Proton pump inhibitor and histamine-2 receptor antagonist use and risk of liver cancer in two population-based studies

Kim Tu Tran, Úna C. McMenamin, Blánaid Hicks, Peter Murchie, Aaron P. Thrift, Helen G. Coleman, Lisa Iversen, Brian T. Johnston, Amanda J. Lee, Chris R. Cardwell

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Proton pump inhibitors (PPIs) and histamine‐2 receptor antagonists (H2RAs) are commonly used. PPIs have been shown to promote liver cancer in rats; however, only one study has examined the association in humans.


To investigate PPIs and H2RAs and risk of primary liver cancer in two large independent study populations.


We conducted a nested case‐control study within the Primary Care Clinical Informatics Unit (PCCIU) database in which up to five controls were matched to cases with primary liver cancer, recorded by General Practitioners. Odds ratios (ORs) and 95% confidence intervals (95% CIs) for associations with prescribed PPIs and H2RAs were calculated using conditional logistic regression. We also conducted a prospective cohort study within the UK Biobank using self‐reported medication use and cancer‐registry recorded primary liver cancer. Hazard ratios (HRs) and 95% CIs were calculated using Cox regression.


In the PCCIU case‐control analysis, 434 liver cancer cases were matched to 2103 controls. In the UK Biobank cohort, 182 of 475 768 participants developed liver cancer. In both, ever use of PPIs was associated with increased liver cancer risk (adjusted OR 1.80, 95% CI 1.34, 2.41 and adjusted HR 1.99, 95% CI 1.34, 2.94 respectively). There was little evidence of association with H2RA use (adjusted OR 1.21, 95% CI 0.84, 1.76 and adjusted HR 1.70, 95% CI 0.82, 3.53 respectively).


We found some evidence that PPI use was associated with liver cancer. Whether this association is causal or reflects residual confounding or reverse causation requires additional research.

Original languageEnglish
Pages (from-to)55-64
Number of pages10
JournalAlimentary Pharmacology & Therapeutics
Issue number1
Early online date9 May 2018
Publication statusPublished - Jul 2018

Bibliographical note

The analysis of UK Biobank has been conducted using the UK Biobank Resource under Application Number 34374. We acknowledge collaboration with the Research Applications and Data Management Team lead by Ms Katie Wilde, University of Aberdeen in conducting this study. KTT is supported by the Vietnam International Education Cooperation Department. Access to PCCIU data was provided by Queen’s University Belfast and the Centre for Academic Primary Care, University of Aberdeen. Access to the UK Biobank was funded by a Cancer Research UK Population Research Postdoctoral Fellowship awarded to ÚCMcM. HGC is a co-investigator of the UKCRC Centre of Excellence for Public Health Northern Ireland.


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