Molecular pathophysiology of portal hypertension

Abstract

Over the past two decades the advances in molecular cell biology have led to significant discoveries about the pathophysiology of portal hypertension (PHT). In particular, great progress has been made in the study of the molecular and cellular mechanisms that regulate the increased intrahepatic vascular resistance (IHVR) in cirrhosis. We now know that the increased IHVR is not irreversible, but that both the structural component caused by fibrosis and the active component caused by hepatic sinusoidal constriction can be, at least partially, reversed. Indeed, it is now apparent that the activation of perisinusoidal hepatic stellate cells, which is a key event mediating the augmented IHVR, is regulated by multiple signal transduction pathways that could be potential therapeutic targets for PHT treatment. Furthermore, the complexity of the molecular physiology of PHT can also be appreciated when one considers the complex signals capable of inducing vasodilatation and hyporesponsiveness to vasoconstrictors in the splanchnic vascular bed, with several vasoactive molecules, controlled at multiple levels, working together to mediate these circulatory abnormalities. Added to the complexity is the occurrence of pathological angiogenesis during the course of disease progression, with recent emphasis given to understanding its molecular machinery and regulation. Although much remains to be learned, with the current availability of reagents and new technologies and the exchange of concepts and data among investigators, our knowledge of the molecular basis of PHT will doubtless continue to grow, accelerating the transfer of knowledge generated by basic research to clinical practice. This will hopefully permit a better future for patients with PHT. (HEPATOLOGY 2015;61:1406-1415 Pathophysiology of Portal HypertensionPortal hypertension (PHT) is a major complication of chronic liver diseases, including cirrhosis of the liver, which are leading causes of death and liver transplantation worldwide. 1,2 The prime determinant of PHT in cirrhosis is the increased intrahepatic vascular resistance (IHVR) that occurs in the cirrhotic liver, which manifests through distortion of the liver vascular architecture caused by fibrosis, scarring, and nodule formation, as well as by hepatic sinusoidal cellular alterations that promote constriction of the hepatic sinusoids. Another further mechanism determining PHT is an increased splanchnic blood flow, partly due to mesenteric arteriolar vasodilatation and decreased vascular responsiveness to endogenous vasoconstrictors. This increased splanchnic blood flow perpetuates and exacerbates portal pressure elevation, promotes ascites and spontaneous bacterial peritonitis, and is associated with the formation of portosystemic collateral vessels and esophageal varices, which are, in turn, responsible for life-threatening consequences like gastroesophageal bleeding, portosystemic encephalopathy, and sepsis. 3 A growing body of evidence indicates that angiogenesis, the formation of new blood vessels from...

PAI-1 4G-4G, MTHFR 677TT, V Leiden 506Q, and Prothrombin 20210A in Splanchnic Vein Thrombosis: Analysis of Individual Patient Data From Three Prospective Studies

“…We think that PAI-1 4G-4G and MTHFR 677TT can increase the inflammation response, participating to the activation of perisinusoidal hepatic stellate cells, causing hepatic fibrosis and augmented intrahepatic vascular resistance typical of the LC, as suggested by Fernandez. 13 V Leiden 506Q was significantly correlated with BCS patients (13/45 patients), confirming other previous articles on BCS, 14,15 but Hardy-Weinberg equilibrium for V Leiden 506Q was respected both in patients with SVT and in HC.…”

Thrombophilic genetic factors PAI-1 4G-4G and MTHFR 677TT as risk factors of alcohol, cryptogenic liver cirrhosis and portal vein thrombosis, in a Caucasian population

“…We suppose that PAI-1 4G-4G and MTHFR 677TT may increase the inflammation response, participating in the activation of perisinusoidal stellate cells, causing hepatic fibrosis and augmented intrahepatic vascular resistance in cirrhosis, as suggested by Fernandez (Fernandez, 2014).…”

Kruppel-like factor 2 inhibit the angiogenesis of cultured human liver sinusoidal endothelial cells through the ERK1/2 signaling pathway

“…Portal hypertension (PHT) is a major complication of liver cirrhosis, which signifies a leading cause for mortality and transplantation [22]. Recent studies considered angiogenesis as an important pathophysiological feature of PHT [23,24]. Furthermore, many studies have demonstrated that angiogenesis inhibitory drugs may be effective in reducing portal pressure, which suggests that anti-angiogenesis could be a valuable therapy for PHT [25,26].…”