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

The most common cause of morbidity and mortality in cirrhotic patients is portal hypertension and bleeding from gastroesophageal varices.Portal hypertension is initiated by increased intrahepatic vascular resistance and a hyperdynamic circulatory state. The latter is distinguished by a high cardiac output, increased total blood volume, and splanchnic vasodilatation, all of which result in increased mesenteric blood flow. The splanchnic and hepatic vascular beds are both targeted by pharmacological management in cirrhotic portal hypertension. Drugs that target the components of the classical renin angiotensin system (RAS), such as angiotensin converting enzyme inhibitors and angiotensin II type receptor 1 blockers, are expected to reduce intrahepatic vascular tone by reducing extracellular matrix deposition and contractile cell vasoactivity, and thus improve portal hypertension. Off-target effects such as systemic hypotension and renal failure have been observed with these medications. As a result, non-selective b-blockers (NSBBs) are the current therapeutic mainstay for preventing variceal bleeding and enhancing patient survival by lowering portal pressure.. These NSBBs function by lowering cardiac output and splanchnic vasodilation, however most patients do not get an adequate therapeutic response, and a large percentage of patients are unable to tolerate these medications. Although statins have been demonstrated to reduce portal pressure and overall mortality in cirrhotic patients when administered alone or in combination with NSBBs, further randomised clinical trials with larger patient populations and specific clinical end points are needed. Recent findings from studies looking into the potential use of blockers of alternate RAS components to inhibit splanchnic vasodilation in portal hypertension provided compelling evidence that could lead to the development of drugs targeting the splanchnic vascular bed to inhibit splanchnic vasodilation in portal hypertension. This review outlines the mechanisms underlying the pathogenesis of portal hypertension and attempts to provide an update on currently available therapeutic approaches in the management of portal hypertension, with a focus on how the alternate RAS could be manipulated in our quest for safe, specific, and effective novel therapies to treat portal hypertension in cirrhosis.