Primary Motility  Disorders of the  Esophagus
 The Esophageal
 Esophagogastric  Junction

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Volume: Barrett's Esophagus
Chapter: Markers

The development of apoptosis as a consequence of experimental duodeno-gastroesophageal reflux

V. Schumpelick, B. Dreuw, N. Ponschek, K. Ophoff, J. Nutzmann (Aachen)

Gastroesophageal reflux disease (GERD) is one of the most frequent gastrointestinal disorders with the main symptoms being heartburn, chest pain and regurgitation. Usually theses symptoms are successfully treated with antacids or acid suppression therapy. However, in a considerable percentage of people, these occasionally symptoms progress to a life affecting disease, that requires inconvenient life style modifications and dietary restrictions in addition to long-term medical therapy. Moreover, the abnormal reflux damages the esophageal mucosa and leads to esophagitis. If reflux persists, esophagitis may progress and complications such as ulcers, strictures, bleeding or Barrett's esophagus may occur. The chronic inflammation will finally damage esophageal motility and leave an organ with complete loss of physiological function.

Recent epidemiologic [1] and experimental work [2-7] supports the hypothesis that chronic GERD has a malignant potential. The exact mechanisms, however, are unknown up to date. Obviously, alkaline reflux in the form of pancreatic secretions with potentiated effects in combination with bile plays an important role [7]. The sequence of events, finally ending in malignant transformation, are increased gastroesophageal reflux (GER) - esophagitis - ulceration - intestinal metaplasia with replacement of squamous epithelium by cylindric epithelium (Barrett's esophagus) - dysplasia - carcinoma. Very interesting in this context is the experiment finding that acid gastric secretion may have a protecting effect against the development of esophageal adenocarcinoma [8]. Long-term medical antacid therapy alone would be therefore ineffective in a double way: it leaves the alkaline reflux untreated, although lowering the extent [9], and reduces the protecting gastric acid environment.

In a recent study Wykypiel et al. found in 39 patients with GERD at different stages and defective lower esophageal sphincter (LES) increased levels of apoptosis compared to normal esophageal mucosa. This finding indicates that the mechanism of apoptosis, which is a physiological mechanisms that protects the organism against uncontrolled growth of cells, is activated by increased GER. Furthermore, in the same study, the increased apoptosis levels fell down to control levels after successful antireflux surgery. The pathogen noxes leading to apoptosis must therefore be searched in the refluxing material. On the other hand, antireflux surgery effectively eliminates these noxes. To our knowledge this is not shown today for medical therapy of GERD.

The study of Wykypiel has shown another remarkable result. Although Barrett's esophagus is an end stage in GERD, the authors did not found increased apoptosis rates in the specialized columnar epithelium of their Barrett's patients. However, in the squamous epithelium surrounding the Barrett mucosa, they found elevated apoptosis rates that changed to normal following antireflux surgery. This may indicate that during the process of reflux induced mucosal damage and consecutive metaplasia, the protective mechanism of apoptosis has been lost. The oncogen p53 seems to play a central role for this. Physiologically, p53 induces apoptosis, but p53 is early mutated in the development of Barrett' esophagus. This process, once initiated, cannot be stopped even when the responsible noxes are eliminated. The progression of Barrett esophagus, however, may be stopped. It is our impression that such findings underline the fact that the diagnosis of Barrett's esophagus without dysplasia but manometric defect of the LES should urgently lead to successful antireflux surgery as long as similar results from medical therapy are missing. This is especially important because the incidence of the adenocarcinoma at the gastroesophageal junction is constantly rising [10].

Elimination of the Barrett mucosa by photodynamic therapy, argon plasma coagulation, ultrasound ablation or other methods prior to antireflux surgery is under discussion today. Taking into account the benefit and risks, such a procedure can only be advised for patients with well documented low-grade dysplasia. After antireflux surgery, mucosal ablation is much more difficult. HGD, with the risk of an already existing malignant degeneration in up to 45%of cases [11], justifies surgical resection or close endoscopic follow-up with and without mucosal ablation.


1. Lagergren J, Bergstrom R, Lindgren A, Nyren O. Symptomatic gastroesophageal reflux as a risk factor for esophageal adenocarcinoma. N Engl J Med 1999;340(11):825-831.

2. Attwood SE, Smyrk TC, DeMeester TR, Mirvish SS, Stein HJ, Hinder RA. Duodenoesophageal reflux and the development of esophageal adenocarcinoma in rats. Surgery 1992;111(5):503-510.

3. 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(3):252-261.

4. Fein M, Ireland AP, Ritter MP, Peters JH, Hagen JA, Bremner CG, DeMeester TR. Duodenogastric reflux potentiates the injurious effects of gastroesophageal reflux. J Gastrointest Surg 1997;1(1):27-33.

5. Fein M, Peters JH, Chandrasoma P, Ireland AP, Oberg S, Ritter MP, Bremner CG, Hagen JA, DeMeester TR. Duodenoesophageal reflux induces esophageal adenocarcinoma without exogenous carcinogen. J Gastrointest Surg 1998;2(3):260-268.

6. Pera M, Cardesa A, Bombi JA, Ernst H, Pera C, Mohr U. Influence of esophagojejunostomy on the induction of adenocarcinoma of the distal esophagus in Sprague-Dawley rats by subcutaneous injection of 2,6dimethylnitrosomorpholine. Cancer Res 1989;49(23):6803-6808.

7. Pera M, Trastek VF, Carpenter HA, Fernandez PL, Cardesa A, Mohr U, Pairolero PC. Influence of pancreatic and biliary reflux on the development of esophageal carcinoma. Ann Thorac Surg 1993;55(6):1386-1392.

8. Ireland AP, Peters JH, Smyrk TC, DeMeester TR, Clark GW, Mirvish SS, Adrian TE. Gastric juice protects against the development of esophageal adenocarcinoma in the rat. Ann Surg 1996;224(3):358-370.

9. Marshall RE, Anggiansah A, Manifold DK, Owen WA, Owen WJ. Effect of omeprazole 20 mg twice daily on duodenogastric and gastro-oesophageal bile reflux in Barrett's oesophagus. Gut 1998;43(5):603-606.

10. Pera M, Cameron AJ, Trastek VF, Carpenter HA, Zinsmeister AR. Increasing incidence of adenocarcinoma of the esophagus and esophagogastric junction. Gastroenterology 1993;104(2):510-513.

11. Wright TA. High-grade dysplasia in Barrett's oesophagus. Br J Surg 1997;84(6):760-766.

Publication date: August 2003 OESO©2015