Proton pump inhibitors and mortality

We read with interest the study by Lo et al about the association of proton pump use with all-cause and cause-specific mortality.1Lo C.-H. et al.Gastroenterology. 2022; 163: 852-861.e2Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar This is a very important subject taking into consideration the many recent reports and the never-ending question of the role of PPIs in gastric cancer. Proton pump inhibitors (PPIs) block the proton pump and thereby inhibit gastric acid secretion, leading to reduced gastric acidity and consequently diminished proteolytic activity of the gastric juice. The main function of the gastric juice is to kill swallowed microorganisms. PPIs would therefore be expected to increase the susceptibility to infections, which clinically has been shown for Clostridium difficile infections.2Martinez E. et al.Pathogens. 2022; 11: 781Crossref PubMed Scopus (5) Google Scholar The main problem with PPIs is hypergastrinemia due to gastric hypoacidity.3Trudeau W.L. et al.N Engl J Med. 1971; 284: 408-412Crossref PubMed Scopus (104) Google Scholar Already in the middle of the 1980s, long-term drug-induced gastric hypoacidity in rodents was shown to induce tumors originating from the gastrin target cell, the enterochromaffin-like (ECL) cell (the sole cell with a gastrin receptor4Bakke I. et al.Scand J Gastroenterol. 2001; 36: 1128-1133Crossref PubMed Scopus (74) Google Scholar). In patients with hypergastrinemia, ECL cells occur in clusters demonstrating self-replication. Gastrin has a marked positive trophic effect on the ECL cell and a less pronounced but general trophic effect on the other cells in the oxyntic mucosa.5Bakke I. et al.Acta Physiol Scand. 2000; 169: 29-37Crossref PubMed Google Scholar Because no gastrin receptor has hitherto been described on the stem cell of the oxyntic mucosa, the general trophic effect of gastrin on the oxyntic mucosa may be indirect by stimulation of release of signal substances from ECL cells. These points of view explain how Helicobacter pylori via inducing hypergastrinemia secondary to oxyntic atrophy6Uemura N. et al.N Engl J Med. 2001; 345: 784-789Crossref PubMed Scopus (3712) Google Scholar can promote both diffuse gastric cancer from the ECL cell and intestinal type from the stem cell.7Waldum H.L. et al.Dig Dis Sci. 2015; 60: 1522-1527Crossref PubMed Scopus (39) Google Scholar Accordingly, gastrin is not a general trophic hormone, but has trophic effects only on the oxyntic mucosa. It is therefore not plausible that gastrin or PPI treatment should play any carcinogenic role in the esophagus or small intestine, which were lumped together with gastric cancer in the recent epidemiologic study.1Lo C.-H. et al.Gastroenterology. 2022; 163: 852-861.e2Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar The combined occurrence of cancers in the esophagus and small intestine is in United States today approximately the same as for gastric cancer alone. The inclusion of the nongastric cancers (not expected to be affected by PPIs) in the evaluation for carcinogenic risk certainly attenuated the possible association between PPI and gastric cancer. Finally, the use of time lag after PPI initiation to avoid protopathic bias may be rational in some settings. However, it is important to realize that individuals with predisposition of a particular outcome may develop disease within a few years after start of PPI exposure. On the other hand, in young individuals without risk factors for gastric cancer, a median observation time of 13.8 years1Lo C.-H. et al.Gastroenterology. 2022; 163: 852-861.e2Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar may even be too short.8Calvete O. et al.Hum Mol Genet. 2015; 24: 2914-2922Crossref PubMed Scopus (54) Google Scholar In conclusion, this new study on the risk of long-term PPI treatment, was apparently not designed to disclose any connection between PPI use and gastric cancer, the most important safety concern with PPI treatment. Knowledge of the pathogenesis of a condition should be taken into consideration also in epidemiologic studies. Association of Proton Pump Inhibitor Use With All-Cause and Cause-Specific MortalityGastroenterologyVol. 163Issue 4PreviewProton pump inhibitor use was not associated with higher risk of death after accounting for reverse causation. Longer duration of proton pump inhibitor use did not confer higher mortality risks. Full-Text PDF ReplyGastroenterologyVol. 164Issue 6PreviewWe thank Drs Waldum and Fossmark1 for their comments on our study.2 We acknowledge that there are plausible biological mechanisms by which proton pump inhibitor (PPI) use may be causally associated with risk of gastric cancer. However, the links between PPI use and gastric cancer in human studies have been inconsistent. Most previous studies studying PPI use and cancer are prone to protopathic bias, whereby PPIs used to relieve preclinical symptoms before formal diagnosis may be assumed to be causally associated with the disease itself. Full-Text PDF