrine and endocrine insufficiency. There is considerable heter- anastomotic strictures related to pancreaticojejunostomy, and
ogeneity in the manifestation and natural history of the condition. postinflammatory strictures after acute or traumatic pancreatitis.
Chronic pancreatitis is classified broadly into chronic calcifying The preferred treatment of symptomatic disease is resection of
pancreatitis, chronic obstructive pancreatitis, and chronic autoim- the obstructed upstream portion of the pancreas, but pancreatic
mune pancreatitis. duct stenting may be an alternative in carefully selected patients
Chronic calcifying pancreatitis is usually characterized by re- who have benign strictures.
current bouts of clinically acute pancreatitis early in the course Chronic autoimmune pancreatitis, simply known as autoim-
of the disease and development of intraductal stones later in the mune pancreatitis (AIP), is a unique form of chronic pancreatitis
disease course. Steatorrhea and diabetes mellitus eventually de- that is characterized histologically by lymphoplasmacytic infil-
velop in most patients. This is the clinical profile of the disease trate and storiform fibrosis and therapeutically by a dramatic re-
that readily comes to mind when the term chronic pancreatitis is sponse to corticosteroids. When so defined, AIP has 2 subtypes,
used in clinical practice. However, about 10% of patients may be type 1 and type 2 (Table 38.1.).
asymptomatic, and the disease is incidentally detected on cross- Type 1 AIP is considered the pancreatic manifestation of a
sectional imaging; nearly half the patients with chronic pancrea- multiorgan fibroinflammatory syndrome known as immunoglob-
titis have not had previous episodes of acute pancreatitis. ulin (Ig)G4-related disease. This syndrome affects not only the
Chronic obstructive pancreatitis results from obstruction of pancreas but also other organs and tissues, including the bile
the pancreatic duct due to any cause. The disease affects only duct, orbital tissue, salivary glands, retroperitoneum, and lymph
the portion of the organ that is upstream of the obstruction. It nodes. Type 1 AIP is a disease of older men. Serum IgG4 levels
is usually not associated with pancreatic duct stone formation. are often elevated in type 1 AIP, and organs and tissues affected
Although patients are often asymptomatic, partial obstruc- by AIP have a lymphoplasmacytic infiltrate that is rich in IgG4-
tion can lead to recurrent bouts of clinically acute pancreatitis positive cells. In type 1 AIP, the pancreas has a typical histo-
logic pattern called lymphoplasmacytic sclerosing pancreatitis,
characterized by a dense lymphoplasmacytic infiltrate around
a
The authors thank Suresh T. Chari, MD, who was the author of the pre- medium-sized ducts, a peculiar swirling (storiform) fibrosis, and
vious version of this chapter (parts of which appear in this edition). an intense inflammation that surrounds veins (obliterative phle-
Abbreviations: AIP, autoimmune pancreatitis; CT, computed tomog- bitis) and spares adjacent arteries.
raphy; ERCP, endoscopic retrograde cholangiopancreatography; EUS, Most commonly, patients presenting with this form of chronic
endoscopic ultrasonography; FE1, fecal elastase-1; Ig, immunoglobulin; pancreatitis have obstructive jaundice that mimics pancre-
MRCP, magnetic resonance cholangiopancreatography; MRI, magnetic atic cancer; they rarely present with clinically acute or painful
resonance imaging chronic pancreatitis. Pancreatic calcification is uncommon in
437
Table 38.1. Demographic, Clinical, and Histologic Features of Autoimmune Pancreatitis (AIP)
AIP type
Featurea Type 1 (LPSP) Type 2 (IDCP)

Age at diagnosis, y 60-70 40-50
Sex predominance Male Equivalent
Acute pancreatitis Rare Most common presentation
Extrapancreatic disease Frequently present, involving bile ducts, Absent
orbit, salivary gland, kidney, and
retroperitoneum
Association with IBD Weak Strong
IgG4 increased 60%-70% of patients Uncommon
Relapses 30%-50% of patients <10% of patients
Storiform fibrosis Prominent Less prominent
Obliterative phlebitis Typical Rare
Granulocyte epithelial lesion Absent Typical
Tissue IgG4-positive cells Abundant; usually >10/HPF Rare; usually <10/HPF
Abbreviations: HPF, high-power field; IBD, inflammatory bowel disease; IDCP, idiopathic duct-centric pancreatitis; Ig,
immunoglobulin; LPSP, lymphoplasmacytic sclerosing pancreatitis.
a
Pancreatic imaging features are similar in both types of AIP; histologically, both types have lymphoplasmacytic infiltrate.
AIP. The inflammatory process in type 1 AIP responds to corti- hereditary pancreatitis in an autosomal dominant pattern. The
costeroid therapy, although relapse is common after withdrawal most frequent variations in PRSS1 associated with pancreatitis
of treatment. If patients have a confirmed diagnosis of type 1 are p.R122H and p.N29I, which have penetrance greater than
AIP but cannot tolerate corticosteroids, rituximab may be used 80%. SPINK1 alterations are frequent in the general population
for initial treatment. Patients with relapsing disease require long- and are associated with an increased risk for pancreatitis; how-
term maintenance immunosuppression with either a low dose of ever, pancreatitis develops in less than 1% of persons who have
corticosteroids or steroid-sparing agents such as azathioprine,
mycophenolate mofetil, or rituximab.
Table 38.2. Etiologic and Risk Factors of Chronic
Type 2 AIP occurs in younger patients and appears to be a
Calcifying Pancreatitis (CP)
pancreas-specific disorder. It is typically not associated with ei-
ther increased serum levels of IgG4 or dense tissue infiltration Etiologic or risk factor Salient features
with IgG4-positive cells. About 15% to 30% of patients with type Alcohol Most common cause of CP in the West
2 AIP have inflammatory bowel disease (predominantly ulcera- CP develops in about 5% of persons with alcohol
tive colitis). Histologically, type 2 AIP (also known as idiopathic use disorder, usually after a long history of
duct-centric pancreatitis) is characterized by neutrophilic infil- alcohol ingestion; occasional binge drinking
trate in the pancreatic duct epithelium (ie, a granulocyte epithelial alone is not sufficient to cause CP, and smoking
lesion), which can lead to ductal obliteration. Type 2 AIP also is a strong cofactor
responds to corticosteroid therapy, and relapses, which are far Smoking Independent risk factor
less common than in type 1 AIP, are treated with corticosteroids. Increased risk for pancreatic calcifications, EPI,
and pancreatic cancer
The rest of the discussion in this chapter is related to chronic
Hereditary Alterations in the cationic trypsinogen gene
calcifying pancreatitis. (PRSS1) are associated with a high-penetrance
(80%) autosomal dominant form of CP,
Etiology and Risk Factors accounting for 1% of all CP cases
Patients present at an early age (first and second
Several conditions are associated with chronic calcifying pan- decades)
creatitis (Table 38.2). The pathogenesis of chronic pancreatitis High risk of pancreatic cancer with time,
is largely unknown. However, clinical acute pancreatitis and the especially for smokers
eventual development of chronic pancreatitis are thought to be Tropical Cause unknown
due to the interaction between genetic and environmental factors. Highest prevalence in South India
Early age at onset (first and second decades)
The synergistic interaction between alcohol use and smoking is
High prevalence (>80%) of diabetes mellitus and
an increasingly recognized risk factor for chronic pancreatitis. calcification at diagnosis
Genes that have been associated with chronic pancreatitis in- Idiopathic Early (juvenile) and late (senile) forms
clude the following: cationic trypsinogen gene (PRSS1; OMIM Juvenile form is associated with alterations in
27600); serine protease inhibitor Kazal-type 1 gene (SPINK1; the CFTR and SPINK1 genes and with other
OMIM 167790); cystic fibrosis transmembrane conductance alterations in the PRSS1 gene, which are
regulator gene (CFTR; OMIM 602421); chymotrypsin C gene also associated with CP (probably as disease
(CTRC; OMIM 601405); and calcium- sensing receptor gene modifiers)
(CASR; OMIM 601199). The claudin-2 gene (CLDN2; OMIM Pain is a common feature of early-onset disease
300520) is associated with accelerated progression from acute Senile form may be painless
Hypertriglyceridemia Triglyceride levels usually >1,000 mg/dL
pancreatitis to chronic pancreatitis in persons who have alcohol-
related disease. Alterations in the PRSS1 gene cause chronic Abbreviation: EPI, exocrine pancreatic insufficiency.
38. Chronic Pancreatitis 439
an alteration. In patients who have a heterozygous SPINK1 al- widely available, with relatively good sensitivity for the diag-
teration, it likely acts as a disease modifier rather than a primary nosis of moderate to severe chronic pancreatitis. The findings,
cause of pancreatitis. Interactions between these genes, other un- however, can be normal in early chronic pancreatitis. Chronic
known genetic factors, and toxic-metabolic factors (eg, alcohol, pancreatitis is diagnosed with CT by the identification of pathog-
smoking, hypertriglyceridemia, and hypercalcemia) are thought nomonic calcifications within the main pancreatic duct or paren-
to lead to recurrent acute and chronic pancreatitis. chyma or calcification within the dilated main pancreatic duct in
combination with parenchymal atrophy (Figure 38.1). CT is also
suitable for the evaluation of pain in a patient with known chronic
Diagnosis pancreatitis, because most complications of chronic pancreatitis,
Although histologic examination is the gold standard for diag- including peripancreatic fluid collections, bile duct obstruction,
nosis of chronic pancreatitis, it often is not available. Without his- and bowel obstruction, can be identified and inflammatory or ne-
tologic study, a combination of morphologic findings on imaging oplastic masses can be visualized.
studies, functional abnormalities, and clinical findings is used to EUS provides high-resolution images of the pancreatic pa-
diagnose chronic pancreatitis. The diagnosis is relatively straight- renchyma and duct. Nine ductal and parenchymal EUS features
forward in the later stages of the disease when calcification and have been identified; the presence of more than 5 features
steatorrhea are present, but the diagnosis is difficult when pan- strongly suggests the diagnosis of pancreatitis with structural
creatic structure and function are not unequivocally abnormal. abnormalities seen on other imaging studies. However, the diag-
Currently available diagnostic modalities are not adequate for nosis of “early” chronic pancreatitis (ie, chronic pancreatitis not
making a firm diagnosis of chronic pancreatitis without obvious evident on other imaging studies) based on EUS changes alone is
changes in structure and function. still controversial. There is considerable interobserver disagree-
ment on the presence or absence of EUS features and their inter-
pretation. Problems with interpretation also may arise for 1) older
Structural Evaluation patients who have senile changes in the pancreas, 2) patients with
The imaging procedures commonly used to evaluate for struc- alcohol use in whom fibrosis may be present but not pancreatitis,
tural changes in the pancreas are computed tomography (CT), 3) patients with increased intrapancreatic fat, and 4) patients who
endoscopic ultrasonography (EUS), magnetic resonance imaging had a recent episode of acute pancreatitis. Currently, the diagnosis
(MRI), and MR cholangiopancreatography (MRCP). Endoscopic of chronic pancreatitis should not be based on EUS criteria alone.
retrograde cholangiopancreatography (ERCP) is no longer ERCP is no longer recommended as a diagnostic tool in the
recommended as a diagnostic test for chronic pancreatitis because evaluation of suspected chronic pancreatitis because of its in-
of the risk of procedural complications and the widespread avail- herent risks of complications (5%). It should be performed only
ability of high-resolution cross-sectional imaging modalities that when therapy is planned (eg, pancreatic duct stone extraction or
are safe and noninvasive. Pancreatic calcification that is suggestive dilation and stent placement for a pancreatic ductal stricture).
but not diagnostic of chronic pancreatitis can be identified on ab- MRCP is noninvasive, avoids the use of ionizing radiation, and
dominal radiographs. However, CT and EUS can be used to detect does not routinely require sedation, making it a diagnostic pro-
small specks of calcification not visible on plain radiographs. CT, cedure of choice for most patients, especially when CT findings
MRI, and EUS all have similar diagnostic sensitivity and speci- are normal and there is reasonable, continued clinical suspicion
ficity for chronic pancreatitis. for the diagnosis of chronic pancreatitis. MRCP avoids the risks
Abdominal CT is a good first test for the evaluation of a pa- associated with ERCP while providing a detailed evaluation of
tient with possible chronic pancreatitis. It is noninvasive and the pancreatic duct. Major lesions such as grossly dilated ducts,
Figure 38.1. Chronic Pancreatitis. A, Contrast-enhanced computed tomography (CT) of the abdomen (coronal view) shows a stone (arrow) in the
dilated main pancreatic duct in the head of the pancreas. B, Contrast-enhanced CT of the abdomen (axial view) shows a dilated main pancreatic duct
in the body (arrow) and tail.
communicating pseudocysts, and even pancreas divisum can be of chronic pancreatitis, it may be absent in up to 10% of patients
detected, but small duct changes and calcifications are not readily overall and more commonly in patients with late-onset (senile)
visualized. Secretin administered intravenously during MRCP idiopathic chronic pancreatitis. Diabetes mellitus and calcifica-
can further enhance pancreatic duct visualization and aid in tion may be absent at diagnosis in patients with alcoholic chronic
the diagnosis of chronic pancreatitis. Secretin-enhanced MRCP pancreatitis, but they are present at diagnosis in more than 80%
can be used to identify subtle morphologic changes suggestive of patients with tropical pancreatitis.
of chronic pancreatitis such as pancreatic duct irregularity and For patients with alcoholic chronic pancreatitis, death often
ectatic side branches, allow for a dynamic assessment of main is related to smoking and nonpancreatic and alcohol- related
pancreatic duct compliance, and assess pancreatic ductal fluid se- complications (especially cancers). For patients with tropical
cretion as a surrogate for exocrine function. pancreatitis, the most common cause of death is diabetes-related
complications; the second most common cause is pancreatic
cancer. Pancreatic cancer can complicate any form of chronic
Functional Testing
pancreatitis, but it is especially common in the hereditary and
The pancreas has great functional reserve, which means it must tropical forms, probably because of the long duration of disease.
be damaged severely before functional loss is recognized clin-
ically. For example, 90% of the pancreas must typically be
destroyed before steatorrhea occurs. Abnormal results of func- Complications
tional testing alone are not diagnostic of chronic pancreatitis, and Diabetes Mellitus
diagnosis requires additional evidence from imaging studies of
structural alteration consistent with chronic pancreatitis. Imaging Progressive decrease in islet cell mass leads to diabetes mellitus
studies by themselves usually are diagnostic by the time steator- in chronic pancreatitis, classified as pancreatogenic diabetes or
rhea develops. type 3c diabetes. Whereas diabetes is common at presentation
Invasive or direct tests of pancreatic function (eg, the “tubed” in the tropical form of chronic pancreatitis, it is usually a late
secretin test) show functional impairment even in the absence of complication in other forms of the disease. Diabetes eventually
steatorrhea. However, these tests are complex, invasive, and not develops in most patients (85%), with or without pancreatic re-
widely available. The only direct pancreatic function test currently section, and nonresective surgery such as ductal drainage does
in use at some centers with available expertise is the endoscopic not prevent it. Even after total pancreatectomy with autologous
pancreatic function test, which involves a periodic collection of islet transplant, most patients are insulin-dependent at 10 years
duodenal fluid for assessment of bicarbonate concentration after after surgery.
administration of intravenous secretin. Noninvasive or indirect
tests of pancreatic function, such as 72-hour fecal fat estimation Steatorrhea
and fecal elastase-1 (FE1) quantification, have poor sensitivity
for the detection of early disease and are not indicated as tests to Steatorrhea usually occurs after more than 90% of the gland has
establish a diagnosis of CP. However, in patients with established been destroyed. Persistent steatorrhea can lead to deficiencies
CP, these stool tests can be used to diagnose exocrine pancre- in fat-soluble vitamins (vitamins A, D, E, and K) and other
atic insufficiency. Although an FE1 level of less than 200 μg/g of micronutrients (zinc, magnesium, and vitamin B12) and malnu-
stool is considered abnormal, values less than 100 µg/g usually trition, weight loss, and osteoporosis. Treatment involves oral
indicate exocrine pancreatic insufficiency, whereas mild to mod- pancreatic enzyme replacement therapy and supplementation
erately decreased FE1 levels (ie, 100-200 μg/g of stool) may be to correct vitamin and micronutrient deficiencies. Pancreatic
indeterminate and require clinical context for accurate interpreta- enzyme replacement therapy is available as uncoated tablets or
tion. FE1 estimation may be falsely low in watery stool samples enteric-coated capsules or microspheres with pH-dependent re-
because of dilution. In patients with diarrhea and a low pretest lease of enzymes. Patients with severe steatorrhea require 30,000
probability of chronic pancreatitis, the FE1 assay can have a high to 45,000 US Pharmacopeia units of lipase per meal and lesser
false-positive result, and an abnormal value should be interpreted amounts with snacks. Enzymes should be given with meals to
with caution. allow proper mixing of food with the enzymes. Acid suppression
may be required to prevent destruction of the enzymes by gastric
acid. Fat-soluble vitamin levels should be measured at baseline
Clinical Features and Natural History and monitored periodically to correct any concomitant nutri-
Abdominal pain is the dominant symptom in the early part of tional deficiencies. Bone mineral density testing should also be
the natural history of chronic pancreatitis, and steatorrhea and considered at baseline, especially in patients with concomitant
diabetes mellitus are the prominent features of late, end-stage dis osteoporosis risk factors.
ease. Pain is usually related to acute inflammatory flares or local
complications, although patients can have chronic persistent pain
Pseudocyst
due to visceral hypersensitivity. Some authors have reported a
painless “burn out” of the pancreas in the late stages of the dis In the early stages of the disease, pseudocysts result from pancre-
ease, but others have reported pain occurring even in late stages. atic duct leakage after an attack of clinically acute pancreatitis.
Complications can occur after acute flares of pancreatitis or from In later stages, ductal dilatation can lead to leakage and the for-
chronic fibrosis in and around the pancreas. mation of pseudocysts from ductal “blowout.” Upstream ductal
The clinical features and natural history of chronic pancrea- obstruction due to stricture or a large stone often results in the ref-
titis can differ remarkably in different forms of chronic pancrea- ormation of pseudocysts after simple enteral drainage (eg, endo-
titis. The age at onset of pain is much younger (first and second scopic cyst drainage). This may require endoscopic intervention
decades of life) in the hereditary and tropical forms of chronic or concomitant drainage of the main pancreatic duct (usually sur-
pancreatitis. Although pain is a dominant feature of most forms gically) or resection of the diseased portion of the gland (or both).
38. Chronic Pancreatitis 441
Biliary Obstruction pancreatitis, and although the severity may fluctuate, it rarely
disappears with time.
Biliary obstruction can result from edema of the head of the gland
A stepwise approach to pain management is recommended.
after an acute attack, compression from a pseudocyst, bile duct
However, the scientific evidence to support any of the measures
entrapment in the fibrotic process involving the head of the gland,
taken (medical, endoscopic, or surgical) is scant, and there are
or complicating pancreatic malignancy in patients with long-
very few well-defined prospective trials that compare groups
standing disease. Acute inflammatory edema of the head of the
receiving therapy with groups receiving either no therapy or a
gland usually responds to conservative management, and com-
competing therapy.
pression of a pseudocyst responds to drainage of the pseudocyst.
An important first step is the assessment of a patient’s pain
Fibrotic stricturing requires endoscopic intervention typically
and its nature, frequency, severity, and effect on quality of life
with a prolonged period of stenting with covered metal biliary
and other activities. Patients who have intermittent (eg, ≤1 ep-
stents and surgical biliary bypass if strictures persist or recur
isode per year), uncomplicated episodes with full function
after appropriate endoscopic intervention. Pancreatic cancer
between episodes are probably better off without potentially inju-
complicating chronic pancreatitis can be difficult to diagnose
rious interventions. Regardless of the severity of pain, all patients
early. The management of pancreatic cancer is described in detail
with chronic pancreatitis should be counseled during each visit
in Chapter 39 (“Pancreatic Neoplasms”).
about abstinence from not only alcohol but also tobacco.
Patients who have more frequent or severe pain and a ten-
Duodenal Obstruction dency to take narcotics for pain control need further evaluation.
The initial evaluation with imaging studies (eg, CT) should be
Potentially reversible gastric outlet obstruction can occur during undertaken to rule out complications of pancreatitis such as per-
an acute flare of pancreatitis when peripancreatic inflammation sistent acute inflammation (inflammatory mass) in the pancreas,
involves the gastroduodenal region. Nasojejunal feeding may pancreatic and peripancreatic fluid collections, biliary obstruc-
be required to maintain nutrition during this period. Patients tion, and duodenal stenosis. Other diagnoses to be considered in
with a persistent fibrotic process involving the duodenum re- the appropriate clinical context are opioid-induced constipation,
quire either surgical bypass of the gastric outlet obstruction or abdominal wall pain, peptic ulcer disease, gallbladder disease,
pancreaticoduodenectomy. and pancreatic cancer. The presence of any of these should lead
to appropriate intervention.
Splenic Vein Thrombosis In patients without the above conditions, medical, endo-
Because of the proximity of the splenic vein to the pancreas, scopic, and surgical options have been attempted. Medical
the vein is often affected by pancreatic inflammation or fibrosis. therapy includes avoidance of a high-fat diet, abstinence from al-
Patients with left-sided portal hypertension (ie, sinistral portal cohol and smoking, and use of pancreatic enzyme replacement
hypertension) can present with gastric variceal bleeding, which therapy, often in association with acid suppression. Endoscopic
is treated with splenectomy. therapy includes sphincterotomy, lithotripsy, and pancreatic duct
stenting. Endoscopic interventions are appropriate before sur-
gical therapy is considered except in patients with a heavy burden
Pancreatic Cancer of stone disease, where surgery has been shown to result in better
Patients with chronic pancreatitis have an increased risk for pan- outcomes. Celiac plexus block (performed with EUS guidance or
creatic cancer. However, screening for early detection of pancre- percutaneously) appears to have limited benefit in patients with
atic cancer in these patients is not recommended because of a chronic pancreatitis. Chronic pancreatitis is a complex disease
lack of effective screening tools. Expert consensus recommends and medical management needs to be individualized according
screening in patients who have hereditary chronic pancreatitis as- to the clinical context, local expertise, and needs of the patient.
sociated with a PRSS1 variant starting at age 40 years or 20 years Surgical therapy is an option for patients who clearly appear
after onset of pancreatitis, whichever is earlier. The carbohydrate to have disabling pancreas-related pain. The choice of operation,
antigen 19-9 level may be falsely high in chronic pancreatitis and if elected, should be based on the morphology of the pancreatic
is therefore not useful for pancreatic cancer screening. duct and the distribution and character of parenchymal disease.
Treatment options include decompressive surgery, such as lat-
eral pancreaticojejunostomy for patients with a dilated pancre-
Management atic duct; partial pancreatic resection for those with a persistent
Abdominal pain is the most dominant and vexing problem in the inflammatory mass; or total pancreatectomy for patients with
management of patients with chronic pancreatitis. It can vary in disease unresponsive to medical therapy and not suitable for
severity from mild, intermittent pain to severe, chronic, debili- other surgical options. A randomized controlled trial comparing
tating pain. In addition to the addiction to alcohol and tobacco pancreaticojejunostomy with endoscopic therapy for chronic pan-
that patients with alcoholic pancreatitis often have, patients creatitis with dilated ducts showed that surgery provided superior
with severe pain also have a considerable potential for addiction results, and a higher proportion of surgical patients reported pain
to narcotics. It is very difficult to assess the true severity of pain relief. However, the 20% to 40% failure rate and the potential
if patients misuse narcotics, and therapeutic interventions often for surgical morbidity and mortality warrant reserving surgical
are seemingly unsuccessful because of continued dependence treatment for patients who have severe pain not responsive to
on narcotics. Apart from these issues, a poor understanding less invasive approaches. In a more recent randomized clinical
of the pathogenesis of pain has made it difficult to rationally trial, which included patients with painful chronic pancreatitis,
manage abdominal pain in patients who have chronic pancre- early surgery resulted in lower pain scores over 18 months when
atitis. Despite some optimism that pancreatic pain eventually compared to an endoscopy- first approach. However, further
“burns out,” most clinicians agree that the pain has a large studies are warranted to ascertain if this difference persists over
negative impact on the quality of life of patients with chronic a longer period.
Suggested Reading with the International Association of Pancreatology, the American

Pancreatic Association, the Japan Pancreas Society, and European
Gardner TB, Adler DG, Forsmark CE, Sauer BG, Taylor JR, Whitcomb Pancreatic Club. Pancreatology. 2020 Jun;20(4):579–85.
DC. ACG clinical guideline: chronic pancreatitis. Am J Gastroenterol. Majumder S, Chari ST. Chronic pancreatitis. Lancet. 2016 May
2020 Mar;115(3):322–39. 7;387(10031):1957–66.
Hegyi P, Parniczky A, Lerch MM, Sheel ARG, Rebours V, Forsmark CE, Nagpal SJS, Sharma A, Chari ST. Autoimmune pancreatitis. Am J
et al. International consensus guidelines for risk factors in chronic Gastroenterol. 2018 Sep;113(9):1301.
pancreatitis: recommendations from the working group for the inter- Vege SS, Chari ST. Chronic pancreatitis. N Engl J Med. 2022 Mar
national consensus guidelines for chronic pancreatitis in collaboration 3;386(9):869–78.
39
Pancreatic Neoplasmsa
JAIME DE LA FUENTE, MD
SHOUNAK MAJUMDER, MD
Pancreatic Ductal Adenocarcinoma Risk Factors for Development of PDAC

Pancreatic ductal adenocarcinoma (PDAC), sometimes referred Early diagnosis of PDAC is uncommon because symptoms de-
to as pancreatic cancer, is a leading cause of cancer death in the velop at a late stage when surgical resection is often not possible.
US. The worldwide trend shows increasing PDAC incidence and
mortality. Survival has improved in recent years, but the overall
5-year survival is only about 11%; it is nearly 50% among per- Table 39.1. American Joint Committee on Cancer, 8th
sons with a diagnosis of localized disease. Less than 20% of Edition, TNM Classification for Staging of Pancreatic Ductal
patients are candidates for surgical resection, and more than 50% Adenocarcinomaa
have metastatic disease at the time of diagnosis (Tables 39.1 and
39.2). In the US, the lifetime risk for PDAC is approximately Category Description
1.6%, and the risk increases with age. In part because of its rel- Primary tumor (T)
atively low incidence, PDAC is the only malignancy among the TX Primary tumor cannot be assessed
5 most lethal cancers in the US for which there is no approved T0 No evidence of a primary tumor
population screening test. Tisb In situ carcinoma
T1 Tumor ≤2 cm in greatest dimension
T2 Tumor >2 cm and ≤4 cm in greatest dimension
T3 Tumor >4 cm in greatest dimension
T4 Tumor involves the celiac axis, superior mesenteric artery,
or common hepatic artery, regardless of size
Regional lymph nodes (N)
a
Randall K. Pearson, MD, is gratefully acknowledged as the author of
NX Regional lymph nodes cannot be assessed
this chapter in previous editions of the book (parts of which appear in
N0 No regional lymph node metastasis
this edition). N1 Metastasis in 1-3 regional lymph nodes
Abbreviations: CA19- 9, carbohydrate antigen 19- 9; CEA, carcino N2 Metastasis in ≥4 regional lymph nodes
embryonic antigen; CT, computed tomography; ENDPAC, Enriching Distant metastasis (M)
New-Onset Diabetes for Pancreatic Cancer; ERCP, endoscopic retro- M0 No distant metastasis
grade cholangiopancreatography; EUS, endoscopic ultrasonography; M1 Distant metastasis
FNA, fine-needle aspiration; FOLFIRINOX, leucovorin, fluorouracil,
irinotecan, and oxaliplatin; IPMN, intraductal papillary mucinous neo- a
Stages are defined in Table 39.2.
plasm; MCN, mucinous cystic neoplasm; MRCP, magnetic resonance b
Includes intraductal papillary mucinous neoplasm with high-grade dysplasia,
cholangiopancreatography; MRI, magnetic resonance imaging; NOD, mucinous neoplasm with high-grade dysplasia, and high-grade intraepithelial
new-onset diabetes; PCL, pancreatic cystic lesion; PCN, pancreatic neoplasia.
cystic neoplasm; PDAC, pancreatic ductal adenocarcinoma; PET, pos- Adapted from Kakar S, Pawlik TM, Allen PJ, Vauthey J-N. Exocrine pancreas.
itron emission tomography; SCN, serous cystic neoplasm; SPN, solid In: Amin MB, Edge SB, Greene FL, et al., eds. AJCC cancer staging manual. 8th
pseudopapillary neoplasm ed. American Joint Committee on Cancer; 2017:337-47; used with permission.
443
Table 39.2. Stage Grouping for Pancreatic Ductal as a new diagnosis of type 2 diabetes within 3 years, has been
Adenocarcinomaa strongly associated with PDAC, especially when it is present in
patients at an advanced age who have unintentional weight loss.
Stage T N M
0 Tis N0 M0
IA T1 N0 M0 Hereditary Pancreatitis
IB T2 N0 M0 Certain genetic variants have been associated with hereditary
IIA T3 N0 M0 pancreatitis. Persons who have hereditary pancreatitis often have
IIB T1 N1 M0
IIB T2 N1 M0
episodes of pancreatitis early in life and have a much higher life-
IIB T3 N1 M0 time risk for PDAC. In light of this increased risk for PDAC,
III T1 N2 M0 the current expert consensus is to consider pancreatic cancer
III T2 N2 M0 screening starting at age 40 years for patients who have heredi-
III T3 N2 M0 tary pancreatitis and certain sequence variants (Table 39.3).
III T4 Any N M0
IV Any T Any N M1
Chronic Pancreatitis
a
TNM staging system is defined in Table 39.1.
Chronic pancreatitis is a well-established risk factor for PDAC.
Adapted from Kakar S, Pawlik TM, Allen PJ, Vauthey J-N. Exocrine pancreas. The risk of PDAC for patients with chronic pancreatitis varies
In: Amin MB, Edge SB, Greene FL, et al., eds. AJCC cancer staging manual. 8th
ed. American Joint Committee on Cancer; 2017:337-47; used with permission. according to the cause of chronic pancreatitis and appears to be
highest for patients with hereditary pancreatitis and for those
with a history of smoking. However, despite the risk association,
A specific cause of PDAC has not been identified, but several risk PDAC occurs infrequently among patients with chronic pancre-
factors have been implicated in its development. atitis, and the cumulative incidence increases with the duration
of the disease. The diagnosis of PDAC in a patient with chronic
Lifestyle and Metabolic Risk Factors pancreatitis can be challenging because both diseases can occur
with similar symptoms, and cross-sectional imaging and endo-
Countries with the greatest PDAC incidence and mortality are
scopic ultrasonography (EUS) have limitations for detection of
those with a high human development index. This index considers
small tumors that are present with mass-forming chronic inflam-
several dimensions, including life expectancy, education, and
mation and calcification.
standard of living. Certain environmental factors that are asso-
ciated with a high human development index are also associated
with increased risk for PDAC. Pancreatic Cystic Lesions
Several modifiable risk factors have been linked to PDAC. Intraductal papillary mucinous neoplasms (IPMNs) are the most
Cigarette smoking is an important risk factor for the development prevalent neoplastic pancreatic cystic lesions (PCLs). Depending
of PDAC that increases the relative risk 1.5-to 3-fold, but the risk on certain clinical and imaging characteristics, surveillance or
decreases considerably if abstinence is maintained for 2 years. surgical excision should be recommended (see the Pancreatic
Alcohol use, especially binge drinking, has also been associated Cystic Lesions section below).
with an increased risk for PDAC. Both obesity and physical inac-
tivity increase the risk for PDAC, and increased weight is linked
to increased risk for PDAC. The association between type 2 dia- Genetic and Familial Risk
betes and PDAC is well described in the literature. Long-standing Although most PDAC cases are sporadic, 5% to 15% occur in
diabetes has been reported to mildly increase risk for PDAC, patients with underlying genetic or familial risk. High-risk
whereas new- onset diabetes (NOD) may occur secondary to individuals are patients who have a family history of PDAC
PDAC and be a harbinger of the disease. NOD, typically defined or pathogenic (or likely pathogenic) germline variants in
Table 39.3. Germline Variants Associated With Pancreatic Ductal Adenocarcinoma in Persons
With a High Risk
Risk estimate for Age to consider
Gene Syndrome pancreatic cancer screening, ya
LKB1/STK11 Peutz-Jeghers syndrome RR 132 35-40
PRSS1 Hereditary pancreatitis SIR 87 40
CDKN2A Familial atypical multiple mole melanoma OR 12-36 40
PALB2b NA OR 14.8 50
MLH1/MSH2/ MSH6b Lynch syndrome OR 6.7-7.8 50
BRCA2b Familial breast and ovarian syndrome OR 6.2-9.1 50
ATMb NA OR 5.7-9.0 50
BRCA1b Familial breast and ovarian syndrome OR 2.6-3.0 50
Abbreviations: NA, not applicable; OR, odds ratio; RR, relative risk; SIR, standardized incidence ratio.
a
Or 10 years earlier than the youngest blood relative with pancreatic cancer.
b
Need at least 1 affected first-degree blood relative with pancreatic cancer to consider screening.
Adapted from de la Fuente J, Kastrinos F, Majumder S. How I approach screening for pancreatic cancer. Am J Gastroenterol.
2021 Aug 1;116(8):1569-71; used with permission.
39. Pancreatic Neoplasms 445
PDAC- susceptibility genes (or both of these criteria). These well-differentiated tumors, which have glandular structures in a
patients have an estimated lifetime risk for PDAC of 5% or more. dense stroma, to poorly differentiated tumors, which have little or
Familial pancreatic cancer kindreds are families with 2 or more no glandular structure or stroma (Figure 39.1). In general, PDAC
first-degree relatives with pancreatic cancer or 3 or more first-or itself is thought to arise from pancreatic intraepithelial neoplasia
second-degree relatives with pancreatic cancer; the lifetime risk consisting of small lesions (<0.5 cm) that can progress from low-
for PDAC increases with the total number of family members grade dysplasia to high-grade dysplasia and eventually to invasive
affected. Certain genetic syndromes are associated with an cancer. Lymphatic spread appears to occur earlier than vascular
increased risk for PDAC; these include Peutz-Jeghers syndrome invasion, which is present in more advanced lesions. Metastatic
(LKB1 [STK11] variant; OMIM 602216) and familial atypical disease occurs mainly in the liver and lungs, but it can also occur
multiple mole melanoma syndrome (CDKN2A variant; OMIM in the adrenals, kidneys, bone, brain, and skin.
600160). Other germline variants associated with an increased
risk for PDAC include BRCA1 (OMIM 113705); BRCA2 (OMIM
600185); ATM (OMIM 607585); PALB2 (OMIM 610355); Diagnosis
MLH1 (OMIM 120436); MSH2 (OMIM 609309); MSH6 (OMIM Patients with pancreatic cancer usually present with symptoms of
600678); and TP53 (OMIM 191170). The specific variants, abdominal pain, back pain, jaundice, weight loss (with or without
syndromes, and risk for PDAC are shown in Table 39.3. anorexia), and early satiety; they may or may not have fatigue.
Current guidelines recommend against screening for PDAC in The most common symptoms are abdominal pain, weight loss,
the general population, but PDAC screening may be considered and fatigue, and less than 10% of patients are asymptomatic at
for patients with a high risk for PDAC after the risks and benefits diagnosis. Jaundice, which occurs in about 50% of patients, is a
have been discussed in detail with the patient (Table 39.3). common presentation when PDAC involves the head of the pan-
Screening, which should be offered only at centers of pancre- creas. Presentation with painless jaundice often indicates resect-
atic excellence, is performed with MR cholangiopancreatography able disease. A small percentage of patients (<5%) present with
(MRCP) and EUS. Typically, screening is annually if patients are otherwise unexplained acute pancreatitis, but most patients who
asymptomatic and if no abnormalities are found on the index im- present with symptoms that bring the cancer to clinical attention
aging; if abnormalities are discovered, individualized treatment already have locally advanced or metastatic disease.
should be undertaken.
✓ Cigarette smoking—risk factor for PDAC that increases the rela- Tumor Markers for Diagnosis
tive risk 1.5-to 3-fold Various tumor markers are increased in patients with pancre-
✓ New-onset diabetes atic cancer, but no reliable biomarker has been identified for
• Defined as a new diagnosis of type 2 diabetes within 3 years
screening or early detection of PDAC. Carbohydrate antigen 19-
• Strongly associated with PDAC, especially in elderly patients
who have unintentional weight loss 9 (CA19-9) is the only blood-based biomarker that is routinely
✓ Most cases of PDAC are sporadic, but 5% to 15% occur in patients used in current clinical practice. However, CA19-9 testing has
with underlying genetic or familial risk limited utility if the biliary tract is obstructed, as even benign
biliary tract obstruction can cause a marked increase in CA19-
9 levels. Approximately 5% to 10% of patients do not express
Lewis blood group antigen (a glycosyl transferase); thus, CA19-9
Pathology would not be detectable in this subgroup, further compromising
PDAC is the most common malignant neoplasm of the pan- the test results. Also, CA19-9 levels are more likely to increase
creas and accounts for up to 85% to 90% of malignant exocrine as the disease advances and becomes metastatic. For early-stage
neoplasms in the pancreas. About 70% of PDACs occur in the or resectable pancreatic cancer (stages I and II), the sensitivity of
head of the pancreas. Histologically, the neoplasms vary from an increased CA19-9 value is reported to be as low as 50%, so
Figure 39.1. Precursor Lesions of Pancreatic Cancer. A, Intraductal papillary mucinous neoplasm with low-grade dysplasia (hematoxylin-eosin;
scale bar =100 µm). B, Intraductal papillary mucinous neoplasm with high-grade dysplasia (hematoxylin-eosin; scale bar =100 µm).
half the patients with disease would not be identified at the stage
appropriate for presymptomatic screening.
As described above, type 2 diabetes can be a consequence
of PDAC. Recent epidemiologic studies have demonstrated the
development of diabetes as a potential biomarker for early de-
tection of PDAC. This NOD can be seen as early as 36 months
before the clinical diagnosis of PDAC. The Enriching New-
Onset Diabetes for Pancreatic Cancer (ENDPAC) model, which
accounts for age at diabetes diagnosis, weight loss, and increased
level of fasting blood glucose, has been proposed to further iden-
tify patients who have NOD and a substantial risk for PDAC.
The ENDPAC model is undergoing prospective validation for
possible use as a clinical practice tool for identifying patients
who may be considered for pancreatic cancer screening. Several
other promising molecular biomarkers are in various stages of
validation for early detection of PDAC.
Imaging Tests for Diagnosis

Multidetector computed tomography (CT) of the abdomen with
multiphase (triple-phase) contrast enhancement (pancreas pro-
tocol CT) should be the primary imaging study for the evalua-
tion of patients with symptoms or imaging findings that suggest
PDAC. PDAC typically appears as an irregular, hypodense lesion
in the pancreas (Figures 39.2 and 39.3). Pancreas protocol CT is
the appropriate study because it can be used to stage the tumor
and provide valuable information about vascular involvement and
resectability. When used for PDAC staging, the 3 phases in the
protocol are 1) arterial phase, which allows for excellent visu-
alization of the celiac and superior mesenteric arteries; 2) late
arterial or pancreatic phase, which allows for optimal contrast be-
tween the normal pancreatic parenchyma and tumor; and 3) portal
phase, which allows for detection of liver metastasis and PDAC
involvement of the portal, superior mesenteric, and splenic veins.
The sensitivity of pancreas protocol CT for detection of primary
lesions is about 90%, but small (<2 cm) primary lesions may be
missed. Other cross-sectional imaging modalities that can be used
Figure 39.3. Hypoechoic Mass in Pancreas. A, Endoscopic

ultrasonogram of the pancreatic head shows a poorly defined hypoechoic
mass that impinges on the portal vein for a distance of 11 mm (indi-
cated by 2 markers). Surgical resection confirmed invasion of the portal
vein. B, Endoscopic ultrasonogram shows fine-needle aspiration of the
mass in A.
include MRI and positron emission tomography (PET). MRI may

provide better evaluation of hepatic lesions when metastatic dis
ease is suspected. The use of PET/CT and PET/MRI is an area of
active study, and the data so far indicate that they are useful for
determining the treatment response of resectable and borderline
resectable tumors being treated with neoadjuvant therapy and in
evaluating for evidence of extrapancreatic metastases.
Figure 39.2. Pancreatic Ductal Adenocarcinoma. Computed tomo- EUS is highly sensitive for detecting small solid tumors, but
gram shows a small hypoattenuating lesion in the head of the pancreas with the advent of multidetector CT, EUS is usually reserved for
(arrow). The superior mesenteric vessels are not involved by the tumor, fine-needle aspiration (FNA) and biopsy of the primary lesion or
which is resectable. suspicious lymph nodes. For resectable PDAC, EUS with FNA
is preferred over percutaneous biopsy. In patients with hepatic palliative medicine specialists, and the goals, values, and perfor-
metastasis, percutaneous liver biopsy is often the preferred mo- mance status of the patient must be considered. Treatment should
dality for diagnosis. Tissue diagnosis in PDAC is important and ideally be done in centers that have a large volume of patients
should be performed even for resectable disease, especially as with PDAC and have access to clinical trials and the necessary
more institutions shift away from upfront surgery toward the use clinical expertise. The only hope for cure involves surgical re-
of neoadjuvant chemotherapy. Not only does this ensure accu- section of the primary tumor with negative surgical margins. The
rate diagnosis that rules out autoimmune pancreatitis and other decision to perform surgical resection must consider staging at
neoplasms that can mimic PDAC, it may also guide the use of diagnosis and whether the patient is a surgical candidate. In a
chemotherapeutic agents according to results of tumor genetic patient with metastatic PDAC, treatment is palliative. In patients
testing. Another recommendation is that all patients with PDAC with borderline resectable disease, the current approach is to con-
should undergo genetic counseling and germline testing for cancer sider neoadjuvant chemoradiotherapy initially, with or without
susceptibility genes. A desmoplastic response may occur in 10% consolidative radiotherapy, with subsequent surgery depending
to 15% of patients with PDAC, so tumor tissue may be difficult to on treatment response and performance status. Although radi-
procure with FNA, necessitating multiple biopsy attempts. ologic downstaging is uncommon, chemotherapy appears to be
Endoscopic retrograde cholangiopancreatography (ERCP) is better tolerated in the preoperative period; in carefully selected
reserved primarily for placement of a common bile duct stent in patients who undergo surgical resection after neoadjuvant
patients who have obstructive jaundice due to PDAC involving therapy, more than 90% have an R0 resection.
the head of the pancreas. Although brush cytology from biliary The management of resectable PDAC is evolving. At many
strictures obtained during ERCP may aid in the diagnosis of centers, even if PDAC is diagnosed at an early resectable stage
PDAC, diagnostic tissue acquisition in current clinical practice is and the tumor is confined to the pancreas, a neoadjuvant approach
primarily performed with EUS as described above. is considered, although an adjuvant treatment approach with up-
front surgery would also be reasonable. Limited data are avail-
✓ Multidetector CT of the abdomen with multiphase (triple-phase) able for comparison of neoadjuvant and adjuvant therapies for
contrast enhancement (pancreas protocol CT)—the primary im- resectable PDAC, and results of ongoing clinical trials are not
aging study for evaluation of patients with symptoms or imaging yet available.
findings that suggest PDAC
Surgery
Staging Pancreatic Tumors The standard operation for PDAC at the head of the pancreas is a
pancreaticoduodenectomy (Whipple procedure), which involves
Pancreas protocol CT is the initial test not only for diagnosis performing a cholecystectomy and removing a portion of the
but also for staging of PDAC because it can help identify distant stomach (at least an antrectomy), the distal bile duct, the head
metastases and vascular involvement. EUS is complementary for of the pancreas, the duodenum, the proximal jejunum, and re-
staging local extent (T staging) and nodal status (N staging). For gional lymph nodes. Reconstruction with gastrojejunostomy,
EUS, operator experience is an important variable. hepaticojejunostomy, and pancreaticojejunostomy is required.
In addition, CT of the chest is recommended for staging, al- Results are good and mortality is low when the operation is
though lung metastasis is uncommon in the absence of liver metas- performed at high-volume centers with experienced surgeons.
tasis or extensive local vascular involvement. Staging laparoscopy Alternative operations include a pylorus-preserving Whipple
with peritoneal fluid cytology is also frequently performed if sur- resection, which has become the surgical standard of care at most
gical resection is a consideration and the patient does not have centers. This preserves the stomach and is a less extensive op-
overt metastatic disease. The staging method currently in use for eration. It has been assumed that this operation, compared with
PDAC is the TNM (tumor, node, metastasis) system from the the Whipple procedure, would improve outcome, especially long-
eighth edition of the cancer staging manual of the American Joint term morbidity related to dumping syndrome and weight loss.
Committee on Cancer (Tables 39.1 and 39.2). Accurate clinical Tumors in the body or tail of the pancreas can be resected with
staging based on imaging at diagnosis can be challenging, espe- distal pancreatectomy and splenectomy. Depending on the vas-
cially for nodal status. In addition to TNM staging, the resectability cular contact of the tumor, venous and arterial reconstructions
of the tumor is typically determined by a multidisciplinary team of can be performed by a select group of highly trained pancreatic
pancreatologists, radiologists, surgeons, and oncologists who clas- surgeons, so patients have a chance at a cure despite vascular in-
sify PDAC as resectable, borderline resectable, locally advanced volvement. In some patients, especially in those with a hereditary
disease, or metastatic disease. The findings from the pancreas predisposition to PDAC, total pancreatectomy may need to be
protocol CT largely guide this categorization depending on which considered. Although surgery provides the only chance of cure,
arterial and venous structures are involved and to what degree. a large proportion of patients who undergo surgical resection for
(The specific details of this categorization are outside the scope pancreatic cancer ultimately die of the disease. New molecular
of this chapter.) Recent evidence supports the use of PET/MRI and imaging tools for early detection of postoperative recurrence
for local tumor staging at diagnosis, detecting occult metastatic and minimal residual disease may improve future long- term
disease, and monitoring treatment response in patients undergoing outcomes of patients with this lethal disease.
neoadjuvant therapy before surgery.
Chemotherapy
Treatment In 2011, a multicenter European trial compared a combination
The treatment of PDAC is best provided by a multidisciplinary chemotherapy regimen of leucovorin, fluorouracil, irinotecan,
team of medical pancreatologists, therapeutic endoscopists, and oxaliplatin (FOLFIRINOX) with single-agent gemcitabine
pancreatobiliary surgeons, medical oncologists, geneticists, and in patients who had metastatic PDAC. The patients who received
FOLFIRINOX had a better objective response rate (32% vs 9%) Pain

and increased overall survival (11.1 months vs 6.8 months), but, Palliation of pain is a major problem in patients with PDAC.
as expected with a multidrug regimen, they had a higher rate of A palliative or pain medicine team with extensive expertise
toxicity (especially neutropenia). For patients with metastatic in management of cancer pain should be involved early in
PDAC, good performance status, and normal or nearly normal the patient’s care to maximize quality of life. A celiac plexus
liver function, FOLFIRINOX is the standard first-line chemo- neurolysis performed percutaneously or with endoscopic ultra-
therapy. Alternatively, gemcitabine in combination with nanopar- sonography is often considered for managing pain in patients
ticle albumin-bound paclitaxel (nab-paclitaxel) can also be used who have unresectable disease. Celiac plexus neurolysis effec-
and typically is better tolerated with improved median overall tively decreases pain in 40% to 80% of patients, typically for 4
survival compared to gemcitabine (8.5 months vs 6.7 months). to 8 weeks, with a definite but limited advantage over analgesic
Among patients with metastatic PDAC and a germline BRCA var- therapy. Although celiac plexus block is reasonably effective
iant, progression-free survival was shown to be longer with use of for short-term pain control, most published data do not show
the poly(adenosine diphosphate–ribose) polymerase (PARP) in- increased survival.
hibitor olaparib compared to placebo (7.4 months vs 3.8 months). If oral analgesia is used to control pain related to pancre-
Adjuvant chemotherapy with a modified dose of FOLFIRINOX atic cancer, the type and dose of medication is determined
(“modified FOLFIRINOX”) is the standard of care in appropri- according to the severity of pain. For example, mild pain may be
ately selected patients with resected PDAC, although less than controlled with acetaminophen (325 mg) in combination with
10% of patients can complete adjuvant therapy after a pancreatic oxycodone (5 mg), 1 or 2 tablets every 4 to 6 hours, whereas
resection. In patients who can tolerate adjuvant therapy, modified more severe pain may require a longer-acting opioid for du-
FOLFIRINOX is associated with significantly longer survival rable pain control in combination with short-acting analgesics
compared to gemcitabine (54.4 months vs 35 months). Precision as needed to control breakthrough pain. Alternatively, a fen-
oncology with tumor molecular and genetic profiling may help tanyl transdermal patch, 25 to 100 mg hourly, is effective for
individualize the choice of treatment regimen in the future. some patients.
The role of neoadjuvant chemoradiotherapy in the man-
agement of PDAC is poorly defined, although its use has been
increasing in recent years. This is largely based on the idea that Nutrition
chemotherapy is better tolerated as part of neoadjuvant therapy, A key component of cancer treatment is to ensure that the
and this greater likelihood of receiving adequate chemotherapy patient’s nutritional status is optimal. Patients with PDAC, es-
will result in improved overall survival. However, there is no pecially those who have tumors in the pancreatic head and con-
high-quality evidence to support this approach. A recent study siderable pancreatic atrophy, frequently have signs of exocrine
indicated that preoperative chemoradiotherapy with gemcitabine pancreatic insufficiency such as steatorrhea and weight loss.
for resectable or borderline resectable pancreatic cancer is not Pancreatic enzyme replacement therapy should be considered
associated with significant improvement in overall survival. This for those patients. The use of pancreatic enzyme replacement
finding has limited clinical relevance, however, since single- therapy improves the quality of life for patients who have
agent gemcitabine is rarely used in current clinical practice. unresectable PDAC.
Randomized controlled trials assessing the effect of neoadjuvant
modified FOLFIRINOX are underway. Clinical trial participa- ✓ Treatment of PDAC
tion should be strongly encouraged, especially among patients • Multidisciplinary team is best: medical pancreatologists, ther-
who have a diagnosis of resectable disease and are undergoing apeutic endoscopists, pancreatobiliary surgeons, medical
neoadjuvant therapy. oncologists, geneticists, and palliative medicine specialists
• Patient’s goals, values, and performance status must be considered
Biliary Obstruction
Biliary obstruction in PDAC typically manifests as painless
jaundice. Pruritus is often the most disabling symptom, and
cholangitis is rare unless instruments have been used in the Box 39.1. Classification of Pancreatic Cystic Lesionsa
biliary tract. The preferred treatment is transpapillary biliary Benign pancreatic cystic lesions
stent placement. In patients undergoing neoadjuvant therapy Benign epithelial cyst/true simple cyst
or destination chemotherapy, a metal biliary stent is preferred Lymphoepithelial cyst
over plastic stents. Percutaneous drainage is used if endo-
Retention cyst
scopic transpapillary drainage fails. EUS-guided transgastric or
transduodenal biliary drainage is a therapeutic alternative for Mucinous nonneoplastic cyst
carefully selected patients. Pancreatic cystic neoplasmsb
Serous cystic neoplasm
Duodenal Obstruction Mucinous cystic neoplasm
Intraductal papillary mucinous neoplasm
In patients presenting with symptoms of gastric outlet obstruc-
tion such as nausea, vomiting, early satiety, and poor oral in- Solid pseudopapillary neoplasm
take, a bypass procedure is often necessary. Although surgical
gastrojejunostomy was the previous standard, therapeutic en-
a
Excludes cystic pancreatic neuroendocrine tumor and cystic degener-
ation of pancreatic adenocarcinoma.
doscopy options have expanded in recent years and include both
duodenal stenting and EUS- guided gastrojejunostomy with a b
Various degrees of malignant potential.
lumen-apposing metal stent.
Table 39.4. Characteristics of Specific Pancreatic Cystic Neoplasms

Intraductal papillary Mucinous cystic Solid pseudopapillary
Characteristic mucinous neoplasm neoplasm Serous cystic neoplasm neoplasm
Patient age at usual 60-70 40-50 50-60 <50
encounter, y
Sex predilection None Female only Female Female
Imaging Typically multifocal cysts Unilocular Typically polycystic honeycomb Commonly body or tail solid
Dilated MPD if involved Body or tail appearance component
Cysts communicate with MPD Central stellate scar
Clinical cyst fluid Elevated CEA Elevated CEA Very low CEA Cytology positive for β-catenin
analysis Mucin stain positive Mucin stain positive
Treatmenta Surveillance or resection Surveillance or resection No surveillance Resection
Resection if large or symptomatic
Abbreviations: CEA, carcinoembryonic antigen; MPD, main pancreatic duct.

a
For surgically fit patients.
Pancreatic Cystic Lesions resected. Although PCNs have malignant potential, the overall
risk of pancreatic cancer is low, and the majority of PCNs never
The malignant potential of PCLs ranges from benign to advanced
require surgical resection. The specific features of each PCN
neoplasia (high-grade dysplasia or cancer). The majority of per-
are used to guide management and determine whether surveil-
sons with PCLs are asymptomatic; therefore, PCLs are usually
lance or surgical resection is required. Table 39.4 summarizes
discovered incidentally on imaging, and the true population prev-
the most common clinical and imaging features of these PCNs
alence of PCLs is unknown. Over the past 2 decades, the increase
that can aid in their diagnosis and management.
in prevalence of PCLs has been attributed to the widespread
availability and use of high-resolution abdominal cross-sectional
imaging. Pooled prevalence of PCLs worldwide is about 8%, but Serous Cystic Neoplasm
the prevalence ranges from less than 1% to 50% depending on Previously called serous cystic adenoma, serous cystic neoplasms
the ages of the patients in the population and the type of imaging (SCNs) are often present in women 50 to 60 years old. SCNs
(ultrasonography, CT, MRI, or EUS) used to detect the PCLs. The commonly occur in 2 forms: microcytic (cystic compartments
prevalence increases with age and is typically higher in studies <2 cm with a honeycomb appearance) and macrocytic (cystic
that used MRI rather than CT. compartments ≥2 cm) (Figure 39.4). A stellate scar is some-
times seen on cross- sectional imaging. Generally, the malig-
Classification and Histology nant potential of SCNs is exceptionally low, although malignant
PCLs can be classified according to their histology into 2 main
categories: benign PCLs, which do not develop into cancer,
and PCLs with malignant potential, which are also called pan-
creatic cystic neoplasms (PCNs). The classification of PCLs is
summarized in Box 39.1.
Surgical pathology is required for definitive classification and
histologic diagnosis of PCLs. Although the imaging appearance
on CT, MRI, or MRCP and the location of the PCL, the age and
sex of the patient, and findings from EUS with FNA for cytology
and cyst fluid analysis can provide clues to the most likely type
of PCL, preoperative histologic diagnosis can be inaccurate in ap-
proximately one-third of patients. PDAC, pancreatic neuroendo-
crine tumors, and rare forms of pancreatic cancer (eg, acinar cell
cancer) can undergo cystic degeneration and thus have a cystic or
solid-cystic radiologic appearance. (Pancreatic neuroendocrine
tumors are discussed in Chapter 6.)
✓ PCLs can be classified histologically into 2 main categories:

• Benign PCLs
• PCLs with malignant potential (also called pancreatic cystic
neoplasms)
Pancreatic Cystic Neoplasms

Figure 39.4. Serous Cystic Neoplasm. Computed tomogram shows
All PCNs have various degrees of malignant potential. They a serous cyst. The mass lesion in the head of the pancreas consists of
are the most commonly encountered PCLs in clinical practice, multiple small cystic lesions (arrow). The findings are typical of serous
and they account for over 80% of all PCLs that are surgically cystic neoplasm.
Figure 39.5. Mucinous Cystic Neoplasm. A, Magnetic resonance image of the abdomen shows a unilocular cyst in the tail of the pancreas. B,
Surgical pathology gross specimen shows ovarian stroma.
transformation has been rarely reported. Therefore, if the diag-

nosis is established, surveillance is typically not recommended,
and SCNs should be resected only if the patient is symptomatic.
Analysis of SCN cyst fluid from EUS FNA shows low levels of
carcinoembryonic antigen (CEA) (<5 ng/mL) and amylase; the
occasional finding of cuboidal glycogen-staining cells on EUS-
guided core biopsy of the cyst wall establishes the histologic
diagnosis.
Mucinous Cystic Neoplasm

Mucinous cystic neoplasms (MCNs) occur almost exclusively
in women 40 to 60 years old. MCNs usually occur as a solitary
unilocular cyst in the body or tail of the pancreas (Figure 39.5)
and are histologically characterized by the presence of ovarian
stroma. On analysis of the cyst fluid, the CEA level is high (>192
Figure 39.6. Intraductal Papillary Mucinous Neoplasm (IPMN). A,

Magnetic resonance cholangiopancreatography shows multifocal pancre-
atic cysts communicating with a dilated main pancreatic duct suggestive Figure 39.7. Fish-Mouth Papilla. Endoscopic image of a fish-
of a mixed IPMN. B, A hypoattenuating mass (black arrow) in the pan- mouth papilla with extruding mucin, which is pathognomonic for main
creatic head is associated with a cystic lesion and dilated main pancreatic duct intraductal papillary mucinous neoplasm. (Adapted from Levy MJ,
duct (white arrow) (diameter, 10 mm) with abrupt cutoff, distal pancreatic Geenen JE. Idiopathic acute recurrent pancreatitis. Am J Gastroenterol.
atrophy, and bile duct dilation; these imaging features are suggestive of ma- 2001 Sep;96[9]‌:2540-55; used with permission of Mayo Foundation for
lignant degeneration of an IPMN. Medical Education and Research.)
Figure 39.8. Solid Pseudopapillary Neoplasm. A, Magnetic resonance image of the abdomen shows a solid-cystic lesion (arrow) in the pancreatic
body. B, Surgical pathology specimen shows positive β-catenin staining (scale bar =20 µm).
ng/mL); the cyst does not communicate with the main pancreatic and they are typically located in the body or tail of the pancreas.
duct. MCNs have moderate malignant potential, so resection is As the name implies, SPNs often have a solid component that is
commonly offered for patients who are young and surgically fit, seen on cross-sectional imaging (Figure 39.8). SPNs have ma-
especially if they have a mural nodule, although surveillance lignant potential, so surgical resection is recommended for all
may be considered for patients who have small asymptomatic patients who have SPN unless surgery would be contraindicated.
MCNs. Surveillance may be recommended for older patients The prognosis is typically good, although SPNs recur or metasta-
if they have comorbidities, small cysts (<4 cm), no high-risk size in 2% to 10% of patients.
features, and the possible need for pancreaticoduodenectomy
because of the location of the MCN. Approach to Managing PCNs
The approach to PCNs is individualized and requires shared
Intraductal Papillary Mucinous Neoplasm decision-making, keeping in mind the patient’s life expectancy,
IPMNs consist of intraductal papillary growth of mucin- comorbidities, wishes, and goals. Figure 39.9 provides a sum-
producing columnar epithelium. They are the most commonly mary and a general framework for approaching PCLs in clinical
encountered PCL in clinical practice. IPMNs can be classified practice.
according to the extent of ductal involvement: branch duct, If a PCN is related to recurrent acute pancreatitis, gastric
main duct, and mixed duct (affecting both branch and main outlet obstruction, biliary obstruction, or abdominal pain,
pancreatic ducts) (Figure 39.6). IPMN is intrinsically a multi- surgical resection may need to be considered. Most PCNs,
focal disease that often manifests as multiple cysts in different however, are discovered incidentally. For these asympto-
regions of the pancreas; when the main pancreatic duct is af- matic PCNs, the initial evaluation should focus on ruling out
fected, the risk of advanced neoplasia is much greater than the presence of advanced neoplasia and determining whether
when only the branch duct is affected. Branch duct IPMNs the next step should be surgical resection or imaging-based
communicate with the main pancreatic duct, although this surveillance. If a patient is not a candidate for pancreatic re-
connection may not always be readily identifiable on cross- section, proceeding further with the clinical investigation is
sectional imaging. Cyst fluid analysis often shows positive typically not necessary because it probably would not change
mucin staining and high levels of CEA (>192 ng/mL) and the clinical outcome.
amylase. The presence of a patulous papilla extruding mucus If the diagnosis of SCN can be established and the patient is
(described as a fish-mouth papilla) is considered pathogno- asymptomatic, further surveillance is usually not recommended.
monic for main duct IPMN (Figure 39.7). IPMNs are often SPNs, however, should be surgically resected at diagnosis be-
encountered in patients 60 to 80 years old, and either surveil- cause they can harbor malignancy, commonly occur in young
lance or surgical resection is almost uniformly recommended patients, and have metastatic potential.
unless the patient has a limited life expectancy or prohibitive Most PCNs encountered in clinical practice are asympto-
surgical risks. matic mucinous PCNs, and IPMNs are the most commonly
encountered. Owing to the risk of potential malignancy, re-
section is recommended for MCNs in patients who have
Solid Pseudopapillary Neoplasm acceptable surgical risk. Specific situations related to surveil-
Solid pseudopapillary neoplasms (SPNs) are rare PCNs with lance for patients with MCN are described above. In patients
malignant potential. They are typically seen in women (>80%) with suspected IPMNs, initial assessment aims to determine
younger than 50 years, although they can be present at any age, whether worrisome features or high-risk stigmata are present
Figure 39.9. Management of Asymptomatic Pancreatic Cystic Lesions (PCLs). Flow diagram shows a general approach to management of asymptomatic PCLs in surgically fit patients. Asterisk
indicates that the PCL subtype should be determined with clinical and imaging criteria and biopsy when available (20%-30% of PCLs are classified incorrectly with the use of only clinical and imaging
criteria). Double asterisk indicates that predictors of advanced neoplasia are listed in Box 39.2.
(Box 39.2). These criteria are described in the international surgical candidate, surgical resection should be strongly
consensus guidelines for management of IPMNs. Patients who considered. In the absence of any of these high-risk features on
have IPMNs with high-risk stigmata should be considered for EUS, imaging-based surveillance (typically with MRI) is often
surgery. When worrisome features are present, further evalua- recommended at various intervals according to PCL size, with
tion with EUS is usually pursued to assess for a mural nodule more frequent surveillance for larger IPMNs initially and then
and features of main pancreatic duct involvement; FNA may be subsequently increased surveillance intervals if the IPMN has
considered for the detection of advanced neoplasia, although been stable.
the sensitivity is low (33%-57%). If any of these higher-risk Approximately one-third of surgically resected IPMNs have
features are detected on EUS and the patient is an appropriate high-grade dysplasia or cancer, and the risk of morbidity and mor-
tality with pancreatic resection must be considered. Hence, regard-
less of the guidelines and expert consensus recommendations, a
Box 39.2. Risk Stratification of Suspected Intraductal value-congruent and evidence-based discussion must occur with
Papillary Mucinous Neoplasms the patient and incorporate input from a multidisciplinary team
of experts to determine whether the best next step is immediate
High-risk stigmataa
surgery, surveillance, or no further follow-up. Ongoing efforts to
MPD ≥10 mm
develop novel biomarkers that accurately detect advanced neo-
Solid malignant-appearing pancreatic mass plasia in patients with IPMNs may further refine management in
Cytology that suggests or is positive for HGD the future with the goal of individualizing risk stratification and
or cancer improving patient outcomes.
Mural nodule ≥5 mm
✓ PCNs in clinical practice
Obstructive jaundice with cyst in pancreatic head
• Most are asymptomatic mucinous PCNs
Main duct features that suggest involvement • IPMNs are the most commonly encountered
(intraductal mucin, fish-mouth papilla, or mural
nodules in MPD)
Worrisome featuresb Suggested Reading
Elevated CA19-9
de la Fuente J, Kastrinos F, Majumder S. How I approach screening
Cyst ≥3 cm for pancreatic cancer. Am J Gastroenterol. 2021 Aug 1;116(8):
Mural nodule <5 mm 1569–71.
MPD 5-9 mm de la Fuente J, Majumder S. Molecular diagnostics and testing for pan-
creatic cysts. Curr Treat Options Gastroenterol. 2020 Jan 27.
Lymphadenopathy Elta GH, Enestvedt BK, Sauer BG, Lennon AM. ACG clinical guide-
Cyst growth ≥5 mm in 2 y line: diagnosis and management of pancreatic cysts. Am J Gastroenterol.
Change in caliber of pancreatic duct with distal 2018 Apr;113(4):464–79.
pancreatic atrophy European Study Group on Cystic Tumours of the Pancreas. European
evidence-based guidelines on pancreatic cystic neoplasms. Gut. 2018
Thickened or enhancing cyst walls May;67(5):789–804.
Pancreatitis Huang J, Lok V, Ngai CH, Zhang L, Yuan J, Lao XQ, et al. Worldwide
burden of, risk factors for, and trends in pancreatic cancer.
Abbreviations: CA19-9, carbohydrate antigen 19-9; HGD, high-grade Gastroenterology. 2021 Feb;160(3):744–54.
dysplasia; MPD, main pancreatic duct. Sharma A, Kandlakunta H, Nagpal SJS, Feng Z, Hoos W, Petersen GM,
et al. Model to determine risk of pancreatic cancer in patients with
a
Strong consideration for surgical treatment.
new-onset diabetes. Gastroenterology. 2018 Sep;155(3):730–9.
b
Individualized monitoring typically with endoscopic ultrasonog- Vege SS, Ziring B, Jain R, Moayyedi P, Clinical Guidelines Committee.
raphy and subsequent periodic surveillance if no high-risk stigmata are American Gastroenterological Association institute guideline on the
identified. diagnosis and management of asymptomatic neoplastic pancreatic
cysts. Gastroenterology. 2015 Apr;148(4):819–22.
40
Gallstonesa,b
ERIC J. VARGAS VALLS, MD, MS
Introduction ✓ Gallbladder disease affects over 20 million people in the US

Over 20 million people in the US are affected by gallbladder- ✓ Of the patients with cholelithiasis, 80% are asymptomatic; the an-
related diseases, and the estimated direct annual costs exceed nual rate of new biliary pain in the first 5 years is 2%
✓ Among patients with cholelithiasis, 90% of complications (cho-
$6.3 billion. The formation of gallstones, cholelithiasis, affects
lecystitis, cholangitis, and gallstone pancreatitis) are preceded by
people throughout the world, but the prevalence varies among an episode of uncomplicated biliary colic
different groups, ranging from 60% to 70% among American
Indians to 5% among persons in sub-Saharan Africa. In the
US, 20% of patients with cholelithiasis have gallstone-related
complications (annual incidence rate, 1%- 4%), and more Embryology, Anatomy, and Physiology
than 700,000 cholecystectomies are performed annually. This
chapter reviews the anatomy, development, physiology, clin- Gallbladder and Cystic Duct Anatomy
ical manifestations, diagnosis, and management of gallstone and The gallbladder, cystic duct, and common bile duct all develop
gallstone-related diseases. from the cystic portion of the hepatic diverticulum in utero and
are fully developed by 12 weeks of gestation. Bile secretion
begins at 16 weeks. The gallbladder is situated primarily in the
a
The author thanks Ferga C. Gleeson, MB, BCh, who was the author of cystic fossa on the posteroinferior aspect of the right hepatic lobe.
the previous version of this chapter. The neck of the gallbladder is connected to the cystic duct, which
b
Portions of this chapter were adapted from Abou-Saif A, Al-Kawas is 3 to 4 cm long and joins the common hepatic duct, forming
FH. Complications of gallstone disease: Mirizzi syndrome, cholecysto the common bile duct. The cystic duct has 5 to 12 oblique folds
choledochal fistula, waand gallstone ileus. Am J Gastroenterol. 2002 that create the spiral valves of Heister. The cystic artery, usually a
Feb;97(2):249-54; Sonmez G, Ozturk E, Mutlu H, Sildiroglu O, Basekim C, branch from the right hepatic artery, courses superior to the cystic
Kizilkaya E. Education and imaging. Hepatobiliary and pancreatic: emphy- duct and reaches the superior aspect of the neck, where it divides
sematous cholecystitis. J Gastroenterol Hepatol. 2007 Nov;22(11):2035;
into superficial and deep branches.
and Attasaranya S, Fogel EL, Lehman GA. Choledocholithiasis, as-
cending cholangitis, and gallstone pancreatitis. Med Clin North Am. 2008
Anatomical variations include gallbladder agenesis, mul-
Jul;92(4):925-60; used with permission. tiple gallbladders, bilobed gallbladder, and double cystic duct.
A Phrygian cap is an inconsequential deformity reflecting kinking
Abbreviations: ASGE, American Society for Gastrointestinal Endoscopy;
AST, aspartate aminotransferase; CT, computed tomography; ERCP, en-
of the gallbladder fossa and is usually noted with computed to-
doscopic retrograde cholangiopancreatography; EUS, endoscopic ultra- mography (CT) or radionuclide hepatobiliary imaging. In a
sonography; FXR, farnesoid X receptor; GBC, gallbladder carcinoma; double gallbladder, each gallbladder may have its own cystic
HIDA, hepatobiliary iminodiacetic acid; MRCP, magnetic resonance duct, or the duct may join and form a common cystic duct before
cholangiopancreatography; TPN, total parenteral nutrition joining the common hepatic duct.
455
Cholesterol Metabolism, Bile, and Bile fibroblast growth factor 19, which is secreted by ileal enterocytes
Acid Synthesis (in response to luminal levels of bile acids) and inhibits the classic
pathway enzyme, 7α-hydroxylase.
The liver is important in regulating total body cholesterol and
The other major components of bile are biliary lipids,
plasma lipid levels; bile and bile acids are especially important.
phospholipids, and cholesterol, which are insoluble in water.
In fact, the 2 main pathways for cholesterol elimination in the
They are secreted into bile as lipid vesicles and are carried in
body are excretion into bile and synthesis of bile acid.
both vesicles and mixed micelles. When the concentration of bile
The major components of bile are water, inorganic solutes,
acids exceeds the critical micellar concentration, bile acids self-
and organic solutes such as bilirubin, bile acids, and biliary lipids.
associate and form micelles capable of solubilizing hydrophobic
Bilirubin is a degradation product of heme and is usually present
lipid molecules in bile or intestinal chyme. Through this process,
as conjugated water-soluble diglucuronide. Gilbert syndrome is a
many lipophilic drugs and steroid hormones are excreted from
common condition (occurring in 10% of the White population),
the body. However, the overall primary function of these micelles
where an alteration in the promoter region of the UGT1A1 gene
is to facilitate fat digestion and absorption.
(OMIM 191740) results in unconjugated hyperbilirubinemia.
The gallbladder concentrates bile 10 times for efficient storage
The unconjugated form of bilirubin precipitates, contributing
during fasting and empties 25% of its contents every 2 hours.
to pigment stones (typically black) or mixed cholesterol stones.
When intraduodenal protein and fat are sensed, cholecystokinin
Bile acids are bipolar water-soluble molecules synthesized from
is released, stimulating contractions of the gallbladder, relaxation
cholesterol in the liver by either the classic pathway with 7α-
of the sphincter of Oddi, and flow of bile to the intestine, which
hydroxylase (predominant) or the alternate pathways with 27-
facilitates fat digestion and absorption. More than 90% of bile
hydroxylase. The classic pathway is regulated by the level of
acids are actively absorbed in the terminal ileum and recycled
cholesterol substrate, hepatocellular bile acid concentration, and
(termed enterohepatic circulation). This cycle occurs 4 to 12
other metabolic and hormonal factors. The primary bile acids
times daily, slowing during fasting and accelerating greatly after
synthesized are cholic acid and chenodeoxycholic acid. Bacteria
a meal (Figure 40.1). Daily bile acid loss is matched by hepatic
in the gut convert them to the secondary bile acids deoxycholic
synthesis of bile; in this way, steady amounts of bile acids are
and lithocholic acids. Overall bile acid synthesis is controlled by
maintained in the body. Several conditions that impair this re-
the nuclear hormone receptor farnesoid X receptor (FXR), with
circulation lead to increased gallstone formation, malabsorption,
primary bile acids serving as the most potent natural ligands
and diarrhea.
of FXR. Another important regulator of bile acid synthesis is
Figure 40.1. Enterohepatic Circulation. A pool of 3 g of bile acid cycles 4 to 12 times daily. Ileal absorption returns 97% of intraluminal bile acids
to the circulation; 90% of bile acids are extracted from the portal system on their first pass through the liver. In health, hepatic synthesis of bile acids
is equivalent to enteric losses. (Adapted from Zucker SD, Gollan JL. Physiology of the liver. In: Haubrich WS, Schaffner F, Berk JE, editors. Bockus
gastroenterology. Vol 3. 5th ed. WB Saunders; 1995: 1858-904; used with permission.)
40. Gallstones 457
Gallstone Epidemiology and Pathogenesis motility is a dominant contributing factor to stone development
during pregnancy because of increased levels of progestin, pro-
The prevalence of cholesterol gallstones varies with geography
longed total parenteral nutrition (TPN) (absence of intraduodenal
and ethnicity. Cholesterol gallstones are rare in populations in
fat and decreased cholecystokinin release), somatostatin therapy,
Africa and most of Asia, they are common in most Western
or a somatostatinoma.
populations (15% of women; 10% of men), and they occur al-
Generally, pigment gallstones are formed by the precipitation
most uniformly in North and South American Indians (80% of
of bilirubin in bile. Black pigment gallstones are formed in sterile
women). For all populations, the prevalence increases with age
gallbladder bile in association with chronic hemolytic states, cir-
and is approximately twice as high in women as in men.
rhosis, Gilbert syndrome, or cystic fibrosis, or they may have no
Gallstones are categorized on the basis of composition as
identifiable cause. These stones are small, irregular, dense, and
cholesterol gallstones (80% of patients) and pigment (black and
insoluble aggregates or polymers of calcium bilirubinate. Brown
brown) gallstones (20%). Each category has a unique structural,
pigment gallstones occur primarily in the bile ducts, where they are
epidemiologic, and risk factor profile (Table 40.1). Cholesterol
related to stasis and chronic bacterial colonization, as may occur
crystal formation requires the presence of 1 or more of the
above strictures or duodenal diverticula after sphincterotomy, or
following: cholesterol supersaturation, accelerated nucleation,
in association with biliary parasites. They are composed of 20%
gallbladder hypomotility, bile stasis, and genetic factors.
cholesterol, they are softer than black pigment gallstones, and
Cholesterol gallstones contain a mixture of cholesterol (50%-
they may soften or disaggregate with ursodeoxycholic acid.
99% by weight), a glycoprotein matrix, and small amounts of
calcium and bilirubin. Cholesterol supersaturation can result ✓ Risk factors for stone formation
from deficient secretion of bile acid or hypersecretion of cho- • Cholesterol stones: obesity, female sex, type 2 diabetes, eth-
lesterol. Bile acid secretion may be diminished because of nicity, rapid weight loss, ileal disease or resection, pregnancy,
decreased synthesis, as occurs with older age or liver disease, or TPN, and medications (eg, estrogens, progestins, lipid-lowering
because of decreased enterohepatic circulation, as occurs with agents, bile acid sequestrants, glucagon-like peptide-1 agonists,
hormonal defects and increased gastrointestinal losses from bile and octreotide)
acid sequestrant therapy or terminal ileal disease, resection, or • Black pigment stones: chronic hemolysis, Gilbert syndrome,
bypass. Additionally, weight loss and decreased fat intake lead TPN, cirrhosis, and old age
• Brown pigment stones: cholecystectomy, recurrent biliary in-
to decreased bile acid synthesis. Cholesterol secretion increases
fection, stasis (eg, duodenal diverticulum and biliary strictures)
with hormonal stimuli (female sex, pregnancy [estrogen], and ex-
ogenous estrogens), obesity, hyperlipidemia, age, chronic liver
disease, and sometimes with excessive dietary polyunsaturated
fats or increased caloric intake. In a supersaturated environment, Clinical Presentation and Complications
gallstone crystals form initially from an imbalance of nucleating
Asymptomatic Cholelithiasis
effects and antinucleating effects of the various proteins in bile
(Figure 40.2 and Box 40.1). The diagnosis of asymptomatic cholelithiasis is the result of
Gallbladder dysmotility results in inadequate clearance of widespread use of abdominal ultrasonography to evaluate non-
crystals and nascent stones. Motility is decreased in the presence specific abdominal symptoms. Approximately 20% of Western
of supersaturated bile even before stone formation. Decreased populations have cholelithiasis, and of these people, 80%
Table 40.1. Types of Stones: Characteristics and Clinical Association

Feature Cholesterol gallstones Black pigment gallstones Brown pigment gallstones
Composition 50%-99% cholesterol by weight Calcium bilirubinate Unconjugated bilirubin, palmitate
Calcium phosphate stearate, cholesterol, and mucin
Color Yellow-brown Black Brown
Consistency Crystalline Hard Soft, greasy
Location Gallbladder or common bile duct (or both) Gallbladder or common bile duct (or Intrahepatic and extrahepatic bile
both) ducts
Radiodensity Lucent (85%) Opaque (>50%) Lucent (100%)
Bile culture Sterile Sterile Infected (eg, Escherichia coli)
Recurrent stones Rare Rare Frequent
Clinical associations Increased losses through the gastrointestinal Chronic hemolytic states (eg, sickle cell Proximal to biliary stricture
tract from bile acid sequestrant therapy disease and mechanical heart valves) Proximal to duodenal diverticulum
Terminal ileal disease, resection, or bypass Cirrhosis (stasis)
Hormonal stimuli (female sex, pregnancy, Gilbert syndrome After sphincterotomy
exogenous estrogens, and progestins) Cystic fibrosis Biliary parasites
Obesity Total parenteral nutrition
Hyperlipidemia May have no identifiable cause
Older age
Chronic liver disease
Excessive dietary polyunsaturated fats or
caloric intake
Pregnancy
Prolonged total parenteral nutrition
Somatostatin therapy
Somatostatinoma
Box 40.1. LITH Genes and Potential Mechanisms

ATP-binding cassette transporter B4: Biliary phospho
lipid secretion is decreased
β3-Adrenergic receptor: Gallbladder hypomotility
Apolipoprotein A-I: Biliary cholesterol secretion is
increased from an increase in reverse cholesterol
transport
Apolipoprotein B: Biliary cholesterol secretion is
increased from a decrease in hepatic VLDL syn
thesis and an increase in intestinal cholesterol
absorption
Cholecystokinin 1 receptor: Gallbladder and small
intestinal hypomotility
Cytochrome P450 7A1 isozyme: Bile salt synthesis is
decreased
Estrogen receptor 2: Cholesterol synthesis is
increased
Figure 40.2. Defects Resulting in Gallstone Formation. Studies Cholesterol ester transfer protein: Hepatic cholesterol
have shown that interactions of 5 defects result in nucleation and crys- uptake is increased from HDL catabolism
tallization of cholesterol monohydrate crystals in bile, with eventual for-
mation of gallstones. Abbreviations: ATP, adenosine triphosphate; HDL, high-density lipo-
protein; VLDL, very low-density lipoprotein.
are asymptomatic when cholelithiasis is initially identified.

Commonly, asymptomatic disease has a benign course and the
Symptomatic Cholelithiasis
proportion of those with disease that evolves from asymptomatic
to symptomatic is relatively low (20% over a lifetime). More than Biliary colic is a relatively specific form of pain secondary to
90% of gallstone disease complications are preceded by an epi- increased pressure in the gallbladder due to hormonal or neural
sode of uncomplicated biliary colic. Thus, while asymptomatic stimulation. This may be triggered by a fatty meal or a stone com-
stones generally do not require therapy, when they become symp- pressed against the gallbladder outlet or cystic duct opening. The
tomatic, cholecystectomy is indicated. pain usually develops rapidly in the epigastrium or right upper
Prophylactic cholecystectomy should be considered, how- quadrant and lasts longer than 30 minutes but not longer than 4
ever, for patients who are planning extensive travel in remote to 6 hours. The likelihood of patients having a severe event or
areas and for American Indian populations, in whom the rela- complication is approximately 1% per year, prompting the rec-
tive risk for stone-associated gallbladder carcinoma (GBC) is 20 ommendation of surgical therapy for symptomatic gallstones.
times higher than for those without stones. The risk of GBC for Histologically, most patients with recurrent biliary colic have
patients who have stones larger than 3 cm is 10-fold higher than chronic cholecystitis.
for patients with stones smaller than 1 cm. Prophylactic chole- Cholecystitis is a syndrome that encompasses a continuum
cystectomy should also be considered for patients treated with of clinicopathologic states. Patients with acute calculous cho-
somatostatin analogues for midgut carcinoids or other neuroen- lecystitis generally present with abdominal pain that lasts
docrine tumors. The adverse effects of these analogues include longer than 6 hours and is accompanied by fever, leukocy-
impairment of gallbladder function, formation of gallstones, tosis, or cholestasis. The diagnostic criteria for acute cholecys-
and cholecystitis. Therefore, prophylactic cholecystectomy titis is based on the Tokyo Guidelines 2018 (Box 40.2). Acute
may be beneficial for this cohort of patients but still needs to calculous cholecystitis is associated with age older than 60 years,
be investigated. Concomitant cholecystectomy at the time of a male sex, type 2 diabetes, history of cardiovascular disease, and
Roux-en-Y gastric bypass for ultrasound-confirmed gallbladder history of cerebrovascular accident or stroke. In an immune-
pathology is feasible and safe and may reduce the potential for compromised patient, it may be related to cytomegalovirus or
future gallbladder-related morbidity. A similar rationale may be Cryptosporidium infections. The most common complication
used when prophylactic splenectomy is performed in patients is gangrene of the gallbladder (20%); therefore, early cholecys-
with hereditary spherocytosis. However, cholecystectomy is not tectomy is recommended for patients who have symptomatic
recommended for asymptomatic patients who have stones and cholelithiasis and these adverse risk factors. However, cholecys-
type 2 diabetes or sickle cell disease if they have regular access tectomy is not indicated for patients who have isolated abnormal
to medical care. results on liver biochemical tests or cholestasis in the absence of
Progressive gallstone dissolution by oral litholysis with hy- choledocholithiasis. For patients who are not surgical candidates,
drophilic ursodiol may be attempted in patients who have mild gallbladder drainage can be achieved with endoscopic retrograde
symptoms and small, uncalcified cholesterol gallstones in a cholangiopancreatography (ERCP) with transpapillary drainage,
functioning gallbladder with a patent cystic duct. This often endoscopic ultrasonography (EUS) for transmural drainage with
requires at least 6 months of therapy and can be costly. Daily a lumen-apposing metal stent, and percutaneous drainage through
ursodiol may reduce the frequency of gallstone formation in a cholecystostomy tube.
patients with obesity who are eating low-calorie diets or who Acute acalculous cholecystitis accounts for 10% of all acute
have had bariatric surgery. episodes, is associated with a high mortality rate, and is difficult to
40. Gallstones 459
larger than 10 mm in diameter should be considered for chole-

Box 40.2. The Tokyo Guidelines 2018 for Diagnosis of cystectomy, as should polyps of any size in patients who have
Acute Cholecystitis cholelithiasis or primary sclerosing cholangitis. In patients older
A. Local signs of inflammation than 50 years or of Indian ethnicity, cholecystectomy should be
1. Right upper quadrant pain, tenderness, or fullness
recommended when the polyp size is greater than 6 mm given the
or mass increased risk for gallbladder cancer in this population. Polyps
that are 5 to 9 mm generally require close surveillance with ab-
2. Positive Murphy sign
dominal ultrasonography in 3 to 6 months.
B. Systemic signs of inflammation
1. Fever
Gallstones and Pregnancy
2. High white blood cell count
3. High C-reactive protein level Symptomatic gallstone disease is the second most common ab-
dominal emergency in pregnant women. Insulin resistance is a
C. Imaging findings that suggest acute cholecystitis
(abdominal ultrasonography, CT, or MRI) risk factor for incidental gallbladder sludge and stones during
pregnancy, even after adjustment for body mass index. Insulin
Suspected diagnosis: 1 item in A and 1 item in B
resistance may be a causal link between obesity and gallstones.
Definite diagnosis: 1 item in A and 1 item in B and C In addition, the pregnant state impairs gallbladder motility and
increases biliary cholesterol saturation. ERCP can be performed
Abbreviations: CT, computed tomography; MRI, magnetic resonance safely during pregnancy but may be associated with an increased
imaging.
rate of post-ERCP pancreatitis compared with the rate for the
Adapted from Yokoe M, Hata J, Takada T, Strasberg SM, Asbun HJ, general population. Studies that compared conservative manage-
Wakabayashi G, et al. Tokyo guidelines 2018: diagnostic criteria and ment with surgical management of cholecystitis showed no sig-
severity grading of acute cholecystitis (with videos). J Hepatobiliary nificant difference in the incidence of preterm delivery or fetal
Pancreat Sci. 2018 Jan;25(1):41-54; used with permission.
mortality. Laparoscopic cholecystectomy is safe in all trimesters.
In 12 reports of gallstone pancreatitis, the fetal mortality rate was
8% for the conservative management group and 2.6% for the
diagnose. It generally occurs in acutely ill, hospitalized patients. surgical management group, suggesting the need for earlier sur-
It also may develop postoperatively and in critically ill patients gical intervention. Hospitalization for gallstone-related disease is
and may be complicated by the development of gangrene, per- common in the first postpartum year, most often for uncompli-
foration, and empyema. Type 2 diabetes, malignant disease, cated cholelithiasis. Risk factors for hospitalization include high
abdominal vasculitis, congestive heart failure, cholesterol em- prepregnancy body mass index, Latino ethnicity, and older ma-
bolization, shock, and cardiac arrest also have been associated ternal age.
with acute acalculous cholecystitis. The overall mortality rate
is 50%. Ultrasonography, CT, and hepatobiliary iminodiacetic
Microlithiasis and Sludge
acid (HIDA) scans are the most useful imaging examinations.
Hyperamylasemia may be a diagnostic clue. Diagnostic laparos- Microliths are a component of biliary sludge, consisting of rel-
copy and, potentially, laparotomy have been recommended by the atively larger particles (1-3 mm) that are essential in the devel-
Society of American Gastrointestinal and Endoscopic Surgeons opment of gallstones. Microscopic examination of bile under
for acute acalculous cholecystitis. Nonsurgical approaches such polarized light can be used to detect cholesterol crystals, which
as transpapillary, transmural, or percutaneous drainage are also are a surrogate marker for biliary sludge and gallstones. The
used when necessary. chemical composition of sludge includes cholesterol monohy-
Between 5% and 40% of all laparoscopic cholecystectomy drate crystals, calcium bilirubinate granules, calcium phosphate
procedures are associated with spillage of gallstones. Gallstones and calcium carbonate crystals, and calcium salts of fatty acids;
also may be dropped during open cholecystectomy, but the larger the composition of sludge correlates well with the composition
operating field makes them easier to retrieve. Dropped gallstones of stones. A higher prevalence of detectable gallbladder sludge is
may mimic colon cancer, liver abscess, subphrenic abscess, peri- noted during pregnancy, TPN (secondary to gallbladder stasis),
toneal metastases, and intra-abdominal actinomycosis. Symptoms weight loss, prolonged fasting, and prolonged treatment with
can present years after the index cholecystectomy, and a high de- octreotide and after intravenous administration of ceftriaxone.
gree of clinical awareness is usually needed for diagnosis. Biliary sludge or microlithiasis may cause acalculous biliary
pain and may obstruct the common bile duct, manifesting as acute
cholangitis or pancreatitis. Consequently, occult microlithiasis
Gallbladder Polyps should be suspected when patients have acute pancreatitis of un-
Polypoid lesions of the gallbladder typically are incidental known origin, particularly if relapses are frequent. Additionally,
findings and indicate any projection of mucosa into the gall- it is a well-recognized complication after liver transplant; in 6%
bladder lumen regardless of neoplastic potential. The majority of patients, cholangiography shows biliary filling defects ulti-
are benign nonneoplastic lesions that include cholesterol polyps mately attributed to sludge-cast, gallstones, or necrotic debris.
(usually pedunculated), adenomyomatosis, and inflammatory Biliary strictures and prestenotic dilatations of the bile ducts are
polyps. Cholesterol polyps are usually smaller than 10 mm in the major reasons for sludge formation.
diameter and appear on ultrasonography as tiny echogenic spots Expectant management is warranted for incidentally detected
or echogenic pedunculated masses without acoustic shadowing. asymptomatic sludge. Similar to that for overt gallstone disease,
Gallbladder polyps can also develop in patients with a congenital treatment is necessary only if patients are symptomatic or have
polyposis syndrome such as Peutz-Jeghers syndrome or familial complications. Endoscopic sphincterotomy with either ursodiol
adenomatous polyposis. Patients with solitary sessile polyps treatment or laparoscopic cholecystectomy is a useful alternative
for patients who have biliary sludge and recurrent obstruction of ✓ Factors associated with gallstone formation—increased choles-
biliary outflow associated with recurrent cholangitis or pancrea- terol excretion, bile acid loss, stasis, and imbalanced nucleation
titis. After liver transplant, biliary sludge should be treated endo- ✓ Laparoscopic cholecystectomy— treatment of choice for both
scopically when biochemical evidence of obstruction or clinical acute calculous and acalculous cholecystitis
signs of infection are evident to avoid graft dysfunction and other ✓ Acalculous cholecystitis
life-threatening complications. • Common in severely ill patients
• Diagnosis requires a high degree of clinical awareness
✓
Choledocholithiasis occurs in 15% of patients with cholelithiasis
Choledocholithiasis
Choledocholithiasis (ie, stones in the common bile duct)
should be suspected in patients who have symptomatic chole-
Ascending Cholangitis
lithiasis or acute biliary pancreatitis and even in patients who
have had cholecystectomy. Choledocholithiasis occurs in 15% Acute cholangitis, or biliary tree infection, occurs as a conse-
of people who have cholelithiasis. Concomitant cholelithiasis quence of biliary tract obstruction that promotes bile stasis and
and choledocholithiasis occur more frequently in elderly Asian bacterial growth. Bacteria ascending from the duodenum are the
patients, in patients with chronic bile duct inflammation (scle- main bacterial entry route. Secondary and less frequent routes of
rosing cholangitis or parasitic infestation), and in patients with entry are the portal venous system and the periportal lymphatic
hypothyroidism. A common bile duct stone detected on any im- system. Most episodes are due to coliforms such as Escherichia
aging is the most reliable predictor of such stones at ERCP or coli, Klebsiella (70% of cases), Enterococcus, Pseudomonas, and
surgery. The American Society for Gastrointestinal Endoscopy anaerobes (Clostridium and Bacteroides) (10% of cases). The
(ASGE) 2019 guidelines recommend 3 criteria for proceeding di- occurrence of bacteremia or endotoxemia correlates directly with
rectly to ERCP before cholecystectomy: 1) choledocholithiasis intrabiliary pressure.
on imaging, 2) total bilirubin greater than 4 mg/dL and a dilated Common bile duct stones are the most common cause, and the
common bile duct, and 3) ascending cholangitis (Figure 40.3). presentation may range from a mild, self-limited process to a se-
If patients do not meet these criteria but a stone is suspected, rious, life-threatening condition that requires urgent intervention.
further diagnostic evaluation such as with EUS, magnetic res- Ascending cholangitis also may be due to a biliary stricture from
onance cholangiopancreatography (MRCP), or cholecystectomy a previous biliary operation, liver transplant, primary sclerosing
with intraoperative cholangiography should be pursued. Those cholangitis, or acquired immunodeficiency syndrome– related
who do not meet any of the criteria should proceed to cholecys- cholangiopathy. In 1877, Charcot described a triad of fever,
tectomy. Endoscopic therapy (therapeutic ERCP) consists of en- right upper quadrant pain, and jaundice; this triad occurs in 50%
doscopic biliary sphincterotomy and stone removal with the use of patients who have cholangitis. The Reynolds pentad, which
of various devices for direct extraction or lithotripsy (mechanical includes hypotension and alteration of consciousness in addition
or electrohydraulic) when necessary. Extracorporeal shock wave to the features of the Charcot triad, is seen less frequently (5% of
lithotripsy of duct stones is clinically approved and feasible but patients). In clinical practice, the Tokyo Guidelines 2018 are fre-
infrequently used. It is coupled with ERCP for the removal of quently used to diagnose and grade acute cholangitis (Box 40.3).
stone debris. Initial therapy should include adequate resuscitation and
Bile duct stones recur in 15% of patients during follow-up. They the empirical use of broad- spectrum antibiotics with ade-
may recur after cholecystectomy. This is thought to be due to bile quate biliary excretion. Useful antibiotics include ampicillin-
stasis and bacterobilia. A small amount of postcholecystectomy sulbactam, piperacillin-tazobactam, third-or fourth-generation
syndromes (in symptomatic patients after cholecystectomy) are re- cephalosporins, quinolones, and carbapenems. Ceftriaxone is as-
lated to a residual stone in a particularly long cystic duct or to the sociated with the appearance of biliary sludge due to calcium salt
relapse of lithiasis in a gallbladder remnant. Common bile duct dil- precipitation, but the sludge should dissipate spontaneously when
atation (≥13 mm) and the presence of a periampullary diverticulum use of the drug is discontinued. Elderly patients, patients with
are risk factors for recurrent stones. a biliary stent in situ, or those who had previous enterobiliary
Figure 40.3. Probability of Choledocholithiasis. The probability of common bile duct stones is based on clinical, laboratory, and ultrasonographic
variables. CBD indicates common bile duct.
40. Gallstones 461
with intrahepatic gallstones. Therapy is directed at duct decom-

Box 40.3. The Tokyo Guidelines 2018 for Diagnosis pression, drainage, stone clearance, and, occasionally, lobar or
of Acute Cholangitis segmental resection for isolated intrahepatic disease. Isolated
A. Systemic inflammation unilateral intrahepatic involvement is most common in the left
1. Fever or shaking chills (or both) hepatic ductal system. Peroral cholangioscopy, through a percu-
taneous tract or ERCP, can occasionally be a successful, mini-
2. High white blood cell count
mally invasive approach depending on clinical expertise.
3. High C-reactive protein level
B. Cholestasis
Sump Syndrome
1. Jaundice (bilirubin ≥2 mg/dL)
2. High ALT, AST, or ALP level In some patients who have had choledochoduodenostomy,
sump syndrome occurs as debris (mainly food) accumulates
C. Imaging
in segments of the native biliary tree. This results in pain and
1. Biliary dilatation cholangitis, requiring native papilla sphincterotomy. However,
2. Evidence of the cause on imaging (eg, stricture, choledochoduodenostomy is rarely performed now, so fewer
stone, or stent) patients have sump syndrome.
Suspected diagnosis: 1 item in A and 1 item in either
B or C
Functional Gallbladder Disorder (Gallbladder
Definite diagnosis: 1 item in A and 1 item in B and Dyskinesia)
1 item in C
Functional gallbladder disorder is characterized by pain
Abbreviations: ALP, alkaline phosphatase; ALT, alanine aminotrans resembling biliary pain in patients who have an ultrasono
ferase; AST, aspartate aminotransferase. graphically normal gallbladder. Synonyms include gall-
Adapted from Kiriyama S, Kozaka K, Takada T, Strasberg SM, Pitt bladder dyskinesia, chronic acalculous gallbladder dysfunction,
HA, Gabata T, et al. Tokyo guidelines 2018: diagnostic criteria and acalculous biliary disease, and biliary dyskinesia (Box 40.4).
severity grading of acute cholangitis (with videos). J Hepatobiliary The estimated prevalence is 10% for men and 20% for women,
Pancreat Sci. 2018 25(1):17-30; used with permission. but the pathogenesis is poorly understood. Even though
evidence-based recommendations cannot be made, the use of a
neuromodulator is reasonable for patients with suspected func-
tional gallbladder disorder. Anticholinergic drugs and narcotics
surgery may benefit from additional enterococcal and anaer- are associated with impaired gallbladder emptying. If symptoms
obic antimicrobial coverage. The timing of biliary decompres-
sion depends on the initial response to antibiotics, and supportive
care can be provided by endoscopic, percutaneous, or surgical
approaches or by multimodal therapy. The ASGE recommends Box 40.4. Rome IV Criteria for the Diagnosis of
ERCP within 48 hours and as soon as possible if the patient has Functional Gallbladder Disorder
no response to initial resuscitation and antibiotic therapy. Several Diagnostic criteria
reports have shown that ERCP after more than 48 hours is asso-
1. Absence of gallstones or other structural pathology
ciated with increased mortality and increased in-hospital length
of stay. ERCP with endoscopic sphincterotomy and common bile and
duct clearance is associated with considerably lower morbidity 2. Presence of biliary pain, defined as epigastric
and mortality than traditional surgical management. If ERCP is pain or right upper quadrant pain (or both), and
not feasible, subsequent EUS-guided biliary drainage or percu- all the following:
taneous or, rarely, surgical decompression, should be pursued, Pain increases to a steady level and lasts ≥30 min
depending on clinical urgency and expertise. In patients with Recurrent episodes occur at different intervals
altered anatomy (eg, Roux-en-Y gastric bypass), percutaneous (not daily)
drainage or EUS-guided biliary drainage may be preferred given Pain is severe enough to interrupt daily functioning
the challenges of altered anatomy at ERCP. or leads to an emergency department visit
Pain is not related to bowel movements (<20%)
Recurrent Pyogenic Cholangitis Pain is not relieved by postural change or acid
suppression <20%)
Patients with recurrent pyogenic cholangitis present with re-
current, progressively severe, and frequent attacks of cholan- Supportive criteria
gitis with associated extensive stone disease, especially of the 1. Low ejection fraction on gallbladder scintig
intrahepatic ducts. Secondary duct dilatation, stricture formation, raphy (HIDA scanning)
and further stone formation become self-perpetuating. This form 2. Normal levels of liver enzymes, conjugated bili
of cholangitis occurs especially in the Asian-Pacific basin. The rubin, and amylase and lipase
pathogenetic mechanism is not understood completely; however,
postulated causes include primary congenital biliary strictures Abbreviation: HIDA, hepatobiliary iminodiacetic acid.
and cysts, biliary parasitic infection (Ascaris lumbricoides, Adapted from Cotton PB, Elta GH, Carter CR, Pasricha PJ, Corazziari
Opisthorchis species, or Opisthorchis sinensis [also known as the ES. Gallbladder and sphincter of Oddi disorders. Gastroenterology.
Chinese liver fluke]), and chronic intrahepatic bacterial coloni- 2016 150(6):1420-9; used with permission.
zation from unclear sources. Ascaris infection is also associated
index hospitalization after their symptoms have resolved. ERCP

Box 40.5. Rome IV Criteria for the Diagnosis of with sphincterotomy is recommended for patients who are not
Functional Biliary Sphincter of Oddi Disorder candidates for surgery or for patients who cannot undergo chole-
Diagnostic criteria cystectomy within a few months.
Gallstone ileus is a disease of the elderly, with a female
1. High liver enzyme levels or dilated bile duct, but
not both predominance. It frequently is preceded by an episode of
acute cholecystitis. The resulting obstruction is a true mechan-
and
ical phenomenon; therefore, the term ileus is a misnomer. The
2. Absence of bile duct stones or other structural cholecystitis-related inflammation and adhesions facilitate the
abnormalities erosion of the offending gallstone through the gallbladder wall,
and forming a cholecystoenteric fistula and facilitating stone passage.
3. Presence of biliary pain, defined as epigastric The duodenal wall is the most common fistula site, but it may
pain or right upper quadrant pain (or both), and occur anywhere in the gastrointestinal tract (colon, stomach, or
all the following: small bowel). An iatrogenic fistula can form after endoscopic
Pain increases to a steady level and lasts ≥30 min sphincterotomy or a surgical choledochoduodenostomy. A stone
Recurrent episodes occur at different intervals smaller than 2 to 2.5 cm usually passes spontaneously through a
(not daily) normal gastrointestinal tract. Stones larger than 5 cm are more
Pain is severe enough to interrupt daily functioning likely to become impacted. The terminal ileum and ileocecal valve
or leads to an emergency department visit are the most common locations because of the relatively narrow
Pain is not related to bowel movements (<20%) lumen and decreased peristalsis. Presenting symptoms may be
intermittent because the passing stone may lodge at various levels
Pain is not relieved by postural change or acid
of the bowel. A passing stone is responsible for 25% of all bowel
suppression (<20%)
obstructions in patients older than 65 years, compared with 1% to
Supportive criteria 3% in all age groups. Abdominal radiography may show bowel
1. Normal levels of amylase and lipase obstruction, pneumobilia, and an abnormally located stone. CT
2. Abnormal results on sphincter of Oddi manometry may be used to identify larger stones, evidence of bowel obstruc-
3. Hepatobiliary scintigraphy tion, and the level of obstruction. Surgical intervention is the
treatment of choice for the majority of patients and may include
Adapted from Cotton PB, Elta GH, Carter CR, Pasricha PJ, Corazziari biliary surgery when the intestinal obstruction is relieved.
ES. Gallbladder and sphincter of Oddi disorders. Gastroenterology. Obstruction at the level of the gastric outlet by a gallstone is
2016 150(6):1420-9; used with permission. called Bouveret syndrome. It is an uncommon form of gallstone
ileus. A single gallstone at least 2.5 cm in diameter is the most
common underlying cause of this syndrome.
Mirizzi syndrome results from a common hepatic duct obstruc-
persist, oral cholecystography should be performed with and tion due to extrinsic compression from an impacted cystic duct
without cholecystokinin stimulation and with measurement of stone. Patients present with a triad of fever, right upper quadrant
the gallbladder ejection fraction (a quantitative measurement of pain, and jaundice, with high levels of bilirubin and alkaline phos-
gallbladder emptying). An alternative and more frequently used phatase. They have an increased risk for gallbladder cancer. Mirizzi
investigation is the HIDA scan to evaluate functional gallbladder syndrome is noted in 1% of patients undergoing biliary surgery. In
disorder. If the ejection fraction is less than 35%, cholecystec- 10% of patients, the cystic duct courses parallel to the extrahepatic
tomy should be considered—but only for patients with classic bile duct and inserts medially into it at the level of the papilla.
biliary symptoms. Functional biliary sphincter of Oddi disorders Emphysematous cholecystitis is a rare form of acute cholecys-
are listed in Box 40.5. titis in which the gallbladder becomes infected with gas-forming
organisms such as Clostridium perfringens, E coli, and Klebsiella
species. Most patients are 50 to 70 years old and, in contrast to
Gallstone Complications
typical patients with acute cholecystitis, men are more likely to be
The incidence of gallstone pancreatitis is increased for women affected than women. Approximately 25% of patients have type 2
older than 60 years. The pathogenesis is thought to be related to diabetes. Although the initial symptoms may be relatively mild,
increased pressure within the pancreatic duct, with biliopancreatic the disorder often progresses rapidly and is associated with a high
reflux, due to passage of a common bile duct stone or an im- risk of gallbladder perforation. The diagnosis can be made with
pacted stone at the level of the papilla. Suspicion of acute gall- plain abdominal radiographs, ultrasonographic studies, or CT. CT
stone pancreatitis is increased if patients have acute pancreatitis is the most sensitive method for detecting small amounts of gas in
associated with abnormal results from liver function tests, evi- the gallbladder wall. Treatment includes intravenous antibiotics
dence of cholelithiasis, or biliary tree dilatation. Transabdominal that cover anaerobic organisms and subsequent early open or
ultrasonography is the most cost-effective initial investigation laparoscopic cholecystectomy. Another option is percutaneous
to document the presence of cholelithiasis, with or without drainage of the gallbladder, particularly in patients who are crit-
common bile duct dilatation. Bowel gas and stones smaller than ically ill. Emphysematous cholecystitis has occurred in patients
4 mm may reduce the overall sensitivity. Pancreatic parenchymal with gallstone cholecystitis or acalculous cholecystitis and has
and peripancreatic inflammatory changes are best detected and been associated with a mortality rate of approximately 15%. This
evaluated with contrast-enhanced CT, which also may show pan- is substantially higher than the mortality rates of 3% to 4% for
creatic neoplasm, pancreatic calcification, or choledocholithiasis. patients with acute cholecystitis without gas-forming organisms.
Because patients have a high risk for recurrence within 30 days Porcelain gallbladder is seen more frequently in women, pri-
after an attack, they should undergo cholecystectomy during the marily in the sixth decade. It can be identified on plain abdominal
40. Gallstones 463
radiographs or CT and is an uncommon finding in chronic cho- and concentrated by the gallbladder. Most gallbladders opacify
lecystitis. Porcelain gallbladder is characterized by extensive cal- after a single oral dose, and 85% to 90% opacify after a second or
cification manifested as a brittle consistency of the wall and is double dose. Nonvisualization of the gallbladder after a reinforced
seen in less than 1% of cholecystectomy specimens, with stones 1-or 2-day study is 95% predictive of gallbladder disease. The
identified in 95% of pathology specimens. The diagnosis of por- use of oral cholecystography has diminished in clinical practice
celain gallbladder is important because of its association with because it is less sensitive (65%-90%) than ultrasonography for
gallbladder cancer. However, making the diagnosis may be diffi- cholelithiasis, and it is not indicated when acute cholecystitis is
cult because rim calcifications in the right upper quadrant may be suspected. Oral cholecystography may be useful when ultrasonog-
due to gallstones or liver, kidney, adrenal, or pancreatic cysts. The raphy does not image the gallbladder and EUS is not available.
incidence of gallbladder cancer in patients with porcelain gall-
bladder ranges from 0% to 20%. Prophylactic cholecystectomy is
HIDA Scanning
the treatment of choice for porcelain gallbladder.
HIDA scanning, also known as cholescintigraphy, may be used
to diagnose acute cholecystitis or to confirm intra-abdominal bile
Clinical Investigations leakage. This method involves noninvasive scanning of gamma
Liver Biochemical Testing emissions after the intravenous administration, liver uptake, and
biliary excretion of technetium iminodiacetic acid derivatives.
Uncomplicated biliary colic usually is not accompanied by
The inability to visualize the gallbladder despite excretion into
changes in hematologic and biochemical test results. However,
the common bile duct at 4 hours after the injection is indicative
the initial evaluation of suspected stone disease should include
of cystic duct obstruction. Nonvisualization of the gallbladder is
serum liver biochemical testing (eg, alanine aminotransferase,
97% sensitive and 96% specific for acute calculous cholecystitis.
aspartate aminotransferase [AST], alkaline phosphatase, and
False-negative results occur with acalculous cholecystitis, and
total bilirubin) and transabdominal ultrasonography of the right
false-positive results occur with chronic cholecystitis and chronic
upper quadrant. Liver biochemical tests may be most useful in
liver disease and during TPN or fasting states.
excluding the presence of common bile duct stones. In a series of
more than 1,000 patients undergoing laparoscopic cholecystec-
tomy, completely normal results on liver biochemical tests had a Transabdominal Ultrasonography
negative predictive value of more than 97%, whereas the positive
Ultrasonography has greater sensitivity for detecting dilatation
predictive value of any abnormal liver biochemical test result was
of the common bile duct than for detecting choledocholithiasis.
only 15%, according to the current guidelines of the ASGE.
It is most sensitive (90%-98%) for the detection of cholelithi-
Patients with cholangitis or pancreatitis associated with ab-
asis (>2 mm) identified as mobile, intraluminal, echogenic,
normal results on serum liver function tests have an increased risk
shadowing particles. Obesity and bowel gas make interpretation
for bile duct stones. The conventional wisdom that the alkaline
challenging, but ultrasonography is relatively inexpensive and
phosphatase level increases more than the AST level in obstructive
noninvasive compared with other imaging options. Cholecystitis
jaundice holds true when jaundice is due to strictures, but in obstruc-
is identified by gallbladder contraction or marked distention with
tive stone disease, the increase in AST may equal that in alkaline
surrounding fluid or wall thickening. Gallbladder thickening also
phosphatase or even exceed it during periods of maximal jaundice
may be due to portal hypertension, ascites, and hypoalbuminemia.
and painful episodes. Occasionally, serum transaminase levels may
The diameter of the common bile duct is normally 3 to 6 mm,
be increased dramatically, mimicking acute viral hepatitis. With bil-
and it may increase with older age. Biliary obstruction should be
iary stones, the increased levels tend to decrease rapidly over several
suspected when the diameter is more than 8 mm in a patient with
days rather than weeks, as with acute viral hepatitis.
a gallbladder in situ. Multiple small stones (<5 mm in diameter),
compared with larger stones, increase the risk of common bile
Biliary Imaging duct migration 4-fold. Transabdominal ultrasonographic exami-
nation of the gallbladder permits the visualization of particles in
Several improvements have been made in biliary imaging.
bile, usually those 2 to 3 mm or more in diameter.
Although ultrasonography is the primary initial modality for the
evaluation of the biliary tree, the advent of and improvements
in CT, magnetic resonance imaging, and EUS techniques have Abdominal CT
resulted in superior detection and characterization of disease.
CT is the best imaging method for the evaluation of possible
complications of biliary stone disease if ultrasonography is subop-
Plain Abdominal Radiography timal, as in patients with fever, right upper quadrant pain, and as-
Plain abdominal radiography can show radiopaque stones (about sociated jaundice. Bowel gas and ribs do not interfere with CT. CT
25% of all stones) and pneumobilia due to a previous biliary is superior to ultrasonography for patients with obesity, in whom
sphincterotomy, a bilioenteric anastomosis or fistula, or an in- imaging is improved by discrete fat planes. CT is not appropriate
competent sphincter, as may occur with duodenal Crohn disease, for the diagnosis of uncomplicated stone disease or evaluation of
duodenal diverticulum, or other periampullary disease. biliary colic because 50% of gallstones are radiolucent on CT.
Oral Cholecystography Endoscopic Ultrasonography
Oral cholecystography involves standard radiographic imaging of Suspected Choledocholithiasis

the right upper quadrant after oral administration of an iodinated The major advantage of EUS in suspected choledocholithiasis,
radiodense contrast agent. Thus, the agent needs to be ingested, as compared with transabdominal ultrasonography, is the ability
absorbed and taken up by the liver, excreted by the biliary system, to position the ultrasound transducer within the duodenal lumen,
a sensitivity of 96% and a specificity of 86% compared with the

corresponding cholecystectomy specimens or long-term clinical
follow-up.
Microlithiasis
EUS has been shown to be as accurate as crystal analysis for the
detection of microlithiasis (Figure 40.5). In approximately 20%
of patients with acute pancreatitis, the cause is not established by
history, physical examination, routine laboratory testing, or ab-
dominal imaging. Recent studies suggest that microlithiasis may
account for an unexplained attack of acute pancreatitis in as many
as 75% of patients with a gallbladder in situ. Sphincter of Oddi
Figure 40.4. Endoscopic Ultrasonographic Image of Choledocho

lithiasis. Echo-rich areas with typical postacoustic shadowing are seen
within the common bile duct.
thereby allowing visualization of the adjacent biliary tree without

interference from intestinal gas or abdominal fat. EUS is particu-
larly important in correctly distinguishing acute biliary pancrea-
titis from other causes of pancreatitis.
Choledocholiths may be mobile, multiple, and of variable
size (Figure 40.4). Occasionally, stones do not show acoustic
shadowing and may be associated with a thickened bile duct wall.
Bile duct sludge is seen as variably shaped and easily distorted
echo-rich structures without acoustic shadowing.
In suspected choledocholithiasis, EUS has a sensitivity of
more than 90% for the detection of common bile duct stones. The
findings compare favorably with those of ERCP and are superior
to those obtained with transabdominal ultrasonography, without
the associated postprocedural ERCP risk of pancreatitis. For
patients with a low or intermediate risk for bile duct stones, EUS
is a cost-effective initial screening study. Comparative controlled
trials of EUS and MRCP have shown that the accuracy of EUS is
comparable to or higher than that of MRCP for the detection of
common bile duct stones.
A recent systematic review has suggested that EUS should
be reserved for the evaluation of patients for whom there is an
intermediate suspicion of common bile duct stones. Although
EUS does not have the therapeutic capacity of ERCP for stone
removal, algorithms have been developed that incorporate its use
into clinical practice. Ultimately, the choice of modality should
be based on clinical suspicion, availability of resources, experi-
ence, and cost.
Cholelithiasis
EUS can be used to reliably identify cholelithiasis, particularly
in patients with obesity and small stones. The appearance is that Figure 40.5. Microlithiasis on Endoscopic Ultrasonography. A,
of a hyperechoic structure within the gallbladder, sometimes The crystals appear as floating hyperechoic foci that move when abdom-
associated with an acoustic shadow. In patients with suspected inal pressure is applied to the right upper quadrant and as layering ma-
gallbladder stone disease but with negative findings on conven- terial indicating sludge. B, Note the presence of a shadowing stone with
tional transabdominal ultrasonographic examinations, EUS has layering sludge.
40. Gallstones 465
Hemorrhagic cholecystitis is a form of acute cholecystitis

often seen in the absence of gallstones. Hemorrhage is identified
by the characteristic appearance of hemoglobin breakdown
products within the wall or lumen of the gallbladder. The use of
MRCP in combination with CT is useful for preoperative diag-
nosis of Mirizzi syndrome.
Percutaneous Transhepatic Cholangiography

Percutaneous transhepatic cholangiography may be favored for
patients with a proximal obstruction (hilar or more proximal) or
surgically distorted gastroduodenal anatomy (especially Roux
limbs but also after a Whipple or Billroth II procedure) and after
failure of previous ERCP, EUS-assisted ERCP, or EUS-guided
biliary drainage. It is almost uniformly successful in patients
with dilated ducts and in 75% to 95% of those with nondilated
ducts. The overall risk, including death, sepsis, bile leaks, and
intraperitoneal bleeding, is 5%.
Endoscopic Retrograde Cholangiopancreatography

ERCP is favored for patients with ascites or coagulation
defects, suspected periampullary or pancreatic neoplasia,
Figure 40.6. Cholesterol Polyps. Endoscopic ultrasonography nondilated ducts, anticipated need for therapeutic maneuvers
shows an echogenic region without acoustic shadowing. (stone removal and stenting), or hypersensitivity to contrast
agents and if use of percutaneous routes has been unsuccessful.
Purely diagnostic use is diminishing rapidly because, for most
dysfunction is most prevalent in patients with recurrent attacks
patients, EUS and MRCP serve this purpose more safely. ERCP
who have previously undergone cholecystectomy. Therefore,
is successful in more than 95% of diagnostic applications, in
EUS is an important diagnostic tool for evaluation of patients
95% of sphincterotomies and complete stone extraction, and
who have unexplained biliary colic.
in 90% of procedures for stenting of malignant obstruction
(Figure 40.7). Nonemergent ERCP in patients 80 years or older
Polyps is reported to be safe and cost-effective, without significantly
With EUS, the normal gallbladder wall is seen as a 2-or 3-layer greater rates of complications or mortality. Intraductal shock
structure: The inner hypoechoic layer corresponds to the muscularis wave lithotripsy is a therapeutic option that may be effective
propria layer and the outer hyperechoic layer corresponds to an ad- despite the difficulties of a large, impacted stone that cannot
ipose layer. Cholesterol polyps are usually smaller than 10 mm in be captured by a basket or a stricture that prohibits delivery of
diameter and appear on ultrasonography as tiny echogenic spots
or echogenic pedunculated masses without acoustic shadowing
(Figure 40.6).
Cholangiography
Cholangiography can be performed either invasively or non
invasively. The selection of MRCP, percutaneous transhepatic
cholangiography, ERCP, or EUS-guided biliary access is based
largely on the clinical setting and institutional expertise.
Magnetic Resonance Cholangiopancreatography

MRCP should be the first examination of choice because it is
less invasive than EUS. MRCP is favored over EUS for frail
patients who are not candidates for conscious sedation and for
patients who have coagulopathy or who need concurrent staging
or evaluation of the liver parenchyma or other organs, especially
when therapeutic intervention is unlikely. MRCP appears to be
a valuable and safe technique for the evaluation of pregnant
patients who have acute pancreaticobiliary disease. Especially
when ultrasonography shows biliary dilatation, MRCP can be
used to determine the cause and prevent unnecessary ERCP by
excluding biliary abnormality. When MRCP results are nega-
tive, EUS is recommended to check for small common bile duct Figure 40.7. Cholesterol Stone Extraction. Multifaceted cholesterol
stones. stones are retrieved at endoscopic retrograde cholangiopancreatography.
Table 40.2. Mimics of Biliary Colic

Box 40.6. Gallstone Treatments
Condition Comments
Indications for cholecystectomy (open or laparoscopic)
Intravenous May lead to formation of crystalline biliary precipitates
Symptomatic cholelithiasis (with or without compli-
ceftriaxone of drug
cations)
therapy Ceftriaxone crystals can induce all potential
Asymptomatic cholelithiasis in patients who are at complications of small bile duct stones, including
increased risk for gallbladder carcinoma or gall biliary colic and pancreatitis
stone complications Erythromycin Manifests as syndrome of pain, fever, and cholestatic
Acalculous cholecystitis hepatotoxicity hepatitis, mimicking acute cholecystitis
Antibiotic history should be elicited during evaluation
Gallstone size >3 cm
of symptoms
Gallbladder polyps >10 mm in diameter (any size Consistent history and associated eosinophilia may
in PSC) help identify syndrome
Porcelain gallbladder Leptospirosis Weil syndrome (characterized by fever, jaundice,
Nonsurgical treatment of gallbladder stones azotemia, and right upper quadrant pain) mimics
acute bacterial cholangitis
Oral bile acid dissolution therapy with ursodiol for Clues to diagnosis include history of exposure risk,
noncalcified stones myalgias, ocular pain, photophobia, azotemia, and
Extracorporeal shock wave lithotripsy abnormal urinalysis findings
Abbreviation: PSC, primary sclerosing cholangitis.
✓ Elective cholecystectomy is required for gallbladder polyps

larger than 10 mm (or any size in patients with primary sclero-
a stone beyond it. The overall risk of the procedure in patients sing cholangitis or concomitant cholelithiasis) owing to increased
with suspected gallstones is 5% for diagnostic procedures and cancer risk
10% for therapy. Risks include death, pancreatitis, infection, se- ✓ Gallstones larger than 3 cm require elective cholecystectomy
dation or cardiovascular events, hemorrhage, and perforation. owing to increased cancer risk
For patients who have gallstone pancreatitis and concomitant
cholangitis, ERCP should be performed within 24 hours. If a per-
sistent common bile duct stone is highly likely (ie, the patient Suggested Reading
has a visible common bile duct stone on noninvasive imaging, a ASGE Standards of Practice Committee, Buxbaum JL, Abbas Fehmi
persistently dilated common bile duct, and jaundice), the patient SM, Sultan S, Fishman DS, Qumseya BJ, et al. ASGE guideline
should undergo ERCP in 48 to 72 hours because data suggest that on the role of endoscopy in the evaluation and management of
ERCP in patients with gallstone pancreatitis without cholangitis choledocholithiasis. Gastrointest Endosc. 2019 Jun;89(6):1075–105.
in less than 48 hours may be harmful. Although data are lacking to Attasaranya S, Fogel EL, Lehman GA. Choledocholithiasis, ascending
support the practice of endoscopic sphincterotomy in the absence cholangitis, and gallstone pancreatitis. Med Clin North Am. 2008
of choledocholithiasis at the time of the procedure, the practice is Jul;92(4):925–60.
a reasonable therapeutic option. ERCP and sphincterotomy alone Buxbaum JL, Buitrago C, Lee A, Elmunzer BJ, Riaz A, Ceppa EP,
may provide adequate long-term therapy for patients who are not et al. ASGE guideline on the management of cholangitis. Gastrointest
Endosc. 2021 Aug;94(2):207–21.
candidates for surgery as previously mentioned. In cases of mild
O’Neill DE, Saunders MD. Endoscopic ultrasonography in
gallstone pancreatitis, cholecystectomy should be performed diseases of the gallbladder. Gastroenterol Clin North Am. 2010
during the same hospital admission if possible and no later than 2 Jun;39(2):289–305.
to 4 weeks after discharge. Plecka Ostlund M, Wenger U, Mattsson F, Ebrahim F, Botha A, Lagergren
Gallstone treatments are listed in Box 40.6, and mimics of bil- J. Population-based study of the need for cholecystectomy after obe-
iary colic are listed in Table 40.2. sity surgery. Br J Surg. 2012 Jun;99(6):864–9.
Tang SJ, Mayo MJ, Rodriguez- Frias E, Armstrong L, Tang L,
✓ Acute cholangitis requires ERCP within 24 to 72 hours according Sreenarasimhaiah J, et al. Safety and utility of ERCP during preg-
to clinical status nancy. Gastrointest Endosc. 2009 Mar;69(3 Pt 1):453–61.
✓ Gallstone pancreatitis with concomitant cholangitis warrants ur- Tse F, Liu L, Barkun AN, Armstrong D, Moayyedi P. EUS: a meta-
gent ERCP within 24 hours analysis of test performance in suspected choledocholithiasis.
Gastrointest Endosc. 2008 Feb;67(2):235–44.
Questions d. Intravenous isotonic fluids

e. Genetic testing for inherited pancreatitis
Abbreviations used: VII.2. A 45-year-old woman has been admitted for pancreatitis after
AIP, autoimmune pancreatitis having undergone ERCP for choledocholithiasis. On the first
CT, computed tomography day of admission, she has mild nausea and epigastric pain, but
ERCP, endoscopic retrograde cholangiopancreatography she is not vomiting and she is passing flatus. She is afebrile and
EUS, endoscopic ultrasonography hemodynamically stable. Which of the following is the correct
IPMN, intraductal papillary mucinous neoplasm management strategy for nutrition in this patient?
MRCP, magnetic resonance cholangiopancreatography a. Initiate TPN
MRI, magnetic resonance imaging b. Place a nasojejunal tube, and feed a low-fat formula
PET, positron emission tomography c. Begin a trial of a liquid-based diet, and advance the diet as
PSC, primary sclerosing cholangitis tolerated
SUN, serum urea nitrogen d. Feed nothing by mouth until the lipase value is normal
TPN, total parenteral nutrition e. Feed nothing by mouth until 3 days after admission
ULRR, upper limit of the reference range
WBC, white blood cell VII.3. A 22-year-old man with Crohn disease has been in the hos-
pital for 5 days for acute pancreatitis after reinitiation of
azathioprine therapy caused a second episode of acute pan-
Multiple Choice (choose the best answer) creatitis. When he was admitted for this episode, CT with a
contrast agent showed a normally enhancing pancreas with
VII.1. A 36- year-
old man with a history of heavy alcohol use
peripancreatic fluid. Although he had modest improvement
presents 8 hours after the onset of acute epigastric abdom-
on the second day of hospitalization after beginning therapy
inal pain that radiates to the midback. The lipase level is
with intravenous fluids, antiemetics, and analgesics, he has
370 U/L (ULRR, 13-60 U/L). Other notable laboratory test
not tolerated an oral diet. His abdomen is visibly more dis-
values are the following: WBC count 11.0×109/L, SUN 31
tended. His WBC count has increased in the past 2 days to
mg/dL, and hematocrit 46%. Triglycerides, calcium, and
17,000/µL; his highest temperature has been 38.5 °C. Which
liver biochemistry values are all within the ULRRs. He is
of the following is the best next step in management?
afebrile, tachycardic (heart rate 110 beats/min), and nor-
motensive. He is visibly uncomfortable and describes having a. Placement of a nasojejunal tube for postpancreatic feeding
nausea in addition to pain. Ultrasonography does not show b. Fecal calprotectin testing
cholelithiasis, and the sonographic Murphy sign is absent. c. Contrast-enhanced CT
Which of the following is the best next step in management? d. Abdominal radiography
e. Intravenous antibiotics
a. Contrast-enhanced CT of the abdomen
b. ERCP VII.4. A 52-year-
old woman with decompensated alcoholic cir-
c. A carbapenem antibiotic rhosis and portal hypertension has been hospitalized in the
467
intensive care unit for severe, necrotizing acute pancrea- c. Hypertension

titis from gallstones. On day 6 of hospitalization, she has an d. Celiac disease
increased requirement for norepinephrine for blood pressure
VII.10. A 45-year-old woman with a family history of melanoma
support, and she has a sudden decrease in the hemoglobin
undergoes genetic counseling and germline genetic testing,
level. She is given blood products and additional intrave-
which identifies a pathogenic germline variant in the
nous fluids. CT with a contrast agent shows dilatation of the
CDKN2A gene. She has no personal history of cancer and no
gastroduodenal artery, and contrast material is visible in a
family history of pancreatic cancer. Which of the following is
walled-off necrotic collection posterior to the duodenal bulb.
Which of the following is the best next step in management?
a. Referral for pancreatic cancer screening
a. Interventional radiology–based targeted coil embolization
b. Baseline and annual testing for serum carbohydrate an-
b. Upper endoscopy with epinephrine injection and hemo-
tigen 19-9
static clip
c. Bilateral mastectomy
c. Upper endoscopy with band ligation
d. Total pancreatectomy with autologous islet cell transplant
d. Surgical exploration of the abdomen
e. Monitoring for signs of further hemodynamic instability VII.11. A 66-year-old man undergoes CT of the abdomen before
elective umbilical hernia repair. CT shows multiple cysts in
VII.5. A 62-year-old man presents to the pancreas clinic for a follow-
the pancreas; the largest measures 3.2 cm. The main pancre-
up visit after a recent hospitalization. He initially presented 6
atic duct is dilated to 6 mm, and some of the cysts commu-
weeks ago with epigastric abdominal pain and a high serum
nicate with it in the head. He does not have abdominal pain,
lipase level (1,270 U/L; ULRR, 13-60 U/L). At that time, CT of
and he has no previous history of pancreatitis. Which of the
the abdomen showed a 5-mm stone in the head of the pancreas
following is the best next step in the management of these
near the ampulla with upstream dilatation of the pancreatic
incidentally detected pancreatic cysts?
duct, a few prominent side branches in the pancreatic tail, and
peripancreatic fat stranding without any fluid collections. No a. EUS
gallstones were seen. He has no prior history of pancreatitis. b. Pylorus-preserving pancreaticoduodenectomy
He was treated with intravenous fluids and analgesics; his con- c. Follow-up MRI of the abdomen in 2 years
dition greatly improved, and he was discharged from the hos- d. No need for further testing or surveillance
pital after 4 days. What is the most likely diagnosis?
VII.12. A 36-year-old woman presents to the emergency department
a. Gallstone pancreatitis after a motor vehicle accident. CT of the abdomen inciden-
b. Alcoholic pancreatitis tally shows a 3-cm solid cystic lesion in the body of the pan-
c. Intraductal papillary mucinous neoplasm creas. At a subsequent follow-up, an EUS-guided biopsy is
d. Autoimmune pancreatitis performed, and the histologic features are consistent with a
solid pseudopapillary neoplasm. What is the recommended
VII.6. A 72-year-old man with a history of nicotine dependance
presents with painless jaundice, and MRI of the ab-
domen shows a mass in the pancreatic head and a distal a. The patient has a benign cystic neoplasm that does not re-
bile duct stricture. EUS-guided biopsy of the mass shows quire further follow-up
lymphoplasmacytic infiltrate and storiform fibrosis with ob- b. Upfront surgical resection should be considered
literative phlebitis without any evidence of neoplasia. What c. Neoadjuvant therapy with subsequent surgery is the pre-
is the best next step in management? ferred approach
d. Imaging surveillance should be performed annually with MRI
a. Treatment with oral prednisone
b. Follow-up biopsy of the pancreas VII.13. A 70-year-old woman presents with right upper quadrant
c. Surgical consultation for pancreaticoduodenectomy abdominal pain, fever, increased WBC count, and total bil-
d. PET/CT irubin of 2 mg/dL. Abdominal ultrasonography shows cho-
lelithiasis and a common bile duct with a normal diameter.
VII.7. A 66- year-
old man with long- standing daily alcohol use
presents with weight loss and diarrhea. CT of the abdomen
with a pancreas protocol shows an atrophic pancreas with a. MRCP
calcification and main pancreatic duct dilatation without a b. Cholecystectomy
pancreatic mass. The fecal elastase concentration is 82 µg/g c. ERCP
(ULRR >200 µg/g). Which of the following is the best next d. EUS and ERCP
step in management?
VII.14. A 60-year-old man with a history of PSC presents for an
a. EUS with direct pancreatic function testing annual follow-up visit. His liver test results are similar to
b. Secretin-enhanced MRCP baseline, and he has not had episodes of cholangitis or in-
c. Pancreatic enzyme replacement therapy fection in the past year. On abdominal ultrasonography, an
d. Fat-restricted diet 8-mm gallbladder polyp is found. What is the best next step
in management?
VII.8. Which of the following genes has pathogenic variants that
are associated with hereditary pancreatitis? a. Repeat ultrasonography in 3 to 6 months
b. Perform MRCP now
a. PRSS1
c. Proceed with ERCP
b. STK11
d. Refer for elective cholecystectomy
c. MLH1
d. CDKN2A VII.15. A 50-year-old man with a history of class 2 obesity (body mass
index 37), type 2 diabetes, hypertension, and high choles-
VII.9. Which of the following is a known risk factor for pancreatic
terol levels underwent Roux-en-Y gastric bypass for weight
ductal adenocarcinoma?
loss. Six months after surgery, he presented with biliary
a. Family history of breast and ovarian cancer colic and was referred for elective cholecystectomy. While
b. Obesity waiting for his surgery date, he presented to the emergency
department with recurrent right upper quadrant abdominal enteral feeding. The lipase concentration is not useful for deter-
pain. On examination, he is afebrile and has jaundice. The mining the severity of pancreatitis or the timing of feeding.
Murphy sign is negative. Laboratory test results are notable
for a WBC count of 10×109/L and total bilirubin of 4 mg/ VII.3. Answer c.
dL. Abdominal ultrasonography showed cholelithiasis, and The patient is most likely showing signs of the evolution of necro-
the distal common bile duct was not visualized. Which of the tizing pancreatitis, which is classically associated with systemic
following is the best next step in management? inflammatory signs. This can be accompanied by ileus or me-
a. Cholecystectomy chanical obstruction of the luminal gastrointestinal tract, which
b. MRCP would explain the patient’s distention and inability to tolerate
c. EUS with ERCP oral intake. Diagnosis of necrotizing pancreatitis is critical for
d. Placement of a percutaneous transhepatic drain both disease prognosis and anticipation of management strategies
VII.16. An 80-year-old man with a history of type 2 diabetes, obesity, as the necrosis becomes organized. This is best evaluated with
and coronary artery disease presents to the medical intensive contrast-enhanced CT to look for areas of malperfusion of the
care unit in shock. He receives fluid resuscitation and begins pancreatic gland. Even though the pancreas showed normal en-
therapy with vasopressors. On examination, he is febrile and hancement on admission, necrotizing pancreatitis tends to de-
has right upper quadrant tenderness. Laboratory test results velop over days after the initial presentation, so reevaluation is
include a WBC count greater than 18×109/L, total bilirubin warranted given the worsening clinical picture. Abdominal ra-
5 mg/dL, aspartate aminotransferase 500 U/L, and alanine
diography may show distended intestine but would not provide
aminotransferase 650 U/ L. Abdominal ultrasonography
shows a distended gallbladder with multiple small stones,
useful clinical information about the specific complications of
a trace of pericholecystic fluid, and a common bile duct di- acute pancreatitis and would delay appropriate testing. Fecal
ameter of 9 mm. Which of the following is the most likely calprotectin testing is not useful for pancreatitis, but it may be
diagnosis? used in certain situations of Crohn disease flare associated with
diarrhea, which this patient does not have. Infection related to
a. Acute calculous cholecystitis
b. Acute acalculous cholecystitis
pancreatic necrosis is extremely rare in the first week of acute
c. Acute cholangitis pancreatitis and is more common in the third or fourth week after
d. Choledocholithiasis presentation. Use of prophylactic antibiotics is not recommended
even if a patient has acute necrotizing pancreatitis because it has
not been shown to reliably decrease the rate of infected necrosis,
Answers systemic complications, or mortality.
VII.1. Answer d. VII.4. Answer a.
Initiation of intravenous isotonic fluids is a pivotal step for organ This patient is having a pseudoaneurysm, a vascular complication
perfusion to counteract the vasodilatory cytokine effect from the of acute pancreatitis that is most common in the gastroduodenal
systemic inflammatory response to pancreatic injury and to help and splenic arteries. Bleeding can be intraluminal or into a fluid
prevent organ failure. The patient’s increased SUN and hematocrit collection, as in this patient. Best care is with prompt, catheter-
suggest intravascular volume depletion. CT is not necessary at this based elimination of the bleeding source through interventional
time because the diagnosis of pancreatitis can be made from the radiology. Endoscopy provides little benefit in the management
clinical picture of pain and the lipase value that is greater than 3 of pseudoaneurysm and would delay appropriate care. Surgical
times the ULRR. Prophylactic antibiotics are not recommended exploration can be carried out if interventional radiologic
for acute pancreatitis and are used only when unstable systemic techniques are not an option but would be contraindicated in a
inflammation cannot reliably be differentiated from sepsis; use of patient with cirrhosis and portal hypertension. Unless it is within
antibiotics is then promptly stopped when results from evaluation the patient-specific goals of care, monitoring would be inappro-
for infection are negative for 48 hours. Genetic testing for acute priate at this time because exsanguination from her splanchnic ar-
pancreatitis is appropriate when patients have a family history of terial source, particularly with this patient’s comorbidities, would
pancreatitis or when other causes are not identified; alcohol-induced almost certainly be associated with a high risk of mortality.
pancreatitis is far more common and is more likely to be the cause
in patients consuming more than 50 g of alcohol daily. Further, both VII.5. Answer b.
volume resuscitation and nutritional support are more appropriate The presence of a pancreatic duct stone indicates underlying
next steps for this patient, and nuanced testing for the cause can be chronic pancreatitis in this patient who presented with an episode
performed later. of acute pancreatitis. Alcohol use is one of the most common
causes of chronic pancreatitis. Gallstone disease, a common
VII.2. Answer c. cause of acute pancreatitis, does not lead to chronic pancreatitis.
For patients with either mild or severe acute pancreatitis, early Intraductal papillary mucinous neoplasm is a pancreatic cystic
feeding is the best nutritional strategy, and the preferred method neoplasm that can be associated with main pancreatic duct dila-
is enteral feeding, which decreases the risk of organ failure and tation. However, in this case dilatation of the duct is secondary to
infection. To avoid unnecessary procedures, patients should be an obstructing pancreatic duct stone. Autoimmune pancreatitis is
given a trial with an oral diet; if the oral diet is not tolerated, na- typically not associated with pancreatic duct dilatation and rarely
sogastric or nasojejunal feeding can be attempted next. If enteral presents with an episode of acute pancreatitis, so it is an unlikely
feeding is not successful, as may happen in patients with severe diagnosis for this patient.
or necrotizing pancreatitis or in those with ileus or obstructive
symptoms from local collections, TPN should be initiated. A VII.6. Answer a.
trial of resting the pancreas is no longer thought to be of thera- The diagnosis is type 1 AIP on the basis of the definitive histo-
peutic benefit for patients with acute pancreatitis who can tolerate logic findings: lymphoplasmacytic infiltrate, storiform fibrosis,
and obliterative phlebitis. The appropriate treatment is oral the CT findings described above. The interval and modality of
prednisone. AIP often mimics pancreatic cancer, and follow-up future surveillance will depend on the EUS results. For a cyst
biopsy and metabolic imaging may be considered if the initial larger than 3 cm in diameter, the surveillance interval is usually
biopsy shows any indication of malignancy or does not show 6 months initially with increases in future intervals if the size of
the histologic hallmarks of AIP. Management of AIP does not the IPMN remains stable. Surveillance is recommended for all
involve surgery. patients with suspected IPMN unless age or comorbidities pre-
clude surgical intervention.
VII.7. Answer c.
For this patient the diagnosis is chronic pancreatitis with exo- VII.12. Answer b.
crine pancreatic insufficiency because imaging showed atrophy Solid pseudopapillary neoplasms are low-grade malignant pan-
and calcification, and the fecal elastase concentration was very creatic cystic neoplasms with metastatic potential; hence, man-
low. The appropriate next step in management is initiation of agement is surgical resection in all patients who are fit to undergo
pancreatic enzyme replacement. Both EUS with endoscopic surgery. Unlike therapy for pancreatic ductal adenocarcinoma,
pancreatic function testing and secretin-enhanced MRCP are neoadjuvant therapy is not appropriate for solid pseudopapillary
diagnostic modalities for chronic pancreatitis that can be used neoplasms.
when the diagnosis is not overt on cross-sectional imaging.
Although excess dietary fat is generally avoided in patients with VII.13. Answer c.
CP, a fat-restricted diet is not necessary if exocrine pancreatic This patient is presenting with acute cholangitis given the evi-
insufficiency is managed appropriately with pancreatic enzyme dence of systemic infection, inflammation, and biochemical evi-
replacement therapy. dence of jaundice. MRCP would not be the best next step because
cholangitis is suspected, and delaying management more than 24
VII.8. Answer a. hours may increase the risk of death. Cholecystectomy is indi-
Alterations in the cationic trypsinogen gene (PRSS1) are the cated after treatment of cholangitis to prevent future attacks, but
most common cause of hereditary pancreatitis. Other genes that it is not the best next step for this patient. EUS with ERCP would
have been implicated include SPINK1 and CFTR. The other be a reasonable step given the high clinical suspicion for cholan-
genes listed are associated with the following heritable cancer gitis. However, even if the EUS were negative for a stone, ERCP
syndromes, not with hereditary pancreatitis: Peutz-Jeghers syn- would still be indicated.
drome (STK11), Lynch syndrome (MLH1), and familial atypical
multiple mole melanoma syndrome (CDKN2A). VII.14. Answer d.
With this patient’s history of PSC, he has a relatively high risk
VII.9. Answer b. for gallbladder cancer. Patients who have PSC and polyps of
Obesity is associated with an increased risk for pancreatic cancer. any measurable size should be referred for elective cholecystec-
Other risk factors include family history of pancreatic cancer, tomy. If the patient did not have PSC, repeating ultrasonography
pathogenic germline variants in pancreatic cancer susceptibility in 3 to 6 months would be appropriate. MRCP is not indicated
genes, smoking, alcohol use, and a history of type 2 diabetes. at this time because the gallbladder polyp was already detected
Family history of breast and ovarian cancer could be related to a with abdominal ultrasonography; however, in some instances, an
germline BRCA variant, which would increase the risk for pan- MRCP is performed instead of abdominal ultrasonography for
creatic cancer, but confirmatory genetic testing would be nec- PSC surveillance for cholangiocarcinoma. ERCP is not indicated
essary. Uncontrolled celiac disease has been associated with for evaluation of gallbladder polyps.
small-bowel cancer but not pancreatic cancer.
VII.15. Answer b.
VII.10. Answer a. This patient has an intermediate risk for choledocholithiasis,
A pathogenic germline variant in the CDKN2A gene indicates the so proceeding to cholecystectomy directly would not be appro-
presence of familial atypical multiple mole melanoma syndrome, priate. Given his altered anatomy, both EUS and ERCP may be
which greatly increases a patient’s lifetime risk for pancreatic challenging and would not be the preferred next step. Placement
cancer. Current expert consensus recommends that pancreatic of a percutaneous transhepatic drain is not indicated for this
cancer surveillance be considered for those patients starting at patient because acute cholangitis is not suspected at this time.
age 40 years or at 10 years before the youngest age at onset of MRCP is the most appropriate of the choices provided. If a stone
exocrine pancreatic cancer in the family. Serum carbohydrate an- is found on MRCP, the patient may benefit from laparoscopic-
tigen 19-9 is not routinely used as a screening test for pancreatic assisted ERCP at the time of cholecystectomy, balloon-assisted
cancer. Prophylactic mastectomy is considered for patients who ERCP, or EUS-assisted ERCP.
have a germline BRCA variant. There is no need for prophylactic
pancreatectomy in patients who have a germline variant in the VII.16. Answer c.
CDKN2A gene. This elderly man has severe acute cholangitis as evidenced
by fever, right upper quadrant pain, hypotension, a relatively
VII.11. Answer a. dilated common bile duct, and high levels of bilirubin, aspar-
The finding of multiple cysts communicating with the main pan- tate aminotransferase, and alanine aminotransferase. Although
creatic duct suggests a diagnosis of IPMN. The finding that the the gallbladder is distended with pericholecystic fluid, distention
main pancreatic duct is dilated to more than 5 mm is a concern can be present in common bile duct obstruction and severe sepsis
that warrants further evaluation with EUS to assess for features with hypoperfusion; therefore, neither calculous cholecystitis nor
of main duct IPMN and other high-risk features that suggest ad- acalculous cholecystitis would be the most likely diagnosis. This
vanced neoplasia. Surgery is typically reserved for IPMNs with patient probably has choledocholithiasis, but the most likely di-
high-risk features, which this patient does not have according to agnosis is cholangitis.
Index
In the digital version, indexed terms that span 2 pages (eg, 52–53) may occasionally appear on only 1 of those pages
Tables, figures, and boxes are indicated by an italic t, f, and b, respectively, after the page number.
Numerics acute phosphate nephropathy, 242 aminosalicylates

5-aminosalicylate (5-ASA) drugs, 191–92, Acute Physiology and Chronic Health Evaluation for IBD, 191–92, 192t, 196
192t, 196 (APACHE) II scoring system, 430, 431t use in pregnancy, 264–65
5-HT (serotonin) receptor agonists, 90 acute porphyrias, 147 aminotransferases, 279
5-hydroxyindoleacetic acid (5-HIAA), 75 adalimumab, 193–94, 266 amoxicillin, 257
6-mercaptopurine, 265 adefovir, 291t ampicillin, 253, 262
6-MP, 193 adefovir dipivoxil, 258 amyloidosis, 115, 147b, 147f, 147, 148f, 150, 155
adenocarcinoma. See esophageal amyloidosis, secondary, 204
α1-antitrypsin deficiency, 345–47, 347f, 355t adenocarcinoma; gastric adenocarcinoma; anastomotic or staple line leaks (ASLs), 161
abdominal pain in IBS, medications for, 235 pancreatic ductal adenocarcinoma anastomotic strictures, gastrojejunal, 161
ablation, local, 308 adenoma, hepatic, 300–2, 302f ANCA (antineutrophil cytoplasmic antibody)-
abnormal liver test results. See liver test results, adenoma-carcinoma sequence in colon cancer, associated vasculitis, 140
abnormal 222f, 222 anesthetics, topical, 253–54
absent contractility, 38, 39f, 43 adenoma detection rate (ADR), 167t, 168 aneurysm
acetaminophen-induced hepatotoxicity, 322– adenovirus, enteric, 208 hepatic artery, 327f, 327
23, 369, 370f adventitia, 35 visceral artery, 140–41
achalasia afferent loop syndrome, 165 angioedema, 152f, 152
diagnosis, 39t, 40–41, 40t, 41f, 42f AFLP (acute fatty liver of pregnancy), 395 ankylosing spondylitis, 200
overview, 40 AIP (autoimmune pancreatitis), 437–38, 438t annular pancreas, 172, 173f
pathophysiology, 40 ALA (aminolevulinic acid) dehydratase anomalous pancreaticobiliary junction (APBJ),
therapy, 41–42 deficiency porphyria, 148 172f, 172
acid clearance in esophagus, 4 alanine aminotransferase (ALT), 279 anorectal manometry, 245, 246
acid exposure time, 12 albendazole, 262 antacids, 56, 255–56, 255t
acid regurgitation, 7–8, 8b albumin, 280, 339 anterior uveitis, 202
acid suppression therapy, 9–10 alcohol-related liver disease antibiotic-dependent chronic pouchitis, 195
acquired von Willebrand disease, 143 alcohol-related cirrhosis, 321–23 antibiotic prophylaxis, 170, 170t, 173,
acute acalculous cholecystitis, 458–59 epidemiology and clinical spectrum, 434
acute fatty liver of pregnancy (AFLP), 395 315–16 antibiotics
acute gastritis, 57–58, 58f ethanol metabolism and pathophysiology, in acute pancreatitis, 434
acute hepatitis, 280–81, 280t, 287, 368–69 316f, 316 for hepatic encephalopathy, 342
acute intermittent porphyria, 147–48 fatty liver, 317, 318f, 319b for IBD, 192
acute liver failure, 283–85, 283t, 293b severe alcohol-related hepatitis, 318–21, liver injury from, 369
acute mesenteric ischemia (AMI), 133t, 134– 319b, 320b for spontaneous bacterial peritonitis, 339
35, 134t, 135f alkaline phosphatase (ALP), 279 use in pregnancy, 253, 265
acute mesenteric venous thrombosis, 326 allograft dysfunction, 403, 404–5 antiemetics, 90
acute pancreatitis ALT (alanine aminotransferase), 279 antimicrobial agents for diarrhea, 211t
clinical presentation and diagnosis, 427–28, alternative therapies for IBS, 236 antineutrophil cytoplasmic antibody (ANCA)-
428b ambulatory pH monitoring for GERD, 10b, associated vasculitis, 140
etiology, 428–29, 429b 11b, 11–14, 13f antireflux surgery, 16–17
gallstone, 462 amebiasis, 215 antiretroviral agents, liver injury from,
medications in pregnancy, 257 American Joint Commission on Cancer system, 369–70
overview, 427 223, 224t antithrombotic agents, management of, 168b,
pathophysiology, 427 AMI (acute mesenteric ischemia), 133t, 134– 168–70, 169t, 170t
prognosis, 435 35, 134t, 135f anti-TNF agents, 193–94, 196–97
severity stratification, 430b, 430–32, 431t, 432f aminolevulinic acid (ALA) dehydratase aortic stenosis, 143
treatment, 432–35 deficiency porphyria, 148 aortoenteric fistulas, 129
471
472 Index
APACHE (Acute Physiology and Chronic Barcelona Clinic Liver Cancer (BCLC) staging carbohydrate malabsorption, 105–6
Health Evaluation) II scoring system, 430, and treatment system, 306, 307f carcinoid crisis, 73
431t bariatric surgery, 121, 388. See also Roux-en-Y carcinoid syndrome, 73, 75–76
APBJ (anomalous pancreaticobiliary junction), gastric bypass carcinoma, hepatocellular, 300, 304–9, 305f,
172f, 172 Barrett esophagus (BE) 306f, 307f
aphthous stomatitis, 201f, 201 epidemiology, 24, 26f cardiovascular diseases, GI manifestations of, 143
appendiceal neuroendocrine tumors, 74–75 general discussion, 23, 24f, 25f cathartic colon, 242
aprepitant, 90 pathophysiology, 23–24 cavernous hemangioma, 298f, 300, 301f
arc risk factors, 24–30, 28f, 30f CD. See Crohn disease
of Barkow, 133–34 BCS (Budd-Chiari syndrome), 328–30, 329b, CDP (contraction deceleration point), 38
of Buhler, 133–34 330t, 399 cecal intubation rate, 167t, 168
of Riolan, 133–34 Behçet disease (BD), 140, 141, 156, 157 cecal patch, 188, 190
arthritis benign liver masses, 300–4 celiac artery compression syndrome, 138–39,
axial, 200 benign rectoanal disease, 131 140f
peripheral, 199–200 benzocaine, 254 celiac disease
ascending cholangitis, 460–61, 461b benzodiazepines, 253 in CF, 151
ascites bile, 456 dermatitis herpetiformis, 111, 113f
evaluation, 335–36, 336b, 336t bile acid synthesis, 456 disorders associated with, 110t
hepatic hydrothorax, 337–38 bile reflux gastropathy, 62 general discussion, 109–11
overview, 335 biliary cirrhosis, primary, 259 histologic findings in, 111f, 112b, 112f
pathogenesis of, 335 biliary colic, mimics of, 466t manifestations of, 110t
refractory, 337–38 biliary disease, 144b, 398 cellular rejection, in liver transplant, 404
therapy for cirrhosis-associated ascites, biliary obstruction, 441, 448 certolizumab pegol, 193–94, 266
336b, 336–37 biliary sludge, 459–60 CF (cystic fibrosis), 150f, 150–51
ASLs (anastomotic or staple line leaks), 161 biliary stents, 172 Chagas disease, 40
aspartate aminotransferase (AST), 279 biliary strictures, 404 chelating agents, 349
aspirin, 53, 56, 57–58 biliary tract disease, in pregnancy, 257 chemical gastropathy, 62
astrovirus, 208 biliary tree infection, 460–61, 461b chest pain, in GERD, 8
asymptomatic cholelithiasis, 457–58 biliopancreatic limb, 160 Chicago Classification, 38, 39f, 40
atrophic chronic gastritis, 58–59, 58t, 59f, 60f, bilirubin, 279–80 Child-Turcotte-Pugh score, 280, 280t
66, 68 Billroth II surgery, 53–54, 54f, 67 cholangiocarcinoma, 298, 300, 309f, 309–11,
atrophy-hypertrophy complex, 309f, 309–10 biological therapy, in pregnancy, 266 310f, 360
attenuated familial adenomatous polyposis biopsy cholangiography, 172, 310, 465
(FAP), 226 in Barrett esophagus, 27–29 cholangitis. See also primary sclerosing
autoimmune atrophic gastritis, 58t, 59, 60f, 62 in cholangiocarcinoma, 310 cholangitis
autoimmune hepatitis in hereditary hemochromatosis, 352–53 ascending, 460–61, 461b
concurrent immune-mediated diseases, 376, liver, 282–83, 290, 291f, 369, 385–87, 386f recurrent pyogenic, 172, 174f, 461
378b biotin deficiency, 120 cholecystitis, 257, 458–59, 459b
diagnosis, 376–77, 377t, 378f, 378t, 379f bismuth, 257 choledocholithiasis, 257, 460f, 460, 463–64,
epidemiology, 375 black pigment gallstones, 457, 457t 464f
etiology, 375–76 Blastocystis hominis, 215 cholelithiasis, 203, 457–59, 464
IBD and, 203 bleeding, portal hypertensive cholescintigraphy, 463
liver transplant, 380 esophageal variceal bleeding, 331–33, 332t cholestatic liver disease. See also primary
pregnancy and, 396–97 gastric consequences leading to, 333–34 sclerosing cholangitis
presentation, 376, 376t overview, 331 abnormal liver test results, 281
relapse, 379 pathogenesis of portal hypertension, 331 causes of cholestasis, 282t
suboptimal response and treatment failure, bleeding risk, in endoscopy, 168b, 168–69 cholestatic hepatitis, 369
379 blue rubber bleb nevus syndrome (BRBNS), differential diagnosis, 357b, 358b
treatment, 377–79, 379f 144, 145f, 145 drug-induced cholestasis, 365, 369
autoimmune pancreatitis (AIP), 437–38, 438t bone disease, 361 management of complications of cholestasis,
autoimmune reaction, drug-induced, 365 botulinum toxin injections, 41, 91 361
axial arthropathy, 200 Bouveret syndrome, 462 overview, 357
azathioprine, 193, 196–97, 265 bowel wall thickening, 137 pregnancy and, 397
azithromycin, 262 Brooke ileostomy, 195f, 195 primary biliary cholangitis, 357–58, 359f
brown pigment gallstones, 457, 457t secondary sclerosing cholangitis, 358b,
Bacillus cereus, 215 Budd-Chiari syndrome (BCS), 328–30, 329b, 360–61
baclofen, 15 330t, 399 cholesterol gallstones, 457, 457t, 465f
bacterascites, 339, 340 budesonide, 192–93, 196 cholesterol metabolism, 456
bacterial infection in pregnancy, 399 chronic calcifying pancreatitis
bacterial overgrowth syndromes, 115–17, 116f, caffeine, 388 clinical features and natural history, 440
116t calcium deficiency, 163t complications, 440–41
bacterial peritonitis, spontaneous, 338f, Cameron lesions, 129 diagnosis, 439f, 439–40
338–40 Campylobacter jejuni, 209, 211t etiology and risk factors, 438–39, 438t
ballooned hepatocytes, 383, 385–86 cancer, colorectal. See colorectal cancer management, 441
balsalazide, 191–92, 192t Candida, 19, 20f overview, 437
Balthazar score, 432 candy cane syndrome, 165 chronic gastritis, 58–61
Index 473
chronic hepatitis, 281, 281t, 287, 368–69 colorectal neoplasia, 221, 224, 227 radiologic features, 188, 189f, 190
chronic hepatitis B infection, 288, 396, 397f common limb/channel, 160 risankizumab for, 194
chronic hepatitis C infection, 396 common variable immunodeficiency (CVID), surgery for, 195, 196f
chronic kidney disease, 153 152 treatment strategies for, 196–97
chronic mesenteric ischemia (CMI), 133t, complex fistula, 197 ustekinumab for, 194
135–36, 136b congenital gastrointestinal motility disorders, vedolizumab for, 194
chronic mesenteric venous thrombosis, 326 85–86 Cronkhite-Canada syndrome, 227
chronic obstructive pancreatitis, 437 connective tissue disease, 5. See also scleroderma cryptogenic cirrhosis, 382f, 383
chronic pancreatitis constipation Cryptosporidium, 211t, 214
clinical features and natural history, 440 assessment of colonic transit, 238–39 culture-negative neutrocytic ascites, 339
complications, 440–41 clinical assessment of, 239, 240b, 240t cutaneous porphyrias, 147, 148
diagnosis, 439f, 439–40 colonic motor physiology and CVID (common variable immunodeficiency),
etiology and risk factors, 438–39, 438t pathophysiology, 237–38, 238f 152
management, 441 definition and classification of, 239 Cyclospora cayetanensis, 211t
medications in pregnancy, 257 in IBS, 235–36 cyclosporine, 193, 260, 265
overview, 437–38 management of, 240–43, 241t cystic fibrosis (CF), 150f, 150–51
CI. See colonic ischemia practical classification of, 239–40, 241f cystic fundic gland polyp, 68
ciprofloxacin, 192 treatment in pregnancy, 260–61 Cystoisospora belli, 211t
cirrhosis constipation-predominant IBS, 239, 239t cysts, simple liver, 303–4, 304f
alcohol-related, 321–23 continent ileostomy, 195f, 195 cytomegalovirus (CMV), 19, 20f, 60f, 60, 398
ascites in, 335–38, 336b contraction deceleration point (CDP), 38
cryptogenic, 382f, 383 contrast dye, use in pregnancy, 254 DAAs (direct-acting antivirals), 293–96, 294f,
kidney function abnormalities in, 340–41 copper deficiency, 121, 163t 295t
NASH, 382f, 383, 389 copper toxicity, 347–50, 348f, 350t, 355t DCI (distal contractile integral), 38
pregnancy and, 397–98 coronavirus, 208 DDs (functional defecatory disorders), 243–46,
cisapride, 15, 255t, 256 Correa cascade, 66f, 66 245f
c-kit, 71 corticosteroids decompression, 90–91
clarithromycin, 257 for IBD, 192–93, 196 defecation, physiology of, 243, 244f
Clostridium difficile infections, 216f, 216–19, in severe alcohol-related hepatitis, 321 Degos disease, 145
217f, 218f, 218t use in pregnancy, 265 delayed gastric emptying, 88
Clostridium perfringens, 215 Cowden disease, 227, 228t delivery phase, 105, 106t
Clouse plot, 38 CRC. See colorectal cancer dermatitis herpetiformis, 111, 113f
CMI (chronic mesenteric ischemia), 133t, CREST syndrome, 5 dermatologic diseases, GI manifestations of,
135–36, 136b Crohn disease (CD) 146f, 146–47
CMV (cytomegalovirus), 19, 20f, 60f, 60, 398 aminosalicylates for, 191–92, 192t dermatologic manifestations of IBD, 200–1,
cobalamin deficiency, 119–20, 163t antibiotics for, 192 201b, 201f, 202f
colchicine, 243 anti-TNF agents for, 193–94 DES (distal esophageal spasm), 38, 39f, 39t, 43
colectomy, 195 azathioprine and 6-MP for, 193 DEXA (dual energy x-ray absorptiometry), 200
collagenous colitis, 189 clinical presentation, 185, 186 dexlansoprazole, 255t, 256
collagen vascular diseases, GI manifestations colorectal cancer and, 204b, 204 DI (distensibility index), 39–40
of, 154–55 corticosteroids for, 192–93 diabetes
colocolonic inhibitory reflexes, 238 cyclosporine for, 193 chronic pancreatitis and, 440
colonic inertia, 240 dermatologic manifestations, 200–1, 201b, gastrointestinal motility disorders and, 86, 86t
colonic ischemia (CI) 201f, 202f GI symptoms in, 153, 154
anatomical considerations, 136 diagnosis, 186 small-bowel diseases and, 115
bleeding in, 131 diet, 186 diarrhea. See also intestinal infections; small-
clinical manifestations of, 136 differential diagnosis, 189b, 189–90 bowel diseases
diagnosis of, 137f, 137, 138f, 139f endoscopic characteristics, 188f, 188, 190 in carcinoid syndrome, 73
epidemiology and pathogenesis, 136 environmental influences, 186 in IBS, 235
frequency of, 133t epidemiology, 185 malabsorption disorders, 107–8, 108t
treatment of, 137, 139t extraintestinal manifestations, 187, 187t in pregnancy, 262–64, 263t
colonic neuroendocrine tumors, 75 genetics, 185–86 in SIBO, 115–17
colonic relaxation, 238 hepatobiliary manifestations, 202b, 202–3 in VIPomas, 78–79
colonic transit, assessment of, 238–39, 245 histology, 188–89 diarrhea-predominant syndrome, 239
colonoscopy, quality metrics for, 167–68, 167t, JAK inhibitors for, 194 diet
168t laboratory findings, 187, 187t colorectal cancer and, 225
colon preparation, 167, 167t, 168t, 253 methotrexate for, 193 gastric adenocarcinoma and, 66–67
colorectal cancer (CRC) miscellaneous complications, 203b, 203–4 in IBD, 186
clinicial features, 221–23, 222f, 223f musculoskeletal manifestations, 199b, in IBS, 236
epidemiologic factors, 223–25 199–200 in severe alcohol-related hepatitis, 320–21
heritable syndromes, 225–27, 226b ocular manifestations, 202b, 202 dietary supplements, liver injury from, 370,
IBD and, 204b, 204 overview, 199 371b
overview, 221 ozanimod for, 195 Dieulafoy lesion, 130f, 130
prevention, 227–29, 228t pancreatic manifestations, 203 diffuse gastric vascular ectasia, 334
staging, 223, 224t physical examination, 187 diffuse large B-cell lymphoma (DLBCL), 70,
treatment of, 229 in pregnancy, 186, 264–67, 264t 71
474 Index
DILI. See drug-induced liver injury EGJ outflow obstruction, 42f, 42–43, 44 erythema nodosum (EN), 201, 202
direct-acting antivirals (DAAs), 293–96, 294f, Ehlers-Danlos syndrome (EDS), 141, 157 erythropoietic protoporphyria, 148f, 148
295t emphysematous cholecystitis, 462 Escherichia coli, 212–13, 213t
direct chemical toxicity, 364 EMR (endoscopic mucosal resection), 29, ESD (endoscopic submucosal
disconnected pancreatic duct syndrome, 435 31f dissection), 29
distal contractile integral (DCI), 38 EN (erythema nodosum), 201, 202 esomeprazole, 255t, 256
distal esophageal spasm (DES), 38, 39f, 39t, encapsulating peritoneal sclerosis (EPS), 153 esophageal adenocarcinoma (EAC)
43 encephalopathy, hepatic, 283, 283t, 341–42 Barrett esophagus and, 23, 26, 27
distal intestinal obstruction syndrome (DIOS), endocrine disorders, GI manifestations of, diagnosis and staging, 31–32, 32t
150f, 150–51 153–54 epidemiology, 30, 31f
distal latency (DL), 38 endometriosis, 157 risk factors for, 31
distensibility index (DI), 39–40 endoscopic eradication therapy, 29, 30 signs and symptoms of, 31
diuretic-intolerant ascites, 337 endoscopic mucosal resection (EMR), 29, 31f esophageal cancer
diuretic-resistant ascites, 337 endoscopic retrograde diagnosis and staging, 31–32, 32t
diverticular bleeding, 130–31 cholangiopancreatography (ERCP) epidemiology, 30, 31f
diverticulitis, 219–20 adverse events, 171 risk factors for adenocarcinoma, 31
DLBCL (diffuse large B-cell lymphoma), biliary stents, 172 risk factors for SCC, 30–31
70, 71 cholangiograms or pancreatograms, 172f, signs and symptoms, 31, 37
dolasetron, 255 172, 173f, 174f esophageal chest pain, 8
domperidone, 90, 255 for gallstones, 465f, 465–66 esophageal dysphagia, 37
donor pool, expansion of, 405 overview, 171–74 esophageal high-resolution manometry
doxycycline, 262–63 pancreatitis and, 429, 434 (HRM), 38f, 38, 39f, 41, 42f
drug-induced liver injury (DILI) endoscopic submucosal dissection esophageal motility
clinical epidemiology, 363–64 (ESD), 29 absent contractility, 43
clinical presentation, 366 endoscopic ultrasonography (EUS), 170–71, achalasia, 40–42, 40t, 41f, 42f
diagnosis, 366–68, 367f, 368b 171f, 171t anatomy, 35, 36f
drugs associated with, 369–71, 370f, endoscopy diagnostic criteria and therapeutic options
371b antibiotic prophylaxis, 170, 170t for, 39t
histologic patterns, 368–69 antireflux procedures, 16–17 distal esophageal spasm, 43
liver biopsy, 369 antithrombotic agents, 168b, 168–70, 169t, EGJ outflow obstruction, 42f, 42–43
mechanisms and classification, 364–65, 170t esophageal dysphagia, 37
364t in Barrett esophagus, 24, 26f, 27, esophageal HRM, 38f, 38, 39f
overview of drug metabolism, 363, 29–30 FLIP planimetry, 38–40, 40f
364b ERCP, 171–73, 172f, 173f, 174f hypercontractile esophagus, 43f, 43
pharmacogenetics, 372 EUS, 170–71, 171f, 171t normal physiology, 35–36
pregnancy and, 399 in GERD, 10b, 10–11, 11f opioid-induced esophageal dysmotility, 44
prognosis, 372 in IBD, 188f, 188 oropharyngeal dysphagia, 36–37, 37f, 37t
risk factors, 365–66 in non-UGI bleeding evaluation, 132 overview, 35
treatment, 371–72 in pregnancy, 252–54, 252t postfundoplication motor disorders, 43
dual energy x-ray absorptiometry (DEXA), quality metrics for colonoscopy, 167–68, post–obesity surgery esophageal
200 167t, 168t dysfunction, 43–44
dumping syndrome, 163–64 ENMZL (extranodal marginal zone B-cell esophageal variceal bleeding, 331–33, 332t
duodenal obstruction, 441, 448 lymphoma), 70, 71 esophagitis
dyspepsia, functional. See functional Entamoeba histolytica, 215 eosinophilic, 17–19, 18f, 19f
dyspepsia entecavir, 259, 291t infectious, 19, 20f
dysphagia enteric adenovirus, 208 pill-induced, 19–20
absent contractility, 43 enteric bacterial infections, 208–14, 209t, esophagogastric junction (EGJ), intestinal
achalasia, 40–42, 40t, 41f, 42f 210t, 211t, 212t metaplasia of, 23, 25f, 26–27
distal esophageal spasm, 43 enteric nervous system, 84 esophagogastroduodenoscopy (EGD), 37, 54
esophageal, 37 enteric neuropathic disorders, 86 ethanol metabolism, 316f, 316
in esophageal cancer, 31 enteric viral infections, 207–8 EUS (endoscopic ultrasonography), 170–71,
in GERD, 7 enterohepatic circulation, 456f, 456, 457 171f, 171t
opioid-induced esophageal dysmotility, 44 enteropathy-associated T-cell lymphoma evacuation proctography, 247
oropharyngeal, 36–37, 37f, 37t (EATL), 111 exercise, in IBS management, 236
postfundoplication motor disorders, 43 eosinophilic esophagitis (EoE), 17–19, 18f, extensive colitis, 191
post–obesity surgery esophageal 19f extraintestinal manifestations of IBD
dysfunction, 43–44 eosinophilic gastritis, 58t, 61, 62f dermatologic, 200–1, 201b, 201f, 202f
eosinophilic gastroenteritis, 113–14 hepatobiliary, 202b, 202–3
EAC. See esophageal adenocarcinoma epidermolysis bullosa, 146, 147 miscellaneous, 203b, 203–4
EATL (enteropathy-associated T-cell epigastric pain syndrome, 91–92 musculoskeletal, 199b, 199–200
lymphoma), 111 episcleritis, 202 ocular, 202b, 202
EBV (Epstein-Barr virus), 398 epithelial cells, 51, 52f overview, 187, 187t, 199
Eckardt score, 40, 40t EPS (encapsulating peritoneal sclerosis), 153 pancreatic, 203
EGD (esophagogastroduodenoscopy), 37, 54 Epstein-Barr virus (EBV), 398 extranodal marginal zone B-cell lymphoma
EGJ (esophagogastric junction), intestinal ERCP. See endoscopic retrograde (ENMZL), 70, 71
metaplasia of, 23, 25f, 26–27 cholangiopancreatography extrinsic neuropathic disorders, 86, 86t
Index 475
familial adenomatous polyposis (FAP), overview, 455 gastroenteritis, 210

225–26, 228t pregnancy and, 398 gastroenteritis, eosinophilic, 113–14
familial pancreatic cancer kindreds, 444–45 Gardner syndrome, 225–26 gastroenteropancreatic neuroendocrine tumors
familial visceral myopathy type II, 87 gastric acid, hypersecretion of, 53–54, 54f (NETs), 72–73
famotidine, 56, 255t, 256 gastric adenocarcinoma gastroesophageal reflux disease (GERD)
fat malabsorption, 106–7 clinical features, 68 Barrett esophagus and, 25
fat-soluble vitamins, 120–21 epidemiology, 65–66 contributing factors, 4–5
fat sparing, 304 pathogenesis, 66f, 66 defined, 3
fat stranding, 137 risk factors, 66–68, 67b, 68b, 68t diagnosis of, 8–14, 9f, 10b, 11b, 11f, 13f
fatty liver, alcoholic, 317, 318f, 319b staging, 69–70, 69t eosinophilic esophagitis, 17–19, 18f, 19f
fecal incontinence, 243, 246–49, 247f, 248f treatment and prognosis, 70 epidemiology of, 5–6, 6f, 7f
fentanyl, 252 tumor features, 68–69, 69f etiology, 3b, 3, 4f
fiber supplementation, 240–42, 248 gastric antral vascular ectasia (GAVE), 62, functional heartburn, 16
fidaxomicin, 263 63f, 130 infectious esophagitis, 19, 20f
fish-mouth papilla, 450f, 451 gastric atrophy, 66 mechanism for extraesophageal symptoms
fish oil supplements, 266–67 gastric bypass, Roux-en-Y. See Roux-en-Y of, 4–5
fistulas gastric bypass medications in pregnancy, 255–57, 255t
aortoenteric, 129 gastric electrical stimulation, 91 pill-induced esophagitis, 19–20
complex, 197 gastric emptying, 84–85, 85f refractory reflux disease, 16b, 16
gastrogastric, 164 gastric factors, in GERD, 4–5 surgical and endoscopic antireflux
hepatic artery–portal vein, 327 gastric intestinal metaplasia (GIM), 66 procedures, 16–17
FLIP (functional lumen imaging probe) gastric lymphoma, 70–71, 71f symptoms of, 7–8, 8b, 8f
planimetry, 38–40, 40f gastric motility, 84–85 treatment for, 14–15, 14t, 15f
flumazenil, 253 gastric neoplasms. See also gastric gastroesophageal scintigraphy, 14
fluorescence in situ hybridization (FISH), adenocarcinoma gastroesophageal varices, 333
310f, 310 frequency of, 65t gastrogastric fistula, 164
flushing, in carcinoid syndrome, 73 gastric lymphoma, 70–71, 71f gastrointestinal manifestations of systemic
focal fat, 304 gastroenteropancreatic NETs, 72–73 disease
focal nodular hyperplasia, 300, 302–3, 303f GISTs, 71–72, 72f cardiovascular diseases, 143
focal segmental ischemia (FSI), 133t, 138, metastatic disease to the stomach, 80, 81f dermatologic diseases, 146f, 146–47
139f NETs and carcinoid syndrome, 73–75, 73t, endocrine disorders, 153–54
folic acid deficiency, 120, 163t 74t, 76t gynecologic conditions, 157
food poisoning, 215, 215t overview, 65 hematologic disorders, 147b, 147f, 147–49,
functional biliary sphincter of Oddi disorder, PNETs, 76–80, 76t, 77f 148f, 149f
461–62, 462b gastric neuroendocrine tumors, 74, 75 immunologic disorders, 152f, 152
functional constipation, 239, 239t gastric peroral endoscopic myotomy miscellaneous conditions, 157
functional defecatory disorders (DDs), (G-POEM), 91 neuromuscular disorders, 154
243–46, 245f gastric polyps, 68 oncologic disorders, 154
functional dyspepsia gastric pouch, 159 overview, 143
definition, 91–92 gastric remnant, 160 pulmonary disorders, 150f, 150–51
diagnostic and treatment algorithms for, 93f gastric varices, 333 renal diseases and hemodialysis, 153f, 153
evaluation and therapy recommendations, gastric vascular ectasia, 62, 63f, 64, 334f, 334 rheumatologic and collagen vascular
93–94 gastrinomas diseases, 154–55
overview, 91 clinical features, 76, 77f systemic lupus erythematosus, 155–56
pathophysiology, 92–93 diagnostic tests, 76–77, 78f vascular diseases, 144–45, 145f
proposed causes of, 91t etiology and pathogenesis, 76, 77f vasculitides, 156f, 156–57
Rome IV criteria for, 91, 92b overview, 76, 76t gastrointestinal motility disorders. See also
functional gallbladder disorder, 461b, 461–62 treatment, 77 gastroparesis
functional heartburn, 12, 16 gastritis congenital disorders, 85–86
functional lumen imaging probe (FLIP) acute, 57–58, 58f enteric or intrinsic neuropathic disorders, 86
planimetry, 38–40, 40f atrophic chronic, 58–59, 59f, 60f extrinsic neuropathic disorders, 86, 86t
functional PNETs, 76 autoimmune atrophic, 59, 60f, 62 functional dyspepsia, 91–94, 91t, 92b, 93f
furazolidone, 263 chronic, 58–61 gastrointestinal neuromuscular function,
definition, 57 83–85, 84f, 85f
gallbladder dyskinesia, 461–62 diagnosis, 57, 58f overview, 83
gallbladder polyps, 459, 465f, 465 eosinophilic, 61, 62f smooth muscle disorders, 86–87
gallstone ileus, 462 infectious, 59–60, 60f gastrointestinal neuromuscular function,
gallstone pancreatitis, 462 lymphocytic, 61f, 61 83–85, 84f, 85f
gallstones multifocal atrophic, 58, 59f gastrointestinal stromal tumors (GISTs),
clinical investigations, 463–66, 464f, 465f nonatrophic chronic, 58, 59f 71–72, 72f
clinical presentation and complications, noninfectious granulomatous, 60–61, 61f gastrointestinal tract, vascular disorders of.
457–63, 459b, 460f, 461b, 462b Sydney System for classification of, 58t See vascular disorders of gastrointestinal
embryology, anatomy, and physiology, gastrocolic reflex, 237 tract
455–56, 456f gastroduodenal manometry, 88f, 88 gastrointestinal tract bleeding
epidemiology and pathogenesis, 457, 457t, gastroenteric neuroendocrine tumors non-UGI bleeding, 130–32
458b, 458f (GNETs), 72–73, 80 UGI bleeding, 127b, 127–30, 130f
476 Index
gastrojejunal anastomosis ulceration, 161–62 functional dyspepsia and, 92, 93–94 hepatitis D virus (HDV), 288t, 292
gastrojejunal anastomotic strictures, 161 gastric adenocarcinoma and, 67 hepatitis E, 296
gastroparesis gastric lymphoma and, 70, 71 hepatobiliary manifestations of IBD, 202b,
classification of, 85t GERD and, 5 202–3
overview, 85 lymphocytic gastritis and, 61 hepatocellular adenomas (HCAs), 301–2
presentation and diagnosis of, 87–89, 89f and NSAIDs, 53 hepatocellular carcinoma (HCC)
treatment of, 89–91 overview, 51 definition, 300
gastropathy pregnancy and, 255t hereditary hemochromatosis and, 351
chemical, 62 PUD and, 52–53, 53f management of, 306–9, 307f
definition, 57 treatment, 55–56, 55t nonalcoholic fatty liver disease and, 389
hypertrophic, 62–63 UGI bleeding and, 129 overview, 304–5
portal hypertensive, 62, 63f, 129, 333–34 HELLP syndrome, 395–96 risk factors, 298
vascular, 62, 63f hemangioma, cavernous, 298f, 300, 301f surveillance and diagnosis, 305f, 305–6,
GAVE (gastric antral vascular ectasia), 62, hematologic disorders, GI manifestations of, 306f
63f, 130 147b, 147f, 147–49, 148f, 149f hepatocellular disorders, 280–81, 280t, 281t
genetics hemobilia, 129 hepatocyte ballooning, 383, 385–86
in alcohol-related liver disease, 316 hemochromatosis, hereditary, 350–55, 352f, hepatocytes, ground-glass, 290
in colorectal cancer, 225–27, 226b 353f, 354t, 355t hepatopathy, ischemic, 327
in drug-induced liver injury, 372 hemochromatosis arthropathy, 351f, 351 hepatorenal syndrome (HRS), 340–41
in gastric adenocarcinoma, 67b, 67, 68t hemodialysis, 153 herbal supplements, liver injury from, 370,
in IBD, 185–86 hemorrhage, after RYGB, 161 371b
in pancreatic ductal adenocarcinoma, hemostasis, therapeutic agents for, 254 hereditary colorectal cancer genetic
444–45, 444t hemosuccus pancreaticus, 129 syndromes, 225–27, 226b
GERD. See gastroesophageal reflux disease Henoch-Schönlein purpura (HSP), 139–40, hereditary coproporphyria, 148
giant migrating complex, 84 156f, 156–57 hereditary diffuse gastric cancer (HDGC),
Giardia lamblia, 211t, 214 hepatic adenoma, 300–2, 302f 67b, 67, 68
giardiasis, 152 hepatic arterial inflow disorders, 325b, 326–28 hereditary hemochromatosis, 350–55, 352f,
GIM (gastric intestinal metaplasia), 66 hepatic arterial outflow disorders, 325b, 353f, 354t, 355t
ginger, 254 328–30 hereditary hemorrhagic telangiectasia (HHT),
GISTs (gastrointestinal stromal tumors), hepatic artery aneurysm, 140–41, 327f, 327 144b, 144f, 144, 145, 327–28
71–72, 72f hepatic artery–portal vein fistulas, 327 hereditary nonpolyposis colorectal cancer
glucagon, 253 hepatic artery thrombosis, 326, 404 (HNPCC), 226b, 226
glucagonomas, 79–80 hepatic decompensation, 402 hereditary pancreatitis, 444, 444t
GNETs (gastroenteric neuroendocrine hepatic encephalopathy, 283, 283t, 341–42 hernias, internal, 162
tumors), 72–73, 80 hepatic hemangioma, 300 herpes simplex virus (HSV), 19, 20f, 398
golimumab, 193–94, 266 hepatic hydrothorax, 337–38 Heyde syndrome, 143
G-POEM (gastric peroral endoscopic hepatic steatosis, 381, 381t, 382, 384–85, 385f HHT (hereditary hemorrhagic telangiectasia),
myotomy), 91 hepatitis. See also specific viruses 144b, 144f, 144, 145, 327–28
graft-vs-host disease (GVHD), 154 acute, 280–81, 280t, 287 high-amplitude propagated contractions, 237
granisetron, 255 autoimmune, 375–80, 396–97 high-grade dysplasia (HGD), 27, 28f, 29–30, 30f
granuloma, 189 cholestatic, 369 high-output heart failure, 144b
granulomatous gastritis, 58t, 60–61, 61f chronic, 281, 281t, 287 high-resolution manometry (HRM), 38f, 38,
ground-glass hepatocytes, 290 DILI and, 368–69 39f, 41, 42f
gynecologic conditions, GI manifestations severe alcohol-related, 318–21, 319b, 320b histamine receptor antagonists, 255t
of, 157 treatment in pregnancy, 257–59 HIV, 296
hepatitis A virus (HAV), 287–88, 288t, 398 HNPCC (hereditary nonpolyposis colorectal
H2-receptor blockers, 15, 56 hepatitis B virus (HBV) cancer), 226b, 226
hamartomatous polyposis syndromes, 227 clinical presentation and natural history, hospitalization, small-bowel diseases in, 115
harmless acute pancreatitis score, 430 282–89, 289f, 289t HRS (hepatorenal syndrome), 340–41
HAV (hepatitis A virus), 287–88, 288t, 398 comparison of viruses, 288t HSP (Henoch-Schönlein purpura), 139–40,
HBeAg-positive chronic hepatitis B phase, diagnostic tests, 280–90, 290t, 291f 156f, 156–57
288–89 epidemiology, 288 HSV (herpes simplex virus), 19, 20f, 398
HBV. See hepatitis B virus HIV and, 296 hydrothorax, hepatic, 337–38
HCAs (hepatocellular adenomas), 301–2 pregnancy and, 396, 397f, 398 hyperbilirubinemia, 281–82
HCC. See hepatocellular carcinoma treatment, 280–81, 291t hypercholesterolemia, 361
HCV. See hepatitis C virus hepatitis C virus (HCV) hypercontractile esophagus, 38, 39f, 39t, 43f,
HDGC (hereditary diffuse gastric cancer), clinical presentation and natural history, 43
67b, 67, 68 292f, 292–93 hyperemesis gravidarum, 392
HDV (hepatitis D virus), 288t, 292 comparison of viruses, 288t hypergastrinemia, 77
heartburn, 7–8, 8b diagnostic tests, 293f, 293 hyperparathyroidism, 154
heart failure, 143, 144 epidemiology, 292 hyperplasia, focal nodular, 300, 302–3, 303f
Helicobacter pylori infection HIV and, 296 hypersecretion of gastric acid, 53–54, 54f
acute gastritis and, 57 pregnancy and, 295, 396, 398 hypersensitivity drug reaction, 365
chronic gastritis and, 58, 59 prevention, 295–96 hyperthyroidism, 154
diagnosis of, 54–55, 54t screening, 293 hypertriglyceridemia, 428–29
esophageal adenocarcinoma and, 31 treatment, 293–95, 294f, 294t, 295t hypertrophic gastropathy, 62–63, 68
Index 477
hyponatremia, 340 inflammatory diarrhea, 107–8

hypothyroidism, 154 infliximab, 193–94, 196–97, 266 janus kinase (JAK) inhibitors, 194
insulinomas, 77–78 juvenile polyposis syndrome, 227, 228t
IBD. See inflammatory bowel disease integrated relaxation pressure (IRP), 38
IBD colitis, unclassified type, 185 interdigestive migrating motor complex, 84f, Kayser-Fleischer rings, 348f, 348
IBS. See irritable bowel syndrome 84 King’s College criteria, 284, 293b
ICP (intrahepatic cholestasis of pregnancy), interface hepatitis, 377, 378f Klippel-Trénaunay-Weber (KTW) syndrome,
392–95 interferon, 259 144–45, 146
idiopathic duct-centric pancreatitis, 438 internal hernias, 162 Kock pouch, 195f, 195
idiosyncratic hepatotoxic reactions, 365 International Club of Ascites, 340
ileal pouch–anal anastomosis (IPAA), 195f, interstitial edematous pancreatitis, 431–32 LA (Los Angeles) classification system, 10,
195 interstitial nephritis, 204 11f, 11
IMA (inferior mesenteric artery), 133–34 intestinal dysmotility, 147b lactulose, 242, 342
immune tolerant phase of hepatitis B intestinal infections lamivudine, 258, 291t
infection, 288 Campylobacter jejuni, 209 lansoprazole, 255t, 256
immunoglobulin A (IgA) vasculitis, 139f, Clostridium difficile, 216f, 216–19, 217f, laparoscopic Heller myotomy (LHM), 41
139–40, 156f, 156–57 218f, 218t laryngeal stenosis, 6f
immunologic disorders, GI manifestations of, diverticulitis, 219–20 laxatives, 242
152f, 152 enteric bacterial, 208–14, 209t, 210t, 211t, left-sided ulcerative colitis, 191
immunomodulators, use in pregnancy, 265–66 212t LES (lower esophageal sphincter), 3–4,
immunosuppression, in liver transplantation, enteric viral, 207–8 35–36, 38f, 38, 41
403, 404t Escherichia coli, 212–13, 213t LGD (low-grade dysplasia), 27, 28f, 29
inactive carrier phase, 288 food poisoning, 215, 215t lichen planus, 146f, 146–47
indeterminate colitis, 185 overview, 207 lidocaine, 253
ineffective esophageal motility, 38, 39f, 39t parasitic intestinal, 214–15 linaclotide, 243
infections, intestinal. See intestinal infections Salmonella, 209–10, 212b, 212t linitis plastica, 66, 68, 69
infectious diarrhea, in pregnancy, 262–64, 263t Shigella, 211–12 lipase, pancreatic, 106–7
infectious esophagitis, 19, 20f traveler’s diarrhea, 215 lipid-lowering agents, 370–71
infectious gastritis, 58t, 59–60, 60f Vibrio, 214 lipotoxicity, 383
inferior mesenteric artery (IMA), 133–34 Yersinia enterocolitica, 214 Listeria monocytogenes, 215
inflammatory back pain, 200 intestinal lymphangiectasia, 114–15, 115f liver biopsy, 282–83, 290, 291f, 369, 385–87,
inflammatory bowel disease (IBD) intestinal metaplasia of cardia/EGJ, 23, 25f, 386f
aminosalicylates for, 191–92, 192t 26–27 liver disease. See also alcohol-related liver
antibiotics for, 192 intestinal pseudo-obstruction disease; cholestatic liver disease;
anti-TNF agents for, 193–94 classification of, 85t metabolic liver diseases; pregnancy, liver
azathioprine and 6-MP for, 193 overview, 85 disease in; vascular diseases of liver
bleeding in, 131 presentation and diagnosis of, 87–89, 89f abnormal liver test results, 279–80, 280t
clinical presentations, 186–90, 187t, 188f, treatment of, 89–91 acute liver failure, 283–85, 283t, 293b
189b, 189f intestinal resections, 108–9 general approach to abnormal test results,
colorectal cancer and, 204b, 204, 224, 228t intraductal papillary mucinous neoplasm 282b, 282
corticosteroids for, 192–93 characteristics of, 449t hepatocellular disorders, 280–81, 280t, 281t
cyclosporine for, 193 general discussion, 450f, 451 hyperbilirubinemia, 281–82
dermatologic manifestations, 200–1, 201b, management of, 451–53, 452f liver biopsy, 282–83
201f, 202f overview, 444 in pregnancy, 257–60, 258t
diagnosis, 186 risk stratification of suspected, 453b Liver Imaging Reporting and Data System
diet, 186 intrahepatic cholestasis of pregnancy (ICP), (LI-RADS), 305f, 305
environmental influences, 186 392–95 liver mass lesions
epidemiology, 185 intrinsic neuropathic disorders, 86 benign, 300–4
genetics, 185–86 IPAA (ileal pouch–anal anastomosis), 195f, cavernous hemangioma, 298f, 300, 301f
hepatobiliary manifestations, 202b, 202–3 195 cholangiocarcinoma, 300, 309f, 309–11, 310f
JAK inhibitors for, 194 iritis, 202 clinical classification of, 298b
methotrexate for, 193 iron deficiency, 121, 163t evaluation, 297–300, 299f
miscellaneous complications, 203b, 203–4 iron metabolism, 351 focal fat or fat sparing, 304
musculoskeletal manifestations, 199b, IRP (integrated relaxation pressure), 38 focal nodular hyperplasia, 300, 302–3, 303f
199–200 irritable bowel syndrome (IBS) hepatic adenoma, 300–2, 302f
ocular manifestations, 202b, 202 diagnosis, 231b, 231, 232f, 233 hepatic hemangioma, 300
overview, 185, 191, 199 epidemiology, 231–32 hepatocellular carcinoma, 300, 304–9,
ozanimod for, 195 health care use, 236 305f, 306f, 307f
pancreatic manifestations, 203 management of, 233–36, 234f liver metastases, 300, 312
pregnancy, 186 overview, 231 malignant, 304–12
in pregnancy, 264–67, 264t pathogenesis, 233 overview, 297
risankizumab for, 194 in pregnancy, 260–62, 261t simple liver cysts, 303–4, 304f
surgery for, 195f, 195, 196f prognosis, 233 liver metastases, 300, 312
treatment strategies for, 196–97 risk factors, 232–33 liver test results, abnormal
ustekinumab for, 194 ischemia, colonic. See colonic ischemia alkaline phosphatase, 279
vedolizumab for, 194 ischemic hepatopathy, 327 aminotransferases, 279
478 Index
liver test results, abnormal (cont.) malignant melanoma, 80, 81f misoprostol, 243
bilirubin, 279–80 Mallory-Weiss tears, 129 mitochondrial neurogastrointestinal
definitions and prevalence, 279 MALS (median arcuate ligament syndrome), encephalomyopathy, 87
general approach to, 282b, 282 138–39, 140f mixed hepatocellular-cholestatic injury, 369
platelet count and other tests, 280 MAP (MUTYH-associated polyposis), 227, Model for End-stage Liver Disease (MELD),
prothrombin time and albumin, 280 228t 280, 306–8, 320, 402–3
scoring systems to assess liver disease marginal artery of Drummond, 133–34 modified Marshall scoring system, 431
severity, 280, 280t marginal ulceration, 161–62 monomicrobial nonneutrocytic bacterascites,
liver transplant Marsh (Oberhuber) classification, 109–10, 339
allocation of organs, 402–3, 403t 112f motility disorders, esophageal. See esophageal
in autoimmune hepatitis, 380 mastocytosis, systemic, 149, 150 motility
cholangiocarcinomas and, 311 MDF (Maddrey discriminant function), motility disorders, gastrointestinal. See
complications after, 403–5 319–20, 320b gastrointestinal motility disorders
contraindications to, 403b Meckel diverticulum, 131 MR proctography, 245
expansion of donor pool, 405 median arcuate ligament syndrome (MALS), mucinous cystic neoplasm, 449t, 450f, 450–51,
in hepatic encephalopathy, 342 138–39, 140f 452f
hepatocellular carcinoma and, 306 megamitochondria, 320 mucosa, 4, 35
immunosuppression, 403, 404t melanosis coli, 242 mucosal erosive disease, 129
indications for, 401b, 401–2, 402b MELD (Model for End-stage Liver Disease), mucosal phase, 105, 106t
King’s College criteria for, 293b 280, 306–8, 320, 402–3 Muir-Torre syndrome, 226
overview, 401 MEN (multiple endocrine neoplasia) multichannel intraluminal impedance, 12–14,
pregnancy and, 260, 398 syndrome, 73 13f
in severe alcohol-related hepatitis, 321 Ménétrier disease, 62–63, 64, 68 multifocal atrophic gastritis, 58, 58t, 59f
in Wilson disease, 350 MEOS (microsomal ethanol-oxidizing multiple endocrine neoplasia (MEN)
local ablation, 308 system), 316f, 316–17 syndrome, 73
long-segment BE, 23, 24, 25f meperidine, 252 multiple sclerosis, 86, 154
Los Angeles (LA) classification system, 10, mesalamine, 191–92, 192t muscular dystrophies, 154
11f, 11 mesenteric hernia, 162 muscularis propria, 35
lower esophageal sphincter (LES), 3–4, mesenteric infarction, 134–35, 135f musculoskeletal manifestations of IBD, 199b,
35–36, 38f, 38, 41 mesenteric ischemia (MI) 199–200
low-grade dysplasia (LGD), 27, 28f, 29 acute, 134–35, 134t, 135f MUTYH-associated polyposis (MAP), 227, 228t
lubiprostone, 242 chronic, 135–36, 136b MWA (microwave ablation), 308
luminal phase, 105, 106t colonic, 136–37, 137f, 138f, 139f, 139t mycobacterium tuberculosis, 59
lupus enteritis, 140f, 140 definition, 133 mycophenolate mofetil, 260
lymphangiectasia, intestinal, 114–15, 115f focal segmental, 138, 139f
lymphocytic colitis, 189 mesenteric vascular anatomy, 133–34 nadolol, 260
lymphocytic gastritis, 58t, 61f, 61 types and frequencies of, 133–34 NAFL (nonalcoholic fatty liver), 381–82, 382f
lymphoma, gastric, 70–71, 71f mesenteric vasculitis, 140 NAFLD. See nonalcoholic fatty liver disease
lymphoplasmacytic sclerosing pancreatitis, mesenteric venous thrombosis, 134, 326 naloxone, 252–53
437 mesocolic hernia, 162 NASH. See nonalcoholic steatohepatitis
Lynch syndrome, 226b, 226, 228t metabolic dysfunction–associated fatty liver NASH cirrhosis, 382f, 383, 389
disease (MAFLD), 381, 382 natalizumab, 266
macroamylasemia, 428 metabolic liver diseases nausea, management in pregnancy, 254–55,
Maddrey discriminant function (MDF), α1-antitrypsin deficiency, 345–47, 347f, 254t
319–20, 320b 355t necrolytic migratory erythema, 79, 80
MAFLD (metabolic dysfunction–associated hereditary hemochromatosis, 350–55, 352f, necrotizing pancreatitis, 431–32, 432f, 434
fatty liver disease), 381, 382 353f, 354t, 355t neoplasms. See also colorectal neoplasms;
magnetic resonance overview, 345b, 345 gastric neoplasms; pancreatic cystic
cholangiopancreatography, 465 Wilson disease, 347–50, 348f, 350t, 355t neoplasms
magnetic resonance enterography, 188, 189f metastases, liver, 300, 312 non-UGI bleeding and, 131
malabsorptive disorders metastatic Crohn disease, 201 UGI bleeding and, 129
carbohydrate malabsorption, 105–6 metastatic disease to the stomach, 80, 81f neostigmine, 90
diarrhea, 107–8, 108t methotrexate, 193, 265 nephrolithiasis, 164, 203
fat malabsorption, 106–7 metoclopramide, 15, 90, 254, 255t, 256 neuroendocrine tumors (NETs)
intestinal resections and shortened bowel, metronidazole, 192, 257, 263 appendiceal, 74–75
108–9 MI. See mesenteric ischemia carcinoid syndrome and, 73
mechanisms of, 106t microbiome, in IBS management, 235 clinical and tumor features, 73, 73t
overview, 105 microlithiasis, 459–60, 464f, 464–65 colonic, 75
protein malabsorption, 107b, 107 microscopic colitis, 189 diagnosis of, 75–76
maldigestion, 105, 106t microsomal ethanol-oxidizing system gastric, 74, 74t
malignant atrophic papulosis, 145 (MEOS), 316f, 316–17 gastroenteropancreatic, 72–73
malignant liver masses microwave ablation (MWA), 308 pancreatic, 76–80, 76t, 77f
cholangiocarcinoma, 309f, 309–11, 310f Milan Criteria, 402b, 402 rectal, 75
hepatocellular carcinoma, 304–9, 305f, milk of magnesia, 242 small intestinal, 74
306f, 307f minerals, 121 WHO histopathologic classification of,
liver metastases, 312 Mirizzi syndrome, 462 75–76, 76t
Index 479
neurologic manifestations of Wilson disease, obstructive sleep apnea, 5 pathogenesis, 73

348 octreotide, 90 somatostatinomas, 80
neuromuscular control of gastrointestinal ocular manifestations VIPoma, 78–79
system, 83–84 of IBD, 202b, 202 pancreatitis, 203, 257. See also acute
neuromuscular disorders, GI manifestations of Wilson disease, 348f, 348 pancreatitis; chronic pancreatitis
of, 154 oculogastrointestinal muscular dystrophy, 87 pancreatograms, 172
niacin deficiency, 120 odynophagia, 7 pantoprazole, 255t, 256
Nissen fundoplication, 16–17 olsalazine, 191–92, 192t paracentesis, 339
nizatidine, 56, 255t, 256 omeprazole, 255t, 256 paraneoplastic syndromes, 157
nodular regenerative hyperplasia, 149f, 149, oncologic disorders, GI manifestations of, 154 parasitic intestinal infections, 211t, 214–15
365 ondansetron, 90, 255 parathyroid disease, 154
NOMI (nonocclusive mesenteric ischemia), 134 opioid-induced esophageal dysmotility, 43, 44 parietal cells, 51, 52f
nonacid reflux, detection of, 12–14, 13f oral lesions, 201f, 201 Parkinson disease, 86, 154
nonalcoholic fatty liver (NAFL), 381–82, 382f Organ Procurement and Transplantation pauciarticular (type 1) peripheral
nonalcoholic fatty liver disease (NAFLD) Network (OPTN), 402b, 402 arthropathies, 187
causes of hepatic steatosis, 381t organs, allocation of, 402–3, 403t PCI (pneumatosis cystoides intestinalis), 155
clinical manifestations, 383–86, 383t, 385f, oropharyngeal dysphagia, 36–37, 37f, 37t PCLs. See pancreatic cystic lesions
386f Osler-Weber-Rendu syndrome, 144b, 144f, 144 PCNs. See pancreatic cystic neoplasms
definition, 315, 381–82, 382f osmotic diarrhea, 108, 108t PD (pneumatic dilation), 41
diagnosis, 386–87 osteoporosis, 200, 361 PDAC. See pancreatic ductal adenocarcinoma
DILI and, 366 ozanimod, 195, 266 peginterferon, 290
epidemiology, 382 PEI (percutaneous ethanol injection), 308
hepatocellular carcinoma screening, 389 PAN (polyarteritis nodosa), 139, 156, 157 peliosis hepatis, 365
pathogenesis, 382–83 pancolitis, 191 pelvic floor function disorders
preventing, 387 pancreatic cancer. See pancreatic ductal fecal incontinence, 246–49, 247f, 248f
prognosis, 387 adenocarcinoma functional defecatory disorders, 243–46,
staging, 387 pancreatic cholera, 78–79 245f
treatment, 387–89, 388b pancreatic cystic lesions (PCLs). See also overview, 243
nonalcoholic steatohepatitis (NASH) pancreatic cystic neoplasms physiology of defecation, 243, 244f
definition, 381–82, 382f characteristics of, 449f pelvic MRI, 248
pathogenesis, 383 classification and histology, 448b, 449 penicillamine, 259, 350t
prevention, 387 management of, 451–53, 452f pentoxifylline, 321
prognosis, 387 overview, 444, 449 PEP (post-ERCP pancreatitis), 171, 173
treatment, 387–89, 388b pancreatic cystic neoplasms (PCNs) peptic ulcer disease (PUD)
nonatrophic chronic gastritis, 58, 58t, 59f intraductal papillary mucinous neoplasm, clinical features, 54
nonerosive reflux disease, 10 450f, 451, 453b diagnosis, 54–55, 54t
nonfunctional PNETs, 76 management of, 451–53, 452f epidemiology, 51
non-HFE hereditary iron overload disorders, mucinous cystic neoplasm, 450f, 450–51 etiology, 52–54, 53f
354t, 355 overview, 449 follow-up and maintenance therapy, 56
noninfectious granulomatous gastritis, 58t, serous cystic neoplasm, 449f, 449–50 overview, 51
60–61, 61f solid pseudopapillary neoplasm, 451f, 451 pathophysiology, 51, 52f
noninflammatory diarrhea, 108 pancreatic divisum, 172, 173f in pregnancy, 56, 257
nonocclusive mesenteric ischemia (NOMI), pancreatic ductal adenocarcinoma (PDAC) prevention, 56
134 chronic calcifying pancreatitis and, 441 treatment, 55–56, 55t
nonselective β-blockers (NSBBs), 332, 333 diagnosis, 445–47, 446f peptic ulcers, 51, 128–29
nonsteroidal anti-inflammatory drugs overview, 443 percutaneous ethanol injection (PEI), 308
(NSAIDs), 53, 56, 57–58, 131, 189–90 pathology, 445f, 445 percutaneous transhepatic cholangiography, 465
non-UGI bleeding, 130–32 risk factors for development of, 443–45, perianal fistulas, 197
nonvariceal gastrointestinal tract bleeding 444t peripheral arthropathy, 187, 199–200
non-UGI bleeding, 130–32 staging, 443t, 444t, 447 peritoneal dialysis, 153
UGI bleeding, 127b, 127–30, 130f treatment, 447–48 peritonitis, spontaneous bacterial, 338f,
norovirus, 208 pancreatic lipase, 106–7 338–40
novel oral anticoagulant agents, 169–70, 170t pancreatic manifestations of IBD, 203 peroral endoscopic myotomy (POEM), 41–42
nudix hydrolase 15 (NUDT15), 193 pancreatic neoplasms. See pancreatic Petersen hernia, 162
nutritional disorders cystic lesions; pancreatic ductal Peutz-Jeghers syndrome, 227, 228t
bariatric surgery and, 121 adenocarcinoma PG (pyoderma gangrenosum), 201f, 201, 202
fat-soluble vitamins, 120–21 pancreatic neuroendocrine tumors (PNETs) phasic colonic contractions, 237
minerals, 121 clinical features, 73 PHH (postprandial hyperinsulinemic
overview, 119 epidemiology, 72 hypoglycemia), 164
after RYGB, 162–63, 163t functional, 76, 76t phlegmonous gastritis, 59
water-soluble vitamins, 119–20 gastrinomas, 76–77, 76t, 77f, 78f pH monitoring for GERD, 10b, 11b, 11–14,
glucagonomas, 79–80 13f
Oberhuber (Marsh) classification, 109–10, insulinomas, 77–78 phosphorus deficiency, 121
112f management principles for, 80 pigment gallstones, 457, 457t
obeticholic acid, 259 nonfunctional, 76 pill-induced esophagitis, 19–20
obstructive defecation, 243–44 overview, 72 piperacillin-tazobactam, 253
480 Index
plasma cell infiltration of hepatic parenchyma, for nausea and vomiting, 254–55, 254t renal diseases, GI manifestations
377, 379f overview, 251 of, 153f, 153
platelet count, 280 for PUD, 257 resistance to activated protein C, 329
plecanatide, 243 primary biliary cholangitis, 357–58, 359f revised Atlanta classification, 431, 431t
PNETs. See pancreatic neuroendocrine primary biliary cirrhosis, 259 RFA (radiofrequency ablation), 29, 308
tumors primary lymphangiectasia, 114 rheumatoid arthritis (RA), 155, 156
pneumatic dilation (PD), 41 primary nonfunction of liver allograft, 403 rheumatologic vascular diseases, GI
pneumatosis cystoides intestinalis (PCI), 155 primary sclerosing cholangitis (PSC) manifestations of, 154–55
PNTML (pudendal nerve terminal motor characteristics in ERCP, 172 ribavirin, 259
latency), 247 cholangiocarcinoma and, 298, 309 riboflavin deficiency, 120
POEM (peroral endoscopic myotomy), 41–42 diagnosis, 358–60, 359f, 360f rifaximin, 263
polyarteritis nodosa (PAN), 139, 156, 157 in IBD, 187, 202–3 risankizumab, 194
polyarticular (type 2) peripheral arthropathies, in pregnancy, 257 risk of bleeding, in endoscopy, 168b,
187 treatment, 360 168–69
polycystic kidney disease, 153f, 153 probiotics, 388 Rome IV criteria, 91, 92b, 231b, 231, 461b,
polyps prochlorperazine, 254 462b
colon, 222, 223f, 227–29 proctitis, 185, 191 rotavirus, 207–8
gallbladder, 459, 465f, 465 proctography, 245, 247 Roux-en-Y gastric bypass (RYGB)
gastric, 68 prokinetics, in GERD management, 15 anatomy and physiology of, 159, 160f
porcelain gallbladder, 462–63 promethazine, 254 definition, 159
porphyria, 147–49, 148f, 150 promotility agents, use in pregnancy, 255t, delayed complications of, 160, 161–65,
porphyria cutanea tarda, 148 256–57 163t
portal hypertension propagated phasic contractions, 237 early complications of, 160–61
esophageal variceal bleeding, 331–33, 332t propofol, 252 endoscopic anatomy of, 160
gastric consequences leading to bleeding, propranolol, 260 esophageal dysfunction after, 43–44
333–34 protein-losing enteropathies, 107, 147b for GERD, 17
overview, 331 protein malabsorption, 107b, 107 overview, 159
pathogenesis of, 331 prothrombin time, 280 Roux limb, 160
in pregnancy, 144b, 260 proton pump inhibitors (PPIs)
in severe alcohol-related hepatitis, 321 for EoE, 18–19 sacroiliitis, 200
portal hypertensive gastropathy, 62, 63f, 129, for functional dyspepsia, 94 saline laxatives, 242
333–34 for GERD, 5f, 14–15, 15f Salmonella, 209–10, 211t, 212b, 212t
portal venous inflow disorders, 325b, 326 pregnancy and, 255t SAP (symptom association probability), 12
post-ERCP pancreatitis (PEP), 171, 173 for PUD, 56 sarcoidosis, 151
postfundoplication motor disorders, 43 for refractory reflux disease, 16b, 16 SARS-CoV-2, 208
post–obesity surgery esophageal dysfunction, pruritus, 361 satellitosis, 320, 385
43–44 PSC. See primary sclerosing cholangitis SBP (spontaneous bacterial peritonitis), 338f,
postprandial distress syndrome, 91–92, 94 pseudoaneurysm, 435 338–40
postprandial hyperinsulinemic hypoglycemia pseudocysts, 431–32, 434, 440 SCD (sickle cell disease), 149f, 149, 150
(PHH), 164 PUD. See peptic ulcer disease scintigraphy, gastroesophageal, 14
pouchitis, 195 pudendal nerve terminal motor latency scleritis, 202
PPIs. See proton pump inhibitors (PNTML), 247 scleroderma
prednisone, 192–93 pudendal neuropathy, 246 GERD and, 5, 6f
preeclamptic liver dysfunction, 395–96 pulmonary disorders, GI manifestations of, GI manifestations, 154–55, 155f, 156
pregnancy 150f, 150–51 overview, 87
gallstones in, 459 pylorus-directed interventions, 91 small-bowel diseases and, 115
hepatitis C virus in, 295 pyoderma gangrenosum (PG), 201f, 201, 202 secondary amyloidosis, 204
IBD in, 186 pyridostigmine, 90 secondary iron overload, 353–54
PUD in, 56 pyridoxine, 120, 254 secondary lymphangiectasia, 114
pregnancy, liver disease in secondary sclerosing cholangitis, 358b,
coincidental diseases discovered during quinolones, 263 360–61
pregnancy, 398–99 secretory diarrhea, 108, 108t
diseases unique to pregnancy, 392–96, 393f RA (rheumatoid arthritis), 155, 156 selective IgA deficiency, 152
overview, 391–92, 391t, 392b rabeprazole, 255t, 256–57 serotonin, 238
preexisting diseases, 396–98 radiofrequency ablation (RFA), 29, 308 serotonin (5-HT) receptor agonists, 90
pregnancy, use of medications in radionuclide scans, 131 serous cystic neoplasm, 449f, 449–50, 449t,
for acute and chronic pancreatitis, 257 rake ulcers, 188f, 188 451, 452f
for biliary tract disease, 257 ranitidine, 255t, 256 serrated polyposis syndrome (SPS), 228t
for endoscopy, 252–54, 252t Ranson criteria, 430b, 430 severe alcohol-related hepatitis, 318–21,
FDA categories for, 251t reactive gastropathy, 62 319b, 320b
for GERD, 255–57, 255t rectal balloon expulsion test, 245 Shigella, 211–12, 211t
for IBD, 264–67, 264t rectal neuroendocrine tumors, 75 shortened bowel, 108–9
for IBS, 260–62, 261t recurrent pyogenic cholangitis, 172, 174f, 461 short-segment BE, 23, 25f
for infectious diarrhea, 262–64, 263t reflux of acid, 12 SIBO (small intestinal bacterial overgrowth),
for liver disease, 257–60, 258t refractory ascites, 337–38 89, 115–17, 116f, 116t, 151, 164
for liver transplant, 260 refractory reflux disease, 16b, 16 sickle cell disease (SCD), 149f, 149, 150
Index 481
simethicone, 253 steatorrhea, 440 tofacitinib, 194, 266

simple fistula, 197 steatosis, 315, 317, 318f, 319b, 365 Tokyo Guidelines 2018, 458, 459b, 460, 461b
simple liver cysts, 303–4, 304f stimulant laxatives, 242 tonic colonic contractions, 237
single-stripe sign, in colonic ischemia, 137, stomach, portal hypertension manifestations topical anesthetics, use in pregnancy, 253–54
138f in, 333–34 toxic megacolon, 187
sinistral portal hypertension, 326 stricturoplasty, 195, 196f TPMT (thiopurine methyltransferase), 193
sinusoidal obstruction syndrome (SOS), 328, subepithelial lesions, endoscopic transarterial chemoembolization (TACE), 308
328t, 365 ultrasonography of, 170–71, 171t transient lower esophageal sphincter
sirolimus, 260 submucosa, 35 relaxation (TLESR), 3–4
sitophobia, 136 subtotal colectomy, 243 transjugular intrahepatic portosystemic shunts
skin lesions, vascular anomalies and, 130 sucralfate, 255t, 256 (TIPSs), 333, 337–38, 342
skip areas, 188f, 188 sulfasalazine, 191–92, 192t, 196 transoral incisionless fundoplication, 17
SLE (systemic lupus erythematosus), 140, sump syndrome, 461 traveler’s diarrhea, 208, 215
155–56 sunflower cataracts, 348f, 348 Trichinella, 211t
SMA (superior mesenteric artery), 133–34 superior mesenteric artery (SMA), 133–34 trientine, 259, 350t
SMA embolus (SMAE), 134 surgery triglycerides, 106–7
small-bowel diseases antireflux, 16–17 trimethobenzamide, 255
amyloidosis, 115 for cholangiocarcinomas, 311 trimethoprim-sulfamethoxazole, 264
celiac disease, 109–11, 110t, 111f, 112b, for gastric adenocarcinoma, 70 tropical sprue, 112–13
112f, 113f for GIST, 72 tuberous sclerosis, 227
diabetes and, 115 for hepatocellular carcinoma, 306–8 tumor necrosis factor antagonists, 371
eosinophilic gastroenteritis, 113–14 for IBD, 195f, 195, 196f Turcot syndrome, 226
in hospitalized patients, 115 for neuromuscular motility disorders, 91 typhoid fever, 210
intestinal lymphangiectasia, 114–15, 115f for pancreatic ductal adenocarcinoma, 447
other conditions, 115 sweet syndrome, 201–2, 202f UES (upper esophageal sphincter), 35–36,
scleroderma and, 115 Sydney System for classification of gastritis, 38f, 38
tropical sprue, 112–13 58t UGI (upper gastrointestinal) tract bleeding,
Whipple disease, 111–12, 113f, 114f symptom association probability (SAP), 12 127b, 127–30
small-bowel motility, 84–85 symptomatic cholelithiasis, 458–59 ulceration, marginal, 161–62
small-bowel obstructions, 162 symptom index, 12 ulcerative colitis (UC)
small-bowel resection, 108–9 symptom sensitivity index, 12 aminosalicylates for, 191–92, 192t
small-bowel transplant, 91 systemic disease, gastrointestinal antibiotics for, 192
small intestinal bacterial overgrowth (SIBO), manifestations of. See gastrointestinal anti-TNF agents for, 193–94
89, 115–17, 116f, 116t, 151, 164 manifestations of systemic disease azathioprine and 6-MP for, 193
small intestinal neuroendocrine tumors, 74, 75 systemic lupus erythematosus (SLE), 140, clinical presentation, 186
small molecules, 266–67 155–56 colorectal cancer and, 204b, 204
SMA thrombus (SMAT), 134 systemic mastocytosis, 149, 150 corticosteroids for, 192–93
smoking systemic sclerosis. See scleroderma cyclosporine for, 193
Barrett esophagus and, 26 dermatologic manifestations, 200–1, 201b,
gastric adenocarcinoma and, 67 TACE (transarterial chemoembolization), 308 201f, 202f
IBD and, 186 tacrolimus, 260, 265 diagnosis, 186
pancreatic ductal adenocarcinoma and, 444 TARE, 308 diet, 186
PUD and, 54 telbivudine, 259, 291t differential diagnosis, 189b, 189–90
smooth muscle disorders, 86–87 tenofovir, 258–59, 291t endoscopic characteristics, 188f, 188, 190
sodium phosphate solution, 242 tetracycline, 257, 262–63 environmental influences, 186
solid pseudopapillary neoplasm, 449t, 451f, thalidomide, 265 epidemiology, 185
451, 452f thiamine deficiency, 120, 163t extraintestinal manifestations, 187, 187t
somatostatinomas, 80 thiopurine methyltransferase (TPMT), 193 genetics, 185–86
sorbitol, 242 thromboembolic event risk, in endoscopy, hepatobiliary manifestations, 202b, 202–3
SOS (sinusoidal obstruction syndrome), 328, 169, 169t histology, 188–89
328t, 365 thromboembolism, 204 JAK inhibitors for, 194
sphincter damage, 246 thrombosis laboratory findings, 187, 187t
sphincter denervation measurements, 247 hepatic artery, 326, 404 methotrexate for, 193
splanchnic circulation, anatomy of, 325–26 mesenteric venous, 326 miscellaneous complications, 203b, 203–4
splanchnic vein thrombosis, 435 splanchnic vein, 435 musculoskeletal manifestations, 199b, 199–200
splenic artery aneurysms, 140–41 splenic vein, 441 ocular manifestations, 202b, 202
splenic vein thrombosis, 441 thumbprinting, in colonic ischemia, 137f, 137 overview, 185, 199
spontaneous bacterial peritonitis (SBP), 338f, thyroid disease, 154 ozanimod for, 195
338–40 tinidazole, 263–64 pancreatic manifestations, 203
spontaneous portosystemic shunts, 342 TIPSs (transjugular intrahepatic portosystemic physical examination, 187
SPS (serrated polyposis syndrome), 228t shunts), 333, 337–38, 342 pregnancy and, 186, 264–67, 264t
squamous cell carcinoma, esophageal, 30–32, TLESR (transient lower esophageal sphincter radiologic features, 188, 190
31f relaxation), 3–4 surgery for, 195f, 195
Staphylococcus aureus, 215 TNM staging system treatment strategies for, 196
statins, 370–71 for esophageal adenocarcinoma, 31–32, 32t ustekinumab for, 194
steatohepatitis, 315 for gastric adenocarcinoma, 69, 69t vedolizumab for, 194
482 Index
ulcerative proctitis, 191 MALS, 138–39, 140f visceral artery aneurysms (VAAs), 140–41
ulcerative proctosigmoiditis, 191 mesenteric ischemia, 133–34 vitamin deficiencies, 119–21, 361
upadacitinib, 194, 266 mesenteric vascular anatomy, 133–34 vomiting, management in pregnancy, 254–55,
upper esophageal sphincter (UES), 35–36, VAAs, 140–41 254t
38f, 38 vasculitis, 139–40, 140f
upper gastrointestinal (UGI) tract bleeding, vascular ectasias, 130, 131 walled-off necrosis (WON), 431–32, 433f,
127b, 127–30 vascular Ehlers-Danlos syndrome (EDS), 141, 434
urgency of endoscopy, determining, 169 157 water brash, 7
ursodeoxycholic acid, 259, 358, 360 vascular gastropathy, 62, 63f watermelon stomach, 62, 63f, 130, 334f, 334
ustekinumab, 194, 266 vasculitides, GI manifestations of, 156f, water-soluble vitamins, 119–20
uveitis, 202 156–57 watery diarrhea, hypokalemia, and
vasculitis, 139–40, 140f achlorhydria (WDHA) syndrome, 78–79
VAAs (visceral artery aneurysms), 140–41 vasoactive intestinal polypeptide (VIP), 78–79 weakly acidic reflux, detection of, 12–14, 13f
vancomycin, 264 vedolizumab, 194, 266 weight loss, 387–88
varices venoocclusive disease, 328, 328t, 365 West Haven criteria, 341
esophageal, 331–33, 332t Verner-Morrison syndrome, 78–79 Whipple disease, 111–12, 113f, 114f
gastric, 333 Vibrio infections, 211t, 214 WHO histopathologic classification of NETs,
variegate porphyria, 148 videofluoroscopic swallow study (VFSS), 36 75–76, 76t
vascular diseases, GI manifestations of, VIP (vasoactive intestinal polypeptide), 78–79 Wilson disease, 259, 347–50, 348f, 350t, 355t,
144–45, 145f VIPoma, 78–79 397
vascular diseases of liver viral hepatitis withdrawal time, 167t, 168
anatomy of splanchnic circulation, 325–26 clinical effects of, 288t witholding medications, in endoscopy,
hepatic arterial inflow disorders, 326–28 comparison of viruses, 288t 169–70
hepatic arterial outflow disorders, 328–30 hepatitis A, 287–88 WON (walled-off necrosis), 431–32, 433f,
overview, 325b, 325 hepatitis B, 288–92, 289f, 289t, 290t, 291f, 434
portal venous inflow disorders, 326 291t
vascular disorders of gastrointestinal tract hepatitis C, 292f, 292–96, 293f, 294f, 294t, Yersinia enterocolitica, 211t, 214
acute mesenteric ischemia, 134–35, 134t, 295t
135f hepatitis D, 292 Zenker diverticulum, 36, 37f
chronic mesenteric ischemia, 135–36, 136b hepatitis E, 296 zinc acetate, 350t
colonic ischemia, 136–37, 137f, 138f, 139f, HIV and, 296 zinc deficiency, 121, 163t
139t overview, 287 Zollinger-Ellison syndrome (ZES), 53–54,
focal segmental ischemia, 138, 139f pregnancy and, 257–59, 398 76–77, 76t, 77f, 78f

Mayo Clinic: Gastroenterology and Hepatology Board

Uploaded by

Copyright:

Available Formats

Mayo Clinic: Gastroenterology and Hepatology Board

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Mayo Clinic: Gastroenterology and Hepatology Board

Uploaded by

Copyright:

Available Formats

MAYO CLINIC

MAYO CLINIC SCIENTIFIC PRESS

Oxford University Press is a department of the University of Oxford. It furthers

List of Contributors xi Questions and Answers 123

4 Peptic Ulcer Disease 51 14 Endoscopy for the Gastroenterology Board

7 Gastrointestinal Motility Disorders 83 15 Inflammatory Bowel Disease: Clinical Aspects 185

20 Irritable Bowel Syndrome 231 31 Cholestatic Liver Disease 357

Section VI Liver 35 Liver Disease in Pregnancy 391

24 Viral Hepatitis 287 Questions and Answers 407

Andres J. Acosta, MD, PhD Nayantara Coelho-​Prabhu, MBBS

Prasad G. Iyer, MD Amy S. Oxentenko, MD

Joseph A. Murray, MD Andrew C. Storm, MD

Seth R. Sweetser, MD Eric J. Vargas Valls, MD, MS

Gastroesophageal Reflux Diseasea

dysfunction, sclerodactyly, and telangiectasia (CREST). Drugs

Intrinsic Mucosal Factors

Figure 1.1. Causes of Increased Exposure of the Esophagus to

Factors Contributing to GERD

straining. The cardia is often submerged under liquid gastric

Obesity has been established as a risk factor for GERD. An

Figure 1.6. Three-​Month Prevalence of Gastroesophageal Reflux

Because cardiac-​related pain may be fatal, a patient who has

syndromes should be evaluated first. For example, patients with

✓ LA grade C or D esophagitis is consistent with severe esophagitis,

Box 1.4. Indications for Ambulatory Esophageal pH

Refractory Reflux Disease rumination or gastroparesis) or functional conditions (eg, func-

✓ EoE can be accompanied by various endoscopic findings, in-

✓ Common causes of infectious esophagitis—​ Candida, HSV,

Barrett Esophagus and Esophageal Cancer

Barrett Esophagus The pathologic criterion is the presence of intestinal meta-

No Dysplasia and LGD High-​Grade Dysplasia

is visualized, the patient undergoes additional EMR or ESD. This

✓ Patients with reasonable life expectancy who have dysplastic BE

areas and in low-​income areas. The higher incidence rates in

Risk Factors for Adenocarcinoma

Signs and Symptoms

Diagnosis and Staging

Table 2.1. TNM Staging System for Esophageal Suggested Reading

Figure 3.1. Layers Within the Wall of the Esophagus.

Multifaceted therapeutic approaches are used in the manage- Esophageal Dysphagia

Esophageal HRM Assessment of HRM With the Chicago

in the Medicare population. The diagnosis tends to be more

The underlying pathogenesis of achalasia is loss of esophageal

with the distal 2 to 3 cm in the stomach. The balloon is sequen- Diagnosis

further into 3 subtypes (Figure 3.8). As outlined above, FLIP pla-

(PPI) therapy. PD, LHM, and POEM are largely considered

✓ Secondary achalasia related to malignancy should be suspected in

EGJ Outflow Obstruction

Hypercontractile Esophagus Absent Contractility

Postfundoplication Motor Disorders

Questions I.2. A 65-​year-​old man presents with a 10-​year history of heart-

Peptic Ulcer Disease

The risk of injury to the gastroduodenal mucosa by aspirin

✓ Most common causes of PUD—​NSAIDs and H pylori infection

H pylori Infection and NSAIDs

ulcers present with epigastric burning or a hunger sensation, es-

hypergastrinemia, hypersecretion of acid, and ulceration prox-

Urea Breath Test

Abbreviation: PPI, proton pump inhibitor.

MAYO CLINIC SCIENTIFIC PRESS

List of Contributors xi Questions and Answers 123

4 Peptic Ulcer Disease 51 14 Endoscopy for the Gastroenterology Board

7 Gastrointestinal Motility Disorders 83 15 Inflammatory Bowel Disease: Clinical Aspects 185

20 Irritable Bowel Syndrome 231 31 Cholestatic Liver Disease 357

Section VI Liver 35 Liver Disease in Pregnancy 391

24 Viral Hepatitis 287 Questions and Answers 407

Andres J. Acosta, MD, PhD Nayantara Coelho-Prabhu, MBBS

Figure 1.6. Three-Month Prevalence of Gastroesophageal Reflux

Because cardiac-related pain may be fatal, a patient who has

✓ Common causes of infectious esophagitis— Candida, HSV,

No Dysplasia and LGD High-Grade Dysplasia

areas and in low-income areas. The higher incidence rates in

Questions I.2. A 65-year-old man presents with a 10-year history of heart-

✓ Most common causes of PUD—NSAIDs and H pylori infection

acid-reduction therapy, or therapy directed toward the underlying

Bhattacharya B. Non-neoplastic disorders of the stomach. In: Iacobuzio-

✓ Stomach—the most frequent extranodal site for lymphoma

Diffuse Large B-Cell Lymphoma

Abbreviations: MEN-1, multiple endocrine neoplasia type 1; ZES, Zollinger-Ellison syndrome.

Table 7.1. Classification of Gastroparesis and Pseudo-obstruction

Malabsorptive Disorders and Diarrhea sodium–glucose-linked transporter 1 (SGLT-1); oral rehydration

small-bowel abnormalities that can lead to fat malabsorption

✓ Iron deficiency anemia—the most common nonclassical feature

✓ Eosinophilic gastroenteritis—clinical manifestations vary depending

may also have small-bowel diverticulosis, another risk factor for

Abbreviations: NSAID, nonsteroidal anti-inflammatory drug; PPI, proton pump

✓ Acute mesenteric ischemia—an abrupt decrease in blood flow to

✓ Most common cause of acute mesenteric ischemia (AMI)—