Reversible factors in portal hypertension

Abstract

Abstract Liver fibrogenesis is a dynamic process involving complex cellular and molecular mechanisms, resulting from the chronic activation of the tissue repair mechanisms that follows repeated liver tissue injury. The role of hepatic stellate cells (HSC) in the progression of liver fibrosis has been extensively characterized. As a consequence of chronic liver tissue damage, HSC, as well as other extracellular matrix‐producing cells (e.g. fibroblasts and myofibroblasts), undergo a process of activation that leads to a phenotype characterized by increased proliferative, motile and contractile properties. Contraction of activated HSC occurs in vitro in response to different vasoconstrictors, and this feature may have important implications in the pathogenesis of portal hypertension and in the contraction of mature scar tissue. Activation of HSC within hepatic sinusoids during chronic liver diseases is a key feature of the capillarization of sinusoids. This latter feature likely represents an initial cause of portal hypertension during the early development of hepatic fibrosis. While fibrosis developing, as an expansion of portal tracts (e.g. in chronic viral hepatitis) constitutes an ‘early presinusoidal resistance locus, fibrosis developing around the centrilobular vein (e.g. alcoholic hepatitis and steatohepatitis) represents a cause of postsinusoidal resistance. In these conditions, in which portal hypertension is not yet clinically evident, the profibrogenic and contractile properties of activated HSC are probably very relevant for the development of portal hypertension. In cirrhotic liver, portal blood flow is largely diverted towards the systemic circulation through portal‐central anastomoses. These neoformed vascular structures, although representing direct connections between the portal and the systemic circulation, follow irregular patterns; they are the site of thrombotic events, and are embedded in developing scar tissue. This tissue is characterized by the presence of different types of extracellular matrix (ECM)‐producing cells, all potentially able to contract in response to vasoconstrictors (e.g. ET‐1) released within cirrhotic liver tissues. It is implicit that cell contraction in response to these agents could be antagonized by autologous vasodilators (e.g. NO) or by drugs with vasodilator properties. Taken together, these biological features represent a ‘reversible’ factor representing a potential targets for pharmacological therapies aimed at reducing portal pressure in patients with cirrhosis.