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February 1990, Volume 40, Issue 2

Review Articles

PATHOPHYSIOLOGY OF GASTROESOPHAGEAL REFLUX: A COLLECTIVE REVIEW

Mohammed H.B. Khoshim  ( Department of Surgery, College of Medicine and King Khalid University Hospital, King Saud University, P.O. Box 7805, Riyadh 11472, Saudi Arabia. )

Gastroesophageal reflux is a very common disease. Almost everybody experiences heartburn from time to time but with different degree of severity. How does reflux occur, and which factors encourage or work against reflux is a very con­troversial matter. This article covers all controver­sial issues about the pathophysiology of gastroeso­phageal reflux and discusses the old and recent understanding of the disease.

PHYSIOLOGY

Esophageal Peristalsis
The esophagus functions primarily to con­duct food from the pharynx to the stomach. It has two types of peristaltic movements1, primary and secondary, where the former is simply a continua­tion of the peristaltic wave that begins in the pharynx, spreads down the esophagus, and reaches the stomach in 5 to 10 seconds2. However, the food usually reaches the stomach a little quicker due to the additional effect of gravity2. The secondary peristalsis originate in the esophagus in response to any food retained in the esophagus. Both types of peristalsis are controlled by the vagal reflexes3.
The lower esophageal sphincter (LES)
This is a zone of increased pressure, about 3 to 5 cm long, at the lower end of the esophagus4,5. Like the upper sphincter, it is always in a state of contractions6, generating this high pressure zone to prevent the reflux of stomach contents into the esophagus. The sphincter relaxes with swallowing and returns back to its high basal pressure as the wave of peristalsis passes. There has been considerable controversy regarding the nature of this sphincter, and the way it generates this high pressure inspite of the fact that there is no anatomical component to this sphincter. At this time7 it appears that the basal LBS pressure is due to its intrinsic myogenic activity and that the increase in pressure (contrac­tion) or the decrease in pressure (relaxation) is under neural and hormonal mechanisms7. The neural control is through the vagus nerve which transmit both excitatory and inbibitory impulses to the sphincter8-11, so both contraction and relaxation is due to these neural impulses, which is now believed to be modulated also by the sympathetic nerves9. The basal tone, however, is not dependent on the vagal innerva­tion10, as it has been shown that cutting the vagi does not abolish the basal LBS pressure in either animals12 or humans13. The basal LBS pressure also is not dependent on the high intra abdominal pressure as the basal LES pressure is maintained when the LBS happens to lie above the diaph­ragm14. The hormonal factor15 has been studied in detail in the last 20 years, and many agents were found either to raise or lower the basal LBS pressure. These are shown6 in Table.

The LBS maintains the ability to raise its resting tone in response to any increase in the intragastric pressure, and this h believed to be mediated by the vagus nerve13,16. However, others still think that this is mainly due to the mechanical compression by the diaphragm or other anatomi­cal structures17,18. The LBS pressure is asymmetric19,20 in both its length and pressure profile. At the lower half, higher pressures are observed on the left side, which is again probably a reflection of the anato­mical position of the distal esophagus. Normal values are thus approximations, usually in the range of 15mm Hg to 22mm Hg and is affected by inspiration also, being higher with inspiration and lower with expiration21.
Pathogenesis of gastroesophageal reflux
A positive pressure gradient exists between the abdominal and thoracic cavity, where the mean pressure in the thoracic esophagus is —15mm Hg to + 5mmHg2 and the mean pressure in the fundus and proximal stomach ranges from 7 mmHg to 50mmHg and is increased while strain­ing and coughing22. Therefore mechanisms must exist to prevent the gastroesophageal reflux.
Defense mechanisms against gastroesophageal reflux
Before 1953, when the presence of the LES was demonstrated by Butin and Sanchez4,5 anatomical factors were thought to be the sole mechanism against GE reflux23. Currently the wide spread belief is that multiple factors must be working together in preventing GE reflux6,24-29 like:
1. Anatomical factors
Although the presence of an anatomical sphincter has been postulated30, the consensus of opinion to date is that no such sphincter really exists31. The different anatomical factors that are thought to help against reflux have been divided into two groups. The first group, called the possible valve mechanism group, include: a mucosal flap32 flutter valve33 acute esophago gastric angle33 , compression by gastric sling fibers34 and the mucosal choke hypothesis proposing that adhesive mucosal forces exist during sphincter closure and help resist its open­ing25. The second group consists of mechanical factors that compress the distal esophagus at or near the hiatus. These include: the diaphragmatic pinch cock35, the phrenoesophageal ligaments35,36. the sling action of the right crus of the diaphragm37,38 and the abdominal segment of the esophagus37,39 being surrounded by the positive intra abdominal pressure.
What gave the anatomical factors even more importance are the facts that:
a. The LES pressure is radially asymmetric19,22 which cannot be accounted for by intrinsic squeeze alone, which theoretically should be symmetrical. This invites the idea of some mechanical factors28 affecting the LES pres­sure.
b. The fact that a modest high pressure zone exists at the hiatus level even when the LES herniates into the chest38,40, forces the idea that the extrinsic diaphragmatic forces must contribute to the intraluminal pressure measured at the hiatal level, when the LES is located within the hiatus.
c. It has been found that when the LES pres­sure is reduced by atrophine, reflux is not enhanced41,42 and that during relaxation of the sphincter, reflux is not always occurring which could be the enhancement of other mechanical factors.
d. The fact that there is an overlap in the LES pressure values between symptomatic and asymptomatic patients suggests the role of factors other than LES pressure alone.
For a long time, hiatus hernia has been thought of as a major factor in the production of reflux. This assumption was based on the high incidence of sliding hiatal hernia in patients with gastroesophageal reflux43,44 and according to this assumption, the mechanical factors described above are disrupted by the presence of such hernia35,45. Others, however, have negated the above assumption by providing the following facts: First, 30% to 50% of the general population have hiatus hernia, and yet only 5% have sig­nificant reflux46. Second, hiatus hernia may be the result of esophagitis caused by reflux47,48. Third, that LES pressure which is considered now as the main factor against reflux is not affected by its anatomical position, as it maintains its com­petence in the chest as well14. Fourth, even if we believe the assumption that hiatus hernia disrupts the anatomical factors, these factors themselves are only one acting defense force among the other five more important forces, which negate the attractive idea that hiatus hernia is a major cause of gastroesophageal reflux. Currently, the presence of hiatus hernia is believed not to be an important issue in the clinical evaluation of patients with gastroesophageal reflux49 and at best is a very minor factor in the production of gastroesophageal reflux50,27.
2. The lower esophageal sphincter: LES
Since early reports about the existence of the lower esophageal sphincter in man4,5,50-52, a great deal of research about the subject has occurred25-27,30,41,53 where the innervation, and the hormonal control of the LES sphincter have been studied in detail. While twenty five years ago, anatomical factors were solely believed to be the main barrier against reflux23, it is now generally accepted that the major abnormality in patients with gastroeso­phageal reflux is the incompetence of the LES54-56. The causes of this incompetence are not known. Cohen37 has postulated that it may result from alterations of one or more of the mechanisms responsible for the sphincter competence and so it could result from abnormalities in the muscle, neural fibers, or gastrointestinal neuropeptides, alone or in combination, and so reflux can occur from decreased tonic activity of excitatory nerves or atrophy of the circular muscle layer as in scleroderma57 or from a functional disorder of the circular muscle induced by circulating hor­mones27. Others have shown that GE reflux itself can damage the cholinergic innervation of the LES and the muscularis propria of the esophagus58. Practically speaking, reflux usually occurs in the recumbent position, while asleep, and in the fasting state and this is due to the decrease in the basal LES pressure which is found inmost patients with symptomatic gastroesophageal reflux. The reduction is usually below 10mmHg and can be as low as 2 or3mmHg. In some patients, reflux occurs while doing exercise, bending over, straining, or wearing tight garments or corsets, and this is explained by the fact that patients with gastroesophageal reflux don’t have the adaptive mechanism that allows the LES pressure to in­crease to a greater degree when the intra ab­dominal pressure is increased during the above mentioned conditions. This adaptive response has been demonstrated clearly in healthy patients. However, its nature is still debated whether it is a neurogenic reflex13,16,59 or purely a mechanical event17,18,60. Although the concept of the LES as the major barrier against reflux is generally ac­cepted54-56,61 and seems attractive, it has come under attack because of some of the discrepancies that have been found with the measurement of the LES pressure. In at least 25% of patients with reflux the basal LES pressure is in the normal range62,63. This has been explained28 by the fact that the basal LES pressure as measured in the laboratory may not always reflect the pressure that is present when the reflux occurs, which is again affected by so many hormones, and the type of diet, e.g., fat, alcohol, etc. It can also be attributed to the fact that the sphincter tone varies considerably during the day, which means that a single measurement does not necessarily reflect the daily events. In a recent study64 using prolonged intraesophageal PH and pressure monitoring, they showed that reflux occurred primarily when the sphincter pressure was low and that transient relaxation of the sphincter was responsible for the reflux eso­phagitis present in some of their patients with the LES pressure within the normal range. Another point is the occurrence of occasional reflux in healthy subjects, that have normal LES pressure, this was clarified again in many studies64-66 where it was shown that transient relaxation of LES that occurred most frequently in subjects with normal LES pressure was responsible for 98% of the reflux episodes, and these were not related to swallowing which is also known to produce tran­sient relaxation of the LES.

ESOPHAGEAL CLEARANCE

Another important line of defense against gastroesophageal reflux and its consequences like esophagitis is the efficacy of esophageal clearance, which determines the duration of esophageal exposure to the noxious reflexed material, and the severity of esophagitis produced67-69. Esophageal clearance depends on three factors, one is the effect of gravity70 second is primary and secondary peristalsis71. third is saliva72. During sleep, however, swallowing cease almost completely73 and the only mechanism available would be secondary peristalsis as the effect of gravity also disappears while awake, primary peristalsis, elicited by swallowing is the main factor that clears the esophagus66 and al­though gastroesophageal reflux often elicits secondary peristalsis, the major mechanism elicit­ing peristalsis is the high frequency of swallow­ing and so primary peristalsis protects against reflux while the person is awake64 and secondary peristalsis works during sleep70. Saliva is found to promote acid clearance from the esophagus72 which can be attributed to the fact that it has a diluent and washing effect, and with its bicar­bonate content (Ph of 7) can neutralize acid very well, in addition, it elicits deglutination71. In patients with reflux, the abnormality is in the increased incidence of non peristaltic contrac­tions at the lower esophagus which cause ineffec­tive clearance of acid7475.
Gastric volumes
It has been shown that as gastric secretory volume is increased, gastroesophageal reflux is increased too76 and that reflux increase sig­nificantly after meals64,77. Gastric volume can be increased due to the following53, (a) volume and composition of ingested material, (b) rate of gastric secretion, (c) rate of gastric emptying, and (d) rate and volume of duodenogastric reflux. So reflux is increased with large meals and fatty foods which in addition to lowering the LES pressure, take longer time to leave the stomach, and thus lead to more reflux78. Patients with duodenal ulcer also have high incidence of reflux disease79 probably because of increased acid volume in the stomach. Delayed gastric emptying80 and im­paired antral motility81,82 has been reported in up to 40 percent of patients with GE reflux, so more volume is available for reflux. Duodenogastric reflux leads to increased volume of the stomach and provides more of the harmful bile to the gastric juice83,84.
Potency of reflux material
The composition of reflux material is very important in determining the severity of symp­toms of gastroesophageal reflux and the degree of esophagitis26,27. It has been shown for example that bile with the gastric acid and pepsin can be more harmful and together form a potent com­bination that leads to reflux disease84 as bile increases the permeability of esophageal mucosa to Hcl85.
Mucosal resistance
The esophageal mucosa is very sensitive to damage from acid, pepsin or bile salts, and the degree of damage may depend on the ability of the mucosa to regenerate.

REFLUX ESOPHAGITIS

Reflux esophagitis is a well documented manifestation of gastroesophageal reflux27,31,86,87 and the severity of the esophagitis parallel the severity of the reflux. Some aspects remain con­troversial. Many cases are known where reflux can be demonstrated radiologically and symptoms are very severe yet with no evidence of esophagitis88 on endoscopy. Other cases show severe esopha­gitis with the patient having minimal symptoms. This has been explained by the fact that eso­phagitis has so many factors that help against it such as the mucosal resistance of the esophagus49. its clearance ability, and the saliva71,72 which make the injury variable from person to person. Esophagitis usually starts with very minimal chan­ges in the basal cell layer of the epithelium, where the mucosa appears grossly normal on endos­copy89. There is increased activity and increased thickness of the basal layer; however, eventually superficial ulceration supervenes, followed by deep ones, this invites healing by granulation tissue which lead to stricture formation.

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