Primary Motility  Disorders of the  Esophagus
 The Esophageal
 Esophagogastric  Junction

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Volume: Barrett's Esophagus
Chapter: Diagnosis

Can the diminution in heartburn symptomatology be explained by impairment in esophageal glycoconjugate (predominantly mucin) secretion?

M. Marcinkiewicz, C. Poplawski, T. Zbroch, Z. Namiot, J. Sarosiek (Kansas City)

This apparently contradictory title has to be addressed within two dimensions: 1) esophageal glycoconjugate (predominantly mucin) secretion in patients with reflux esophagitis, and 2) esophageal glycoconjugate secretion in patients with Barrett's esophagus. It is well established that the integrity of the esophageal mucosa depends upon en equilibrium between aggressive factors and protective mechanisms [1-4]. Aggressive factors are represented by components of gastric (acid and pepsin) and duodenal (bile acids, trypsin, chymotrypsin, potentially phospholipase A2 and lysolecithin) secretions [2, 5, 6]. Protective mechanisms are operating within three overlapping defenses: 1) preepithelial, 2) epithelial, and 3) postepithelial [1, 2, 5].

Since aggressive factors in patients with gastroesophageal reflux disease (GERD) always operate from the luminal side of the esophageal mucosa, pre-epithelial defense, operating as a mucus-buffers layer, becomes the culprit of mucosal protection [1, 2, 7-11].

There are two major components of pre-epithelial defense in humans: 1) protective factors secreted by the salivary glands and, 2) protective factors elaborated within the esophageal mucosa and submucosal mucous glands [2]. Pre-epithelial mucosal defense exists as a mucus-buffer layer covering the esophageal mucosa in humans and is designated to absorb the major brunt of the injurious effects of the acid-pepsin-bile acids triad. The thickness of mucus-buffer layer is approximately 95 ▒ 12 Ám [4]. This mucus-buffer layer is capable to maintain the pH gradient from acidic on its luminal side to near neutral at its apical cell membrane perimeter [12]. This pH gradient is less potent than that recorded in the human gastric mucosa but stronger than that present within the duodenal mucosa [12]. The role of the mucus-buffer layer includes partial neutralization of hydrogen ion diffusing towards the esophageal mucosa, retardation of the rate of diffusion of hydrogen ion, prevention the diffusion of pepsin by serving as a substrate for its proteolytic activity, and retardation of diffusion of bile acids [2, 4, 7].

We have recently demonstrated that the esophageal mucosal exposure to saline resulted in a continuous release of esophageal glycoconjugate (predominantly mucin) into the perfusate [7]. This indicates a steady rate of glycoconjugate secretion from submucosal mucous glands and deposition on the surface of the mucosa. Mucus layer components, especially its architectural scaffold, glycoconjugate, were subsequently released into the perfusing solution [7]. Lowering the intraluminal pH to 2.1 resulted in inhibition of the rate of glycoconjugate release into the perfusate solution suggesting inhibition of glycoconjugate secretion from submucosal glands or inhibition of its luminal release from the mucus layer. However, the subsequent exposure of the esophageal mucosa to HCl/pepsin, mimicking the natural gastroesophageal reflux scenario, resulted in a significant increase in the rate of glycoconjugate release into the perfusing solution after partial digestion of their polypeptide core protein by proteolytically active pepsin [7].

In patients with grade II reflux esophagitis the basal rate of esophageal glycoconjugate (mucin) release was similar to corresponding values recorded in controls [11]. This rate, however, was significantly lower during the mucosal exposure to HCl/pepsin solution which suggests decline of its content within the mucus layer. This hypothesis has been confirmed by a significant decline of esophageal glycoconjugate secretion both in basal conditions and after mucosal exposure to HCl/pepsin in patients with grade III reflux esophagitis [11]. This impairment in the rate of release of the esophageal glycoconjugate persisted even after healing of endoscopic changes implying that the esophageal glycoconjugate deficiency is a preexisting condition and may facilitate the development of reflux esophagitis. This phenomenon could be of clinical relevance considering the fact that patients with endoscopically positive GERD, especially with more severe erosive reflux esophagitis, grade III, are more likely to subsequently develop intestinal metaplasia within the lower esophageal mucosal segment, and become Barrett's esophagus.

In patients with Barrett's esophagus the secretory capacity of columnar epithelium, in terms of mucin and buffers, helps the secretion from esophageal submucosal mucous glands in mucosal protection from the potential injury by refluxate. Therefore, the thickness of the mucus-bicarbonate layer is greater reaching 0.215 ▒ 0.035 Ám [4]. Although this layer is adequate for mucosal protection and even elimination of heartburn symptoms in some Barrett's esophagus patients, it fails, however, in Barrett's esophagus subjects who subsequently develop low-grade dysplasia (LGD), high-grade dysplasia (HGD) and ultimately adenocarcinoma [13]. Furthermore, patients with Barrett's esophagus who lack heartburn symptomatology are unlikely to experience enhanced salivary mucin and buffers secretion mediated by the esophago-salivary reflex, thus, may represent subpopulation with greater propensity for the development of further mucosal injury and complications. Considering the fact that two virtually constant histologic features of dysplasia are mucin depletion and prominent cytoplasmic basophilia, one may assume that the thickness of the mucus layer in patients with Barrett's esophagus accompanied by LGD and especially HGD could be further significantly compromised. The quantity and the quality of the glycoconjugate component of the mucus-buffers layer in patients with Barrett's esophagus at various stages of the development of dysplasia and adenocarcinoma requires further clinical investigation.


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6. Mittal RK, Reuben A, Whitney JO, McCallum RW. Do bile acids reflux into the esophagus? Gastroenterology 1994;92:371-375.

7. Namiot Z, Sarosiek J, Rourk RM, McCallum RW. Human esophageal secretion: mucosal response to luminal acid and pepsin. Gastroenterology 1994;106:973-981.

8. Sarosiek J, Namiot Z, Piascik R, Hetzel DP, Rourk RM, Edmunds MC, Daniel TM, McCallum RW. What part do the mucous cells of submucosal mucous glands play in the esophageal pre-epithelial barrier? In: Giuli R, Tytgat GNJ, DeMeester TR Galmiche JP, eds.The esophageal mucosa. Amsterdam, Lausanne, New York, Oxford, Shannon, Tokyo: Elsevier, 1994:278-290.

9. Rourk RM, Namiot Z, Sarosiek J, Yu Z, McCallum RW. Diminished content of esophageal epidermal growth factor in patients with reflux esophagitis. Am J Gastroenterol 1994;89:1177-1184.

10. Rourk RM, Namiot Z, Sarosiek J, Yu Z, McCallum RW. Impairment of salivary epidermal growth factor secretory response to esophageal mechanical and chemical stimulation in patients with reflux esophagitis. Am J Gastroenterol 1994;89:237-244.

11. Namiot Z, Sarosiek J, Marcinkiewicz M, Edmunds MC, McCallum RW. Declined human esophageal mucin secretion in patients with severe reflux esophagitis. Dig Dis Sci 1994;39:2523-2529.

12. Quigley EMM, Turnberg LA. pH of the microclimate lining human gastric and duodenal mucosa in vivo: studies in control subjects and in duodenal ulcer patients. Gastroenterology 1987;92:1976-1984.

13. Clark GW, Smyrk TC, Mirvish SS, Anselmino M, Yamashita Y, Hinder RA, DeMeester TR, Birt DF. Effect of gastroduodenal juice and dietary fat on the development of Barrett's esophagus and esophageal neoplasia: an experimental rat model. Ann Surg Oncol 1994;1:252-261.

Publication date: August 2003 OESO©2015