title: Association between heterozygosity for HFE gene mutations and hepatitis viruses in hepatocellular carcinoma.
abstract: Hepatitis B virus (HBV) and hepatitis C virus (HCV) infections are strong and independent risk factors for hepatocellular carcinoma (HCC) development. Patients with hereditary hemochromatosis (HH) are considered at risk of developing cancer. However, the interaction between HFE gene mutations and hepatitis viruses for HCC development has not been systematically searched for. To assess the interaction between HFE gene mutations and exogenous risk factors in the risk of HCC occurrence, a case-only approach, in which just a series of patients is enrolled, was used. Three hundred three cirrhotic patients (231 males, 72 females) from five liver units in different geographic areas of Italy, who developed HCC during regular follow-up between January 1999 and March 2003, and whose blood DNA was available, were analyzed. In all subjects, hepatitis B surface antigen (HBsAg), anti-HCV and HFE gene mutations were assayed; alcohol intake was recorded by history. The interaction between HFE genotypes and hepatitis viruses for HCC was estimated by multivariate analysis adjusting for the confounding effect of alcohol intake, area of residence and months of follow-up. Of the 303 HCC cases, 12 (4.0%) were heterozygous for the C282Y mutation, 93 (30.7%) for the H63D, and 198 (65.3%) homozygous for the wild allele. Multivariate analysis showed that C282Y heterozygous males were 3.8-fold (95% CI=1.0-15.2) more likely to be HBV positive and that H63D heterozygous females were 6.0-fold (95% CI=1.2-113.8) more likely to be HCV positive than wild type subjects. In conclusion, given the association between C282Y mutation and HBV infection in male patients with HCC, a careful evaluation and follow-up should be considered in the C282Y-positive subjects with hepatitis B virus related liver disease. The interaction between the H63D mutation and HCV, observed only in women, may reflect a higher sensitivity to H63D-induced iron metabolism abnormalities and a reduced antioxidant capability in the presence of an even minor increase of iron which may occur as a consequence of the coexistence of hepatitis C infection and heterozygosity for HH.
authors.affiliation: Dipartimento Medicina Interna, Ospedale Maggiore IRCCS, Via F Sforza 35, 20122 Milano, Italy.
authors.forename: Anna Ludovica
authors.initials: AL
authors.lastname: Fracanzani
authors.forename: Silvia
authors.initials: S
authors.lastname: Fargion
authors.forename: Maria Antonietta
authors.initials: MA
authors.lastname: Stazi
authors.forename: Luca
authors.initials: L
authors.lastname: Valenti
authors.forename: Pietro
authors.initials: P
authors.lastname: Amoroso
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Cariani
authors.forename: Angelo
authors.initials: A
authors.lastname: Sangiovanni
authors.forename: Maurizio
authors.initials: M
authors.lastname: Tommasini
authors.forename: Angelo
authors.initials: A
authors.lastname: Rossini
authors.forename: Cristina
authors.initials: C
authors.lastname: Bertelli
authors.forename: Erika
authors.initials: E
authors.lastname: Fatta
authors.forename: Valeria
authors.initials: V
authors.lastname: Patriarca
authors.forename: Sonia
authors.initials: S
authors.lastname: Brescianini
authors.forename: Tomaso
authors.initials: T
authors.lastname: Stroffolini
mesh_terms: D000914:Antibodies, Viral / Q000097:blood; D006528:Carcinoma, Hepatocellular / Q000453:epidemiology / Q000235:genetics* / Q000821:virology*; D005260:Female; D005500:Follow-Up Studies; D000071020:Hemochromatosis Protein; D016174:Hepacivirus / Q000276:immunology; D006514:Hepatitis B Surface Antigens / Q000097:blood; D006518:Hepatitis Viruses / Q000302:isolation & purification*; D006579:Heterozygote; D015395:Histocompatibility Antigens Class I / Q000235:genetics*; D006801:Humans; D007501:Iron / Q000378:metabolism; D008103:Liver Cirrhosis; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D015999:Multivariate Analysis; D009154:Mutation; D012307:Risk Factors; D012737:Sex Factors
chemical_list: D000914:Antibodies, Viral; C103673:HFE protein, human; D000071020:Hemochromatosis Protein; D006514:Hepatitis B Surface Antigens; D015395:Histocompatibility Antigens Class I; D008565:Membrane Proteins; D007501:Iron