Alcohol increases reactive oxygen species (ROS) formation in hepatocyte mitochondria and by reduced nicotinamide adenine dinucleotide phosphate oxidases and myeloperoxidase (MPO) in Kupffer cells and liver-infiltrating neutrophils. Manganese superoxide dismutase (MnSOD) converts superoxide anion into hydrogen peroxide, which, unless detoxified by glutathione peroxidase or catalase (CAT), can form the hydroxyl radical with iron. Our aim was to determine whether Ala16Val-superoxide dismutase 2 (SOD2), G-463A-MPO, or T-262C-CAT dimorphisms modulate the risks of hepatocellular carcinoma (HCC) and death in alcoholic cirrhosis. Genotypes and the hepatic iron score were assessed in 190 prospectively followed patients with alcoholic cirrhosis. During follow-up (61.1 ؎ 2.7 months), 51 patients developed HCC, and 71 died. The T-262C-CAT dimorphism did not modify hepatic iron, HCC, or death. The GG-MPO genotype did not modify iron but increased the risks of HCC and death. The hazard ratio (HR) was 4.7 (2.1-10.1) for HCC and 3.6 (1.9-6.7) for death. Carriage of one or two Ala-SOD2 allele(s) was associated with higher liver iron scores and higher risks of HCC and death. The 5-year incidence of HCC was 34.4% in patients with both the GG-MPO genotype and one or two Ala-SOD2 alleles, 5.1% in patients with only one of these two traits, and 0% in patients with none of these traits. Corresponding 5-year death rates were 37.6%, 11.6%, and 5%. Conclusion: The combination of the GG-MPO genotype (leading to high MPO expression) and at least one Ala-SOD2 allele (associated with high liver iron score) markedly increased the risks of HCC occurrence and death in patients with alcoholic cirrhosis. (HEPATOLOGY 2009;50:1484-1493.)
O xidative stress plays an important role in the pathogenesis of alcoholic cirrhosis and its complications. 1 Together with cytokine-mediated apoptosis, reactive oxygen species (ROS) could cause cell death and the possible development of liver failure. 1 ROS could also cause DNA damage, somatic mutations, and the possible development of a hepatocellular carcinoma (HCC). 1 Functional genetic polymorphisms affect both prooxidant and antioxidant enzymes. Myeloperoxidase (MPO) is expressed in neutrophils and Kupffer cells, 2 which are involved in the pathogenesis of alcoholic liver disease. 3 MPO catalyzes the reaction of H 2 O 2 with Cl Ϫ to form the highly reactive hypochlorous acid (HOCl) and anion (OCl Ϫ ). 4 A G3 A base exchange at position Ϫ463 affects the MPO promoter. 5 The GG-MPO genotype is associated with higher MPO protein expression than the GA-MPO or AA-MPO genotypes 6 and is a risk factor for cirrhosis in patients with hemo-