Effect of Candesartan in Alcoholic Liver Fibrosis

Beneficial Effect of Angiotensin-blocking Agent Candesartan on Alcoholic Liver Fibrosis: A Randomized Controlled Trial

Background: Alcohol is one of principal causes of hepatic fibrosis. Although the most effective treatment for alcoholic hepatic fibrosis is abstinence of alcohol consumption, additive treatment to reduce the accumulation of scar tissue can accelerate the improvement of hepatic fibrosis in alcoholic liver disease. The renin-angiotensin system can be an attractive antifibrotic target in liver. Several lines of evidence indicate that overproduction of angiotensin II(ANG II) in chronic liver injury stimulates the activation of hepatic stellate cells(HSCs) attributed to fibrogenesis. Additionally, the antifibrotic effect of ANG II blocking agent has been shown in various animal models and hepatitis C patients. Hence, drugs that inhibit the renin-angiotensin system have promise in ameliorating hepatic fibrosis in chronic liver injury. However, no study has been conducted in patients with alcoholic liver disease to evaluate the effect ANG II type I receptor blocking agent on hepatic fibrosis. Aim: This study aimed to investigate the safety and the efficacy of chronic administration of candesartan to hepatic fibrosis patients with alcoholic liver disease. Methods 1) Patients with liver fibrosis(F2) were randomized to receive either the angiotensin receptor blocker(ARB), candesartan(8 mg/day) with ursodeoxycholic acid(UDCA)(600 mg/day)(n = 42), or UDCA alone(n = 43) as control for 6 months. 2)All enrolled patients underwent liver biopsies twice for measurement of fibrosis score, area of fibrosis and alpha-smooth muscle actin(SMA) positive and hydroxyproline. 3) Transforming growth factor-beta1(TGF-beta1), 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 group(42 patients): oral candesartan at a daily dose of 8 mgin addition to ursodeoxycholic acid (UDCA, 600 mg/day) for 6 months. UDCA group(43 patients): oral ursodeoxycholic acid (UDCA, 600 mg/day) only for 6 months

Inclusion Criteria: Clinical diagnosis of alcoholic liver disease METAVIR fibrosis score ≥ 2 in liver biopsy Alcohol intake has stop during at least 6 months until study enrollment Exclusion Criteria: Hepatocellular carcinoma or other malignancy Clinically decompensated cirrhosis (Total bilirubin ≥ 5mg/dL or variceal hemorrhage or ascites development or hepatic encephalopathy developement) Chronic liver disease related with other causes except alcohol

Yonsei University Wonju College of Medicine Department of Internal Medicine Devision of Gastroenterology and Hepatology

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