Beneficial effects of candesartan, an angiotensin-blocking agent, on compensated alcoholic liver fibrosis - A randomized open-label controlled study

Background Recent studies have shown that the renin-angiotensin system is implicated in hepatic fibrogenesis in vitro and in vivo. However, no study was done in humans with alcoholic liver disease. Aim To investigate the antifibrotic effect of angiotensin II type 1 receptor (AT1-R) blocking agents (ARB) in patients with alcoholic liver disease. Methods The primary outcome was improvement in patients' histological features. Eighty-five patients with compensated alcoholic liver fibrosis (=F2) which was confirmed by baseline liver biopsy were randomized (intention-to-treat (ITT)) to receive either ARB, candesartan (8mg/day) with ursodeoxycholic acid (UDCA) (600mg/day) (n=42) or UDCA alone (n=43) as control for 6months and follow-up liver biopsies were conducted. Results According to the Laennec fibrosis system, candesartan showed significantly higher rates of histological improvements (ITT, 33.3% vs. 11.6%, P=0.020). In addition, the fibrosis score was significantly reduced from 3.4 +/- 1.4 to 3.1 +/- 1.5 (P=0.005) in the candesartan group. Candesartan also reduced the area of fibrosis and a-smooth muscle actin positive from 11.3 +/- 6.0 to 8.3 +/- 4.7 and 28.7 +/- 10.5 to 23.9 +/- 10.3 (%), and the hydroxyproline levels (mu g/g liver tissue) from 7.8 +/- 2.4 to 6.3 +/- 1.7 respectively (P<0.05). In addition, the relative expression of transforming growth factor-beta 1(TGF-beta 1), collagen-1, AT1-R, tissue inhibitor of metalloproteinase 1 (TIMP-1), metalloproteinases2 (MMP2), Rac1 and p22phox by real-time RT-PCR decreased in the candesartan group (P<0.05). Mean arterial blood pressure in the candesartan group decreased mildly but significantly (P<0.001). No significant complications and side effects were observed during the present study. Conclusions Administration of ARB in compensated alcoholic liver disease induces improvement of fibrosis in histological and quantitative measurements.