Pathophysiology of gastroesophageal reflux disease

Nicholas E. Diamant

doi:doi:10.1038/gimo21

PART 1 Oral cavity, pharynx and esophagus

GI Motility online (2006) doi:10.1038/gimo21
Published 16 May 2006

Pathophysiology of gastroesophageal reflux disease

Nicholas E. Diamant, M.D.

About the contributor

View article related content

Top

Key Points

Gastroesophageal reflux disease (GERD) includes all consequences of reflux of acid or other irritants from the stomach into the esophagus. The main cause of gastroesophageal reflux is incompetence of the antireflux barriers at the esophagogastric junction.

Gastric pepsin duodenal contents exacerbate the action of acid and deleterious effect on the production of esophagitis.

The antireflux barriers include two "sphincter" mechanisms: the lower esophageal sphincter (LES), and the crural diaphragm that functions as an external sphincter.

Gastroesophageal reflux occurs when LES pressure is lower than the intragastric pressure such as in LES hypotension, increased frequency of transient lower esophageal sphincter relaxation (TLESR), when the intragastric pressure increases.

The severity of GERD increases progressively with reflux that is mainly in the postprandial period to that in the upright posture, to that in the supine or that is bipositional reflux. Nighttime reflux leads to severe GERD.

Hiatal hernia results from multiple mechanisms and is associated with a decreased LES pressure, decreased acid clearance, increased reflux, and more severe esophagitis.

Mucosal defense mechanisms may be overcome by prolonged exposure of the esophageal mucosa to a pH <4 that may lead to severe and complicated esophagitis.

Esophageal mucosal inflammation may affect nerves and muscle that alter LES function and esophageal body motility. A vicious cycle of inflammation and impaired motility may cause progressive disease.

Patients with GERD may develop endoscopically visible erosive esophagitis or endoscopically negative nonerosive or negative endoscopy reflux disease (NERD). In NERD, factors such as visceral hypersensitivity or more proximal reflux of acid or nonacid material may be important. Acid and inflammatory mediators may gain access to sensory pathways and produce symptoms either by a direct action on the nerves or by producing abnormal muscle contraction.

Top

Introduction

The factors generally accepted as important for the development of gastroesophageal reflux disease (GERD) have been well documented (Table 1).^1,^2,³ Abnormality of any one of these factors holds the potential to disturb the normal equilibrium. These factors include gastric acid and other refluxed contents; delayed gastric emptying; structural and physiologic antireflux mechanisms at the gastroesophageal region; transient lower esophageal sphincter relaxation (TLESR); esophageal clearance mechanisms; ingested irritants; ingested substances that alter gastric, lower esophageal sphincter (LES), or esophageal motor function; mucosal integrity and defense mechanisms; visceral hypersensitivity; and genetic factors.

Table 1: Factors important to the development of gastroesophageal reflux disease (GERD)

Full size table

Despite the many factors that operate, four main fundamental factors stand out as most important: (1) gastric acid; (2) the structural integrity, function, and competence of the LES that either prevent or allow reflux; (3) the esophageal mucosal defense mechanisms that are primarily called into play when there is excess exposure of the mucosa to gastric acid; and (4) the sensory mechanisms that speak to symptoms. That is, an incompetent gastroesophageal reflux mechanism allows abnormal amounts of gastric acid to enter the esophagus, where the acid burden causes mucosal damage and/or symptoms (Figure 1). When mucosal damage occurs (esophagitis), a vicious cycle can ensue to accentuate and maintain the GERD (Figure 2). Then both more acid reflux and decreased clearance of the acid can prolong contact of the acid with the esophageal mucosa.

Figure 1: A simple overview of the pathogenesis of gastroesophageal reflux disease.

Figure 2: Gastroesophageal reflux disease initiates a vicious cycle of increasing esophageal acid exposure.

LES, lower esophageal sphincter. (Source: AGA teaching unit 7, Neurogastroenterology and Motility: Upper GI Tract, slide 34., used with permission. Copyright American Gastroenterological Association, Bethesda, MD.)

The GERD category also encompasses a group of patients that have nonerosive or negative endoscopy reflux disease (NERD). In these patients, esophageal acid exposure may be normal and factors such as visceral hypersensitivity or more proximal reflux of acid or nonacid material may be important.^2,⁴

Top

Gastric Acid and Other Refluxed Substances

Gastric Acid

The normal physiology of acid secretion is well understood, and is not discussed here. Reflux of acid is the dominant irritant to the esophagus in the development and progression of GERD, although the presence of bile and other compounds in gastric juice may contribute to the "reflux burden" when combined with the acid or on their own.⁵ The reflux burden of acid requires the presence of acid secretion, and is further determined by dysfunction of the gastroesophageal competence mechanism that allows increased reflux, and by decreased esophageal clearance that increases contact time of acid with the mucosa.⁶ However, there are a number of relevant issues that arise in regard to gastric acid secretion and the development of GERD. Two issues have attracted considerable attention and controversy: (1) Is GERD associated with increased acid secretion? and (2) Does the effect of Helicobacter pylori infection on acid secretion impact on the development of GERD?

Levels of Gastric Acid Secretion

Acid suppression results in successful treatment of esophagitis.⁷ This response has raised the possibility that elevated levels of acid secretion would increase the "acid burden" that impacts on the esophagus and could be associated with the propensity to develop esophagitis, whereas decreased gastric acid secretion could result in a decrease in GERD and its complications. The arguments in this regard have surfaced recently in relation to the effects of H. pylori infection on acid secretion before and after the treatment of the infection, and the prevalence and development of esophagitis.^6,^8,^9,^10,^11,^12,^13,^14,¹⁵

Despite the intuitive logic that increased gastric acid secretion should increase the prevalence of esophagitis, there is little or no evidence to support this conclusion for the usual cases of GERD. Marked increases in gastric secretion as with Zollinger-Ellison syndrome are an exception. In an earlier study, the presence of esophagitis was not associated with elevated levels of acid secretion or with a lower gastric pH than in normal subjects.¹⁶ A more recent study indicated that mild erosive esophagitis can occur in the presence of decreased as well as normal acid secretion,¹⁷ and in the absence of Barrett's esophagus, acid secretion in patients with esophagitis is not different from that in normal subjects.¹⁸ This information suggests that beyond a certain level of gastric acid secretion, other factors are more important in determining the "acid burden" that produces esophagitis or other manifestations of GERD.

H. Pylori and Gastric Acid

On the other hand, there is evidence accumulating that decreased acid secretion with H. pylori infection of the stomach or atrophic gastritis is associated with decreased prevalence of esophagitis. This conclusion derives from many studies that demonstrate that the prevalence of H. pylori infection is less in patients with esophagitis (Figure 3).^6,¹² For example in Japan, the prevalence of H. pylori is as high as 71% in asymptomatic subjects, but only 30% in patients with esophagitis, and is reported as low as 0% in patients with long segment Barrett's.¹⁸ A similar decreased prevalence of H. pylori in patients with esophagitis is also seen in other reports from the Far East^19,^20,^21,^22,²³ as well as from North America.^24,^25,^26,^27,^28,^29,³⁰ The relationship, however, is not a simple one, and the effect of the infection on acid secretion is determined by a number of factors including the location and extent of the infection, the severity of the inflammation, which in part is determined by the strain of H. pylori, and the degree of gastric atrophy.

Figure 3: The odds ratio (95% confidence intervals) for prevalence of H. pylori in patients with esophagitis in North America^{24, 25, 26, 27, 28, 29, 30} and the Far East.^{19, 20, 21, 22, 23}

The large diamonds represent the summary odds ratio for each geographic area. The largest boxes represent studies with large sample sizes. (Source: Pandolfino et al.⁶, with permission from Blackwell Publishers.)

Antral gastritis, often associated with duodenal ulcer disease,³¹ can be associated in fact with increased acid secretion resulting from suppression of somatostatin release and therefore a reduction in its ability to inhibit gastrin release. Gastrin levels, therefore, increase.³² On the other hand, corpus gastritis results in decreased acid secretion largely owing to inflammatory damage to the parietal cells.³³ The effect is compounded if gastric atrophy results.³⁴ Commonly, the infection and inflammation tend to be more generalized and the effect to reduce acid secretion more prominent when the corpus is involved. Corpus gastritis is associated with a 54% reduced risk of esophagitis.²⁵

The CagA, iceA1, and vac s1 types of H. pylori generally are more virulent strains, produce a more severe gastritis, are more commonly associated with ulcer disease, and are less commonly seen in GERD patients.^35,^36,³⁷ This inverse relationship of GERD with more virulent strains of H. pylori may not be evident with milder degrees of esophagitis.³⁸ Nevertheless, the bulk of evidence indicates that reduced acid secretion such as in the presence of H. pylori infection of the stomach is associated with a decreased prevalence of esophagitis. The protective effect also appears to apply to decreasing complications of GERD such as Barrett's esophagus.¹⁸

The efficacy of reducing acid secretion in the treatment of esophagitis, and the potential protective effect of reduced acid secretion with H. pylori infection, has led to some concerns. Would the treatment of H. pylori infection with an increase of acid secretion to at least normal levels lead to an increase in the incidence of esophagitis, and to a poor response to acid-suppression therapy of esophagitis or to higher recurrence rates after treatment? Presumably these adverse results would occur in those cases where more severe extensive gastritis involving the gastric corpus was reversed by treatment of the H. pylori.

Generally, treatment of H. pylori has not resulted in an increase in GERD in patients with gastric or duodenal ulcer unless other risk factors are present.^8,^11,³⁹ Studies that include other types of subjects indicate that H. pylori treatment may increase acid secretion and the prevalence of mild esophagitis, more commonly if corpus gastritis was present or if other factors that predispose to reflux such as a hiatus hernia were also present.^13,^23,⁴⁰

The presence of H. pylori has no significant effect on the successful treatment of reflux esophagitis with a proton pump inhibitor.^15,^41,⁴² The consensus is that eradication of H. pylori infection does not compromise acid-suppression treatment of esophagitis, and is not associated with an increased incidence of esophagitis recurrence with treatment of the esophagitis.^8,^14,^43,⁴⁴ The relapse rate may be reduced, presumably if the infection has caused significant gastric atrophy and decreased acid secretion.⁴¹ Therefore, at present, there is no convincing evidence that the presence of H. pylori infection with its effect to reduce gastric acid secretion should preclude eradication of the infection because of concerns related to GERD or its treatment. Other factors are more important in determining the "acid burden" that produces esophagitis or other manifestations of GERD. Further, eradication of H. pylori has other potential benefits including removing a major risk factor for ulcer disease and a link to development of gastric cancer.

Other Refluxed Substances

The reflux of gastric content also includes pepsin and substances such as bile and pancreatic and intestinal enzymes from the duodenum. Although pepsin is activated at a pH <4, and the combination of acid plus pepsin is potentially more injurious to esophageal mucosa than acid alone,^45,⁴⁶ the levels of pepsin in gastric juice and the maximum output of pepsin are not different in patients with or without esophagitis.¹⁶ That is, an acid pH is required for the deleterious effects of pepsin to become active. However, in this regard, the presence and amount of gastric acid are still of prime importance.

The role of duodenogastroesophageal reflux still remains controversial, although newer measurement techniques that measure bile content and assess the presence and movement of refluxed liquid in the esophagus are providing further insights. The presence of duodenogastroesophageal reflux alone as measured by bilirubin content did not produce esophagitis in partial gastrectomy patients. Patients with both acid and duodenal content in the esophagus had a high frequency (67%) of esophagitis,⁴⁷ and duodenogastric reflux is more common in GERD patients with stricture or Barrett's esophagus.⁴⁸ The frequency of esophageal exposure to both acid and duodenal content increases, acid and bile in tandem, and is highest in patients with complicated Barrett's esophagus.⁵ Therefore, as with pepsin, the presence of acid in the gastroesophageal refluxate is required for the duodenal content to have its potential deleterious effect on the production of esophagitis.

Whether duodenogastroesophageal reflux is important in the production of NERD is also still controversial.⁴⁹ Perfusion of bile acids into the esophagus of humans can cause pain.⁵⁰ Multichannel intraluminal impedence techniques, often combined with pH and bilirubin measurements, have started to explore this issue in normal subjects as well as in patients with GERD.^4,^51,⁵² It is clear that when acid is suppressed, gastroesophageal reflux of nonacid content still occurs and can be readily measured with impedence techniques, and can be associated with symptoms.^53,^54,⁵⁵ The importance of these findings awaits further study.

Top

Antireflux Mechanisms at the Gastroesophageal Region

The antireflux mechanism has at least two "sphincter" mechanisms: the intrinsic muscular sphincter known as the lower esophageal sphincter (LES), and the diaphragm that functions as an external sphincter-like mechanism.⁵⁶ The presence of a hiatus hernia impacts unfavorably on both of these sphincter mechanisms. Other structures such as the phrenoesophageal ligament help maintain the anatomic integrity of the region, but their function otherwise is not established.⁵⁷

The Lower Esophageal Sphincter

Normal Physiology

The LES is tonically closed at rest, maintaining an average pressure of about 20 mmHg, and serves to prevent gastroesophageal reflux. The circumferential profile is asymmetrical with the higher pressures in the left lateral portion of the sphincter.^58,⁵⁹ To allow passage of a bolus, LES pressure falls within 1.5 to 2.5 seconds of a swallow and remains low for 6 to 8 seconds as the peristaltic contraction transverses the esophageal body. Two main peripheral neurons mediate active contraction and relaxation of the LES, acetylcholine being the excitatory neurotransmitter and nitric oxide the main inhibitory neurotransmitter. Relaxation of the LES can also in part occur when tonic vagal cholinergic excitation to the LES is turned off with a swallow.⁶⁰

The intrinsic LES in the humans is composed of at least two muscles. The circular muscle forms only a partial ring (or semicircular clasp), and the gastric sling muscle runs on the left lateral aspect to complete this portion of the sphincter (Figure 4).⁶¹ The LES circular clasp and sling muscles are functionally different in many ways, each with unique contractile properties. The circular clasp muscle has significant spontaneous tone, whereas the sling muscle has little tone and is more responsive to cholinergic stimulation.^62,^63,⁶⁴ The higher pressure in the left lateral position of the sling is reduced by atropine, whereas the pressure in the remainder of the LES circumference is unchanged by cholinergic blockade.^62,⁶³ Furthermore, these two muscles demonstrate differences in resting membrane potential and voltage-gated K⁺ ion channel densities,⁶⁵ and in the L-type Ca²⁺ channel and calcium handling.^66,⁶⁷ For example, although influx of extracellular calcium is central to the maintenance of myogenic tone and acetylcholine (ACh)-induced contractility in both LES muscles, this influx occurs through an L-type Ca²⁺ channel in LES circular muscle, and a nifedipine-insensitive, non–L-type Ca²⁺ channel in sling muscle. It is not clear whether the circular muscle of the very distal esophageal body also contributes as part of the proximal LES.

Figure 4: The structure of the lower esophageal sphincter (LES).

GER, gastroesophageal reflux. (Source: Liebermann-Meffert D et al.⁶¹, with permission from American Gastroenterological Association.)

These regional differences in the LES dictate that the mechanisms maintaining resting LES tone will be different for the LES smooth muscles—cholinergic excitation for the sling, and intrinsic myogenic tone for the circular clasp muscle—and set the basal conditions for the mechanisms necessary for LES relaxation. The circular clasp muscle with its high resting intrinsic tone is relaxed predominantly by release of nitric oxide (NO). There is little effect of NO on the sling muscle,⁶⁸ and relaxation of the sling muscle is likely due predominantly to turning off its cholinergic excitation. That is, the dominant innervation of the circular clasp muscle is nitrergic and inhibitory, whereas that of the sling is cholinergic and excitatory.

The presence and location of the sling muscle has also been linked to maintenance of the acute angle of His at the greater curve aspect of the gastroesophageal junction, and the formation of a flap valve function that could also serve as an antireflux mechanism.⁶⁹ This aspect remains controversial.

Pathophysiology: Low LES Pressure and TLESR

Gastroesophageal reflux occurs when LES pressure is lower than intragastric pressure. Under normal circumstances a small amount of reflux occurs when LES pressures are low with a swallow and during TLESR, and when increases in intraabdominal pressure or intragastric pressure overcome the resting LES pressure. The TLESR is independent of a swallow. Transient relaxation of the sphincter that is independent of a swallow can also occur with pharyngeal stimulation. However, these relaxations are different from the regular TLESR and do not appear to be associated with reflux. Their relaxation is less pronounced and they do not involve inhibition of the diaphragm.^70,^71,⁷²

The nature of the LES changes and function associated with abnormal gastroesophageal reflux in the usual patients with GERD are well described and in large part determine the patterns, timing, and degree of reflux. In both patients and normal subjects, the TLESR in the face of a normal LES pressure is the most common mechanism of reflux, accounting for virtually all episode in normals and about two thirds in GERD patients.^73,⁷⁴ Transient LES relaxation occurs largely in the postprandial period,^73,⁷⁵ the increasing frequency of TLESR after a meal attributed to gastric distention.⁷⁶ Not surprisingly and particularly in GERD patients, reflux with increases in intraabdominal pressure and free reflux through an abnormal low-pressure sphincter make up the remainder of the episodes.⁷³

The resting pressure varies considerably throughout the day, and even normal physiologic events and daily activities provide times when LES pressures are lower and increase the potential for gastroesophageal reflux. The LES pressure increases in the recumbent position.^77,⁷⁸ Fasting, pressures are higher during phase III of the migrating motor complex (MMC) and lowest during phase I.⁷⁹ Feeding is often associated with a drop in LES pressure, resulting in large part from the secretion of hormones such as secretin and cholecystokinin (CCK) with fat intake,^80,⁸¹ or from the nature of the food itself or its contents, such as with chocolate,⁸² alcohol,⁸³ and caffeine.⁸⁴ Even colonic fermentation can lower LES pressure, the mechanism being unclear.⁸⁵ Smoking decreases LES pressure,⁸⁶ as does pregnancy, the latter due in part to the hormone progesterone.⁸⁷ Many other hormones, neurotransmitters, and ingested medications can alter LES pressure, and those that do, such as anticholinergic drugs, nitrates, calcium channel blockers, and certain prostaglandins, can potentially predispose to gastroesophageal reflux.

The increased acid load in GERD patients and its relationship to low LES pressure and the severity of the esophagitis is also reflected in the pattern of reflux. The severity of GERD increases progressively from postprandial to upright, to supine, to bipositional reflux. A structural defect as reflected by decreased LES pressure and length is also significantly more common with supine and bipositional reflux⁸⁸ (Figure 5). Therefore, reflux that occurs at night as well as during the day is particularly bad. That is, in addition to the absence of the beneficial effects of gravity, many of the physiologic changes that occur with sleep also favor development of GERD.^89,⁹⁰ This aspect is discussed below.

Figure 5: Body position and gastroesophageal reflux causing mucosal injury.

OR, odds ratio; CI, confidence interval. (Source: Campos et al.⁸⁸, with permission from American Medical Association )

Low LES pressure and abnormal reflux can also occur in certain diseases, most commonly with the collagen vascular disorders such as scleroderma, where damage to the muscle and to the excitatory cholinergic innervation occur.⁹¹

The acid load to the esophagus is greater in GERD patients, in part because more TLESRs are associated with reflux even though the number of TLESRs is more or less similar.^74,⁹² In addition, the duration of the relaxation with a TLESR is longer than that with a swallow.⁹³ The physiologic reason for the increased frequency of TLESR-associated reflux in GERD patients is unknown. The increase is not associated with changes in gastric compliance or meal-induced gastric relaxation in reflux patients.⁹⁴ The mechanism likely relates to other factors such as the presence of a hiatus hernia.^92,⁹⁵ In certain disorders, GERD may be associated with an increased frequency of TLESR as well, such as in obesity owing perhaps to increased sensitivity to distention,⁹⁶ and in diabetes owing to the effect of hyperglycemia.⁹⁷ Of particular interest is the effect of atropine. Although atropine decreases LES pressure, the frequency of TLESR is decreased and gastroesophageal reflux in fact decreases in both normal subjects and patients with GERD.^98,⁹⁹ A central mechanism has been proposed for the decrease in TLESR,¹⁰⁰ although atropine could potentially act peripherally as well by blocking the muscarinic-1 receptor that is present on the inhibitory nitrergic neuron of the LES.¹⁰¹

Pathophysiology: Differences in LES Circular and Gastric Sling Muscles

Knowledge of the regional clasp and sling differences has obvious clinical and therapeutic implications. However, virtually all of the clinical studies to date have not considered this aspect. Similarly, the studies of the effect of inflammation on the LES in vivo or in vitro have been directed only at the circular muscle. Nevertheless, attention to these differences holds the potential to give new insights for a better understanding of the pathogenesis of LES disorders, and consequently the rationale for old and new directions for therapy of these disorders. For example, in patients with gastroesophageal reflux the sling contraction could be augmented by pharmacologic manipulation of its cholinergic control, and gives credence to the use of cholinergic agonists in raising LES pressure for treatment of gastroesophageal reflux.¹⁰² Similarly, the surgical management of reflux could be tailored to the sling or circular muscle depending on careful three-dimensional pressure imaging of the LES in GERD patients.⁵⁹ Significant attention has been directed to pharmacologic manipulation of the nitrergic control of the TLESR in patients with reflux.^103,¹⁰⁴ As noted above, the dominant innervation of the circular muscle is nitrergic and inhibitory, whereas that of the sling is cholinergic and excitatory. Therefore, manipulation of the TLESR presumably is directed primarily at the circular muscle, although the role of the sling in the TLESR is unknown. The sling may also be involved through turning off of excitation or activation of its neural inhibition.

The additional role of the sling in maintaining an acute angle at the gastroesophageal junction remains controversial. An increase in the angle following partial gastrectomy is associated with increased reflux and reflux symptoms.¹⁰⁵ In the presence of a hiatus hernia, the radial asymmetry of the LES pressure profile disappears, in part owing to removal of the external diaphragmatic sphincter.¹⁰⁶ Presumably the sling also loses some of its sphincter function through either the anatomic distortion produced by the hernia or the effect of inflammation such as carditis and esophagitis on the muscle. This aspect requires further study.

Top

The Diaphragm

Normal Physiology

The distal esophagus passes through the diaphragmatic hiatus that is usually formed by the right crus of the diaphragm. As a result the diaphragm can function as an "external sphincter" by compressing the gastroesophageal junction; this compression increases LES pressure by 10 to 100 mmHg with each inspiration, depending on the intensity of the inspiration.^107,¹⁰⁸ Increases in intraabdominal pressure also increase LES pressure, in part through contraction of the diaphragm.¹⁰⁹ The crural portion of the diaphragm relaxes with a swallow and the TLESR, and with belching and vomiting. The relaxation of the crural portion during the TLESR enhances the potential for gastroesophageal reflux, especially if LES pressure is low.

In the presence of a hiatus hernia, the diaphragmatic sphincter is distanced from the gastroesophageal junction and therefore loses its ability to function as an antireflux mechanism.

Phrenoesophageal Ligament

The phrenoesophageal ligament is a distinct structure that attaches the gastroesophageal junction to the diaphragm. It is stretched in hiatal hernia (Figure 6) (Figure 7). Its relationship to GERD has been the subject of controversy over the years.^110,^111,¹¹² Nevertheless, its structure and placement provide good arguments for future studies to examine its functional role, and the nature of antireflux surgery that would take this role into consideration.⁵⁷

Figure 6: The phrenoesophageal ligament at the gastroesophageal junction in normal and hiatal hernia.

Figure 7: Attachment of phrenoesophageal ligand to lower esophageal sphincter.

Note that the upper attachment of the ligament is at the level of the muscular ring (A ring) and the lower attachment is at the level of the mucosal ring (Schatzi, B ring) (Source: Netter medical illustration used with permission of Elsevier. All rights reserved.)

The "ligament" has two layers, a thin layer arising from the endothoracic fascia and a thicker circumferential continuation of the transversalis (endoabdominal) fascia. Before entering the esophageal wall, two leaves are formed. A thinner lower leaf runs caudally and attaches to the esophageal wall just above the angle of His, whereas the upper thicker leaf runs cranially to fuse with the esophageal adventitia above the diaphragm. The ligament is composed of abundant collagen and elastic fibers and some interspersed smooth muscle cells. The upper leaf is firmly attached to the esophagus with collagenous extensions that penetrate to the level of the submucosa, whereas the lower leaf only blends with the adventitia. The leaves become somewhat attenuated with age—the lower leaf more so, and this leaf can disappear.

The structure and attachment of the ligament provide a logical basis for its potential function. Its elastic properties and firm attachment superiorly would serve to limit displacement of the esophagus into the thorax and draw it back into position, while minimizing circumferential traction on the LES region. Attenuation of the ligament with age would facilitate the development of hiatus hernia.

Hiatus Hernia

Some notes on hiatus hernia and its relationship to GERD are made above. In brief, (1) reflux is facilitated by the presence of a hiatus hernia, the reflux increasing as hernia size increases.^92,^95,^113,^114,^115,¹¹⁶ (2) The LES pressure is decreased, and the compliance of the LES and the cross-sectional area are increased in GERD patients, and are greatest in those with hiatus hernia.^106,¹¹⁷ (3) The combination of a low-pressure sphincter and hiatus hernia is most common in patients with severe esophagitis and its complications, although the presence of a hiatus hernia alone also signals the presence of increased reflux and more severe esophagitis.^115,¹¹⁸ (4) Esophageal clearance of acid is decreased in the presence of a hiatus hernia.^119,¹²⁰

The mechanisms whereby the hiatus hernia is related to a decreased LES pressure, decreased acid clearance, and increased reflux are multiple and not fully understood: (1) The low LES pressure results in part from removal of the external diaphragmatic sphincter,¹⁰⁶ and in addition from inflammatory effects on the intrinsic sphincter muscles and their innervation (see below). (2) Although the physiologic reason for the increased proportion of TLESR that are associated with reflux in GERD patients is unknown, the mechanism may relate to the presence of a hiatus hernia.^92,⁹⁵ The frequency and the number of common cavity phenomena of TLESR decrease after a fundoplication antireflux repair, perhaps owing to alteration of the fundal and vagal afferent mechanisms that induce TLESR.^121,^122,¹²³ (3) The hernia acts as a reservoir, the diaphragm trapping acid therein, allowing for re-reflux of acid and perhaps increased tendency to inflammation at the cardia (carditis).^124,¹²⁵ (5) Stretch from the lower arm of the phrenoesophageal ligament could potentially put circumferential traction on the LES, especially in younger patients before degeneration of the ligament occurs with aging.⁵⁷

Mucosal Defense Mechanisms and Inflammation

With gastroesophageal reflux, a greater duration of exposure of the esophagus to a pH <4 leads to increasing severity of esophagitis and its complications (Figure 7).^5,⁴⁸ Both the LES mechanisms that produce excess reflux of acid and the esophageal body motility disorders that result in prolonged acid exposure to the mucosa contribute to the duration of the exposure.

Inflammation: LES and Esophageal Motility

As noted above, some diseases such as scleroderma can lead to GERD through damage to neural control and muscle resulting in hypomotility of the LES and esophageal body. More commonly, the presence of inflammation of the mucosa and esophageal wall is associated with decreased LES pressure and esophageal motility that can impact on the acid burden to the mucosa through increased reflux and delayed esophageal clearance.¹²⁶ In the body, both decreased amplitude of the primary and secondary peristaltic waves, and failed peristalsis are common. Irregular contractions can also occur.^20,^118,^126,^127,^128,^129,¹³⁰ A vicious cycle results (Figure 2). Both a low LES pressure and disturbed esophageal motility are more common and pronounced in patients with more severe esophagitis, but because of the vicious cycle it is not clear which is the cart and which the horse.

Nevertheless, evidence is accumulating that inflammation affects nerves and muscle to alter LES and esophageal body motility. Both a decrease in cholinergic excitatory and an increase in nitrergic and other inhibitory mechanisms appear to be involved. This combination would result in hypomotility. The studies have involved only the circular muscle and not the sling.

The decrease in cholinergic excitation may have a vagal component.¹³¹ Animal experiments and studies of human LES tissue demonstrate a decrease in local cholinergic excitation,^132,^133,¹³⁴ and major changes in calcium stores¹³⁵ and in the intracellular pathways that mediate tone, and excitation contraction coupling in response to acetylcholine (ACh).¹³⁶ In particular, prostanoids are involved. Inflammatory mediators such as interleukin-1B (IL-1B) and increases of reactive oxygen species (e.g. H₂O₂) are associated with increases in prostaglandin E₂ (PGE₂) and an isoform of PGE₂. Prostaglandin E₂ relaxes the LES, whereas the isoform of PGE₂ blocks prostaglandin F_2a (PGF_2a)-mediated contraction.¹³⁷ Prostaglandin E_2a along with thromboxane A₂/B₂ are important in maintenance of LES tone, and blockade of PGE_2a activity further reduces LES tone.¹³⁸ Recent studies also indicate that inflammation induces the production of IL-6 in the mucosa and that IL-6, but not (IL-1B), leads to an increase of H₂O₂ in the muscle.¹³⁹ The H₂O₂ appears to be the main culprit that causes increases in platelet-activating factor (PAF) and PGE₂, both of which can act to reduce both ACh release¹⁴⁰ and LES muscle tone.¹⁴¹ Earlier studies indicated that inhibition of prostaglandin synthesis with indomethacin prevented or corrected esophagitis-associated LES hypotension, presumably through a reduction of PGE₂.¹⁴² Esophageal IL-8 is also increased in reflux esophagitis, and presumably enhances neutrophil trafficking.¹⁴³

In addition to prostanoid effects, inflammation is associated with increased NO in esophageal tissues^134,¹⁴⁴ and evidence of increased activity of the nitrergic inhibitory innervation.^132,¹³⁴ These changes also result in low LES pressure and decreased esophageal body motility.

Of interest, acid infusion causes shortening of the esophagus¹⁴⁵ in response in part to inflammatory mediators,¹⁴⁶ and NO contracts longitudinal esophageal smooth muscle.¹⁴⁷ These responses to acid and acid-induced inflammation have been proposed as potential factors contributing to the development of hiatus hernia.

Sensory Mechanisms and Symptoms

Although acid or inflammatory mediators are accepted as putative initiators of esophageal symptoms, the mechanisms whereby these gain access to sensory pathways and subsequently produce symptoms either directly or through other events such as abnormal muscle contraction remain the subject of controversy, speculation, and research.^49,^148,¹⁴⁹ A number of issues remain in this area: (1) Why do patients experience heartburn in the absence of abnormal acid exposure or esophagitis (NERD)?^150,¹⁵¹ (2) Why do some patients with severe esophagitis and complications such as Barrett's esophagus have absent or little heartburn?¹⁵² (3) Is visceral hypersensitivity peripheral and/or central, hyperalgesia or allodynia?^152,^153,^154,^155,¹⁵⁶ (4) Do sensations such as heartburn arise from abnormal contractions such as sustained esophageal contractions of circular or longitudinal muscle, and/or distention,^156,^157,¹⁵⁸ and is more proximal reflux important?^2,⁴ (5) Is mucosal dysfunction that produces abnormal tissue resistance an explanation for some or all of the controversy?¹⁴⁸ (6) Do the age and sex of the patients play a role?^159,^160,¹⁶¹ (7) To what extent is NERD a "functional" disorder" of the esophagus?¹⁶²

Other Factors

Gastric emptying. Gastric emptying as determined recently by a standardized technique confirms that delayed emptying is common in GERD patients, present in 26% of patients on the basis of retention at 4 hours.¹⁶³ There are cogent reasons to suppose that delayed emptying could lead to GERD, including increased gastric content that could increase the frequency of TLESR and gastric acid secretion.¹⁶⁴ However, there is little evidence to support this conclusion, as most patients do not have delayed gastric emptying and the delay is probably only an enhancing cofactor in a minority of patients. In fact, in some patents with foregut symptoms, delayed gastric emptying may be associated with decreased postprandial reflux.¹⁶⁵ Similarly, in children there is no definite relationship of delayed gastric emptying to GERD unless other abnormality such as malrotation of the stomach is present.^166,¹⁶⁷

Saliva and acid neutralization. Acid neutralization by swallowed saliva serves to "clear" the remaining acid after the bolus is emptied from the esophagus, and does so in a stepwise fashion with each swallow-induced peristaltic contraction.¹⁶⁸ Acid secretion increases in both normal subjects and patients with reflux esophagitis,¹⁶⁹ the increase related primarily to the appearance of heartburn.¹⁷⁰ There is no evidence that a defect in salivary flow or acid neutralizing capacity contributes to the development of GERD in the usual patient. In diseases associated with the sicca complex there is no increase in reflux symptoms,¹⁷¹ although in some such patients decreased salivary flow may be associated with esophageal injury.¹⁷²

Sleep. Although the frequency of reflux episodes decreases during sleep,^75,¹⁷³ many of the physiologic changes that occur with sleep favor development of GERD.^89,⁹⁰ These changes include (1) increased acid secretion that can also be seen as "nocturnal breakthrough" in GERD patients on proton pump therapy^174,^175,¹⁷⁶; (2) a marked decrease in acid clearance with enhanced proximal migration owing to loss of gravitational effects in the supine position,^177,¹⁷⁸ decreased frequency of swallowing and therefore of primary peristalsis,^179,¹⁸⁰ decreased saliva production,¹⁸¹ decreased perception of heartburn⁸⁹; and (3) changes in the gastric slow-wave electrical activity¹⁸² that could predispose to decreased gastric emptying.¹⁸³ Other factors such as sleep apnea and its relationship to obesity are also linked to GERD.^89,¹⁸⁴ The mechanism for this relationship is unclear and may relate to apnea-related changes in intrathoracic pressure, or to obesity-related factors such as increased intraabdominal pressure and hiatus hernia.^185,¹⁸⁶

Obesity. The relationship of obesity to GERD is controversial. Obesity has been found to be a risk factor for GERD,¹⁸⁷ and weight loss may¹⁸⁸ or may not¹⁸⁹ be associated with improvement in GERD symptoms. Another study has found no relationship of obesity with GERD symptoms.¹⁹⁰ Any relationship may in large part be determined by the presence of hiatus hernia in obese patients.¹⁸⁶

Genetics. There is considerable evidence that there exists an inherited tendency to develop GERD.^191,^192,¹⁹³ The evidence has derived largely from epidemiologic and family studies^194,^195,^196,¹⁹⁷ and twin studies.^198,¹⁹⁹ Many issues remain unresolved and the stimulus for continuing research: (1) Pediatric and adult GERD have both similar and different clinical features that will impact on genetic studies.²⁰⁰ (2) There may be a predetermined genetic predisposition to develop different phenotypes of GERD (NERD, erosive esophagitis, and Barrett's esophagus).¹⁹² This issue is particularly relevant to the relationship of GERD to adenocarcinoma of the esophagus.^197,²⁰¹ (3) Some of the genetic predisposition to develop GERD likely rests in the risk factors such as obesity and hiatus hernia.^202,²⁰³ (4) Chromosomal determinants demonstrate a multitude of identifiable relationships because of the many factors involved in the pathogenesis of GERD. For example, mapping of a gene on chromosome 13q14 has been found in some patients²⁰⁴ but not in others.²⁰⁵

Top

Conclusion

Gastroesophageal reflux disease has a multifactorial pathogenesis. Therefore, future studies must explore the many factors involved. A number of factors that impact on the mechanisms regulating competence of the gastroesophageal junction are of particular importance: (1) Structure and function of the phrenoesophageal ligament: its degeneration with age may predispose to development of hiatus hernia. Should surgeons take another look at reconstituting this structure? (2) Many agents that either increase or decrease the TLESR through central or peripheral action have already been addressed. Studies should take a closer look at the anticholinergic drugs, particularly M₁ antagonists that could act at the peripheral nitrergic inhibitory neuron. (3) The marked regional differences in the properties of the LES circular clasp and sling muscle components hold the potential to explore differential abnormalities of these in GERD, and the potential for new medical and surgical approaches to therapy. Further study is needed to determine the relationship of the distal esophageal body circular smooth muscle to the LES and GERD. (4) The sensory and cognitive-behavioral aspects of patients with NERD require careful study to link the physiologic and psychological aspects, as has been done with patients with other disorders that have a major "functional" component such as nonulcer dyspepsia and irritable bowel syndrome.

Article related content

Hiatus herniaOverview Esophageal motility disordersReview Nonerosive reflux disease Reflux esophagitis and peptic strictures Barrett's esophagus Barrett's adenocarcinoma Hiatus hernia Eosinophilic esophagitis
Esophageal motility > disordersSynopsis Clinical disorders of oral, pharyngeal and esophageal motilityReview Laryngeal and pharyngeal complications of gastroesophageal reflux disease Gastroesophageal reflux and asthma Gastroesophageal reflux and chronic coughOverview Esophageal motility disordersReview Heartburn and esophageal pain Endoscopic evaluation of esophageal motility disorders Esophageal manometry Gastroesophageal reflux monitoring: pH and impedance Nonerosive reflux disease Reflux esophagitis and peptic strictures Barrett's esophagus Barrett's adenocarcinoma Hiatus hernia Eosinophilic esophagitis Medical management of gastroesophageal reflux disease Endoscopic therapy for gastroesophageal reflux disease Surgical therapy for gastroesophageal reflux disease Pathophysiology of achalasia and diffuse esophageal spasm Medical and endoscopic management of achalasia Surgical treatment for achalasia Oral, pharyngeal and esophageal motility disorders in systemic diseases Oral, pharyngeal, and esophageal motor disorders in infants and children Oral, pharyngeal and esophageal motor function in aging Pharyngeal and esophageal diverticula, rings, and webs
Esophagus > eosinophiliic esophagitisOverview Esophageal motility disordersReview Nonerosive reflux disease Reflux esophagitis and peptic strictures Barrett's esophagus Barrett's adenocarcinoma Hiatus hernia Eosinophilic esophagitis
Esophagus > nonpeptic esophagitisReview Nonerosive reflux disease Reflux esophagitis and peptic strictures Barrett's esophagus Barrett's adenocarcinoma Hiatus hernia Eosinophilic esophagitis
Esophagus > Barrett's adenocarcinomaReview Nonerosive reflux disease Reflux esophagitis and peptic strictures Barrett's esophagus Barrett's adenocarcinoma Hiatus hernia Eosinophilic esophagitis
Esophagus > irritable esophagus syndromeOverview Esophageal motility disordersReview Nonerosive reflux disease Reflux esophagitis and peptic strictures Barrett's esophagus Barrett's adenocarcinoma Hiatus hernia Eosinophilic esophagitis
Esophagus > reflux esophagitisOverview Esophageal motility disordersReview Nonerosive reflux disease Reflux esophagitis and peptic strictures Barrett's esophagus Barrett's adenocarcinoma Hiatus hernia Eosinophilic esophagitis
Esophagus > Barrett's esophagusOverview Esophageal motility disordersReview Nonerosive reflux disease Reflux esophagitis and peptic strictures Barrett's esophagus Barrett's adenocarcinoma Hiatus hernia Eosinophilic esophagitis
Non-erosive reflux diseaseOverview Esophageal motility disordersReview Nonerosive reflux disease Reflux esophagitis and peptic strictures Barrett's esophagus Barrett's adenocarcinoma Hiatus hernia Eosinophilic esophagitis
Esophagus > peptic stricturesOverview Esophageal motility disordersReview Nonerosive reflux disease Reflux esophagitis and peptic strictures Barrett's esophagus Barrett's adenocarcinoma Hiatus hernia Eosinophilic esophagitis
Gastroesophageal reflux disease > pathophysiologyOverview Esophageal motility disordersReview Nonerosive reflux disease Reflux esophagitis and peptic strictures Barrett's esophagus Barrett's adenocarcinoma Hiatus hernia Eosinophilic esophagitis Pathophysiology of achalasia and diffuse esophageal spasm Medical and endoscopic management of achalasia Surgical treatment for achalasia

Top

References

Castell DO, Murray JA, Tutuian R, Orlando RC, Arnold R. Review article: the pathophysiology of gastro-oesophageal reflux disease-oesophageal manifestations. Aliment Pharmacol Ther 2004;20(suppl 9):14–25.
Quigley EM. New developments in the pathophysiology of gastro-oesophageal reflux disease (GERD): implications for patient management. Aliment Pharmacol Ther 2003;17(suppl 2):43–51.
Kahrilas PJ. GERD pathogenesis, pathophysiology, and clinical manifestations. Cleve Clin J Med 2003;70(suppl 5):S4–19.
Balaji NS, Blom D, DeMeester TR, Peters JH. Redefining gastroesophageal reflux (GER). Surg Endosc 2003;17:1380–1385. | ChemPort |
Vaezi MF, Richter JE. Role of acid and duodenogastroesophageal reflux in gastroesophageal reflux disease. Gastroenterology 1996;111:1192–1199. | Article | PubMed | ChemPort |
Pandolfino JE, Howden CW, Kahrilas PJ. H. pylori and GERD: is less more? Am J Gastroenterol 2004;99:1222–1225. | Article |
Armstrong D. Review article: gastric pH-the most relevant predictor of benefit in reflux disease? Aliment Pharmacol Ther 2004;20(suppl 5):19–26; discussion 38–39.
Sharma P, Vakil N. Review article: Helicobacter pylori and reflux disease. Aliment Pharmacol Ther 2003;17:297–305. | Article | ChemPort |
McColl KE. Review article: Helicobacter pylori and gastro-oesophageal reflux disease-the European perspective. Aliment Pharmacol Ther 2004;20(suppl 8):36–39.
Haruma K. Review article: influence of Helicobacter pylori on gastro-oesophageal reflux disease in Japan. Aliment Pharmacol Ther 2004;20(suppl 8):40–44.
Raghunath AS, Hungin AP, Wooff D, Childs S. Systematic review: the effect of Helicobacter pylori and its eradication on gastro-oesophageal reflux disease in patients with duodenal ulcers or reflux oesophagitis. Aliment Pharmacol Ther 2004;20:733–744. | Article | ChemPort |
Raghunath AS, Hungin AP, Wooff D, Childs S. Prevalence of Helicobacter pylori in patients with gastro-oesophageal reflux disease: systematic review. BMJ 2003;326:737. | Article |
Wu JC, et al. Effect of Helicobacter pylori eradication on oesophageal acid exposure in patients with reflux oesophagitis. Aliment Pharmacol Ther 2002;16:545–552. | Article | ChemPort |
Guliter S, Kandilci U. The effect of Helicobacter pylori eradication on gastroesophageal reflux disease. J Clin Gastroenterol 2004;38:750–755.
Muramatsu A, et al. Evaluation of treatment for gastro-oesophageal reflux disease with a proton pump inhibitor, and relationship between gastro-oesophageal reflux disease and Helicobacter pylori infection in Japan. Aliment Pharmacol Ther 2004;20(suppl 1):102–106.
Hirschowitz BI. A critical analysis, with appropriate controls, of gastric acid and pepsin secretion in clinical esophagitis. Gastroenterology 1991;101:1149–1158. | ChemPort |
Shimatani T, et al. Gastric acid normosecretion is not essential in the pathogenesis of mild erosive gastroesophageal reflux disease in relation to Helicobacter pylori status. Dig Dis Sci 2004;49:787–794. | Article |
Abe Y, et al. The prevalence of Helicobacter pylori infection and the status of gastric acid secretion in patients with Barrett's esophagus in Japan. Am J Gastroenterol 2004;99:1213–1221. | Article |
Wu JC, et al. Prevalence and distribution of Helicobacter pylori in gastroesophageal reflux disease: a study from the East. Am J Gastroenterol 1999;94:1790–1794. | Article | ChemPort |
Shirota T, et al. Helicobacter pylori infection correlates with severity of reflux esophagitis: with manometry findings. J Gastroenterol 1999;34:553–559. | Article | ChemPort |
Mihara M, et al. Low prevalence of H. pylori infection in patients with reflux esophagitis. Gut 1996;39:A94.
Haruma K, et al. Negative association between Helicobacter pylori infection and reflux esophagitis in older patients: case-control study in Japan. Helicobacter 2000;5:24–29. | Article | PubMed | ISI | ChemPort |
Koike T, et al. Increased gastric acid secretion after Helicobacter pylori eradication may be a factor for developing reflux oesophagitis. Aliment Pharmacol Ther 2001;15:813–820. | Article | ChemPort |
Vaezi MF, et al. CagA-positive strains of Helicobacter pylori may protect against Barrett's esophagus. Am J Gastroenterol 2000;95:2206–2211. | Article | ChemPort |
El-Serag HB, et al. Corpus gastritis is protective against reflux oesophagitis. Gut 1999;45:181–185. | PubMed | ISI | ChemPort |
Goldblum JR, et al. Inflammation and intestinal metaplasia of the gastric cardia: the role of gastroesophageal reflux and H. pylori infection. Gastroenterology 1998;114:633–639. | Article | PubMed | ISI | ChemPort |
Varanasi RV, Fantry GT, Wilson KT. Decreased prevalence of Helicobacter pylori infection in gastroesophageal reflux disease. Helicobacter 1998;3:188–194. | Article | PubMed | ISI | ChemPort |
Vicari JJ, et al. The seroprevalence of cagA-positive Helicobacter pylori strains in the spectrum of gastroesophageal reflux disease. Gastroenterology 1998;115:50–57. | Article | PubMed | ISI | ChemPort |
Schubert TT, Schnell GA. Prevalence of Campylobacter pylori in patients undergoing upper endoscopy. Am J Gastroenterol 1989;84:637–642. | ChemPort |
Fallone CA, et al. Association of Helicobacter pylori genotype with gastroesophageal reflux disease and other upper gastrointestinal diseases. Am J Gastroenterol 2000;95:659–669. | Article | ChemPort |
Schultze V, et al. Differing patterns of Helicobacter pylori gastritis in patients with duodenal, prepyloric, and gastric ulcer disease. Scand J Gastroenterol 1998;33:137–142. | ChemPort |
Calam J. The somatostatin-gastrin link of Helicobacter pylori infection. Ann Med 1995;27:569–573. | ChemPort |
Sipponen P, Hyvarinen H, Siurala M H. pylori corpus gastritis-relation to acid output. J Physiol Pharmacol 1996;47:151–159. | ChemPort |
Koike T, et al. Helicobacter pylori infection inhibits reflux esophagitis by inducing atrophic gastritis. Am J Gastroenterol 1999;94:3468–3472. | Article | ChemPort |
Arents NL, et al. The importance of vacA, cagA, and iceA genotypes of Helicobacter pylori infection in peptic ulcer disease and gastroesophageal reflux disease. Am J Gastroenterol 2001;96:2603–2608. | Article | ChemPort |
Fallone CA, Barkun AN. H. pylori-infected gastroesophageal reflux disease patients harbor less virulent strains. Am J Gastroenterol 2002;97:1065. | Article |
Graham DY, Yamaoka Y H. pylori and cagA: relationships with gastric cancer, duodenal ulcer, and reflux esophagitis and its complications. Helicobacter 1998;3:145–151. | Article | ChemPort |
Leodolter A, et al. Helicobacter pylori genotypes and expression of gastritis in erosive gastro-oesophageal reflux disease. Scand J Gastroenterol 2003;38:498–502. | ChemPort |
Fukuchi T, et al. Influence of cure of Helicobacter pylori infection on gastric acidity and gastroesophageal reflux: study by 24-h pH monitoring in patients with gastric or duodenal ulcer. J Gastroenterol 2005;40:350–360. | Article |
Hamada H, et al. High incidence of reflux oesophagitis after eradication therapy for Helicobacter pylori: impacts of hiatal hernia and corpus gastritis. Aliment Pharmacol Ther 2000;14:729–735. | Article | ChemPort |
Calleja JL, Suarez M, De Tejada AH, Navarro A. Helicobacter pylori infection in patients with erosive esophagitis is associated with rapid heartburn relief and lack of relapse after treatment with pantoprazole. Dig Dis Sci 2005;50:432–439. | Article |
Wit NJ, et al. Treatment of gastro-oesophageal reflux disease with rabeprazole in primary and secondary care: does Helicobacter pylori infection affect proton pump inhibitor effectiveness? Aliment Pharmacol Ther 2004;20:451–458. | Article | ChemPort |
Moayyedi P, et al. Helicobacter pylori eradication does not exacerbate reflux symptoms in gastroesophageal reflux disease. Gastroenterology 2001;121:1120–1126. | Article | PubMed | ISI | ChemPort |
Schwizer W, et al. Helicobacter pylori and symptomatic relapse of gastro-oesophageal reflux disease: a randomised controlled trial. Lancet 2001;357:1738–1742. | Article | ChemPort |
Vaezi MF, Singh S, Richter JE. Role of acid and duodenogastric reflux in esophageal mucosal injury: a review of animal and human studies. Gastroenterology 1995;108:1897–1907. | Article | ChemPort |
Richter J. Do we know the cause of reflux disease? Eur J Gastroenterol Hepatol 1999;1:S3–S9.
Vaezi MF, Richter JE. Contribution of acid and duodenogastro-oesophageal reflux to oesophageal mucosal injury and symptoms in partial gastrectomy patients [see comment]. Gut 1997;41:297–302. | ChemPort |
Stein HJ, Barlow AP, DeMeester TR, Hinder RA. Complications of gastroesophageal reflux disease. Role of the lower esophageal sphincter, esophageal acid and acid/alkaline exposure, and duodenogastric reflux. Ann Surg 1992;216:35–43. | ChemPort |
Tack J, Fass R. Review article: approaches to endoscopic-negative reflux disease: part of the GERD spectrum or a unique acid-related disorder? Aliment Pharmacol Ther 2004;19(suppl 1):28–34.
Siddiqui A, Rodriguez-Stanley S, Zubaidi S, Miner PBJr. Esophageal visceral sensitivity to bile salts in patients with functional heartburn and in healthy control subjects. Dig Dis Sci 2005;50:81–85. | Article | PubMed |
Shay S, et al. Twenty-four hour ambulatory simultaneous impedance and pH monitoring: a multicenter report of normal values from 60 healthy volunteers. Am J Gastroenterol 2004;99:1037–1043. | Article | PubMed | ISI |
Sifrim D, et al. Composition of the postprandial refluxate in patients with gastroesophageal reflux disease. Am J Gastroenterol 2001;96:647–655. | Article | ChemPort |
Vela MF, et al. Simultaneous intraesophageal impedance and pH measurement of acid and nonacid gastroesophageal reflux: effect of omeprazole. Gastroenterology 2001;120:1599–1606. | Article | PubMed | ISI | ChemPort |
Tamhankar AP, et al. Omeprazole does not reduce gastroesophageal reflux: new insights using multichannel intraluminal impedance technology. J Gastrointest Surg 2004;8:888–896. | Article |
Todd JA, Basu KK, de Caestecker JS. Normalization of oesophageal pH does not guarantee control of duodenogastro-oesophageal reflux in Barrett's oesophagus. Aliment Pharmacol Ther 2005;21:969–975. | Article | ChemPort |
Mittal RK, Balaban DH. The esophagogastric junction. N Engl J Med 1997;336:924–932. | Article | PubMed | ChemPort |
Kwok H, Marriz Y, Al-Ali S, Windsor JA. Phrenoesophageal ligament re-visited. Clin Anat 1999;12:164–170. | Article | ChemPort |
Winans CS. Manometric asymmetry of the lower-esophageal high-pressure zone. Dig Dis Sci 1977;22:348–354. | ChemPort |
Stein HJ, Liebermann-Meffert D, DeMeester TR, Siewert JR. Three-dimensional pressure image and muscular structure of the human lower esophageal sphincter. Surgery 1995;117:692–698. | ChemPort |
Miolan JP, Roman C. Activity of vagal efferent fibres innervating the smooth muscle of the dog's cardia [French]. J Physiologie 1978;74:709–723. | ChemPort |
Liebermann-Meffert D, Allgower M, Schmid P, Blum AL. Muscular equivalent of the lower esophageal sphincter. Gastroenterology 1979;76:31–38. | PubMed | ChemPort |
Preiksaitis HG, Diamant NE. Regional differences in the cholinergic activity of muscle fibers from the human gastroesophageal junction. Am J Physiol 1997;272:G1321–G1327. | ChemPort |
Richardson BJ, Welch RW. Differential effect of atropine on rightward and leftward lower esophageal sphincter pressure. Gastroenterology 1981;81:85–89. | ChemPort |
Muinuddin A, Xue S, Diamant NE. Regional differences in the response of feline esophageal smooth muscle to stretch and cholinergic stimulation. Am J Physiol Gastrointest Liver Physiol 2001;281:G1460–G1467. | ChemPort |
Salapatek AM, Ji J, Muinuddin A, Diamant NE. Potassium channel diversity within the muscular components of the feline lower esophageal sphincter. Can J Physiol Pharmacol 2004;82:1006–1017. | Article | ChemPort |
Muinuddin A, Kang Y, Gaisano HY, Diamant NE. Regional differences in L-type Ca2+ channel expression in feline lower esophageal sphincter. Am J Physiol Gastrointest Liver Physiol 2004;287:G772–G781. | Article | ChemPort |
Muinuddin A, Neshatian L, Gaisano HY, Diamant NE. Calcium source diversity in feline lower esophageal sphincter circular and sling muscle. Am J Physiol Gastrointest Liver Physiol 2004;286:G271–277. | Article | ChemPort |
L'Heureux M-C, Muinuddin A, Gaisano HY, Diamant NE. Feline lower esophageal sphincter sling and circular muscles have different functional inhibitory neuronal responses. Am J Physiol Gastrointest Liver Physiol 2006;290(1):G23–G29.
Hill LD, et al. The gastroesophageal flap valve: in vitro and in vivo observations. Gastrointest Endosc 1996;44:541–547. | Article | ChemPort |
Mittal RK, Chiareli C, Liu J, Shaker R. Characteristics of lower esophageal sphincter relaxation induced by pharyngeal stimulation with minute amounts of water. Gastroenterology 1996;111:378–384. | Article | ChemPort |
Noordzij JP, et al. The effect of mechanoreceptor stimulation of the laryngopharynx on the oesophago-gastric junction. Neurogastroenterol Motil 2000;12:353–359. | Article | PubMed | ChemPort |
Pouderoux P, Verdier E, Kahrilas PJ. Patterns of esophageal inhibition during swallowing, pharyngeal stimulation, and transient LES relaxation. Lower esophageal sphincter. Am J Physiol Gastrointest Liver Physiol 2003;284:G242–247. | ChemPort |
Dodds WJ, et al. Mechanisms of gastroesophageal reflux in patients with reflux esophagitis. N Engl J Med 1982;307:1547–1552. | ChemPort |
Mittal RK, McCallum RW. Characteristics and frequency of transient relaxations of the lower esophageal sphincter in patients with reflux esophagitis. Gastroenterology 1988;95:593–599. | PubMed | ChemPort |
Dent J, et al. Mechanism of gastroesophageal reflux in recumbent asymptomatic human subjects. J Clin Invest 1980;65:256–267. | PubMed | ChemPort |
Mittal RK, Holloway RH, Penagini R, Blackshaw LA, Dent J. Transient lower esophageal sphincter relaxation. Gastroenterology 1995;109:601–610. | Article | PubMed | ChemPort |
Babka JC, Hager GW, Castell DO. The effect of body position on lower esophageal sphincter pressure. Am J Dig Dis 1973;18:441–442. | Article | ChemPort |
Sears VWJr, Castell JA, Castell DO. Comparison of effects of upright versus supine body position and liquid versus solid bolus on esophageal pressures in normal humans. Dig Dis Sci 1990;35:857–864. | Article | PubMed |
Dent J, Dodds WJ, Sekiguchi T, Hogan WJ, Arndorfer RC. Interdigestive phasic contractions of the human lower esophageal sphincter. Gastroenterology 1983;84:453–460. | ChemPort |
Nebel OT, Castell DO. Lower esophageal sphincter pressure changes after food ingestion. Gastroenterology 1972;63:778–783. | ChemPort |
Nebel OT, Castell DO. Inhibition of the lower oesophageal sphincter by fat-a mechanism for fatty food intolerance. Gut 1973;14:270–274. | ChemPort |
Wright LE, Castell DO. The adverse effect of chocolate on lower esophageal sphincter pressure. Am J Dig Dis 1975;20:703–707. | Article | ChemPort |
Hogan WJ, DeAndrade SRV, Winship DH. Ethanol-induced acute esophageal motor dysfunction. J Appl Physiol 1972;32:755–760. | ChemPort |
Dennish GW, Castell DO. Caffeine and the lower esophageal sphincter. Am J Dig Dis 1972;17:993–996. | Article | ChemPort |
Piche T, et al. Modulation by colonic fermentation of LES function in humans. Am J Physiol Gastrointest Liver Physiology 2000;278:G578–584. | ChemPort |
Dennish GW, Castell DO. Inhibitory effect of smoking on the lower esophageal sphincter. N Engl J Med 1971;284:1136–1137. | PubMed | ISI | ChemPort |
Baron TH, Richter JE. Gastroesophageal reflux disease in pregnancy [Review]. Gastroenterol Clin North Am 1992;21:777–791. | ChemPort |
Campos GM, et al. The pattern of esophageal acid exposure in gastroesophageal reflux disease influences the severity of the disease. Arch Surg 1999;134:882–887; discussion 887–888. | ChemPort |
Orr WC, Heading R, Johnson LF, Kryger M. Review article: sleep and its relationship to gastro-oesophageal reflux. Aliment Pharmacol Ther 2004;20(suppl):39–46.
Pasricha PJ. Effect of sleep on gastroesophageal physiology and airway protective mechanisms. Am J Med 2003;115(suppl):144S–118S.
Cohen S, et al. The pathogenesis of esophageal dysfunction in scleroderma and Raynaud's disease. J Clin Invest 1972;51:2663–2668. | ChemPort |
van Herwaarden MA, Samsom M, Smout AJ. Excess gastroesophageal reflux in patients with hiatus hernia is caused by mechanisms other than transient LES relaxations. Gastroenterology 2000;119:1439–1446. | ChemPort |
Holloway RH, Penagini R, Ireland AC. Criteria for objective definition of transient lower esophageal sphincter relaxation. Am J Physiol 1995;268:G128–133. | PubMed | ChemPort |
Penagini R, et al. Motor function of the proximal stomach and visceral perception in gastro-oesophageal reflux disease. Gut 1998;42:251–257. | ChemPort |
Kahrilas PJ, Shi G, Manka M, Joehl RJ. Increased frequency of transient lower esophageal sphincter relaxation induced by gastric distention in reflux patients with hiatal hernia. Gastroenterology 2000;118:688–695. | Article | ChemPort |
Hirsch DP, Mathus-Vliegen EM, Dagli U, Tytgat GN, Boeckxstaens GE. Effect of prolonged gastric distention on lower esophageal sphincter function and gastroesophageal reflux. Am J Gastroenterol 2003;98:1696–1704. | Article | ChemPort |
Zhang Q, et al. Effect of hyperglycemia on triggering of transient lower esophageal sphincter relaxations. Am J Physiol Gastrointest Liver Physiol 2004;286:G797–803. | Article | ChemPort |
Mittal RK, Holloway R, Dent J. Effect of atropine on the frequency of reflux and transient lower esophageal sphincter relaxation in normal subjects. Gastroenterology 1995;109:1547–1554. | Article | ChemPort |
Lidums I, Checklin H, Mittal RK, Holloway RH. Effect of atropine on gastro-oesophageal reflux and transient lower oesophageal sphincter relaxations in patients with gastro-oesophageal reflux disease. Gut 1998;43:12–16. | ChemPort |
Fang JC, Sarosiek I, Yamamoto Y, Liu J, Mittal RK. Cholinergic blockade inhibits gastro-oesophageal reflux and transient lower oesophageal sphincter relaxation through a central mechanism. Gut 1999;44:603–607. | ChemPort |
Gilbert R, Rattan S, Goyal RK. Pharmacologic identification, activation and antagonism of two muscarine receptor subtypes in the lower esophageal sphincter. J Pharmacol Exp Ther 1984;230:284–291. | PubMed | ChemPort |
Farrell RL, Roling GT, Castell DO. Cholinergic therapy of chronic heartburn. A controlled trial. Ann Intern Med 1974;80:573–576. | ChemPort |
Holloway RH. Systemic pharmacomodulation of transient lower esophageal sphincter relaxations. Am J Med 2001;111(suppl 8A):178S–185S.
Hirsch DP, Tytgat GN, Boeckxstaens GE. Transient lower oesophageal sphincter relaxations-a pharmacological target for gastro-oesophageal reflux disease? Aliment Pharmacol Ther 2002;16:17–26. | Article | PubMed | ChemPort |
Fujiwara Y, et al. Gastroesophageal reflux after distal gastrectomy: possible significance of the angle of His. Am J Gastroenterol 1998;93:11–15. | Article | ChemPort |
Kahrilas PJ, Lin S, Chen J, Manka M. The effect of hiatus hernia on gastro-oesophageal junction pressure. Gut 1999;44:476–482. | ChemPort |
Mittal RK, Rochester DF, McCallum RW. Effect of the diaphragmatic contraction on lower oesophageal sphincter pressure in man. Gut 1987;28:1564–1568. | ChemPort |
Mittal RK, Rochester DF, McCallum RW. Electrical and mechanical activity in the human lower esophageal sphincter during diaphragmatic contraction. J Clin Invest 1988;81:1182–1189. | ChemPort |
Mittal RK, et al. Human lower esophageal sphincter pressure response to increased intra-abdominal pressure. Am J Physiol 1990;258:G624–G630. | ChemPort |
Bombeck CT, Dillard DH, Nyhus LM. Muscular anatomy of the gastroesophageal junction and role of phrenoesophageal ligament; autopsy study of sphincter mechanism. Annals of Surgery 1966;164:643–654. | ChemPort |
Eliska O. Phreno-oesophageal membrane and its role in the development of hiatal hernia. Acta Anat 1973;86:137–150. | ChemPort |
Gray SW, Rowe JSJr, Skandalakis JE. Surgical anatomy of the gastroesophageal junction. Am Surg 1979;45:575–587. | ChemPort |
Ott DJ, Gelfand DW, Chen YM, Wu WC, Munitz HA. Predictive relationship of hiatal hernia to reflux esophagitis. Gastrointest Radiol 1985;10:317–320. | Article | ChemPort |
Sloan S, Rademaker AW, Kahrilas, PJ. Determinants of gastroesophageal junction incompetence: hiatal hernia, lower esophageal sphincter, or both? Ann Intern Med 1992;117:977–982. | ChemPort |
Jones MP, et al. Hiatal hernia size is the dominant determinant of esophagitis presence and severity in gastroesophageal reflux disease. Am J Gastroenterol 2001;96:1711–1717. | Article | ChemPort |
Fein M, et al. Role of the lower esophageal sphincter and hiatal hernia in the pathogenesis of gastroesophageal reflux disease. J Gastrointest Surg 1999;3:405–410. | Article | ChemPort |
Pandolfino JE, Shi G, Trueworthy B, Kahrilas PJ. Esophagogastric junction opening during relaxation distinguishes nonhernia reflux patients, hernia patients, and normal subjects. Gastroenterology 2003;125:1018–1024. | Article | PubMed |
Dent J, Holloway RH, Toouli J, Dodds WJ. Mechanisms of lower oesophageal sphincter incompetence in patients with symptomatic gastrooesophageal reflux. Gut 1988;29:1020–1028. | PubMed | ChemPort |
Mittal RK, Lange RC, McCallum RW. Identification and mechanism of delayed esophageal acid clearance in subjects with hiatus hernia. Gastroenterology 1987;92:130–135. | PubMed | ChemPort |
Sloan S, Kahrilas PJ. Impairment of esophageal emptying with hiatal hernia. Gastroenterology 1991;100:596–605. | ChemPort |
Scheffer RC, et al. Reduced tLESR elicitation in response to gastric distension in fundoplication patients. Am J Physiol Gastrointest Liver Physiol 2003;284:G815–820. | ChemPort |
Sarani B, Chan T, Wise R, Evans S. Nissen fundoplication has a vagolytic effect on the lower esophageal sphincter. Surg Endosc 2003;17:1206–1211. | Article | ChemPort |
Bahmeriz F, Dutta S, Allen CJ, Pottruff CG, Anvari M. Does laparoscopic antireflux surgery prevent the occurrence of transient lower esophageal sphincter relaxation? Surg Endosc 2003;7:1050–1054.
Csendes A, et al. 'Carditis': an objective histological marker for pathologic gastroesophageal reflux disease. Dis Esoph 1998;11:101–105. | ChemPort |
Peitz U, Vieth M, Malfertheiner P. Carditis at the interface between GERD and Helicobacter pylori infection. Dig Dis 2004;22:120–125. | Article | ChemPort |
Kahrilas PJ, Dodds WJ, Hogan WJ. Effect of peristaltic dysfunction on esophageal volume clearance. Gastroenterology 1988;94:73–80. | PubMed | ChemPort |
Kahrilas PJ, et al. Esophageal peristaltic dysfunction in peptic esophagitis. Gastroenterology 1986;91:897–904. | PubMed | ChemPort |
Achem AC, Achem SR, Stark ME, DeVault KR. Failure of esophageal peristalsis in older patients: association with esophageal acid exposure. Am J Gastroenterol 2003;98:35–39. | Article |
Wong WM, et al. Pathophysiology of gastroesophageal reflux diseases in Chinese-role of transient lower esophageal sphincter relaxation and esophageal motor dysfunction. Am J Gastroenterol 2004;99:2088–2093. | Article |
Wu JC, et al. Dysfunction of oesophageal motility in Helicobacter pylori-infected patients with reflux oesophagitis. Aliment Pharmacol Ther 2001;15:1913–1919. | Article | ChemPort |
Ogilvie AL, James PD, Atkinson M. Impairment of vagal function in reflux oesophagitis. Q J Med 1985;54:61–74. | ChemPort |
Salapatek AM, Diamant NE. Assessment of neural inhibition of the lower esophageal sphincter in cats with esophagitis. Gastroenterology 1993;104:810–818. | ChemPort |
Biancani P, Barwick K, Selling J, McCallum R. Effects of acute experimental esophagitis on mechanical properties of the lower esophageal sphincter. Gastroenterology 1984;87:8–16. | ChemPort |
Tomita R, Tanjoh K, Fujisaki S, Fukuzawa M. Physiological studies on nitric oxide in the lower esophageal sphincter of patients with reflux esophagitis. Hepatogastroenterology 2003;50:110–114. | ChemPort |
Rich H, Dong Song U, Behar J, Kim N, Biancani P. Experimental esophagitis affects intracellular calcium stores in the cat lower esophageal sphincter. Am J Physiol 1997;272:G1523–G1529. | ChemPort |
Sohn UD, et al. Acute experimental esophagitis activates a second signal transduction pathway in cat smooth muscle from the lower esophageal sphincter. J Pharmacol Exp Ther 1997;283:1293–1304. | PubMed | ChemPort |
Cheng L, Cao W, Behar J, Biancani P, Harnett KM. Inflammation induced changes in arachidonic acid metabolism in cat LES circular muscle. Am J Physiol Gastrointest Liver Physiol 2005;288:G787–G797. | Article | ChemPort |
Cao WB, et al. Group I secreted PLA2 and arachidonic acid metabolites in the maintenance of cat LES tone. Am J Physiol 1999;277:G585–598. | PubMed | ChemPort |
Cheng L, et al. In vitro model of acute esophagitis in the cat. Am J Physiol Gastrointest Liver Physiol 2005;289:G860–869. | Article | ChemPort |
Cheng L, et al. Platelet-activating factor and prostaglandin E₂ impair esophageal ACh release in experimental esophagitis. Am J Physiol Gastrointest Liver Physiol 2005;289:G418–428. | Article | ChemPort |
Cheng L, et al. Hydrogen peroxide reduces lower esophageal sphincter tone in human esophagitis. Gastroenterology 2005;129:1675–1685. | Article | PubMed | ChemPort |
Eastwood GL, Beck BD, Castell DO, Brown FC, Fletcher JR. Beneficial effect of indomethacin on acid-induced esophagitis in cats. Dig Dis Sci 1981;26:601–608. | Article | ChemPort |
Isomoto H, et al. Enhanced expression of interleukin-8 and activation of nuclear factor kappa-B in endoscopy-negative gastroesophageal reflux disease. Am J Gastroenterol 2004;99:589–597. | Article | ChemPort |
Liu B, et al. Esophageal dysmotility and the change of synthesis of nitric oxide in a feline esophagitis model. Dis Esoph 2002;15:193–198.
Paterson WG, Kolyn DM. Esophageal shortening induced by short-term intraluminal acid perfusion in opossum: a cause for hiatus hernia? Gastroenterology 1994;107:1736–1740. | ChemPort |
Paterson WG. Role of mast cell-derived mediators in acid-induced shortening of the esophagus. Am J Physiol 1998;37:G385–G388.
Zhang Y, Paterson WG. Nitric oxide contracts longitudinal smooth muscle of opossum esophagus via excitation-contraction coupling. J Physiol 2001;536:133–140. | Article | ChemPort |
Barlow WJ, Orlando RC. The pathogenesis of heartburn in nonerosive reflux disease: a unifying hypothesis. Gastroenterology 2005;128:771–778. | Article | PubMed |
Frazzoni M, De Micheli E, Zentilin P, Savarino V. Pathophysiological characteristics of patients with non-erosive reflux disease differ from those of patients with functional heartburn. Aliment Pharmacol Ther 2004;20:81–88. | Article | PubMed | ChemPort |
Trimble KC, Pryde A, Heading RC. Lowered oesophageal sensory thresholds in patients with symptomatic but not excess gastro-oesophageal reflux: evidence for a spectrum of visceral sensitivity in GORD. Gut 1995;37:7–12. | PubMed | ChemPort |
Shi G, Bruley des Varannes S, Scarpignato C, LeRhun M, Galmiche J-P. Reflux related symptoms in patients with normal oesophageal exposure to acid. Gut 1995;37:457–464. | ChemPort |
Byrne PJ, Mulligan ED, O'Riordan J, Keeling PW, Reynolds J. V. Impaired visceral sensitivity to acid reflux in patients with Barrett's esophagus. The role of esophageal motility^*. Dis Esoph 2003;16:199–203. | ChemPort |
Mehta AJ, de Caestecker JS, Camm AJ, Northfield TC. Sensitization to painful distention and abnormal sensory perception in the esophagus. Gastroenterology 1995;108:311–319. | Article | ChemPort |
Sarkar S, et al. Central neural mechanisms mediating human visceral hypersensitivity. Am J Physiol Gastrointest Liver Physiol 2001;281:G1196–1202. | ChemPort |
Howard PJ, Maher L, Pryde A, Heading RC. Symptomatic gastro-oesophageal reflux, abnormal oesophageal acid exposure, and mucosal acid sensitivity are three separate, though related, aspects of gastro-oesophageal reflux disease. Gut 1991;32:128–132. | ChemPort |
Fass R, et al. Differential effect of long-term esophageal acid exposure on mechanosensitivity and chemosensitivity in humans. Gastroenterology 1998;115:1363–1373. | Article | PubMed | ChemPort |
Takeda T, Nabae T, Kassab G, Liu J, Mittal RK. Oesophageal wall stretch: the stimulus for distension induced oesophageal sensation. Neurogastroenterol Motil 2004;16:721–728. | Article | ChemPort |
Hu WH, Martin CJ, Talley NJ. Intraesophageal acid perfusion sensitizes the esophagus to mechanical distension: a Barostat study. Am J Gastroenterol 2000;95:2189–2194. | Article | ChemPort |
Lin M, Gerson LB, Lascar R, Davila M, Triadafilopoulos G. Features of gastroesophageal reflux disease in women. Am J Gastroenterol 2004;99:1442–1447. | Article |
Fass R, Pulliam G, Johnson C, Garewal HS, Sampliner RE. Symptom severity and oesophageal chemosensitivity to acid in older and young patients with gastro-oesophageal reflux. Age Ageing 2000;29:125–130. | Article | ChemPort |
Johnson DA, Fennerty MB. Heartburn severity underestimates erosive esophagitis severity in elderly patients with gastroesophageal reflux disease. Gastroenterology 2004;126:660–664. | Article |
Bradley LA, Richter JE, Scarinci IC, Haile JM, Schan CA. Psychosocial and psychophysical assessments of patients with unexplained chest pain. Am J Med 1992;92(5A):65S–73S.
Buckles DC, Sarosiek I, McMillin C, McCallum RW. Delayed gastric emptying in gastroesophageal reflux disease: reassessment with new methods and symptomatic correlations. Am J Med Sci 2004;327:1–4.
Holloway RH, Hongo M, Berger K, McCallum RW. Gastric distention: a mechanism for postprandial gastroesophageal reflux. Gastroenterology 1985;89:779–784. | ChemPort |
Yamashita Y, Mason RJ, Demeester TR. Postprandial acid reflux is reduced by delayed gastric emptying. J Smooth Muscle Res 2003;39:87–93. | Article |
Penagini R, et al. Relationship between motor function of the proximal stomach and transient lower oesophageal sphincter relaxation after morphine. Gut 2004;53:1227–1231. | Article | ChemPort |
Demirbilek S, et al. Delayed gastric emptying in gastroesophageal reflux disease: the role of malrotation. Pediatr Surg Int 2005;21:423–427. | Article | PubMed | ISI |
Helm JF, et al. Effect of esophageal emptying and saliva on clearance of acid from the esophagus. N Engl J Med 1984;310:284–288. | ChemPort |
Sonnenberg A, et al. Salivary secretion in reflux esophagitis. Gastroenterology 1982;83:889–895. | ChemPort |
Helm JF, Dodds WJ, Hogan WJ. Salivary response to esophageal acid in normal subjects and patients with reflux esophagitis. Gastroenterology 1987;93:1393–1397. | ChemPort |
Mang F-W, et al. Primary biliary cirrhosis, sicca complex, and dysphagia. Dysphagia 1997;12:167–170. | Article | ChemPort |
Korsten MA, et al. Chronic xerostomia increases esophageal acid exposure and is associated with esophageal injury. Am J Med 1991;90:701–706. | ChemPort |
Johnson LF, DeMeester TR. Twenty-four-hour pH monitoring of the distal esophagus. A quantitative measure of gastroesophageal reflux. Am J Gastroenterol 1974;62(4):325–332.
Peghini PL, Katz PO, Castell DO. Ranitidine controls nocturnal gastric acid breakthrough on omeprazole: a controlled study in normal subjects. Gastroenterology 1998;115:1335–1339. | Article | PubMed | ISI | ChemPort |
Fackler WK, Ours TM, Vaezi MF, Richter JE. Long-term effect of H2RA therapy on nocturnal gastric acid breakthrough. Gastroenterology 2002;122:625–632. | Article | PubMed | ISI | ChemPort |
Moore JG. Circadian dynamics of gastric acid secretion and pharmacodynamics of H2 receptor blockade. Ann N Y Acad Sci 1991;618:150–158.
Orr WC, Elsenbruch S, Harnish MJ, Johnson LF. Proximal migration of esophageal acid perfusions during waking and sleep. Am J Gastroenterol 2000;95:37–42. | Article | ChemPort |
Orr WC, Robinson MG, Johnson LF. Acid clearance during sleep in the pathogenesis of reflux esophagitis. Dig Dis Sci 1981;26:423–427. | Article | ChemPort |
Kahrilas PJ, et al. Effect of sleep, spontaneous gastroesophageal reflux, and a meal on upper esophageal sphincter pressure in normal human volunteers. Gastroenterology 1987;92:466–471. | PubMed | ChemPort |
Lear CS, Flanagan JBJr, Moorrees CF. The frequency of deglutition in man. Arch Oral Biol 1965;10:83–100. | PubMed | ChemPort |
Schneyer LH, Pigman W, Hanahan L, Gilmore RW. Rate of flow of human parotid, sublingual, and submaxillary secretions during sleep. J Dent Res 1956;35:109–114. | ChemPort |
Elsenbruch S, Orr WC, Harnish MJ, Chen JD. Disruption of normal gastric myoelectric functioning by sleep. Sleep 1999;22:453–458. | ChemPort |
Goo RH, Moore JG, Greenberg E, Alazraki NP. Circadian variation in gastric emptying of meals in humans. Gastroenterology 1987;93:515–518. | ChemPort |
Suganuma N, et al. Association of gastroesophageal reflux disease with weight gain and apnea, and their disturbance on sleep. Psychiatry Clin Neurosci 2001;55:255–256. | Article | ChemPort |
Mercer CD, Rue C, Hanelin L, Hill LD. Effect of obesity on esophageal transit. Am J Surg 1985;149:177–181. | ChemPort |
Wilson LJ, Ma W, Hirschowitz BI. Association of obesity with hiatal hernia and esophagitis. Am J Gastroenterol 1999;94:2840–2844. | Article | PubMed | ISI | ChemPort |
Locke GR3rd, Talley NJ, Fett SL, Zinsmeister AR, Melton LJ3rd. Risk factors associated with symptoms of gastroesophageal reflux. Am J Med 1999;106:642–649. | Article | PubMed | ISI |
Fraser-Moodie CA, et al. Weight loss has an independent beneficial effect on symptoms of gastro-oesophageal reflux in patients who are overweight. Scand J Gastroenterol 1999;34:337–340. | ChemPort |
Kjellin A, Ramel S, Rossner S, Thor K. Gastroesophageal reflux in obese patients is not reduced by weight reduction. Scand J Gastroenterol 1996;31:1047–1051. | ChemPort |
Lagergren J, Bergstrom R, Nyren O. No relation between body mass and gastro-oesophageal reflux symptoms in a Swedish population based study. Gut 2000;47:26–29. | Article | PubMed | ISI | ChemPort |
Post JC, Ze F, Ehrlich GD. Genetics of pediatric gastroesophageal reflux. Curr Opin Allergy Clin Immunol 2005;5:5–9. | ChemPort |
Fass R. Distinct phenotypic presentations of gastroesophageal reflux disease: a new view of the natural history. Dig Dis 2004;22:100–107. | Article |
Orenstein SR, Shalaby TM, Barmada MM, Whitcomb DC. Genetics of gastroesophageal reflux disease: a review. J Pediatr Gastroenterol Nutr 2002;34:506–510. | Article |
Trudgill NJ, Kapur KC, Riley SA. Familial clustering of reflux symptoms [see comments]. Am J Gastroenterol 1999;94:1172–1178. | Article | ChemPort |
Locke GRI, Talley NJ, Fett SL, Zinsmeister AR, Melton LJI. Prevalence and clinical spectrum of gastroesophageal reflux: a population-based study in Olmsted County, Minnesota. Gastroenterology 1997;112:1448–1546. | PubMed | ISI |
Romero Y, et al. Familial aggregation of gastroesophageal reflux in patients with Barrett's esophagus and esophageal adenocarcinoma. Gastroenterology 1997;113:1449–1456. | Article | PubMed | ISI | ChemPort |
Drovdlic CM, et al. Demographic and phenotypic features of 70 families segregating Barrett's oesophagus and oesophageal adenocarcinoma. J Med Genet 2003;40:651–656. | Article | ChemPort |
Mohammed I, Cherkas LF, Riley SA, Spector TD, Trudgill NJ. Genetic influences in gastro-oesophageal reflux disease: a twin study. Gut 2003;52:1085–1089. | Article | ChemPort |
Cameron AJ, et al. Gastroesophageal reflux disease in monozygotic and dizygotic twins. Gastroenterology 2002;122:55–59. | Article | PubMed | ISI |
Orenstein SR. Infantile reflux: different from adult reflux. Am J Med 1997;103:114S–119S. | Article | PubMed | ChemPort |
Fitzgerald RC. Complex diseases in gastroenterology and hepatology: GERD, Barrett's, and esophageal adenocarcinoma. Clin Gastroenterol Hepatol 2005;3:529–537. | Article | ChemPort |
Carre IJ, Johnston BT, Thomas PS, Morrison PJ. Familial hiatal hernia in a large five generation family confirming true autosomal dominant inheritance. Gut 1999;45:649–652. | ChemPort |
Goodman RM, Wooley CF, Ruppert RD, Freimanis AK. A possible genetic role in esophageal hiatus hernia. J Hered 1969;60:71–74. | ChemPort |
Hu FZ, et al. Fine mapping a gene for pediatric gastroesophageal reflux on human chromosome 13q14. Hum Genet 2004;114:562–572. | Article | ChemPort |
Orenstein SR, et al. Autosomal dominant infantile gastroesophageal reflux disease: exclusion of a 13q14 locus in five well characterized families. Am J Gastroenterol 2002;97:2725–2732. | Article | ChemPort |

Review

Pathophysiology of gastroesophageal reflux disease

View article related content

Key Points

Introduction

Table 1: Factors important to the development of gastroesophageal reflux disease (GERD)

Figure 1: A simple overview of the pathogenesis of gastroesophageal reflux disease.

Figure 2: Gastroesophageal reflux disease initiates a vicious cycle of increasing esophageal acid exposure.

Gastric Acid and Other Refluxed Substances

Gastric Acid

Levels of Gastric Acid Secretion

H. Pylori and Gastric Acid

Figure 3: The odds ratio (95% confidence intervals) for prevalence of H. pylori in patients with esophagitis in North America^{24, 25, 26, 27, 28, 29, 30} and the Far East.^{19, 20, 21, 22, 23}

Other Refluxed Substances

Antireflux Mechanisms at the Gastroesophageal Region

The Lower Esophageal Sphincter

Normal Physiology

Figure 4: The structure of the lower esophageal sphincter (LES).

Pathophysiology: Low LES Pressure and TLESR

Figure 5: Body position and gastroesophageal reflux causing mucosal injury.

Pathophysiology: Differences in LES Circular and Gastric Sling Muscles

The Diaphragm

Normal Physiology

Phrenoesophageal Ligament

Figure 6: The phrenoesophageal ligament at the gastroesophageal junction in normal and hiatal hernia.

Figure 7: Attachment of phrenoesophageal ligand to lower esophageal sphincter.

Hiatus Hernia

Mucosal Defense Mechanisms and Inflammation

Inflammation: LES and Esophageal Motility

Sensory Mechanisms and Symptoms

Other Factors

Conclusion

Article related content

Ancillary details

References

Main navigation

Extra navigation

ARTICLE NAVIGATION - ARTICLE TOOLS

ARTICLE NAVIGATION