Proton Pump Inhibitors and Odds of Cholangiocarcinoma

A Retrospective Case-control Study

Jianping Xiong; Yaqin Wang; Weiyu Xu; Zhisong Liu; Haochen Wang; Zhiyuan Zhang; Yanjing Han; Chao Yin; Shasha Cao; Zheran Yang; Tianhao Su; Jian Wei; Guang Chen; Long Jin


Liver International. 2020;40(11):2848-2857. 

In This Article

Abstract and Introduction


Background & Aims: Proton pump inhibitors (PPIs) have been reported to be associated with cholangitis and might possibly be carcinogenic. However, few studies have been conducted to investigate the association of PPIs with cholangiocarcinoma (CCA). Thus, a hospital-based case-control study was carried out in China to explore the association between PPIs and CCA.

Methods: In this study, 1468 CCA cases (826 intrahepatic cholangiocarcinoma (ICC) and 642 extrahepatic cholangiocarcinoma (ECC)) were included, which were observed at Beijing Friendship Hospital, from February 2002 to October 2018. We retrospectively extracted PPI use and other possible risk factors from clinical records, followed by an investigation of the relationship with CCA via calculation of odds ratios (ORs), adjusted odds ratios (AORs), and 95% confidence intervals (CIs) using logistic regression analysis.

Results: PPIs were used by 135 (9.2%) CCA cases and 173 (5.9%) controls. We found that PPI use was associated with a 1.61-fold elevated CCA odds (P < .001) (AOR = 1.61, 95% CI = 1.28–2.05; P < .001). After stratification by CCA subtypes, the AORs of PPIs were consistent for both CCA subtypes, with ORs of 1.36 (AOR = 1.36, 95% CI = 1.02–1.83; P = .003) and 1.95 (AOR = 1.95, 95% CI = 1.46–2.62; P < .001) for ICC and ECC respectively. Our results also showed that PPI use was slightly linked to the odds of CCA in a dose-dependent manner.

Conclusion: PPI use was correlated with a significant 61% increased odds of CCA, particularly in the ECC. However, the retrospective design and observational nature cannot establish causation. Larger scale, multi-centre prospective studies are required for further validation.


Proton pump inhibitors (PPIs) can effectively inhibit the production of gastric acid, and as a result, they have been extensively used in the world.[1] At present, PPIs are generally recommended for the prevention of various gastrointestinal diseases (GIDs), including peptic ulcer disease and gastroesophageal reflux disease (GERD), together with gastrointestinal bleeding among vulnerable people, like the use of dual antiplatelet therapy in preventing heart disease in individuals with vascular disease.[2,3] In view of the large population of patients receiving PPI therapy, which in many cases is long-term therapy, ensuring the safety of this therapy is of considerable importance to public health.[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] Gastrin, produced by G cells in the gastric antrum, stimulates enterochromaffin cells to release histamine, which in turn causes increased acid production by parietal cells via histamine receptors.[6] Gastrin secretion increases in response to PPI-induced hypochlorhydria. A 2- to 6-fold increase in serum gastrin levels is common among patients receiving long-term therapy.[7] Gastrin has growth-promoting effects on a number of epithelial cell types, including cells located in the stomach.[8] It is biologically plausible that the trophic effects of gastrin may increase the chance of sporadic mutations in normal cells and/or enhance the proliferation and progression of neoplastic tissues or their precursors.[9] In addition to cancer observed in the stomach, hypergastrinemia in PPI users was associated with pancreatic cancer and periampullary cancer.[10,11] A recent observational study also demonstrated that PPIs might increase the risk of hepatocellular carcinoma.[12] Additionally, PPI use may alter the gut microbiome environment and increase the risk of biliary tract inflammation,[13–15] and chronic biliary tract inflammation is a recognized contributor to bile duct carcinogenesis.[16] However, the associations of PPI use with the risk of cholangiocarcinoma (CCA) are scarce and poorly understand.

CCA is a malignancy originating from the epithelium of the bile duct, which was initially described by Durand Fardel in 1840.[17] The incidence of CCA ranked second in all primary liver carcinomas, accounting for 3% of all gastrointestinal malignancies and 10%-25% of liver malignancies.[18] Moreover, in recent decades, the incidence of CCA has continued to increase. In the past 20 years, the incidence of CCA in the United States has increased by 165%.[19] In addition, the prognosis of CCA is very poor. The relative 1-, 3- and 5-year survival rates have been shown to be 25%, 9.7% and 6.8%, respectively, almost without any change in recent decades.[20] Furthermore, the cause of CCA is not yet fully understood, with only several confirmed risk factors of CCA, especially chronic biliary tract inflammation.[21] Thus, we conducted a case-control study in a large CCA cohort to determine whether there is an association between PPI use and CCA development.