Reply to comment: Proton Pump Inhibitor Use and Risk of Hepatocellular Carcinoma

We appreciate the comments by Lai on our study.1 We completely agree that proton pump inhibitor (PPI) use is not associated with an increased risk of hepatocellular carcinoma (HCC) development in patients with chronic hepatitis B or C. However, another recent nested case‐control study, using the Taiwan National Health Insurance (NHI) database, showed that PPI use might increase the risk of HCC in patients without hepatitis B or C infection.2 The different results between Shao et al. and our study may be attributed to the different study designs (case‐control study vs. cohort study) and subjects (nonviral hepatitis vs. viral hepatitis). Because the majority (>80%) of HCC patients in Taiwan and East Asia have an active ongoing or resolved viral hepatitis, our study might provide more clinical implications for patients who bear a higher risk of developing HCC.3 Regarding the nonviral etiology of HCC, Lai conducted a cohort study using the Taiwan NHI database, and it showed that incidences of HCC were similar between PPI users and non‐PPI users after excluding alcohol‐related disease, cirrhosis, hepatitis B infection, hepatitis C infection, other chronic hepatitis, and diabetes mellitus.4 Furthermore, another recent meta‐analysis of five observational studies demonstrated that PPI use was not associated with an increased risk of HCC.5 The results were consistent after excluding two studies that enrolled patients with chronic hepatitis B or C. Taken together, most published human studies of PPI use and HCC risk have revealed weak associations and are prone to residual confounding or protopathic bias, both in terms of viral etiology and nonviral etiology of HCC.2 Based on these studies, PPI use is not associated with an increased risk of developing HCC both in patients with and those without viral hepatitis. The overinterpretation and sensationalization of medical studies has led to public misinformation and should not be overextrapolated to alter clinical practice. Therefore, more prospective, large‐scale, randomized controlled clinical trials with long‐term follow‐up studies are warranted to establish the relationship between PPI use and HCC.