Failure of the anti-reflux barrier is considered the most important factor in the pathogenesis of GERD. It is presently accepted that the two major elements that compose the anti-reflux barrier are the lower esophageal sphincter (LES) and the crural diaphragm. The LES is a thickened ring of tonically contracted circular smooth muscle that generates a 2-4 cm high pressure zone at the gastroesophageal junction and serves as a mechanical barrier between the stomach and the esophagus. The right crus of the diaphragm encircles the LES by the phreno-esophageal ligament and thus provides additional mechanical support. Both structures generate a high-pressure zone in the distal esophagus (15 mmHg to 30 mmHg above gastric pressure). Failure of one or both of these complimentary structures may lead to incompetence of the anti-reflux barrier resulting in pathological gastroesophageal reflux. The variations in LES pressure are usually coupled with esophageal and gastric contractions, while the pressure contributed by the crural diaphragm is in response to physical activity such as inspiration, coughing, Valsalva maneuver, abdominal compression and others. Myogenic and neurogenic mechanisms control the LES resting tone during both feeding and resting state.
LES resting pressure exhibits a significant diurnal variation. During daytime, LES pressure is lower in comparison to the postprandial and nighttime periods . Additionally, various substances such as hormones, drugs and foods influence the LES basal pressure. Substances that increase LES pressure include gastrin, motilin, substance P, alfa-adrenergic antagonists, beta-adrenergic agonists, protein, histamine, me-toclopramide and prostaglandin F2a. Substances that decrease LES basal pressure include secretin, chole-cystokinin, glucagon, somatostatin, progesterone, alfa-adrenergic agonists, beta-adrenergic antagonists, fat, chocolate, ethanol, peppermint, theophylline, prosta-glandin E2, serotonin, morphine, calcium channel blockers, diazepam and barbiturates .
Originally, gastroesophageal reflux was thought to occur across a hypotensive LES. However, the LES basal pressure is variable in patients with GERD, and in most cases within the normal limits . However, patients with erosive esophagitis or Barrett's esophagus demonstrate a significantly lower mean LES basal pressure than patients with non-erosive reflux disease
(NERD) . In patients with NERD, the mean LES basal pressure is similar to normal controls. For most patients with GERD, the predominant mechanism of gastroesophageal reflux is transient lower esophageal sphincter relaxation (TLESR) of an otherwise normal LES (normal resting pressure) . Physiologic reflux occurs mainly in an upright posture, postprandially
. This reflux is facilitated by episodes of inappropriate transient LES relaxation. TLESRs are spontaneous, abnormally prolonged episodes of LES relaxation, which are not preceded by a swallow or peristalsis ,
. Transient LES relaxation is a neural reflex, mediated through the brainstem, and the vagus nerve is its efferent pathway . Gastric distension and pharyn-geal stimulation have been demonstrated to elicit such relaxation . This is considered the only mechanism of reflux in people without GERD and in most of those with GERD. GERD patients demonstrate prolonged postprandial receptive relaxation of the fundus leading to a delayed emptying of the proximal stomach , .
TLESRs have been established as the primary mechanism for gastroesophageal reflux in normal subjects and patients with GERD -. They also serve as the underlying mechanism for belching, which may suggest some relationship with gastro-esophageal reflux. Although, previous studies suggested that patients with GERD experience more TLESRs than healthy controls, recent trials found no increased rate of TLESRs in patients with GERD. However, TLESR was more likely to be associated with acid reflux in patients with GERD (65%) when compared to healthy controls (35%) , . Additionally, it appears that TLESR is the main underlying mechanism responsible for gastroesophageal reflux events in patients with NERD. In NERD patients, who represent the majority of patients seen for reflux symptoms, TLESR rather than hypotensive LES accounts for most gastroesophageal reflux events. In the presence of hiatal hernia, which affects up to 70% of the erosive esophagitis patients, other mechanisms than TLESR play an important role, such as abnormally low LES basal pressure and stress reflux. In NERD patients on the other hand hiatal hernia is relatively uncommon (~30%).
Reduced LES basal pressure and stress reflux are other mechanisms that affect primarily patients with erosive esophagitis. Dent et al  evaluated GERD pa tients with different phenotypic presentations of GERD and found that with increasing severity of esophagitis, absent basal LES pressure became a more common mechanism, accounting for 23% of gastroesophageal reflux episodes in patients with severe erosive esophagitis. Stress reflux is another mechanism responsible for ga-stroesophageal reflux in which increase in intra-ab-dominal pressure overwhelms the counter response of the LES and the crural diaphragm resulting in gastro-esophageal reflux.
Hiatal hernia is an important factor in the pathogenesis of GERD as it interferes directly with the antireflux barrier. The role of hiatal hernia in aggravating gastroesophageal reflux is discussed in another chapter.
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