Issn Print: 0192-0790
Publication Date: 2001/07/01
Increasing Concerns About Chronic Proton Pump Inhibitor Use
Excerpt
Elevated serum gastrin levels are found in gastric hypersecretory states (such as Zollinger–Ellison syndrome and multiple endocrine neoplasia type 1), in hyposecretory conditions (acquired or iatrogenic), or occasionally without obvious explanation. Reduced gastric acid secretion (i.e., achlorhydria or profound hypochlorhydria) is, by far, the most common cause of hypergastrinemia. 1 Initially, gastrin was used as a diagnostic tool or, in the pentagastrin form, as a research stimulant for gastric secretion. As drugs demonstrating potent gastric acid inhibition were developed (H 2 -receptor antagonists, proton pump inhibitors [PPIs]), concern over drug-induced hypergastrinemia focused on trophic effects on the parietal cell mass and possible rebound hypersecretion on medication discontinuation. 2 It became apparent that the Helicobacter pylori status of the patient was of key significance, as gastrin concentrations during omeprazole therapy, for instance, are higher by 50% to 100% in the blood of H. pylori–positive patients. Helicobacter pylori infection itself has been shown to increase gastrin secretion either indirectly by inhibition of somatostatin secretion or through a direct effect on antral G cells. Helicobacter pylori infection also influences the effect of omeprazole on intragastric acidity and, therefore, the rate of antral gastrin release. 1 Finally the genotypic and phenotypic expression of cytochrome 450 (CYP2C19) determines the rate of metabolism of omeprazole and, therefore, plasma gastrin concentrations. 3 A dosage of 20 mg/d of omeprazole in a group of heterogenous extensive metabolizers (with respect to CYP2C19) increased the 24-hour intragastric pH (pH 5.5) significantly more than in a group of normal homogenous extensive metabolizers (pH 3.1), with plasma gastrin concentrations increased by 157% compared with 16%, respectively. A total of 25% to 30% of whites and about 60% of Asians are either poor metabolizers or heterogenous extensive metabolizers. So, knowing the CYP2C19 activity may in the future become important or even necessary in evaluating studies on response to therapy. Finally, among heterozygotes, the increase in plasma gastrin is more pronounced in H. pylori–positive patients than in those without infection (226% and 80%, respectively), again demonstrating the influence of H. pylori infection on gastric secretion. 3
In this issue of the Journal, Ligumsky et al. 4 compare the effects of omeprazole 20 mg daily or every other day on symptom recurrence and serum gastrin levels. They argue that the maintenance of normal levels of serum gastrin is desirable by implying that there is a putative effect of hypergastrinemia on colorectal cancer genesis. The expressed concern is that hypergastrinemia may promote tissue growth and tumorigenesis and, therefore, that measures to reduce gastrin elevations in response to PPIs are desirable. Revisiting this topic in the context of increasing concerns over chronic PPI therapy, especially in Barrett's esophagus, seems warranted.
Small, multicentric, noninvasive carcinoid tumors have been identified in gastric mucosa in Zollinger–Ellison syndrome. There are focal areas of enterochromaffin-like cell hyperplasia in patients with Zollinger–Ellison, but also in the mucosa of patients with pernicious anemia and achlorhydria. Historically, these are not thought to progress or imply increased patient risk. 1 If there were a cancer risk, it should be greatest in patients with Zollinger–Ellison because almost all gastrin-secreting islet cell tumors contain multiple hormones, including adrenocorticotrophic hormone, glucagon, melanocyte stimulating hormone, parathyroid hormone, growth releasing factor, insulin, vasoactive intestinal peptide, and pancreatic polypeptide. These are usually clinically silent, and no increased risk of tumors (other than primary islet cell tumor) has been demonstrated.
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