Beneficial effect of angiotensin-blocking agent candesartan on compensated alcoholic liver fibrosis : a randomized controlled trial

Abstract

[한글]

[영문]Recent studies have shown that the renin-angiotensin system is implicated in hepatic fibrogenesis in vitro and in vivo. However no study was done via histology in humans with alcoholic liver disease. We prospectively studied the antifibrotic effect of angiotensin II blocking agents (ARB) in patients with alcoholic liver disease. Patients with compensated alcoholic liver fibrosis (? Fibrosis stage 2, F2) were randomized to receive either the ARB, candesartan (8 mg/day) with ursodeoxycholic acid(UDCA)(600 mg/day)(n = 37), or UDCA alone(n = 36) as control for 6 months. All enrolled patients underwent liver biopsies twice at baseline and 6 months later for measurement of fibrosis score, area of fibrosis and α-smooth muscle actin (SMA) positive and hydroxyproline. Transforming growth factor-?1(TGF-?1), collagen-1, angiotensin II type I receptor (AT1-R), tissue inhibitor of metalloproteinase-1(TIMP-1), Rac1 and p22phox which represent oxidant stress were also measured by real-time RT?PCR before and after 6 months of therapy. Candesartan reduced the fibrosis score according to the Laennec fibrosis system from 3.4±1.4 to 3.0±1.0 (P < 0.05). Candesartan also reduced the area of fibrosis and α-smooth muscle actin (SMA) positive from 11.2±6.0 to 8.2±5.1 and 27.4±10.6 to 22.3±9.4, and hydroxyproline levels (?g/g liver tissue) from 7.8±2.6 to 5.9±1.9, respectively (P < 0.05). In addition, the relative expression of TGF-?1, collagen-1, AT1-R, TIMP-1, Rac1 and p22phox by real-time RT-PCR were decreased in the candesartan group (P < 0.05). No significant complication and side effect was observed during the present study. In conclusion, administration of ARB in compensated alcoholic liver disease induces decrease of fibrosis in both histological and quantitative measurements. These results provide an evidence for a beneficial role of ARB in compensated alcohol-related liver fibrosis.