Version July 2025
INTRODUCTION —
Some degree of gastroesophageal reflux is physiologic. Physiologic reflux episodes typically occur postprandially, are short-lived, asymptomatic, and rarely occur during sleep. Pathologic reflux is associated with symptoms or mucosal injury (esophagitis) and often occurs nocturnally. In general, the term gastroesophageal reflux disease (GERD) is applied to patients with symptoms suggestive of reflux or complications thereof, but not necessarily with esophageal inflammation. Reflux esophagitis describes a subset of patients with GERD who have endoscopic evidence of esophageal erosions, described in the Los Angeles classification as mucosal breaks [1], usually confined to the area of the gastroesophageal junction.
The pathophysiology of GERD will be reviewed here. The clinical manifestations and diagnosis of this disorder are discussed separately. (See "Clinical manifestations and diagnosis of gastroesophageal reflux in adults".)
MECHANISMS OF GASTROESOPHAGEAL REFLUX DISEASE —
The development of GERD reflects an imbalance between injurious or symptom-eliciting factors (reflux events, acidity of refluxate, esophageal sensitivity) and defensive factors (esophageal acid clearance, mucosal integrity) (algorithm 1) [2,3]. The extent of mucosal injury is proportional to the frequency of reflux events, the duration of esophageal mucosal acidification, and the caustic potency of refluxed fluid. Although the same can be said of symptom severity, it is complicated by the added determinant of esophageal hypersensitivity [4].
Esophagitis results from cytokine-triggered inflammation rather than a direct chemical effect of prolonged exposure to acid, pepsin, and bile on the esophageal epithelium, the "burn" hypothesis [5-7]. This is substantiated by the observation that histopathologic events during the development of esophagitis (lymphocytic inflammation, dilated intercellular spaces) occur deep in the epithelium, not at the luminal surface, and that regenerative changes (basal cell hyperplasia, papillary elongation) are initiated prior to the development of surface necrosis that was formerly hypothesized as the stimulus for those changes. Cytokine-triggered inflammation may also cause alterations in mucosal permeability and esophageal sensitivity in the absence of esophagitis.
The antireflux barrier — GERD exists as a spectrum that includes reflux esophagitis, nonerosive reflux disease, extraesophageal GERD, reflux hypersensitivity, and Barrett's esophagus [4]. Within this wide spectrum, the dominance of a defective antireflux barrier as the primary pathophysiologic determinant differs widely, being greater for entities with esophagitis or sequalae of esophagitis and nonerosive reflux disease with quantitatively abnormal esophageal acid exposure on pH-metry [8]. Within the realm of esophagitis, high-grade esophagitis (Los Angeles grade C or D) implies greater antireflux barrier dysfunction than low-grade esophagitis (Los Angeles grade A or B) [9].
The antireflux barrier is a complex entity, representing a fascinating interplay between anatomical structure and physiology. Functionally, the antireflux barrier prevents reflux of gastric fluid into the distal esophagus during recumbence, in the face of abrupt increases in intra-abdominal pressure, or during swallow-induced lower esophageal sphincter (LES) relaxation. At other times, it is permissive of venting gas from the stomach or vomiting. Moreover, the antireflux barrier reacts to counter abrupt increases in intra-abdominal pressure with an equally abrupt contraction. In brief, it is a very dynamic entity.
Historically, three major concepts have been proposed that promote antireflux barrier competence: the LES as an intrinsic esophageal sphincter, the crural diaphragm as an extrinsic sphincter, and the gastroesophageal flap valve, wherein the distal half of the LES (which is normally intra-abdominal) enters the saccular stomach at an oblique angle, termed the angle of His [10]. Notably, these mechanisms are strongly interdependent [11], each with its own functional profile. The LES, with its muscular architecture inclusive of the gastric sling fibers and distal esophageal circular muscle forms a "noose" around the gastroesophageal junction, both maintaining gastroesophageal junction closure in the absence of crural diaphragm contraction and forming the angle of His when the gastroesophageal complex is in its normal subdiaphragmatic location [12,13]. The crural diaphragm with the rapidly reactive properties of skeletal muscle and independent neural control by phrenic nerve branches contracts vigorously to angulate the esophagus at the gastroesophageal junction and pinch the proximal part of the LES during inspiration and abdominal straining [14]. Notably, the shallow inspiratory contractions of the crural diaphragm are maintained during swallow-induced LES relaxation, resulting in a pulsatile bolus flow into the stomach and preventing swallow-induced reflux that might otherwise occur during inspiration when intra-abdominal pressure exceeds chest pressure [15]. The flap valve is a one-way valve that opens when intraesophageal pressure exceeds intragastric pressure, as occurs during peristaltic transport, and closes by collapsing on itself when intragastric pressure exceeds intraesophageal pressure, as occurs with gastric distention [16,17].
The antireflux barrier is dynamic. In addition to preventing fluid reflux, it is permissive of venting gas from the stomach (ie, belching). Belching occurs by a mechanosensitive vagovagal reflex, termed a transient LES relaxation, which not only disables the antireflux barrier, but actually facilitates the occurrence of gastroesophageal reflux despite only a minimal pressure differential between the stomach and distal esophagus [18,19]. However, because of the minimal intraluminal pressure, transient LES relaxations are normally associated with minimal dimensions of gastroesophageal junction opening, which is ultimately governed by the compliance of the esophageal wall. This effectively restricts the flow of fluid while facilitating the venting of gas from the stomach on account of the fact that the flow rate into the esophagus is directly proportional to the luminal opening diameter of the gastroesophageal junction (to the fourth power) and inversely proportional to fluid viscosity, which is 56-fold greater for water than air [20,21]. The physiological components of a transient LES relaxation are complete and prolonged LES relaxation, complete prolonged inhibition of the crural diaphragm, and contraction of the longitudinal muscle of the distal esophagus pulling the gastroesophageal junction through the diaphragmatic hiatus into the mediastinum and transforming its anatomical configuration from that of a gastroesophageal flap valve with an acute angle of His to that of an inverted funnel [18,22]. The stimulus for transient LES relaxation is gastric distention, which can be experimentally induced by gas insufflation into the stomach [23].
Dysfunction of the antireflux barrier — The most dominant epidemiological variables associated with the development of reflux disease are advancing age and abdominal obesity [24]. Both of these factors are also associated with an increased prevalence of hiatus hernia, the size of which is a dominant determinant of esophagitis presence and severity [25,26]. The common understanding of hiatus hernia is that the anatomical gastroesophageal junction, or the LES, has migrated from its native location just within and below the diaphragm to an abnormal location terminating at, or some distance above, the crural diaphragm. However, in the context of antireflux barrier function, this is an oversimplification because it ignores how each of the three components of antireflux barrier function might then be compromised. Consider the anatomical perturbations potentially imposed by hiatus hernia: widening of the diaphragmatic hiatus [27]; attenuation of the phrenoesophageal ligament and loosening of the attachment between the esophagus and hiatus; loss of the intra-abdominal segment of the distal LES, and repositioning of the LES out of the abdomen and into the mediastinum. Some of the physiological consequences of these perturbations are: diminished sphincteric function of the crural diaphragm during inspiration and abdominal straining [28]; loss of the crural diaphragm's ability to prevent reflux during swallow-induced LES relaxation, most evident with recumbency; complete disabling of the flap valve mechanism which requires an acute angle of His in an intra-abdominal pressure environment such that increased intragastric pressure presses the flap against the intra-abdominal LES segment (which is no longer present); weakening of the intrinsic LES which is now challenged rather than bolstered by the pressure changes during the respiratory cycle [29]; increased compliance of gastroesophageal junction during transient LES relaxations because of dilatation of the surrounding hiatus, leading to greater dimensions of sphincter opening when relaxed and loss of its ability to restrict the associated reflux to gas [20,21]; and a reduced threshold for eliciting transient LES relaxations in the setting of hiatus hernia because this is a mechanosensitive reflex [23].
Disruption of the antireflux barrier exists along a spectrum of severity, much of which is reflected in anatomical distortion of the native esophagogastric junction not always radiographically evident as an overt hiatal hernia. An initiative by the American Foregut Society (AFS) aimed to stratify the degree of esophagogastric junction disruption based on a novel endoscopic assessment of esophagogastric junction integrity [10]. The AFS hiatus grade differs from prior such assessments, most notably the Hill classification, in several ways: it specifies that the endoscopic technique should mechanical challenge the esophagogastric junction to elicit anatomic disruption that may not be otherwise evident and it characterizes esophagogastric junction integrity in three domains, the length of axial herniation gauged by separation between the squamocolumnar junction and the crural diaphragm indentation in centimeters, the diameter of the diaphragmatic hiatus (which normally should not even be visible from within the stomach), gauged by comparison to the diameter of the endoscope in a distended retroflexed view, and the presence or absence of the gastroesophageal flap valve. The grading scale ranges from I to IV with only grade I being indicative of an intact esophagogastric junction.
Characteristics of the refluxate — The intragastric pH and the amount of time the refluxate is in contact with the esophageal mucosa are important determinants of the extent of esophageal mucosal injury. The degree of mucosal damage is more significant if the refluxate pH is less than two and/or if pepsin is present in the refluxate. Bile acids have also been implicated in the development of esophagitis, especially in patients with increased duodenogastric reflux following gastric surgery [30].
Impaired esophageal acid clearance — Following a reflux event, esophageal acid clearance begins with emptying the refluxed fluid from the esophagus by peristalsis and is completed by titration of the residual acid with swallowed saliva (figure 1). Prolongation of esophageal acid clearance time (the period that the esophageal pH <4) has been observed in approximately one half of patients with esophagitis [31]. The two major causes of this problem are impaired esophageal emptying and impaired salivary function.
Impaired esophageal emptying — The process of normal acid clearance involves peristalsis as well as the swallowing bicarbonate-rich saliva. Peristalsis clears gastric fluid from the esophagus, whereas the swallowing of saliva (pH of 7.8 to 8.0) neutralizes any remaining acid. Both primary and secondary peristalsis are essential mechanisms of esophageal clearance. Abnormal acid clearance improves with an erect posture, suggesting that gravity can compensate for impaired fluid emptying.
Two mechanisms of impaired esophageal emptying have been identified:
●Ineffective esophageal motility – Ineffective esophageal motility can be manifest as either failed or hypotensive (distal contractile integral <450 mmHg cm/s) peristaltic contractions [32,33]. Ineffective esophageal motility becomes more common with increasing severity of esophagitis [34]. It is likely that acute dysfunction associated with active esophagitis is partially reversible, while chronic dysfunction associated with stricturing or extensive fibrosis is not.
●Re-reflux – Re-reflux or retrograde bolus flow associated with hiatal hernias during recumbence also impairs esophageal emptying [15,35]. In one report, for example, this was demonstrated with almost 50 percent of test swallows in patients with hernias large enough to be evident between swallows, both impairing bolus transfer to the stomach and prolonging the process of esophageal acid clearance [15].
The potential for re-reflux may be aggravated by the acid pocket, which is composed of the newly secreted acid that layers above the ingested food in the most proximal gastric cardia, becoming highly acidic within 15 minutes of eating [36,37]. The net result is much greater acid exposure just above the squamocolumnar junction compared to more proximal locations, especially in patients with hiatal hernias. This likely explains the propensity of the distal esophagus to develop mucosal erosions and, by extension, metaplasia [38-40].
Diminished salivary function — Reduced salivation or diminished salivary neutralizing capacity also prolongs acid clearance. Approximately 7 mL of saliva will neutralize 1 mL of 0.1N hydrochloric acid, with 50 percent of the neutralizing capacity being attributable to salivary bicarbonate. The normal rate of salivation is about 0.5 mL/min; maneuvers that increase salivation (eg, oral lozenges or gum chewing) will hasten esophageal acid clearance. Diminished salivation as occurs during sleep explains why reflux events during sleep or immediately prior to going to sleep are associated with markedly prolonged acid clearance times. Cigarette smokers have prolonged esophageal acid clearance times due to hyposalivation, presumably due to the anticholinergic properties of nicotine. In one study, smokers without symptoms of reflux disease were found to have acid clearance times 50 percent longer than those of nonsmokers; furthermore, the salivary titratable base content of the smokers was only 60 percent of the age-matched nonsmokers [41]. Chronic xerostomia is associated with prolonged esophageal acid exposure and esophagitis in a subset of patients [42].
Esophageal sensitivity and hypersensitivity — There is substantial variability in the type and severity of symptoms among GERD patients, and there is only poor correlation between the subjective severity of symptoms and the objective severity of mucosal damage [43,44]. Further, patients with quantitatively normal esophageal pH-metry might correlate troublesome symptoms with "physiological" reflux episodes, presumably owing to esophageal hypersensitivity. Moreover, some patients report constant heartburn that is not associated with any detectable reflux, an entity referred to as functional heartburn [43]. At the other extreme are patients, particularly some with severe obesity, with esophageal hyposensitivity, developing severe lesions (high grade esophagitis, peptic stricture, Barrett's esophagus) with minimal or absent symptoms [44,45].
The symptom experience is presumably mediated by stimulation of afferent nerves in the esophageal mucosa, the location of which normally varies along the length of the esophagus. In the distal esophagus, nerve fibers are predominantly located deep in the epithelium, while in the proximal esophagus, they are concentrated near the luminal surface [46], an observation thought to explain the heightened sensitivity of the proximal esophagus to reflux. Similarly, esophageal mucosal innervation of patients with nonerosive reflux disease is more superficial than that of normal subjects, patients with erosive reflux disease, or patients with Barrett's esophagus, leading to speculation that this might be the explanation for acid hypersensitivity. This hypothesis was further bolstered by the demonstration of transient receptor potential vanilloid type-1 (TRPV1) expression on these superficial sensory nerves. TRPV1 is often involved in nociceptive pathways and can be activated by H+, thereby offering a mechanism by which luminal acid can stimulate the perception of heartburn, despite there being an intact esophageal epithelium as in nonerosive reflux disease [47].
OTHER POTENTIAL ETIOLOGIC FACTORS —
Several factors may contribute to development of pathologic reflux by exacerbating the mechanical or functional impairment of the esophagogastric junction (EGJ).
Obesity — Obesity is an independent risk factor for GERD symptoms and erosive esophagitis [48,49]. In a cross-sectional survey of 10,545 women, increasing body mass index was associated with a significant increase in frequency of GERD symptoms; even moderate weight gain in women of normal weight was associated with symptom exacerbation [50]. The estimated odds ratios for heartburn and acid regurgitation occurring at least once a week in overweight or obesity are 1.82 and 2.91, respectively [51].
Several mechanisms have been proposed by which obesity contributes to reflux. In an observational study that included 285 patients with GERD in whom anthropometric variables were correlated with findings on manometry, there was a significant correlation of body mass index and waist circumference with intragastric pressure and the gastroesophageal pressure gradient [52]. Obesity was also associated with disruption of the EGJ leading to a hiatal hernia and increased esophageal acid exposure [53,54].
Pregnancy and exogenous estrogen — Heartburn occurs with 30 to 50 percent of pregnancies. This is likely due to hormonal (estrogen and progesterone reducing LES tone) and possible mechanical factors (gravid uterus elevating intra-abdominal pressure). Estrogen replacement therapy in postmenopausal women also appears to modestly increase the risk of heartburn [55]. (See "Maternal adaptations to pregnancy: Gastrointestinal tract".)
Diet and medications — Specific foods (fat, chocolate, peppermint), caffeine, alcohol, smoking, and several drugs (eg, anticholinergics, nitrates, calcium channel blockers, erectile dysfunction medicines, tricyclic antidepressants, opioids, theophylline, diazepam, barbiturates) can cause or exacerbate reflux by inducing LES hypotension [56]. Medications that cause delayed gastric emptying, such as glucagon-like peptide 1 receptor agonists, may also lead to the development of GERD [57,58].
Psychosocial factors — Patients with heartburn often report symptom exacerbations during periods of psychological stress or sleep deprivation [59,60]. Similarly, symptom severity is affected by psychosocial comorbidities. Hypervigilance is a mechanism that leads to heightened awareness and amplification of sensations [61]. This increased awareness of symptoms can generate a learned fear response, resulting in a vicious cycle of autonomic nervous system arousal that leads to unconscious behaviors to avoid the symptom. Hypervigilance can occur in all phenotypes of GERD, including nonerosive disease and erosive esophagitis, and strongly correlates with reported symptom severity [62].
Helicobacter pylori — The link between GERD and Helicobacter pylori is complex and, in many cases, H. pylori may actually be protective against GERD. (See "Helicobacter pylori and gastroesophageal reflux disease".)
INFORMATION FOR PATIENTS —
UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topics (see "Patient education: Hiatal hernia (The Basics)")
SUMMARY AND RECOMMENDATIONS
●Mechanisms – The development of gastroesophageal reflux disease (GERD) reflects the balance between injurious or symptom-eliciting factors (reflux events, acidity of refluxate, esophageal hypersensitivity) and defensive factors (esophageal acid clearance, mucosal integrity). The extent of mucosal injury is proportional to the frequency of reflux events, the duration of mucosal acidification, and the caustic potency of refluxed fluid (algorithm 1). (See 'Mechanisms of gastroesophageal reflux disease' above.)
●Antireflux barrier
•Physiologic competence – The three dominant physiological mechanisms promoting gastroesophageal junction competence are the lower esophageal sphincter (LES) as an intrinsic esophageal sphincter; the crural diaphragm as an extrinsic sphincter; and the gastroesophageal flap valve, wherein the distal half of the LES (which is normally intra-abdominal) enters the saccular stomach at an oblique angle, termed the angle of His. (See 'The antireflux barrier' above.)
•Dysfunction – Dysfunction of the antireflux barrier occurs through complex mechanisms representing a fascinating interplay between anatomical structure and physiology. Dominant determinants are advancing age, obesity, and the progressive anatomical degradation of the esophagogastric junction, culminating in the development of overt hiatus hernia. (See 'Dysfunction of the antireflux barrier' above.)
•Role in pathophysiology of GERD – GERD is a heterogeneous diagnosis defined by either the development of troublesome symptoms (heartburn, regurgitation, chest pain) or esophagitis, wherein mucosal erosions are evident on endoscopy. Within this spectrum, the dominance of a defective antireflux barrier as the primary pathophysiologic determinant differs widely, being greater for entities with esophagitis or sequalae of esophagitis.
●Esophageal acid clearance – Esophageal acid clearance is accomplished with emptying the refluxed fluid from the esophagus by peristalsis and the titration of the residual acid by swallowed saliva. Reduced salivation or diminished salivary neutralizing capacity prolong acid clearance. In patients with hiatus hernia, esophageal acid clearance may be impaired due to ineffective esophageal motility and re-reflux of fluid from the hernia. (See 'Impaired esophageal acid clearance' above.)
●Esophageal sensitivity – A major determinant of heartburn severity irrespective of the presence or absence of esophagitis is esophageal hypersensitivity. Emerging evidence suggests this to be related to an abnormally superficial location of esophageal sensory nerves exposing them to noxious luminal content coupled with psychosocial factors tending to amplify perceived symptom severity. (See 'Esophageal sensitivity and hypersensitivity' above.)
