Association Between Proton Pump Inhibitors and the Risk of Hepatocellular Carcinoma

Y.-H. J. Shao; T.-S. Chan; K. Tsai; S.-Y. Wu


Aliment Pharmacol Ther. 2018;48(4):460-468. 

In This Article

Abstract and Introduction


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.


Proton pump inhibitors (PPIs) are the most potent inhibitors of gastric acid secretion.[1,2] H–K–ATPase constitutes the final pathway through which HCl is secreted into the gastric lumen, where it hydrolyses dietary proteins as well as maintains a sterile environment.[1] PPIs inhibit H–K–ATPase[1] and substantially reduce acid secretion with a long duration of action.[3,4] Consequently, PPIs are commonly prescribed for patients with gastro–oesophageal reflux disease (GERD), peptic oesophagitis and oesophagitis–associated symptoms.[3,4]

One of the clinical consequences of strong and long–term acid suppression is hypergastrinemia. The resultant hypergastrinemia increases the risk of cancer development.[5] First, hyperplasia of enterochromaffin–like cells (ECL cells) was observed in rodents receiving PPIs,[6] leading to gastric carcinoid tumours. Although gastric carcinoid tumours have not been detected in humans since the introduction of PPIs, hyperplasia of ECL cells was observed in clinical studies.[7] Moreover, fundic gland polyposis was observed in patients receiving potent and prolonged antisecretory therapy.[8] In addition to cancer observed in the stomach, hypergastrinemia in PPI users was associated with pancreatic cancer,[9] periampullary cancers,[5] colorectal cancer,[10] lung cancer[11] and ovarian cancer.[12]

Reports on the hepatotoxicity of PPIs are scarce in the literature.[13–15] However, a recent study used genome–wide transcriptional expression data from cultured human cells treated with bioactive molecules to study the carcinogenic effect of compounds on the human liver.[16] A PPI was reported to exhibit a notable genetic expression similar to well–known carcinogens in the liver;[16,17] however, its carcinogenicity remains unknown. Moreover, PPIs allow the proliferation of cells with fatal mutations, and they thus increase the risks of cancers.[18] The mechanism is probably indirect and involves the induction of oxidative stress and production of reactive oxygen species that further damage DNA. Repeated DNA damage likely increases the mutation rate, including that of tumour suppressor genes and oncogenes.[19] The mutation burden engendered by dose–dependent PPI use in tumour suppressor genes and oncogenes might affect the onset of hepatocellular carcinoma (HCC).[20,21] In addition to the reported association between HCC risk and PPI use at the molecular level, we hypothesised that PPI use increases the risk of HCC. In this study, we examined the association between PPI use and the risk of HCC and the impact of long–term PPI use.