Coffee, including caffeinated and decaffeinated coffee, and the risk of hepatocellular carcinoma: a systematic review and dose-response meta-analysis

Abstract

Objectives: To examine the association between coffee, including caffeinated and decaffeinated coffee, with hepatocellular carcinoma (HCC) and assess the influence of HCC aetiology and pre-existing liver disease.

Design: We performed a systematic review and meta-analysis. We calculated relative risks (RRs) of HCC according to caffeinated and decaffeinated coffee consumption using a random-effects dose-response meta-analysis. We tested for modification of the effect estimate by HCC aetiology and pre-existing liver disease. We judged the quality of evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) criteria.

Results: We found 18 cohorts, involving 2 272 642 participants and 2905 cases, and 8 case-control studies, involving 1825 cases and 4652 controls. An extra two cups per day of coffee was associated with a 35% reduction in the risk of HCC (RR 0.65, 95% CI 0.59 to 0.72). The inverse association was weaker for cohorts (RR 0.71, 95% CI 0.65 to 0.77), which were generally of higher quality than case-control studies (RR 0.53, 95% CI 0.41 to 0.69). There was evidence that the association was not significantly altered by stage of liver disease or the presence/absence of high alcohol consumption, high body mass index, type 2 diabetes mellitus, smoking, or hepatitis B and C viruses. An extra two cups of caffeinated and decaffeinated coffee (2 and 3 cohort studies, respectively) were associated with reductions of 27% (RR 0.73, 95% CI 0.63 to 0.85) and 14% (RR 0.86, 95% CI 0.74 to 1.00) in the risk of HCC. However, due to a lack of randomised controlled trials, potential publication bias and there being no accepted definition of coffee, the quality of evidence under the GRADE criteria was 'very low'.

Conclusions: Increased consumption of caffeinated coffee and, to a lesser extent, decaffeinated coffee are associated with reduced risk of HCC, including in pre-existing liver disease. These findings are important given the increasing incidence of HCC globally and its poor prognosis.

Keywords: HCC; coffee; hepatocellular carcinoma; liver disease; meta-analysis.

Figure 1

An illustration showing how the studies included in this meta-analysis were reviewed and selected. HCC, hepatocellular carcinoma; HCV, hepatitis C virus.

Figure 2

A forest plot illustrating RRs of HCC for an extra two cups of coffee per day. The RRs as reported by the individual studies are shown as squares. The sizes of the squares represent the weightings in the random-effects model. The pooled RRs (from cohorts, case–control studies and all studies) are shown as diamonds. HCC, hepatocellular carcinoma; RR, relative risks.

Figure 3

Results of a cubic spline dose–response meta-analysis of the association between coffee and hepatocellular carcinoma.

Figure 4

Filled funnel plot for the risk of HCC per extra two cups of coffee daily. Black circles represent the included studies found by our search, while white circles represent the ‘missing’ unpublished studies detected in the trim-and-fill analysis. HCC, hepatocellular carcinoma; RR, relative risk.