Neurogastroenterology & Motility

Neurogastroenterol Motil (2015) 27, 12021213 doi: 10.1111/nmo.12611

REVIEW ARTICLE

Pathophysiology of gastroesophageal reflux disease: new

understanding in a new era

T. V. K. HERREGODS , A. J. BREDENOORD & A. J. P. M. SMOUT

Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands

Key Messages

The aim of this review is to provide an overview of the current understanding of the pathophysiological
mechanisms causing GERD and the factors which influence perception.
Pathophysiological factors involved in reflux include: sliding hiatus hernia, low LES pressure, TLESRs, the acid
pocket, obesity, increased distensibility of the EGJ, prolonged esophageal clearance, and delayed gastric
emptying.
Mechanisms influencing perception of GERD symptoms include: acidity of reflux, proximal extent, presence of
gas in the refluxate, duodenogastroesophageal reflux, longitudinal muscle contraction, mucosal integrity, and
peripheral and central sensitization.
Further research of the pathophysiology of GERD remains necessary despite the recent advances in our
understanding.

Abstract ageal sphincter relaxation, the acid pocket, obesity,

Background The prevalence of gastroesophageal reflux
disease (GERD) has increased in the last decades and
it is now one of the most common chronic diseases.
Throughout time our insight in the pathophysiology of
GERD has been characterized by remarkable back
and forth swings, often prompted by new investiga-
tional techniques. Even today, the pathophysiology of
GERD is not fully understood but it is now recognized
to be a multifactorial disease. Among the factors that
have been shown to be involved in the provocation or
increase of reflux, are sliding hiatus hernia, low lower
esophageal sphincter pressure, transient lower esoph-
Address for Correspondence
Prof. Dr. A. J. P. M. Smout, Department of Gastroenterology
and Hepatology, Academic Medical Center Amsterdam,
Meibergdreef 9, room C2-326, 1105 AZ Amsterdam-Zuidoost,
The Netherlands.
Tel: +31 20 5667375; fax: +31(0)205669478;
e-mail: a.j.smout@amc.uva.nl
Received: 10 February 2015
Accepted for publication: 5 May 2015
increased distensibility of the esophagogastric junc-
tion, prolonged esophageal clearance, and delayed
gastric emptying. Moreover, multiple mechanisms
influence the perception of GERD symptoms, such as
the acidity of the refluxate, its proximal extent, the
presence of gas in the refluxate, duodenogastroesoph-
ageal reflux, longitudinal muscle contraction, mucosal
integrity, and peripheral and central sensitization.
Understanding the pathophysiology of GERD is
important for future targets for therapy as proton
pump inhibitor-refractory GERD symptoms remain a
common problem. Purpose In this review we provide
an overview of the mechanisms leading to reflux and
the factors influencing perception, in the light of
historical developments. It is clear that further
research remains necessary despite the recent
advances in the understanding of the pathophysiology
of GERD.
Keywords GERD, hiatus hernia, lower esophageal
sphincter, pathophysiology, reflux perception.

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Volume 27, Number 9, September 2015
Abbreviations: DIS, dilated intercellular spaces; EGJ,
esophagogastric junction; GERD, gastroesophageal
reflux disease; LES, lower esophageal sphincter; NERD,
non-erosive reflux disease; PPI, proton pump inhibitor;
TLESR, transient lower esophageal sphincter relaxa-
tion.
INTRODUCTION
Gastroesophageal reflux disease (GERD) has become
more common in the last decades and is now one of the
most prevalent chronic diseases, with prevalence esti-
mates up to 27.8% in North America and up to 25.9%
in Europe, and evidence suggesting an increase, partic-
ularly in North America and East Asia, since 1995.1
Gastroesophageal reflux disease is associated with a
large range of symptoms, which can be split into
typical and atypical reflux symptoms. Typical symp-
toms consist of heartburn and acid regurgitation, while
atypical symptoms are more controversial and diverse,
consisting of non-cardiac chest pain, chronic cough,
hoarseness, globus, and throat irritation.2
Throughout time our understanding of the patho-
physiology of GERD has evolved with some remark-
able back and forth swings from one view to another
prompted by new investigational techniques. Heinrich
Quincke first mentioned reflux-induced esophageal
ulceration in his description of three postmortem cases
in 1879, which was followed by a paper in 1935 by
Winkelstein who corroborated the concept of reflux
esophagitis,3 but also linked its presence to the symp-
tom heartburn. In 1951, Allison demonstrated the
association between esophagitis and hiatus hernia.4
Subsequently, hiatus hernia was regarded as synony-
mous to GERD until 1972, at which point Cohen et al.
found a consistently hypotensive lower esophageal
sphincter (LES) in patients with GERD.3 This new
knowledge overshadowed hiatus hernia as a patho-
physiological factor for quite some time and it was no
sooner than in the year 2000 that van Herwaarden
et al. demonstrated that a low LES pressure was
frequently associated with reflux episodes in hiatus
hernia but only rarely in GERD patients without a
hiatus hernia.5 Meanwhile, by 1976, Dent et al. had
developed their sleeve sensor which allowed for con-
tinuous LES pressure measurement.6 This technique
led to the observation, published in 1980, that 98% of
reflux episodes in recumbent subjects were associated
with transient (530 s) episodes of (inappropriate)
complete LES relaxation (TLESR) instead of being
related to a persistently low LES pressure.7 The use
of the Dent sleeve discouraged thinking about hiatus
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Pathophysiology of GERD
hernia and multiple publications implicating TLESRs
as a major role in the etiology of GERD saw the light.
Subsequent studies emphasized that TLESRs are the
major determinant of reflux in healthy volunteers,8
that they are physiological due to their involvement in
belching,9 and that the incidence of TLESRs and the
proportion of TLESRs associated with reflux are not
higher in GERD patients than in asymptomatic vol-
unteers. However, in GERD patients TLESRs are twice
as likely to be associated with acid reflux.10 Subse-
quently, the development of ambulatory esophageal pH
monitoring resulted in recognition of non-erosive
reflux disease (NERD), which was followed by the
production of impedance monitoring that led to the
awareness that reflux of gas and liquid can cause
symptoms regardless of acidity.11 The abundant use of
proton pump inhibitors (PPI) prompted the problem of
refractory symptoms attributable to GERD and it was
only by 2006 that the Montreal definition of GERD
was developed which defined GERD as a condition
which develops when the reflux of stomach contents
causes troublesome symptoms and/or complica-
tions.12
Apart from factors that promote the occurrence of
reflux, there are also factors that increase the percep-
tion of reflux. The awareness that the latter can be of
great importance, in particular in patients in whom
reflux is not severe and does not lead to esophagitis,
has grown in recent years. The aim of this review is to
outline the current knowledge of the contributing
factors leading to GERD. An overview of the factors
which play a role in the provocation and perception of
reflux is shown in Fig. 1.
WHAT MAKES REFLUX OCCUR?
Sliding hiatus hernia
Our acceptance of the importance of hiatus hernia in
the pathophysiology of GERD has varied significantly
over the past few decades. From the first mention of an
association between GERD and hiatus hernia in the
1950s4 up to the 1970s, reflux was considered depen-
dent on the presence of a hiatus hernia. This perception
changed with the development of manometric tech-
niques, which caused interest to shift toward the LES.
It is only in the last decade that hiatus hernia has
regained its place in the spotlight.
The esophagogastric junction (EGJ) functions as an
antireflux barrier and consists of the smooth muscle of
the LES which is surrounded by oblique gastric fibers.
These are anchored to the striated muscle of the
crural diaphragm by the phreno-esophageal ligament.13
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T. V. K. Herregods et al. Neurogastroenterology and Motility

Central sensitization

Reflux characteristics:
- Acidity of reflux
Peripheral sensitization
- Proximal extent
Mucosal integrity
- Gas reflux
- Duodenogastroesophageal
reflux Esophageal clearance
Longitudinal muscle contractions

Sliding hiatus hernia

Low LES pressure
TLESRs
Increased distensibility EGJ

Acid pocket
Delayed gastric emptying

Obesity Figure 1 Overview of the factors which play

a role in the provocation and perception of
reflux. The factors which provoke or
increase reflux are illustrated in black while
the factors which influence perception are
shown in red.

A hiatus hernia is defined as the proximal displace-
ment of the EGJ causing the intrinsic sphincter to lie
proximal to the hiatus formed by the crural dia-
phragm,13 which is likely caused by the weakening or
rupture of the phreno-esophageal ligament.14 There is
incontrovertible evidence that patients with hiatus
hernia have more reflux episodes and greater esopha-
geal acid exposure than patients without hiatus her-
nia,5 and that on endoscopy, patients with a hiatal
hernia have more severe esophagitis.15 Moreover, it has
been demonstrated that a larger hiatal hernia is
associated with a greater esophageal acid exposure
and prolonged acid clearance times.16
Many studies have been performed to unravel the
mechanisms by which a hiatus hernia causes GERD.
Typically, during straining-associated increased
abdominal pressure and during inspiration, there is a
contraction of the crural diaphragm causing an
increase in LES pressure which compensates for the
increased pressure gradient between the stomach and
the esophagus.13 In the resting state the crural dia-
phragm also affects LES pressure, which has been
confirmed by a study showing that in patients with
hiatus hernia there are two high-pressure gradients,
one of which is located at the level of the LES and the
other at the level of the crural diaphragm.17 In patients
with a hiatus hernia there is no overlap between the
LES and the crural diaphragm, resulting in a more
incompetent anti-reflux barrier and thus an increased
likelihood of reflux. The importance of the crural
diaphragm is further outlined in a study which dem-
onstrated that an impaired crural diaphragm function
was strongly associated with GERD.18 Moreover, it has
been demonstrated that distension causes a greater
increase in the cross-sectional area of the EGJ in
patients with a hiatus hernia than in patients
without and thus this larger opening could allow
more reflux of fluid to occur.19 Furthermore, Kahrilas
et al. concluded that gastric distension with contin-
uous air infusion led to a greater increase in
frequency of TLESRs in patients with a hiatal hernia
compared to those without.20 However, this was
contradicted by a study which concluded that the
frequency of TLESRs was not increased in patients
with hiatus hernia.5
Sliding hiatus hernia is not an all or none phenom-
enon; smaller hernias may come and go.21 When a
hiatus hernia is in the non-reduced state there is
approximately two times more acid and non-acid reflux
than in the reduced state. Bredenoord et al. demon-
strated that the increased reflux in the non-reduced
state is brought about by mechanisms other than
TLESRs.22 Another proposed mechanism by which
hiatus hernia leads to GERD is that gastric content is
trapped in the hiatus hernia sac (between the LES
proximally and the crural diaphragm distally) which
refluxes during subsequent swallow-induced relax-
ations of the LES.23 Since patients with a hiatus hernia
have an impaired esophageal clearance,15,21,24 the acid
clearance will be impaired. Finally, small separations
between the two pressure peaks can be difficult to
observe and as a result small hernias can remain
undetected while pathophysiological implications
could still occur.25 It is thus clear that a hiatal hernia
can lead to GERD through a variety of different
mechanisms.

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Volume 27, Number 9, September 2015
Low LES pressure
The findings by Cohen et al., which led to a shift in
interest in the 1970s from the hiatus hernia to the
LES,3 were later attributed to the presence of advanced
erosive disease in the study population.26 However, the
temporary newfound interest in the LES resulted in
studies evaluating the LES structure and the factors
that have an effect on the LES pressure, such as
endogenous hormones and food type.27,28 The impor-
tance of the intra-abdominal length of the esophagus as
a determinant of reflux was evaluated and it was found
that a shorter intra-abdominal length caused more
reflux.29 Currently, it is clear that basal LES pressure is
a less relevant pathophysiological factor as only a
minority of patients with GERD have a constant low
LES pressure.30 However, recent studies using high-
resolution manometry suggest that novel parameters
such as a low LES pressure integral31 or a low EGJ
contractile integral32,33 are associated with gastro-
esophageal reflux.
Transient lower esophageal sphincter relaxation
With the invention of the Dent sleeve in 19766 came
the discovery of the TLESR.7 TLESRs are a vagal nerve
mediated phenomenon34 and were believed to be of
great importance in the pathophysiology of GERD as
multiple studies illustrated that reflux episodes
occurred almost entirely during TLESRs,8,34 rather
than during intervals of persistently low basal LES
pressure.7 It was found that 94% of reflux episodes in
controls were caused by TLESRs.8 TLESRs persist for
1045 s or more, occur more frequently after meals and
in the erect posture, are triggered by gastric distension
(through stretch receptors35) as a mechanism for gas
venting from the stomach during belching,36 and are
more frequent during a diet rich in indigestible carbo-
hydrates due to colonic fermentation with excess
release of agents such as glucagon-like peptide-1.37 As
time progressed, studies demonstrated that patients
with reflux disease do not have more frequent TLESRs
than controls, but instead, TLESRs in GERD patients
are more likely to be associated with acid reflux.10,38
Acid pocket
A long ignored paradox in GERD was that most acid
reflux episodes occur in the postprandial period39
whereas intragastric pH is at its highest after a meal
as a result of the buffering effect of food.40 In 2001,
Fletcher et al.41 investigated this paradox using a dual
pH electrode pull-through technique from the proximal
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Pathophysiology of GERD
stomach, through the EGJ and into the esophagus.
They confirmed that after meals, the esophageal
refluxate was frequently more acidic than the body of
the stomach and accounted this to an acid pocket at
the EGJ which escaped the buffering effect of the
meals. The authors hypothesized that this acid pocket
was formed due to meal-stimulated acid mixing poorly
with the chyme in the proximal stomach. Pandolfino
et al. demonstrated that the proximal margin of the
acid pocket may extend into and even across the LES
and that pocket extension correlates with GERD and
hiatus hernia severity.42 Another study also observed a
proximal extent of the acid pocket and noted that the
pocket was significantly larger in GERD patients, and
that the position is largely influenced by the presence
of a hiatus hernia.43 The authors suggest that, for the
development of GERD, the position of the acid pocket
is more relevant than its length. With a supradiaphrag-
matic localization of the acid pocket they noted that
7485% of all TLESRs resulted in acidic reflux while
only 720% of the TLESRs had acidic reflux with an
infradiaphragmatic localization. Additionally they
stress the importance of a hiatal hernia as a larger
hiatal hernia captures the acid pocket in the hiatal sac
leading to increased reflux.43 Results of a study by
Rohof et al. support the importance of the position of
the acid pocket as acid reflux mainly occurred during a
supradiaphragmatic localization of the acid pocket
(91%) compared to an infradiaphragmatic localization
(11%) and confirm that the position is mainly influ-
enced by the presence of a hiatal hernia.44 Further-
more, another study showed that the acid pocket can
also act as a reservoir from which reflux occurs in
patients using PPIs.45 Proton pump inhibitors did,
however, reduce the size of the acid pocket and led to a
more frequent localization below the diaphragm.45
Increased distensibility of EGJ
Radiographic studies in which the distensibility of the
EGJ was investigated have shown that GERD patients
have a more compliant LES, both in rest and during
deglutitive relaxation,19,46 particularly so in patients
with a hiatus hernia. It has been suggested that the
increased distensibility may explain the reduced ability
to restrict reflux to gas (belching) in GERD patients
compared to controls.19 Recently, the functional
lumen imaging probe (FLIP) was produced which
employs the principle of impedance planimetry to
measure distensibility.47 In a study by Kwiatek et al.,48
the EndoFLIP was used and a two- to threefold
increased EGJ distensibility in the GERD patients
was found compared with controls.48 However, others
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Volume 27, Number 9, September 2015
94 Calabrese C, Bortolotti M, Fabbri A,
Areni A, Cenacchi G, Scialpi C,
Miglioli M, Di Febo G. Reversibility
of GERD ultrastructural alterations
and relief of symptoms after omep-
razole treatment. Am J Gastroenter-
ol 2005; 100: 53742.
95 Xue Y, Zhou LY, Lin SR. Dilated
intercellular spaces in gastroesopha-
geal reflux disease patients and the
changes of intercellular spaces after
omeprazole treatment. Chin Med J
2008; 121: 1297301.
96 Farre R, Fornari F, Blondeau K, Vieth
M, De Vos R, Bisschops R, Mertens
V, Pauwels A et al. Acid and weakly
acidic solutions impair mucosal
integrity of distal exposed and prox-
imal non-exposed human oesopha-
gus. Gut 2010; 59: 1649.
97 Vela MF, Craft BM, Sharma N, Free-
man J, Hazen-Martin D. Refractory
heartburn: comparison of intercellu-
lar space diameter in documented
GERD vs. functional heartburn. Am
J Gastroenterol 2011; 106: 84450.
98 Monkemuller K, Wex T, Kuester D,
Fry LC, Kandulski A, Kropf S, Roess-
ner A, Malfertheiner P. Role of tight
junction proteins in gastroesopha-
geal reflux disease. BMC Gastroen-
terol 2012; 12: 128.
99 Jovov B, Que J, Tobey NA, Djukic Z,
Hogan BL, Orlando RC. Role of E-
cadherin in the pathogenesis of gas-
troesophageal reflux disease. Am J
Gastroenterol 2011; 106: 103947.
100 Wex T, Monkemuller K, Stahr A,
Kuester D, Fry LC, Volkel S, Kan-
dulski A, Roessner A et al. Gastro-
oesophageal reflux disease is associ-
ated with up-regulation of desmo-
somal components in oesophageal
mucosa. Histopathology 2012; 60:
40515.
101 Farre R, Blondeau K, Clement D,
Vicario M, Cardozo L, Vieth M,
Mertens V, Pauwels A et al. Evalu-
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rity by the intraluminal impedance
technique. Gut 2011; 60: 88592.
102 Weijenborg PW, Rohof WO, Akker-
mans LM, Verheij J, Smout AJ, Bre-
denoord AJ. Electrical tissue
impedance spectroscopy: a novel
device to measure esophageal muco-
sal integrity changes during endos-
copy. Neurogastroenterol Motil
2013; 25: 574e458.
103 Kandulski A, Weigt J, Caro C, Je-
chorek D, Wex T, Malfertheiner P.
Esophageal intraluminal baseline
impedance differentiates gastro-
esophageal reflux disease from func-
tional heartburn. Clin Gastroenterol
Hepatol 2014; 13: 107581.
104 Rinsma NF, Farre R, Bouvy ND,
Masclee AA, Conchillo JM. The
effect of endoscopic fundoplication
and proton pump inhibitors on
baseline impedance and heartburn
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105 de Bortoli N, Martinucci I, Savarino
E, Tutuian R, Frazzoni M, Piaggi P,
Bertani L, Furnari M et al. Associa-
tion between baseline impedance
values and response proton pump
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burn. Clin Gastroenterol Hepatol
2014; 13: 10821088.e1.
106 Ates F, Yuksel ES, Higginbotham T,
Slaughter JC, Mabary J, Kavitt RT,
Garrett CG, Francis D. Mucosal
impedance discriminates GERD
from non-GERD conditions. Gastro-
enterology 2015; 148: 33443.
107 Knowles CH, Aziz Q. Visceral
hypersensitivity in non-erosive
reflux disease. Gut 2008; 57: 67483.
108 Matthews PJ, Aziz Q, Facer P, Davis
JB, Thompson DG, Anand P.
Increased capsaicin receptor TRPV1
nerve fibres in the inflamed human
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oesophagus. Eur J Gastro Hepatol
2004; 16: 897902.
109 Shieh KR, Yi CH, Liu TT, Tseng HL,
Ho HC, Hsieh HT, Chen CL. Evi-
dence for neurotrophic factors asso-
ciating with TRPV1 gene expression
in the inflamed human esophagus.
Neurogastroenterol Motil 2010; 22:
9717, e252.
110 Ma J, Altomare A, Rieder F, Behar J,
Biancani P, Harnett KM. ATP: a
mediator for HCl-induced TRPV1
activation in esophageal mucosa.
Am J Physiol Gastrointest Liver
Physiol 2011; 301: G107582.
111 Lawal A, Kern M, Sanjeevi A, Anto-
nik S, Mepani R, Rittmann T, Hus-
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Neurocognitive processing of esoph-
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insula and cingulate gyrus. Am J
Physiol Gastrointest Liver Physiol
2008; 294: G78794.
112 Sarkar S, Aziz Q, Woolf CJ, Hobson
AR, Thompson DG. Contribution of
central sensitisation to the develop-
ment of non-cardiac chest pain.
Lancet 2000; 356: 11549.
113 Anand P, Aziz Q, Willert R, van
Oudenhove L. Peripheral and central
mechanisms of visceral sensitiza-
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Motil 2007; 19(1 Suppl): 2946.
114 Phillips ML, Gregory LJ, Cullen S,
Coen S, Ng V, Andrew C, Giampie-
tro V, Bullmore E et al. The effect of
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115 Kern M, Hofmann C, Hyde J, Shaker
R. Characterization of the cerebral
cortical representation of heartburn
in GERD patients. Am J Physiol
Gastrointest Liver Physiol 2004;
286: G17481.
Volume 27, Number 9, September 2015
and a delayed esophageal clearing time have also been
linked to obesity.66
Other risk factors Other risk factors for GERD include
smoking, heavy alcohol use, pregnancy, but also
medications such as anticholinergic drugs, selective-
serotonin re-uptake inhibitor antidepressant drugs,
and inhaled bronchodilators are associated with
GERD.67,68
HOW DOES REFLUX LEAD TO
SYMPTOMS?
The pathophysiology of GERD is influenced by the
severity and frequency of reflux, yet severe symptoms
can be present in patients with relatively low esoph-
ageal acid exposure and, conversely, patients with high
acid exposure can have few symptoms.69 On the one
hand, it was demonstrated that patients with Barretts
esophagus have a reduced sensitivity to acid perfusion
tests compared to GERD patients without a Barretts
esophagus,70 which is presumably due to damaging of
the peripheral nerve endings.71 On the other hand,
NERD patients often report severe symptoms but can
have physiological acid exposure. These observations
strongly suggest that factors besides acid reflux play
part in the symptoms of GERD.
Reflux characteristics
Acidity of reflux: acid and non-acid reflux For many
years it has been acknowledged that reflux with a pH
>4 can also induce reflux symptoms. In 1989, a study
assessed the pain sensitivity of the esophageal mucosa
by infusion of an array of HCl solutions with different
pH and concluded that pH >4 can induce heartburn.72
This is supported by a study which studied reflux
symptoms in 20 patients after cessation of acid-
suppressive therapy and concluded that a substantial
minority (14.8%) of symptomatic reflux episodes were
weakly acidic.11 However, heartburn and regurgitation
symptoms were found to be more likely evoked by
reflux episodes with a larger pH drop. A similar study
was performed in patients who continued taking PPIs
at least twice daily during the test.73 This study
confirmed the importance of non-acid reflux in
patients taking PPIs as 19% of symptoms were due to
non-acid reflux. In a systematic review it was con-
cluded that in patients with GERD who are not taking
a PPI, 37% of reflux episodes are weakly acidic or
weakly alkaline, while in patients taking PPIs this was
increased to 80%.74 Emerenziani et al. conducted a
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Pathophysiology of GERD
study in NERD patients and concluded that the
symptomatic weakly acidic reflux episodes were pre-
ceded (in the last 1530 min) by higher cumulative
acid exposure than the asymptomatic refluxes.75 These
studies illustrate the importance of non-acid reflux in
the perception of reflux symptoms.
Proximal extent In 1995, Weusten et al. demonstrated
that acid reflux episodes with a high proximal extent
are more likely to be perceived.76 This was confirmed
using impedance monitoring and it was shown that all
types of reflux episodes with a high proximal extent
(acid and non-acid) are more likely to be symptom-
atic.11 Other studies suggest that patients with severe
esophagitis tend to have a higher average proximal
extent than patients with mild esophagitis,77 and that
proximal extent is lower in NERD patients compared
to patients with esophagitis.78 A suggested explanation
for this heightened perception in reflux episodes with
a high proximal extent is that reflux episodes with
larger volumes reach higher levels, resulting in a
greater mechanical (distension) and chemical (acid)
stimulation of afferent nerves.69 The relevance of
distention of the esophagus for symptom perception
is underlined by studies in patients on PPI therapy as
proximal extent is associated with reflux perception
despite a decreased acidity.79 Moreover, a study using
esophageal balloon distension has shown that GERD
patients have lower thresholds and thus an increased
mechanosensitivity.80
Gas reflux It has been demonstrated that, in NERD
patients, the probability of reflux perception is signif-
icantly enhanced by the presence of gas in the reflux-
ate.81 Furthermore, even pure gas reflux episodes can
lead to symptoms.11 Bravi et al. concluded that some
PPI-refractory GERD patients swallow air more fre-
quently during meals and also have more reflux
episodes which contain gas.82 Gas reflux could lead
to symptoms by triggering mechanoreceptors by esoph-
ageal luminal distention.69
Duodenogastroesophageal reflux Gastroesophageal reflux
can also contain noxious constituents other than acid,
such as pepsin, trypsin, or bile acids. Using the
spectrophotometric Bilitec device, designed to measure
bilirubin concentration in the esophagus, it was
observed that in GERD patients off-PPI only 69% of
reflux symptoms are associated with bile reflux and
12% with mixed (acid-bile) reflux.83,84 In vitro studies
using cultures of human squamous epithelium have
shown that the combination of bile acids and pepsin
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T. V. K. Herregods et al.
can disrupt the epithelial barrier function and induce
mucosal damage.85
Longitudinal muscle contraction
In 1999, Balaban et al. conducted a study using
continuous high-frequency intraluminal ultrasonogra-
phy to evaluate contractions of the longitudinal
muscle layer in patients with chest pain by measuring
the esophageal muscle thickness. They frequently
found sustained esophageal longitudinal contractions
preceding episodes of chest pain.86 It was found that
these contractions can also lead to a heartburn sensa-
tion in GERD patients.87 A possible mechanism by
which these contractions can lead to reflux symptoms
is transient ischemia of the esophageal wall, which is
corroborated by the results of a study conducted on a
rat model.88 Moreover, it has been demonstrated that
TLESRs are associated with a distinct pattern of
longitudinal muscle contraction which is similar in
duration to the duration of a TLESR and which is
associated with a reduced esophageal wall blood
perfusion.89
Mucosal integrity
The healthy esophagus is lined with a tight barrier of
squamous epithelium which keeps noxious substances
in the lumen separated from peripheral nociceptors. In
patients with esophagitis there is a clear breach in this
barrier allowing components of the refluxate to reach
the nociceptors in the lamina propria.69 However, this
clear breach is not visible in many of the GERD
patients who have a normal gastroscopy. In recent
years microscopic impairment of the esophageal
mucosa has been suggested as a pathophysiologic
factor in the development of symptoms in NERD
patients as an association between impaired mucosal
integrity and experimental sensitivity to acid seems to
be present.90
Mucosal factors Using transmission electron micros-
copy, it has been demonstrated that acid perfusion
in vivo in the lower esophagus of a rabbit leads to
dilated intercellular spaces (DIS) in the epithelial
tissue.91 It has been suggested that DIS is caused by
ionic flow (including chloride ions) through the epi-
thelium due to an initial increased permeability. This
is subsequently followed osmotically by water which
enters the intercellular spaces causing dilation.92 In
1996, Tobey et al. were the first to demonstrate the
presence of DIS as a result of reflux damage in GERD
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Neurogastroenterology and Motility
patients.93 Furthermore, it has been demonstrated that
PPI therapy reverses DIS.94,95 More recently, it has
been shown that, in healthy subjects, DIS can be
induced not only by acid (pH 2.0) but also by weakly
acidic solutions (pH 5.5) and that distal perfusions also
provoke DIS in more proximal, non-exposed mucosa.96
It is important to note that, in this experiment, most
healthy subjects did not perceive heartburn, despite the
presence of DIS, thus casting doubt upon the existence
of a direct relationship between DIS and reflux symp-
toms. Another study found that measurement of DIS
could help to distinguish GERD from functional
heartburn in patients with remaining symptoms
despite PPI treatment as DIS was increased in the
refractory GERD patients but not in those with
functional heartburn.97
In addition to morphological signs of impairment
of the mucosal barrier in GERD, functional signs of
weakening of the barrier can be found. Cell-to-cell
adhesion proteins (such as tight junctions,98 e-cadh-
erin99 and desmosomes100) maintain the integrity of
the esophageal epithelium and compartmentalize the
mucosal from the serosal side of the epithelium. This
compartmentalization can also be assessed by mea-
suring the transmucosal potential difference using
the Using chamber technique. Using this technique,
the esophageal epithelium in GERD patients was
found to have an increased in vitro permeability
compared to controls99 and this was associated with
the proteolytic cleavage of e-cadherin,99 demonstrat-
ing the importance of the cell-to-cell adhesion pro-
teins. These findings are supported by in vivo
studies101,102 which found measurement of baseline
impedance values, using both multichannel intralu-
minal impedance monitoring101,103 and electrical
tissue impedance spectroscopy,102 to be a good
method to evaluate the permeability of the esopha-
geal mucosa.
Recent studies have shown that low baseline imped-
ance values are associated with an increased acid
exposure,103 and a reduction of acid exposure -
achieved by PPI therapy or endoscopic fundoplication
- results in an increase in baseline impedance in GERD
patients.104 It has been suggested that baseline imped-
ance can be used as a diagnostic tool in patients with
reflux symptoms refractory to PPI treatment.103,105
Recently, a technique has also been described in which
an impedance measurement catheter is passed through
the working channel of the endoscope, allowing local-
ized measurement of the mucosal impedance.106 Using
this technique the existence of decreased baseline
impedance in GERD patients was confirmed.
2015 John Wiley & Sons Ltd
Volume 27, Number 9, September 2015
Sensitization
Peripheral sensitization Perception of GERD symp-
toms can be the consequence of a heightened sensitivity
of the esophagus to a variety of stimuli. Excessive
stimulation of the peripheral receptors of the afferent
nerve endings can lead to an upregulation of these
receptors through the release of intracellular inflamma-
tory mediators and thus lead to a reduced threshold of
transduction.107 This primary sensitization results in a
hypersensitivity at the site of injury. Various receptors
have been found to be involved in peripheral sensitiza-
tion, including the transient receptor vanilloid 1
(TRPV1) receptor, the TRPV4- and the TRPA1-receptor,
the acid-sensitivity ion channels, and the purinergic
(P2X) receptors.69 TRPV1-receptor expression is higher
in the inflamed esophageal mucosa.108,109 It has been
proposed that TRPV1 activation due to acid-induced
inflammation results in the synthesis and release of
substance P and calcitonin gene-related peptide from
submucosal neurons and of platelet-activating factor
by the epithelial cells.110 Both platelet-activating
factor and substance P are important inflammatory
mediators,110 thus promoting further inflammation
which could lead to an increased mucosal permeabil-
ity and further peripheral sensitization.
Central sensitization Not only peripheral but also
central sensitization plays an essential role in esoph-
ageal hypersensitivity. Acid stimulation of the esoph-
agus also sensitizes the insula and cingulate cortex to
subliminal and liminal non-painful mechanical stim-
ulations.111 Similar results were found using electrical
stimuli.112 The suggested mechanism is that enhanced
nociceptor input results in repetitive signaling cas-
cades in the spinal dorsal horn neurons which subse-
quently lead to facilitated excitatory synaptic
responses and depressed inhibition, resulting in ampli-
fied responses to both noxious and innocuous
inputs.113 Using functional magnetic resonance imag-
ing, the effects of negative and neutral emotional
states on the perception of non-painful esophageal
distension was examined. Interestingly, it was found
that the same stimulus was perceived more intensely
during a negative emotional context and was associ-
ated with an increased cortical activity in the anterior
insula and the dorsal anterior cingulate gyri than
during a neutral emotional context.114 Moreover, it has
been demonstrated that acid exposure in GERD
patients leads to a more rapid and greater cerebral
activity than in healthy controls.115
2015 John Wiley & Sons Ltd
Pathophysiology of GERD
SUMMARY
Our views on the pathophysiology of GERD have
changed rather dramatically in the last decades. The
developments in pathophysiological insight have not
always been characterized by gradual evolvement, but
remarkable thought swings occurred, in particular
concerning the role of hiatus hernia. It is now
generally recognized that GERD is a multifactorial
disease. In this review, we have highlighted the two
important areas of interest. The first of these regards
the mechanisms by which reflux occurs and the
factors that facilitate these, which include hiatus
hernia, low LES pressure, TLESRs, the acid pocket,
obesity, increased distensibility of the EGJ, prolonged
esophageal clearance and delayed gastric emptying.
The second area involves the factors which influence
perception of GERD symptoms, including acidity of
reflux, the proximal extent of the reflux, gas reflux,
duodenogastroesophageal reflux, longitudinal muscle
contraction, mucosal integrity and peripheral and
central sensitization.
Despite the recent advances in our understanding of
the mechanisms underlying symptoms and signs of
GERD, further research remains necessary. Better
understanding of the pathophysiology of GERD is
important in uncovering new targets for therapy as
many GERD patients have persistent symptoms
despite PPI treatment. As the disease is multifactorial,
treatment focusing on other factors than acid suppres-
sion could be beneficial.
FUNDING
T.V.K. Herregods is funded by the European Unions Seventh
Framework Programme under REA grant agreement no. 607652
(NeuroGut).
CONFLICTS OF INTEREST
AJB received research funding from Endostim, Medical Measure-
ment Systems, Danone and Given and received speaker and/or
consulting fees from MMS, Astellas, AstraZeneca and Almirall;
TH and AS report no potential conflicts of interest relevant to this
article.
AUTHOR CONTRIBUTION
TH designed the review, drafted the manuscript, revised the
article critically for important intellectual content, and approved
the final submitted draft; AJB and AS designed the review,
critically revised the manuscript for important intellectual con-
tent, and approved the final submitted draft.
1209
T. V. K. Herregods et al.
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