Alcoholic Liver Disease: Mark E. Mailliard, Michael F. Sorrell

European Association for the Study of the Liver: EASL Recom- TABLE 335-1 Risk Factors for Alcoholic
ctors for Alcoholic Liver Disease 2399

mendations on treatment of hepatitis C 2016. J Hepatol 2016 in press.
RISK FACTOR COMMENT
Available at http://dx.doi.org/10.1016/j. jhep.2016.09.001. Accessed
Quantity In men, 40–80 g/d of ethanol produces fatty liver;
September 22, 2016. 160 g/d for 10–20 years causes hepatitis or
Lok ASG et al: Antiviral therapy for chronic hepatitis B viral infection cirrhosis. Only 15% of alcoholics develop alcoholic
in adults: A systematic review and meta-analysis. Hepatology 63:284, liver disease.
2016. Gender Women exhibit increased susceptibility to alcoholic
Manns MP et al: AASLD Practice Guidelines: Diagnosis and manage- liver disease at amounts >20 g/d; two drinks per day
ment of autoimmune hepatitis. Hepatology 51;2193, 2010. is probably safe.
Pawlotsky J-M et al: From non-A, non-B hepatitis to hepatitis C virus Hepatitis C HCV infection concurrent with alcoholic liver disease
cure. J Hepatol 62:S87, 2015. is associated with younger age for severity, more
Terrault N et al: AASLD guidelines for treatment of chronic hepatitis B. advanced histology, and decreased survival.
Hepatology 63:261, 2016. Genetics Patatin-like phospholipase domain-containing protein
Wedemeyer H et al: Peginterferon plus adefovir versus either drug 3 (PNPLA3) has been associated with alcoholic
cirrhosis.
alone for hepatitis delta. N Engl J Med 364:322, 2011.
Fatty liver Alcohol injury does not require malnutrition, but
obesity and nonalcoholic fatty liver are risk factors.
Patients should receive vigorous attention to
nutritional support.
335 Alcoholic Liver Disease

Mark E. Mailliard, Michael F. Sorrell
differences result from poorly understood effects of estrogen, propor-
tion of body fat, and the gastric metabolism of alcohol. Obesity, a high-
fat diet, and the protective effect of coffee have been postulated to play
a part in the development of the pathogenic process.
Chronic infection with hepatitis C virus (HCV) (Chap. 334) is an
Chronic and excessive alcohol ingestion is a major cause of liver disease important comorbidity in the progression of alcoholic liver disease to
and is responsible for nearly 50% of the mortality from all cirrhosis. cirrhosis in chronic drinkers. Even light to moderate alcohol intake of
CHAPTER 335 Alcoholic Liver Disease

The pathology of alcoholic liver disease consists of three major lesions, 15–30 g/d increases the risk of cirrhosis and hepatocellular cancer in
with the progressive injury rarely existing in a pure form: (1) fatty liver, HCV-infected individuals. Patients with both alcoholic liver injury and
(2) alcoholic hepatitis, and (3) cirrhosis. Fatty liver is present in >90% HCV infection develop decompensated liver disease at a younger age
of daily as well as binge drinkers. A much smaller percentage of heavy and have poorer overall survival. Increased liver iron stores and, rarely,
drinkers will progress to alcoholic hepatitis, thought to be a precursor porphyria cutanea tarda can occur as a consequence of the overlapping
to cirrhosis. The prognosis of severe alcoholic liver disease is dismal; injurious processes secondary to alcohol and HCV infection.
the mortality of patients with alcoholic hepatitis concurrent with cir- The pathogenesis of alcoholic liver injury is unclear. The present con-
rhosis is nearly 60% at 4 years. Although alcohol is considered a direct ceptual foundation is that alcohol acts as a direct hepatotoxin and that
hepatotoxin, only between 10 and 20% of alcoholics will develop alco- malnutrition does not have a major role. Ingestion of alcohol initiates
holic hepatitis. The explanation for this apparent paradox is unclear but an inflammatory cascade by its metabolism, resulting in a variety of
involves the complex interaction of facilitating factors such as drinking metabolic responses. Steatosis from lipogenesis, fatty acid synthesis, and
patterns, diet, obesity, and gender. There are no diagnostic tools that depression of fatty acid oxidation appears secondary to effects on sterol
can predict individual susceptibility to alcoholic liver disease. regulatory transcription factor and peroxisome proliferator-activated
receptor α (PPAR-α). Intestinal-derived endotoxin initiates a pathogenic
■ GLOBAL CONSIDERATIONS process through toll-like receptor 4 and tumor necrosis factor α (TNF-α)
Alcohol is the world's third largest risk factor for disease bur- that facilitates hepatocyte apoptosis and necrosis. The cell injury and
den. The harmful use of alcohol results in about 3.5 million endotoxin release initiated by ethanol and its metabolites also activate
deaths worldwide each year. Most of the mortality attributed innate and adaptive immunity pathways releasing proinflammatory
to alcohol is secondary to cirrhosis. Mortality from cirrhosis is directly cytokines (e.g., TNF-α), chemokines, and proliferation of T and B cells.
related to alcohol consumption, with the Eastern European countries The effect of chronic ethanol ingestion on intestinal permeability influ-
the most significantly burdened. Cirrhosis and its complications are ences liposaccharide hepatic influx as well as microbiome dysbiosis,
closely correlated with volume of alcohol consumed per capita popula- further contributing to the pathogenic process. The production of toxic
tion and are regardless of gender. protein-aldehyde adducts, generation of reducing equivalents, and oxi-
dative stress also play a role. Hepatocyte injury and impaired regener-
■ ETIOLOGY AND PATHOGENESIS ation following chronic alcohol ingestion are ultimately associated with
Quantity and duration of alcohol intake are the most important risk fac- stellate cell activation and collagen production; key events in fibrogen-
tors involved in the development of alcoholic liver disease (Table 335-1). esis. The resulting fibrosis from continuing alcohol use determines the
The roles of beverage type(s), i.e., wine, beer, or spirits, and pattern of architectural derangement of the liver and associated pathophysiology.
drinking (daily versus binge drinking) are less clear. Progress beyond
the fatty liver stage seems to require additional risk factors that remain ■ PATHOLOGY
incompletely defined. Although there are genetic predispositions for The liver has a limited repertoire in response to injury. Fatty liver is the
alcoholism (Chap. 445), gender is a strong determinant for alcoholic initial and most common histologic response to hepatotoxic stimuli,
liver disease. Women are more susceptible to alcoholic liver injury including excessive alcohol ingestion. The accumulation of fat within the
when compared to men. They develop advanced liver disease with perivenular hepatocytes coincides with the location of alcohol dehydroge-
substantially less alcohol intake. In general, the time it takes to develop nase, the major enzyme responsible for alcohol metabolism. Continuing
liver disease is directly related to the amount of alcohol consumed. It is alcohol ingestion results in fat accumulation throughout the entire hepatic
useful in estimating alcohol consumption to understand that one beer, lobule. Despite extensive fatty change and distortion of the hepatocytes
four ounces of wine, or one ounce of 80% spirits all contain ~12 g of with macrovesicular fat, the cessation of drinking results in normalization
alcohol. The threshold for developing alcoholic liver disease is higher of hepatic architecture and fat content. Alcoholic fatty liver has tradition-
in men (>14 drinks per week), while women are at increased risk for ally been regarded as entirely benign, but similar to the spectrum of non-
liver injury by consuming >7 drinks per week. Gender-dependent alcoholic fatty liver disease, the appearance of steatohepatitis and certain
Harrisons_20e_Part10_p2177-p2450.indd 2399 6/1/18 2:15 PM

2400 pathologic features such as giant mitochondria, perivenular fibrosis, and as 4.6 X (the prolongation of the prothrombin time above control [sec-
macrovesicular fat may be associated with progressive liver injury. onds]) + serum bilirubin (mg/dL) can identify patients with a poor
The transition between fatty liver and the development of alcoholic prognosis (discriminant function >32). A Model for End-Stage Liver
hepatitis is blurred. The hallmark of alcoholic hepatitis is hepatocyte Disease (MELD) score (Chap. 338) ≥21 also is associated with signifi-
injury characterized by ballooning degeneration, spotty necrosis, poly- cant mortality in alcoholic hepatitis. The presence of ascites, variceal
morphonuclear infiltrate, and fibrosis in the perivenular and perisinusoi- hemorrhage, deep encephalopathy, or hepatorenal syndrome predicts
dal space of Disse. Mallory-Denk bodies are often present in florid cases a dismal prognosis. The pathologic stage of the injury can be helpful in
but are neither specific nor necessary to establish the diagnosis. Alcoholic predicting prognosis. Liver biopsy should be performed whenever pos-
hepatitis is thought to be a precursor to the development of cirrhosis. sible to establish the diagnosis and to guide the therapeutic decisions.
However, like fatty liver, it is potentially reversible with cessation of
drinking. Cirrhosis is present in up to 50% of patients with biopsy-proven TREATMENT
alcoholic hepatitis, and its regression is uncertain, even with abstention.
Alcoholic Liver Disease
■ CLINICAL FEATURES
The clinical manifestations of alcoholic fatty liver are subtle and charac- Complete abstinence from alcohol is the cornerstone in the treatment
teristically detected as a consequence of the patient's visit for a seemingly of alcoholic liver disease. Improved survival and the potential for
unrelated matter. Previously unsuspected hepatomegaly is often the only reversal of histologic injury regardless of the initial clinical pre-
clinical finding. Occasionally, patients with fatty liver will present with sentation are associated with total avoidance of alcohol ingestion.
right upper quadrant discomfort, nausea, and, rarely, jaundice. Differenti- Referral of patients to experienced alcohol counselors and/or alco-
ation of alcoholic fatty liver from nonalcoholic fatty liver is difficult unless hol treatment programs should be routine in the management of
an accurate drinking history is ascertained. In every instance where liver patients with alcoholic liver disease. Attention should be directed
disease is present, a thoughtful and sensitive drinking history should be to the nutritional and psychosocial states during the evaluation and
obtained. Standard, validated questions accurately detect alcohol-related treatment periods. Because of data suggesting that the pathogenic
problems (Chap. 445). Alcoholic hepatitis is associated with a wide gamut mechanisms in alcoholic hepatitis involve cytokine release and
of clinical features. Fever, spider nevi, jaundice, and abdominal pain the perpetuation of injury by immunologic processes, glucocorti-
simulating an acute abdomen represent the extreme end of the spectrum, coids have been extensively evaluated in the treatment of alcoholic
while many patients will be entirely asymptomatic. Portal hypertension, hepatitis. Patients with severe alcoholic hepatitis, defined as a dis-
ascites, or variceal bleeding can occur in the absence of cirrhosis. Recogni- criminant function >32 or MELD >20, should be given prednisone,
tion of the clinical features of alcoholic hepatitis is central to the initiation 40 mg/d, or prednisolone, 32 mg/d, for 4 weeks, followed by a ste-
of an effective and appropriate diagnostic and therapeutic strategy. It is roid taper (Fig. 335-1). Exclusion criteria include active gastrointesti-
PART 10
important to recognize that patients with alcoholic cirrhosis often exhibit nal bleeding, renal failure, or pancreatitis. Patients with infection can
clinical features identical to other causes of cirrhosis. be concurrently treated with antibiotics and steroids. Women with
encephalopathy from severe alcoholic hepatitis may be particularly
■ LABORATORY FEATURES good candidates for glucocorticoids. A Lille score >0.45, at http://
Patients with alcoholic liver disease are often identified through routine
Disorders of the Gastrointestinal System
www.lillemodel.com, uses pretreatment variables plus the change in

screening tests. The typical laboratory abnormalities seen in fatty liver are total bilirubin at day 7 of glucocorticoids to identify those patients
nonspecific and include modest elevations of aspartate aminotransferase unresponsive to therapy.
(AST), alanine aminotransferase (ALT), and γ-glutamyl transpeptidase The role of TNF-α expression and receptor activity in alco-
(GGTP), often accompanied by hypertriglyceridemia and hyperbiliru- holic liver injury has led to an examination of pentoxifylline, the
binemia. In alcoholic hepatitis and in contrast to other causes of fatty nonspecific TNF inhibitor, either by itself, or with glucocorticoids
liver, AST and ALT are usually elevated two- to sevenfold. They are rarely for severe alcoholic hepatitis. In one study, pentoxifylline demon-
>400 IU, and the AST/ALT ratio is >1 (Table 335-2). Hyperbilirubinemia strated an improved survival in the therapy of severe alcoholic
is accompanied by modest increases in the alkaline phosphatase level. hepatitis, primarily due to a decrease in hepatorenal syndrome.
Derangement in hepatocyte synthetic function indicates more serious Subsequent clinical trials failed to find an increased benefit from
disease. Hypoalbuminemia and coagulopathy are common in advanced pentoxifylline, either by itself or in combination with prednisolone
liver injury. Ultrasonography is useful in detecting fatty infiltration of (Fig. 335-2).
the liver and determining liver size. The demonstration by ultrasound of
portal vein flow reversal, ascites, and intraabdominal venous collaterals
indicates serious liver injury with less potential for complete reversal.
100
■ PROGNOSIS 84.6 3.4%
Critically ill patients with alcoholic hepatitis have short-term (30-day)
mortality rates >50%. Severe alcoholic hepatitis is heralded by coagul- p = .001
75
Cumulativesurvival, %
opathy (prothrombin time increased >5 s), anemia, serum albumin con-
centrations <25 g/L (2.5 mg/dL), serum bilirubin levels >137 μmol/L
65.1 4.8%
(8 mg/dL), renal failure, and ascites. A discriminant function calculated
50
TABLE 335-2 Laboratory Diagnosis of Alcoholic Fatty Liver and
Alcoholic Hepatitis
TEST COMMENT 25
AST Increased two- to sevenfold, <400 IU/L, greater than ALT
ALT Increased two- to sevenfold, <400 IU/L
AST/ALT Usually >1 0
GGTP Not specific to alcohol, easily inducible, elevated in all forms 0 7 14 21 28
of fatty liver Days
Bilirubin May be markedly increased in alcoholic hepatitis despite FIGURE 335-1 Effect of glucocorticoid therapy of severe alcoholic hepatitis on
modest elevation in alkaline phosphatase short-term survival: the result of a meta-analysis of individual data from three
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; studies. Prednisolone, solid line; placebo, dotted line. (Adapted from P Mathurin
GGTP, γ-glutamyl transpeptidase. et al: J Hepatol 36:480, 2002, with permission from Elsevier Science.)

as greater than one drink per day in women or two drinks per day in 2401
Alcoholic Hepatitis men), they are considered to have NAFLD. NAFLD is strongly associ-
ated with overweight/obesity and insulin resistance. However, it can
also occur in lean individuals and is particularly common in those with
Alcohol abstinence a paucity of adipose depots (i.e., lipodystrophy). Ethnic/racial factors
Nutritional support also appear to influence liver fat accumulation; the documented prev-
alence of NAFLD is lowest in African Americans (~25%), highest in
Americans of Hispanic ancestry (~50%), and intermediate in American
Discriminant function ≥32 whites (~33%).
or MELD ≥21 NAFLD encompasses a spectrum of liver pathology with different
(with absence of co-morbidity) clinical prognoses. The simple accumulation of triglyceride within
hepatocytes (hepatic steatosis) is on the most clinically benign extreme
of the spectrum. On the opposite, most clinically ominous extreme,
No GI bleeding, renal are cirrhosis (Chap. 337) and primary liver cancer (Chap. 78). The risk
failure, or pancreatitis of developing cirrhosis is extremely low in individuals with chronic
hepatic steatosis, but increases as steatosis becomes complicated by
histologically conspicuous hepatocyte death and inflammation (i.e.,
nonalcoholic steatohepatitis [NASH]). NASH itself is also a heteroge-
Prednisolone 32
or Prednisone 40 mg
neous condition; sometimes it improves to steatosis or normal histol-
p.o daily for 4 weeks ogy, sometimes it remains relatively stable for years, but sometimes
it results in progressive accumulation of fibrous scar that eventuates
in cirrhosis. Once NAFLD-related cirrhosis develops, the annual inci-
FIGURE 335-2 Treatment algorithm for alcoholic hepatitis. As identified by a
calculated discriminant function >32 or MELD >20 (see text), patients with severe dence of primary liver cancer can be as high as 3%.
alcoholic hepatitis, without the presence of gastrointestinal bleeding, renal failure Abdominal imaging is not able to determine which individuals with
or pancreatitis would be candidates for glucocorticoids. NAFLD have associated liver cell death and inflammation (i.e., NASH),
and specific blood tests to diagnose NASH are not yet available. How-
ever, population-based studies that have used elevated serum ALT as a
Liver transplantation is an accepted indication for treatment in marker of liver injury indicate that about 6–8% of American adults have
CHAPTER 336 Nonalcoholic Fatty Liver Diseases and Nonalcoholic Steatohepatitis

select patients with complications of cirrhosis secondary to alcohol serum ALT elevations that cannot be explained by excessive alcohol
abuse. Outcomes are equal or superior to other indications for trans- consumption, other known causes of fatty liver disease (Table 336-1),
plantation. In general, transplant candidacy should be reevaluated viral hepatitis, or drug-induced or congenital liver diseases. Because
after a defined period of sobriety. Patients presenting with alcoholic the prevalence of such “cryptogenic” ALT elevations increases with
hepatitis have been largely excluded from transplant candidacy
because of the perceived risk of increased surgical mortality and
high rates of recidivism following transplantation. A European TABLE 336-1 Alternative Causes of Hepatic Steatosis
multidisciplinary group has reported excellent long-term transplant
outcomes in highly selected patients with florid alcoholic hepatitis.
General application of transplantation in such patients must await
confirmatory outcomes.
■ FURTHER READING
Mathurin P et al: Corticosteroids improves short-term survival in
patients with severe alcoholic hepatitis (AH): Individual data analysis
of the last three randomized placebo controlled double blind trials of
corticosteroids in severe AH. J Hepatol 36:480, 2002.
Sanyal AJ et al: Alcoholic and nonalcoholic fatty liver disease.
Gastroenterology 150:8 (suppl), 2016.
Thurz MR et al: Prednisolone or pentoxifylline for alcoholic hepatitis.
N Engl J Med 372:1619, 2015.
(see Table 336-2)
336 Nonalcoholic Fatty Liver

Diseases and Nonalcoholic
Steatohepatitis
Manal F. Abdelmalek, Anna Mae Diehl
■ INCIDENCE, PREVALENCE, AND NATURAL HISTORY

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic
liver disease in many parts of the world, including the United States.
Population-based abdominal imaging studies have demonstrated fatty
hemolytic anemia, elevated liver enzymes,
liver in at least 25% of American adults. Because the vast majority of
low platelet count)
these subjects deny hazardous levels of alcohol consumption (defined

NAFLD will remain a major cause of chronic liver disease worldwide TABLE 337-1 Causes of Cirrhosis 2405
for the foreseeable future. Alcoholism Cardiac cirrhosis
■ FURTHER READING Chronic viral hepatitis Inherited metabolic liver disease
Angulo P et al: Fibrosis in nonalcoholic fatty liver disease: Mecha- Hepatitis B Hemochromatosis
nisms and clinical implications. Semin Liver Dis 35:132, 2015. Hepatitis C Wilson’s disease
Chalasani N et al: The diagnosis and management of non-alcoholic Autoimmune hepatitis α1 Antitrypsin deficiency
fatty liver disease: Practice guideline by the American Gastroentero- Nonalcoholic steatohepatitis Cystic fibrosis
logical Association, American Association for the Study of Liver Dis- Biliary cirrhosis Cryptogenic cirrhosis
eases, and American College of Gastroenterology. Gastroenterology Primary biliary cholangitis
142:1592, 2012. Primary sclerosing cholangitis
European Association for the Study of the Liver (EASL); Euro-
Autoimmune cholangiopathy
pean Association for the Study of Diabetes (EASD); European
Association for the Study of Obesity (EASO): EASL-EASD-EASO
Clinical Practice Guidelines for the management of non-alcoholic
fatty liver disease. J Hepatol 64:1388, 2016. The complications of cirrhosis are basically the same regardless of the
Sanyal AJ et al: Pioglitazone, vitamin E, or placebo for nonalcoholic etiology. Nonetheless, it is useful to classify patients by the cause of
steatohepatitis. N Engl J Med 362:1675, 2010. their liver disease (Table 337-1); patients can be divided into broad
groups with alcoholic cirrhosis, cirrhosis due to chronic viral hepatitis,
biliary cirrhosis, and other, less common causes such as cardiac cirrho-
sis, cryptogenic cirrhosis, and other miscellaneous causes.
ALCOHOLIC CIRRHOSIS
Excessive chronic alcohol use can cause several different types of
chronic liver disease, including alcoholic fatty liver, alcoholic hepatitis,
337 Cirrhosis and Its and alcoholic cirrhosis. Furthermore, use of excessive alcohol can con-
tribute to liver damage in patients with other liver diseases, such as
Complications hepatitis C, hemochromatosis, and fatty liver disease related to obesity.
Chronic alcohol use can produce fibrosis in the absence of accompa-
CHAPTER 337 Cirrhosis and Its Complications

Bruce R. Bacon nying inflammation and/or necrosis. Fibrosis can be centrilobular,
pericellular, or periportal. When fibrosis reaches a certain degree,
there is disruption of the normal liver architecture and replacement of
liver cells by regenerative nodules. In alcoholic cirrhosis, the nodules
Cirrhosis is a condition that is defined histopathologically and has a
are usually <3 mm in diameter; this form of cirrhosis is referred to as
variety of clinical manifestations and complications, some of which
micronodular. With cessation of alcohol use, larger nodules may form,
can be life-threatening. In the past, it has been thought that cirrhosis
resulting in a mixed micronodular and macronodular cirrhosis.
was never reversible; however, it has become apparent that when the
underlying insult that has caused the cirrhosis has been removed, there Pathogenesis Alcohol is the most commonly used drug in the
can be reversal of fibrosis. This is most apparent with the successful United States, and more than two-thirds of adults drink alcohol each
treatment of chronic hepatitis C; however, reversal of fibrosis is also year. Thirty percent have had a binge within the past month, and
seen in patients with hemochromatosis who have been successfully over 7% of adults regularly consume more than two drinks per day.
treated and in patients with alcoholic liver disease who have discon- Unfortunately, more than 14 million adults in the United States meet
tinued alcohol use. the diagnostic criteria for alcohol abuse or dependence. In the United
Regardless of the cause of cirrhosis, the pathologic features consist States, chronic liver disease is the tenth most common cause of death
of the development of fibrosis to the point that there is architectural in adults, and alcoholic cirrhosis accounts for ~40% of deaths due to
distortion with the formation of regenerative nodules. This results in a cirrhosis.
decrease in hepatocellular mass, and thus function, and an alteration of Ethanol is mainly absorbed by the small intestine and, to a lesser
blood flow. The induction of fibrosis occurs with activation of hepatic degree, through the stomach. Gastric alcohol dehydrogenase (ADH)
stellate cells, resulting in the formation of increased amounts of col- initiates alcohol metabolism. Three enzyme systems account for metab-
lagen and other components of the extracellular matrix. olism of alcohol in the liver. These include cytosolic ADH, the microso-
Clinical features of cirrhosis are the result of pathologic changes mal ethanol oxidizing system (MEOS), and peroxisomal catalase. The
and mirror the severity of the liver disease. Most hepatic pathologists majority of ethanol oxidation occurs via ADH to form acetaldehyde,
provide an assessment of grading and staging when evaluating liver which is a highly reactive molecule that may have multiple effects. Ulti-
biopsy samples. These grading and staging schemes vary between mately, acetaldehyde is metabolized to acetate by aldehyde dehydro-
disease states and have been developed for most conditions, including genase (ALDH). Intake of ethanol increases intracellular accumulation
chronic viral hepatitis, nonalcoholic fatty liver disease, and primary of triglycerides by increasing fatty acid uptake and by reducing fatty
biliary cholangitis. Advanced fibrosis usually includes bridging fibrosis acid oxidation and lipoprotein secretion. Protein synthesis, glycosy-
with nodularity designated as stage 3 and cirrhosis designated as stage lation, and secretion are impaired. Oxidative damage to hepatocyte
4. Patients who have cirrhosis have varying degrees of compensated membranes occurs due to the formation of reactive oxygen species;
liver function, and clinicians need to differentiate between those who acetaldehyde is a highly reactive molecule that combines with proteins
have stable, compensated cirrhosis and those who have decompen- to form protein-acetaldehyde adducts. These adducts may interfere
sated cirrhosis. Patients who have developed complications of their with specific enzyme activities, including microtubular formation and
liver disease and have become decompensated should be considered hepatic protein trafficking. With acetaldehyde-mediated hepatocyte
for liver transplantation. Many of the complications of cirrhosis will damage, certain reactive oxygen species can result in Kupffer cell acti-
require specific therapy. Portal hypertension is a significant complicating vation. As a result, profibrogenic cytokines are produced that initiate
feature of decompensated cirrhosis and is responsible for the develop- and perpetuate stellate cell activation, with the resultant production of
ment of ascites and bleeding from esophagogastric varices, two com- excess collagen and extracellular matrix. Connective tissue appears in
plications that signify decompensated cirrhosis. Loss of hepatocellular both periportal and pericentral zones and eventually connects portal
function results in jaundice, coagulation disorders, and hypoalbumine- triads with central veins forming regenerative nodules. Hepatocyte
mia and contributes to the causes of portosystemic encephalopathy. loss occurs, and with increased collagen production and deposition,

2406 Laboratory tests may be completely normal in patients with early
compensated alcoholic cirrhosis. Alternatively, in advanced liver
disease, many abnormalities usually are present. Patients may be
anemic either from chronic GI blood loss, nutritional deficiencies, or
hypersplenism related to portal hypertension, or as a direct suppres-
sive effect of alcohol on the bone marrow. A unique form of hemolytic
anemia (with spur cells and acanthocytes) called Zieve’s syndrome can
occur in patients with severe alcoholic hepatitis. Platelet counts are
often reduced early in the disease, reflective of portal hypertension
with hypersplenism. Serum total bilirubin can be normal or elevated
with advanced disease. Direct bilirubin is frequently mildly elevated
in patients with a normal total bilirubin, but the abnormality typically
progresses as the disease worsens. Prothrombin times are often pro-
longed and usually do not respond to administration of parenteral
vitamin K. Serum sodium levels are usually normal unless patients
FIGURE 337-1 Palmar erythema. This figure shows palmar erythema in a patient
have ascites and then can be depressed, largely due to ingestion of
with alcoholic cirrhosis. The erythema is peripheral over the palm with central excess free water. Serum alanine and aspartate aminotransferases
pallor. (ALT, AST) are typically elevated, particularly in patients who con-
tinue to drink, with AST levels being higher than ALT levels, usually
by a 2:1 ratio.
together with continuing hepatocyte destruction, the liver contracts Diagnosis Patients who have any of the above-mentioned clinical
and shrinks in size. This process generally takes from years to decades features, physical examination findings, or laboratory studies should
to occur and requires repeated insults. be considered to have alcoholic liver disease. The diagnosis, however,
Clinical Features The diagnosis of alcoholic liver disease requires requires accurate knowledge that the patient is continuing to use and
an accurate history regarding both amount and duration of alcohol abuse alcohol. Furthermore, other forms of chronic liver disease (e.g.,
consumption. Patients with alcoholic liver disease can present with chronic viral hepatitis or metabolic or autoimmune liver diseases) must
nonspecific symptoms such as vague right upper quadrant abdominal be considered or ruled out, or if present, an estimate of relative causal-
pain, fever, nausea and vomiting, diarrhea, anorexia, and malaise. ity along with the alcohol use should be determined. Liver biopsy can
PART 10
Alternatively, they may present with more specific complications of be helpful to confirm a diagnosis, but generally when patients present
chronic liver disease, including ascites, edema, or upper gastrointes- with alcoholic hepatitis and are still drinking, liver biopsy is withheld
tinal (GI) hemorrhage. Many cases present incidentally at the time of until abstinence has been maintained for at least 6 months to determine
autopsy or elective surgery. Other clinical manifestations include the residual, nonreversible disease.
development of jaundice or encephalopathy. The abrupt onset of any In patients who have had complications of cirrhosis and who
of these complications may be the first event prompting the patient continue to drink, there is a <50% 5-year survival. In contrast, in
to seek medical attention. Other patients may be identified in the patients who are able to remain abstinent, the prognosis is significantly
course of an evaluation of routine laboratory studies that are found to improved. In patients with advanced liver disease, the prognosis
be abnormal. On physical examination, the liver and spleen may be remains poor; however, in individuals who are able to remain absti-
enlarged, with the liver edge being firm and nodular. Other frequent nent, liver transplantation is a viable option.
findings include scleral icterus, palmar erythema (Fig. 337-1), spider
angiomas (Fig. 337-2), parotid gland enlargement, digital clubbing,
muscle wasting, or the development of edema and ascites. Men may TREATMENT
have decreased body hair and gynecomastia as well as testicular atro- Alcoholic Cirrhosis
phy, which may be a consequence of hormonal abnormalities or a direct
toxic effect of alcohol on the testes. In women with advanced alcoholic Abstinence is the cornerstone of therapy for patients with alcoholic
cirrhosis, menstrual irregularities usually occur, and some women may liver disease. In addition, patients require good nutrition and long-
be amenorrheic. These changes are often reversible following cessation term medical supervision to manage underlying complications that
of alcohol ingestion. may develop. Complications such as the development of ascites
and edema, variceal hemorrhage, or portosystemic encephalopathy
all require specific management and treatment. Glucocorticoids are
occasionally used in patients with severe alcoholic hepatitis in the
absence of infection. Survival has been shown to improve in cer-
tain studies. Treatment is restricted to patients with a discriminant
function (DF) value of >32. The DF is calculated as the serum total
bilirubin plus the difference in the patient’s prothrombin time com-
pared to control (in seconds) multiplied by 4.6. In patients for whom
this value is >32, there is improved survival at 28 days with the use
of glucocorticoids.
Other therapies that have been used include oral pentoxifylline,
which decreases the production of tumor necrosis factor α (TNF-α)
and other proinflammatory cytokines. In contrast to glucocorticoids,
with which complications can occur, pentoxifylline is relatively easy
to administer and has few, if any, side effects. A variety of nutritional
therapies have been tried with either parenteral or enteral feedings;
however, it is unclear whether any of these modalities have signifi-
cantly improved survival.
FIGURE 337-2 Spider angioma. This figure shows a spider angioma in a patient Recent studies have used parenterally administered inhibitors of
with hepatitis C cirrhosis. With release of central compression, the arteriole fills TNF-α such as infliximab or etanercept. Early results have shown
from the center and spreads out peripherally. no adverse events; however, there was no clear-cut improvement in

survival. Anabolic steroids, propylthiouracil, antioxidants, colchic- series have demonstrated that patients with decompensated liver 2407
ine, and penicillamine have all been used but do not show clear-cut disease can become compensated with the use of antiviral therapy
benefits and are not recommended. directed against hepatitis B. Currently available therapy includes
As mentioned above, the cornerstone to treatment is cessation of lamivudine, adefovir, telbivudine, entecavir, and tenofovir. Interferon
alcohol use. Recent experience with medications that reduce crav- α can also be used for treating hepatitis B, but it should not be used
ing for alcohol, such as acamprosate calcium, has been favorable. in cirrhotics. The majority of patients being treated for hepatitis B are
Patients may take other necessary medications even in the presence receiving either entecavir or tenofovir (see Chap. 334).
of cirrhosis. Acetaminophen use is often discouraged in patients Treatment of patients with cirrhosis due to hepatitis C used to be
with liver disease; however, if no more than 2 g of acetaminophen more difficult because the side effects of pegylated interferon and
per day are consumed, there generally are no problems. ribavirin therapy were difficult to manage. Over the last several
years, interferon-based regimens have been replaced by direct-
■ CIRRHOSIS DUE TO CHRONIC VIRAL HEPATITIS B OR C acting antiviral protocols that are highly successful (>95% cure rate),
Of patients exposed to the hepatitis C virus (HCV), ~80% well tolerated, usually of short duration (8–12 weeks), but costly.
develop chronic hepatitis C, and of those, about 20–30% will These medications have truly revolutionized the treatment of hepa-
develop cirrhosis over 20–30 years. Many of these patients titis C (see Chap. 334).
have had concomitant alcohol use, and the true incidence of cirrhosis
due to hepatitis C alone is unknown. Nonetheless, this represents a CIRRHOSIS FROM AUTOIMMUNE HEPATITIS
significant number of patients. It is expected that an even higher per- AND NONALCOHOLIC FATTY LIVER DISEASE
centage will go on to develop cirrhosis over longer periods of time. In Other causes of posthepatitic cirrhosis include autoimmune hepatitis
the United States, ~5 to 6 million people have been exposed to HCV, and cirrhosis due to nonalcoholic steatohepatitis. Many patients with
with about 4–5 million who are chronically viremic. Worldwide, about autoimmune hepatitis (AIH) present with cirrhosis that is already
170 million individuals have hepatitis C, with some areas of the world established. Typically, these patients will not benefit from immuno-
(e.g., Egypt) having up to 15% of the population infected. HCV is a suppressive therapy with glucocorticoids or azathioprine because the
noncytopathic virus, and liver damage is probably immune-mediated. AIH is “burned out.” In this situation, liver biopsy does not show a
Progression of liver disease due to chronic hepatitis C is characterized significant inflammatory infiltrate. Diagnosis in this setting requires
by portal-based fibrosis with bridging fibrosis and nodularity develop- positive autoimmune markers such as antinuclear antibody (ANA)
ing, ultimately culminating in the development of cirrhosis. In cirrhosis or anti-smooth-muscle antibody (ASMA). When patients with AIH
due to chronic hepatitis C, the liver is small and shrunken with charac- present with cirrhosis and active inflammation accompanied by ele-

teristic features of a mixed micro- and macronodular cirrhosis seen on vated liver enzymes, there can be considerable benefit from the use of
liver biopsy. In addition to the increased fibrosis that is seen in cirrhosis immunosuppressive therapy.
due to hepatitis C, an inflammatory infiltrate is found in portal areas Patients with nonalcoholic steatohepatitis are increasingly being
with interface hepatitis and occasionally some lobular hepatocellular found to have progressed to cirrhosis. With the epidemic of obesity
injury and inflammation. In patients with HCV genotype 3, steatosis is that continues in Western countries, more and more patients are
often present. identified with nonalcoholic fatty liver disease (Chap. 336). Of these,
Similar findings are seen in patients with cirrhosis due to a significant subset has nonalcoholic steatohepatitis and can progress
chronic hepatitis B. Of adult patients exposed to hepatitis B, to increased fibrosis and cirrhosis. Over the past several years, it has
about 5% develop chronic hepatitis B, and about 20% of those been increasingly recognized that many patients who were thought
patients will go on to develop cirrhosis. Special stains for hepatitis B to have cryptogenic cirrhosis in fact have nonalcoholic steatohepatitis.
core (HBc) and hepatitis B surface (HBs) antigen will be positive, and As their cirrhosis progresses, they become catabolic and then lose the
ground-glass hepatocytes signifying HBs antigen (HBsAg) may be telltale signs of steatosis seen on biopsy. Management of complications
present. In the United States, there are about 2 million carriers of hepa- of cirrhosis due to either AIH or nonalcoholic steatohepatitis is similar
titis B, whereas in other parts of the world where hepatitis B virus to that for other forms of cirrhosis.
(HBV) is endemic (i.e., Asia, Southeast Asia, sub-Saharan Africa), up to
15% of the population may be infected, having acquired the infection ■ BILIARY CIRRHOSIS
vertically at the time of birth. Thus, over 300–400 million individuals Biliary cirrhosis has pathologic features that are different from either
are thought to have hepatitis B worldwide. Approximately 25% of alcoholic cirrhosis or posthepatitic cirrhosis, yet the manifestations of
these individuals may ultimately develop cirrhosis. end-stage liver disease are the same. Cholestatic liver disease may result
from necroinflammatory lesions, congenital or metabolic processes, or
Clinical Features and Diagnosis Patients with cirrhosis due external bile duct compression. Thus, two broad categories reflect the
to either chronic hepatitis C or B can present with the usual symptoms anatomic sites of abnormal bile retention: intrahepatic and extrahepatic.
and signs of chronic liver disease. Fatigue, malaise, vague right upper The distinction is important for obvious therapeutic reasons. Extrahe-
quadrant pain, and laboratory abnormalities are frequent presenting patic obstruction may benefit from surgical or endoscopic biliary tract
features. Diagnosis requires a thorough laboratory evaluation, includ- decompression, whereas intrahepatic cholestatic processes will not
ing quantitative HCV RNA testing and analysis for HCV genotype, or improve with such interventions and require a different approach.
hepatitis B serologies to include HBsAg, anti-HBs, HBeAg (hepatitis B The major causes of chronic cholestatic syndromes are primary
e antigen), anti-HBe, and quantitative HBV DNA levels. biliary cholangitis (PBC), autoimmune cholangitis (AIC), primary
sclerosing cholangitis (PSC), and idiopathic adulthood ductopenia.
These syndromes are usually clinically distinguished from each other
TREATMENT by antibody testing, cholangiographic findings, and clinical presenta-
Cirrhosis due to Chronic Viral Hepatitis B or C tion. However, they all share the histopathologic features of chronic
cholestasis, such as cholate stasis; copper deposition; xanthomatous
Management of complications of cirrhosis revolves around specific transformation of hepatocytes; and irregular, so-called biliary fibrosis.
therapy for treatment of whatever complications occur (e.g., esoph- In addition, there may be chronic portal inflammation, interface activ-
ageal variceal hemorrhage, development of ascites and edema, or ity, and chronic lobular inflammation. Ductopenia is a result of this
encephalopathy). In patients with chronic hepatitis B, numerous progressive disease as patients develop cirrhosis.
studies have shown beneficial effects of antiviral therapy, which is
effective at viral suppression, as evidenced by reducing aminotrans- ■ PRIMARY BILIARY CHOLANGITIS
ferase levels and HBV DNA levels, and improving histology by PBC is seen in about 100–200 individuals per million, with a strong
reducing inflammation and fibrosis. Several clinical trials and case female preponderance and a median age of around 50 years at the

2408 time of diagnosis. The cause of PBC is unknown; it is characterized middle-aged women. AMA testing may be negative, and it should
by portal inflammation and necrosis of cholangiocytes in small- and be remembered that as many as 10% of patients with PBC may be
medium-sized bile ducts. Cholestatic features prevail, and biliary AMA-negative. Liver biopsy is most important in this setting of
cirrhosis is characterized by an elevated bilirubin level and progres- AMA-negative PBC. In patients who are AMA-negative with cholestatic
sive liver failure. Liver transplantation is the treatment of choice liver enzymes, PSC should be ruled out by way of cholangiography.
for patients with decompensated cirrhosis due to PBC. A variety of
therapies have been proposed, but ursodeoxycholic acid (UDCA) has
been the only approved treatment that has some degree of efficacy by
TREATMENT
slowing the rate of progression of the disease. In 2016, obeticholic acid Primary Biliary Cholangitis
was approved for use in PBC patients with an inadequate response
to UDCA. Several other agents are in varying stages of development. Treatment of the typical manifestations of cirrhosis is no different
Antimitochondrial antibodies (AMA) are present in about 90% of for PBC than for other forms of cirrhosis. UDCA has been shown
patients with PBC. These autoantibodies recognize intermitochondrial to improve both biochemical and histologic features of the disease.
membrane proteins that are enzymes of the pyruvate dehydrogenase Improvement is greatest when therapy is initiated early; the likelihood
complex (PDC), the branched-chain 2-oxoacid dehydrogenase com- of significant improvement with UDCA is low in patients with PBC
plex, and the 2-oxogluterate dehydrogenase complex. Most relate to who present with manifestations of cirrhosis. UDCA is given in doses
pyruvate dehydrogenase. These autoantibodies are not pathogenic but of 13–15 mg/kg per day; the medication is usually well-tolerated,
rather are useful markers for making a diagnosis of PBC. although some patients have worsening pruritus with initiation of
therapy. A small proportion of patients may have diarrhea or head-
Pathology Histopathologic analyses of liver biopsies of patients ache as a side effect of the drug. UDCA has been shown to slow the
with PBC have resulted in identifying four distinct stages of the disease rate of progression of PBC, but it does not reverse or cure the dis-
as it progresses. The earliest lesion is termed chronic nonsuppurative ease. About 30 to 40% of patients with PBC do not have a satisfactory
destructive cholangitis and is a necrotizing inflammatory process of the response to UCDA; about half of these patients will have significant
portal tracts. Medium and small bile ducts are infiltrated with lympho- improvement with obeticholic acid. Patients with PBC require long-
cytes and undergo duct destruction. Mild fibrosis and sometimes bile term follow-up by a physician experienced with the disease. Certain
stasis can occur. With progression, the inflammatory infiltrate becomes patients may need to be considered for liver transplantation should
less prominent, but the number of bile ducts is reduced and there is their liver disease decompensate.
proliferation of smaller bile ductules. Increased fibrosis ensues with the The main symptoms of PBC are fatigue and pruritus, and symp-
expansion of periportal fibrosis to bridging fibrosis. Finally, cirrhosis, tom management is important. Several therapies have been tried
which may be micronodular or macronodular, develops. for treatment of fatigue, but none of them has been successful;
PART 10
frequent naps should be encouraged. Pruritus is treated with anti-

Clinical Features Currently, most patients with PBC are diag- histamines, narcotic receptor antagonists (naltrexone), and rifampin.
nosed well before the end-stage manifestations of the disease are Cholestyramine, a bile salt–sequestering agent, has been helpful in
present, and, as such, most patients are actually asymptomatic. When some patients but is somewhat tedious and difficult to take. Plasma-
symptoms are present, they most prominently include a significant pheresis has been used rarely in patients with severe intractable pru-
degree of fatigue out of proportion to what would be expected for either ritus. There is an increased incidence of osteopenia and osteoporosis
the severity of the liver disease or the age of the patient. Pruritus is seen in patients with cholestatic liver disease, and bone density testing
in ~50% of patients at the time of diagnosis, and it can be debilitating. should be performed. Treatment with a bisphosphonate should be
It might be intermittent and usually is most bothersome in the evening. instituted when bone disease is identified.
In some patients, pruritus can develop toward the end of pregnancy,
and there are examples of patients having been diagnosed with choles-
tasis of pregnancy rather than PBC. Pruritus that presents prior to the ■ PRIMARY SCLEROSING CHOLANGITIS
development of jaundice indicates severe disease and a poor prognosis. As in PBC, the cause of PSC remains unknown. PSC is a chronic
Physical examination can show jaundice and other complications of cholestatic syndrome that is characterized by diffuse inflammation and
chronic liver disease including hepatomegaly, splenomegaly, ascites, fibrosis involving the entire biliary tree, resulting in chronic cholestasis.
and edema. Other features that are unique to PBC include hyperpig- This pathologic process ultimately results in obliteration of both the
mentation, xanthelasma, and xanthomata, which are related to the intra- and extrahepatic biliary tree, leading to biliary cirrhosis, portal
altered cholesterol metabolism seen in this disease. Hyperpigmentation hypertension, and liver failure. The cause of PSC remains unknown
despite extensive investigation into various mechanisms related to
is evident on the trunk and the arms and is seen in areas of exfoliation
bacterial and viral infections, toxins, genetic predisposition, and immu-
and lichenification associated with progressive scratching related to
nologic mechanisms, all of which have been postulated to contribute to
the pruritus. Bone pain resulting from osteopenia or osteoporosis is
the pathogenesis and progression of this syndrome.
occasionally seen at the time of diagnosis.
Pathologic changes that can occur in PSC show bile duct prolifer-
Laboratory Findings Laboratory findings in PBC show choles- ation as well as ductopenia and fibrous cholangitis (pericholangitis).
tatic liver enzyme abnormalities with an elevation in γ-glutamyl trans- Often, liver biopsy changes in PSC are not pathognomonic, and estab-
peptidase and alkaline phosphatase (ALP) along with mild elevations lishing the diagnosis of PSC must involve imaging of the biliary tree.
in aminotransferases (ALT and AST). Immunoglobulins, particularly Periductal fibrosis is occasionally seen on biopsy specimens and can be
IgM, are typically increased. Hyperbilirubinemia usually is seen once quite helpful in making the diagnosis. As the disease progresses, biliary
cirrhosis has developed. Thrombocytopenia, leukopenia, and anemia cirrhosis is the final, end-stage manifestation of PSC.
may be seen in patients with portal hypertension and hypersplenism. Clinical Features The usual clinical features of PSC are those
Liver biopsy shows characteristic features as described above and found in cholestatic liver disease, with fatigue, pruritus, steatorrhea,
should be evident to any experienced hepatopathologist. Up to 10% of deficiencies of fat-soluble vitamins, and the associated consequences.
patients with characteristic PBC will have features of AIH as well and As in PBC, the fatigue is profound and nonspecific. Pruritus can often
are defined as having “overlap” syndrome. These patients are usually be debilitating and is related to the cholestasis. The severity of pruri-
treated as PBC patients and may progress to cirrhosis with the same tus does not correlate with the severity of the disease. Metabolic bone
frequency as typical PBC patients. Some patients require immunosup- disease, as seen in PBC, can occur with PSC and should be treated (see
pressive medications as well. above).
Diagnosis PBC should be considered in patients with chronic Laboratory Findings Patients with PSC typically are identi-
cholestatic liver enzyme abnormalities. It is most often seen in fied in the course of an evaluation of abnormal liver enzymes. Most

patients have at least a twofold increase in ALP and may have elevated may be normal or slightly increased with AST usually higher than 2409
aminotransferases as well. Albumin levels may be decreased, and ALT. It is unlikely that patients will develop variceal hemorrhage or
prothrombin times are prolonged in a substantial proportion of patients encephalopathy.
at the time of diagnosis. Some degree of correction of a prolonged
prothrombin time may occur with parenteral vitamin K. A small subset Diagnosis The diagnosis is usually made in someone with clear-cut
of patients have aminotransferase elevations greater than five times the cardiac disease who has an elevated ALP and an enlarged liver. Liver
upper limit of normal and may have features of AIH on biopsy. These biopsy shows a pattern of fibrosis that can be recognized by an experi-
individuals are thought to have an overlap syndrome between PSC and enced hepatopathologist. Differentiation from Budd-Chiari syndrome
AIH. Autoantibodies are frequently positive in patients with the overlap (BCS) can be made by seeing extravasation of red blood cells in BCS,
syndrome, but are typically negative in patients who only have PSC. but not in cardiac hepatopathy. Venoocclusive disease can also affect
One autoantibody, the perinuclear antineutrophil cytoplasmic antibody hepatic outflow and has characteristic features on liver biopsy. Venooc-
(p-ANCA), is positive in about 65% of patients with PSC. Over 50% of clusive disease can be seen under the circumstances of conditioning for
patients with PSC also have ulcerative colitis (UC); accordingly, once a bone marrow transplant with radiation and chemotherapy; it can also
diagnosis of PSC is established, colonoscopy should be performed to be seen with the ingestion of certain herbal teas as well as pyrrolizidine
look for evidence of UC. alkaloids. This is typically seen in Caribbean countries and rarely in the
United States. Treatment is based on management of the underlying
Diagnosis The definitive diagnosis of PSC requires cholangio- cardiac disease.
graphic imaging. Over the last several years, magnetic resonance imag-
ing (MRI) with magnetic resonance cholangiopancreatography (MRCP)
has been used as the imaging technique of choice for initial evaluation.
OTHER TYPES OF CIRRHOSIS
There are several other less common causes of chronic liver disease that
Once patients are screened in this manner, some investigators feel that
can progress to cirrhosis. These include inherited metabolic liver dis-
endoscopic retrograde cholangiopancreatography (ERCP) should also
eases such as hemochromatosis, Wilson’s disease, α1 antitrypsin (α1AT)
be performed to be certain whether or not a dominant stricture is pres-
deficiency, and cystic fibrosis. For all of these disorders, the manifesta-
ent. Typical cholangiographic findings in PSC are multifocal stricturing
tions of cirrhosis are similar, with some minor variations, to those seen
and beading involving both the intrahepatic and extrahepatic biliary
in other patients with other causes of cirrhosis.
tree. However, although involvement may be of the intrahepatic bile
Hemochromatosis is an inherited disorder of iron metabolism that
ducts alone or of the extrahepatic bile ducts alone, more commonly, both
results in a progressive increase in hepatic iron deposition, which, over
are involved. These strictures are typically short and with intervening
time, can lead to a portal-based fibrosis progressing to cirrhosis, liver
segments of normal or slightly dilated bile ducts that are distributed

failure, and hepatocellular cancer. While the frequency of hemochro-
diffusely, producing the classic beaded appearance. The gallbladder and
matosis is relatively common, with genetic susceptibility occurring in
cystic duct can be involved in up to 15% of cases. Patients with high-
1 in 250 individuals, the frequency of end-stage manifestations due to
grade, diffuse stricturing of the intrahepatic bile ducts have an overall
the disease is relatively low, and fewer than 5% of those patients who
poor prognosis. Gradually, biliary cirrhosis develops, and patients will
are genotypically susceptible will go on to develop severe liver disease
progress to decompensated liver disease with all the manifestations of
from hemochromatosis. Diagnosis is made with serum iron studies
ascites, esophageal variceal hemorrhage, and encephalopathy.
showing an elevated transferrin saturation and an elevated ferritin
level, along with abnormalities identified by HFE mutation analysis.
TREATMENT Treatment is straightforward, with regular therapeutic phlebotomy.
Primary Sclerosing Cholangitis Wilson’s disease is an inherited disorder of copper homeostasis with
failure to excrete excess amounts of copper, leading to an accumulation
There is no specific proven treatment for PSC. A recently completed in the liver. This disorder is relatively uncommon, affecting 1 in 30,000
study of high-dose (20 mg/kg per day) UDCA was found to be harm- individuals. Wilson’s disease typically affects adolescents and young
ful. Some clinicians use UDCA at “PBC dosages” of 13–15 mg/kg adults. Prompt diagnosis before end-stage manifestations become irre-
per day with anecdotal improvement. Endoscopic dilatation of versible can lead to significant clinical improvement. Diagnosis requires
dominant strictures can be helpful, but the ultimate treatment is determination of ceruloplasmin levels, which are low; 24-h urine cop-
liver transplantation. A dreaded complication of PSC is the devel- per levels, which are elevated; typical physical examination findings,
opment of cholangiocarcinoma, which is a relative contraindication including Kayser-Fleischer corneal rings; and characteristic liver biopsy
to liver transplantation. Symptoms of pruritus are common, and the findings. Treatment consists of copper-chelating medications.
approach is as mentioned previously for this problem in patients α1AT deficiency results from an inherited disorder that causes abnor-
with PBC (see above). mal folding of the α1AT protein, resulting in failure of secretion of that
protein from the liver. It is unknown how the retained protein leads to
■ CARDIAC CIRRHOSIS liver disease. Patients with α1AT deficiency at greatest risk for devel-
oping chronic liver disease have the ZZ phenotype, but only about
Definition Patients with long-standing right-sided congestive heart 10–20% of such individuals will develop chronic liver disease. Diagno-
failure may develop chronic liver injury and cardiac cirrhosis. This is an sis is made by determining α1AT levels and phenotype. Characteristic
increasingly uncommon, if not rare, cause of chronic liver disease given periodic acid–Schiff (PAS)-positive, diastase-resistant globules are seen
the advances made in the care of patients with heart failure. on liver biopsy. The only effective treatment is liver transplantation,
which is curative.
Etiology and Pathology In the case of long-term right-sided
Cystic fibrosis is an uncommon inherited disorder affecting whites
heart failure, there is an elevated venous pressure transmitted via the
of northern European descent. A biliary-type cirrhosis can occur, and
inferior vena cava and hepatic veins to the sinusoids of the liver, which
some patients derive benefit from the chronic use of UDCA.
become dilated and engorged with blood. The liver becomes enlarged
and swollen, and with long-term passive congestion and relative
ischemia due to poor circulation, centrilobular hepatocytes can become MAJOR COMPLICATIONS OF CIRRHOSIS
necrotic, leading to pericentral fibrosis. This fibrotic pattern can extend The clinical course of patients with advanced cirrhosis is often compli-
to the periphery of the lobule outward until a unique pattern of fibrosis cated by a number of important sequelae that can occur regardless of
causing cirrhosis can occur. the underlying cause of the liver disease. These include portal hyper-
tension and its consequences of gastroesophageal variceal hemorrhage,
Clinical Features Patients typically have signs of congestive heart splenomegaly, ascites, hepatic encephalopathy, spontaneous bacterial
failure and will manifest an enlarged firm liver on physical examina- peritonitis (SBP), hepatorenal syndrome (HRS), and hepatocellular
tion. ALP levels are characteristically elevated, and aminotransferases carcinoma (Table 337-2).

2410 TABLE 337-2 Complications of Cirrhosis splenic vein thrombosis. Posthepatic causes encompass those affecting
Portal hypertension Coagulopathy the hepatic veins and venous drainage to the heart; they include BCS,
Gastroesophageal varices Factor deficiency
venoocclusive disease, and chronic right-sided cardiac congestion.
Intrahepatic causes account for over 95% of cases of portal hyperten-
Portal hypertensive gastropathy Fibrinolysis
sion and are represented by the major forms of cirrhosis. Intrahepatic
Splenomegaly, hypersplenism Thrombocytopenia
causes of portal hypertension can be further subdivided into presinu-
Ascites Bone disease soidal, sinusoidal, and postsinusoidal causes. Postsinusoidal causes
Spontaneous bacterial peritonitis Osteopenia include venoocclusive disease, whereas presinusoidal causes include
Hepatorenal syndrome Osteoporosis congenital hepatic fibrosis and schistosomiasis. Sinusoidal causes are
Type 1 Osteomalacia related to cirrhosis from various causes.
Type 2 Hematologic abnormalities Cirrhosis is the most common cause of portal hypertension in the
Hepatic encephalopathy Anemia United States, and clinically significant portal hypertension is present
Hepatopulmonary syndrome Hemolysis in >60% of patients with cirrhosis. Portal vein obstruction may be
Portopulmonary hypertension Thrombocytopenia idiopathic or can occur in association with cirrhosis or with infection,
Malnutrition Neutropenia
pancreatitis, or abdominal trauma.
Coagulation disorders that can lead to the development of portal
vein thrombosis include polycythemia vera; essential thrombocytosis;
deficiencies in protein C, protein S, antithrombin 3, and factor V Leiden;
■ PORTAL HYPERTENSION and abnormalities in the gene-regulating prothrombin production.
Portal hypertension is defined as the elevation of the hepatic venous Some patients may have a subclinical myeloproliferative disorder.
pressure gradient (HVPG) to >5 mmHg. Portal hypertension is caused
by a combination of two simultaneously occurring hemodynamic Clinical Features The three primary complications of portal
processes: (1) increased intrahepatic resistance to the passage of blood hypertension are gastroesophageal varices with hemorrhage, ascites,
flow through the liver due to cirrhosis and regenerative nodules, and and hypersplenism. Thus, patients may present with upper GI bleed-
(2) increased splanchnic blood flow secondary to vasodilation within ing, which, on endoscopy, is found to be due to esophageal or gastric
the splanchnic vascular bed. Portal hypertension is directly responsible varices; with the development of ascites along with peripheral edema;
for the two major complications of cirrhosis: variceal hemorrhage and or with an enlarged spleen with associated reduction in platelets and
ascites. Variceal hemorrhage is an immediate life-threatening problem with white blood cells on routine laboratory testing.
a 20–30% mortality rate associated with each episode of bleeding. The ESOPHAGEAL VARICES Over the last decade, it has become common prac-
PART 10
portal venous system normally drains blood from the stomach, intes- tice to screen known cirrhotics with endoscopy to look for esophageal
tines, spleen, pancreas, and gallbladder, and the portal vein is formed by varices. Such screening studies have shown that approximately one-
the confluence of the superior mesenteric and splenic veins. Deoxygen- third of patients with histologically confirmed cirrhosis have varices.
ated blood from the small bowel drains into the superior mesenteric vein Approximately 5–15% of cirrhotics per year develop varices, and it
along with blood from the head of the pancreas, the ascending colon, is estimated that the majority of patients with cirrhosis will develop
and part of the transverse colon. Conversely, the splenic vein drains the varices over their lifetimes. Furthermore, it is anticipated that roughly
spleen and the pancreas and is joined by the inferior mesenteric vein, one-third of patients with varices will develop bleeding. Several factors
which brings blood from the transverse and descending colon as well predict the risk of bleeding, including the severity of cirrhosis (Child’s
as from the superior two-thirds of the rectum. Thus, the portal vein nor- class, MELD score); the height of wedged-hepatic vein pressure; the size
mally receives blood from almost the entire GI tract. of the varix; the location of the varix; and certain endoscopic stigmata,
The causes of portal hypertension are usually subcategorized as including red wale signs, hematocystic spots, diffuse erythema, bluish
prehepatic, intrahepatic, and posthepatic (Table 337-3). Prehepatic color, cherry red spots, or white-nipple spots. Patients with tense ascites
causes of portal hypertension are those affecting the portal venous sys- are also at increased risk for bleeding from varices.
tem before it enters the liver; they include portal vein thrombosis and
Diagnosis In patients with cirrhosis who are being followed chron-
ically, the development of portal hypertension is usually revealed by
the presence of thrombocytopenia; the appearance of an enlarged
TABLE 337-3 Classification of Portal Hypertension spleen; or the development of ascites, encephalopathy, and/or esoph-
Prehepatic ageal varices with or without bleeding. In previously undiagnosed
Portal vein thrombosis patients, any of these features should prompt further evaluation to
Splenic vein thrombosis determine the presence of portal hypertension and liver disease.
Massive splenomegaly (Banti’s syndrome) Varices should be identified by endoscopy. Abdominal imaging, either
Hepatic by computed tomography (CT) or MRI, can be helpful in demonstrat-
Presinusoidal ing a nodular liver and in finding changes of portal hypertension
Schistosomiasis
with intraabdominal collateral circulation. If necessary, interventional
radiologic procedures can be performed to determine wedged and free
Congenital hepatic fibrosis
hepatic vein pressures that will allow for the calculation of a wedged-
Sinusoidal
to-free gradient, which is equivalent to the portal pressure. The average
Cirrhosis—many causes normal wedged-to-free gradient is 5 mmHg, and patients with a gradi-
Alcoholic hepatitis ent >12 mmHg are at risk for variceal hemorrhage.
Postsinusoidal
Hepatic sinusoidal obstruction (venoocclusive syndrome)
Posthepatic TREATMENT
Budd-Chiari syndrome Variceal Hemorrhage
Inferior vena caval webs
Cardiac causes Treatment for variceal hemorrhage as a complication of portal hyper-
Restrictive cardiomyopathy tension is divided into two main categories: (1) primary prophylaxis
Constrictive pericarditis and (2) prevention of rebleeding once there has been an initial
variceal hemorrhage. Primary prophylaxis requires routine screening
Severe congestive heart failure
by endoscopy of all patients with cirrhosis. Once varices that are at

increased risk for bleeding are identified, primary prophylaxis can 2411
be achieved either through nonselective beta blockade or by variceal
MANAGEMENT OF RECURRENT
band ligation. Numerous placebo-controlled clinical trials of either VARICEAL HEMORRHAGE
propranolol or nadolol have been reported in the literature. The Recurrent acute bleeding
most rigorous studies were those that only included patients with
significantly enlarged varices or with hepatic vein pressure gradients
>12 mmHg. Patients treated with beta blockers have a lower risk of Endoscopic therapy
variceal hemorrhage than those treated with placebo over 1 and 2 +/–
years of follow-up. There is also a decrease in mortality related to Pharmacologic therapy
variceal hemorrhage. Unfortunately, overall survival was improved
in only one study. Further studies have demonstrated that the degree
Control of bleeding
of reduction of portal pressure is a significant feature to determine
success of therapy. Therefore, it has been suggested that repeat
measurements of hepatic vein pressure gradients may be used to
guide pharmacologic therapy; however, this may be cost-prohibitive. Compensated cirrhosis Decompensated cirrhosis
Several studies have evaluated variceal band ligation and variceal Child’s class A Child’s class B or C
sclerotherapy as methods for providing primary prophylaxis.
Endoscopic variceal ligation (EVL) has achieved a level of success
Surgical shunt Transplant evaluation
and comfort with most gastroenterologists who see patients with vs TIPS
these complications of portal hypertension. Thus, in patients with
cirrhosis who are screened for portal hypertension and are found to Endoscopic therapy or
have large varices, it is recommended that they receive either beta Liver transplantation beta blockers
blockade or primary prophylaxis with EVL.
The approach to patients once they have had a variceal bleed is
first to treat the acute bleed, which can be life-threatening, and then Consider TIPS
to prevent further bleeding. Prevention of further bleeding is usually
accomplished with repeated variceal band ligation until varices are Liver transplantation
obliterated. Treatment of acute bleeding requires both fluid and

blood-product replacement as well as prevention of subsequent
bleeding with EVL. FIGURE 337-3 Management of recurrent variceal hemorrhage. This algorithm
describes an approach to management of patients who have recurrent bleeding
The medical management of acute variceal hemorrhage includes from esophageal varices. Initial therapy is generally with endoscopic therapy often
the use of vasoconstricting agents, usually somatostatin or octreo- supplemented by pharmacologic therapy. With control of bleeding, a decision
tide. Vasopressin was used in the past but is no longer commonly needs to be made as to whether patients should go on to a surgical shunt or TIPS
used. Balloon tamponade (Sengstaken-Blakemore tube or Minnesota (if they are Child’s class A) and be considered for transplant, or if they should
tube) can be used in patients who cannot get endoscopic therapy have TIPS and be considered for transplant (if they are Child’s class B or C). TIPS,
immediately or who need stabilization prior to endoscopic therapy. transjugular intrahepatic portosystemic shunt.
Control of bleeding can be achieved in the vast majority of cases;
however, bleeding recurs in the majority of patients if definitive
endoscopic therapy has not been instituted. Octreotide, a direct once varices have been obliterated, the need for beta blockade is
splanchnic vasoconstrictor, is given at dosages of 50–100 μg/h by lessened. Despite successful variceal obliteration, many patients will
continuous infusion. Endoscopic intervention is used as first-line still have portal hypertensive gastropathy from which bleeding can
treatment to control bleeding acutely. Some endoscopists will use occur. Nonselective beta blockade may be helpful to prevent further
variceal injection therapy (sclerotherapy) as initial therapy, partic- bleeding from portal hypertensive gastropathy once varices have
ularly when bleeding is vigorous. Variceal band ligation is used to been obliterated (Fig. 337-3).
control acute bleeding in over 90% of cases and should be repeated Portosystemic shunt surgery is less commonly performed with
until obliteration of all varices is accomplished. When esophageal the advent of TIPS; nonetheless, this procedure should be consid-
varices extend into the proximal stomach, band ligation is less suc- ered for patients with good hepatic synthetic function who could
cessful. In these situations, when bleeding continues from gastric benefit by having portal decompressive surgery.
varices, consideration for a transjugular intrahepatic portosystemic
shunt (TIPS) should be made. This technique creates a portosys-
temic shunt by a percutaneous approach using an expandable ■ SPLENOMEGALY AND HYPERSPLENISM
metal stent, which is advanced under angiographic guidance to the Congestive splenomegaly is common in patients with portal hyper-
hepatic veins and then through the substance of the liver to create tension. Clinical features include the presence of an enlarged spleen
a direct portocaval shunt. This offers an alternative to surgery for on physical examination and the development of thrombocytopenia
acute decompression of portal hypertension. Encephalopathy can and leukopenia in patients who have cirrhosis. Some patients will
occur in as many as 20% of patients after TIPS and is particularly have fairly significant left-sided and left upper quadrant abdominal
problematic in elderly patients and in patients with preexisting pain related to an enlarged and engorged spleen. Splenomegaly itself
encephalopathy. TIPS should be reserved for individuals who fail usually requires no specific treatment, although splenectomy can be
endoscopic or medical management or who are poor surgical risks. successfully performed under very special circumstances.
TIPS can sometimes be used as a bridge to transplantation. Surgical Hypersplenism with the development of thrombocytopenia is a
esophageal transsection is a procedure that is rarely used and gen- common feature of patients with cirrhosis and is usually the first indi-
erally is associated with a poor outcome. cation of portal hypertension.
MANAGEMENT OF RECURRENT VARICEAL HEMORRHAGE
■ ASCITES
Once patients have had an acute bleed and have been managed suc-
cessfully, attention should be paid to preventing recurrent bleeding. Definition Ascites is the accumulation of fluid within the peri-
This usually requires repeated variceal band ligation until varices toneal cavity. Overwhelmingly, the most common cause of ascites is
are obliterated. Beta blockade may be of adjunctive benefit in portal hypertension related to cirrhosis; however, clinicians should
patients who are having recurrent variceal band ligation; however, remember that malignant or infectious causes of ascites can be present

2412 to percussion. Subtle amounts of ascites can be detected by ultrasound
DEVELOPMENT OF ASCITES IN CIRRHOSIS or CT scanning. Hepatic hydrothorax is more common on the right side
Cirrhosis and implicates a rent in the diaphragm with free flow of ascitic fluid
into the thoracic cavity.
When patients present with ascites for the first time, it is recom-
Portal hypertension mended that a diagnostic paracentesis be performed to characterize
the fluid. This should include the determination of total protein and
albumin content, blood cell counts with differential, and cultures.
Splanchnic vasodilation
In the appropriate setting, amylase may be measured and cytology
performed. In patients with cirrhosis, the protein concentration of the
ascitic fluid is quite low, with the majority of patients having an ascitic
↑ Splanchnic pressure Arterial underfilling fluid protein concentration <1 g/dL. The development of the serum
ascites-to-albumin gradient (SAAG) has replaced the description of
Lymph formation exudative or transudative fluid. When the gradient between the serum
Activation of albumin level and the ascitic fluid albumin level is >1.1 g/dL, the cause
vasoconstrictors and of the ascites is most likely due to portal hypertension; this is usually
Formation of ascites
antinatriuretic factors*
in the setting of cirrhosis. When the gradient is <1.1 g/dL, infectious or
malignant causes of ascites should be considered. When levels of ascitic
Plasma volume fluid proteins are very low, patients are at increased risk for develop-
Sodium retention
expansion
ing SBP. A high level of red blood cells in the ascitic fluid signifies a
traumatic tap or perhaps a hepatocellular cancer or a ruptured omental
FIGURE 337-4 Development of ascites in cirrhosis. This flow diagram illustrates varix. When the absolute level of polymorphonuclear leukocytes is
the importance of portal hypertension with splanchnic vasodilation in the >250/μL, the question of ascitic fluid infection should be strongly
development of ascites. *Antinatriuretic factors include the renin-angiotensin-
aldosterone system and the sympathetic nervous system.
considered. Ascitic fluid cultures should be obtained using bedside
inoculation of culture media.
as well, and careful differentiation of these other causes are obviously TREATMENT
important for patient care.
Ascites
Pathogenesis The presence of portal hypertension contributes to
PART 10
the development of ascites in patients who have cirrhosis (Fig. 337-4). Patients with small amounts of ascites can usually be managed
There is an increase in intrahepatic resistance, causing increased por- with dietary sodium restriction alone. Most average diets in the
tal pressure, but there is also vasodilation of the splanchnic arterial United States contain 6–8 g of sodium per day, and if patients eat
system, which, in turn, results in an increase in portal venous inflow. at restaurants or fast-food outlets, the amount of sodium in their
Both of these abnormalities result in increased production of splanch- diet can exceed this amount. Thus, it is often extremely difficult to
nic lymph. Vasodilating factors such as nitric oxide are responsible for get patients to change their dietary habits to ingest <2 g of sodium
the vasodilatory effect. These hemodynamic changes result in sodium per day, which is the recommended amount. Patients are frequently
retention by causing activation of the renin-angiotensin-aldosterone surprised to realize how much sodium is in the standard U.S. diet;
system with the development of hyperaldosteronism. The renal effects thus, it is important to make educational pamphlets available to the
of increased aldosterone leading to sodium retention also contribute to patient. Often, a simple recommendation is to eat fresh or frozen
the development of ascites. Sodium retention causes fluid accumula- foods, avoiding canned or processed foods, which are usually pre-
tion and expansion of the extracellular fluid volume, which results in served with sodium. When a moderate amount of ascites is present,
the formation of peripheral edema and ascites. Sodium retention is the diuretic therapy is usually necessary. Traditionally, spironolactone
consequence of a homeostatic response caused by underfilling of the at 100–200 mg/d as a single dose is started, and furosemide may be
arterial circulation secondary to arterial vasodilation in the splanchnic added at 40–80 mg/d, particularly in patients who have peripheral
vascular bed. Because the retained fluid is constantly leaking out of the edema. In patients who have never received diuretics before, the fail-
intravascular compartment into the peritoneal cavity, the sensation of ure of the above-mentioned dosages suggests that they are not being
vascular filling is not achieved, and the process continues. Hypoalbu- compliant with a low-sodium diet. If compliance is confirmed and
minemia and reduced plasma oncotic pressure also contribute to the ascitic fluid is not being mobilized, spironolactone can be increased
loss of fluid from the vascular compartment into the peritoneal cavity. to 400–600 mg/d and furosemide increased to 120–160 mg/d. If
Hypoalbuminemia is due to decreased synthetic function in a cirrhotic ascites is still present with these dosages of diuretics in patients who
liver. are compliant with a low-sodium diet, then they are defined as hav-
ing refractory ascites, and alternative treatment modalities including
Clinical Features Patients typically note an increase in abdomi- repeated large-volume paracentesis or a TIPS procedure should be
nal girth that is often accompanied by the development of peripheral considered (Fig. 337-5). Recent studies have shown that TIPS, while
edema. The development of ascites is often insidious, and it is surpris- managing the ascites, does not improve survival in these patients.
ing that some patients wait so long and become so distended before Unfortunately, TIPS is often associated with an increased frequency
seeking medical attention. Patients usually have at least 1–2 L of fluid of hepatic encephalopathy and must be considered carefully on a
in the abdomen before they are aware that there is an increase. If ascitic case-by-case basis. The prognosis for patients with cirrhosis with
fluid is massive, respiratory function can be compromised, and patients ascites is poor, and some studies have shown that <50% of patients
will complain of shortness of breath. Hepatic hydrothorax may also survive 2 years after the onset of ascites. Thus, there should be
occur in this setting, contributing to respiratory symptoms. Patients consideration for liver transplantation in patients with the onset of
with massive ascites are often malnourished and have muscle wasting ascites.
and excessive fatigue and weakness.
Diagnosis Diagnosis of ascites is by physical examination and is ■ SPONTANEOUS BACTERIAL PERITONITIS
often aided by abdominal imaging. Patients will have bulging flanks, SBP is a common and severe complication of ascites characterized by
may have a fluid wave, or may have the presence of shifting dullness. spontaneous infection of the ascitic fluid without an intraabdominal
This is determined by taking patients from a supine position to lying on source. In patients with cirrhosis and ascites severe enough for hospi-
either their left or right side and noting the movement of the dullness talization, SBP can occur in up to 30% of individuals and can have a

the prognosis is poor unless transplant can be achieved within a short 2413
TREATMENT OF REFRACTORY ASCITES period of time.
Refractory ascites
■ HEPATIC ENCEPHALOPATHY
Portosystemic encephalopathy is a serious complication of chronic
Large volume paracentesis (LVP) + albumin liver disease and is broadly defined as an alteration in mental status
and cognitive function occurring in the presence of liver failure. In
acute liver injury with fulminant hepatic failure, the development of
Dietary sodium restriction + diuretics encephalopathy is a requirement for a diagnosis of fulminant failure.
Encephalopathy is much more commonly seen in patients with chronic
liver disease. Gut-derived neurotoxins that are not removed by the
Ascites reaccumulation
liver because of vascular shunting and decreased hepatic mass get to
the brain and cause the symptoms that we know of as hepatic encepha-
lopathy. Ammonia levels are typically elevated in patients with hepatic
Consider TIPS Continue LVP with Consider liver encephalopathy, but the correlation between severity of liver disease
albumin as needed transplantation and height of ammonia levels is often poor, and most hepatologists do
not rely on ammonia levels to make a diagnosis. Other compounds and
FIGURE 337-5 Treatment of refractory ascites. In patients who develop azotemia metabolites that may contribute to the development of encephalopathy
in the course of receiving diuretics in the management of their ascites, some will include certain false neurotransmitters and mercaptans.
require repeated large-volume paracentesis (LVP), some may be considered for
transjugular intrahepatic portosystemic shunt (TIPS), and some would be good Clinical Features In acute liver failure, changes in mental status
candidates for liver transplantation. These decisions are all individualized. can occur within weeks to months. Brain edema can be seen in these
patients, with severe encephalopathy associated with swelling of the
gray matter. Cerebral herniation is a feared complication of brain
25% in-hospital mortality rate. Bacterial translocation is the presumed edema in acute liver failure, and treatment is meant to decrease edema
mechanism for development of SBP, with gut flora traversing the intes- with mannitol and judicious use of intravenous fluids.
tine into mesenteric lymph nodes, leading to bacteremia and seeding In patients with cirrhosis, encephalopathy is often found as a result
of the ascitic fluid. The most common organisms are Escherichia coli and of certain precipitating events such as hypokalemia, infection, an
other gut bacteria; however, gram-positive bacteria, including Strepto- increased dietary protein load, or electrolyte disturbances. Patients

coccus viridans, Staphylococcus aureus, and Enterococcus sp., can also be may be confused or exhibit a change in personality. They may actually
found. If more than two organisms are identified, secondary bacterial be quite violent and difficult to manage; alternatively, patients may
peritonitis due to a perforated viscus should be considered. The diag- be very sleepy and difficult to rouse. Because precipitating events
nosis of SBP is made when the fluid sample has an absolute neutrophil are so commonly found, they should be sought carefully. If patients
count >250/μL. Bedside cultures should be obtained when ascitic fluid have ascites, this should be tapped to rule out infection. Evidence of
is tapped. Patients with ascites may present with fever, altered mental GI bleeding should be sought, and patients should be appropriately
status, elevated white blood cell count, and abdominal pain or discom- hydrated. Electrolytes should be measured and abnormalities cor-
fort, or they may present without any of these features. Therefore, it is rected. In patients presenting with encephalopathy, asterixis is often
necessary to have a high degree of clinical suspicion, and peritoneal present. Asterixis can be elicited by having patients extend their arms
taps are important for making the diagnosis. Treatment is commonly and bend their wrists back. In this maneuver, patients who are enceph-
with a third-generation cephalosporin. In patients with variceal hemor- alopathic have a “liver flap”—that is, a sudden forward movement
rhage, the frequency of SBP is significantly increased, and prophylaxis of the wrist. This requires patients to be able to cooperate with the
against SBP is recommended when a patient presents with upper GI examiner and obviously cannot be elicited in patients who are severely
bleeding. Furthermore, in patients who have had an episode(s) of SBP encephalopathic or in hepatic coma.
and recovered, once-weekly administration of antibiotics is used as The diagnosis of hepatic encephalopathy is clinical and requires an
prophylaxis for recurrent SBP. experienced clinician to recognize and put together all of the various
features. Often when patients have encephalopathy for the first time,
■ HEPATORENAL SYNDROME they (and/or their caregivers) are unaware of what is transpiring, but
HRS is a form of functional renal failure without renal pathology that once they have been through the experience for the first time, they
occurs in about 10% of patients with advanced cirrhosis or acute liver can identify when this is developing in subsequent situations and
failure. There are marked disturbances in the arterial renal circulation can often self-medicate to impair the development or worsening of
in patients with HRS; these include an increase in vascular resistance encephalopathy.
accompanied by a reduction in systemic vascular resistance. The reason
for renal vasoconstriction is most likely multifactorial and is poorly
understood. The diagnosis is made usually in the presence of a large TREATMENT
amount of ascites in patients who have a stepwise progressive increase Hepatic Encephalopathy
in creatinine. Type 1 HRS is characterized by a progressive impairment
in renal function and a significant reduction in creatinine clearance Treatment is multifactorial and includes management of the above-
within 1–2 weeks of presentation. Type 2 HRS is characterized by a mentioned precipitating factors. Sometimes hydration and correc-
reduction in glomerular filtration rate with an elevation of serum crea- tion of electrolyte imbalance are all that is necessary. In the past,
tinine level, but it is fairly stable and is associated with a better outcome restriction of dietary protein was considered for patients with
than that of type 1 HRS. encephalopathy; however, the negative impact of that maneuver on
HRS is often seen in patients with refractory ascites and requires overall nutrition is thought to outweigh the benefit when treating
exclusion of other causes of acute renal failure. Treatment has, unfor- encephalopathy, and it is thus discouraged. There may be some
tunately, been difficult, and in the past, dopamine or prostaglandin benefit to replacing animal-based protein with vegetable-based
analogues were used as renal vasodilating medications. Carefully protein in some patients with encephalopathy that is difficult to
performed studies have failed to show clear-cut benefit from these manage. The mainstay of treatment for encephalopathy, in addition
therapeutic approaches. Currently, patients are treated with midodrine, to correcting precipitating factors, is to use lactulose, a nonabsorb-
an α-agonist, along with octreotide and intravenous albumin. The best able disaccharide, which results in colonic acidification. Catharsis
therapy for HRS is liver transplantation; recovery of renal function ensues, contributing to the elimination of nitrogenous products in
is typical in this setting. In patients with either type 1 or type 2 HRS, the gut that are responsible for the development of encephalopathy.

2414 Runyon BA: Introduction to the revised American Association for the
The goal of lactulose therapy is to promote 2–3 soft stools per day.
Patients are asked to titrate their amount of ingested lactulose to Study of Liver Diseases practice guideline management of adult patients
achieve the desired effect. Poorly absorbed antibiotics are often with ascites due to cirrhosis: Update 2012. Hepatology 57:1651, 2013.
used as adjunctive therapies for patients who have a difficult time Terrault NA et al: AASLD guidelines for treatment of chronic
with lactulose. The alternating administration of neomycin and hepatitis B. Hepatology 63:261, 2016.
metronidazole has been used in the past to reduce the individual Vilstrup H et al: Hepatic encephalopathy in chronic liver disease: 2014
side effects of each: neomycin for renal insufficiency and ototox- Practice Guideline by the American Association for the Study of Liver
icity and metronidazole for peripheral neuropathy. More recently, Diseases and the European Association for the Study of the Liver.
rifaximin at 550 mg twice daily has been very effective in treating Hepatology 60:715, 2014.
encephalopathy without the known side effects of neomycin or met-
ronidazole. Zinc supplementation is sometimes helpful in patients
with encephalopathy and is relatively harmless. The development
of encephalopathy in patients with chronic liver disease is a poor
prognostic sign, but this complication can be managed in the vast
338 Liver Transplantation

majority of patients.
■ MALNUTRITION IN CIRRHOSIS Raymond T. Chung, Jules L. Dienstag

Because the liver is principally involved in the regulation of protein
and energy metabolism in the body, it is not surprising that patients
with advanced liver disease are commonly malnourished. Once Liver transplantation—the replacement of the native, diseased liver by
patients become cirrhotic, they are more catabolic, and muscle protein a normal organ (allograft)—has matured from an experimental pro-
is metabolized. There are multiple factors that contribute to the mal- cedure reserved for desperately ill patients to an accepted, lifesaving
nutrition of cirrhosis, including poor dietary intake, alterations in gut operation applied more optimally in the natural history of end-stage
nutrient absorption, and alterations in protein metabolism. Dietary liver disease. The preferred and technically most advanced approach
supplementation for patients with cirrhosis is helpful in preventing is orthotopic transplantation, in which the native organ is removed and
patients from becoming catabolic. the donor organ is inserted in the same anatomic location. Pioneered
in the 1960s by Thomas Starzl at the University of Colorado and,
■ ABNORMALITIES IN COAGULATION
later, at the University of Pittsburgh and by Roy Calne in Cambridge,
Coagulopathy is almost universal in patients with cirrhosis. There
PART 10
England, liver transplantation is now performed routinely worldwide.

is decreased synthesis of clotting factors and impaired clearance of
Success measured as 1-year survival has improved from ~30% in the
anticoagulants. In addition, patients may have thrombocytopenia
1970s to >90% today. These improved prospects for prolonged survival
from hypersplenism due to portal hypertension. Vitamin K–dependent
resulted from refinements in operative technique, improvements in
clotting factors are factors II, VII, IX, and X. Vitamin K requires biliary
organ procurement and preservation, advances in immunosuppressive
excretion for its subsequent absorption; thus, in patients with chronic

therapy, and, perhaps most influentially, more enlightened patient
cholestatic syndromes, vitamin K absorption is frequently diminished.
selection and timing. Despite the perioperative morbidity and mor-
Intravenous or intramuscular vitamin K can quickly correct this abnor-
tality, the technical and management challenges of the procedure, and
mality. More commonly, the synthesis of vitamin K–dependent clotting
its costs, liver transplantation has become the approach of choice for
factors is diminished because of a decrease in hepatic mass, and, under
selected patients whose chronic or acute liver disease is progressive,
these circumstances, administration of parenteral vitamin K does not
life-threatening, and unresponsive to medical therapy. Based on the
improve the clotting factors or the prothrombin time. Platelet function
current level of success, the number of liver transplants has continued
is often abnormal in patients with chronic liver disease, in addition to
to grow each year; in 2017, 8082 patients received liver allografts in the
decreases in platelet levels due to hypersplenism.
United States. Still, the demand for new livers continues to outpace
■ BONE DISEASE IN CIRRHOSIS availability; as of 2018, 13,925 patients in the United States were on
Osteoporosis is common in patients with chronic cholestatic liver a waiting list for a donor liver. In response to this drastic shortage of
disease because of malabsorption of vitamin D and decreased calcium donor organs, many transplantation centers supplement cadaver-organ
ingestion. The rate of bone resorption exceeds that of new bone forma- liver transplantation with living-donor transplantation.
tion in patients with cirrhosis, resulting in bone loss. Dual x-ray absorp-
tiometry (DEXA) is a useful method for determining osteoporosis or INDICATIONS
osteopenia in patients with chronic liver disease. When a DEXA scan Potential candidates for liver transplantation are children and adults
shows decreased bone mass, treatment should be administered with who, in the absence of contraindications (see below), suffer from severe,
bisphosphonates that are effective at inhibiting resorption of bone and irreversible liver disease for which alternative medical or surgical treat-
efficacious in the treatment of osteoporosis. ments have been exhausted or are unavailable. Timing of the operation
is of critical importance. Indeed, improved timing and better patient
■ HEMATOLOGIC ABNORMALITIES IN CIRRHOSIS selection are felt to have contributed more to the increased success of
Numerous hematologic manifestations of cirrhosis are present, includ- liver transplantation in the 1980s and beyond than all the impressive
ing anemia from a variety of causes including hypersplenism, hemo- technical and immunologic advances combined. Although the disease
lysis, iron deficiency, and perhaps folate deficiency from malnutrition. should be advanced, and although opportunities for spontaneous or
Macrocytosis is a common abnormality in red blood cell morphology medically induced stabilization or recovery should be allowed, the pro-
seen in patients with chronic liver disease, and neutropenia may be cedure should be done sufficiently early to give the surgical procedure
seen as a result of hypersplenism. a fair chance for success. Ideally, transplantation should be considered
in patients with end-stage liver disease who are experiencing or have
■ FURTHER READING experienced a life-threatening complication of hepatic decompensa-
AASLD/IDSA HCV Guidance Panel: Hepatitis C guidance: AASLD- tion or whose quality of life has deteriorated to unacceptable levels.
IDSA recommendations for testing, managing, and treating adults Although patients with well-compensated cirrhosis can survive for
infected with hepatitis C virus. Hepatology 62:932, 2015. many years, many patients with quasi-stable chronic liver disease have
Garcia-Tsao G et al: Prevention and management of gastroesophageal much more advanced disease than may be apparent. As discussed
varices and variceal hemorrhage in cirrhosis. Am J Gastroenterol below, the better the status of the patient prior to transplantation, the
102:2086, 2007. higher will be its anticipated success rate. The decision about when to

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European Association for the Study of the Liver: EASL Recom- TABLE 335-1 Risk Factors for Alcoholic

ctors for Alcoholic Liver Disease 2399

335 Alcoholic Liver Disease

CHAPTER 335 Alcoholic Liver Disease

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www.lillemodel.com, uses pretreatment variables plus the change in

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CHAPTER 336 Nonalcoholic Fatty Liver Diseases and Nonalcoholic Steatohepatitis

336 Nonalcoholic Fatty Liver

■ INCIDENCE, PREVALENCE, AND NATURAL HISTORY

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CHAPTER 337 Cirrhosis and Its Complications

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CHAPTER 337 Cirrhosis and Its Complications

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frequent naps should be encouraged. Pruritus is treated with anti-

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CHAPTER 337 Cirrhosis and Its Complications

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CHAPTER 337 Cirrhosis and Its Complications

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CHAPTER 337 Cirrhosis and Its Complications

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338 Liver Transplantation

■ MALNUTRITION IN CIRRHOSIS Raymond T. Chung, Jules L. Dienstag

England, liver transplantation is now performed routinely worldwide.

excretion for its subsequent absorption; thus, in patients with chronic

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