351 Reversibility of cirrhosis is associated with decrease of liver related complications

HEPATOLOGY, Vol. 38, No. 4, Suppl. 1, 2003

AASLD ABSTRACTS

35O ADIPONECTIN, AN ADIPOCYTOKINE, ATTENUATES CARBON-TETRACHLORIDE INDUCED LIVER FIBROSIS IN MICE. Yoshihiro Kamada, Shinji Tamura, Shinichi Kiso, Hitoshi

Matsumoto, Yukiko Saji, Yuichi Yoshida, Koji Fukui, Norikazu Maeda, Hitoshi Nishizawa, Hiroyuki Nagaretani, Yoshihisa Okamoto, Shinji Kihara, Jun-ichiro Miyagawa, Tohru Funahashi, Yuji Matsuzawa, Osaka University Graduate School of Medicine, Suita, Osaka, Japan Background & Aims: Hepatic cirrhosis is six times more prevalent in obese individuals than in the general population, and obesity is one of the risk factors for liver fibrosis in which plasma adiponectin levels are decreased. Adiponectin is an adipocytokine, which we previously identified by screening adipose-specific genes in the h u m a n cDNA project. Hepatic stellate cells (HSCs) play central roles in liver fibrosis. W h e n they are activated, they undergo transformation to myofibroblast-like cells, then proliferate, migrate, produce transforming growth factor-/31 (TGF-/31), and various extracellular matrix proteins, and express a-smooth muscle actin (a-SMA). We previously reported that adiponectin suppresses not only the proliferation and migration of HSCs, but also the TGF-/31-induced fibrogenic gene expression in HSCs. Adiponectin could have biological significances in liver fibrosis. In this study, in order to clarify the effect of adiponectin on liver fibrosis in vivo, we tested the role of adiponectin on liver fibrosis using adiponectin-knockout (KO) mice and adenovirus mediated adiponectin expression system. Methods: (1) To investigate the anti-fibrogenic effects of physiological concentrations of adiponectin, male wild type (WT) mice and KO mice were used. Mice were each injected with a dose of carbon-tetrachloride (CC14) (300 /A/kg/bw) intraperitoneally twice a week for 12 weeks to induce liver fibrosis. (2) To investigate the anti-fibrogenic effects of excessive concentrations of adiponectin, male WT mice were used. Mice were injected CC14 (1000/~I/kg/bw) intraperitoneally twice a week for 12 weeks. Mice were divided into 6 groups. Control, received an injection of corn oil only; Gr.1, mice treated with CC14 for 12 weeks; Gr.2, mice treated with CC14 for 12 weeks after infusion of adenovirus producing adiponectin (AdADN); Gr.3, mice treated with CC14 for 12 weeks after infusion of adenovirus producing/3-galactosidase (AdLacZ); Gr.4, mice treated with CC14 for 12 weeks with AdADN infusion at 6 week; Gr.5, mice treated with CC14 for 12 weeks with AdLacZ infusion at 6 week. Results: (1) KO mice showed extensive liver fibrosis with an enhanced expression of TGF-/31 and connective tissue growth factor (CTGF) compared to wild type (WT) mice (P<0.05). The hydroxyproline content and the numbers of a-SMA positive cells in mice liver significantly increased in KO mice. (2) The fibrosis areas were significantly decreased in Gr.2 and Gr.4 compared to those in Gr.3 and Gr.5, respectively. The hydroxyproline content in mice liver significantly decreased in Gr.2 and Gr.4 compared to that in Gr.3 and Gr.5, respectively. Moreover, in Gr.4, the hydroxyproline content was significantly decreased compared to that in 6-weeks of CC14 treatment even though CC14 was given for an additional 6-weeks (total 12 weeks). Conclusions: The findings indicate that adiponectin attenuates liver fibrosis and could be a novel approach in its prevention. Disclosures:

329A

Koji Fukui - No relationships to disclose Tohru Funahashi - No relationships to disclose Yoshihiro Kamada - No relationships to disclose Shinji Kihara - No relationships to disclose Shinichi Kiso - No relationships to disclose Norikazu Maeda - No relationships to disclose Hitoshi Matsumoto - No relationships to disclose Yuji Matsuzawa - No relationships to disclose Jun-ichiro Miyagawa - No relationships to disclose Hiroyuki Nagaretani - No relationships to disclose Hitoshi Nishizawa - No relationships to disclose Yoshihisa Okamoto - No relationships to disclose Yukiko Saji - No relationships to disclose Shinji Tamura - No relationships to disclose Yuichi Yoshida - No relationships to disclose

351 REVERSIBILITY OF CIRRHOSIS IS ASSOCIATED WITH DECREASE OF LIVER RELATED COMPLICATIONS. Serpaggi

Jeanne, Assistance Publique des H6pitaux de Paris, Paris, France Aim: To assess the impact of cirrhosis reversibility on survival and occurrence of cirrhosis complications. Methods: Retrospective analysis of patients with biopsy-proven cirrhosis and post treatment biopsy between january 1980 and may 2002. Resolution of cirrhosis was defined as a decrease of the Metavir fibrosis score - 2 after blinded analysis by two independent pathologists. Results: Etiologies of cirrhosis were the following: HCV (75%), HBV (11.8%), alcohol (5.9%), auto-immune (7.3%). Twenty-one (13 HCV, 3 HBV, and 5 auto-immune, all Child-Pugh A stage) of the 136 cirrhotic patients (15.3%) showed reversibility of cirrhosis. The mean time between first and last biopsies was 54 _+ 26 and 43 _+ 26 months for patients with or without regression, respectively ( p 0.07). The mean decrease of activity and fibrosis scores by METAVIR was 1.37 _+ 1.07 and 2.57 _+ 0.75 respectively for patients with and 0.53 _+ 1.06 and 0.11 _+ 0.32 for patients without reversibility of cirrhosis, respectively (ANOVA, p - 0.00). The rate of sustained response to treatment in patients with or without reversibility of cirrhosis was significantly different: 95% vs 34% (p - 0.00). Among the 16 patients with regressive viral cirrhosis, 15 were sustained virologic responders (33.8% of the total of complete responders) and I biological responder. In the 10 patients with auto-immune cirrhosis, all responded to immunosuppressive therapy (steroid and azathioprine) and 5 (50%) had reversibility of cirrhosis. During the follow-up (mean duration of follow-up: 84.3 _+ 31 months in patients with reversibility vs 84.5 -+ 33.5 months in the other group, p - 0.98), there were less liver cirrhosis complications (0% vs 25.2%, p - 0.02) and a trend to a decrease in mortality (0% vs 17.4%, p - 0.08) in patients with reversibility. Conclusions: Complete regression of cirrhosis associated with a sustained decrease or suppression of the necro-inflammation leads to decrease of liver-related morbidity, which may result in improvement of survival. Disclosures: Serpaggi Jeanne - No relationships to disclose