Introduction

Hypergastrinemia, caused by chronic atrophic gastritis or Helicobacter pylori (H. pylori) associated pangastritis, is associated with an increased risk of non-cardia gastric cancer. Recent studies have also found an increased risk of gastric cancer in long-term proton pump inhibitor (PPI) users. Patients with chronic atrophic gastritis also have an increased risk of neuroendocrine neoplasms (NEN) due to hypergastrinemia. However, whether long-term PPI use increases the risk of gastric NEN has not been assessed in the general population.

Aims & Methods

The aim of the present study was to assess the risk of gastric NEN among long-term PPI users in a multinational population-based study from the Nordic countries (Denmark, Finland, Iceland, Norway, and Sweden). The study was based on the Nordic Gastric and Esophageal Tumor Study (NordGETS), which is a population-based multinational sex, age, calendar year, and country matched case-control study including all adults (≥18 years of age) with a diagnosis of gastric or esophageal tumor in the Nordic countries. In the present study, the cases were incident gastric NEN identified in the cancer registries and the exposure was long-term use of PPI categorised into three equal-sized groups (tertiles) of defined daily doses (DDDs) from the medication registries of the Nordic countries between 1996 and 2020. Multivariable logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs), adjusted for chronic atrophic gastritis, NEN in the duodenum or pancreas, and H. pylori infection identified in the patient registries and medication registries.

Results

In total, 1,790 gastric NEN case patients were compared to 17,897 control participants. After a one-year run-in period, the median follow-up was 11.8 years. The risk of incident gastric NEN increased in PPI users compared to non-users in a dose-dependent manner. The adjusted OR for incident gastric NEN was 1.83 (95% CI 1.56 to 2.15) in the highest tertile of PPI use (>385 DDDs, entire drug history) compared to no PPI use (Table). The risk was higher in the younger age group (<65 years) than the older age group (≥65 years) and the estimates were consistent when excluding individuals with chronic atrophic gastritis, other NENs, and H. pylori.

Conclusion

In this population-based study from the five Nordic countries the risk of gastric NEN was increased in PPI users compared to non-users of PPI in a seemingly dose-dependent manner. The risk was higher in younger age groups of PPI users compared to older age groups.

Disclosure

No conflicts of interest