Proton pump inhibitors use and risk of liver cancer: Concerns to be addressed

Proton pump inhibitors (PPIs) are among the most commonly prescribed medications for managing gastroesophageal reflux disease, peptic ulcer disease, and the eradication of Helicobacter pylori infection.1 However, the association between PPIs use and an increased risk of developing cancer remains unclear, particularly for cancers of the gastrointestinal tract and liver.2-6 One proposed mechanism for the potential carcinogenicity of PPIs is their potent suppression of gastric acid production, which could lead to hypergastrinemia. Hypergastrinemia may promote carcinogenesis in the digestive system due to the pro-growth effects of gastrin on tissues such as the pancreas, stomach, colon, and esophageal mucosa.7 In addition, long-term use of PPIs may alter gut microbiome diversity and increase the risk of enteric infection and hepatic inflammation, which could contribute to the development of liver fibrosis, a critical factor in hepatic carcinogenesis.8, 9 Hepatocellular carcinoma (HCC) is the most common primary liver cancer and the fourth leading cause of cancer-related deaths worldwide. Several risk factors for HCC have been identified, including hepatitis B or C virus infection, fatty liver disease, and liver cirrhosis.10 Our previous study in a Taiwanese population-based cohort, using a propensity score matching analysis, demonstrated that PPIs use is not associated with an increased risk of developing HCC among patients with chronic hepatitis B or C.4 Similarly, another study from a nationally representative Korean cohort found no increased risk of HCC associated with PPIs use in selected population, such as those with obesity, older age, or chronic liver diseases.5 However, two previous meta-analyses have reported conflicting results regarding the relationship between PPIs use and HCC risk.11, 12 Furthermore, our recent Taiwanese population-based cohort study showed that long-term PPIs use in HCC patients after hepatectomy might be associated with longer recurrence-free survival.13 In Advances in Digestive Medicine, Yi and colleagues investigated the association between PPIs use and the risk of hepatobiliary cancer, presenting newly available evidence.14 Their meta-analysis revealed a significant association between PPIs use and an increased risk of hepatobiliary cancer (95% confidence interval 1.44–1.98, p < .001). However, the association observed in this and previous studies was weak, lacked a dose-dependent effect, and the reported odds ratios were less than 3, suggesting that residual confounding rather than causality might be responsible for the findings.15 In conclusion, the relationship between PPI use and the risk of liver cancer remains controversial. It is crucial to avoid the inappropriate long-term use of PPIs. Nonetheless, the overinterpretation and sensationalization of these studies have led to public misinformation. Therefore, more prospective, large-scale, randomized controlled clinical trials with long-term follow-up are needed to further investigate the association between PPI use and liver cancer. The authors declare no conflicts of interest.