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Proton pump inhibitors increase the risk of cholecystitis: a population-based case–control study
  1. Shih-Chieh Chuang1,2,
  2. Che-Chen Lin3,4,
  3. Cheng-Yuan Peng1,2,
  4. Wen-Hsin Huang1,2,
  5. Wen-Pang Su1,2,
  6. Shih-Wei Lai1,5,
  7. Hsueh-Chou Lai2,6
  1. 1 School of Medicine, China Medical University, Taichung, Taiwan
  2. 2 Division of Hepatogastroenterology, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan
  3. 3 Management Office for Health Data, China Medical University Hospital, Taichung, Taiwan
  4. 4 Department of Health Risk Management, China Medical University, Taichung, Taiwan
  5. 5 Department of Family Medicine, China Medical University Hospital, Taichung, Taiwan
  6. 6 School of Chinese Medicine, China Medical University, Taichung, Taiwan
  1. Correspondence to Dr Hsueh-Chou Lai, Hepatobiliary section, Division of Hepatogastroenterology, Department of Internal Medicine, China Medical University Hospital, China Medical University/Hospital, Taichung City 40447, Taiwan; t674233{at}

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We read with great interest the article by Cheung et al 1 reporting long-term exposure to proton pump inhibitors (PPIs) following Helicobacter pylori (HP) eradication associated with increased risk of gastric cancer. PPIs are widely used worldwide to treat gastro-oesophageal reflux disorder, peptic ulcer and HP, but multiple reports have found they got some negative effects, such as increasing risk of the intra-abdominal infection, like spontaneous bacterial peritonitis,2 pseudomembranous colitis,3 liver abscess4 and affecting the gut microbiome.5 6 PPIs may theoretically increase risk of gaining acute cholecystitis due to the increasing the number of enteric organisms and risk of secondary infection; however, few reports have supported this hypothesis. Thus, we conducted a nationwide population-based case–control study to analyse the relationship between PPI exposure and incidence rate of cholecystitis.

We use the National Health Insurance Research Database in Taiwan of 2002–2011 to established a population-based case–control study design which selected cholecystitis and control groups and compared differences with PPI use. The control group included randomly selected individuals without a history of cholecystitis, frequency matched at a ratio of 1:4, with matching criteria including age, sex and history of gallstone. Both study groups excluded individuals receiving cholecystectomy and those with a history of hepatocellular carcinoma, bile duct cancer or pancreatic cancer prior to the index date.

This study involved a total of 3192 patients with cholecystitis and 12 768 controls (table 1). Besides the matching factor of gallstone, the proportion of comorbidity was higher in the cholecystitis group than in control group. We also observed that there were more PPI users in the cholecystitis group than the control group (36% vs 29.0%, p<0.0001). The crude OR of cholecystitis risk was 1.38 (95% CI 1.27 to 1.49) for PPI users compared with PPI non-users (table 2), and after adjusting for the comorbidities, the PPI users still had a 1.23-fold increased risk of cholecystitis compared with the PPI non-users (OR=1.23, 95% CI 1.13 to 1.34).

Table 1

Demographic status and comorbidity compared between control group and cholecystitis group

Table 2

OR for cholecystitis risk for the PPI users compared with PPI non-users

We hypothesised that PPIs decreased the secretion of gastric acid and increased the pH environment of the stomach, reducing the bactericidal activity and allowing pathogens to pass through the stomach to the duodenum, thereby increasing the risk of retrograding to the biliary system, and thus, elevating the incidence of biliary tract infection including acute cholecystitis. One study7 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 cholecystitis, thus, strengthening our hypothesis.

In conclusion, PPI use increased the incidence of acute cholecystitis 1.23-fold compared with the control group. Despite the wide use of PPIs in past years, physicians should judge the advantages and disadvantages and not overuse these drugs.


The authors thank the National Health Research Institute of Taiwan for the use of the National Health Insurance Program (NHIRD).


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  • Contributors S-CC: study conception and design and initial draft of manuscript; C-CL: data analysis and interpretation and initial draft of manuscript; C-YP, W-HH. S-WP, S-WL: concept of the study; H-CL: interpretation and manuscript draft and revision and guarantor of the article.

  • Funding This study was supported in part by the National Sciences Council, Executive Yuan (grant number NSC 99-2621-M-039-001), China Medical University Hospital (grant number 1MS1), Taiwan Ministry of Health and Welfare Clinical Trial Center (grant number MOHW106-TDU-B-212-113004).

  • Disclaimer This study is based on data from the National Health Insurance Research Database provided by the Bureau of National Health Insurance, Department of Health, Taiwan and managed by the National Health Research Institutes. The interpretations and conclusions contained herein do not represent the opinion of these agencies and institutions.

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; internally peer reviewed.

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