Chapter 2

THE PATHOPHYSIOLOGY OF GERD

R. Dickman and R. Fass

The Neuro-Enteric Clinical Research Group, Section of Gastroenterology, Department of Medicine, Southern Arizona VA Health Care System
and University of Arizona School of Medicine, Tucson, AZ, USA

Abbreviations used: GERD – gastroesophageal into symptom generation in GERD disclosed the im-
reflux disease; LES – lower esophageal sphincter; portant role of altered esophageal sensation. Recent
NERD – non-erosive reflux disease; TLESR – tran- studies have demonstrated that peripheral and central
sient lower esophageal sphincter relaxation. factors are pivotal for the emergence of symptoms after
gastroesophageal reflux had occurred; supporting the
view that GERD is a sensory-motor disorder rather
than motor disorder alone.
Introduction The primary pathophysiologic event in GERD is
the movement of acid, pepsin, and other injurious
The understanding of the pathophysiology of gastro- substances from the stomach into the esophagus.
esophageal reflux disease (GERD) has evolved in the This event also occurs as part of normal physiology,
last decade primarily by recognizing the multitude of but results in GERD when symptoms or tissue dam-
factors that contribute to the emergence of the disorder age occurs. Esophageal mucosal injury in GERD
(Fig. 1). These factors may overlap in some patients results when mucosal defensive factors are over-
and differ in others. GERD is primarily considered a whelmed by refluxate, occurring secondary to com-
motility disorder, because dysfunction of the anti-reflux promised anti-reflux barrier, decreased effective
barrier is still considered as a prerequisite for the devel- esophageal acid clearance, abnormal mucosal defen-
opment of the disease. However, recent investigation sive factors and so on.

Fig. 1. A summary of the diverse etiological factors that result in gastroesophageal reflux and symptoms
14 Chapter 2

Anti-reflux barrier (NERD) [3]. In patients with NERD, the mean LES
basal pressure is similar to normal controls. For most
Failure of the anti-reflux barrier is considered the most patients with GERD, the predominant mechanism of
important factor in the pathogenesis of GERD. It is gastroesophageal reflux is transient lower esophageal
presently accepted that the two major elements that sphincter relaxation (TLESR) of an otherwise normal
compose the anti-reflux barrier are the lower esophageal LES (normal resting pressure) [4]. Physiologic reflux
sphincter (LES) and the crural diaphragm. The LES is a occurs mainly in an upright posture, postprandially
thickened ring of tonically contracted circular smooth [5]. This reflux is facilitated by episodes of inappropri-
muscle that generates a 2–4 cm high pressure zone at ate transient LES relaxation. TLESRs are spontane-
the gastroesophageal junction and serves as a mechani- ous, abnormally prolonged episodes of LES relaxation,
cal barrier between the stomach and the esophagus. The which are not preceded by a swallow or peristalsis [4],
right crus of the diaphragm encircles the LES by the [6]. Transient LES relaxation is a neural reflex, medi-
phreno-esophageal ligament and thus provides addi- ated through the brainstem, and the vagus nerve is its
tional mechanical support. Both structures generate a efferent pathway [7]. Gastric distension and pharyn-
high-pressure zone in the distal esophagus (15 mmHg geal stimulation have been demonstrated to elicit such
to 30 mmHg above gastric pressure). Failure of one or relaxation [8]. This is considered the only mechanism
both of these complimentary structures may lead to in- of reflux in people without GERD and in most of
competence of the anti-reflux barrier resulting in patho- those with GERD. GERD patients demonstrate pro-
logical gastroesophageal reflux. The variations in LES longed postprandial receptive relaxation of the fundus
pressure are usually coupled with esophageal and gastric leading to a delayed emptying of the proximal stom-
contractions, while the pressure contributed by the cru- ach [9], [10].
ral diaphragm is in response to physical activity such as TLESR s have been established as the primary
inspiration, coughing, Valsalva maneuver, abdominal mechanism for gastroesophageal reflux in normal sub-
compression and others. Myogenic and neurogenic jects and patients with GERD [11]–[13]. They also
mechanisms control the LES resting tone during both serve as the underlying mechanism for belching,
feeding and resting state. which may suggest some relationship with gastro-
LES resting pressure exhibits a significant diurnal esophageal reflux. Although, previous studies sug-
variation. During daytime, LES pressure is lower in gested that patients with GERD experience more
comparison to the postprandial and nighttime periods TLESR s than healthy controls, recent trials found no
[1]. Additionally, various substances such as hor- increased rate of TLESR s in patients with GERD.
mones, drugs and foods influence the LES basal pres- However, TLESR was more likely to be associated
sure. Substances that increase LES pressure include with acid reflux in patients with GERD (65%) when
gastrin, motilin, substance P, alfa-adrenergic antago- compared to healthy controls (35%) [11], [14]. Addi-
nists, beta-adrenergic agonists, protein, histamine, me- tionally, it appears that TLESR is the main underlying
toclopramide and prostaglandin F2a. Substances that mechanism responsible for gastroesophageal reflux
decrease LES basal pressure include secretin, chole- events in patients with NERD. In NERD patients,
cystokinin, glucagon, somatostatin, progesterone, alfa- who represent the majority of patients seen for reflux
adrenergic agonists, beta-adrenergic antagonists, fat, symptoms, TLESR rather than hypotensive LES
chocolate, ethanol, peppermint, theophylline, prosta- accounts for most gastroesophageal reflux events. In
glandin E2, serotonin, morphine, calcium channel the presence of hiatal hernia, which affects up to 70%
blockers, diazepam and barbiturates [2]. of the erosive esophagitis patients, other mechanisms
Originally, gastroesophageal reflux was thought to than TLESR play an important role, such as abnor-
occur across a hypotensive LES. However, the LES mally low LES basal pressure and stress reflux. In
basal pressure is variable in patients with GERD, and NERD patients on the other hand hiatal hernia is re-
in most cases within the normal limits [3]. However, latively uncommon (
30%).
patients with erosive esophagitis or Barrett’s esopha- Reduced LES basal pressure and stress reflux are
gus demonstrate a significantly lower mean LES basal other mechanisms that affect primarily patients with
pressure than patients with non-erosive reflux disease erosive esophagitis. Dent et al [5] evaluated GERD pa-
Dickman R and Fass R 15

tients with different phenotypic presentations of GERD Peristaltic dysfunction of the esophageal body in
and found that with increasing severity of esophagitis, GERD is well documented [16], [17]. Esophageal
absent basal LES pressure became a more common peristaltic dysfunction is increasingly observed with
mechanism, accounting for 23% of gastroesophageal re- more severe grades of erosive esophagitis and particu-
flux episodes in patients with severe erosive esophagitis. larly in patients with Barrett’s esophagus [3]. There
Stress reflux is another mechanism responsible for ga- has been a long-standing argument as to whether the
stroesophageal reflux in which increase in intra-ab- observed esophageal dysmotility precedes or is caused
dominal pressure overwhelms the counter response of by GERD [16]. However, studies have demonstrated
the LES and the crural diaphragm resulting in gastro- that elimination of acid reflux and even esophageal
esophageal reflux. mucosal healing do not result in normalization of
Hiatal hernia is an important factor in the patho- esophageal body motility.
genesis of GERD as it interferes directly with the anti- Impairment of primary esophageal peristalsis has
reflux barrier. The role of hiatal hernia in aggravating been suggested as the predominant underlying motil-
gastroesophageal reflux is discussed in another chapter. ity abnormality that leads to prolonged acid clearance
[13], [18], [19]. Non-transmitted peristalsis, failed
contractions and simultaneous esophageal contractions
Esophageal dysmotility are ineffective in clearing the volume of the refluxate.
Gastroesophageal reflux is the result of transient LES Ineffective esophageal motility, defined by the pres-
relaxation, stress reflux or an abnormally low LES pres- ence of abnormally low amplitude ( 30 mmHg)
sure (free reflux or the common cavity phenomenon) contractions in the distal esophagus (30% or more of
(see Fig. 2). wet swallows) were also found to be associated with
The goal of normal esophageal peristalsis and grav- prolonged esophageal acid clearance in both the
ity is to eliminate nearly all of the refluxate from the upright and recumbent positions. In more advance
esophagus, allowing the residual acid to be neutralized cases of GERD, absence of distal esophageal peristalsis
effectively by bicarbonate-rich saliva [15]. Impairment can be observed. Patients with scleroderma or mixed
of acid clearance can be secondary to either peristaltic connective tissue disorder demonstrate involvement of
dysfunction and/or re-reflux (the to-and-fro move- the smooth muscle portion of the esophagus. Deposi-
ment of the refluxate), which are seen in association tion of collagen which replaces muscle tissue results in
with hiatal hernia. significant reduction of distal esophageal amplitude
contractions and in severe cases complete elimination
of distal esophageal peristalsis. Additionally, damage
to the LES results in reduced mean LES basal pres-
sure and in advanced cases disappearance of the LES
high pressure zone. As a result, both disorders may be
associated with severe forms of GERD (peptic stric-
ture, Barrett’s esophagus and even adenocarcinoma of
the esophagus).
Another motor abnormality of GERD patients
refers to failed secondary peristalsis of the esopha-
geal body. After a reflux episode, secondary peristal-
sis is the first motor event involved in acid clearance
[14]. In comparison with normal controls, GERD
patients exhibit a lower occurrence of secondary
Fig. 2. Demonstration of the 3 underlying mechanisms that peristalsis (18% and 40% of the events, respectively)
can lead to gastroesophageal reflux. They include, inappropri- [20]–[22]. Interestingly, this abnormality does not
ate transient lower esophageal sphincter relaxation, reduced correlate with defective primary peristalsis [14].
lower esophageal sphincter basal pressure leading to “free Although previously suggested, salivary gland dys-
reflux’’ and stress reflux (with permission from [13]) function was not found to be an important factor in
16 Chapter 2

GERD patients [23]. However, patients with reduced documented in the esophagus in conjunction with
salivary production like those with Sjörgen’s syndrome acid reflux. Studies have also demonstrated that simul-
or active smokers are at higher risk for increased taneous exposure to acid and duodenogastroesopha-
esophageal acid exposure and esophageal mucosal geal reflux is higher in the more severe presentations
injury. Lastly, some investigators have suggested that of GERD. Barrett’s esophagus, for example, exhibited
the epidermal growth factor content in the saliva of the highest esophageal acid and duodenogastroeso-
GERD patients may be altered, resulting in reduced phageal reflux exposure [33]–[35]. However, in pa-
rate of esophageal mucosal healing [24]. tients with either long- or short-segment Barrett’s
esophagus as compared to controls there was no asso-
ciation between history of gastric surgery and the
The refluxate
presence of Barrett’s esophagus, suggesting that duo-
There is evidence to suggest that both acid and denogastroesophageal reflux without acid may not be
duodenal contents, mainly pepsin (an acid activated sufficient to cause Barrett’s esophagus [13], [18].
proteolytic enzyme) and bile salts (conjugated and de- Whilst the concept has been entertained in the
conjugated), are noxious to the esophageal mucosa past, there is no strong evidence to suggest that
[25], [26]. However, typically gastric content is acidic, hypersecretion of gastric acid plays an important role
making acid and pepsin the main noxious agents in in the pathogenesis of GERD [11], [12], [14].
the refluxate. Original studies reported that deconju-
gated bile salts and pancreatic enzymes are rendered
Helicobacter pylori
ineffective at acidic pH (inactivated) [27], [28]. Fur-
thermore, bile salts do not reach cytotoxic concentra- See the chapter Helicobacter pylori and GERD.
tions in the refluxate and typical signs of bile acid
injury are usually missing [29]. These include intracel-
Gastric dysmotility
lular bile salt deposits and membrane microvesicula-
tion [30]–[32]. Moreover, the effectiveness of PPIs in Approximately 20%–40% of the patients with GERD
healing esophageal erosions serves as another evidence may have delayed gastric emptying, but there is no di-
to support the role of acid as the main mechanism that rect correlation between the degree of the delay and
underlies esophageal mucosal injury. the severity of GERD [11], [12], [15]. However, slow
Presently, we are unable to measure bile reflux di- proximal gastric emptying in patients with GERD
rectly. Bilirubin, which can be detected in the refluxate correlated with increase in 24-hour esophageal pH
by Bilitec 2000 (a spectrophotometric system that monitoring values, number of reflux episodes per hour
measures bilirubin concentration within the esopha- and postprandial acid exposure.
gus, independent of pH), has been used as a surrogate
marker for bile reflux. However, experts elected to use
Esophageal mucosal defense mechanisms
the term duodenogastroesophageal reflux (DGER) in-
stead of bile reflux to denote that Bilitec measures du- The esophageal defensive system includes several basic
odenal contents, which may include bile, pancreatic mechanisms. The anti-reflux barrier (LES and the cru-
enzymes and pancreatic juice. However, duodeno- ral diaphragm) and the clearance mechanism that limit
gastroesophageal reflux alone does not appear to cause the frequency and volume of the refluxate as well as the
significant damage to the esophageal mucosa but may duration [36]. The third defense mechanism is the
act synergistically with acid reflux to produce erosive esophageal mucosal resistance, which prevents injury
esophagitis. By using 24-hour esophageal pH monitor- by acid, pepsin and other components of the refluxate.
ing and Bilitec 2000 in patients with GERD, Vaezi Tissue resistance is constituted of structures grouped in
et al [33] demonstrated that symptoms or esophageal three areas: pre-epithelial, epithelial and post-epithelial
lesions were relatively uncommon even after partial [36]. The pre-epithelial defense is relatively limited.
gastrectomy, where bile reflux is an important compo- The esophagus has no well-defined mucus layer and its
nent of the refluxate. Furthermore, according to this lumen to surface pH gradient creates only a modest re-
study, duodenogastroesophageal reflux was usually duction in luminal acidity [36]. The epithelial area
Dickman R and Fass R 17

consists of cell membranes and intercellular junctional is responsible for symptom generation in GERD [39].
complexes, which block acid and pepsin diffusion, Reducing acid exposure in patients with GERD ap-
intercellular buffers such as bicarbonate that neutralizes pears to normalize the sensitivity to acid [40]. How-
acid and cell membrane ion transporters for cytosolic ever, the emergence of symptoms in patients with a
acid extrusion [36] (Fig. 3). normal esophageal mucosa and thus without obvious
Exchangers at the baso-lateral membrane can inflammation remains perplexing, particularly among
restore intracellular pH by exchanging intracellular patients with functional heartburn where little or no
H
for extracellular Na
or intracellular Cl for extra- reflux actually occurs.
cellular HCO3. The post-epithelial area consists of Both animal models and human studies have dem-
an adequate mucosal blood flow to remove noxious onstrated dilation of intercellular spaces during or
elements and supply nutrients for maintenance and re- following esophageal mucosal acid exposure [41], [42].
pair mechanisms [36]. These mucosal findings were evident regardless of the
Studies have also shown that GERD patients with presence or absence of esophageal inflammation [42],
or without esophagitis have dilated intracellular spaces [43]. It is assumed that these morphological changes
(DIS), as documented by transmission electron micros- result in an increase in paracellular permeability, allow-
copy, which may lead to increase in esophageal per- ing acid to reach sensory nerve endings located with-
meability to hydrogen ions [37]. Dilated intercellular in the intercellular spaces [44]. However, this altered
spaces and reduced mucin production improve after permeability does not explain symptoms in GERD,
anti-secretory therapy, suggesting that these abnormal- specifically in NERD and in functional heartburn as
ities are caused by gastroesophageal reflux [37], [38]. most acid reflux events ( 95%) that occur in these pa-
tients are never perceived and symptoms occur even in
the absence of acid reflux, suggesting the importance of
Mechanisms for heartburn other factors in modulating esophageal acid perception.
The mechanisms by which patients with GERD de- Heartburn symptoms may represent activation of a
velop symptoms remain incompletely understood. It common pathway in response to different intra-esopha-
is postulated that sensitization of esophageal chemo- geal stimuli. Hypersensitivity to physiological amounts
receptors either directly by exposure to acid reflux or of acid appears to be the underlying mechanism for
indirectly through release of inflammatory mediators heartburn in the hypersensitive esophagus subgroup
(functional heartburn). This hypersensitivity to acid
may stem from peripheral sensitization of esophageal
afferents, leading to heightened responses to luminal
stimuli or altered modulation of afferent neural function
at the level of the spinal dorsal root or the central ner-
vous system [45]. What leads to the development of
such hypersensitivity remains an area of controversy. In
healthy subjects, Sarkar et al have recently demonstrated
that infusion of 0.1 N hydrochloric acid into the distal
esophagus for 30 minutes increased the subsequent sen-
sory responses to electrical stimulation in the non-
exposed proximal esophagus [46]. In comparison,
patients with non-cardiac chest pain already had lower
resting esophageal pain thresholds in the proximal
esophagus, which fell further and for a longer duration
than in healthy subjects after acidification of the distal
Fig. 3. Epithelial defenses against acid injury that include, cell esophagus. These patients also demonstrated a decrease
membrane, intercellular junctional complexes, intracellular in pain thresholds in the anterior chest wall. Therefore,
buffering and HCO3 and H
extrusion process (with permis- this study showed the development of secondary allody-
sion from [67]) nia (visceral hypersensitivity to innocuous stimulus in
18 Chapter 2

normal tissue that is in proximity to the site of tissue in- reflux events. However, proximal migration of the acid
jury) in healthy subjects and non-cardiac chest pain pa- reflux events has been shown repeatedly to be associa-
tients. In the latter group this phenomenon is amplified ted with a higher likelihood of symptom perception.
and lasts longer. The resulting visceral and somatic The most common trigger for GERD symptoms
hypersensitivity is likely due to central sensitization. is a meal; in particular if the meal is high in fat. How-
The increased excitability of spinal cord neurons ap- ever, the mechanism by which fat exacerbates symp-
pears to be the result of activation of nociceptive C toms in patients with GERD remains controversial.
fibers due to local tissue injury induced by acid infusion Meyer et al found that fat infusion into the duode-
into the distal esophagus. If extrapolated clinically, this num of subjects with GERD significantly shortened
study suggests that prior injury to the esophageal mu- latency to onset of heartburn and intensified the per-
cosa may lead to the development of central sensitiza- ception of acid induced heartburn [49]. The me-
tion and visceral hyperalgesia in a subset of patients chanisms by which luminal fat and potentially other
long after the local injury has healed. nutrients may modulate the perception of esophageal
To date, only a few studies have attempted to as- stimuli remains unclear, but may involve cholecysto-
sess the cortical processing of esophageal acid expo- kinin or other gut neurotransmitters, hormones, and
sure sensation in humans. Kern et al [47] evaluated enzymes. While many of these peptides may exert a
activation of cerebral cortical responses to esophageal local action leading to symptoms, it is also conceiva-
mucosal acid exposure using functional magnetic reso- ble that their action may also involve central neural
nance imaging (f MRI). Ten healthy subjects under- pathways. It is even possible that other substances in
went intra-esophageal perfusion of 0.1 N hydrochloric the refluxate (pepsin, bile) or volume per se are the di-
acid over 10 minutes. None of the study subjects re- rect cause of symptoms.
ported GERD symptoms during the acid perfusion. Several studies have recently speculated that central
Cerebral cortical activity was concentrated in the pos- and peripheral neural mechanisms modulate esopha-
terior cingulate, and the parietal and anteromesial
frontal lobes. The superior frontal lobe regions activat-
ed in this study corresponded to Brodmann’s areas 31,
the insula, operculum and the anterior cingulate. Furt-
her studies are needed to assess cerebral cortical activa-
tion in symptomatic GERD patients undergoing
esophageal acid perfusion. In addition, it would be of
great interest to determine if there are differences in
central processing of an intra-esophageal stimulus be-
tween GERD patients and those with NERD or func-
tional heartburn.
Patients with GERD do not perceive most acid re-
flux events. Many patients and healthy subjects dem-
onstrate multiple acid reflux events on pH testing but
often report few, if any, heartburn episodes. It has been
estimated that no more than 5% of all acid reflux
events (pH  4) produce symptoms, either in patients
with or without esophageal mucosal injury [48]. This
intriguing observation raises the obvious question of
what in a specific acid reflux event leads to its con-
scious perception. It is not clear if a specific acid reflux
event is the determining factor in triggering symptoms Fig. 4. Proposed conceptual model for esophageal symptom
or rather the actual hydrogen ion concentration (H
) generation. Central and peripheral mechanisms enhance per-
of the refluxate, the summation of several short reflux ception of intra-esophageal events (either physiological or
events, or an increased number and/or duration of acid pathological), leading to symptom generation [68]
Dickman R and Fass R 19

geal perception [50], [51] (Fig. 4). Psychological suggest that mechanical stimuli and motor events may
comorbidity (anxiety, stress, depression, etc.) can mod- be perceived as heartburn by some patients, even in
ulate esophageal perception and cause patients to per- the absence of actual acid reflux.
ceive low intensity esophageal stimuli as being painful Bile reflux has been suggested as a possible cause for
[Gut: 27], [52]. These psychological factors seem to be heartburn symptoms in patients with NERD, but no
associated with patients paying an excessive attention study to date has specifically evaluated the role of bile
(hypervigilance) to intra-esophageal events and thus acid in symptom generation in this group. Assessment of
perceiving or interpreting these esophageal events as bilirubin pigment spectrophotometrically, a proxy indi-
being painful [53]. Stress has been implicated by 64% cator for bile reflux, revealed a close correlation between
of GERD patients as an important cause for symptom a combination of both acid and duodenogastroesopha-
exacerbation [54]. However, several studies have failed geal reflux and severity of GERD, as determined by the
to demonstrate an increase in acid reflux during stress- presence of esophageal mucosal injury and GERD com-
ful stimuli [55]–[57]. Nevertheless, interventions plications [33]. However, symptoms were not specifi-
aimed at reducing stress (hypnosis and muscle relaxa- cally examined in this study. The combined reflux was
tion) have produced subjective improvement in reflux documented in only 50% of NERD patients compared
symptoms ratings [57], [58]. In a study assessing the with 79% in erosive esophagitis and 95% in Barrett’s
effect of psychologically induced stress on symptom esophagus. Others have shown that the mean fasting
perception in GERD patients, stress reduced percep- gastric bile acid concentration in patients with NERD is
tion thresholds and enhanced the perception of acid not significantly elevated compared with healthy con-
during infusion, regardless of the degree of esophageal trols [51]. Future studies are needed to further determine
mucosal injury [59]. if bile acid is a contributing factor for symptoms in pa-
A recent study demonstrated that increased basal tients with GERD.
sympathetic activity and lower vagal activity, as mea- Recent studies using simultaneous intra-esophageal
sured by power spectral analysis of heart rate vari- impedance and pH measurement demonstrated non-
ability, are associated with increased sensitivity to acidic gastroesophageal reflux (liquid, gas or mixture of
intra-esophageal acid perfusion in patients with gas and liquid) that was similarly frequent in patients
non-cardiac chest pain compared with healthy with GERD and normal controls [62]. However, more
matched controls [60]. acidic reflux occurred in symptomatic patients with
These data support the concept of humoral, neural, GERD. Vela et al [63] with a similar technique, ob-
and psychological factors being associated with an in- served that during treatment of GERD patients with a
creased susceptibility to symptoms such as heartburn PPI, postprandial reflux became predominately non-
but do not provide at this point a satisfactory mecha- acidic. Although less than acidic reflux, non-acidic re-
nistic explanation. However, recent advances in our flux was also associated with classic GERD symptoms.
understanding of the mucosal and esophageal neural It has yet to be determined if the content or volume is
response to reflux begin to address this deficiency. responsible for GERD symptoms in the studied sub-
There are mounting data to suggest that the axiom jects. Additionally, as with acid reflux, most of the non-
“no acid no heartburn’’ is obsolete. Non-acid intra- acidic reflux events are not perceived.
esophageal stimuli may also lead to the development
of heartburn. Esophageal balloon distension induces
Genetic factors
heartburn symptoms in a large subset of normal sub-
jects and reproduces typical heartburn in half of Familial aggregation for GERD, in general, was not
GERD patients [39]. Furthermore, high frequency demonstrated, but investigators were able to document
intra-luminal ultrasonography has demonstrated a a significant rate of familial occurrence for both
close correlation between heartburn episodes and Barrett’s esophagus and esophageal adenocarcinoma
abnormally long durations of longitudinal muscle con- [64], [65]. Recently, a large twin study has shown an
tractions in the esophagus [61]. These muscle contrac- increased concordance for GERD in monozygotic
tions and consequent heartburn episodes can occur in pairs, compared with dizygotic pairs, suggesting that
the absence of acid reflux. Thus, both of these studies genetic factors accounted for 31% of the liability to
20 Chapter 2

GERD in the U.S. population [11], [66]. Further- [12] Cameron AJ (1999) Barrett’s esophagus: prevalence
more, a genetic linkage study in pediatric GERD and size of hiatal hernia. Am J Gastroenterol 94:
population mapped a locus in chromosome 13q14. 2054–2059
Although the importance of this locus was refuted by [13] Dodds WJ, Dent J, Hogan WJ, Helm JF, Hauser R,
a subsequent study, it did not completely exclude the Patel GK, Egide MS (1982) Mechanisms of gastroeso-
possibility of genetic factors in GERD. phageal reflux in patients with reflux esophagitis. N
Engl J Med 307: 1547–1552
[14] Penagini R, Carmagnola S, Cantu P (2002) Review ar-
ticle: gastro-oesophageal reflux disease – pathophysio-
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