Review Angiotensin converting enzyme inhibitors and angiotensin II antagonists as therapy in chronic liver disease

Portal hypertension is the major complication of chronic liver disease and is associated with reduced survival. Pharmacological treatment is based on the premise that a sustained reduction in portal pressure will reduce the consequences of portal hypertension—that is, variceal bleeding, hepatic encephalopathy, and development of ascites. Non-selective â-blockers have proved eVective in reducing portal pressure by lowering splanchnic blood inflow and are used in primary and secondary prevention of variceal bleeding. 5 However, the mean decrease in portal pressure in response to propranolol is only approximately 15% and one third of cirrhotic patients do not respond despite adequate blockade. During the last decade, increased knowledge of the pathophysiology of portal hypertension has resulted in the use of new pharmacological targets; most importantly for the reduction of intrahepatic resistance, which is now recognised to be due in part to activated stellate cell contraction (myofibroblasts). These represent mesenchymal cells that reside in the perisinusoidal space of Disse and resemble tissue pericytes, a cell type with smooth muscle features that is thought to regulate blood flow via pericapillary constriction. During liver injury they undergo “activation”, characterised by production of increased amounts of extracellular matrix and are responsible for fibrosis. Moreover, experimental data provide strong evidence that activated stellate cells are contractile and may regulate sinusoidal blood flow, especially in the injured liver. The renin-angiotensin-aldosterone system (RAAS) is usually activated in patients with liver cirrhosis and this represents a homeostatic response to counterbalance the vasodilatation, arterial hypotension, and renal hypoperfusion observed in portal hypertension. Plasma renin activity (PRA) is elevated in cirrhotics and is correlated with the hepatic venous pressure gradient (HVPG). Angiotensin II (ANG-II) is considered a potential mediator of intrahepatic portal hypertension because its plasma levels are elevated in cirrhosis, and infusion of ANG-II induces a rise in portal pressure. Enhancement of the adrenergic vasoconstrictor influence on the portal system, direct contractile influence on activated stellate cells, and sodium and fluid retention induced by stimulation of aldosterone secretion are possible mechanisms that contribute to the portal hypertensive eVect of ANG-II. Hence, in theory, blockade of the RAAS by angiotensin converting enzyme (ACE) inhibitors/ANG-II receptor antagonists should be beneficial for improvement of fluid and salt secretion and reduce portal pressure in cirrhotic patients. ACE inhibitors block the RAAS preventing the conversion of inactive angiotensin I to active ANG-II, and may improve portal hypertension. However, concerns have been raised about their safety because of arterial hypotension and deterioration of renal function. Orally active ANG-II receptor antagonists represent the most recent therapeutic development in the inhibition of RAAS. They are eVective and safe in the control of systemic hypertension acting through specific AT1 receptors. Recently, the ANG-II receptor antagonists losartan and irbesartan have been studied in portal hypertensive patients with promising results. 21 We review the therapeutic eVects of these drugs in cirrhotic patients.