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Cirrhotic portal hypertension: From pathophysiology to novel therapeutics

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...

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Autores principales: Gunarathne, Lakmie S, Rajapaksha, Harinda, Shackel, Nicholas, Angus, Peter W, Herath, Chandana B
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Baishideng Publishing Group Inc 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7596642/
https://www.ncbi.nlm.nih.gov/pubmed/33177789
http://dx.doi.org/10.3748/wjg.v26.i40.6111
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author Gunarathne, Lakmie S
Rajapaksha, Harinda
Shackel, Nicholas
Angus, Peter W
Herath, Chandana B
author_facet Gunarathne, Lakmie S
Rajapaksha, Harinda
Shackel, Nicholas
Angus, Peter W
Herath, Chandana B
author_sort Gunarathne, Lakmie S
collection PubMed
description 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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spelling pubmed-75966422020-11-10 Cirrhotic portal hypertension: From pathophysiology to novel therapeutics Gunarathne, Lakmie S Rajapaksha, Harinda Shackel, Nicholas Angus, Peter W Herath, Chandana B World J Gastroenterol Review 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. Baishideng Publishing Group Inc 2020-10-28 2020-10-28 /pmc/articles/PMC7596642/ /pubmed/33177789 http://dx.doi.org/10.3748/wjg.v26.i40.6111 Text en ©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved. http://creativecommons.org/licenses/by-nc/4.0/ This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial.
spellingShingle Review
Gunarathne, Lakmie S
Rajapaksha, Harinda
Shackel, Nicholas
Angus, Peter W
Herath, Chandana B
Cirrhotic portal hypertension: From pathophysiology to novel therapeutics
title Cirrhotic portal hypertension: From pathophysiology to novel therapeutics
title_full Cirrhotic portal hypertension: From pathophysiology to novel therapeutics
title_fullStr Cirrhotic portal hypertension: From pathophysiology to novel therapeutics
title_full_unstemmed Cirrhotic portal hypertension: From pathophysiology to novel therapeutics
title_short Cirrhotic portal hypertension: From pathophysiology to novel therapeutics
title_sort cirrhotic portal hypertension: from pathophysiology to novel therapeutics
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7596642/
https://www.ncbi.nlm.nih.gov/pubmed/33177789
http://dx.doi.org/10.3748/wjg.v26.i40.6111
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