ORIGINAL PAPER Flavonoid intake and liver cancer: a case–control study in Greece Pagona Lagiou Æ Marta Rossi Æ Areti Lagiou Æ Anastasia Tzonou Æ Carlo La Vecchia Æ Dimitrios Trichopoulos Received: 14 November 2007 / Accepted: 27 February 2008 / Published online: 19 March 2008 Ó Springer Science+Business Media B.V. 2008 Abstract In the context of a case–control study under- taken in Greece, we examined the role of six flavonoid classes in the etiology of hepatocellular carcinoma (HCC), by viral status, and of cholangiocarcinoma (CAC). Data and blood samples were collected between 1995 and 1998. Information about dietary intakes and covariates, including chronic infection with hepatitis B (HBV) and C (HCV) virus, were available for 250 HBV and/or HCV positive HCC cases, 83 HBV and HCV negative HCC cases, six CAC cases, and 360 hospital controls. In logistic regression models including gender, age, education, tobacco smoking, and total energy intake, there were no distinct patterns with respect to either HCC virus positive and HCC virus negative in relation to total flavonoids or any class of flavonoids, with the exception of flavones. Flavone intake, mostly derived from spinach and peppers, was inversely associated with both virus positive (P-trend, 0.049) and virus negative (P-trend, 0.084) HCC. There was also a suggestion of an inverse association of CAC with flavan-3- ols, anthocyanidins, and total flavonoids which, however, has to be taken with due caution on account of the small number of cases of this rare tumor. We conclude that flavones may be inversely associated with HCC risk, irre- spective of its dominant etiology (viral or non viral). Keywords Flavonoids Á Flavones Á Hepatocellular carcinoma Á Liver cancer Á Cholangiocarcinoma Introduction Flavonoids are a group of over 5,000 polyphenolic com- pounds present in fruit, vegetables, and beverages of plant origin [1]. Due to their antioxidant, antimutagenic, and antiproliferative properties in vitro [2–4], they have been hypothesized to be responsible, at least in part, for the favorable effects of fruit and vegetables against various chronic diseases, including some common neoplasms. Flavonoids have been inversely associated with the risk of cancers of the upper aerodigestive tract [5–7], stomach [8, 9], colorectum [10–12], lung [13, 14], urinary tract [15–17], as well as breast [18–20]. With respect to liver cancer, several studies have reported an inverse association between vegetable and possibly fruit consumption and risk of hepatocellular car- cinoma (HCC) [21–25], although other studies, two of which from Greece, did not support this association P. Lagiou Á A. Lagiou Á A. Tzonou Á D. Trichopoulos Department of Hygiene and Epidemiology, School of Medicine, University of Athens, 75 M. Asias Street, Goudi, 115 27 Athens, Greece M. Rossi (&) Á C. La Vecchia Dipartimento di Epidemiologia Generale, Istituto di Ricerche Farmacologiche ‘‘Mario Negri’’, Via La Masa 19, 20156 Milan, Italy e-mail: mrossi@marionegri.it A. Lagiou Faculty of Health and Welfare Professions, Athens Technological Institute, 274 Thivon Avenue, Athens, Greece C. La Vecchia Istituto di Statistica Medica e Biometria ‘‘G. A. Maccacaro’’, Universita ` degli Studi di Milano, Milan, Italy D. Trichopoulos Department of Epidemiology, Harvard School of Public Health, 677 Huntington Avenue, Boston, MA 02115, USA 123 Cancer Causes Control (2008) 19:813–818 DOI 10.1007/s10552-008-9144-7