Coffee Consumption and Risk of Gallbladder Cancer in a Prospective Study

Susanna C. Larsson; Edward L. Giovannucci; Alicja Wolk

Disclosures

J Natl Cancer Inst. 2016;109(3) 

Abstract and Introduction

Abstract

Evidence indicates that coffee consumption may reduce the risk of gallstone disease, which is strongly associated with increased risk of gallbladder cancer. The association between coffee consumption and gallbladder cancer incidence was examined in a prospective cohort study of 72 680 Swedish adults (aged 45 − 83 years) who were free of cancer and reported their coffee consumption at baseline. Gallbladder cancers were ascertained by linkage with the Swedish Cancer Register. The data were analyzed using Cox proportional hazards regression models. Statistical tests were two-sided. During 967 377 person-years of follow-up, 74 gallbladder cancer case patients were identified. Compared with consumption of one or less cups of coffee per day, the multivariable hazard ratios were 0.76 (95% confidence interval [CI] = 0.41 to 1.41) for two cups per day, 0.50 (95% CI = 0.24 to 1.06) for three cups per day, and 0.41 (95% CI = 0.20 to 0.83) for four or more cups per day. In conclusion, coffee consumption is associated with a reduced risk of gallbladder cancer.

Introduction

The etiology of gallbladder cancer is poorly understood, but gallstone disease has consistently been associated with a substantial increased risk.[1] It is plausible therefore that factors that influence gallstone formation may affect the risk of developing gallbladder cancer. One such factor is coffee, which contains constituents that could influence processes involved in the formation of cholesterol gallstones. Coffee consumption stimulates cholecystokinin release,[2] enhances gallbladder contraction,[2] and decreases cholesterol crystallization in bile.[3] Prospective studies have reported an inverse association between high coffee consumption and risk of gallstone disease.[4] Coffee consumption has also been inversely associated with risk of gallbladder cancer in case-control studies[5–7] but not in a single cohort study of Japanese adults.[8] Given the scarcity of prospective data on coffee consumption and risk of gallbladder cancer, we investigated this association in a prospective study of Swedish adults.

Data were derived from the Swedish Mammography Cohort and the Cohort of Swedish Men, which are prospective cohorts in central Sweden. In the late autumn of 1997, 39 227 women and 48 850 men completed a 350-item questionnaire concerning diet and other risk factors for cancer.[9] A total of 72 680 participants (31 261 women and 41 419 men) age 45–83 years were included in the analysis after the following exclusions: incorrect or missing personal identification number; previous diagnosis of cancer in the Swedish Cancer Register; cholecystectomy (information from the Swedish Patient Register) before baseline; and missing response on coffee consumption (5.6% missing). Ethical approval was acquired from the Regional Ethical Review Board at Karolinska Institutet in Stockholm, Sweden. The completion of the questionnaire was considered to imply informed consent. The Swedish Mammography Cohort and the Cohort of Swedish Men are registered at clinicaltrials.gov as NCT01127698 and NCT01127711, respectively.

At baseline, participants reported their average daily or weekly consumption of coffee (in cups, 1 cup = 150 mL) over the past year on a questionnaire. The question on coffee has been validated by comparing it with four seven-day dietary records in a random sample of 111 women from the cohort; the correlation coefficient was 0.61.[10] Information on education, smoking, body mass index (derived from weight and height [kg/m2]), and other risk factors for cancer was acquired from the baseline questionnaire. Information on diabetes was obtained from the National Swedish Diabetes and Patient Registers and self-reports. Cases of gallbladder cancer, defined by the International Classification of Diseases 10th revision (ICD-10, code C23.9), were ascertained by linkage with the Swedish Cancer Register, which is over 96% complete.[11]

Follow-up time was calculated from January 1, 1998, until the first of the following: date of diagnosis of gallbladder cancer, cholecystectomy, death (information from the Swedish Cause of Death Register), or December 31, 2012. Cox proportional hazards regression models with age as the time scale and stratified by sex were used to estimate hazard ratios (HRs) with corresponding 95% confidence intervals (CIs). The assumption of proportionality was verified using Schoenfeld residuals. Apart from age and sex, multivariable models were adjusted for education, smoking, body mass index, and diabetes. Further adjustment for physical activity, waist circumference, and intakes of total energy, alcohol, tea, milk, and sweetened beverages did not change the results. Thus, those variables were not included in the multivariable model. Interaction by sex was tested based on the likelihood ratio test by introducing interaction terms into the multivariable Cox model. All statistical tests were two-sided, and a P value of less than .05 was considered statistically significant. All analyses were performed using SAS (version 9.4, SAS Institute, Cary, NC).

Compared with participants with low coffee consumption (nondrinkers and drinkers of one or less cups per day), those with high coffee consumption were somewhat younger and less likely to have a postsecondary education and diabetes, but were more likely to be current smokers (Table 1). During 13.3 years (967 377 person-years) of follow-up, 74 gallbladder cancer case patients (55 women and 19 men) were ascertained. Compared with consumption of one or less cups of coffee per day, the multivariable hazard ratios of gallbladder cancer were 0.76 (95% confidence interval [CI] = 0.41 to 1.41) for two cups per day, 0.50 (95% CI = 0.24 to 1.06) for three cups per day, and 0.41 (95% CI = 0.20 to 0.83) for four or more cups per day (Table 2). The age- and sex-adjusted incidence rates of gallbladder cancer for individuals who consumed one or less cups per day and four or more cups per day of coffee were, respectively, 13 and 5 per 100 000 person-years. Every one-cup per day increase in coffee consumption was associated with a 14% (95% CI = 0% to 26%) lower risk of gallbladder cancer. No interaction by sex was observed (P interaction = .55). Results remained after excluding case patients diagnosed within the first year of follow-up (multivariable HR for highest vs lowest category = 0.46, 95% CI = 0.22 to 0.96) and after excluding diabetics (HR = 0.38, 95% CI = 0.18 to 0.79). Coffee consumption was not associated with total extrahepatic biliary tract cancer, including cancers of the gallbladder (n = 74 case patients), ampulla of Vater (ICD-10 code C24.1, n = 7 case patients), and bile ducts (ICD-10 codes C24.0, C24.8, and C24.9; n = 53 case patients; HR for highest vs lowest category = 0.78, 95% CI = 0.45 to 1.36).

Strengths of this study are the prospective design and the objective and almost complete case ascertainment through linkage with the Swedish Cancer Register. As coffee consumption was assessed with a self-administered questionnaire at baseline, only some misclassification of exposure was inevitable. Furthermore, because of the observational design, the possibility that residual confounding may have influenced the findings cannot be excluded. However, the results persisted after adjustment for potential confounders. Despite the large sample size and relatively long follow-up, the number of case patients was limited.

In conclusion, coffee consumption was observed to be associated with a reduced risk of gallbladder cancer. A potential protective association between coffee consumption and risk of gallbladder cancer may be mediated via reduced gallstone formation (2,3) or through other mechanisms such as reduction of oxidative damage and inflammation and regulation of DNA repair, phase II enzymatic activity, apoptosis, angiogenesis, and metastasis (12).

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