The association of coffee intake with liver cancer risk is mediated by biomarkers of inflammation and hepatocellular injury: data from the European Prospective Investigation into Cancer and Nutrition123

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ABSTRACT

Background: Higher coffee intake has been purportedly related to a lower risk of liver cancer. However, it remains unclear whether this association may be accounted for by specific biological mechanisms.

Objective: We aimed to evaluate the potential mediating roles of inflammatory, metabolic, liver injury, and iron metabolism biomarkers on the association between coffee intake and the primary form of liver cancer—hepatocellular carcinoma (HCC).

Design: We conducted a prospective nested case-control study within the European Prospective Investigation into Cancer and Nutrition among 125 incident HCC cases matched to 250 controls using an incidence-density sampling procedure. The association of coffee intake with HCC risk was evaluated by using multivariable-adjusted conditional logistic regression that accounted for smoking, alcohol consumption, hepatitis infection, and other established liver cancer risk factors. The mediating effects of 21 biomarkers were evaluated on the basis of percentage changes and associated 95% CIs in the estimated regression coefficients of models with and without adjustment for biomarkers individually and in combination.

Results: The multivariable-adjusted RR of having ≥4 cups (600 mL) coffee/d compared with <2 cups (300 mL)/d was 0.25 (95% CI: 0.11, 0.62; P-trend = 0.006). A statistically significant attenuation of the association between coffee intake and HCC risk and thereby suspected mediation was confirmed for the inflammatory biomarker IL-6 and for the biomarkers of hepatocellular injury glutamate dehydrogenase, alanine aminotransferase, aspartate aminotransferase (AST), γ-glutamyltransferase (GGT), and total bilirubin, which—in combination—attenuated the regression coefficients by 72% (95% CI: 7%, 239%). Of the investigated biomarkers, IL-6, AST, and GGT produced the highest change in the regression coefficients: 40%, 56%, and 60%, respectively.

Conclusion: These data suggest that the inverse association of coffee intake with HCC risk was partly accounted for by biomarkers of inflammation and hepatocellular injury.

Keywords:

biomarkers
coffee
European Prospective Investigation into Cancer and Nutrition
liver cancer
mediation

ABBREVIATIONS

AFP
α-fetoprotein
ALT
alanine aminotransferase
AST
aspartate aminotransferase
CRP
C-reactive protein
EPIC
European Prospective Investigation into Cancer and Nutrition
GGT
γ-glutamyltransferase
GLDH
glutamate dehydrogenase
HBsAg
hepatitis B surface antigen
HCC
hepatocellular carcinoma
HCV
hepatitis C virus
HMW
high molecular weight
NAFLD
nonalcoholic fatty liver disease

Cited by (0)

1

Supported by the Federal Ministry of Education and Research; the German Research Foundation; a grant from the German Research Foundation (DFG NO446/7-1), Germany; and the French National Cancer Institute (grant no. 2009-139). The coordination of EPIC is financially supported by the European Commission (DG-SANCO) and the International Agency for Research on Cancer. The national cohorts are supported by the Danish Cancer Society (Denmark); Ligue Contre le Cancer, Institut Gustave Roussy, Mutuelle Générale de l’Education Nationale, and Institut National de la Santé et de la Recherche Médicale (France); Deutsche Krebshilfe, Deutsches Krebsforschungszentrum (Germany); The Hellenic Health Foundation (Greece); Italian Association for Research on Cancer, National Research Council, and AIRE-ONLUS Ragusa, AVIS Ragusa, Sicilian Government (Italy); Dutch Ministry of Public Health, Welfare and Sports, Netherlands Cancer Registry, LK Research Funds, Dutch Prevention Funds, Dutch Zorg Onderzoek Nederland, World Cancer Research Fund, and Statistics Netherlands (Netherlands); European Research Council (grant no. ERC-2009-AdG 232997), Nordforsk, and Nordic Center of Excellence Programme on Food, Nutrition and Health (Norway); Health Research Fund, RETICC (RD12/0036/0018) of the Spanish Ministry of Health, and regional governments of Andalucía, Asturias, Basque Country, Murcia (no. 6236), and Navarra (Spain); Swedish Cancer Society, Swedish Scientific Council, and regional governments of Skåne and Västerbotten (Sweden); and Cancer Research UK, Medical Research Council, Stroke Association, British Heart Foundation, Department of Health, Food Standards Agency, and Wellcome Trust (United Kingdom).

1

Supplemental Table 1 is available from the “Online Supporting Material” link in the online posting of the article and from the same link in the online table of contents at http://ajcn.nutrition.org.

3

D Trichopoulos is deceased.

Copyright © 2015 American Society for Nutrition. Published by Elsevier Inc.