The association of Helicobacter pylori infection with acid/peptic disorders of the gastrointestinal tract has proved to be a thought-provoking clinical discovery. Given the volume of information disseminated about the subject in literature, symposia, lectures, and pharmaceutical company brochures, it is difficult to believe that Warren and Marshall [2, 3] provided the initial observation about H. pylori only a decade ago. Although the etiologic role that H. pylori plays in peptic ulcer disease is debated, a clear association exists between infection with the organism and significant upper gastrointestinal disease, and an emerging body of evidence indicates that eradication of the organism helps to treat the disease and prevent its relapse. In this setting, it is intriguing to note that H. pylori infection causes hypergastrinemia. Gastrin is the hormone primarily responsible for acid secretion induced by a meal; thus it is tempting to implicate the hypergastrinemia in H. pylori infection as the cause of excess acid secretion and, therefore, of the ulcers in peptic ulcer disease. Alas, the pathophysiology of disease is never so simple. Although patients who have ulcers and H. pylori infection do have increased gastric acid secretion [4], their acid secretory rates are not necessarily reduced by eradication of H. pylori and concomitant reduction of serum gastrin levels. Another hormone that may be important is somatostatin, which, in the stomach, is a potent inhibitor of both gastrin and gastric acid secretion. In H. pylori, there is a reduction in the number of somatostatin-containing D cells, the content of somatostatin, and somatostatin gene expression in the stomach [5, 6]. All of these changes are reversed after eradication of the organism. Thus, it may be a complex interplay between hormonal stimulants and inhibitors of gastric acid secretion as well as the cascade of inflammatory responses elicited by infection that lead to acid and peptic disorders.

If the problems of H. pylori infection and hypergastrinemia were limited to ulcer disease, there would be only modest clinical concern. However, a more ominous finding is the association between H. pylori infection and adenocarcinoma of the stomach. The matched odds ratio for developing adenocarcinoma with infection is reported to be 18.0 for women and 9.0 for blacks [7]. Because gastrin is a well-recognized growth factor that is trophic to the oxyntic mucosa of the stomach, it is of particular interest that women with H. pylori infection have higher serum gastrin levels than men with infection [4]. For further clues regarding the potential importance of hypergastrinemia in the pathophysiology of gastric cancer, one might examine patients with atrophic gastritis or the Zollinger-Ellison syndrome, both of which are associated with chronic hypergastrinemia. However, long-term data are not available in patients with the Zollinger-Ellison syndrome inasmuch as until just a few years ago most patients with the disorder received total gastrectomies to treat their recalcitrant ulcers. Patients with atrophic gastritis have only modest increase in risk for gastric cancer in the United States. In Japan, however, the incidence of gastric cancer is very high, and the disease usually occurs in the setting of gastric atrophy and, parenthetically, H. pylori infection. Evidence links hypergastrinemia with nongastric cancers as well. The initial description of gastrin receptors in colon cancers [8] and the in-vivo data suggesting the responsiveness of these tumors to the growth-promoting effects of gastrin [9] have been followed by human studies indicating that patients with colon cancer have higher basal and meal-stimulated serum gastrin levels than control subjects [10]. The potential role of gastrin in human malignancies clearly needs further attention.

The most potent regulator of gastrin secretion is the level of acid in the stomach. In a classic feedback loop, gastrin stimulates acid secretion and acid, in turn, inhibits gastrin secretion. In the absence of gastric acid, as noted in patients with atrophic gastritis, serum gastrin levels can be high. The advent of potent acid secretory inhibitors, such as omeprazole for the treatment of peptic ulcer disease, coupled with the requirement for near-complete suppression of acid for prolonged periods in treating gastroesophageal reflux disease, has created the potential for a large population of patients with chronic hypergastrinemia. It is important to note that the level of serum gastrin correlates directly with the level of acid suppression and not with the use of any particular anti-secretory drug [11]. In animal models, hypergastrinemia induced by anti-secretory agents has been associated with hyperplasia of the enterochromaffin-like cells in the stomach with progression to carcinoid tumors. The disturbing aspect of these animal studies is that there are clear human correlates. Proliferation of enterochromaffin-like cells is a well-described finding in patients with pernicious anemia and atrophic gastritis as well as in the Zollinger-Ellison syndrome. In some patients with pernicious anemia, primary gastric carcinoid tumors have been described [12]. The issue is somewhat more complex in the Zollinger-Ellison syndrome. In the series of 200 patients with the Zollinger-Ellison syndrome reported by investigators at the National Institutes of Health, 40 had the syndrome in association with multiple endocrine neoplastic type I tumors, and 13% of these patients had carcinoid tumors, whereas only 1 of the remaining 160 (0.6%) had the same finding [13]. Thus, other factors, perhaps genetic, appears to predispose certain patients with hypergastrinemia to develop carcinoid tumors with prolonged hypergastrinemia, even though virtually everyone may develop enterochromaffin-like hyperplasia. It is reassuring that in an extensive study involving 74 patients treated with high-dose (40 to 60 mg daily) omeprazole for up to 84 months in Germany, no patient with a carcinoid tumor or remarkable cellular atypia was found [14]. Nevertheless, there is clearly a need for physician awareness of the potential long-term problems associated with hypergastrinemia resulting from therapy with potent inhibitors of gastric acid secretion.

The importance of gastrin in the three relatively common clinical circumstances I have described represents only the beginning of a large body of information on gastrointestinal hormones that physicians may have to incorporate into their daily practices. It should not be surprising that peptide hormones, the substances that play a critical role in interorgan or intercellular communication, would be of such great clinical importance.