A PILOT-STUDY OF THE EFFECTS OF D-ALPHA-TOCOPHEROL ON HEPATIC STELLATE CELL ACTIVATION IN CHRONIC HEPATITIS-C

Background & Aims: Oxidative stress mediates activation and stimulates collagen production of cultured hepatic stellate (Ito) cells. The aim of this study was to assess whether oxidative stress contributes to h epatic fibrogenesis in chronic hepatitis C. Methods: In liver biopsy s pecimens of patients with chronic hepatitis C, the following fibrogene sis cascade was analyzed: (1) oxidative stress, determined by the pres ence of malondialdehyde protein adducts; (2) activation of stellate ce lls as indicated by their expression of alpha-smooth muscle actin; (3) stimulation of c-myb expression in stellate cells, a critical step in the activation of these cells; and (4) induction of collagen gene exp ression as detected by in situ hybridization. Results: Treatment with da-tocopherol (1200 IU/day for 8 weeks) in 6 of these patients, who we re refractory to interferon therapy, prevented the fibrogenesis cascad e observed before antioxidant treatment. In addition, d-alpha-tocopher ol treatment significantly decreased the carbonyl modifications of pla sma proteins, a sensitive index of oxidative stress. However, 8 weeks of d-alpha-tocopherol treatment did not significantly affect serum ala nine aminotransferase levels, hepatitis C virus titers, or histologica l degree of hepatocellular inflammation or fibrosis. Conclusions: Thes e data suggest that enhanced oxidative stress initiates a fibrogenesis cascade in the liver of patients with chronic hepatitis C.