Proton Pump Inhibitor and Histamine–2 Receptor Antagonist Use and Risk of Liver Cancer in Two Population–Based Studies

K. T. Tran; Ú. C. McMenamin; B. Hicks; P. Murchie; A. P. Thrift; H. G. Coleman; L. Iversen; B. T. Johnston; A. J. Lee; C. R. Cardwell


Aliment Pharmacol Ther. 2018;48(1):55-64. 

In This Article

Abstract and Introduction


Background: 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.

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

Methods: 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.

Results: 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).

Conclusions: 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.


Primary liver cancer is the fifth most common cancer in men and ninth in women in the world.[1] Recently, the incidence and mortality from liver cancer has increased markedly both in the UK[2] and USA.[3] The low estimates of 5 year relative survival of 15% in the USA,[4] and 8% in the UK,[5] highlight the importance of preventing liver cancer.

Proton pump inhibitors (PPIs) and histamine-2 receptor antagonists (H2RAs) are widely prescribed medications, used primarily for the treatment of peptic ulcers, dyspepsia, and gastro-oesophageal reflux disease (GERD). Despite their widespread use, there have been concerns about potential adverse effects of PPIs[6,7] and H2RAs[8] potentially caused by a range of mechanisms including the reduced absorption of nutrients,[9] hypergastrinemia[10] and the overgrowth of bacteria (due to lower stomach acid levels).[8,11] Many studies have investigated the effect of PPIs and H2RAs on the stomach,[12,13] and particularly on gastric cancer risk.[14,15] Recently, additional concerns have been raised about the effects that PPIs and H2RAs have upon the liver. A recent animal study found that PPIs promote progression of alcoholic liver disease, non–alcoholic fatty liver disease, and non–alcoholic steatohepatitis in mice[16] due to an overgrowth of bacteria. Likewise, in another animal study, PPI use was shown to promote liver tumors in rats.[17]

Despite these findings, only one previous observational study has examined the association between PPI and H2RA use and the risk of primary liver cancer in humans.[18] That case–control study, which only investigated hepatocellular carcinoma (HCC), and not intrahepatic bile duct carcinoma (IBDC), observed a marked increase in risk of HCC with H2RA use but not PPI use. We therefore examined the association between use of PPIs and H2RAs and the risk of primary liver cancer using data from two independent UK datasets.