Study On Cirrhotic Portal Hypertension: An Approach from Pathophysiology to Novel Therapeutics

Portal hypertension and bleeding from gastric varices are the most common causes of morbidity and mortality in cirrhotic patients. Increased intrahepatic vascular resistance and a hyperdynamic circulatory condition cause portal hypertension. High cardiac output, higher total blood volume, and splanchnic vasodilation characterise the latter, all of which result in increased mesenteric blood flow. In cirrhotic portal hypertension, pharmacological therapy targets both the splanchnic and hepatic vascular beds. Drugs that target the classic renin-angiotensin system’s components (RAS), Angiotensin converting enzyme inhibitors and angiotensin II type receptor 1 blockers, for example, are believed to treat portal hypertension by lowering intrahepatic vascular tone by reducing extracellular matrix deposition and contractile cell vasoactivity. These drugs have been linked to side effects such as systemic hypotension and renal failure. As a result, non-selective -blockers (NSBBs) have become the standard of care for reducing variceal bleeding and improving patient mortality by lowering portal pressure. These NSBBs work by decreasing cardiac output and increasing splanchnic vasodilation. However, the majority of patients do not receive an acceptable therapeutic response, and a significant proportion of patients are unable to handle these drugs. Although statins have been shown to lower portal pressure and overall mortality in cirrhotic patients when used alone or in conjunction with NSBBs, they are not without side effects. There is a need for more randomised clinical studies with larger patient populations and precise clinical end goals. Recent findings from research into the potential use of alternate RAS component blockers to inhibit splanchnic vasodilation in portal hypertension provided compelling evidence that could lead to the development of drugs that target the splanchnic vascular bed to inhibit splanchnic vasodilation in portal hypertension. This review outlines the pathogenesis of portal hypertension and attempts to provide an update on current therapeutic approaches in the management of portal hypertension, with a focus on how the alternate RAS could be manipulated in our search for safe, specific, and effective novel therapies to treat portal hypertension in cirrhosis.

Author (S) Details

Lakmie S. Gunarathne
Department of Medicine, Melbourne Medical School, The University of Melbourne, Heidelberg, VIC 3084, Australia.

Harinda Rajapaksha
Oracle for Research, Oracle Australia, VIC 3000, Australia.

Nicholas Shackel
ANZAC Research Institute, Concord, NSW 2139, Australia.

Peter W. Angus
Department of Gastroenterology, Austin Health, Heidelberg, VIC 3084, Australia.

Chandana B. Herath
Department of Medicine, Melbourne Medical School, The University of Melbourne, Heidelberg, VIC 3084, Australia and South Western Sydney Clinical School, Faculty of Medicine, University of New South Wales, Ingham Institute for Applied Medical Research, Liverpool, NSW 2170, Australia.

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