We read with interest the article by Klinkenberg-Knol and coworkers [1] on omeprazole safety and the accompanying editorial by Freston [2]. Although the report by Klinkenberg-Knol and colleagues [1] offered a well-balanced description of gastrin values and micronodular neuroendocrine cell hyperplasia in the oxyntic mucosa of many patients receiving omeprazole maintenance treatment, the editorial [2] tended to underestimate the risks for hypergastrinemia. Thus, it was not considered that the maximal functional and trophic effects of gastrin in the rat and in humans on the enterochromaffin-like (ECL) cell are reached at a concentration of less than 500 pM [3]. Therefore, greatly elevated gastrin values in patients with pernicious anemia are irrelevant. It is speculative to propose that the ECL-cell hyperplasia in patients with omeprazole-induced hypergastrinemia is the result of gastritis [4] because it is well known that hypergastrinemia itself is sufficient to provoke such changes in animals. Klinkenberg-Knol and colleagues reported that many patients retained food in the stomach, which could have contributed to the hypergastrinemia. This food retention could, however, be secondary to the omeprazole treatment [5]. Also, Larsson and colleagues from the Hassle Group have reported such a finding at high omeprazole doses in the rat.

Considering that carcinogenesis is often a process that requires decades, and that neuroendocrine cells (including ECL cells) [3] may give rise to malignant gastric tumors, it seems biased to conclude that there is a "diminishing concern about omeprazole-induced hypergastrinemia" [2]. It should be realized that ECL cell-derived tumors developed in rats after lifelong hypergastrinemia and that an observation period of a few years is far too brief to exclude serious long-term consequences in humans. The micronodular neuroendocrine cell hyperplasia reported by Klinkenberg-Knol and colleagues resembles the changes occurring in rats before the development of carcinoid tumors. Therefore, iatrogenic hypergastrinemia should be avoided, particularly in younger persons.