What is basically wrong with the LES in reflux disease?
PJ. Kahrilas (Chicago)
Although gastroesophageal reflux disease (GERD) is multifactorial in etiology with potentially important modifying roles played by mucosal defensive factors, the effectiveness of esophageal acid clearance, and differences in the causticity of refluxate, the key event in the pathogenesis of GERD is reflux of noxious substances from the stomach into the esophagus. The modifiers alluded to above may change the threshold that distinguishes asymptomatic reflux from symptomatic reflux in terms of the number of reflux events required, but, regardless, reflux events are a prerequisite for the development of GERD. Under normal circumstances, gastroesophageal reflux is prevented by an antireflux barrier located at the gastroesophageal junction.
The antireflux barrier is an anatomically complex zone whose integrity has been attributed to lower esophageal sphincter (LES) pressure, extrinsic compression of the LES by the crural diaphragm, the intra-abdominal location of the LES, the phrenoesophageal ligament and maintenance of an acute angle of His. Although there is probably some merit to each of these possibilities, supporting evidence is more compelling in some cases than in others. Quite possibly, competence of the antireflux barrier is attributable to multiple factors and progressive incompetence occurs as more antireflux mechanisms are disabled. The antireflux barrier needs to be dynamic because it must guard against reflux in a variety of circumstances. For example, the intra-abdominal segment of the LES may be important in preventing reflux during swallowing, the diaphragmatic crus may be of cardinal importance during abdominal straining and resting LES pressure may be of primary importance during restful recumbency. The rate at which reflux events are incurred would then increase progressively as each of these protective mechanisms is compromised.
The complexity of the antireflux barrier has led investigators to a variety of conclusions regarding which is the most important mechanism of reflux. The three different prevailing opinions are that the dominant mechanism of reflux is by transient lower esophageal sphincter relaxations, a result of anatomic disruption of the diaphragmatic sphincter probably associated with a hiatal hernia, or simply a result of a hypotensive LES. Individuals can be found exemplifying each of these mechanisms; however, what proportion of the entire GERD population can be attributed to each mechanism remains a hotly debated issue. Rather than argue their relative importance, the aim of this discussion is to relay the evidence for these impairments of the antireflux barrier.
Transient lower esophageal sphincter relaxations
Studies in normal volunteers  and in GERD patients [2-4] have demonstrated the phenomenon of transient lower esophageal sphincter relaxation (tLESR). The descriptor "transient" distinguishes a tLESR from a swallow-induced LES relaxation. Transient LESRs appear without an antecedent pharyngeal contraction, persist for longer periods (5-30 s) than do swallow-induced LES relaxations, and are generally unaccompanied by esophageal peristalsis. There is compelling evidence that tLESRs account for the majority of reflux events in normal individuals or in patients with normal LES pressure at the time of reflux. However, the likelihood of reflux during a particular tLESR is influenced by both the circumstances of the recording and the temporal proximity to a meal, with different investigators reporting reflux during as many as 93%  or as few as 9-15% [5,6] of tLESRs. What has become increasingly clear is the role of tLESRs as a component of the belch reflex [7,8], The frequency of tLESRs is greatly increased in humans [7,8] or dogs  by distension of the stomach by gas as it is in the upright as opposed to the supine posture . Some investigators have suggested that tLESRs are "subthreshold swallows" in response to pharyngeal stimulation in the opossum  or humans. However, other investigators find no more than a chance co-occurrence of minor submental EMG activity and tLESRs . In view of the circumstances in which they appear, it seems most likely that tLESRs are a physiologic response to gastric distension by food or gas and are the mechanism responsible for gas venting of the stomach.
Hypotensive lower esophageal sphincter
The LES is a 3-4 cm long segment of tonically contracted smooth muscle at the distal end of the esophagus. Resting tone of the LES normally varies from 10 to 30 mmHg relative to intragastric pressure. Lower esophageal sphincter pressure is lowest in the postprandial period and highest at night . Intra-abdominal pressure, gastric distension, peptides, hormones, various foods, and many drugs affect the LES pressure. The mechanism of LES tonic contraction seems to be a property of the muscle itself rather than of nerves affecting the sphincter. Pressure within the
sphincter is minimally affected following the elimination of neural activity by close intra-arterial injection of tetrodotoxin . Furthermore, biochemical evidence suggests that the properties of the sphincter are defined by properties of the circular muscle. Nonetheless, 50-70% of LES tone of humans can be inhibited by atropine . Such influences may be especially important in modification of closure force in response to stimuli such as feeding and fasting.
Diminished LES pressure can be associated with gastroesophageal reflux by two mechanisms, stress reflux and free reflux. Stress reflux results when a relatively hypotensive LES is overcome and "blown open" by an abrupt increase of intra-abdominal pressure. Substantial data have accumulated suggesting that stress reflux is unlikely when the LES pressure is greater than 10 mmHg [2,4,6]. However, it should be noted that these studies were not controlled for the potential effect of a hiatal hernia and a recent investigation suggests that for a given LES pressure, the susceptibility to stress reflux is directly related to the presence and size of hiatal hernia . The other mechanism by which diminished LES pressure is associated with gastroesophageal reflux is free reflux. Free reflux is characterized by a fall in intraesophageal pH, without an identifiable change in either intragastric or LES pressure observed when the resting LES pressure is within 0-4 mmHg of intragastric pressure [2,4],
A puzzling clinical observation supporting the importance of tLESRs is that only a minority of individuals with GERD have a hypotensive LES when determined by isolated fasting measurements [15,16]. This observation can be somewhat reconciled when one considers the dynamic nature of LES pressure. The isolated fasting measurement is probably useful only in identifying patients with a grossly hypotensive LES who are constantly susceptible to stress reflux. However, there is probably a larger group of patients with mild or moderate GERD susceptible to stress reflux when their LES pressure has been temporarily diminished as a result of specific foods, drugs, or habits [2,6].
Hiatal hernia and the diaphragmatic sphincter
Manometric recordings of LES pressure are often characterized by inspiratory augmentation previously attributed to catheter movement. However, more recent evidence in both cats and humans suggests that these inspiratory increases result from contraction of the diaphragmatic crus that encircles the LES . Despite pinning the manometric catheter in place, the inspiratory augmentation of LES pressure persists. The amplitude of respiratory oscillations increases with increased respiratory effort and are eliminated by manual hyperventilation. The augmentation of LES pressure observed during sustained inspiration, corresponds both temporally and quantitatively with the augmentation of crural EMG activity and this augmented LES pressure is observed to obscure the intrinsic LES relaxation induced by esophageal distension . Intrinsic LES tone is equivalent to manometrically recorded end expiratory tone, suggesting that in normal circumstances the diaphragm contributes only to the inspiratory augmentation of LES pressure.
The physiologic relevance of the augmentation of gastroesophageal junction pressure attributable to the crural diaphragm pertains to the condition of hiatal hernia, a condition that may be associated with its anatomic disruption. Observations of the antireflux mechanism during stress maneuvers such as leg raising and abdominal compression suggest a "pinchcock effect" of crural contraction that effectively augments the antireflux barrier . Patients with a substantial hiatal hernia, regardless of whether or not they had a hypotensive LES, have been shown to incur an increased number of acid reflux episodes in response to these same stress maneuvers .
3. Dodds WJ, Kahrilas PJ, Dent J, Hogan WJ, Kern MK, Arndorfer RC. Analysis of spontaneous gastroesophageal reflux and esophageal acid clearance in patients with reflux esophagitis. J Gastroint Motil 1989;2:79.