Background: Proton pump inhibitor (PPI) use has been reported to be associated with liver damage and might possibly be carcinogenic. Aims: We examined whether long-term PPI use increases the risk of hepatocellular carcinoma (HCC) in patients without viral hepatitis B or C. Methods: We conducted a nested case-control study in a cohort of patients without viral hepatitis in Taiwan from 2000 to 2013. In total, 29 473 HCC cases and 294 508 matched controls were included. Moreover, we identified prescriptions for PPI and durations between the PPI index date and cancer diagnosis date (or the corresponding date in controls). Results: The adjusted odds ratio (AOR) for HCC associated with PPI use was 2.86 (95% confidence interval [CI], 2.69-3.04). Considering the use of PPIs determined according to cumulative defined daily dose (cDDD) subgroups, a dose-response effect was observed in patients exposed to 29-180, 181-240, 241-300, and 300+ cDDDs of PPIs. The AORs were 2.74 (95% CI, 2.57-2.93), 2.98 (95% CI, 2.50-3.56), 3.23 (95% CI, 2.59-4.02), and 3.43 (95% CI, 2.94-4.00) in the 29-180, 181-240, 241-300, and 300+ cDDD groups, respectively, compared with the 0-28 cDDD group. A sensitivity analysis revealed a consistent association between PPI use and the risk of HCC in subpopulations stratified by risk factors associated with HCC. Conclusions: This observational study demonstrated that PPIs might increase the risk of HCC.

Original languageEnglish
Pages (from-to)460-468
Number of pages9
JournalAlimentary Pharmacology and Therapeutics
Issue number4
Early online dateJun 13 2018
Publication statusPublished - Aug 2018

ASJC Scopus subject areas

  • Gastroenterology
  • Pharmacology (medical)
  • Hepatology


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