INTRODUCTION — Some degree of reflux is physiologic [1]. Physiologic reflux episodes typically occur postprandially, are short-lived, asymptomatic, and rarely occur during sleep. Pathologic reflux is associated with symptoms or mucosal injury 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 inflammation.
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 gastroesophageal reflux disease (GERD) reflects an imbalance between injurious or symptom-eliciting factors (reflux events, acidity of refluxate, esophageal hypersensitivity) and defensive factors (esophageal acid clearance, mucosal integrity) [2,3]. 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. 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 [5-7]. This is substantiated by the observation that histopathological events in 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 esophageal sensitivity in the absence of esophagitis.
Gastroesophageal junction incompetence — The antireflux barrier at the gastroesophageal junction is anatomically and physiologically complex and vulnerable to several potential mechanisms of reflux. The three dominant pathophysiologic mechanisms causing esophagogastric junction (EGJ) incompetence are:
●Transient lower esophageal sphincter relaxations (TLESRs)
●A hypotensive lower esophageal sphincter (LES)
●Anatomic disruption of the gastroesophageal junction, often associated with a hiatal hernia
Although examples of each have been documented in mechanistic studies, their relative importance continues to be debated. The evolving concept is that the dominant mechanism varies as a function of disease severity with TLESRs predominating with mild disease, and mechanisms associated with a hiatus hernia and/or a weak sphincter predominating with more severe disease [8].
Transient lower esophageal sphincter relaxations — TLESR is part of the physiological mechanism of belching. TLESR is an active, vagally mediated reflex allowing air to escape from the stomach [9,10]. A primary determinant of reflux disease is an increased proportion of TLESRs that are associated with acid reflux rather than gas venting alone [11].
TLESR involves not only LES relaxation, but also crural diaphragmatic inhibition, esophageal shortening by contraction of its longitudinal muscle, and contraction of the costal diaphragm [12]. There are several major differences between TLESR and swallow-induced LES relaxation: TLESRs occur without an associated pharyngeal contraction, are unaccompanied by esophageal peristalsis, and persist for longer periods (>10 seconds) as compared with swallow-induced LES relaxations. The frequency of TLESRs is increased by distension of the stomach or by assuming an upright posture.
Acid reflux with TLESRs can result from increased compliance of the EGJ as a consequence of weakening or dilatation of the diaphragmatic hiatus [11]. Increased compliance leads to an increased luminal cross-sectional area during opening that in turn results in an increased volume of reflux and a reduced ability to limit refluxate to gas. TLESRs can be inhibited by gamma aminobutyric acid receptor type B agonists (eg, baclofen). (See "Non-acid reflux: Clinical manifestations, diagnosis, and management", section on 'Reflux inhibitors'.)
Hypotensive lower esophageal sphincter — Only a minority of individuals with GERD have a grossly hypotensive LES (<10 mmHg) when determined during fasting measurements [13]. Factors that can reduce LES pressure include gastric distension, cholecystokinin, smoking, and specific foods and medications [14]. (See 'Diet and medications' below.)
Gastroesophageal reflux can occur with diminished LES pressure either by strain-induced reflux or free reflux:
●Strain-induced reflux occurs when a hypotensive LES is overcome and "blown open" by an abrupt increase of intra-abdominal pressure. Manometric data suggest that strain-induced reflux is relatively unusual unless the LES pressure is less than 4 mmHg [15]. Free reflux also occurs in the setting of a very hypotensive LES, with the only distinction being that there is no observed increase in intra-abdominal pressure associated with the fall in intraesophageal pH.
Anatomic disruption of the gastroesophageal junction — Laxity in the LES-crural diaphragm attachment, hiatus hernia, increased EGJ distensibility, and increased intra-abdominal pressure can contribute to mechanical impairment of the EGJ. (See 'Hiatus hernia' below.)
Physiologically, both the diaphragm and the LES contribute to gastroesophageal sphincter competence and EGJ pressure. Observations of the antireflux mechanism during maneuvers such as leg raising and abdominal compression suggest a "pinchcock" effect of crural contraction that augments the antireflux barrier. The susceptibility to reflux under circumstances of abrupt increases of intraabdominal pressure (eg, during bending or coughing) depends upon both the instantaneous LES pressure and the diaphragmatic sphincter [16].
Characteristics of the refluxate — The intragastric pH and the amount of time the refluxate is in contact with the 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 been implicated in the development of esophagitis primarily in patients with increased duodenogastric reflux following gastric surgery [17].
Impaired esophageal acid clearance — Following reflux, 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 (when the esophageal pH <4) has been observed in approximately one half of patients with esophagitis [18]. 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 of salivary bicarbonate. 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 [19]. Ineffective esophageal motility becomes more common with increasing severity of esophagitis [13]. 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 flow associated with hiatal hernias also impairs esophageal emptying [20,21]. In one report, for example, re-reflux was seen with almost 50 percent of test swallows in patients with nonreducing hernias (evident between swallows), impairing both esophageal emptying and esophageal acid clearance [21].
The potential for re-reflux may be aggravated by the presence of an acid pocket in the most proximal gastric cardia that escapes the buffering effects of food and remains highly acidic during the postprandial period [22,23]. The net result is much greater acid exposure just above the squamocolumnar junction compared to more proximal locations, likely explaining the propensity of the distal esophagus to develop mucosal erosions [24,25].
Diminished salivary function — Reduced salivation or diminished salivary neutralizing capacity also prolongs acid clearance. Approximately 7 ml of saliva will neutralize 1 ml of 0.1 N HCl, 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 during sleep, for example, 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. 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 [26]. Chronic xerostomia is associated with prolonged esophageal acid exposure and esophagitis in a subset of patients [27].
Impaired defense against epithelial injury — Age and nutritional status influence the ability of the mucosa to withstand injury. Esophageal mucosa possesses morphologic and physiologic defenses against reflux injury at the epithelial and post-epithelial levels [28]. These mechanisms include the following:
●Epithelial tight junctions – The main defense against reflux injury is the epithelial barrier itself. The esophageal mucosa is a relatively "tight" epithelium, resistant to ionic movements at the intercellular as well as the cellular level because of the tight junctions and the lipid-rich matrix in the intercellular space [29]. This mucosa can retard hydrogen ion penetration in the face of ion gradients of greater than 5 pH units.
●Hydrogen ion extrusion – Two pH-activated acid extruding processes are located on esophageal membranes: a Na+/H+ exchanger; and a sodium dependent Cl-/HCO3- exchanger [30]. Once extruded, the hydrogen ions are buffered by extracellular bicarbonate in equilibrium with the blood. Thus, blood flow is the main post-epithelial defense. Blood flow increases in response to luminal acid, delivering more bicarbonate to the intercellular space as well as providing nutrients for metabolic activity [31].
Esophageal hypersensitivity — Increased mucosal sensitivity to acid can also contribute to symptoms of heartburn. Heartburn in patients with normal esophageal acid exposure can be related to enhanced perception of "physiological reflux" (reflux hypersensitivity) [8].
OTHER ETIOLOGIC FACTORS — Several factors contribute to development of pathological reflux by mechanical or functional impairment of the esophagogastric junction (EGJ).
Hiatus hernia — The severity of reflux esophagitis correlates with the size of hiatus hernia [32]. There are several mechanisms underlying the development of GERD in patients with a hiatus hernia. Mechanisms include impairment of the crural diaphragmatic component of the EGJ, low LES pressure, and a reduced threshold for eliciting transient lower esophageal sphincter relaxation (TLESR) in response to gastric distension [33-35]. In patients with a hiatus hernia, the supradiaphragmatic location of the postprandial acid pocket just distal of the squamocolumnar junction also contributes to the number of TLESRs associated with acid reflux [36]. Hiatal hernias are also associated with prolonged recumbent acid clearance times due to ineffective esophageal motility and re-reflux, both of which impair esophageal emptying. (See 'Impaired esophageal acid clearance' above and "Hiatus hernia" and 'Transient lower esophageal sphincter relaxations' above.)
Obesity — Obesity is a risk factor for GERD and erosive esophagitis [37]. In a cross-sectional survey of 10,545 women, increasing body mass index was associated with a significant increase in frequency of GERD symptoms [38]. Even moderate weight gain in women of normal weight was associated with exacerbation of symptoms.
The mechanisms by which obesity contributes to reflux are incompletely understood. 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 [39]. Obesity was also associated with disruption of the EGJ leading to a hiatal hernia and increased esophageal acid exposure [40,41]. (See 'Hiatus hernia' above.)
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). Estrogen replacement therapy in postmenopausal women also appears to modestly increase the risk of heartburn [42]. (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, tricyclic antidepressants, opioids, theophylline, diazepam, barbiturates) can cause or exacerbate reflux by inducing LES hypotension.
UNCLEAR ROLE OF HELICOBACTER PYLORI — The link between gastroesophageal reflux disease (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
●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.)
●The three dominant pathophysiologic mechanisms causing gastroesophageal junction incompetence are: transient lower esophageal sphincter relaxations (TLESRs), a hypotensive lower esophageal sphincter (LES), and anatomic disruption of the gastroesophageal junction, often associated with a hiatal hernia. (See 'Gastroesophageal junction incompetence' above and 'Hiatus hernia' above.)
●A primary determinant of reflux disease is an increased proportion of TLESRs that are associated with reflux of acid rather than only gas. (See 'Transient lower esophageal sphincter relaxations' above.)
●A minority of individuals with GERD have a grossly hypotensive LES (<10 mmHg) when determined during fasting measurements. However, periods of gross LES hypotension may result from gastric distension, smoking and specific foods and medications. (See 'Hypotensive lower esophageal sphincter' above and 'Diet and medications' above.)
●Hiatus hernia is associated with progressive disruption of the diaphragmatic sphincter, resulting in increased susceptibility to reflux with abrupt increases of intra-abdominal pressure. Hiatus hernia is also associated with a reduced threshold for eliciting TLESRs in response to gastric distension and malfunction of the gastroesophageal barrier during periods of low LES pressure. (See 'Anatomic disruption of the gastroesophageal junction' above and 'Hiatus hernia' above.)
●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 from the hernia. (See 'Impaired esophageal acid clearance' above.)
●Heartburn in patients with normal esophageal acid exposure may be related to heightened esophageal sensitivity (also called reflux hypersensitivity). (See 'Esophageal hypersensitivity' above.)
