Proton Pump Inhibitor Use, Hypergastrinemia, and Gastric Carcinoids—What Is the Relationship?

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.

Gastric neuroendocrine tumours from long‐term proton pump inhibitor users are indolent tumours with good prognosis

“…Gastric neuroendocrine tumours diagnosed in such patients have only been rarely reported. [20][21][22][23][24][25][26] Among the nine cases we found in the literature, none developed additional tumours during follow-up (Table S1; please see the review article by McCarthy 26 for more details and discussion). This difference may, in part, be explained by the prolonged follow-up period and larger sample size of our cohort.…”

“…19 However, gastric neuroendocrine tumours diagnosed in long-term PPI users have only rarely been reported in literature. [20][21][22][23][24][25][26] When encountered in daily pathology and clinical practice, such tumours pose a challenge to tumour subtyping, prognostic prediction and clinical management. In particular, it is unclear if these tumours can be classified as Type III sporadic tumours.…”

“…Chronic PPI use is associated with persistent hypergastrinaemia throughout treatment in 80–100% of patients 19 . However, gastric neuroendocrine tumours diagnosed in long‐term PPI users have only rarely been reported in literature 20–26 . When encountered in daily pathology and clinical practice, such tumours pose a challenge to tumour subtyping, prognostic prediction and clinical management.…”

Updates in drug-induced acute pancreatitis

“…Of note, acidsuppressing drugs can be prescribed for a prodrome of acute pancreatitis [25]. It was determined that hypergastrinemia induced by continuous use of proton pump inhibitors (PPIs) can stimulate pancreatic enzyme secretion eventually resulting in pancreatitis [26]. The literature contains several case reports of omeprazole-, pantoprazole-, and lansoprazole-induced pancreatitis.…”

Editorial: “Stardust gastric mucosa” – A novel and consistent marker of vonoprazan safety during follow‐up?

“…Even if this lesion is morphologically distinct from those seen with PPI therapy, stardust gastric mucosa may also be a consequence of vonoprazan‐induced hypergastrinaemia, which is observed more frequently than with PPI use, 2 and is a known possible risk factor of neuroendocrine tumors 7 . In their discussion, Yoshizaki et al mentioned that stardust gastric mucosa was not associated with cancer.…”