title: Impact of inhibitors of the Renin-Angiotensin-aldosterone system on liver fibrosis and portal hypertension.
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 (AT(1) receptor) not only in heart and kidney, but also in liver tissue. Stimulation of the AT(1) receptor promotes the transformation of the quiescent HSC into the myofibroblast like activated HSC and the synthesis of transforming growth factor-beta1 (TGF-beta), 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, AT(1) 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 AT(1) 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.
authors.affiliation: Department of Gastroenterology and Hepatology, University Hospital, University of Cologne, Germany.
authors.forename: U
authors.initials: U
authors.lastname: Töx
authors.forename: H M
authors.initials: HM
authors.lastname: Steffen
mesh_terms: D015195:Drug Design; D006801:Humans; D006975:Hypertension, Portal / Q000503:physiopathology*; D008099:Liver / Q000503:physiopathology; D008103:Liver Cirrhosis / Q000503:physiopathology*; D012084:Renin-Angiotensin System / Q000187:drug effects*