Can We StoP Worrying about Long-term PPIs and Gastric Cancer Risk?

Proton pump inhibitors (PPI) are a cornerstone of management for many digestive diseases. While chronic PPI use induces physiologic changes including gastric acid suppression and hypergastrinemia, existing data are conflicting on whether this impacts the risk of gastric cancer among PPI users. Sassano and colleagues utilized pooled case-control data from five studies in the Stomach cancer Pooling (StoP) Project to investigate the association between PPI use and histologically confirmed gastric cancer. Short-term PPI use (6 months) was associated with increased risk of gastric cancer, but no association was found between long-term PPI use (3 years or more) and gastric cancer. Although the authors relied on patient-reported PPI use data, and data related to Helicobacter pylori infection and eradication rates were missing, no histologic gastric cancer subtypes in this international case-control study were associated with any PPI use. Currently reported findings provide patients and clinicians with reassuring observations that long-term PPI use does not significantly increase gastric cancer risk. The relationship identified among short-term PPI users may reflect reverse causality. Our understanding will be furthered by additional assessment of potential confounders, including comorbid conditions, PPI metabolism, and social determinants of health. See related article by Sassano et al., p. 1174.

The Role of Phosphate in Alcohol-Induced Experimental Pancreatitis.

BACKGROUND & AIMS: Heavy alcohol consumption is a common cause of acute pancreatitis; however, alcohol abuse does not always result in clinical pancreatitis. As a consequence, the factors responsible for alcohol-induced pancreatitis are not well understood. In experimental animals, it has been difficult to produce pancreatitis with alcohol. Clinically, alcohol use predisposes to hypophosphatemia, and hypophosphatemia has been observed in some patients with acute pancreatitis. Because of abundant protein synthesis, the pancreas has high metabolic demands, and reduced mitochondrial function leads to organelle dysfunction and pancreatitis. We proposed, therefore, that phosphate deficiency might limit adenosine triphosphate synthesis and thereby contribute to alcohol-induced pancreatitis. METHODS: Mice were fed a low-phosphate diet (LPD) before orogastric administration of ethanol. Direct effects of phosphate and ethanol were evaluated in vitro in isolated mouse pancreatic acini. RESULTS: LPD reduced serum phosphate levels. Intragastric administration of ethanol to animals maintained on an LPD caused severe pancreatitis that was ameliorated by phosphate repletion. In pancreatic acinar cells, low-phosphate conditions increased susceptibility to ethanol-induced cellular dysfunction through decreased bioenergetic stores, specifically affecting total cellular adenosine triphosphate and mitochondrial function. Phosphate supplementation prevented ethanol-associated cellular injury. CONCLUSIONS: Phosphate status plays a critical role in predisposition to and protection from alcohol-induced acinar cell dysfunction and the development of acute alcohol-induced pancreatitis. This finding may explain why pancreatitis develops in only some individuals with heavy alcohol use and suggests a potential novel therapeutic approach to pancreatitis. Finally, an LPD plus ethanol provides a new model for studying alcohol-associated pancreatic injury.