Functional aspects on the pathophysiology of portal hypertension in cirrhosis

Abstract

Hepatic Hemodynamic Laboratory, Liver Unit, IMDIM, Hospital Clinic, Institut d’Investigacions Biomediques August Pi i Sunyer (IDIBAPS)and CIBERehd, SpainPortal hypertension is a severe and frequent complication ofchronic liver disease. Its consequences, bleeding from gastro-esophageal varices and portal hypertensive gastropathy, ascites,spontaneous bacterial peritonitis, hepatorenal syndrome, hepato-pulmonary/portopulmonary syndromes, and hepatic encephalop-athy, represent the first cause of death and liver transplantationin patients with cirrhosis. The primary factor in the developmentof portal hypertension is a marked increase in hepatic vascularresistance (HVR) to portal blood flow, which was classicallyattributed to distortion of the liver architecture inherent to cir-rhosis. However, over the past 20 years, a better understandingof the liver microcirculation has demonstrated that a dynamiccomponent due to an increased hepatic vascular tone furthercontributes to augment HVR. Secondarily to the increased HVR,there is a progressive splanchnic vasodilatation that incrementsportal blood flow, which aggravates and perpetuates the portalhypertension syndrome [1] (Fig. 1).Intrahepatic vascular regulationThe analysis of the structural factors (fibrosis, vascular remodel-ing, vascular occlusion, nodule formation) contributing toincrease HVR is out of the scope of this review that will focuson the dynamic component of the increased HVR.During progression to cirrhosis, sinusoidal endothelial cells(SEC) become dysfunctional and among other features acquire avasoconstrictor phenotype, characterized by elevated productionof vasoconstrictors and reduced release of vasodilators. Theresulting imbalance promotes the contraction of different cellsof the cirrhotic liver, such as hepatic stellate cells (HSC), portalmyofibroblasts and vascular smooth muscle cells that lead toincreased hepatic vascular tone and portal pressure. HSC in turnalso experience a profound phenotypical transformation, withmorphologic and functional consequences: loss of vitamin Adroplets, alpha-smooth muscle actin overexpression, hyper-response to vasoconstrictors and enhanced proliferative and fibr-ogenic activity. Interestingly, in experimental models of cirrhosis,strategies aimed at improving the hepatic vascular tone by tar-geting SEC have also been shown to improve liver fibrosis. Thismay be due to the fact that cellular phenotype alterations sharepathophysiological mechanisms, but also because SEC phenotypeamelioration positively affects HSC phenotype [2].Increase of vasoconstrictors in the liverIncreasedactivityof several endogenous vasoconstrictors,such asendothelin, norepinephrine, angiotensin II, vasopressin, leukotri-enes, and thromboxane A