Iron overload is associated with hepatic oxidative damage to DNA in nonalcoholic steatohepatitis.
Several lines of evidence have suggested that oxidative stress plays an important role for the pathogenesis of nonalcoholic steatohepatitis (NASH). Therefore, by using immunohistochemical staining of liver biopsy samples, we measured hepatic 7,8-dihydro-8-oxo-2' deoxyguanosine (8-oxodG), a DNA base-modified product generated by hydroxyl radicals, of 38 NASH patients and compared with 24 simple steatosis and 10 healthy subjects. Relation of hepatic 8-oxodG with clinical, biochemical, and histologic variables and changes after iron reduction therapy (phlebotomy plus iron-restricted diet) were also examined. Hepatic 8-oxodG levels were significantly higher in NASH compared with simple steatosis (17.5 versus 2.0 8-oxodG-positive cells/10(5) microm(2); P < 0.0001). 8-oxodG was significantly related to iron overload condition, glucose-insulin metabolic abnormality, and severities of hepatic steatosis in NASH patients. Logistic regression analysis also showed that hepatic iron deposit and insulin resistance were independent variables associated with elevated hepatic 8-oxodG. After the iron reduction therapy, hepatic 8-oxodG levels were significantly decreased (from 20.7 to 13.8 positive cells/10(5) microm(2); P < 0.01) with concomitant reductions of serum transaminase levels in NASH patients. In conclusion, iron overload may play an important role in the pathogenesis of NASH by generating oxidative DNA damage and iron reduction therapy may reduce hepatocellular carcinoma incidence in patients with NASH.
Fujita
Naoki
N
Department of Gastroenterology and Hepatology, Division of Clinical Medicine and Biomedical Science, Institute of Medical Sciences, Mie University Graduate School of Medicine, Tsu, Mie, Japan. nfujita@clin.medic.mie-u.ac.jp
Miyachi
Hirohide
H
Tanaka
Hideaki
H
Takeo
Masaki
M
Nakagawa
Naoki
N
Kobayashi
Yoshinao
Y
Iwasa
Motoh
M
Watanabe
Shozo
S
Takei
Yoshiyuki
Y
D000080242:8-Hydroxy-2'-Deoxyguanosine; D000328:Adult; D000368:Aged; D000704:Analysis of Variance; D006528:Carcinoma, Hepatocellular / Q000209:etiology / Q000517:prevention & control; D016022:Case-Control Studies; D004249:DNA Damage; D003849:Deoxyguanosine / Q000031:analogs & derivatives* / Q000378:metabolism; D005234:Fatty Liver / Q000209:etiology* / Q000473:pathology; D005260:Female; D006801:Humans; D007333:Insulin Resistance; D019190:Iron Overload / Q000150:complications* / Q000473:pathology / Q000628:therapy; D008111:Liver Function Tests; D008113:Liver Neoplasms / Q000209:etiology / Q000517:prevention & control; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D018384:Oxidative Stress; D012720:Severity of Illness Index; D018709:Statistics, Nonparametric
D000080242:8-Hydroxy-2'-Deoxyguanosine; D003849:Deoxyguanosine