Impact of Inhibitors of the Renin-Angiotensin-Aldosterone System on Liver Fibrosis and Portal Hypertension

U.      Tox; H.   M.   Steffen

doi:10.2174/092986706779026138

Abstract

Morbidity and mortality of chronic liver disease are primarily caused by liver cirrhosis and portal hypertension, both of them secondary disorders of progressive liver fibrosis. The main fibrogenic cell type in the liver, the hepatic stellate cell (HSC), is activated and stimulated by several factors, among which the renin-angiotensin-aldosterone system (RAAS) plays a major role. Angiotensin II induces various profibrotic pathways via the angiotensin II receptor type 1 (AT1 receptor) not only in heart and kidney, but also in liver tissue. Stimulation of the AT1 receptor promotes the transformation of the quiescent HSC into the myofibroblast like activated HSC and the synthesis of transforming growth factor- 1 (TGF-7bgr;), the major profibrotic cytokine in the liver. In addition, aldosterone has been suggested to induce profibrotic effects in chronic heart and liver disease. This review focuses on the concept that inhibitors of the RAAS retard or even reverse liver fibrosis and reduce portal hypertension. Angiotensin converting enzyme (ACE) inhibitors, AT1 receptor antagonists, and aldosterone antagonists have been demonstrated to reduce the proliferation of HSC, to decrease the synthesis of profibrotic molecules, and to have the potential to improve liver fibrosis. However, side-effects such as systemic hypotension may impair the clinical application of RAAS inhibitors in patients with liver cirrhosis and portal hypertension. Also, efficacy may be limited by the downregulation of AT1 receptors in advanced fibrosis, which has been observed in animal and human studies. Randomized clinical studies are essential to evaluate, whether this approach is beneficial in patients with chronic liver disease and progressive fibrosis.

Keywords: Liver fibrosis, portal hypertension, renin-angiotensin-aldosterone system, AT1 receptor blocker, ACE inhibitor, aldosterone antagonist, aliskiren

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