Copyright ©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Oct 28, 2020; 26(40): 6111-6140
Published online Oct 28, 2020. doi: 10.3748/wjg.v26.i40.6111
Cirrhotic portal hypertension: From pathophysiology to novel therapeutics
Lakmie S Gunarathne, Harinda Rajapaksha, Nicholas Shackel, Peter W Angus, Chandana B Herath
Lakmie S Gunarathne, Chandana B Herath, Department of Medicine, Melbourne Medical School, The University of Melbourne, Heidelberg, VIC 3084, Australia
Harinda Rajapaksha, School of Molecular Science, College of Science, Health and Engineering, La Trobe University, Bundoora, VIC 3086, 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, South Western Sydney Clinical School, Faculty of Medicine, University of New South Wales, Ingham Institute for Applied Medical Research, 1 Campbell Street, Liverpool, NSW 2170, Australia
Author contributions: Gunarathne LS and Herath CB contributed to the concept, and designed and wrote the manuscript; Rajapaksha H, Shackel N and Angus PW contributed by critically reviewing and editing the manuscript; Angus PW and Herath CB approved the final version of the manuscript.
Supported by National Health and Medical Research Council (NHMRC) of Australia Project Grants, No. APP1124125.
Conflict-of-interest statement: The authors declare that they have no conflict of interest.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (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. See:
Corresponding author: Chandana B Herath, PhD, Senior Lecturer, South Western Sydney Clinical School, Faculty of Medicine, University of New South Wales, Ingham Institute for Applied Medical Research, 1 Campbell Street, Liverpool, NSW 2170, Australia.
Received: July 31, 2020
Peer-review started: July 31, 2020
First decision: August 22, 2020
Revised: August 28, 2020
Accepted: September 17, 2020
Article in press: September 17, 2020
Published online: October 28, 2020

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.

Keywords: Portal hypertension, Cirrhosis, Intrahepatic vascular resistance, Hyperdynamic circulatory state, Splanchnic vasodilatation, Portal blood flow, Non-selective beta-blockers, Alternate renin angiotensin system

Core Tip: Cirrhosis is a major cause of death and affects over 300 million people worldwide. Portal hypertension is a life-threatening complication of cirrhosis, characterized by splanchnic vasodilatation, the formation of varices and variceal bleeding, which account for much of the mortality and morbidity in cirrhotic patients. Current “gold standard” clinical treatment is non-selective -blockers; however, their efficacy and tolerability are suboptimal. Recent findings from the author’s laboratory and others suggest that the alternate renin angiotensin system is a potential target to design and develop novel therapeutics to inhibit splanchnic vasodilatation in cirrhotic portal hypertension.