We read with great interest the article by Chuang et al 1 confirming proton pump inhibitor (PPI) use is associated with increased risk of cholecystitis.1 PPIs are a potent class of agents used to suppress gastric acid secretion and are among the most commonly prescribed medications globally.2 Presently, PPIs are routinely recommended for several GI disorders, including GORD, and as prophylaxis against peptic ulcer disease and GI bleeding in susceptible populations, such as individuals on dual antiplatelet therapy for secondary prevention of cardiovascular disease.3–5 In view of the large population of patients receiving PPI therapy, in many cases long-term therapy, ensuring the safety of PPI therapy is of considerable public health importance.6 Recently, PPIs have been reported to be associated with cholecystitis and might possibly be carcinogenic.1 However, no research has been conducted to investigate the association of PPIs with gallbladder cancer (GBC). Herein, a hospital-based case–control study was carried out in China to explore the association between PPIs and GBC risk.
A hospital-based case–control study was performed by enrolling 3030 subjects (606 subjects with pathologically diagnosed GBC as well as 2424 healthy controls) from the Beijing Friendship Hospital of the Capital Medical University, Beijing, China, from February 2002 to October 2018. Differences in PPI use were compared between the GBC and control groups. Cases were frequency-matched 1 to 4 with controls (without a history of GBC) in the Health Screening Center of Beijing Friendship Hospital from May 2012 through January 2019 for age, sex and history of gallstone. Both study groups excluded individuals receiving cholecystectomy prior to the index date.
In this case–control study, 44 of 606 (7.3%) patients with GBC and 109 of 2424 (4.5%) controls have been exposed to PPI 28 cumulative defined daily dose (cDDD) (table 1). When comparing ever users of PPI with non-PPI users, we found PPI use was associated with 1.56-fold elevated GBC risk (p<0.0001) (OR=1.56, 95% CI 1.07 to 2.19; p=0.005) (table 2). Next, we determined the impact of dose and duration of PPI use on GBC risk (table 2). The ORs were 1.42 (95% CI 0.80 to 2.41), 1.67 (95% CI 1.03 to 2.76) and 2.69 (95% CI 1.15 to 7.28) in the 28–90, 91–180 and 180+ cDDD groups, respectively, compared with the ≤27 cDDD group (table 2). In considering the use of PPI according to cDDD subgroups, the risk significantly increased, and the highest dose–response effect was found in patients with PPI exposure of 180+ cDDD groups (p for trend <0.0001) (table 2). When stratified by duration of PPI use as >3 years or ≤3 years, the ORs were 1.79 (95% CI 1.03 to 3.10) and 2.41 (1.05 to 4.93) for PPI use of >3 years and ≤3 years, respectively (table 2).
Table 1.
Baseline characteristics of GBC cases and controls
| Characteristics | GBC, n=606 (%) | Controls, n=2424 (%) | P value* |
| Age (years) | 0.955 | ||
| <60 | 226 (32.3) | 907 (37.4) | |
| ≥60 | 380 (62.7) | 1517 (62.6) | |
| Sex | |||
| Male | 195 (32.1) | 781 (32.2) | |
| Female | 411 (67.9) | 1643 (67.8) | 0.984 |
| Gallstones | 119 (19.7) | 480 (19.8) | 0.927 |
| Infectious diseases | |||
| HBV | 59 (9.7) | 104 (4.3) | <0.001 |
| HCV | 27 (4.5) | 41 (1.7) | <0.001 |
| Fatty liver disease | 75 (12.4) | 191 (7.9) | <0.001 |
| Alcohol intake | 156 (25.8) | 393 (16.2) | <0.001 |
| Smoking | 204 (33.6) | 448 (18.5) | <0.001 |
| Diabetes mellitus | 123 (20.3) | 187 (7.7) | 0.002 |
| Dyslipoproteinaemia | 176 (29.0) | 373 (15.4) | <0.001 |
| Hypertension | 78 (12.9) | 347 (14.3) | 0.36 |
| Obesity | 138 (22.7) | 330 (13.6) | <0.001 |
| Coronary artery disease | 134 (22.1) | 625 (25.8) | 0.062 |
| Aspirin use | 142 (23.5) | 926 (38.2) | <0.001 |
| PPI use | 44 (7.3) | 109 (4.5) | 0.005 |
| Duration of use (years) | |||
| ≤3 | 19 (3.1) | 43 (1.8) | 0.034 |
| <3 | 9 (1.5) | 15 (0.6) | 0.031 |
| Dose (cDDD) | |||
| 0–27 | 562 (92.7) | 2291 (95.5) | |
| 28–90 | 15 (2.5) | 45 (1.9) | 0.219 |
| 91–180 | 23 (3.8) | 55 (2.3) | 0.036 |
| >180 | 6 (1.0) | 7 (0.3) | 0.018 |
*P value for difference between total GBC cases and controls.
cDDD, cumulative defined daily dose; GBC, gallbladder cancer; PPI, proton pump inhibitor.
Table 2.
OR and 95% CI of GBC associated with PPI use and other covariates
| Variables | OR (95% CI) | P value |
| Infectious diseases | ||
| HBV | 2.31 (1.72 to 3.25)* | <0.001 |
| HCV | 2.65 (1.44 to 4.36)* | <0.001 |
| Fatty liver disease | 1.63 (1.20 to 2.03)* | <0.001 |
| Alcohol intake | 1.68 (1.44 to 2.19)* | <0.001 |
| Smoking | 2.23 (1.84 to 2.73)* | <0.001 |
| Diabetes mellitus | 2.54 (1.87 to 3.41)* | 0.002 |
| Dyslipoproteinaemia | 2.15 (1.72 to 2.66)* | <0.001 |
| Hypertension | 0.88 (0.67 to 1.15) | 0.36 |
| Obesity | 2.12 (1.68 to 2.46)* | <0.001 |
| Coronary artery disease | 0.81 (0.56 to 1.15) | 0.062 |
| Aspirin use | 0.49 (0.38 to 0.63)* | <0.001 |
| PPI use | 1.56 (1.07 to 2.19)* | 0.005 |
| Duration of use (years) | ||
| ≤3 | 1.79 (1.03 to 3.10)* | 0.034 |
| >3 | 2.41 (1.05 to 4.93)* | 0.031 |
| Dose (cDDD) | ||
| 0–27 | ||
| 28–90 | 1.42 (0.80 to 2.41) | 0.219 |
| 91–180 | 1.67 (1.03 to 2.76)* | 0.036 |
| >180 | 2.69 (1.15 to 7.28)* | 0.018 |
*Adjusted OR was estimated using conditional logistic regression adjusted for other covariates listed in the table.
cDDD, cumulative defined daily dose; GBC, gallbladder cancer; PPI, proton pump inhibitor.
This observation is biologically plausible as supported by preclinical studies of GBC and other cancers. It is hypothesised that hypochlorhydria induced by daily PPI use produces periods during the day in which the pH of the gastric juice is at or near neutral pH levels.7 8 A study by Shindo et al 7 showed that hypochlorhydria can induce major changes in the gastric flora and affect the pH of small bowel fluid to allow bacterial overgrowth thereby increasing the risk of retrograding to the biliary system and thus elevating the incidence of biliary tract infection,1 and biliary tract infection is a recognised risk factor for GBC.9 Thus, our study may indirectly support the results of Chuang et al 1 that PPI use increased the incidence of cholecystitis.1
In conclusion, this hospital-based case–control study indicates PPI use as a significant risk factor for GBC progression, which seems to be dose-dependent.
Footnotes
Contributors: JX and YW contributed to the conception of the article, initiated the draft of the article, revised the article and contributed equally to the article. GC conducted the data analysis and revised the article. LJ revised the article and is the guarantor of the article.
Funding: This work was supported by grants from the research and demonstration of clinical diagnosis and treatment technology, Beijing Municipal Commission of Science and Technology (Z191100006619030), and 'Sailing' plans of clinical technology innovation project in 2018, Beijing Municipal Hospital Administration (XMLX201801).
Disclaimer: The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. No additional external funding received for this study.
Map disclaimer: None declared.
Competing interests: None declared.
Patient and public involvement: Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.
Patient consent for publication: Not required.
Ethics approval: This study gained approval from the Institutional Review Board of the Beijing Friendship Hospital of Capital Medical University, Beijing, China.
Provenance and peer review: Not commissioned; externally peer reviewed.
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