EXCESS IRON INDUCES HEPATIC OXIDATIVE STRESS AND TRANSFORMING-GROWTH-FACTOR BETA-1 IN GENETIC HEMOCHROMATOSIS

Genetic hemochromatosis (GH) is associated with excess iron deposition in hepatocytes, which results in progressive hepatic injury. The path ogenesis of hepatic injury in GH is poorly understood. In this study, we found enhanced oxidative stress in patients with GH, as evidenced b y hepatic malondialdehyde (MDA)-protein adducts and by increased oxida tively modified serum proteins. MDA-lysine epitopes and oxidatively mo dified serum proteins, as well as immunoglobulin G autoantibodies agai nst MDA-lysine epitopes, were increased in untreated GH patients and t o a lesser extent in GH heterozygotes compared with normal individuals , These markers of ongoing oxidative stress decreased with phlebotomy treatment in GH patients. In addition, TGF-beta 1 colocalized with hep atic iron and MDA protein adducts in hepatocytes and sinusoidal cells of hepatic acinar zone 1 and normalized after iron removal, Our data s uggest that iron overload increases both lipid peroxidation and TGF-be ta 1 expression, which together could promote hepatic injury and fibro genesis.