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    Cirrhotic portal hypertension: From pathophysiology to novel therapeutics

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    Author
    Gunarathne, LS; Rajapaksha, H; Shackel, N; Angus, PW; Herath, CB
    Date
    2020-10-28
    Source Title
    World Journal of Gastroenterology
    Publisher
    BAISHIDENG PUBLISHING GROUP INC
    University of Melbourne Author/s
    Herath, Chandana
    Affiliation
    Medicine and Radiology
    Metadata
    Show full item record
    Document Type
    Journal Article
    Citations
    Gunarathne, L. S., Rajapaksha, H., Shackel, N., Angus, P. W. & Herath, C. B. (2020). Cirrhotic portal hypertension: From pathophysiology to novel therapeutics. WORLD JOURNAL OF GASTROENTEROLOGY, 26 (40), pp.6111-6140. https://doi.org/10.3748/wjg.v26.i40.6111.
    Access Status
    Open Access
    URI
    http://hdl.handle.net/11343/253016
    DOI
    10.3748/wjg.v26.i40.6111
    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.

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