Risk factors and mechanisms of hepatocarcinogenesis with special emphasis on alcohol and oxidative stress.
Hepatocellular cancer is the fifth most frequent cancer in men and the eighth in women worldwide. Established risk factors are chronic hepatitis B and C infection, chronic heavy alcohol consumption, obesity and type 2 diabetes, tobacco use, use of oral contraceptives, and aflatoxin-contaminated food. Almost 90% of all hepatocellular carcinomas develop in cirrhotic livers. In Western countries, attributable risks are highest for cirrhosis due to chronic alcohol abuse and viral hepatitis B and C infection. Among those with alcoholic cirrhosis, the annual incidence of hepatocellular cancer is 1-2%. An important mechanism implicated in alcohol-related hepatocarcinogenesis is oxidative stress from alcohol metabolism, inflammation, and increased iron storage. Ethanol-induced cytochrome P-450 2E1 produces various reactive oxygen species, leading to the formation of lipid peroxides such as 4-hydroxy-nonenal. Furthermore, alcohol impairs the antioxidant defense system, resulting in mitochondrial damage and apoptosis. Chronic alcohol exposure elicits hepatocyte hyperregeneration due to the activation of survival factors and interference with retinoid metabolism. Direct DNA damage results from acetaldehyde, which can bind to DNA, inhibit DNA repair systems, and lead to the formation of carcinogenic exocyclic DNA etheno adducts. Finally, chronic alcohol abuse interferes with methyl group transfer and may thereby alter gene expression.
Seitz
Helmut K
HK
Department of Medicine and Laboratory of Alcohol Research, Liver Disease and Nutrition, Salem Medical Center, D-69121 Heidelberg, Germany. helmut_karl.seitz@urz.uni-heidelberg.de
Stickel
Felix
F
D000428:Alcohol Drinking / Q000453:epidemiology / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000453:epidemiology / Q000209:etiology* / Q000378:metabolism; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism; D004260:DNA Repair; D000431:Ethanol / Q000378:metabolism / Q000633:toxicity; D005260:Female; D006801:Humans; D007249:Inflammation / Q000378:metabolism / Q000503:physiopathology; D007501:Iron / Q000378:metabolism; D008113:Liver Neoplasms / Q000453:epidemiology / Q000209:etiology* / Q000378:metabolism; D008297:Male; D008954:Models, Biological; D018384:Oxidative Stress / Q000502:physiology; D012176:Retinoids / Q000378:metabolism; D012307:Risk Factors
D012176:Retinoids; D000431:Ethanol; D007501:Iron; D019392:Cytochrome P-450 CYP2E1