title: New cellular and molecular targets for the treatment of portal hypertension.
abstract: Portal hypertension (PH) is a common complication of chronic liver disease, and it determines most complications leading to death or liver transplantation in patients with liver cirrhosis. PH results from increased resistance to portal blood flow through the cirrhotic liver. This is caused by two mechanisms: (a) distortion of the liver vascular architecture and (b) hepatic microvascular dysfunction. Increment in hepatic resistance is latterly accompanied by splanchnic vasodilation, which further aggravates PH. Hepatic microvascular dysfunction occurs early in the course of chronic liver disease as a consequence of inflammation and oxidative stress and determines loss of the normal phenotype of liver sinusoidal endothelial cells (LSEC). The cross-talk between LSEC and hepatic stellate cells induces activation of the latter, which in turn proliferate, migrate and increase collagen deposition around the sinusoids, contributing to fibrogenesis, architectural disruption and angiogenesis. Therapy for PH aims at correcting these pathophysiological abnormalities: liver injury, fibrogenesis, increased hepatic vascular tone and splanchnic vasodilatation. Continuing liver injury may be counteracted specifically by etiological treatments, while architectural disruption and fibrosis can be ameliorated by a variety of anti-fibrogenic drugs and anti-angiogenic strategies. Sinusoidal endothelial dysfunction is ameliorated by statins and other drugs increasing NO availability. Splanchnic hyperemia can be counteracted by non-selective beta-blockers (NSBBs), vasopressin analogs and somatostatin analogs. Future treatment of portal hypertension will evolve to use etiological treatments together with anti-fibrotic agents and/or drugs improving microvascular function in initial stages of cirrhosis (pre-primary prophylaxis), while NSBBs will be added in advanced stages of the disease.
authors: Barcelona Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clínic-Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), University of Barcelona, Rosselló 149, 4th Floor, 08036, Barcelona, Spain, jgracia@clinic.cat.
authors: Jordi
authors: J
authors: Gracia-Sancho
authors: Raquel
authors: R
authors: Maeso-Díaz
authors: Anabel
authors: A
authors: Fernández-Iglesias
authors: María
authors: M
authors: Navarro-Zornoza
authors: Jaime
authors: J
authors: Bosch
mesh_terms: D000085:Acetates / Q000627:therapeutic use; D000975:Antioxidants / Q000627:therapeutic use; D001708:Biopterins / Q000031:analogs & derivatives / Q000627:therapeutic use; D002635:Chenodeoxycholic Acid / Q000031:analogs & derivatives / Q000627:therapeutic use; D003521:Cyclopropanes; D042783:Endothelial Cells / Q000187:drug effects; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use; D006975:Hypertension, Portal / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D020024:Leukotriene Antagonists / Q000627:therapeutic use; D008102:Liver Circulation / Q000187:drug effects; D008103:Liver Cirrhosis / Q000150:complications / Q000188:drug therapy*; D055806:Microvessels / Q000187:drug effects* / Q000503:physiopathology; D058990:Molecular Targeted Therapy; D009281:Naphthalenes / Q000627:therapeutic use; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D011422:Propionates / Q000627:therapeutic use; D011804:Quinolines / Q000627:therapeutic use; D013440:Sulfides; D014655:Vascular Resistance / Q000187:drug effects
chemical_list: D000085:Acetates; D000975:Antioxidants; D003521:Cyclopropanes; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D020024:Leukotriene Antagonists; D009281:Naphthalenes; D011422:Propionates; D011804:Quinolines; D013440:Sulfides; C464660:obeticholic acid; D002635:Chenodeoxycholic Acid; D001708:Biopterins; C501362:terutroban; C003402:sapropterin; C093875:montelukast