Gastroenterology 2018;154:277–288
GERD
Pathophysiology of Gastroesophageal Reflux Disease
Jan Tack1 John E. Pandolfino2
1
Translational Research Center for Gastrointestinal Disorders, University of Leuven, Belgium; and 2Division of Gastroenterology
and Hepatology, Northwestern University Feinberg School of Medicine, Chicago, Illinois
The pathogenesis of gastroesophageal reflux disease
(GERD) is complex and involves changes in reflux
exposure, epithelial resistance, and visceral sensitivity. The
gastric refluxate is a noxious material that injures the
esophagus and elicits symptoms. Esophageal exposure to
gastric refluxate is the primary determinant of disease
severity. This exposure arises via compromise of the
anti-reflux barrier and reduced ability of the esophagus to
clear and buffer the refluxate, leading to reflux disease.
However, complications and symptoms also occur in the
context of normal reflux burden, when there is either poor
epithelial resistance or increased visceral sensitivity.
Reflux therefore develops via alterations in the balance of
aggressive and defensive forces.
Keywords: Esophageal Motility; Esophageal Sensitivity; Acid
Exposure; Transient Lower Esophageal Sphincter Relaxations;
Hiatal Hernia.
G astroesophageal reflux disease (GERD) is defined as
the presence of symptoms or complications that are
directly related to the retrograde flow of gastric contents
into the esophagus.1 A certain degree of reflux is
normal—development of GERD requires either increased
esophageal exposure to gastric juice or a reduced threshold
for epithelial injury and symptom perception. This balance
among reflux exposure, epithelial resistance, and visceral
sensitivity is delicate, and can be altered by perturbations in
physiologic and anatomical factors that either promote or
impede reflux into the esophagus, or protect or injure the
epithelium from exposure to gastric juice.
Under normal circumstances, reflux into the esophagus
is prevented by the anti-reflux barrier, which is a complex
anatomic zone made up of multiple components, including
the lower esophageal sphincter, the extrinsic crural
diaphragm, and the supporting structures of the gastro-
esophageal flap valve. When these protective components
are compromised, the deleterious effects are additive,
resulting in increasing numbers of reflux events and
increasingly abnormal esophageal reflux exposure. When
gastric juice enters the esophagus, protective factors help
clear the refluxate from the esophagus and protect the
epithelium. Breakdown of these protective forces promotes
reflux disease. However, complications and symptoms can
also occur in individuals with a normal reflux burden, when
there is either poor epithelial resistance or increased
visceral sensitivity. The pathogenesis of reflux disease is
therefore complex and determined by interactions among
multiple aggressive and defensive factors.
We review the pathophysiology of GERD in the context of
abnormalities related to reflux exposure and abnormalities
related to epithelial resistance and visceral hypersensitivity.
These exist in a continuum that determines severity of reflux
disease. It is important to consider this balance in attempting
to understand mechanisms of pathogenesis in each patient.
Reflux Exposure
GERD develops via reflux of noxious gastric juice into the
esophagus.1 Excessive reflux exposure is normally pre-
vented as a function of the anti-reflux barrier and the direct
result of an impaired anti-reflux barrier is an increased
number of reflux events via an increasing diversity of
mechanisms of reflux. Once reflux has occurred, injury and
symptoms are regulated by the duration of exposure and
causticity of the gastric juice. The duration of reflux expo-
sure is determined by the effectiveness of esophageal reflux
clearance, the dominant determinants of which are peri-
stalsis, salivation, and the presence of a hiatus hernia. Ab-
normalities of esophageal clearance are probably the major
determinants for development of esophagitis, whereas
esophageal sensitivity is a major determinant of GERD
symptom perception.
Abbreviations used in this paper: EGJ, esophagogastric junction; GERD,
gastroesophageal reflux disease; LES, lower esophageal sphincter;
NERD, nonerosive reflux disease; PAR2, protease-activated receptor 2;
PPI, proton pump inhibitor; tLESR, transient lower esophageal sphincter
relation; TRVP1, transient receptor potential vanilloid type-1.
Most current article
© 2018 by the AGA Institute
0016-5085/$36.00
https://doi.org/10.1053/j.gastro.2017.09.047
 278 Tack and Pandolfino
Gastric Refluxate
Gastric juice is a noxious blend of acid, bile, and digestive
enzymes that help digest food so that it can be delivered to
GERD
the small intestine. This material is caustic and can therefore
injure most epithelial layers unless proper protective
measures are in place to buffer the acid and protect the
mucosa from inflammation and other direct effects of the
refluxate. Although all of the components can injure and
irritate the esophagus, acid is the primary determinant of
esophagitis and reflux symptoms. However, studies have
indicated that abnormal acid secretion is not the primary
defect of GERD, because gastric acid secretion is similar
between asymptomatic individuals and GERD patients.2
Although hypersecretory states, such as Zollinger-Ellison
disease, are associated with severe reflux disease, the mere
presence of normal gastric juice in the esophagus is enough
to injure and irritate the esophagus. Despite the multitude
of studies in animal models, human translational
investigations, and clinical trials focused on acid suppres-
sion, many people have been misled into thinking that GERD
can result from too little acid in the stomach. Some
researchers have advocated for recklessly increasing acid
levels in patients with GERD using various concoctions with
pH values <4.0. These approaches have placed patients with
severe GERD at high risk for complications and death, and
should be aggressively discouraged. Acid suppression is the
first-line treatment for GERD, based on sound experimental
and clinical data.
In addition to acid, other components of gastric juice,
such as bile, digestive enzymes, microbial pathogens, and
other noxious factors can damage the esophagus and cause
symptoms.3–6 In patients given high doses of proton pump
inhibitors (PPIs), gastric juice typically remains acidic,
termed weakly acidic reflux. Reflux of weakly acidic gastric
content has been implicated in the generation of symptoms
(regurgitation, based primarily on the volume delivered into
the esophagus, and possibly oropharynx, but also heart-
burn) and lesions.7 Pepsin also contributes to mucosal
injury—even small amounts can injure the esophagus.5,6
However, this effect is most deleterious in an acidic envi-
ronment, because most pepsins are inactive at pH 4.5–7.0.5,6
Bile acids can alter the integrity of the mucosal barrier by
disrupting cell function and damaging membrane structure.4
Bile is secreted into the proximal small intestine. However,
abnormal secretory patterns and antro-duodenal dysmotility
can increase the amount of bile in the stomach. Esophageal
exposure to bile mixed with acid is associated with more se-
vere grades of esophagitis3,4 and this is believed to be related
to a shift toward higher levels of conjugated bile acids. Ana-
lyses of the association of acid and bile reflux (quantified
using bilirubin absorbance) with GERD lesions support the
hypothesis that the presence and severity of erosive esoph-
agitis depend mostly on acid reflux, whereas the presence of
Barrett’s esophagus depends on exposure to acid and bile.8
Although, bile acids and pepsin are important constituents
of a noxious gastric refluxate, there are no treatments that
target these components. Treatment has focused on acid
suppression and anti-reflux procedures.
Gastroenterology Vol. 154, No. 2
Although there has been substantial interest in the effects
of the microbiome on development of gastrointestinal
disease, there have been few studies of the roles of bacteria in
development of GERD, outside of its well-established
relationship with Helicobacter pylori infection. Studies have
associated changes in the esophageal microbiota with GERD,
and especially with Barrett’s esophagus.9 Further studies are
needed to clarify whether these contribute to development or
are consequences of reflux.
Epidemiology studies have reported inverse time trends
in the prevalence of GERD and H pylori
related peptic ulcer
disease, indicating an interaction that involves the pattern of
gastritis.10,11 It appears that body-predominant H pylori
decreases gastric acid secretion by reducing the overall
volume of parietal cell mass, whereas antral-predominant
H pylori increases acid secretion, based on alterations in
negative feedback inhibition via D-cell interference in the
antrum. Regardless, perturbations of other components of
reflux pathophysiology are required for reflux disease to
develop; abnormal acid secretion in and of itself is
inadequate to induce symptoms of GERD.
The distribution and volume of gastric juice within the
stomach may also be important in the pathogenesis of GERD.
Although many patients with GERD have abnormal gastric
emptying,12 it is difficult to prove that this causes
GERD—gastric emptying studies are typically reserved for
patients with refractory disease and those with nausea and
vomiting. More recently, there has been interest in the
distribution of gastric juice in terms of its relationship to the
postprandial acid pocket13 and anatomical variants, such as
the cascade stomach (retroflexed gastric fundus, which pref-
erentially fills upon ingestion).14 The acid pocket is a gastric
juice layer that resides above the ingested food bolus and is
positioned just below the esophagogastric junction (EGJ) in
normal postprandial conditions. Studies have shown that the
acid pocket is associated with proximal extension in GERD, and
that the position of the acid pocket is altered in patients with
hiatus hernia to promote acid reflux.15 These findings support
that the role of the proximal stomach in GERD, but studies are
needed to better understand how gastric accommodation and
distribution of the acid pocket can alter GERD severity.
Reflux Events
Reflux exposure begins with reflux events; the anti-reflux
barrier is the primary determinant of reflux event burden and
the mechanisms of reflux. The anti-reflux barrier is a complex
anatomic high-pressure zone that arises via synergy between
the lower esophageal sphincter and the crural diaphragm.16
The function of this barrier is maintained by the architec-
ture of the gastroesophageal flap valve,17 which is supported
by the phrenoesophageal ligament and the gastric sling fibers
of the gastric cardia. These supporting structures help
maintain position of the intrinsic lower esophageal sphincter
within the extrinsic crural diaphragm, such that the 2 can
overlap and create a more effective barrier. Severity of reflux
correlates with the severity of dysfunction of each of the
individual component of the anti-reflux barrier.
January 2018
The lower esophageal sphincter (LES) is a short segment
of tonically contracted smooth muscle at the distal end of the
esophagus; its resting tone varies among healthy individuals,
from 10 to 30 mmHg, relative to intragastric pressure. This
typically provides a sufficient barrier to offset the gastro-
esophageal pressure gradient across the EGJ. Large fluctua-
tions of LES pressure occur throughout the day, with
increases that exceed 80 mmHg with the migrating motor
complex and smaller fluctuations, toward lower pressure, in
the postprandial state.18 Overall, LES pressure is affected by
myogenic and neurogenic factors; these are modified by
intra-abdominal pressure, gastric distention, peptides, hor-
mones, foods, and medications.19 Physiology studies showed
the anti-reflux barrier high-pressure zone to extend distal to
the squamocolumnar junction, so structures in the proximal
stomach appear to be involved beyond the LES.20 Anatomical
studies attribute this distal portion of the anti-reflux barrier
to a fold-like function related to the opposing sling and clasp
fibers of the gastric cardia. This has been conceptualized as a
flap valve and the anatomy of this area can be graded using
the Hill classification to predict reflux severity.17 Of note, this
distal aspect of the EGJ is particularly vulnerable to disrup-
tion because of anatomical changes at the hiatus—its entire
mechanism of action is predicated on maintaining its native
geometry and attachments.
Figure 1. The gastro-
esophageal junction.
Absence (left panel) and
the presence (right panel)
of a hiatal hernia.
Pathophysiology of GERD 279
Surrounding the LES at the level of the squamocolumnar
junction is the diaphragmatic hiatus, most commonly
comprised of the right diaphragmatic crus. The hiatus is a
GERD
teardrop-shaped canal of about 2 cm along its major axis.
Physiology studies led to the 2-sphincter hypothesis for main-
tenance of EGJ competence, indicating the LES and the sur-
rounding crural diaphragm have independent sphincter
functions.16 Physiology studies by Mittal et al21 demonstrated
that augmentation of EGJ pressure via many activities can be
attributed to contraction of the crural diaphragm. In patients
with hiatus hernia, crural diaphragm function is potentially
compromised by its axial displacement,22 and potentially by
radial disruption, due to atrophy secondary to dilatation of the
hiatus23 (Figure 1). The effects of hiatus hernia, the size of which
correlates with susceptibility to reflux elicited by straining
maneuvers, was demonstrated in studies of normal volunteers
compared to GERD patients with and without hiatus hernia.24
Another effect that hiatus hernia exerts on the anti-reflux
barrier is to diminish the intraluminal pressure within the
EGJ. Studies in animal models found that simulating the effect
of hiatus hernia by severing the phrenoesophageal ligament
reduced the LES pressure, and that the subsequent repair of
the ligament restored the LES pressure to levels similar to
baseline.25 Similarly, manometric studies, which produced a
topographic representation of the EGJ high-pressure zone in
 280 Tack and Pandolfino Gastroenterology Vol. 154, No. 2

patients with hiatus hernia, revealed distinct intrinsic

sphincter and hiatal canal pressure components, each of
which was of lower magnitude than the EGJ pressure of a
GERD

comparator group of healthy individuals.26

Reflux Mechanisms
Reflux usually occurs via 4 mechanisms: transient lower
esophageal sphincter relations (tLESRs), low LES pressure,
swallow-associated LES relaxations, and straining during
periods with low LES pressure (Figure 2). Mechanisms that
prevent against reflux vary with physiologic circumstances
and the anatomy of the EGJ. For example, the crural
diaphragm may be of cardinal importance with abrupt
increases in intra-abdominal pressure and straining and this
may be altered in hiatus hernia. In contrast, basal LES
pressure may be of primary importance during restful
recumbency and in the postprandial state, and a hypotensive
LES may predispose patients to more reflux at night and after
meals. If any of these protective mechanisms are compro-
mised, the harmful effects are additive, increasing numbers of
reflux events and abnormal esophageal reflux exposure.
There is convincing evidence that tLESRs are the most
frequent mechanism for reflux during periods of normal LES
pressure (>10 mmHg). By definition, transient LES
relaxations occur independently of swallowing, are not
accompanied by peristalsis, are accompanied by diaphrag-
matic inhibition, and persist for longer periods than swallow-
induced LES relaxations (>10 seconds).27–29 The dominant
stimulus for tLESRs is distension of the proximal stomach,
which stimulates the intraganglionic lamellar ending found at
the receptor end of vagal afferents.30 These fibers project to
the nucleus tractus solitarii in the brainstem and subse-
quently to the dorsal motor nuclei of the vagus. Dorsal motor
nucleus neurons project to inhibitory neurons localized Figure 2. Mechanisms of reflux, determined by high-
within the myenteric plexus of the distal esophagus and an resolution manometry. Color-scaled esophageal pressure
integrated motor response involving LES relaxation through topography and overlaid impedance tracings were spaced
reflex inhibitory responses, longitudinal muscle contraction at 3-cm intervals. (Top panel) Example of a transient
that reduces EGJ obstruction through tension-mediated LES LES relaxation with reflux. The LESR occurs and is followed
closely by crural inhibition (CI), so both sphincters are
relaxation and repositioning of the LES above the crura, crural
inhibited. There is a small increase in intragastric pressure
diaphragmatic inhibition, and contraction of the costal dia- that elicits liquid reflux through the EGJ (drop in imped-
phragm as the final effector state of the tLESR reflex.29,31 ance) into the proximal esophagus noted by the red arrow.
Several neurotransmitters and receptors are involved in There is an intermittent supragastric belch denoted by the
control and modulation of tLESRs. These include g-amino dashed white lines with upper esophageal sphincter (UES)
butyric acid, which activates g-amino butyric acid-B opening. The end event of the tLESR is a sporadic
receptors in the brain stem and on vagal afferents; gluta- secondary contraction in the distal esophagus, followed
closely by a dry swallow with primary peristalsis to clear the
mate, which binds metabotropic glutamate-5 receptors in the
event. (Bottom) This is an example of re-reflux after a
brain stem; and endocannabinoids, which bind cannabinoid swallow in a small hiatus hernia. The LES and crural
type 1 receptors in the brain.32 diaphragm (CD) are separated and the hernia is pressurized
Although transient LES relaxations typically account for after the swallow (circle). Immediately after the swallow, the
up to 90% of reflux events in normal subjects or GERD after contraction resolves and the incompetent LES
patients without hiatus hernia, patients with hiatus hernia does not generate a high-pressure zone and the liquid in
have a more heterogeneous mechanistic profile, with reflux the hernia escapes through the LES noted by the red arrow
and drop along the impedance tracings. The liquid extends
episodes frequently occurring in the context of low LES into the body of the esophagus extending to just below
pressure, straining, and swallow-associated LES the UES. The bolus is eventually cleared out of the
relaxation.33 These observations support the hypothesis esophageal body by a swallow and secondary peristaltic
that the functional integrity of the EGJ depends on the contraction.
January 2018 Pathophysiology of GERD 281

intrinsic LES and extrinsic sphincter function of the function. However, another important component that can
diaphragmatic hiatus. In essence, gastroesophageal reflux impede reflux clearance is hiatus hernia—this anatomic
requires 2 hits to the EGJ. Patients with a normal EGJ abnormality is associated with re-reflux during swallowing,

GERD
require inhibition of the intrinsic LES and extrinsic crural which circumvents the emptying function of peristalsis.
diaphragm for reflux to occur; this occurs in the setting of a
tLESR. In contrast, patients with hiatal hernia can have a
Impaired Esophageal Emptying
pre-existing compromise of the hiatal sphincter. In these
Impaired esophageal emptying is an important risk
patients, reflux can occur with only relaxation of the
factor for GERD, identified because reflux symptoms are
intrinsic LES, and may occur during periods of LES
reduced when patients are moved to an upright position,
hypotension or even during deglutitive relaxation. In fact,
which allows gravity to empty the esophagus.40 Gravity is
swallow-associated reflux is a mechanism that is unique to
complemented by esophageal peristalsis, which is induced
hiatus hernia,34 although it is also observed in patients with
by mechanoreceptors in the esophageal body that strip the
surgical manipulation of the foregut, such as gastric bypass
esophagus clear using lumen occluding antegrade
or laparoscopic gastric bands.
contractions. These events are termed secondary peristalsis
GERD can occur in the context of diminished LES
because the stimulus that elicits these contractions is not
pressure, either by strain-induced or free reflux.24,35
related to swallowing. However, primary peristalsis is also
Strain-induced reflux occurs when a hypotensive LES is
an important factor in esophageal emptying in GERD and
blown open in association with an abrupt increase of
assessment of peristaltic function during swallowing is a
intra-abdominal pressure.24 Data from manometry studies
valuable surrogate for disease severity in GERD.41–43
indicate that this rarely occurs when the LES pressure is
Peristaltic dysfunction is an important contributor to
>10 mmHg.24,35 It is also a rare occurrence in patients
severity of esophagitis. The level of acid exposure has been
without hiatus hernia33 or an altered gastroesophageal flap
directly linked to the degree of ineffective or weak
valve (III or greater), so that the anatomy of the gastro-
peristalsis.42,43 Weak peristalsis has been defined using
esophageal flap valve does augment during periods of rapid
various measures of peristaltic vigor; the classic threshold
intragastric pressure. Free reflux is characterized by a
for an effective contraction associated with intact bolus
decrease in intra-esophageal pH without an identifiable
clearance is an amplitude of >30 mmHg. However, advances
change in either intragastric pressure or LES pressure.
in manometric technique have shown that, in addition to the
Episodes of free reflux are observed only when the LES
overall vigor of contraction, regional defects in the wave
pressure is within 0–4 mmHg of intragastric pressure; this
front >5 cm can be associated with poor bolus clearance
is observed in patients with end-stage scleroderma or after
and GERD.44 As for all measures associated with reflux
surgical myotomy in patients with achalasia.
disease, peristaltic dysfunction in and of itself is not
pathognomonic of reflux disease and should be considered
across the spectrum of dysfunction and in the context of
Esophageal Clearance
other anatomic and physiologic abnormalities.
After a reflux event occurs, the duration that the
Hiatus hernia also can impair esophageal emptying.
esophageal mucosa remains exposed to the gastric juice is
Concurrent pH recording and scintigraphy above the EGJ
called the reflux exposure time or bolus contact time.
showed that impaired clearance was caused by re-reflux of
Exposure of the mucosa to caustic and irritating compo-
fluid from the hernia sac during swallowing.45 This
nents of the gastric juice leads to injury, inflammation, and
observation was subsequently confirmed radiographically,
symptoms; prolonged acid clearance correlates with the
in an analysis of esophageal emptying in patients with
severity of esophagitis and the presence of Barrett’s meta-
reducing and nonreducing hiatus hernias.46 The efficacy of
plasia.36–38 However, the threshold for these responses and
emptying was significantly reduced in groups with hernia
complications vary, and is likely to be influenced by the
compared to individuals without hernia, but emptying, in
integrity of the epithelium.36–39 Conventional assessment of
particular, was compromised in patients with nonreducing
esophageal clearance has therefore focused on pH measures,
hiatus hernia. Patients with nonreducing hernias were the
and esophageal acid clearance time is determined by the
only group that had retrograde flow of fluid from the hernia
time at which the esophageal lumen is acidified to a pH of
during deglutitive relaxation.
<4 after a reflux event. Although this analysis focuses on
acidity, newer methodologies have used impedance as a
signal to analyze bolus presence and clearance.38 These Effects of Saliva
tools have been useful in identifying subpopulations that Salivary neutralizing represents another important
will respond to acid suppression, and this highlights the protective measure of esophageal reflux clearance. Saliva
importance of reflux exposure beyond acid.39 contains bicarbonate, which buffers acid, and growth
Esophageal bolus and acid clearance begins with factors, such as epidermal growth factor, which promote
peristalsis after the reflux event occurs, and this is mucosal repair and defenses. Although this component is
complemented by additional buffering from swallowed often lumped into clearance mechanisms, it does not aid in
saliva. Therefore, the 2 main potential causes of prolonged the removal of bolus. Instead, it provides an important
reflux exposure and acid clearance are impaired esophageal protective neutralizing effect that helps restore a normal pH
emptying via peristaltic dysfunction and impaired salivary and thereby reduces acid contact time in the lumen.47
 282 Tack and Pandolfino
Reduced salivation has been associated with prolonged acid
clearance times, such as during sleep, when salivation is
reduced and reflux events tend to be associated with more
GERD
prolonged acid clearance. Similarly, but on a more
exaggerated spectrum, chronic xerostomia is also associated
with prolonged acid clearance and more severe esophagi-
tis.48 However, outside of these extreme examples, there has
been no overt difference in the quantitative and qualitative
aspects of saliva in individuals with vs without GERD.
Non-Esophageal Symptoms of
Gastroesophageal Reflux Disease
By exposing the esophagus to refluxate, GERD induces
esophageal symptoms (heartburn, regurgitation, and
esophageal chest pain) and lesions (reflux esophagitis,
strictures, and Barrett’s esophagus).1 However, GERD has
also been implicated in the pathogenesis of a number of
so-called atypical or extra-esophageal symptom manifesta-
tions, including ear, nose, and throat (laryngitis and
pharyngitis); pulmonary (asthma and cough); and dental
(dental erosion) disorders.1 There is controversy over the
role of GERD in the pathogenesis of these disorders,
and little is known about the pathophysiology of
extra-esophageal GERD manifestations.49,50
Extra-esophageal manifestations of GERD could arise
through a direct reflux mechanism, in which
micro-aspiration of gastric contents causes damage to ear,
nose, and throat (laryngopharyngeal reflux) or respiratory
epithelia. This mechanism is supported by studies showing
reflux into the upper airways using pharyngeal pH moni-
toring or analysis of gastric juice components (pepsin and
bile) in broncho-alveolar lavage fluid. However, there is no
evidence from large subsets of patients with presumed
extra-esophageal manifestations of GERD for direct
reflux exposure of supra-esophageal tissues—even when
gastro-esophageal reflux events correlate with extra-
esophageal events (such as bronchoconstriction during
esophageal acidification). For these cases, the esophageal-
airway reflex theory proposes an indirect mechanism, in
which distal esophageal reflux stimulates vago–vagal reflex
pathways, leading to changes in function and complications
in extra-esophageal segments (bronchoconstriction, cough,
and altered upper airway reactivity or sensitivity).49,50
Effects of Obesity
The relationship between obesity and GERD cannot be
ignored in a discussion focused on pathophysiology; GERD
correlates with obesity, and there is a logical explanation for
this. Movement of gastric juice from the stomach into the
esophagus is determined by the pressure gradient between
the abdomen and the chest. Multiple studies have shown
that intragastric pressure is higher in obese patients,51,52
and that pressure correlates with body mass index and
waist circumference.53 Increased intra-abdominal pressure
can also increase strain on the anti-reflux barrier, so obesity
is associated with a higher risk of hiatus hernia. These
factors provide a recipe for severe reflux disease, supported
Gastroenterology Vol. 154, No. 2
by clinical studies. Interestingly, small amounts of weight
loss (approximately 10–15 lb) can reduce GERD
symptoms.54 The direct effect of weight loss could be to
reduce the pressure gradient and burden on the anti-reflux
barrier.
Sensitivity to Reflux Episodes
Symptoms are the main reason that patients with
suspected GERD consult a physician and adhere to therapy,
whereas symptoms refractory to standard medical therapy
are the main reason for additional investigations and
considering referral for surgery.55 Acid perfusion studies
established that HCl at pH 2 induces heartburn in GERD
patients, indicating the role of acid in inducing heartburn.56
However, the relationship between reflux events and
symptom occurrence is poorly understood and varies. In
ambulatory pH-monitoring studies of patients off PPI
therapy, as many as half of the reported heartburn episodes
in GERD patients were associated with acid reflux,
indicating involvement of other factors.57,58
Changes in esophageal sensitivity are important
determinants of symptoms during reflux events.59–61
Several studies have identified groups of patients with
normal esophageal reflux exposure; in these patients, reflux
events correlate with heartburn perception.59–62 According
to the Rome IV consensus, these patients are now catego-
rized as having reflux hypersensitivity.60 These observa-
tions are consistent with the concept of esophageal
hypersensitivity.60,61 Conversely, studies using esophageal
acid perfusion and balloon distention reported decreased
sensitivity to these stimuli in patients with Barrett’s
esophagus, and this could contribute to the lower symptom
perception in these patients.62,63 Ambulatory pH monitoring
studies confirmed that similar amounts of acid exposure
were less likely to be perceived by Barrett’s patients
compared to GERD patients without Barrett’s esophagus.63
These observations support the role of esophageal
sensitivity in determining symptoms in GERD. Hypersensi-
tivity is believed to contribute to refractory GERD symptoms
and has received the most attention.60–62
Esophageal Sensitivity
Increased sensitivity to acid reflux has been implicated
in lower therapeutic response to acid suppression in
patients with nonerosive reflux disease (NERD). Modified
Bernstein acid perfusion studies showed that sensitivity to
esophageal acid perfusion was increased in patients with
erosive reflux disease and NERD.64,65 Increased sensitivity
to esophageal acid perfusion has been reported in patients
with acid-sensitive esophagus (characterized by normal acid
exposure but a correlation between symptoms and acid
reflux events), whereas patients with Barrett’s esophagus or
functional heartburn (characterized by normal acid
exposure and no correlation between symptoms and reflux
events) are less sensitive to esophageal-acid perfusion.65–68
Mechanosensitivity could also contribute to
reflux-related symptoms. Patients with erosive GERD do not
have altered mechanosensitivity of the esophagus compared
January 2018 Pathophysiology of GERD 283

with controls, but patients with acid-sensitive esophagus or mechanical, and chemical stimulation of the esophagus
true NERD have increased sensitivity to esophageal balloon compared to healthy volunteers.75
distention.61 Balloon distention studies have shown that Taken together, these findings indicate that esophageal

esophageal distention induces heartburn, and that the
proximal esophagus is more sensitive than the distal
esophagus.69,70 Activation of mechanosensitive afferent
pathways, when the esophagus is distended during reflux
events, is therefore an important mechanism of symptom
generation during weakly acidic reflux. For example, this
might occur in patients with symptoms despite adequate
acid suppressive therapy.60,61
High proximal extent of the refluxate also determines
whether a reflux event causes symptoms. This could reflect
a phenomenon of spatial summation of the triggering
stimulus, but could also indicate a mechanical factor—a
higher refluxate volume would be more likely to induce
symptoms.58,71 In support of the mechanical factor, proxi-
mally extending reflux events that contain air are more
likely to induce symptoms than proximally extending reflux
events that contain only liquid.72
Increased esophageal sensitivity may also involve other
sensory modalities. Studies that used a multimodal esoph-
ageal stimulation probe found patients with NERD to be
hypersensitive to heat stimuli and to have increased referral
areas in response to esophageal stimulation.73 In patients
with NERD, sensitivity to esophageal electrical stimulation
increased with lower esophageal acid exposure.74 Patients
with PPI-refractory GERD are hypersensitive to thermal,
GERD
sensitivity contributes to symptom expression in patients
with GERD. Patients with Barrett’s esophagus have lower
sensitivity, but sensitivity increases as reflux exposure
decreases over the spectrum from erosive disease to NERD
and reflux hypersensitivity (Figure 3). Esophageal sensi-
tivity is determined by the strength of activation of sensory
receptors in the gastrointestinal tract and by processing in
the central nervous system, which can lead to amplification
or suppression of the afferent signal that is being trans-
mitted to cortical areas involved in perception.76,77 Periph-
eral and central mechanisms can increase signal
transmission following stimuli; each has been implicated
in the pathogenesis of esophageal hypersensitivity.76,77
Peripheral mechanisms refer to processes leading to
increased sensitivity and activity of esophageal sensory
afferents and their receptors. Central mechanisms are
processes that increase sensitivity and activity of dorsal
horn neurons of the spinal cord and higher centers involved
in processing incoming signals from the esophagus.76,77
Peripheral Mechanisms
Nerve endings, thought to mediate the sensitivity to
refluxed gastric contents, are present in the submucosal
layer, implicating that the refluxate signal needs to cross the

Figure 3. Phenotypes of
GERD and effects of
pathogenetic features.
Increasing reflux exposure,
increasing symptom asso-
ciation probability (SAP),
increasing mucosal perme-
ability, increasing visceral
sensitivity, increasing psy-
chological comorbidities.
*The presence and role of
esophageal (hyper) sensi-
tivity in the functional
heartburn group are less
clear, indicated by the
transparent box. In this
group, central processes,
such as hypervigilance and
psychosocial comorbid-
ities, rather than esophageal
events, are thought to be
the main determinants of
symptom occurrence.
 284 Tack and Pandolfino
mucosal barrier to allow symptom perception.78 Decreased
resistance to transmucosal passage by components of the
refluxate is one potential peripheral mechanism of esopha-
GERD
geal hypersensitivity to reflux. Several studies have
demonstrated loss of mucosal barrier function in GERD,
which may allow luminal content an easier passage to nerve
endings and increased symptoms.77–81 Loss of mucosal
integrity has been shown in vitro, using measurements of
transmucosal resistance or flux of molecules across the
mucosa of esophageal endoscopic biopsies mounted in
Ussing chambers.78,79 The morphologic correlate of this loss
of mucosal integrity is the finding of dilated intercellular
spaces, studied by histology or, most accurately, by electron
microscopy of esophageal biopsies.78–81 More recently,
baseline impedance as evaluated using esophageal
pH-impedance catheters or a dedicated through-the-scope
catheter, has been validated as a marker of loss of
mucosal barrier function.82–84
Several studies have shown increased mucosal perme-
ability (or decreased baseline impedance) in patients with
nonerosive and erosive (in the noneroded sections) reflux
disease. Most studies also found the same in patients with
reflux hypersensitivity, but this was not found consistently
in functional heartburn.65,67,78–80,83–85 However, in func-
tional heartburn, the subgroup with signs of impaired
mucosal integrity (low baseline impedance) has been shown
to respond better to PPI therapy.86,87 These observations
closely link the presence of dilated intercellular spaces or
loss of esophageal mucosal integrity to the presence of
pathologic and/or symptomatic gastroesophageal reflux.
Dilated intercellular spaces and decreased mucosal
impedance can be a consequence of acid reflux. In healthy
individuals, these abnormalities can be induced by esopha-
geal acid perfusion, and in patients these alterations
decrease with acid-suppressive therapy.81,82,88 Acid, as well
as bile, was shown to dilate intercellular spaces and increase
mucosal permeability in studies of animal models and
perfusion studies of healthy individuals.88,89 However, ani-
mal studies found stress to be involved in pathogenesis of
dilated intercellular spaces,90 providing a peripheral
component to a pathophysiologic factor that is usually
considered to act centrally.
The studies discussed indicate that acid-sensitive re-
ceptors, expressed on submucosal nerve endings, are the
sensory transductor for reflux-induced symptoms. These
studies provide evidence that dilated intercellular spaces
are a consequence of luminal aggressive refluxate factors
that allow luminal contents to activate nerve endings,
leading to symptom generation.78 More recent studies in
animals and in human esophageal cells have implicated
esophageal epithelial cells in reflux sensing and shown that
reflux induces an inflammatory reaction in the submucosal
layer, which leads to dilated intercellular spaces.91,92 A
study of 12 patients with grade C esophagitis found inter-
ruption of PPI therapy to result in submucosal infiltration
by T cells and dilated intercellular spaces in the basal layer,
in areas with intact mucosal surface.93
The presence and density of reflux-sensing receptors
might also determine symptom occurrence during reflux
Gastroenterology Vol. 154, No. 2
events. Increased expression or function of these receptors
is another potential peripheral mechanism of esophageal
hypersensitivity to reflux. The most important candidate
receptors involved in sensing the presence of reflux in the
esophagus are the transient receptor potential vanilloid
type-1 (TRPV1), acid-sensitive ion channels, and the
protease-activated receptor 2 (PAR2), which are all
expressed in human esophageal mucosa.94 Esophageal
sensitivity to reflux might be affected by the number of
receptors and their activation status. Increased expression
of the TRPV1 receptor has been reported in patients with
reflux esophagitis.95 However, this occurred in a setting of
increased nerve fiber density, which could be a reaction to
reflux-associated inflammation, so the effects of increased
TRPV1 expression are unclear.
Cultured human esophageal epithelial cells have been
shown to express TRPV1 and acid-sensitive ion channels.
Upon activation by (weakly) acidic solutions, these release
adenosine triphosphate, which has been proposed to be a
neurotransmitter involved in signaling pain and inducing
inflammation.92 Activation of PAR2 sensitizes cultured hu-
man esophageal epithelial cells to acid, in part through
phosphorylation of TRPV1. This could be a pathway through
which mast cell activation (releasing the PAR2 activator
tryptase) or duodenogastroesophageal reflux (containing
the PAR2 activator trypsin) sensitizes the esophagus to
(weak) acid. There have been no studies of this sensitization
pathway in animal models, but PAR2 is up-regulated in
esophageal tissues of patients with GERD; up-regulation
correlated with expression of inflammatory mediators
(interleukin 8) and microscopic changes, including dilated
intercellular spaces.96
Central Mechanisms
Central mechanisms, attributed to altered processing of
afferent signals from the esophagus, have also been impli-
cated in the pathogenesis of esophageal hypersensitivity.
These could involve amplification of incoming signals and
lack of inhibition by descending anti-nociceptive pathways.
These are regulated by factors that affect central mecha-
nisms, such as stress, anxiety, and personality traits.59–61,76,77
Neurotransmitter systems involved in anti-nociceptive cen-
tral effects include endogenous opioids, endocannabinoids,
and serotonin.76 Activation of n-methyl D aspartate receptors
affects sensitization of dorsal horn neurons.76,77
Most patients with GERD report that stress exacerbates
their symptoms.97 Acute stressors exacerbated heartburn
symptoms in GERD patients by enhancing the perceptual
response to esophageal acid exposure or acid perfusion.64,98
Stress is often presumed to alter central processing of
afferent signals, such as heartburn, but animal studies
showed that acute stress led to dilation of intercellular
spaces in the esophagus, which could also account for the
increased sensitivity to reflux.90 In healthy individuals,
administration of corticotropin-releasing hormone, which
mediates the response of the gastrointestinal tract to stress,
increased sensitivity of the esophagus to mechanical
distention but not acid, heat, or electrical stimulation.99
January 2018
Psychosocial comorbidities also determine the severity
of GERD symptoms and response to therapy. Patients with
symptoms of GERD symptoms often have anxiety and
depression.100 GERD patients with depression, or especially
anxiety, have greater effects of symptoms and lower quality
of life, even though reflux parameters do not differ from
those of GERD patients without these comorbidities.101
Patients with GERD have increased sensitivity to acid
perfusion after a night of sleep deprivation compared with a
good night of rest,102 and sleep deprivation has been shown
to lead to loss of analgesic actions.103 The sensitizing effect
of sleep deprivation, and also of anxiety and depression,
could reflect decreased activity of anti-nociceptive path-
ways. Anti-nociceptive pathways prevent afferent nocicep-
tive information from reaching the gastrointestinal tract.76
Future Directions
The pathophysiology of GERD continues to be an area of
ongoing research, with advances in technology contributing
to changing concepts. Current knowledge is derived from
research that has focused on reflux exposure and reflux
sensitivity. Consideration of motor and anatomical factors
allows a better understanding of causes of reflux exposure.
The nature of the refluxate determines its impact on
occurrence of symptoms, lesions, and complications. Sen-
sory mechanisms determine the relationship between reflux
exposure and symptom generation. Key factors are mucosal
barrier function, expression and sensitivity of sensory
nerves, and modulation at the central nervous system level.
Central nervous system responses are modulated by factors
such as stress and psychosocial comorbidities. Increasing
our understanding of the pathophysiologic mechanisms of
GERD symptoms and lesions should lead to novel, more
effective, or better-targeted treatment options for individual
patients.
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Received May 17, 2017. Accepted September 8, 2017.
Reprint requests
Address requests for reprints to: Jan Tack, MD, PhD, Translational Research
Center for Gastrointestinal Disorders (TARGID), University of Leuven,
Herestraat 49, 3000 Leuven, Belgium. e-mail: jan.tack@kuleuven.be;
Fax: þ3216349914.
Conflicts of interest
The authors disclose the following: Jan Tack has provided scientific advice to
Abide Therapeutics, Alfa Wassermann, Allergan, Chr. Hansen, Danone, Genfit,
Ironwood, Janssen, Kyowa Kirin, Menarini, Mylan, Novartis, Nutricia, Ono
Pharma, Rhythm, Shionogi, Shire, SK Life Science, Takeda, Theravance
Biopharma, Tsumura, Yuhan, Zealand, and Zeria; has received research
grants or support from Abide Therapeutics, Shire, and Zeria; and has served
on speakers’ bureaus for Abbott, Allergan, AstraZeneca, Janssen, Kyowa
Kirin, Menarini, Mylan, Novartis, Shire, Takeda, and Zeria. John Pandolfino is
a speaker for Astra Zeneca and Takeda, a speaker and consultant for
Medtronic, Sandhill, and Torax, and a consultant for Impleo, and has stock
options in Gastrodyne.