Longterm Effects of Chronic Hypergastrinemia on gastric mucosal endocrine cells

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Chronic hypergastrinemia causes proliferation of enterochromaffin-like cells (ECL cells) which can process to the development of carcinoid tumors, some of which are malignant. With the increased chronic use for common conditions such as gastroesophageal reflux disease (GERD), of H-+-K-+ ATPase inhibitors (omeprazole, etc.), which are potent acid suppressants and cause hypergastrinemia in <80% of patients, there is increased concern over the longterm gastric effects on ECL cells of chronic hypergastrinemia. Currently, it is unclear in humans, the time course of changes with hypergastrinemia in ECL cells, their severity with prolonged treatment, factors that contribute to carcinoid development or the best means to identify gastric carcinoids. Patients with Zollinger-Ellison syndrome (ZES) have life-long hypergastrinemia because most are not cured and therefore are excellent models to study these gastric effects. Furthermore, 25% of patients with ZES have MEN-1 which predisposes them to the development of gastric carcinoids and hence have accelerated development of these tumors. To address the frequency and severity of gastric ECL changes that occur with chronic hypergastrinemia, the frequency of carcinoid tumors, the best methods to detect them and the identification of contributing factors, a prospective study has been started. This study involves systematic gastric biopsies at regular intervals from 8 fixed areas in the stomach on a large cohort of patients with ZES. Furthermore, similar studies are being performed on patients with chronic atrophic gastritis, which also results in chronic hypergastrinemia. All biopsies are analyzed for changes in the ECL cells, the degree of inflammation, morphologic changes and changes in other proteins that may parallel the extent of ECL changes or contribute to their proliferations such as the expression of alpha-HCG. All high risk patients also undergo gastric endoscopic ultrasonography (EUS) to attempt to localize carcinoid tumors. Comparison of the ability of biopsy, endoscopy and EUS to assess advanced ECL changes and the location and extent of gastric carcinoid tumors will be possible from this study. This study should allow definition of the time course, extent of ECL change as well as the definition of the best methods to follow patients with chronic hypergastrinemia to detect carcinoid tumors and assess their extent.