Nahon Pierre, Sutton Angela, Rufat Pierre, Ziol Marianne, Akouche Hassan, Laguillier Christelle, Charnaux Nathalie, Ganne-Carrié Nathalie, Grando-Lemaire Véronique, N'Kontchou Gisèle, Trinchet Jean-Claude, Gattegno Liliane, Pessayre Dominique, Beaugrand Michel
Service d'Hépatologie, Hôpital Jean Verdier, AP-HP, Bondy, France.
Hepatology. 2009 Nov;50(5):1484-93. doi: 10.1002/hep.23187.
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%.
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.
酒精会增加肝细胞线粒体中活性氧（ROS）的形成，并通过库普弗细胞和肝脏浸润中性粒细胞中还原型烟酰胺腺嘌呤二核苷酸磷酸氧化酶和髓过氧化物酶（MPO）的作用来增加ROS形成。锰超氧化物歧化酶（MnSOD）将超氧阴离子转化为过氧化氢，除非被谷胱甘肽过氧化物酶或过氧化氢酶（CAT）解毒，否则过氧化氢会与铁形成羟基自由基。我们的目的是确定Ala16Val-超氧化物歧化酶2（SOD2）、G-463A-MPO或T-262C-CAT基因多态性是否会调节酒精性肝硬化患者肝细胞癌（HCC）的风险和死亡风险。对190例接受前瞻性随访的酒精性肝硬化患者进行了基因型和肝脏铁评分评估。在随访期间（61.1±2.7个月），51例患者发生了HCC，71例死亡。T-262C-CAT基因多态性并未改变肝脏铁水平、HCC或死亡情况。GG-MPO基因型并未改变铁水平，但增加了HCC和死亡的风险。HCC的风险比（HR）为4.7（2.1-10.1），死亡的风险比为3.6（1.9-6.7）。携带一个或两个Ala-SOD2等位基因与较高的肝脏铁评分以及较高的HCC和死亡风险相关。同时具有GG-MPO基因型和一个或两个Ala-SOD2等位基因的患者中，HCC的5年发病率为34.4%，仅具有这两种特征之一的患者中为5.1%，而不具有这些特征的患者中为0%。相应的5年死亡率分别为37.6%、11.6%和5%。
GG-MPO基因型（导致MPO高表达）和至少一个Ala-SOD2等位基因（与高肝脏铁评分相关）的组合显著增加了酒精性肝硬化患者发生HCC和死亡的风险。
