Accepted Manuscript

Pathophysiology of Gastroesophageal Reflux Disease

Jan Tack, John E. Pandolfino

PII: S0016-5085(17)36248-0
DOI: 10.1053/j.gastro.2017.09.047
Reference: YGAST 61481

To appear in: Gastroenterology

Accepted Date: 8 September 2017

Please cite this article as: Tack J, Pandolfino JE, Pathophysiology of Gastroesophageal Reflux Disease,
Gastroenterology (2017), doi: 10.1053/j.gastro.2017.09.047.

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 ACCEPTED MANUSCRIPT

Pathophysiology of Gastroesophageal Reflux Disease

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Jan Tack and John E. Pandolfino **

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*Translational Research Center for Gastrointestinal Disorders (TARGID),
University of Leuven, Belgium

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** Division of Gastroenterology and Hepatology,
Northwestern University Feinberg School of Medicine, Chicago, IL

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Conflict of interest:

Jan Tack:
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has provided scientific advice to Abide Therapeutics, Alfa Wassermann, Allergan, Chr. Hansen,
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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 severed on speakers’ bureaus for Abbott, Allergan, AstraZeneca,
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Janssen, Kyowa Kirin, Menarini, Mylan, Novartis, Shire, Takeda and Zeria.

John Pandolfino:
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Astra Zeneca [speaker], Takeda [speaker], Medtronic [speaker, consultant], Sandhill [speaker,
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consultant], Torax [speaker, consultant], Impleo [consultant], Gastrodyne [stock options]

 ACCEPTED MANUSCRIPT

Abstract

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

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noxious material that injures the esophagus and elicits symptoms. Esophageal exposure to gastric

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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,

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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

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sensitivity. Reflux therefore develops via alterations in the balance of aggressive and defensive
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forces.
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Gastroesophageal 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

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symptom perception. This balance among reflux exposure, epithelial resistance, and visceral

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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

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exposure to gastric juice.

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Under normal circumstances, reflux into the esophagus is prevented by the anti-reflux
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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
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gastroesophageal flap valve. When these protective components are compromised, the
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deleterious effects are additive, resulting in increasing numbers of reflux events and increasingly
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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
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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
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increased visceral sensitivity. The pathogenesis of reflux disease is therefore complex and
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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
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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.

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Reflux Exposure

GERD develops via reflux of noxious gastric juice into the esophagus1. Excessive reflux

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exposure is normally prevented as a function of the anti-reflux barrier and the direct result of an

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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

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duration of exposure and causticity of the gastric juice. The duration of reflux exposure is
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determined by the effectiveness of esophageal reflux clearance, the dominant determinants of

which are peristalsis, salivation, and the presence of a hiatus hernia. Abnormalities of esophageal
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clearance are probably the major determinants for development of esophagitis, whereas
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esophageal sensitivity is a major determinant of GERD symptom perception.

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Gastric refluxate
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Gastric juice is a noxious blend of acid, bile, and digestive enzymes that help digest food so that

it can be delivered to the small intestine. This material is caustic and can therefore injure most
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epithelial layers, unless proper protective measures are in place to buffer the acid and protect the
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mucosa from inflammation and other direct effects of the refluxate. Although all 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 patients2.
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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 suppression, many people have

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been misled into thinking that GERD can result from too little acid in the stomach. Some

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researchers have advocated for recklessly increasing acid levels in patients with GERD using

various concoctions with pH values below 4.0. These approach have placed patients with severe

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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.

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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-
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In patients given high doses of proton pump inhibitors (PPIs), gastric juice typically remains
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acidic, termed weakly acidic reflux. Reflux of weakly acidic gastric content has been implicated
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in the generation of symptoms (regurgitation, based primarily on the volume delivered into the

esophagus, and possibly oropharynx, but also heartburn) and lesions.7 Pepsin also contributes to
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mucosal injury—even small amounts can injure the esophagus.5,6 However, this effect is most

deleterious in an acidic environment, because most pepsins are inactive at pH 4.5–7.0.5,6

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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 severe grades

of esophagitis3,4 and this is believed to be related to a shift toward higher levels of conjugated
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bile acids. Analyses 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

esophagitis depends 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

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noxious gastric refluxate, there are no treatments that target these components. Treatment has

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focused on acid suppression and anti-reflux procedures.

Although there has been substantial interest in the effects of the microbiome on

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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

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infection. Studies have associated changes in the esophageal microbiota with GERD, and
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especially with Barrett’s esophagus.9 Further studies are needed to clarify whether these

contribute to development or are consequences of reflux.

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Epidemiology studies have reported inverse time trends in the prevalence of GERD and
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H pylori-related peptic ulcer disease, indicating an interaction that involves the pattern of
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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
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acid secretion, based on alterations in negative feedback inhibition via D-cell interference in the
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antrum. Regardless, perturbations of other components of reflux pathophysiology are required

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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
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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 post-

prandial acid pocket13 and anatomical variants, such as the cascade stomach (retroflexed gastric

fundus, which preferentially fills upon ingestion)14. The acid pocket is a gastric juice layer that

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resides above the ingested food bolus and is positioned just below the esophago-gastric junction

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(EGJ) in normal post-prandial 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

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with hiatus hernia to promote acid reflux15. These findings support that the role of the proximal

stomach in GERD, but studies are needed to better understand how gastric accommodation and

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distribution of the acid pocket can alter GERD severity.
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Reflux events

Reflux exposure begins with reflux events; the anti-reflux barrier is the primary determinant of
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reflux event burden and the mechanisms of reflux. The anti-reflux barrier is a complex anatomic
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high-pressure zone that arises via synergy between the lower esophageal sphincter and the crural

diaphragm16. The function of this barrier is maintained by the architecture of the

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gastroesophageal flap valve,17 which is supported by the phrenoesophageal ligament and the
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gastric sling fibers of the gastric cardia. These supporting structures help maintain position of the
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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.

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
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10 to 30 mmHg, relative to intragastric pressure. This typically provides a sufficient barrier to

offset the gastro-esophageal pressure gradient across the esophago-gastric junction. Large

fluctuations 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 post-

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prandial state18. Overall, LES pressure is affected by myogenic and neurogenic factors; these are

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modified by intra-abdominal pressure, gastric distention, peptides, hormones, foods, and

medications19. Physiology studies showed the anti-reflux barrier high-pressure zone to extend

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distal to the squamo-columnar 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

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barrier to a fold-like function related to the opposing sling and clasp fibers of the gastric cardia.
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This has been conceptualized as a flap valve and the anatomy of this area can be graded using the

Hill classification to predict reflux severity17. Of note, this distal aspect of the EGJ is particularly
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vulnerable to disruption, because of anatomical changes at the hiatus—its entire mechanism of

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action is predicated on maintaining its native geometry and attachments.

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Surrounding the LES at the level of the SCJ is the diaphragmatic hiatus, most commonly

comprised of the right diaphragmatic crus. The hiatus is a teardrop-shaped canal of about 2 cm
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along its major axis. Physiology studies led to the 2-sphincter hypothesis for maintenance of EGJ

competence, indicating the LES and the surrounding crural diaphragm have independent
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sphincter functions16. Physiology studies by Mittal et al demonstrated that augmentation of EGJ

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pressure via many activities can be attributed to contraction of the crural diaphragm 21. 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

hiatus 23 (Figure 1). The effects of hiatus hernia, whose size correlates with susceptibility to
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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

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intraluminal pressure within the EGJ. Studies in animal models found that simulating the effect

of hiatus hernia by severing the phreno-esophageal ligament reduced the LES pressure, and that

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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-

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pressure zone in patients with hiatus hernia, revealed distinct intrinsic sphincter and hiatal canal

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pressure components, each of which was of lower magnitude than the EGJ pressure of a
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comparator group of healthy individuals 26.
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Reflux Mechanisms
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Reflux usually occurs via 4 mechanisms: transient lower esophageal sphincter relations
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(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
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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
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be altered in hiatus hernia. In contrast, basal LES pressure may be of primary importance during
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restful recumbency and in the post-prandial state and a hypotensive LES may predispose patients

to more reflux at night and after meals. If any of these protective mechanisms are compromised,

the harmful effects are additive, increasing numbers of reflux events and abnormal esophageal

reflux exposure.
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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

diaphragmatic inhibition, and persist for longer periods than swallow-induced LES relaxations

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(>10 seconds) 27-29. The dominant stimulus for tLESRs is distension of the proximal stomach,

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which stimulates the intra-ganglionic lamellar ending or IGLE found at the receptor end of vagal

afferents 30. These fibers project to the nucleus tractus solitarii in the brainstem and subsequently

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to the dorsal motor nuclei of the vagus. Dorsal motor nucleus neurons project to inhibitory

neurons localized within the myenteric plexus of the distal esophagus and an integrated motor

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response involving LES relaxation through reflex inhibitory responses, longitudinal muscle
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contraction that reduces EGJ obstruction through tension-mediated LES relaxation and

repositioning of the LES above the crura, crural diaphragmatic inhibition, and contraction of the
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costal diaphragm as the final effector state of the tLESR reflex.29,31 Several neurotransmitters and
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receptors are involved in control and modulation of tLESRs. These include gamma-amino
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butyric acid (GABA), which activates GABA-B receptors in the brain stem and on vagal

afferents, glutamate, which binds metabotropic glutamate-5 receptors in the brain stem, and
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endocannabinoids, which bind cannabinoid type 1 receptors in the brain.32

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Although transient LES relaxations typically account for up to 90% of reflux events in
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normal subjects or GERD patients without hiatus hernia, patients with hiatus hernia have a more

heterogeneous mechanistic profile, with reflux episodes frequently occurring in the context of

low LES pressure, straining, and swallow-associated LES relaxation 33. These observations

support the hypothesis that the functional integrity of the EGJ depends on the intrinsic LES and

extrinsic sphincter function of the diaphragmatic hiatus. In essence, gastroesophageal reflux

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requires 2 hits to the EGJ. Patients with a normal EGJ require inhibition of the intrinsic LES and

extrinsic crural diaphragm for reflux to occur; this occurs in the setting of a tLESR. In contrast,

patients with hiatal hernia can have a pre-existing compromise of the hiatal sphincter. In these

patients, reflux can occur with only relaxation of the intrinsic LES, and may occur during periods

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of LES hypotension or even during deglutitive relaxation. In fact, swallow-associated reflux is a

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mechanism that is unique to hiatus hernia,34 although it is also observed in patients with surgical

manipulation of the foregut, such as gastric bypass or laparoscopic gastric bands.

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GERD can occur in the context of diminished LES pressure, either by strain-induced or

free reflux.24,35 Strain-induced reflux occurs when a hypotensive LES is blown open in

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association with an abrupt increase of intra-abdominal pressure 24. Data from manometry studies
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indicate that this rarely occurs when the LES pressure is greater than 10 mmHg 24, 35. It is also a

rare occurrence in patients without hiatus hernia 33 or an altered gastroesophageal flap valve (III
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or greater), so that the anatomy of the gastroesophageal flap valve does augment during periods
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of rapid intragastric pressure. Free reflux is characterized by a decrease in intra-esophageal pH

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without an identifiable change in either intragastric pressure or LES pressure. Episodes of free

reflux are observed only when the LES pressure is within 0–4 mmHg of intragastric pressure;
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this is observed in patients with end-stage scleroderma or after surgical myotomy in patients with

achalasia.
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Esophageal clearance

After a reflux event occurs, the duration that the esophageal mucosa remains exposed to the

gastric juice is called the reflux exposure time or bolus contact time. Exposure of the mucosa to

caustic and irritating components of the gastric juice leads to injury, inflammation, and
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symptoms; prolonged acid clearance correlates with the severity of esophagitis and the presence

of Barrett’s metaplasia.36-38 However, the threshold for these responses and complications vary

and is likely to be influenced by the integrity of the epithelium 36-39. Conventional assessment of

esophageal clearance has therefore focused on pH measures, and esophageal acid clearance time

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is determined by the time where the esophageal lumen is acidified to a pH of less than 4 after a

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reflux event. Although this analysis focuses on acidity, newer methodologies have used

impedance as a signal to analyze bolus presence and clearance 38. These tools have been useful in

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identifying subpopulations that will respond to acid suppression and this highlights the

importance of reflux exposure beyond acid.39

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Esophageal bolus and acid clearance begins with peristalsis after the reflux event occurs

and this is complemented by additional buffering from swallowed saliva. Therefore, the 2 main
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potential causes of prolonged reflux exposure and acid clearance are impaired esophageal

emptying via peristaltic dysfunction and impaired salivary function. However, another important
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component that can impede reflux clearance is hiatus hernia—this anatomical abnormality is
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associated with re-reflux during swallowing, which circumvents the emptying function of

peristalsis.
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Impaired esophageal emptying

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Impaired esophageal emptying is an important risk factor for GERD, identified because reflux

symptoms are reduced when patients are moved to an upright position, which allows gravity to

empty the esophagus.40 Gravity is complemented by esophageal peristalsis, which is induced by

mechanoreceptors in the esophageal body that strip the esophagus clear using lumen occluding
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antegrade contractions. These events are termed secondary peristalsis, because the stimulus that

elicits these contractions is not related to swallowing. However, primary peristalsis is also an

important factor in esophageal emptying in GERD and assessment of peristaltic function during

swallowing is a valuable surrogate for disease severity in GERD.41-43

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Peristaltic dysfunction is an important contributor to severity of esophagitis. The level of

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acid exposure has been directly linked to the degree of ineffective or weak peristalsis42,43. Weak

peristalsis has been defined using various measures of peristaltic vigor; the classic threshold for

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an effective contraction associated with intact bolus clearance is an amplitude of greater than 30

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mmHg. However, advances in manometric technique have shown that in addition to the overall
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vigor of contraction, regional defects in the wave front greater than 5 cm can be associated with

poor bolus clearance and GERD44. As for all measures associated with reflux disease, peristaltic
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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 other anatomic and physiologic
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abnormalities.
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Hiatus hernia also can impair esophageal emptying. Concurrent pH recording and
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scintigraphy above the EGJ showed that impaired clearance was caused by re-reflux of fluid

from the hernia sac during swallowing 45. This observation was subsequently confirmed
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radiographically, in an analysis of esophageal emptying in patients with reducing and non-

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reducing hiatus hernias 46. The efficacy of emptying was significantly reduced in groups with

hernia compared to individuals without hernia, but emptying, in particular, was compromised in

patients with non-reducing hiatus hernia. Patients with non-reducing hernias were the only group

that had retrograde flow of fluid from the hernia during deglutitive relaxation.
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Effects of saliva

Salivary neutralizing represents another important protective measure of esophageal reflux

clearance. Saliva contains bicarbonate, which buffers acid, and growth factors such as epidermal

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growth factor, which promote mucosal repair and defenses. Although this component is often

lumped into clearance mechanisms, it does not aid in the removal of bolus. Instead, it provides

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an important protective neutralizing effect that helps restore a normal pH and thereby reduces

acid contact time in the lumen.47 Reduced salivation has been associated with prolonged acid

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clearance times, such as during sleep, when salivation is reduced and reflux events tend to be

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associated with more prolonged acid clearance. Similarly, but on a more exaggerated spectrum,
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chronic xerostomia is also associated with prolonged acid clearance and more severe

esophagitis.48 However, outside of these extreme examples, there has been no overt difference in
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the quantitative and qualitative aspects of saliva in individuals with vs without GERD.
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Non-esophageal Symptoms of GERD

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By exposing the esophagus to refluxate, GERD induces esophageal symptoms (heartburn,

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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-
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called atypical or extra-esophageal symptom manifestations, including ear, nose, and throat
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(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

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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 monitoring or analysis of gastric

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juice components (pepsin and bile) in broncho-alveolar lavage fluid. However, there is no

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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

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events correlate with extra-esophageal events (such as bronchoconstriction during esophageal

acidification). For these cases, the esophageal-airway reflex theory proposes an indirect

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mechanism, in which distal esophageal reflux stimulates vago–vagal reflex pathways, leading to
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changes in function and complications in extra-esophageal segments (bronchoconstriction, cough,

and altered upper airway reactivity or sensitivity).49,50

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Effects of obesity
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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.
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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
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pressure is higher in obese patients,51,52 and that pressure correlates with body mass index and
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waist circumference53. Increased intraabdominal 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 by clinical studies. Interestingly, small amounts of

weight loss (approximately 10–15 lbs) 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.
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Sensitivity to Reflux Episodes

Symptoms are the main reason that patients with suspected GERD consult a physician and to

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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

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established that HCl at pH 2 or lower induces heartburn in GERD patients, indicating the role of

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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

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PPI therapy, as many as half of the reported heartburn episodes in GERD patients were
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associated with acid reflux, indicating involvement of other factors.57,58

Changes in esophageal sensitivity are important determinants of symptoms during reflux

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events.59-61 Several studies have identified groups of patients with normal esophageal reflux
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exposure; in these patients, reflux events correlate with heartburn perception.59-62 According to
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the Rome IV consensus, these patients are now categorized as having reflux hypersensitivity.60

These observations are consistent with the concept of esophageal hypersensitivity.60,61

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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
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lower symptom perception in these patients.62,63 Ambulatory pH monitoring studies confirmed

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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. Hypersensitivity is believed to

contribute to refractory GERD symptoms and has received the most attention.60-62
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Esophageal sensitivity

Increased sensitivity to acid reflux has been implicated in lower therapeutic response to acid

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suppression in patients with non-erosive reflux disease (NERD). Modified Bernstein acid

perfusion studies showed that sensitivity to esophageal acid perfusion was increased in patients

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with erosive reflux disease and NERD.64,65 Increased sensitivity to esophageal acid perfusion has

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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

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esophagus or functional heartburn (characterized by normal acid exposure and no correlation
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between symptoms and reflux events) are less sensitive to esophageal-acid perfusion.65-68

Mechano-sensitivity could also contribute to reflux-related symptoms. Patients with

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erosive GERD do not have altered mechano-sensitivity of the esophagus, compared with controls,
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but patients with acid-sensitive esophagus or true NERD have increased sensitivity to esophageal
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balloon distention.61 Balloon distention studies have shown that esophageal distention induces

heartburn, and that the proximal esophagus is more sensitive than the distal esophagus.69,70
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Activation of mechanosensitive afferent pathways, when the esophagus is distended during

reflux events, is therefore an important mechanism of symptom generation during weakly acidic
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reflux. For example, this might occur in patients with symptoms despite adequate acid
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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
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induce symptoms.58,71 In support of the mechanical factor, proximally extending reflux events

that contain air are more likely to induce symptoms than proximally extending reflux events that

contain only liquid.72

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Increased esophageal sensitivity may also involve other sensory modalities. Studies that

used a multi-modal esophageal stimulation probe found patients with NERD to be hypersensitive

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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

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esophageal acid exposure.74 Patients with PPI-refractory GERD are hypersensitive to thermal,

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mechanical, and chemical stimulation of the esophagus compared to healthy volunteers.75
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Taken together, these findings indicate that esophageal sensitivity contributes to

symptom expression in patients with GERD. Patients with Barrett’s esophagus have lower
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sensitivity, but sensitivity increases as reflux exposure decreases, over the spectrum from erosive
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disease to NERD and reflux hypersensitivity (Figure 3). Esophageal sensitivity is determined by

the strength of activation of sensory receptors in the gastrointestinal tract and by processing in
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the central nervous system, which can lead to amplification or suppression of the afferent signal
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that is being transmitted to cortical areas involved in perception.76,77 Peripheral and central

mechanisms can increase signal transmission following stimuli; each has been implicated in the
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pathogenesis of esophageal hypersensitivity.76,77 Peripheral mechanisms refer to processes

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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
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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 mucosal barrier to

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allow symptom perception.78 Decreased resistance to transmucosal passage by components of the

refluxate is one potential peripheral mechanism of esophageal hypersensitivity to reflux. Several

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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

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integrity has been shown in vitro, using measurements of transmucosal resistance or flux of

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molecules across the mucosa of esophageal endoscopic biopsies mounted in Ussing
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chambers.78,79 The morphological correlate of this loss of mucosal integrity is the finding of

dilated intercellular spaces, studied by histology or, most accurately, by electron microscopy of
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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

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loss of mucosal barrier function.82-84

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Several studies have shown increased mucosal permeability (or decreased baseline
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impedance) in patients with non-erosive and erosive (in the non-eroded sections) reflux disease.

Most studies also found the same in patients with reflux hypersensitivity, but this was not
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consistently found in functional heartburn.65,67,78-80,83-85 However, in functional heartburn, the

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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 pathological and/or

symptomatic gastro-esophageal reflux.

 ACCEPTED MANUSCRIPT

Dilated intercellular spaces and decreased mucosal impedance can be a consequence of

acid reflux. In healthy individuals, these abnormalities can be induced by esophageal 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

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studies of animal models and perfusion studies of healthy individuals.88,89 However, animal

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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 (see

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below).

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The studies discussed indicate that acid-sensitive receptors, expressed on submucosal
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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
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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
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epithelial cells in reflux sensing and shown that reflux induces an inflammatory reaction in the
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submucosal layer, which leads to dilated intercellular spaces.91,92 A study of 12 patients with

grade C esophagitis found interruption of PPI therapy to result in submucosal infiltration by T

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cells and dilated intercellular spaces in the basal layer, in areas with intact mucosal surface.93
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The presence and density of reflux-sensing receptors might also determine symptom
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occurrence during reflux 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
 ACCEPTED MANUSCRIPT

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

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are unclear.

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Cultured human esophageal epithelial cells have been shown to express TRPV1 and acid-

sensitive ion channels. Upon activation by (weakly) acidic solutions, these release ATP, which

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has been proposed to be neurotransmitter involved in signaling pain and inducing

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inflammation.92 Activation of PAR2 sensitizes cultured human esophageal epithelial cells to acid,
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in part through phosphorylation of TRPV1. This could be a pathway through which mast cell

activation (releasing the PAR2 activator tryptase) or duodeno-gastro-esophageal reflux

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(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 upregulated in esophageal
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tissues of patients with GERD; upregulation correlated we expression of inflammatory mediators

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(interleukin 8) and microscopic changes including dilated intercellular spaces.96

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Central mechanisms
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Central mechanisms, attributed to altered processing of afferent signals from the esophagus, have
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also been implicated 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 mechanisms, such as stress, anxiety,

and personality traits.59-61,76,77 Neurotransmitter systems involved in anti-nociceptive central

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effects include endogenous opioids, endocannabinoids, and serotonin.76 Activation of n-methyl

D aspartate (NMDA) receptors affects sensitization of dorsal horn neurons.76,77

Most patients with GERD report that stress exacerbates their symptoms.97 Acute stressors

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exacerbated heartburn symptoms in GERD patients by enhancing the perceptual response to

esophageal acid exposure or acid perfusion.98,99 Stress is often presumed to alter central

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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

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sensitivity to reflux.90 In healthy individuals, administration of corticotropin-releasing hormone,

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which mediates the response of the gastrointestinal tract to stress, increased sensitivity of the
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esophagus to mechanical distention but not acid, heat, or electrical stimulation.100

Psychosocial co-morbidities also determine the severity of GERD symptoms and

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response to therapy. Patients with symptoms of GERD symptoms often have anxiety and

depression.101 GERD patients with depression, or especially anxiety, have greater effects of
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symptoms and lower quality of life, even though reflux parameters do not differ from those of
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GERD patients without these co-morbidities.102

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Patients with GERD have increased sensitivity to acid perfusion after a night of sleep

deprivation compared with a good night of rest,103 and sleep deprivation has been shown to lead
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to loss of analgesic actions.104 The sensitizing effect of sleep deprivation, and also of anxiety and
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depression, could reflect decreased activity of anti-nociceptive pathways. Anti-nociceptive

pathways prevent afferent nociceptive information from reaching the gastrointestinal tract.76

Future Directions
 ACCEPTED MANUSCRIPT

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

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determines its impact on occurrence of symptoms, lesions, and complications. Sensory

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mechanisms determine the relationship between reflux exposure and symptom generation. Key

factors are mucosal barrier function, expression and sensitivity of sensory nerves, and

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modulation at the central nervous system level. Central nervous system responses are modulated

by factors such as stress and psycho-social co-morbidities. Increasing our understanding of the

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pathophysiologic mechanisms of GERD symptoms and lesions should lead to novel, more
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effective or better-targeted treatment options for individual patients.
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Figure Legends

Figure 1. The Gastro-esophageal Junction. Panels show the absence (left) and the presence

(right) of a hiatal hernia.

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Figure 2. Mechanisms of reflux, determined by high-resolution manometry. Color-scaled

esophageal pressure topography and overlaid impedance tracings were spaced at 3 cm intervals.

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(Top panel) Example of a transient LES relaxation with reflux. The LESR occurs and is followed

closely by crural inhibition (CI), so both sphincters are inhibited. There is a small increase in

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intragastric pressure that elicits liquid reflux through the EGJ (drop in impedance) into the
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proximal esophagus noted by the red arrow. There is an intermittent supragastric belch denoted

by the dashed white lines with UES opening. The end event of the tLESR is a sporadic secondary
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contraction in the distal esophagus followed closely by a dry swallow with primary peristalsis to
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clear the event. (Bottom) This is an example of re-reflux after a swallow in a small hiatus hernia.
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The LES and CD are separated and the hernia is pressurized after the swallow (circle).

Immediately after the swallow, the aftercontraction resolves and the incompetent LES does not
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generate a high-pressure zone and the liquid in the hernia escapes through the LES noted by the

red arrow and drop along the impedance tracings. The liquid extends into the body of the
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esophagus extending to just below the UES. The bolus is eventually cleared out of the
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esophageal body by a swallow and secondary peristaltic contraction.

Figure 2. Phenotypes of GERD and Effects of Pathogenetic Features. Increasing reflux

exposure, increasing symptom association probability (SAP), increasing mucosal permeability,

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increasing visceral sensitivity, increasing psychological co-morbidities. *The presence and role

of esophageal (hyper)sensitivity in the functional heartburn group are less clear, indicated by the

transparent box. In this group, central processes such as hypervigilance and psychosocial co-

morbidities, rather than esophageal events, are thought to be the main determinants of symptom

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