Abstract
Neuroendocrine tumors (NETs) throughout the body are the focus of much current interest. Most occur in the gastrointestinal tract and have shown a major increase in incidence over the past 30 years, roughly paralleling the world-wide increase in the use of proton pump inhibitor (PPI) drugs. The greatest rise has occurred in gastric carcinoids (g-NETs) arising from enterochromaffin-like (ECL) cells. These tumors are long known to occur in auto-immune chronic atrophic gastritis (CAG) and Zollinger-Ellison syndrome (ZES), with or without multiple endocrine neoplasia type-1 (MEN-1), but the incidences of these conditions do not appear to have increased over the same time period. Common to these disease states is persistent hypergastrinemia, generally accepted as causing g-NETs in CAG and ZES, and postulated as having similar tumorigenic effects in PPI users. In efforts to study the increase in their occurrence, g-NETs have been classified in a number of discussed ways into different grades that differ in their incidence and apparent pathogenesis. Based on a large amount of experimental data, tumorigenesis is mediated by gastrin’s effects on the CCK2R-receptor on ECL-cells that in turn leads to hyperplasia, dysplasia, and finally neoplasia. However, in all three conditions, the extent of response of ECL-cells to gastrin is modified by a number of genetic influences and other underlying risk factors, and by the duration of exposure to the hormonal influence. Data relating to trophic effects of hypergastrinemia due to PPI use in humans are reviewed and, in an attached Appendix A, all 11 reports of g-NETs that occurred in long-term PPI users in the absence of CAG or ZES are summarized. Mention of additional suspected cases reported elsewhere are also listed. Furthermore, the risk in humans may be affected by the presence of underlying conditions or genetic factors, including their PPI-metabolizer phenotype, with slow metabolizers likely at increased risk. Other problems in estimating the true incidence of g-NETs are discussed, relating to non-reporting of small tumors and failure of the Surveillance, Epidemiology, and End Results Program (SEER) and other databases, to capture small tumors or those not accorded a T1 rating. Overall, it appears likely that the true incidence of g-NETs may be seriously underestimated: the possibility that hypergastrinemia also affects tumorigenesis in additional gastrointestinal sites or in tumors in other organ systems is briefly examined. Overall, the risk of developing a g-NET appears greatest in patients who are more than 10 years on drug and on higher doses: those affected by chronic H. pylori gastritis and/or consequent gastric atrophy may also be at increased risk. While the overall risk of g-NETs induced by PPI therapy is undoubtedly low, it is real: this necessitates caution in using PPI therapy for long periods of time, particularly when initiated in young subjects.
Highlights
Following a century of evolving terminology, gastric carcinoids, the term most used by clinicians and tIhnte
There are eleven cases reported in whom gastric carcinoid (g-neuroendocrine tumors (NETs)) tumors developed while the patient was using a pump inhibitor (PPI), and in whom evidence of Zollinger-Ellison syndrome (ZES)/multiple endocrine neoplasia type-1 (MEN-1) or gastric oxyntic mucosal atrophy was lacking [12,35,36,37,38,39,40,41]
Neuroendocrine tumors (NETs), related similar tumors occur in other organs
Summary
Following a century of evolving terminology, gastric carcinoids, the term most used by clinicians and tIhnte. In the case of type-2 tumors, in patients with MEN-1, a hereditary condition caused by mutations which inactivate the tumor suppressor gene MEN1, the tumorigenic influence of gastrin may be accentuated by reduced tumor suppression, an additional factor in inducing carcinoids [16], it must be pointed out that despite the fact that using villin-Cre to delete the MEN1 locus in the gastrointestinal epithelium generated hypergastrinemia, G-cell hyperplasia and epithelial dysplasia, no ECL tumors developed [17] This suggests that more than one alteration to this genome may be required for the genesis of type-2 NETs in MEN-1, or that deletions or heterozygosity in the somatostatin genome may be involved [18,19]. This background brings us to examine the essential question, whether or not prolonged hypergastrinemia due to PPI therapy induces gastric carcinoid formation in humans?
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