Online Submissions: http://www.wjgnet.

com/1007-9327office
wjg@wjgnet.com
doi:10.3748/wjg.v16.i30.3745

World J Gastroenterol 2010 August 14; 16(30): 3745-3749

ISSN 1007-9327 (print)

2010 Baishideng. All rights reserved.

TOPIC HIGHLIGHT
Marco G Patti, MD, Professor, Director, Series Editor

Gastroesophageal reflux disease: From pathophysiology to

treatment
Fernando A Herbella, Marco G Patti
Fernando A Herbella, Marco G Patti, Department of Surgery,
University of Chicago Pritzker School of Medicine, Chicago, IL
60637, United States
Author contributions: Herbella FA wrote the manuscript; Patti
MG revised the manuscript.
Correspondence to: Marco G Patti, MD, Professor, Director,
Department of Surgery, University of Chicago Pritzker School of
Medicine, 5841 S. Maryland Ave, MC 5095, Room G-201, Chicago, IL 60637, United States. mpatti@surgery.bsd.uchicago.edu
Telephone: +1-773-7024763 Fax: +1-773-7026120
Revised: June 7, 2010
Received: April 24, 2010
Accepted: June 14, 2010
Published online: August 14, 2010

dre, CHU de Bordeaux, 1 rue Jean Burguet, 33075 Bordeaux

Cedex, France
Herbella FA, Patti MG. Gastroesophageal reflux disease: From
pathophysiology to treatment. World J Gastroenterol 2010;
16(30): 3745-3749 Available from: URL: http://www.wjgnet.
com/1007-9327/full/v16/i30/3745.htm DOI: http://dx.doi.
org/10.3748/wjg.v16.i30.3745

INTRODUCTION
Gastroesophageal reflux disease (GERD) is a very prevalent disease. Population studies have repeatedly shown
GERD-related symptoms in a significant proportion
of adults. The Montreal consensus conference defined
GERD as a condition which develops when the reflux
of gastric contents causes troublesome symptoms and/or
complications[1]. However, this definition did not include details of the pathophysiology of the disease and
its implications for treatment. The Brazilian consensus
conference considered GERD to be a chronic disorder
related to the retrograde flow of gastro-duodenal contents
into the esophagus and/or adjacent organs, resulting in a
spectrum of symptoms, with or without tissue damage[2].
This definition recognizes the chronic character of the
disease, and acknowledges that the refluxate can be gastric
and duodenal in origin, with important implications for
the treatment of this disease.
This review focuses on the pathophysiology of GERD
and its implications for treatment.

Abstract
This review focuses on the pathophysiology of gastroesophageal reflux disease (GERD) and its implications
for treatment. The role of the natural anti-reflux mechanism (lower esophageal sphincter, esophageal peristalsis, diaphragm, and trans-diaphragmatic pressure
gradient), mucosal damage, type of refluxate, presence
and size of hiatal hernia, Helicobacter pylori infection,
and Barretts esophagus are reviewed. The conclusions
drawn from this review are: (1) the pathophysiology of
GERD is multifactorial; (2) because of the pathophysiology of the disease, surgical therapy for GERD is the
most appropriate treatment; and (3) the genesis of
esophageal adenocarcinoma is associated with GERD.
2010 Baishideng. All rights reserved.

Key words: Gastroesophageal reflux disease; Pathophysiology; Acid reflux; Non-acid reflux; Esophageal manometry; Ambulatory pH; Barretts esophagus; Esophageal
adenocarcinoma

GERD - ROLE OF NATURAL ANTI-REFLUX

MECHANISMS
Although all normal individuals experience some sort of
physiological gastroesophageal reflux, a highly efficient
barrier exists between the stomach and the esophagus.
From the esophageal side, esophageal clearance is pro-

Peer reviewers: Wojciech Blonski, MD, PhD, University of

Pennsylvania, GI Research-Ground Centrex, 3400 Spruce St,
Philadelphia, PA 19104, United States; Frank Zerbib, MD, PhD,
Professor, Department of Gastroenterology, Hopital Saint An-

WJG|www.wjgnet.com

3745

August 14, 2010|Volume 16|Issue 30|

Herbella FA et al . Pathophysiology of gastroesophageal reflux

distention is probably involved[11,13]. It has been shown

that a mechanically incompetent LES is progressively associated with worse mucosal damage[7].
At the present time, there are no medications used
in clinical practice that act on the LES. Some studies
are presently conducted using inhibitors of the GABA
type B receptor, especially baclofen, but the effect of
this medication is still not clear. These data underline
that an incompetent LES represents a mechanical and
permanent defect of the gastroesophageal barrier. Only
fundoplication can correct the functional and mechanical profile of the LES, therefore resulting in control of
any type of reflux from the stomach into the esophagus.

moted by peristalsis and salivary production. A valve

mechanism exists between the esophagus and the stomach, formed by the lower esophageal sphincter (LES),
the diaphragm, the His angle, the Gubaroff valve and the
phrenoesophageal membrane.
Peristalsis
Esophageal peristalsis is an important component of the
antireflux mechanism because it is the main determinant
of esophageal clearance of the refluxate. Defective peristalsis is associated with severe GERD, both in terms of
symptoms and of mucosal damage[3]. As matter of fact,
the composite reflux score (DeMeester score)[4] includes in
its calculation two indirect measurements of esophageal
clearance (number of reflux episodes longer than 5 min
and length of the longest episode). In addition, the average esophageal clearance time can be calculated by dividing the total minutes the pH is below 4 by the number of
reflux episodes. This association also explains the high
prevalence and severity of GERD in systemic diseases that
affects peristalsis, such as connective tissue disorders[5].
It is known that 40%-50% of patients with GERD
have abnormal peristalsis[3]. This dysmotility is particularly severe in about 20% of patients because of very
low amplitude of peristalsis and/or abnormal propagation of the peristaltic waves (ineffective esophageal
motility)[6]. Esophageal clearance is slower than normal,
therefore, the refluxate is in contact with the esophageal
mucosa for a longer period of time and it is able to reach
more often the upper esophagus and pharynx. Thus,
these patients are prone to severe mucosal injury (including Barretts esophagus) and frequent extra-esophageal
symptoms such as cough[6,7].
It is still unclear whether esophageal dysmotility is
a primary condition that leads to GERD, or it is a consequence of esophageal inflammation. Medical therapy
does not ameliorate esophageal peristalsis[8,9]. However it
has been shown that effective fundoplication improves
the abnormal peristalsis in most patients[10].

Diaphragm
The crus of the diaphragm provides an extrinsic component to the gastroesophageal barrier. This pinchcock
action of the diaphragm is particularly important as a
protection against reflux induced by sudden increases in
intra-abdominal pressure[13]. This mechanism is obviously disrupted by the presence and size of a hiatal hernia.
Increase of thoraco-abdominal pressure gradient
Abnormal gastric emptying might contribute to GERD
by increasing intra-gastric pressure. Patients with suspected abnormal gastric emptying should be tested with
nuclear markers[14] or ultrasound[15]. If slow emptying is
diagnosed, appropriate therapy should be considered.
Medication such as metoclopramide and Nissen fundoplication improve gastric emptying[16].
There is also strong evidence of a possible link between obesity and GERD. Specifically, it has been shown
that there is a dose-response relationship between increasing body mass index (BMI) and prevalence of GERD and
its complications[17-19]. Some studies have reported that
morbidly obese patients with GERD have a higher incidence of incompetent LES, transient LES relaxation and
impaired esophageal motility than non-obese patients with
GERD[8,20,21]. However, a detailed mathematical analysis
has shown that the severity of GERD (based on the DeMeester score) is associated with BMI[22], which suggests
that obesity plays an independent role in the pathophysiology GERD, mainly through increased abdominal pressure[18,23].
The association of different pulmonary diseases and
GERD has recently gained renewed interest[24]. It has
been shown that patients with end-stage lung disease have
a high prevalence of GERD; up to 70%[25]. Although in
these patients pan-esophageal motor dysfunction is frequently found[25], a more negative thoracic pressure with
an increase in the gradient between intra-gastric and intrathoracic pressure might also contribute.

LES
Physiologically, the LES is a 3-4-cm-long segment of
tonically contracted smooth muscle at the distal end of
the esophagus[11]. It is intuitive that the LES creates a high
pressure zone between the esophagus and the stomach
that prevents reflux. An effective LES must have an adequate total and intra-abdominal length, and an adequate
resting pressure[12]. However, a normal LES pressure does
not exclude GERD, because abnormal transient relaxation might occur. Periodic relaxation of the LES in normal individuals has been termed transient lower esophageal sphincter relaxation (TLESR), to distinguish it from
relaxation triggered by swallowing. TLESR accounts for
the physiological reflux found in normal subjects. When
it becomes more frequent and prolonged, TLESR can
contribute to reflux disease, and this phenomenon appears to explain the reflux seen in the 40% of patients
with GERD whose resting LES pressure is normal. What
determines TLESR is unknown, but postprandial gastric

WJG|www.wjgnet.com

GERD: ROLE OF MUCOSAL DAMAGE

Increasing severity of esophagitis is associated with increasing acid exposure[26]; however, erosive esophagitis is
present in only 50% of GERD patients[7]. Some experts
believe that the erosive and non-erosive forms of the

3746

August 14, 2010|Volume 16|Issue 30|

Herbella FA et al . Pathophysiology of gastroesophageal reflux

to positive abdominal pressure and acts as a valve[34]. In

addition, TLESR seems to occur more frequently when
a hiatal hernia is present. Not surprisingly, the presence
and size of a hiatal hernia are associated with a more incompetent LES (the pinchcock action of the diaphragm
is absent), defective peristalsis, more severe mucosal
damage, and increased acid exposure[36].
Hiatal hernia is associated with early recurrence and
failure of medical therapy for GERD[34]. The reduction
of a hiatal hernia with narrowing of the esophageal hiatus is a key element in fundoplication and its omission or
failure is a cause of recurrence of GERD.

disease might actually account for different subsets of

the disease; others believe that they represent two different and progressive stages of the disease.
It is still unclear if mucosal inflammation is a cause
or a consequence of GERD. Evidence has shown that
esophagitis is associated with esophageal body dysmotility[7]. However, it is still unclear if it is the cause or the
effect of the altered peristalsis. We do know that medical therapy for GERD does not ameliorate esophageal
peristalsis[8,9], whereas surgical therapy clearly results in
improvement[10].

GERD: ROLE OF THE REFLUXATE

GERD: ROLE OF HELICOBACTER PYLORI

As previously mentioned, gastric and duodenal contents

can reflux into the esophagus and adjacent organs. Gastric
hydrochloric acid has long been recognized as harmful to
the esophagus[27]. However, gastro-esophageal refluxate
contains a variety of other noxious agents, including pepsin[26]. Currently, it is recognized that this component of
the refluxate (commonly called bile reflux and identified
by the Bilitec bile reflux monitor using bilirubin as a marker) is composed of bile salts and pancreatic enzymes[26],
and is also injurious to the esophageal mucosa. It causes
symptoms[28], and could be linked to the development of
Barretts esophagus[29] and esophageal adenocarcinoma[30].
Besides the constituents of the refluxate, symptom
perception and mucosal damage also appear to be linked
to the patterns of esophageal exposure and the volume
of the refluxate. Individuals are more likely to perceive
a reflux event if the refluxate has a high proximal extent
and a large volume[26].
Acid suppression is the main treatment for GERD. It
has evolved from topical alkaline antacids to very effective proton pump inhibitors (PPIs). Several studies have
shown the efficacy of PPIs in almost neutralizing gastric
acid. These medications make the refluxate less aggressive, which leads to symptom amelioration and healing
of esophagitis[31]. However, they do not stop reflux or
cure GERD, as different studies with intraluminal impedance technology have shown that PPI therapy alters
the pH of the refluxate but does not change the occurrence and number of reflux episodes [32,33]. Currently,
there is no specific medication that controls non-acid reflux. On the other hand, fundoplication blocks any type
of gastric refluxate because it restores the competence
of the gastroesophageal junction.

The association of GERD and Helicobacter pylori (H. pylori)

is very controversial. While some argue that the infection
might play a role in the prevention of GERD by altering
the nature of the refluxate (gastritis leading to achlorhydria), others find no link between the infection and esophageal diseases[37,38].
Prevalence studies seem to suggest that H. pylori infection is inversely associated with reflux esophagitis in
some populations[37]. Eradication studies also suggest that
H. pylori infection is protective with respect to GERD[37].
If H. pylori protects against GERD, a logical assumption would be that it also protects against adenocarcinoma
development. Furthermore, adenocarcinoma incidence
is rising worldwide; however, the increasing pace is slow
in underdeveloped countries, exactly where H. pylori incidence is higher. Indeed, the majority of epidemiological
studies have found a protective association, and the results
of three recently published meta-analyses have shown that
H. pylori colonization of the stomach is associated with a
nearly 50% reduction in cancer risk[39].

GERD AND BARRETTS ESOPHAGUS

The history of Barretts esophagus has been complicated
by different opinions on the genesis of the disease[40]. Currently, it is unquestionable that Barretts esophagus is an
acquired disease caused by GERD, although risk factors
and innate predisposition are still been scrutinized. Also,
it is believed that most, if not all, esophageal adenocarcinoma arises in Barretts mucosa[41].
With regard to GERD pathophysiology, Barretts
esophagus represents an end stage form of the disease.
It encompasses pan-esophageal motor dysfunction that
is characterized by abnormalities in esophageal peristalsis,
defective LES, and bile reflux[42]. Most authors consider
this form of GERD to be a surgical disease[43], based on
the aforementioned points.

GERD: ROLE OF HIATAL HERNIA

Hiatal hernia and GERD were once considered synonyms and hiatal hernia was considered a sine qua non
condition for GERD to occur[34,35]. Currently, it is well
known that both conditions can exist independently.
However, it is recognized that hiatal hernia disrupts most
of the natural antireflux mechanisms, and is considered
an independent factor for GERD[26]. The simple presence of an abdominal portion of the esophagus is considered an antireflux mechanism, because it is submitted

WJG|www.wjgnet.com

FROM PATHOPHYSIOLOGY TO
TREATMENT
The simultaneous use of intra-esophageal impedance and
pH measurement of acid and non-acid gastroesophageal

3747

August 14, 2010|Volume 16|Issue 30|

Herbella FA et al . Pathophysiology of gastroesophageal reflux

reflux has clearly shown that treatment with PPIs only

changes the pH of the refluxate, without stopping reflux through a functionally or mechanically incompetent
LES[44]. For instance, using this technology, Vela et al[44]
have shown that during treatment with omeprazole, postprandial reflux still occurs but it becomes predominantly
non-acid. In a study in normal subjects, Vela and colleagues also have shown that baclofen, a GABA B antagonist, is able to reduce both acid and non-acid reflux by
decreasing TLESR, the primary mechanism for both acid
and non-acid reflux[45]. This study signals an important
shift toward treatment focused on the competence of
the LES rather than the pH of the refluxate alone. This
goal can also be achieved by fundoplication; an operation
that can be done laparoscopically with a short hospital
stay, minimal postoperative discomfort, fast recovery
time and excellent results[46-49]. Long-term studies have
shown that fundoplication controls symptoms in 93% of
patients after 5 years and in 89% after 10 years[46]. The
operation controls reflux because it improves esophageal
motility, both in terms of LES competence and quality
of esophageal peristalsis[10]. Control of reflux is not influenced by the pattern of reflux, and is equally effective
when reflux is upright, supine or bipositional[47]. In addition, the operation is equally safe and effective in young
or elderly patients[48]. Concern has been raised about the
presence of postoperative dysphagia. In our experience,
this occurs in about 8% of patients, irrespective of the
type of fundoplication, and it resolves spontaneously in
all but a few patients in a few months, without requiring
re-intervention[49].
It is important to select the best treatment for the individual patient based on a review of symptoms, age, sex,
esophageal function, and type of refluxate. We feel that
laparoscopic fundoplication is indicated in the following
circumstances: when heartburn and regurgitation are not
affected by medical treatment; when it is thought that
cough is induced by reflux (Mainie et al[50] have shown that
patients with a positive symptom index resistant to PPIs
with non-acid or acid reflux demonstrated by multichannel intraluminal impedance-pH monitoring can be treated
successfully by laparoscopic Nissen fundoplication); poor
patient compliance; cost of medical therapy if more than
one pill/day of PPI is needed (most insurance companies in the United States pay for one pill/day only); and
postmenopausal women with osteoporosis. It has been
shown that PPIs and histamine-2 receptor antagonists can
increase the risk of hip and femur fractures[51]. Therefore,
medical treatment is not advisable for young and very
symptomatic patients.
Finally, in a recently published meta-analysis of medical vs surgical management for GERD, Wileman et al[52]
have shown that, in adults, laparoscopic fundoplication
is more effective than medical management for the treatment of GERD in the short to medium term. Surgery,
however, carries some risk and its application should be
individualized and the decision to undergo fundoplication should be based on patient and surgeon preference.

WJG|www.wjgnet.com

CONCLUSION
The pathophysiology of GERD is clearly multifactorial.
While medical therapy can only affect gastric acid production, fundoplication restores the function of the LES and
improves esophageal peristalsis. In addition, fundoplication stops any type of refluxate because it restores the
competence of the gastroesophageal junction. It seems
that fundoplication alone does not cause regression of
Barretts esophagus and does not prevent the development of adenocarcinoma. It will be important to study in
patients with Barretts esophagus the long-term effect of
surgery in association with new treatment modalities such
as radiofrequency ablation (RFA) and endoscopic mucosal
resection (EMR). The combination should be more effective than monotherapy, because RFA and EMR eliminate
the metaplastic or dysplastic epithelium, while fundoplication stops reflux, which is the original cause of Barretts
esophagus.

REFERENCES
1

3
4
5

6
7
8
9

10
11
12
13
14

3748

Vakil N, van Zanten SV, Kahrilas P, Dent J, Jones R. The

Montreal definition and classification of gastroesophageal
reflux disease: a global evidence-based consensus. Am J Gastroenterol 2006; 101: 1900-1920; quiz 1943
Moraes-Filho J, Cecconello I, Gama-Rodrigues J, Castro L,
Henry MA, Meneghelli UG, Quigley E. Brazilian consensus
on gastroesophageal reflux disease: proposals for assessment, classification, and management. Am J Gastroenterol
2002; 97: 241-248
Diener U, Patti MG, Molena D, Fisichella PM, Way LW.
Esophageal dysmotility and gastroesophageal reflux disease.
J Gastrointest Surg 2001; 5: 260-265
Johnson LF, Demeester TR. Twenty-four-hour pH monitoring of the distal esophagus. A quantitative measure of gastroesophageal reflux. Am J Gastroenterol 1974; 62: 325-332
Patti MG, Gasper WJ, Fisichella PM, Nipomnick I, Palazzo
F. Gastroesophageal reflux disease and connective tissue
disorders: pathophysiology and implications for treatment. J
Gastrointest Surg 2008; 12: 1900-1906
Patti MG, Perretta S. Gastro-oesophageal reflux disease: a
decade of changes. Asian J Surg 2003; 26: 4-6
Meneghetti AT, Tedesco P, Damani T, Patti MG. Esophageal
mucosal damage may promote dysmotility and worsen esophageal acid exposure. J Gastrointest Surg 2005; 9: 1313-1317
Xu JY, Xie XP, Song GQ, Hou XH. Healing of severe reflux
esophagitis with PPI does not improve esophageal dysmotility. Dis Esophagus 2007; 20: 346-352
McDougall NI, Mooney RB, Ferguson WR, Collins JS, McFarland RJ, Love AH. The effect of healing oesophagitis on
oesophageal motor function as determined by oesophageal
scintigraphy and ambulatory oesophageal motility/pH
monitoring. Aliment Pharmacol Ther 1998; 12: 899-907
Herbella FA, Tedesco P, Nipomnick I, Fisichella PM, Patti
MG. Effect of partial and total laparoscopic fundoplication
on esophageal body motility. Surg Endosc 2007; 21: 285-288
Kahrilas PJ. Anatomy and physiology of the gastroesophageal junction. Gastroenterol Clin North Am 1997; 26: 467-486
Zaninotto G, DeMeester TR, Schwizer W, Johansson KE,
Cheng SC. The lower esophageal sphincter in health and disease. Am J Surg 1988; 155: 104-111
Patti MG, Gantert W, Way LW. Surgery of the esophagus.
Anatomy and physiology. Surg Clin North Am 1997; 77:
959-970
Mariani G, Boni G, Barreca M, Bellini M, Fattori B, AlSharif

August 14, 2010|Volume 16|Issue 30|

Herbella FA et al . Pathophysiology of gastroesophageal reflux

15
16

17

18
19
20

21

22

23
24
25

26

27
28

29

30
31
32

33

A, Grosso M, Stasi C, Costa F, Anselmino M, Marchi S, Rubello D, Strauss HW. Radionuclide gastroesophageal motor
studies. J Nucl Med 2004; 45: 1004-1028
Dietrich CF, Braden B. Sonographic assessments of gastrointestinal and biliary functions. Best Pract Res Clin Gastroenterol
2009; 23: 353-367
Lindeboom MY, Ringers J, van Rijn PJ, Neijenhuis P, Stokkel
MP, Masclee AA. Gastric emptying and vagus nerve function after laparoscopic partial fundoplication. Ann Surg 2004;
240: 785-790
Murray L, Johnston B, Lane A, Harvey I, Donovan J, Nair P,
Harvey R. Relationship between body mass and gastro-oesophageal reflux symptoms: The Bristol Helicobacter Project.
Int J Epidemiol 2003; 32: 645-650
Fisichella PM, Patti MG. Gastroesophageal reflux disease
and morbid obesity: is there a relation? World J Surg 2009; 33:
2034-2038
El-Serag HB, Graham DY, Satia JA, Rabeneck L. Obesity is
an independent risk factor for GERD symptoms and erosive
esophagitis. Am J Gastroenterol 2005; 100: 1243-1250
Quiroga E, Cuenca-Abente F, Flum D, Dellinger EP, Oelschlager BK. Impaired esophageal function in morbidly
obese patients with gastroesophageal reflux disease: evaluation with multichannel intraluminal impedance. Surg Endosc
2006; 20: 739-743
Merrouche M, Sabat JM, Jouet P, Harnois F, Scaringi S, Coffin B, Msika S. Gastro-esophageal reflux and esophageal motility disorders in morbidly obese patients before and after
bariatric surgery. Obes Surg 2007; 17: 894-900
Herbella FA, Sweet MP, Tedesco P, Nipomnick I, Patti MG.
Gastroesophageal reflux disease and obesity. Pathophysiology and implications for treatment. J Gastrointest Surg 2007;
11: 286-290
Pandolfino JE, El-Serag HB, Zhang Q, Shah N, Ghosh SK,
Kahrilas PJ. Obesity: a challenge to esophagogastric junction
integrity. Gastroenterology 2006; 130: 639-649
Sweet MP, Patti MG, Hoopes C, Hays SR, Golden JA. Gastrooesophageal reflux and aspiration in patients with advanced
lung disease. Thorax 2009; 64: 167-173
Sweet MP, Herbella FA, Leard L, Hoopes C, Golden J, Hays
S, Patti MG. The prevalence of distal and proximal gastroesophageal reflux in patients awaiting lung transplantation.
Ann Surg 2006; 244: 491-497
Tack J, Koek G, Demedts I, Sifrim D, Janssens J. Gastroesophageal reflux disease poorly responsive to single-dose proton
pump inhibitors in patients without Barrett's esophagus: acid
reflux, bile reflux, or both? Am J Gastroenterol 2004; 99: 981-988
Herbella FA, Nipominick I, Patti MG. From sponges to capsules. The history of esophageal pH monitoring. Dis Esophagus 2009; 22: 99-103
Agrawal A, Roberts J, Sharma N, Tutuian R, Vela M, Castell DO. Symptoms with acid and nonacid reflux may be
produced by different mechanisms. Dis Esophagus 2009; 22:
467-470
Peters JH, Avisar N. The molecular pathogenesis of Barrett's
esophagus: common signaling pathways in embryogenesis
metaplasia and neoplasia. J Gastrointest Surg 2010; 14 Suppl 1:
S81-S87
Theisen J, Peters JH, Fein M, Hughes M, Hagen JA, Demeester SR, Demeester TR, Laird PW. The mutagenic potential of duodenoesophageal reflux. Ann Surg 2005; 241: 63-68
Katz PO, Zavala S. Proton pump inhibitors in the management of GERD. J Gastrointest Surg 2010; 14 Suppl 1: S62-S66
Tamhankar AP, Peters JH, Portale G, Hsieh CC, Hagen JA,
Bremner CG, DeMeester TR. Omeprazole does not reduce
gastroesophageal reflux: new insights using multichannel
intraluminal impedance technology. J Gastrointest Surg 2004;
8: 890-897; discussion 897-898
Blonski W, Vela MF, Castell DO. Comparison of reflux frequency during prolonged multichannel intraluminal impedance and pH monitoring on and off acid suppression therapy.

34
35
36

37
38
39
40
41

42
43

44

45

46

47

48

49

50

51

52

J Clin Gastroenterol 2009; 43: 816-820

Gordon C, Kang JY, Neild PJ, Maxwell JD. The role of the
hiatus hernia in gastro-oesophageal reflux disease. Aliment
Pharmacol Ther 2004; 20: 719-732
van Herwaarden MA, Samsom M, Smout AJ. The role of
hiatus hernia in gastro-oesophageal reflux disease. Eur J Gastroenterol Hepatol 2004; 16: 831-835
Patti MG, Goldberg HI, Arcerito M, Bortolasi L, Tong J, Way
LW. Hiatal hernia size affects lower esophageal sphincter
function, esophageal acid exposure, and the degree of mucosal injury. Am J Surg 1996; 171: 182-186
Metz DC, Kroser JA. Helicobacter pylori and gastroesophageal reflux disease. Gastroenterol Clin North Am 1999; 28:
971-985, viii
Souza RC, Lima JH. Helicobacter pylori and gastroesophageal reflux disease: a review of this intriguing relationship.
Dis Esophagus 2009; 22: 256-263
Kamangar F, Chow WH, Abnet CC, Dawsey SM. Environmental causes of esophageal cancer. Gastroenterol Clin North
Am 2009; 38: 27-57, vii
Herbella FA, Matone J, Del Grande JC. Eponyms in esophageal surgery, part 2. Dis Esophagus 2005; 18: 4-16
Chandrasoma P, Wickramasinghe K, Ma Y, DeMeester T. Is
intestinal metaplasia a necessary precursor lesion for adenocarcinomas of the distal esophagus, gastroesophageal junction and gastric cardia? Dis Esophagus 2007; 20: 36-41
Ang D, Blondeau K, Sifrim D, Tack J. The spectrum of motor
function abnormalities in gastroesophageal reflux disease
and Barrett's esophagus. Digestion 2009; 79: 158-168
Patti MG, Arcerito M, Feo CV, Worth S, De Pinto M, Gibbs
VC, Gantert W, Tyrrell D, Ferrell LF, Way LW. Barrett's esophagus: a surgical disease. J Gastrointest Surg 1999; 3: 397-403;
discussion 403-404
Vela MF, Camacho-Lobato L, Srinivasan R, Tutuian R, Katz
PO, Castell DO. Simultaneous intraesophageal impedance
and pH measurement of acid and nonacid gastroesophageal reflux: effect of omeprazole. Gastroenterology 2001; 120:
1599-1606
Vela MF, Tutuian R, Katz PO, Castell DO. Baclofen decreases acid and non-acid post-prandial gastro-oesophageal
reflux measured by combined multichannel intraluminal
impedance and pH. Aliment Pharmacol Ther 2003; 17: 243-251
Dallemagne B, Weerts J, Markiewicz S, Dewandre JM,
Wahlen C, Monami B, Jehaes C. Clinical results of laparoscopic fundoplication at ten years after surgery. Surg Endosc
2006; 20: 159-165
Meneghetti AT, Tedesco P, Galvani C, Gorodner MV, Patti
MG. Outcomes after laparoscopic Nissen fundoplication are
not influenced by the pattern of reflux. Dis Esophagus 2008;
21: 165-169
Tedesco P, Lobo E, Fisichella PM, Way LW, Patti MG. Laparoscopic fundoplication in elderly patients with gastroesophageal reflux disease. Arch Surg 2006; 141: 289-292; discussion
292
Patti MG, Robinson T, Galvani C, Gorodner MV, Fisichella
PM, Way LW. Total fundoplication is superior to partial fundoplication even when esophageal peristalsis is weak. J Am
Coll Surg 2004; 198: 863-869; discussion 869-870
Mainie I, Tutuian R, Agrawal A, Adams D, Castell DO.
Combined multichannel intraluminal impedance-pH monitoring to select patients with persistent gastro-oesophageal
reflux for laparoscopic Nissen fundoplication. Br J Surg 2006;
93: 1483-1487
Corley DA, Kubo A, Zhao W, Quesenberry C. Proton Pump
Inhibitors and Histamine-2 Receptor Antagonists Are Associated With Hip Fractures Among At-Risk Patients. Gastroenterology 2010; Epub ahead of print
Wileman SM, McCann S, Grant AM, Krukowski ZH, Bruce J.
Medical versus surgical management for gastro-oesophageal
reflux disease (GORD) in adults. Cochrane Database Syst Rev
2010; 3: CD003243
S- Editor Wang YR L- Editor Kerr C E- Editor Lin YP

WJG|www.wjgnet.com

3749

August 14, 2010|Volume 16|Issue 30|