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Title: Cirrhotic portal hypertension: From pathophysiology to novel therapeutics.
Austin Authors: Gunarathne, Lakmie S;Rajapaksha, Harinda;Shackel, Nicholas;Angus, Peter W ;Herath, Chandana B
Affiliation: School of Molecular Science, College of Science, Health and Engineering, La Trobe University, Bundoora, VIC 3086, Australia
Gastroenterology and Hepatology
ANZAC Research Institute, Concord, NSW 2139, Australia
Department of Medicine, Melbourne Medical School, The University of Melbourne, Heidelberg, VIC 3084, Australia
Issue Date: 28-Oct-2020
Date: 2020-10-28
Publication information: World Journal of Gastroenterology 2020; 26(40): 6111-6140
Abstract: Portal hypertension and bleeding from gastroesophageal varices is the major cause of morbidity and mortality in patients with cirrhosis. Portal hypertension is initiated by increased intrahepatic vascular resistance and a hyperdynamic circulatory state. The latter is characterized by a high cardiac output, increased total blood volume and splanchnic vasodilatation, resulting in increased mesenteric blood flow. Pharmacological manipulation of cirrhotic portal hypertension targets both the splanchnic and hepatic vascular beds. Drugs such as angiotensin converting enzyme inhibitors and angiotensin II type receptor 1 blockers, which target the components of the classical renin angiotensin system (RAS), are expected to reduce intrahepatic vascular tone by reducing extracellular matrix deposition and vasoactivity of contractile cells and thereby improve portal hypertension. However, these drugs have been shown to produce significant off-target effects such as systemic hypotension and renal failure. Therefore, the current pharmacological mainstay in clinical practice to prevent variceal bleeding and improving patient survival by reducing portal pressure is non-selective -blockers (NSBBs). These NSBBs work by reducing cardiac output and splanchnic vasodilatation but most patients do not achieve an optimal therapeutic response and a significant proportion of patients are unable to tolerate these drugs. Although statins, used alone or in combination with NSBBs, have been shown to improve portal pressure and overall mortality in cirrhotic patients, further randomized clinical trials are warranted involving larger patient populations with clear clinical end points. On the other hand, recent findings from studies that have investigated the potential use of the blockers of the components of the alternate RAS provided compelling evidence that could lead to the development of drugs targeting the splanchnic vascular bed to inhibit splanchnic vasodilatation in portal hypertension. This review outlines the mechanisms related to the pathogenesis of portal hypertension and attempts to provide an update on currently available therapeutic approaches in the management of portal hypertension with special emphasis on how the alternate RAS could be manipulated in our search for development of safe, specific and effective novel therapies to treat portal hypertension in cirrhosis.
DOI: 10.3748/wjg.v26.i40.6111
Journal: World Journal of Gastroenterology
PubMed URL: 33177789
Type: Journal Article
Subjects: Alternate renin angiotensin system
Hyperdynamic circulatory state
Intrahepatic vascular resistance
Non-selective beta-blockers
Portal blood flow
Portal hypertension
Splanchnic vasodilatation
Appears in Collections:Journal articles

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