Tierexperimentelle Untersuchungen zur Karzinogenese durch duodenogastralen Reflux

Abstract

Background: The fact that the incidence of Barrett carcinoma is rapidly increasing has renewed interest on the mechanisms of carcinogenesis induced by duodenogastric reflux (DGR). The aim was to investigate whether DGR is carcinogenic in the rodent esophagus and whether carcinogenesis is caused by nitroso bile acids. Methods: Experiment I: 77 Sprague-Dawley rats (8 weeks old) were operated in three groups: (A) Esophagojejunostomy to induce mixed reflux of acid and DGR; (B) gastrectomy and esophagojejunostomy to induce DGR alone; and (C) gastrectomy and Roux-en-Y reconstruction to divert reflux. The incidence of columnar lining and carcinoma was compared after 16 weeks. Experiment 2: Preop, 2 and 6 weeks after operation DGR was analyzed for bacterial contamination with standard methods, for bile acids and nitroso compounds with high performance liquid chromatography coupled with mass spectroscopy (HPLC-MS), and for genotoxicity with the micronucleus test (n = 15). Results 1. DGR induced columnar lining in 85% and adenocarcinoma in 48% of the animals with reflux (A + B). There was no difference between group A and B. The control group C had significantly less columnar lining and adenocarcinoma. 2. Elimination of the food passage through the stomach resulted in bacterial overgrowth with fecal bacteria (E. coli, proteus, enterococcus). In each sample, primary and secondary bile acids were identified by HPLC-MS. Despite using highly specific techniques nitro so compounds were not detected (selective reaction monitoring, detection limit < 1 ‰ of bile acid concentration). In the micronucleus test DGR was cytotoxic, but not genotoxic. Conclusion: DGR is carcinogenic in the rodent esophagus. The nitrosation of bile acids could be excluded as the relevant mechanism of carcinogenesis. The observed cytotoxicity suggests that chronic inflammation of the esophageal mucosa is the main mechanism of carcinogenesis induced by DGR. Chronic esophageal injury is caused by bile acids and pancreatic enzymes in DGR which act synergistically with acid reflux.