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


Data showing an association of PPI use and CCA odds are lacking. Only one nested case-control study from Taiwan detected a significant association between PPI use and the risk of CCA.[33] However, the dose and duration of PPI use was not defined in that study. Additionally, patients' lifestyle, alcohol and smoking, which are important factors associated with cancer, were not assessed. This is the largest study to explore the relationship of PPI use with CCA odds, including ICC and ECC, and the results support that PPI use is significantly related to CCA progression, especially ECC.

Our study indicated that long-term use of PPIs was related to the odds of CCA. With the support of preclinical studies of CCA and other cancers, this observation is biologically reasonable. Firstly, it has been shown that pronounced acid suppression can significantly increase serum gastrin levels of individuals. The prolongation and increase in gastrin levels can stimulate the increase in intermediate products that have nutritional effects on the normal gastrointestinal mucosa, and can stimulate carcinogenesis. A large number of in vitro and in vivo studies have investigated the nutritional effects of gastrin on a variety of cancers, including gastric cancer, colon cancer, pancreatic cancer and liver cancer.[34,35] A study has demonstrated increased expression of gastrin and its receptors in cholangiocarcinoma.[36] Secondly, it is speculated that long-term use of PPIs might induce a metaplasia-dysplasia-carcinoma sequence. If a PPI fails to inhibit gastric acid secretion, then unconjugated bile salts may diffuse into the epithelial cells and cause mucosal metaplasia.[11] Pharmacologically, hypochlorhydria caused by daily PPI use produces periods during the day in which the pH of the gastric juice is at or near neutral pH levels.[37] A study by Shindo et al indicated that hypochlorhydria can cause obvious changes in the gastric flora and affect the pH of intestinal fluid, resulting in bacterial overgrowth.[37] Moreover, Shindo et al's study revealed that PPI treatment in patients with gastric ulcers results in bacterial overgrowth in the gastrointestinal tract.[37] Conversely, these bacteria alter the metabolism of bile acids through increased conjugation and fat malabsorption, as evidenced by glycine-1-14C-labeled glycocholate and breath analysis studies.[38] A substantial body of evidence suggests that bile acids play a role in the development of cholangiocarcinoma.[39] Bile acids promote cholangiocarcinoma cell invasive growth and cholangiocyte proliferation through activation of sphingosine 1-phosphate receptor 2.[39] However, PPIs decrease the secretion of gastric acid and increase the pH environment of the stomach, reducing bactericidal activity and allowing pathogens to pass through the stomach to the duodenum, thereby increasing the odds of retrograde to the biliary system and thus elevating the incidence of biliary tract infection.[13] One study enrolled 211 PPI users and studied their stool samples, which contained a significant increase in bacteria—genera Enterococcus, Streptococcus, Staphylococcus and Escherichia coli—some of which are also common pathogens in acute cholangitis.[40] Notably, cholangitis is a recognized risk factor for cholangiocarcinoma.[16] Finally, a large proportion of PPI users are currently infected with or have a history of H pylori infection. Some studies suggest that H pylori, especially cagA-positive strains, may be involved in the pathogenesis of hepatobiliary diseases, especially CCA, through enhanced biliary cell inflammation and proliferation.[41]

Certain limitations should also be noted in this study. Firstly, this was a single-centre retrospective study, and selection bias was inevitable even though the inclusion and exclusion criteria were strictly followed. Secondly, diagnostic bias might affect the results of this research. CCA may be more likely to be diagnosed among PPI users than non-users since PPIs users undergo routine physical examination. This tendency may result in an overestimated odds of CCA among PPI users compared with non-users. Additionally, patients with CCA need to take PPI frequently because of some complications, such as gastrointestinal bleeding. Thus, risk factors (using PPI) may be affected by their outcome (CCA development). To reduce selection bias, propensity score was applied to select the two groups with and without CCA using a 1:2 ratio. These chosen age, gender, medication and comorbidities can help to clarify the significant influence of PPI on CCA odds. Thirdly, the majority of patients may have taken more than one type of PPI, and we could not completely account for the interaction of different PPIs. Fourthly, we were not able to obtain detailed information on the amount and duration of potentially relevant chemopreventive drugs that alter the odds of CCA, such as metformin, aspirin or statin. Aspirin use is related to a significantly decreased risk of CCA.[42] Metformin use is markedly associated with a decreased odds of having ICC.[22] Recently, a case-control study has suggested that statins decrease the risk of ECC and may improve survival in patients with ECC.[43]

In conclusion, this is a large study aiming to explore the association of PPI application with CCA odds, which indicates that PPI use is significantly associated with CCA development. Moreover, it is mildly associated with the CCA odds in a dose-dependent manner. However, case-control studies, because of their typically retrospective nature, can be used to establish a correlation between PPI use and the odds of CCA, but they cannot establish causation. Thus, larger scale, multi-centre prospective studies are required for further validation.