Prediagnostic circulating vitamin D levels and risk of hepatocellular carcinoma in European populations: A nested case-control study
Potential conflict of interest: Nothing to report.
This work was supported by the French National Cancer Institute (L'Institut National du Cancer; INCA) (grant number 2009-139; PI: M. Jenab). 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 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 (INSERM) (France); Deutsche Krebshilfe, Deutsches Krebsforschungszentrum (DKFZ); and Federal Ministry of Education and Research (Germany); Hellenic Health Foundation (Greece); Italian Association for Research on Cancer (AIRC); National Research Council; and AIRE-ONLUS Ragusa, AVIS Ragusa, Sicilian Government (Italy); Associazione Italiana per la Ricerca sul Cancro-AIRC-Italy (Florence, Italy); Dutch Ministry of Public Health, Welfare and Sports (VWS); Netherlands Cancer Registry (NKR); LK Research Funds; Dutch Prevention Funds; Dutch ZON (Zorg Onderzoek Nederland); World Cancer Research Fund (WCRF); and Statistics Netherlands (the Netherlands); European Research Council (ERC) (grant number ERC-2009-AdG 232997), Nordforsk, Nordic Center of Excellence Programme on Food, Nutrition and Health, European Research Council, Norwegian Cancer Society and Norwegian Research Council (Norway); Health Research Fund (FIS); Regional Governments of Andalucía, Asturias, Basque Country, Murcia (No. 6236) and Navarra; and ISCIII RETIC (RD06/0020) (Spain); Swedish Cancer Society; Swedish Scientific Council; and Regional Government of Skåne and Västerbotten (Sweden); Cancer Research UK; Medical Research Council; Stroke Association; British Heart Foundation; Department of Health; Food Standards Agency; and Wellcome Trust (UK). The funding sources had no influence on the design of the study; the collection, analysis, and interpretation of data; the writing of the report; or the decision to submit the article for publication.
See Editorial on Page 1130
The association between vitamin D status and hepatocellular carcinoma (HCC) has not been well investigated, despite experimental evidence supporting an important role of vitamin D in liver pathophysiology. Our objective was to investigate the association between prediagnostic circulating 25-hydroxyvitamin D [25(OH)D] serum levels and the risk of HCC in a prospective, nested case-control study among 520,000 participants in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Each case (n = 138) diagnosed between 1992 and 2010 was matched to one control by age, sex, study center, date and time of blood collection, and fasting status. Serum baseline levels of 25(OH)D were measured by liquid chromatography/tandem mass spectrometry. Multivariable incident rate ratios (IRRs) of HCC associated with continuous (per 10 nmol/L) or categorical levels (tertiles or a priori-defined categories) of prediagnostic 25(OH)D were calculated using conditional logistic regression. Higher 25(OH)D levels were associated with a 49% reduction in the risk of HCC (highest versus lowest tertile: multivariable IRR = 0.51, 95% confidence interval [CI], 0.26 to 0.99; Ptrend = 0.04; per 10 nmol/L increase: IRR = 0.80, 95% CI, 0.68-0.94). The finding did not vary substantially by time from enrolment to diagnosis, and did not change after adjustment for biomarkers of preexisting liver damage, nor chronic infection with hepatitis B or C viruses. The findings were not modified by body size or smoking status. Conclusion: In this prospective study on western European populations, serum levels of 25(OH)D were inversely associated with the risk of HCC. Given the rising incidence of this cancer in low-risk developed countries and the strong public health interest surrounding the potentially cancer-protective roles of vitamin D, additional studies in different populations are required. (Hepatology 2014;60:1222–1230)