Effect of angiotensin receptor antagonist on liver fibrosis in early stages of chronic hepatitis C

Several lines of evidence1,2 have shown that angiotensin II (ANGII) participates in the development of hepatic fibrosis and that blockade of ANGII signaling can attenuate experimental liver fibrosis. We examined the effect of losartan, an angiotensin II type 1 (AT1) receptor antagonist, on plasma transforming growth factor 1 (TGF1) in patients with early stages of hepatic fibrosis of chronic hepatitis C. To determine the histologic effect of losartan on hepatic fibrosis, treatment and control groups were assessed by liver biopsy specimens before and after drug administration.3,4 The patients with early stages of hepatic fibrosis were chosen because the adverse effect of AT1 receptor antagonist in patients with advanced cirrhosis is controversial.5-7 This study consisted of 30 consecutive patients with early stages of chronic hepatitis C (21 men and 9 women; mean age, 55 years). The patients were randomized into 2 groups, one given oral losartan at a daily dose of 50 mg (losartan group) in addition to ursodeoxycholic acid (UDCA, 600 mg/d) and the other given no treatment except UDCA administration (control group). Plasma TGF1 (Quantikine immunoassay system; R&D Systems, Inc., Minneapolis, MN) and serum type IV collagen (enzyme-linked immunoassay; Fuji Pharmaceuticals Co., Tokyo, Japan) concentrations were compared before and after treatment in each group. All patients underwent liver biopsy before study entry and again at the completion of the study period. All histologic determinations were performed blindly by a single pathologist (S.S.) according to the METAVIR scoring system. Pairs of biopsy specimens taken at baseline and at study completion were morphometrically compared to assess the effect of losartan on the degree of hepatic fibrosis. Detailed morphometric analyses using a tablet measuring device for micromeasurement (Krypton-40; Flovel, Tokyo, Japan) were performed. The degree of fibrosis was expressed as the percentage of the total area measured. Mean blood pressure in the losartan group showed a slight but significant decrease (P .001). However, no patient had a hypotensive reaction during the losartan treatment. Losartan was well tolerated by all patients. Serum alanine transaminase (ALT) levels in the losartan group had a slight reduction (P .05) (Table 1). Other liver function tests did not change in either group. Serum HCV-RNA levels had not changed after the study in both groups. Serum type IV collagen in the losartan group significantly decreased after administration (P .05), unlike the controls. Plasma TGF1 concentrations in the losartan group showed a significant decrease with the drug (P .001). The fibrosis score was not significantly different before and after the study in the losartan group. However, in the losartan group, fibrosis area showed a significant decrease (P .001) although validity of the morphometrical analysis is still controversial.8 These results suggest that AT1 receptor antagonist may have a beneficial role in the early stages of hepatic fibrosis of patients with hepatitis C. In the present study we used UDCA as a control. Although there have been some reports showing positive results with UDCA in hepatitis C,9 others have reported negative results.10 What is needed is a randomized, placebo-controlled trial without administration of UDCA to confirm the benefit of AT1 receptor antagonists for hepatic fibrosis in chronic hepatitis C.