Primary Motility  Disorders of the  Esophagus
 The Esophageal
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 Barrett's
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OESO©2015
 
Volume: The Esophagogastric Junction
Chapter: GER and barrier dysfunction
 

Is pepsin concentration related to the amount or duration of acid exposure?

How can the delayed acid clearance observed in gastroesophageal reflux disease patients with hiatal hernia be interpreted?

R.L. Brown, J. Sarosiek, R.W. McCallum (Kansas City)

Pepsin is produced in its proenzyme form (pepsinogen) within the chief cells located deep in the glands of the gastric body. High performance ion chromatography has characterized five subgroups of human pepsin [1]. Pepsin acts as a potent proteolytic enzyme cleaving proteins into peptides in the gastric lumen at a low pH. Food related chemical and mechanical factors initiated stimulate acid secretion that is accompanied by the release of pepsinogens from the chief cell. Pepsinogens are rapidly converted to pepsin in the acidic milieu. Due to its proteolytic quality, pepsin is potentially injurious to alimentary tract mucosa [2].

The role of pepsin in gastroesophageal reflux disease (GERD) has been well studied in animals and humans. In 1969, Goldberg concluded that the combination of HCl and pepsin was responsible for injury to the intact feline esophagus [3]. In this study, esophageal damage occurred with either a very high concentration of acid (pH 1.0 - 1.3), or lower acid concentrations (pH 1.6 - 2.0) in the presence of pepsin. No esophageal injury was noted at pH > 2.3. Therefore, although high concentration of acid alone could cause esophagitis
(pH < 1.3), the addition of pepsin was necessary to cause esophagitis in the physiologic range of gastric pH (pH 1.6 - 2.0). Based on these results, Goldberg concluded that the key caustic agent in reflux esophagitis was pepsin, and the primary role of HCl was to provide an acidic environment in which pepsin was optimally active. Goldberg also noted that the concentration of pepsin above a specific threshold produced no further esophageal injury. In 1982, Lillemoe et al. corroborated that an acid infusion alone did not induce changes in mucosal permeability, but the addition of pepsin was necessary to induce these changes [4].

Whether gastric secretion rates of HCl and pepsin predispose a patient to esophagitis is controversial. While Hirschowitz indicated no increased risk of esophagitis in patients with higher gastric secretions of acid and pepsin [5], Mulholland et al. found patients with Barrett's esophagus to have higher HCl and pepsin secretion rates [6]. Likewise, Miller et al. found patients with Zollinger-Ellison syndrome to have significantly higher rates of esophagitis than controls [7]. The risk of esophagitis directly relates to the duration of exposure to HCl and pepsin. Studies measuring acid and pepsin in the esophagus have shown a correlation between acid and pepsin exposure and the degree of esophagitis. Using an esophageal aspiration technique, Bremner et al. found significantly higher amounts of acid in the distal esophagus of those patients with esophagitis [8]. Similarly, Gotley et al. found esophageal pepsin concentrations in patients with complicated GERD (stricture and Barrett's) to be higher than in those with uncomplicated GERD [9].

Despite definitive evidence implicating pepsin and HCl as the most significant aggressive factors in GERD, it is important to realize that the amount of exposure does not always correlate directly with the amount of esophageal injury. Other variables like salivary and esophageal protective factors probably account for the variability of esophageal damage in patients with GERD. These salivary and esophageal protective factors are influenced by pepsin and HCl. Our group found that esophageal prostaglandin E2 (PGE2) release is significantly impaired in normal controls after infusion of HCl and significantly enhanced after the addition of pepsin [10]. We propose this phenomenon occurred secondary to the retention of PGE2 in the esophageal mucous layer after HCl exposure and subsequent release of PGE2 after digestion of the mucous layer by pepsin [11] (Figure 1). Additionally, we found patients with reflux esophagitis to have significantly reduced release of esophageal epidermal growth factor (eEGF) in response to perfusion with saline, HCl, and HCl/pepsin indicating a possible defect in local protection [12].

Reflux of duodenal contents has also been implicated in the pathogenesis of GERD. Recent evidence indicates that duodenogastric reflux may cause reflux symptoms but must coexist with acid and pepsin to induce esophageal injury [13]. A recent study by Sears and Richter found aggressive acid suppression with omeprazole 20 mg twice daily to dramatically reduce the amount of gastroduodenal reflux as measured by bilirubin absorbance [14].

Figure 1. The role of the mucous layer in the esophageal mucosal barrier. (From [12].)
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Effective acid clearance plays a vital role in protection of the esophagus from potential injury. Knowing that acid and pepsin are damaging to the esophagus, the duration of acid exposure correlates with the severity of GERD. On average, reflux patients have acid clearance times that are two to three times longer than those of normal controls [15, 16]. Clearance of gastric refluxate from the esophagus occurs via two mechanisms: primary large volume clearance by esophageal peristalsis, and salivary buffering of the residual acid in the distal esophagus. Defects in either of these mechanisms promote GERD. Patients with abnormal esophageal peristalsis (scleroderma) develop more GERD, and patients with prolonged acid exposure tend to develop peristaltic dysfunction that correlates directly with esophagitis [17]. The reversibility of esophageal motor impairment in GERD patients has not been agreed upon. Some authors suggest a return of normal esophageal motility after fundoplication [18], while more recent evidence indicates a more permanent impairment of motor function [19, 20].

The role of hiatal hernia in GERD is controversial. Although only about one half of the patients that have hiatal hernias have esophagitis by endoscopy, most patients with esophagitis have hiatal hernias [21]. One postulated mechanism by which hiatal hernia cause reflux esophagitis is a delay of normal acid clearance from the esophagus. The role of hiatal hernia in acid clearance has been studied by our group [22]. By using concurrent pH recording and esophageal scintiscanning comparing a group of reflux patients with and without hiatal hernias, we found the hiatal hernia patients to have delayed acid clearance secondary to a re-reflux phenomenon from the hernia sac during swallowing (Figure 2). This re-reflux characteristic was seen in fifteen out of the twenty hiatal hernia patients that were studied.

Figure 2. Effect of hiatal hernia on radionuclide acid clearance in a hiatal hernia subject. The subject swallowed at 30 second intervals after the injection of a 15 ml bolus of 0.1 N HCl labeled with 22 microCi of technetium sulfur colloid. The vertical axis represents the region from the sternal notch to the stomach. The horizontal axis is the time scale. Black area represents radioactivity. Soon after injection, the radioactivity is cleared to the stomach. However, note the re-reflux event occurring with each of the first three swallows as the labeled acid transiently flows back into the esophagus. (From [22] with permission.)
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In summary, GERD is a multifaceted disease. The balance of aggressive and protective factors in the esophagus probably predicts which patient will have reflux esophagitis or not. Pepsin is undeniably the most significant causative factor in GERD. The role of pepsin and its dependence on an acidic environment is well understood. Unlike acid and pepsin, the role of gastroduodenal reflux in GERD is still controversial. The contribution of other factors in the pathogenesis of GERD including impairment of local protective factors (salivary and esophageal growth factors, buffers, mucosal barriers), hiatal hernia and other mechanical features of the gastro-esophageal junction all predispose a patient to the spectrum of GERD. A great deal of work remains in defining the clinical predisposition and explaining the wide variation of clinical presentations in those patients with GERD.

References

1. Jones A, Balan K, Jenkins S, Sutton R, Critchley M, Roberts N. Assay of gastrin and individual pepsin in human gastric juice. J Clin Pathol 1993;46:254-258.

2. Tang J, Wong R. Evolution in the structure and function of aspartic proteases. J Cell Biochem 1987;3353-3363.

3. Goldberg H, Dodds W, Gee S, Montgomery C, Zboralske F. Role of acid and pepsin in acute experimental esophagitis. Gastroenterology 1969;56:223-230.

4. Lillemoe K, Johnson LF, Harmon JW. Role of the components of the gastroduodenal contents in experimental acid esophagitis. Surgery 1982;92:276-284.

5. Hirschowitz B. A critical analysis with appropriate controls of gastric acid and pepsin secretion in clinical esophagitis. Gastroenterology 1991;101:1149-1158.

6. Mulholland M, Reid B, Levine D, Rubin C. Elevated gastric acid secretion in patients with Barrett's metaplastic epithelium. Dig Dis Sci 1989;34:1329-1335.

7. Miller L, Vinayek F, Gardner J, Jensen R, Maton P. Reflux esophagitis in patients with Zollinger-Ellison syndrome. Gastroenterology 1990;98:341-346.

8 Bremner RM, Crookes P, DeMeester TR, Peters J, Stein HJ. Concentration of refluxed acid and esophageal mucosal injury. Am J Surg 1992;164:522-527.

9. Gotley D, Morgan A, Ball D, Owen R, Cooper M. Composition of gastro-oesophageal refluxate. Gut 1991;32:1093-1099.

10. Sarosiek J, Zhongjian Y, Zbigniew N, Rourk M, Hetzel D, McCallum RW. Impact of acid and pepsin on human esophageal prostaglandins. Am J Gastroenterol 1994;89:588-594.

11. Sarosiek J, McCallum RW. The evolving appreciation of the role of esophageal mucosal protection in pathophysiology of gastroesophageal reflux disease. Pract Gastroenterol 1994;28:20J-20Q.

12. Namiot Z, Sarosiek J, Rourk R, Hetzel D, McCallum RW. Human esophageal secretions: mucosal response to luminal acid and pepsin. Gastroenterology 1994;106:973.

13. Champion G, Richter JE, Vaezi M, Singh S, Alexander R. Duodenogastroesophageal reflux: relationship to pH and importance in Barrett's esophagus. Gastroenterology 1994;107:747-754.

14. Sears R, Champion G, Richter JE. Characteristics of partial gastrectomy patients with esophageal symptoms of duodenogastric reflux. Am J Gastroenterol 1995;90:211-215.

15. DeMeester TR, Johnson LF, Joseph GJ, Toscano MS, Hall AW, Skinner DB. Patterns of gastroesophageal reflux in health and disease. Ann Surg 1976;184:459-470.

16. Johnson LF. 24-hour pH monitoring in the study of gastroesophageal reflux. J Clin Gastroenterol 1980;2:387.

17. Kahrilas PJ, Dodds WJ, Hogan WJ, Kern M, Arndorfer R, Reece A. Esophageal peristaltic dysfunction in peptic esophagitis. Gastroenterology 1986;91:897-904.

18. Gill R, Bowes K, Murphy P, Kingma Y. Esophageal motor abnormalities in gastroesophageal reflux and the effects of fundoplication. Gastroenterology 1986;91:364-369.

19. Behar J, Sheahan D, Biancani P. Medical and surgical management of reflux esophagitis, a 38-month report on a prospective clinical trial. N Engl J Med 1975;293:263-268.

20. Eckardt V. Does healing of esophagitis improve esophageal motor function? Dig Dis Sci 1988;33:161-165.

21. Berstad A, Weber R, Froyshov L, Hoel B, Hauer Jensen M. Relationship of hiatus hernia to reflux oesophagitis. Scand J Gastroenterol 1986;21:55-58.

22. Mittal RK, Lange R, McCallum RW. Identification of mechanism of delayed esophageal acid clearance in subjects with hiatus hernia. Gastroenterology 1987;92:130-135.


Publication date: May 1998 OESO©2015