Primary Motility  Disorders of the  Esophagus
 The Esophageal
 Esophagogastric  Junction

  Browse by Author
  Browse by Movies
Volume: Barrett's Esophagus
Chapter: Pathophysiology

What is known about the pattern of acid exposure on differentiation in Barrett's esophagus? What is the significance of microvilli formations? What is the relationship between cell differentiation and proliferation?

R.C. Fitzgerald, R. Lascar, G. Triadafilopoulos (Palo Alto)

Acid exposure on differentiation of Barrett's esophagus

Because Barrett's esophagus develops in patients with chronic gastroesophageal reflux disease (GERD), it has been suggested that esophageal acid exposure plays an important etiologic role. Several 24-hour ambulatory pH monitoring studies have shown that patients with Barrett's esophagus have more esophageal acid exposure than healthy controls or patients with mild GERD but a degree of exposure similar to patients with severe esophagitis. The greater acid exposure in Barrett's esophagus results from longer duration of periods of acid reflux rather than from a greater number of reflux episodes; Barrett's esophagus patients have more episodes of acid reflux that persist for longer than 5 minutes [1]. The impact of acid exposure on cell proliferation and differentiation was evaluated ex vivo using biopsy specimens from Barrett's esophagus and normal esophagus [2]. In order to simulate physiologic conditions, the explants were exposed in culture to acidified medium (pH 3.5) either continuously for 24 hours or as a 1-hour pulse and compared with samples cultured in a pH 7.4 medium. Cell differentiation was quantified by Villin expression, which was present in 25% of Barrett's esophagus specimens before organ culture. After 6 or 24 hours of continuous exposure to acid, Villin expression was detected in 50% and 83% of specimens, respectively, whereas it did not increase when incubated in pH 7.4 medium. The changes in Villin expression correlated with ultra-structural maturation of the brush border, which contained long, fairly uniform microvilli on the apical surface. In contrast, Villin expression was not increased by pulse exposure to acid nor was it detected in any specimens from normal esophagus. Therefore, acid affects cell differentiation in Barrett's esophagus in a fashion dependent on the pattern of acid exposure. Continuous acid exposure promotes a differentiated phenotype, whereas pulse acid exposure favors an undifferentiated phenotype. If these data accurately reflect what happens in Barrett's esophagus, then variable patterns of esophageal acid exposure typical with reflux may be expected to contribute to the heterogeneous epithelium seen in Barrett's esophagus and the variable risk for progression to adenocarcinoma. Cells exposed to continuous acid or no acid would be expected to undergo differentiation and have a lower risk for progressing to dysplasia. These data have implications for therapy. Since continuous acid exposure rarely if ever occurs in Barrett's esophagus and patients have pulses of acid reflux at baseline, acid suppression will need to be very profound and continuous to completely abolish esophageal acid exposure and favor a more differentiated state in Barrett's esophagus epithelium.

Clinical implications

In a recent clinical study, endoscopic biopsy specimens from 42 Barrett's esophagus patients, including 14 patients with dysplasia, were analyzed before and after 6 months of treatment with lansoprazole at daily doses of 15 to 60 mg [3]. At baseline, 1 patient had endoscopic evidence of erosive esophagitis, but the rest of the patients did not have evidence of esophagitis, ulcer, or stricture. When completely asymptomatic, the patients underwent 24-hour ambulatory pH monitoring while continuing to receive proton pump inhibitor (PPI) therapy. Patients were grouped according to whether they had normalization of intraesophageal pH (n = 26) or abnormal esophageal acid exposure (n = 16). The groups were comparable with regard to patients demographics, magnitude of reflux symptoms before therapy, Barrett's esophagus segment length, presence and size of hiatal hernia, and manometric characteristics. Endoscopy specimens were analyzed for the cell proliferation marker proliferating cell nuclear antigen (PCNA) and the differentiation marker Villin. In the group of patients with normalized intraesophageal pH, PCNA expression declined significantly from a median of 22% of cells to 4.8% of cells and Villin expression increased significantly by 4-fold. In contrast, PCNA and Villin expression were essentially unchanged in the group with persisting abnormal esophageal acid exposure. There was a strong negative correlation between Villin and PCNA expression in these biopsy specimens (r = 0.79; p < 0.001). In the subset of patients with dysplasia, PCNA expression was strongly correlated with the degree of dysplasia (r = 0.76; p < 0.001), but Villin expression was unrelated. These findings indicate that dysplasia is unrelated to cell differentiation but strongly correlates with cell proliferation. It could thus be inferred that effective intraesophageal acid suppression by decreasing cell proliferation may reduce dysplasia.

This study did not find a significant reduction in dysplasia with normalization of intraesophageal acid exposure during the 6-month study period. Low-grade dysplasia (LGD) was present at baseline in four patients of the group with normalized acid exposure; it resolved in three patients and persisted in the other patient after 6 months of PPI therapy. However, indefinite dysplasia and LGD each developed in one patient. In the group with abnormal acid exposure, 1 patient had high-grade dysplasia (HGD) and 3 patients had LGD; at 6 months, dysplasia resolved in the patient with HGD and progressed to HGD in 1 patient, became indefinite in 1 patient, and regressed in 1 patient with LGD at baseline. In addition, LGD developed in 1 patient from this group. It may have been that the study duration was too short and the patients too few to yield meaningful data on the effects of reduced cell proliferation and increased differentiation on dysplasia.


Barrett's esophagus is a complex, heterogeneous epithelium on both the cellular and molecular levels. A promising area of investigation may be the exploration of the interplay between host factors such as cell differentiation, proliferation, and genetic changes and environmental factors such as esophageal acid exposure. The recent evidence [2] indicating that acid exposure in a pattern simulating reflux is associated with increased cell proliferation, which correlates with dysplasia and that proliferation can be reduced significantly by normalization of intraesophageal pH with PPI therapy is intriguing. Longer follow-up studies with larger numbers of patients will be needed to determine whether reduced cell proliferation and enhanced differentiation resulting from effective acid suppression is in fact accompanied by decreased rates of dysplasia or cancer.


1. Niemantsverdriet E, Timmer R, Breumelhof R, Smout AJPM. The roles of excessive gastro-oesophageal reflux, disordered oesophageal motility and decreased mucosal sensitivity in the pathogenesis of Barrett's oesophagus. Eur J Gastroenterol Hepatol 1997;9:515-519.

2. Fitzgerald RC, Omary MB, Triadafilopoulos G. Dynamic effects of acid on Barrett's esophagus. An ex vivo proliferation and differentiation model. J Clin Invest 1996;98:2120-2128.

3. Ouatu-Lascar R, Fitzgerald RC, Triadafilopoulos G. Differentiation and proliferation in Barrett's esophagus and the effects of acid suppression. Gastroenterology 1999;117:327-3 35.

Publication date: August 2003 OESO©2015