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 (8 mg/day) with ursodeoxycholic acid (UDCA) (600 mg/day) (n = 42) or UDCA alone (n = 43) as control for 6 months 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 α-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 (μg/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-β1(TGF-β1), 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.