Download PDF
Semin Liver Dis 2019; 39(04): 483-501
DOI: 10.1055/s-0039-1693115
Review Article
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Vascular Targets for the Treatment of Portal Hypertension

Ksenia Brusilovskaya
1   Vienna Hepatic Hemodynamic Lab (HEPEX), Medical University of Vienna, Vienna, Austria
2   Department of Medicine III, Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria
,
Philipp Königshofer
1   Vienna Hepatic Hemodynamic Lab (HEPEX), Medical University of Vienna, Vienna, Austria
2   Department of Medicine III, Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria
,
Philipp Schwabl
1   Vienna Hepatic Hemodynamic Lab (HEPEX), Medical University of Vienna, Vienna, Austria
2   Department of Medicine III, Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria
,
Thomas Reiberger
1   Vienna Hepatic Hemodynamic Lab (HEPEX), Medical University of Vienna, Vienna, Austria
2   Department of Medicine III, Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria
› Author Affiliations
Further Information

Publication History

Publication Date:
17 July 2019 (online)

   Permissions and Reprints

Abstract

Portal hypertension is the main driver for severe complications in patients with liver cirrhosis. With improved understanding of molecular pathways that promote hepatic vascular remodeling, vasoconstriction, and sinusoidal capillarization potential vascular targets for the treatment of portal hypertension have been identified. Inhibition of vascular endothelial and platelet-derived growth factors–driven angiogenesis has been shown to reduce portal pressure and decrease hepatic inflammation. Angiopoietin/Tie signaling represents additional promising vascular targets in liver disease. The eNOS-NO-sGC-cGMP pathway modulates sinusoidal vasoconstriction and capillarization. Nuclear farnesoid X receptor (FXR) agonists decrease intrahepatic vascular resistance by inhibition of fibrogenesis and sinusoidal remodeling. Statins ameliorate endothelial dysfunction, decrease portal pressure, and reduce fibrogenesis. Anticoagulation with low-molecular heparin or anti-Xa inhibitors improved portal hypertension by deactivation of hepatic stellate cells and potentially via reduction of sinusoidal microthrombosis. This review summarizes important vascular targets for treatment of portal hypertension that have shown promising results in experimental studies.

Keywords

portal hypertension - fibrosis - angiogenesis - sGC - FXR - anticoagulation - statins
 

  • References

  • 1 Bataller R, Brenner DA. Liver fibrosis. J Clin Invest 2005; 115 (02) 209-218
    CrossrefPubMedSearch in Google Scholar
  • 2 Neuschwander-Tetri BA. Non-alcoholic fatty liver disease. BMC Med 2017; 15 (01) 45
    CrossrefPubMedSearch in Google Scholar
  • 3 Schuppan D, Afdhal NH. Liver cirrhosis. Lancet 2008; 371 (9615): 838-851
    CrossrefPubMedSearch in Google Scholar
  • 4 Bosch J, Pizcueta P, Feu F, Fernández M, García-Pagán JC. Pathophysiology of portal hypertension. Gastroenterol Clin North Am 1992; 21 (01) 1-14
    PubMedSearch in Google Scholar
  • 5 García-Pagán JC, Gracia-Sancho J, Bosch J. Functional aspects on the pathophysiology of portal hypertension in cirrhosis. J Hepatol 2012; 57 (02) 458-461
    CrossrefPubMedSearch in Google Scholar
  • 6 Pinzani M, Rosselli M, Zuckermann M. Liver cirrhosis. Best Pract Res Clin Gastroenterol 2011; 25 (02) 281-290
    CrossrefPubMedSearch in Google Scholar
  • 7 Bolognesi M, Di Pascoli M, Verardo A, Gatta A. Splanchnic vasodilation and hyperdynamic circulatory syndrome in cirrhosis. World J Gastroenterol 2014; 20 (10) 2555-2563
    CrossrefPubMedSearch in Google Scholar
  • 8 Martell M, Coll M, Ezkurdia N, Raurell I, Genescà J. Physiopathology of splanchnic vasodilation in portal hypertension. World J Hepatol 2010; 2 (06) 208-220
    CrossrefPubMedSearch in Google Scholar
  • 9 Sumanovski LT, Battegay E, Stumm M, van der Kooij M, Sieber CC. Increased angiogenesis in portal hypertensive rats: role of nitric oxide. Hepatology 1999; 29 (04) 1044-1049
    CrossrefPubMedSearch in Google Scholar
  • 10 Fernandez M, Mejias M, Angermayr B, Garcia-Pagan JC, Rodés J, Bosch J. Inhibition of VEGF receptor-2 decreases the development of hyperdynamic splanchnic circulation and portal-systemic collateral vessels in portal hypertensive rats. J Hepatol 2005; 43 (01) 98-103
    CrossrefPubMedSearch in Google Scholar
  • 11 Geerts AM, De Vriese AS, Vanheule E. , et al. Increased angiogenesis and permeability in the mesenteric microvasculature of rats with cirrhosis and portal hypertension: an in vivo study. Liver Int 2006; 26 (07) 889-898
    CrossrefPubMedSearch in Google Scholar
  • 12 Fernandez M, Vizzutti F, Garcia-Pagan JC, Rodes J, Bosch J. Anti-VEGF receptor-2 monoclonal antibody prevents portal-systemic collateral vessel formation in portal hypertensive mice. Gastroenterology 2004; 126 (03) 886-894
    CrossrefPubMedSearch in Google Scholar
  • 13 Bismuth M, Funakoshi N, Cadranel JF, Blanc P. Hepatic encephalopathy: from pathophysiology to therapeutic management. Eur J Gastroenterol Hepatol 2011; 23 (01) 8-22
    CrossrefPubMedSearch in Google Scholar
  • 14 Bleibel W, Al-Osaimi AMS. Hepatic encephalopathy. Saudi J Gastroenterol 2012; 18: 301-309
    CrossrefPubMedSearch in Google Scholar
  • 15 McPhail MJ, Bajaj JS, Thomas HC, Taylor-Robinson SD. Pathogenesis and diagnosis of hepatic encephalopathy. Expert Rev Gastroenterol Hepatol 2010; 4 (03) 365-378
    CrossrefPubMedSearch in Google Scholar
  • 16 Tsai MH. Splanchnic and systemic vasodilatation: the patient. J Clin Gastroenterol 2007; 41 (Suppl. 03) S266-S271
    CrossrefPubMedSearch in Google Scholar
  • 17 Bosch J, Arroyo V, Betriu A. , et al. Hepatic hemodynamics and the renin-angiotensin-aldosterone system in cirrhosis. Gastroenterology 1980; 78 (01) 92-99
    CrossrefPubMedSearch in Google Scholar
  • 18 Mandorfer M, Bota S, Schwabl P. , et al. Nonselective β blockers increase risk for hepatorenal syndrome and death in patients with cirrhosis and spontaneous bacterial peritonitis. Gastroenterology 2014; 146 (07) 1680-90.e1
    CrossrefPubMedSearch in Google Scholar
  • 19 Reiberger T, Mandorfer M. Beta adrenergic blockade and decompensated cirrhosis. J Hepatol 2017; 66 (04) 849-859
    CrossrefPubMedSearch in Google Scholar
  • 20 Reiberger T, Ulbrich G, Ferlitsch A. , et al; Vienna Hepatic Hemodynamic Lab. Carvedilol for primary prophylaxis of variceal bleeding in cirrhotic patients with haemodynamic non-response to propranolol. Gut 2013; 62 (11) 1634-1641
    CrossrefPubMedSearch in Google Scholar
  • 21 Rector Jr WG. Drug therapy for portal hypertension. Ann Intern Med 1986; 105 (01) 96-107
    PubMedSearch in Google Scholar
  • 22 Bosch J. Carvedilol: the β-blocker of choice for portal hypertension?. Gut 2013; 62 (11) 1529-1530
    CrossrefPubMedSearch in Google Scholar
  • 23 Bosch J, Kravetz D, Mastai R. , et al. Effects of somatostatin in patients with portal hypertension. Horm Res 1988; 29 (2-3): 99-102
    CrossrefPubMedSearch in Google Scholar
  • 24 Reynaert H, Geerts A. Pharmacological rationale for the use of somatostatin and analogues in portal hypertension. Aliment Pharmacol Ther 2003; 18 (04) 375-386
    CrossrefPubMedSearch in Google Scholar
  • 25 Miñano C, Garcia-Tsao G. Clinical pharmacology of portal hypertension. Gastroenterol Clin North Am 2010; 39 (03) 681-695
    CrossrefPubMedSearch in Google Scholar
  • 26 Manolakopoulos S, Triantos C, Theodoropoulos J. , et al. Antiviral therapy reduces portal pressure in patients with cirrhosis due to HBeAg-negative chronic hepatitis B and significant portal hypertension. J Hepatol 2009; 51 (03) 468-474
    CrossrefPubMedSearch in Google Scholar
  • 27 Rincon D, Ripoll C, Lo Iacono O. , et al. Antiviral therapy decreases hepatic venous pressure gradient in patients with chronic hepatitis C and advanced fibrosis. Am J Gastroenterol 2006; 101 (10) 2269-2274
    CrossrefPubMedSearch in Google Scholar
  • 28 Puente Á, Cabezas J, López Arias MJ. , et al. Influence of sustained viral response on the regression of fibrosis and portal hypertension in cirrhotic HCV patients treated with antiviral triple therapy. Rev Esp Enferm Dig 2017; 109 (01) 17-25
    PubMedSearch in Google Scholar
  • 29 Afdhal N, Everson GT, Calleja JL. , et al. Effect of viral suppression on hepatic venous pressure gradient in hepatitis C with cirrhosis and portal hypertension. J Viral Hepat 2017; 24 (10) 823-831
    CrossrefPubMedSearch in Google Scholar
  • 30 Mandorfer M, Kozbial K, Schwabl P. , et al. Sustained virologic response to interferon-free therapies ameliorates HCV-induced portal hypertension. J Hepatol 2016; 65 (04) 692-699
    CrossrefPubMedSearch in Google Scholar
  • 31 Mueller EW, Rockey ML, Rashkin MC. Sunitinib-related fulminant hepatic failure: case report and review of the literature. Pharmacotherapy 2008; 28 (08) 1066-1070
    CrossrefPubMedSearch in Google Scholar
  • 32 Tugues S, Fernandez-Varo G, Muñoz-Luque J. , et al. Antiangiogenic treatment with sunitinib ameliorates inflammatory infiltrate, fibrosis, and portal pressure in cirrhotic rats. Hepatology 2007; 46 (06) 1919-1926
    CrossrefPubMedSearch in Google Scholar
  • 33 Van Steenkiste C, Geerts A, Vanheule E. , et al. Role of placental growth factor in mesenteric neoangiogenesis in a mouse model of portal hypertension. Gastroenterology 2009; 137 (06) 2112-24.e1 , 6
    CrossrefPubMedSearch in Google Scholar
  • 34 Chan C-C. Portal-systemic collaterals and hepatic encephalopathy. J Chin Med Assoc 2012; 75 (01) 1-2
    CrossrefPubMedSearch in Google Scholar
  • 35 Schwabl P, Payer BA, Grahovac J. , et al. Pioglitazone decreases portosystemic shunting by modulating inflammation and angiogenesis in cirrhotic and non-cirrhotic portal hypertensive rats. J Hepatol 2014; 60 (06) 1135-1142
    CrossrefPubMedSearch in Google Scholar
  • 36 Reiberger T, Angermayr B, Schwabl P. , et al. Sorafenib attenuates the portal hypertensive syndrome in partial portal vein ligated rats. J Hepatol 2009; 51 (05) 865-873
    CrossrefPubMedSearch in Google Scholar
  • 37 Gana JC, Serrano CA, Ling SC. Angiogenesis and portal-systemic collaterals in portal hypertension. Ann Hepatol 2016; 15 (03) 303-313
    CrossrefPubMedSearch in Google Scholar
  • 38 Ma R, Chen J, Liang Y. , et al. Sorafenib: A potential therapeutic drug for hepatic fibrosis and its outcomes. Biomed Pharmacother 2017; 88: 459-468
    CrossrefPubMedSearch in Google Scholar
  • 39 Mejias M, Garcia-Pras E, Tiani C, Miquel R, Bosch J, Fernandez M. Beneficial effects of sorafenib on splanchnic, intrahepatic, and portocollateral circulations in portal hypertensive and cirrhotic rats. Hepatology 2009; 49 (04) 1245-1256
    CrossrefPubMedSearch in Google Scholar
  • 40 Van Steenkiste C, Ribera J, Geerts A. , et al. Inhibition of placental growth factor activity reduces the severity of fibrosis, inflammation, and portal hypertension in cirrhotic mice. Hepatology 2011; 53 (05) 1629-1640
    CrossrefPubMedSearch in Google Scholar
  • 41 Fernandez M, Mejias M, Garcia-Pras E, Mendez R, Garcia-Pagan JC, Bosch J. Reversal of portal hypertension and hyperdynamic splanchnic circulation by combined vascular endothelial growth factor and platelet-derived growth factor blockade in rats. Hepatology 2007; 46 (04) 1208-1217
    CrossrefPubMedSearch in Google Scholar
  • 42 Fernández M, Semela D, Bruix J, Colle I, Pinzani M, Bosch J. Angiogenesis in liver disease. J Hepatol 2009; 50 (03) 604-620
    CrossrefPubMedSearch in Google Scholar
  • 43 Corpechot C, Barbu V, Wendum D. , et al. Hypoxia-induced VEGF and collagen I expressions are associated with angiogenesis and fibrogenesis in experimental cirrhosis. Hepatology 2002; 35 (05) 1010-1021
    CrossrefPubMedSearch in Google Scholar
  • 44 Lee JS, Semela D, Iredale J, Shah VH. Sinusoidal remodeling and angiogenesis: a new function for the liver-specific pericyte?. Hepatology 2007; 45 (03) 817-825
    CrossrefPubMedSearch in Google Scholar
  • 45 Abraldes JG, Iwakiri Y, Loureiro-Silva M, Haq O, Sessa WC, Groszmann RJ. Mild increases in portal pressure upregulate vascular endothelial growth factor and endothelial nitric oxide synthase in the intestinal microcirculatory bed, leading to a hyperdynamic state. Am J Physiol Gastrointest Liver Physiol 2006; 290 (05) G980-G987
    CrossrefPubMedSearch in Google Scholar
  • 46 Huang HC, Haq O, Utsumi T. , et al. Intestinal and plasma VEGF levels in cirrhosis: the role of portal pressure. J Cell Mol Med 2012; 16 (05) 1125-1133
    CrossrefPubMedSearch in Google Scholar
  • 47 Pinter M, Sieghart W, Reiberger T, Rohr-Udilova N, Ferlitsch A, Peck-Radosavljevic M. The effects of sorafenib on the portal hypertensive syndrome in patients with liver cirrhosis and hepatocellular carcinoma--a pilot study. Aliment Pharmacol Ther 2012; 35 (01) 83-91
    CrossrefPubMedSearch in Google Scholar
  • 48 Watanabe K, Hasegawa Y, Yamashita H. , et al. Vasohibin as an endothelium-derived negative feedback regulator of angiogenesis. J Clin Invest 2004; 114 (07) 898-907
    CrossrefPubMedSearch in Google Scholar
  • 49 Coch L, Mejias M, Berzigotti A. , et al. Disruption of negative feedback loop between vasohibin-1 and vascular endothelial growth factor decreases portal pressure, angiogenesis, and fibrosis in cirrhotic rats. Hepatology 2014; 60 (02) 633-647
    CrossrefPubMedSearch in Google Scholar
  • 50 Furutani Y, Shiozaki-Sato Y, Hara M, Sato Y, Kojima S. Hepatic fibrosis and angiogenesis after bile duct ligation are endogenously expressed vasohibin-1 independent. Biochem Biophys Res Commun 2015; 463 (03) 384-388
    CrossrefPubMedSearch in Google Scholar
  • 51 Ho T-C, Chen S-L, Shih S-C. , et al. Pigment epithelium-derived factor is an intrinsic antifibrosis factor targeting hepatic stellate cells. Am J Pathol 2010; 177 (04) 1798-1811
    CrossrefPubMedSearch in Google Scholar
  • 52 Mejias M, Coch L, Berzigotti A. , et al. Antiangiogenic and antifibrogenic activity of pigment epithelium-derived factor (PEDF) in bile duct-ligated portal hypertensive rats. Gut 2015; 64 (04) 657-666
    CrossrefPubMedSearch in Google Scholar
  • 53 Marra F, Gentilini A, Pinzani M. , et al. Phosphatidylinositol 3-kinase is required for platelet-derived growth factor's actions on hepatic stellate cells. Gastroenterology 1997; 112 (04) 1297-1306
    CrossrefPubMedSearch in Google Scholar
  • 54 Pinzani M, Gesualdo L, Sabbah GM, Abboud HE. Effects of platelet-derived growth factor and other polypeptide mitogens on DNA synthesis and growth of cultured rat liver fat-storing cells. J Clin Invest 1989; 84 (06) 1786-1793
    CrossrefPubMedSearch in Google Scholar
  • 55 Pinzani M, Milani S, Herbst H. , et al. Expression of platelet-derived growth factor and its receptors in normal human liver and during active hepatic fibrogenesis. Am J Pathol 1996; 148 (03) 785-800
    PubMedSearch in Google Scholar
  • 56 Reichenbach V, Fernández-Varo G, Casals G. , et al. Adenoviral dominant-negative soluble PDGFRβ improves hepatic collagen, systemic hemodynamics, and portal pressure in fibrotic rats. J Hepatol 2012; 57 (05) 967-973
    CrossrefPubMedSearch in Google Scholar
  • 57 Hennenberg M, Trebicka J, Stark C, Kohistani AZ, Heller J, Sauerbruch T. Sorafenib targets dysregulated Rho kinase expression and portal hypertension in rats with secondary biliary cirrhosis. Br J Pharmacol 2009; 157 (02) 258-270
    CrossrefPubMedSearch in Google Scholar
  • 58 Lin HC, Huang YT, Yang YY. , et al. Beneficial effects of dual vascular endothelial growth factor receptor/fibroblast growth factor receptor inhibitor brivanib alaninate in cirrhotic portal hypertensive rats. J Gastroenterol Hepatol 2014; 29 (05) 1073-1082
    CrossrefPubMedSearch in Google Scholar
  • 59 Yang YY, Liu RS, Lee PC. , et al. Anti-VEGFR agents ameliorate hepatic venous dysregulation/microcirculatory dysfunction, splanchnic venous pooling and ascites of NASH-cirrhotic rat. Liver Int 2014; 34 (04) 521-534
    CrossrefPubMedSearch in Google Scholar
  • 60 Uschner F, Nikolova I, Klein S. , et al. The multikinase inhibitor regorafenib improves portal hypertension in presence and absence of cirrhosis in rats. J Hepatol 2016; 64: S134-S135
    PubMedSearch in Google Scholar
  • 61 Qu K, Huang Z, Lin T. , et al. New insight into the anti-liver fibrosis effect of multitargeted tyrosine kinase inhibitors: from molecular target to clinical trials. Front Pharmacol 2016; 6: 300
    PubMedSearch in Google Scholar
  • 62 Thabut D, Routray C, Lomberk G. , et al. Complementary vascular and matrix regulatory pathways underlie the beneficial mechanism of action of sorafenib in liver fibrosis. Hepatology 2011; 54 (02) 573-585
    CrossrefPubMedSearch in Google Scholar
  • 63 Wang Y, Gao J, Zhang D, Zhang J, Ma J, Jiang H. New insights into the antifibrotic effects of sorafenib on hepatic stellate cells and liver fibrosis. J Hepatol 2010; 53 (01) 132-144
    CrossrefPubMedSearch in Google Scholar
  • 64 Coriat R, Gouya H, Mir O. , et al. Reversible decrease of portal venous flow in cirrhotic patients: a positive side effect of sorafenib. PLoS One 2011; 6 (02) e16978
    CrossrefPubMedSearch in Google Scholar
  • 65 D'Amico M, Mejías M, García-Pras E. , et al. Effects of the combined administration of propranolol plus sorafenib on portal hypertension in cirrhotic rats. Am J Physiol Gastrointest Liver Physiol 2012; 302 (10) G1191-G1198
    CrossrefPubMedSearch in Google Scholar
  • 66 Vandewynckel YP, Laukens D, Devisscher L. , et al. Placental growth factor inhibition modulates the interplay between hypoxia and unfolded protein response in hepatocellular carcinoma. BMC Cancer 2016; 16: 9
    CrossrefPubMedSearch in Google Scholar
  • 67 Heindryckx F, Coulon S, Terrie E. , et al. The placental growth factor as a target against hepatocellular carcinoma in a diethylnitrosamine-induced mouse model. J Hepatol 2013; 58 (02) 319-328
    CrossrefPubMedSearch in Google Scholar
  • 68 Raevens S, Geerts A, Paridaens A. , et al. Placental growth factor inhibition targets pulmonary angiogenesis and represents a therapy for hepatopulmonary syndrome in mice. Hepatology 2018; 68 (02) 634-651
    CrossrefPubMedSearch in Google Scholar
  • 69 Taura K, De Minicis S, Seki E. , et al. Hepatic stellate cells secrete angiopoietin 1 that induces angiogenesis in liver fibrosis. Gastroenterology 2008; 135 (05) 1729-1738
    CrossrefPubMedSearch in Google Scholar
  • 70 Pauta M, Ribera J, Melgar-Lesmes P. , et al. Overexpression of angiopoietin-2 in rats and patients with liver fibrosis. Therapeutic consequences of its inhibition. Liver Int 2015; 35 (04) 1383-1392
    CrossrefPubMedSearch in Google Scholar
  • 71 Ward NL, Haninec AL, Van Slyke P. , et al. Angiopoietin-1 causes reversible degradation of the portal microcirculation in mice: implications for treatment of liver disease. Am J Pathol 2004; 165 (03) 889-899
    CrossrefPubMedSearch in Google Scholar
  • 72 Schwabl P, Mandorfer M, Steiner S. , et al. Interferon-free regimens improve portal hypertension and histological necroinflammation in HIV/HCV patients with advanced liver disease. Aliment Pharmacol Ther 2017; 45 (01) 139-149
    CrossrefPubMedSearch in Google Scholar
  • 73 Lefere S, Van de Velde F, Hoorens A. , et al. Angiopoietin-2 promotes pathological angiogenesis and is a therapeutic target in murine nonalcoholic fatty liver disease. Hepatology 2019; 69 (03) 1087-1104
    CrossrefPubMedSearch in Google Scholar
  • 74 Faillaci F, Marzi L, Critelli R. , et al. Liver angiopoietin-2 is a key predictor of de novo or recurrent hepatocellular cancer after hepatitis C virus direct-acting antivirals. Hepatology 2018; 68 (03) 1010-1024
    CrossrefPubMedSearch in Google Scholar
  • 75 Abou-Alfa GK, Blanc JF, Miles S. , et al. Phase II study of first-line trebananib plus sorafenib in patients with advanced hepatocellular carcinoma. Oncologist 2017; 22 (07) 780-e65
    CrossrefPubMedSearch in Google Scholar
  • 76 Mittal MK, Gupta TK, Lee FY, Sieber CC, Groszmann RJ. Nitric oxide modulates hepatic vascular tone in normal rat liver. Am J Physiol 1994; 267 (3 Pt 1): G416-G422
    PubMedSearch in Google Scholar
  • 77 Gupta TK, Toruner M, Chung MK, Groszmann RJ. Endothelial dysfunction and decreased production of nitric oxide in the intrahepatic microcirculation of cirrhotic rats. Hepatology 1998; 28 (04) 926-931
    CrossrefPubMedSearch in Google Scholar
  • 78 Loureiro-Silva MR, Cadelina GW, Groszmann RJ. Deficit in nitric oxide production in cirrhotic rat livers is located in the sinusoidal and postsinusoidal areas. Am J Physiol Gastrointest Liver Physiol 2003; 284 (04) G567-G574
    CrossrefPubMedSearch in Google Scholar
  • 79 Iwakiri Y, Kim MY. Nitric oxide in liver diseases. Trends Pharmacol Sci 2015; 36 (08) 524-536
    CrossrefPubMedSearch in Google Scholar
  • 80 Wiest R, Groszmann RJ. The paradox of nitric oxide in cirrhosis and portal hypertension: too much, not enough. Hepatology 2002; 35 (02) 478-491
    CrossrefPubMedSearch in Google Scholar
  • 81 Gracia-Sancho J, Laviña B, Rodríguez-Vilarrupla A. , et al. Increased oxidative stress in cirrhotic rat livers: a potential mechanism contributing to reduced nitric oxide bioavailability. Hepatology 2008; 47 (04) 1248-1256
    PubMedSearch in Google Scholar
  • 82 Mookerjee RP, Vairappan B, Jalan R. The puzzle of endothelial nitric oxide synthase dysfunction in portal hypertension: the missing piece?. Hepatology 2007; 46 (03) 943-946
    CrossrefPubMedSearch in Google Scholar
  • 83 Vairappan B. Endothelial dysfunction in cirrhosis: role of inflammation and oxidative stress. World J Hepatol 2015; 7 (03) 443-459
    CrossrefPubMedSearch in Google Scholar
  • 84 McNaughton L, Puttagunta L, Martinez-Cuesta MA. , et al. Distribution of nitric oxide synthase in normal and cirrhotic human liver. Proc Natl Acad Sci U S A 2002; 99 (26) 17161-17166
    CrossrefPubMedSearch in Google Scholar
  • 85 Duong HT, Dong Z, Su L. , et al. The use of nanoparticles to deliver nitric oxide to hepatic stellate cells for treating liver fibrosis and portal hypertension. Small 2015; 11 (19) 2291-2304
    CrossrefPubMedSearch in Google Scholar
  • 86 Matei V, Rodríguez-Vilarrupla A, Deulofeu R. , et al. The eNOS cofactor tetrahydrobiopterin improves endothelial dysfunction in livers of rats with CCl4 cirrhosis. Hepatology 2006; 44 (01) 44-52
    CrossrefPubMedSearch in Google Scholar
  • 87 Reverter E, Mesonero F, Seijo S. , et al. Effects of sapropterin on portal and systemic hemodynamics in patients with cirrhosis and portal hypertension: a bicentric double-blind placebo-controlled study. Am J Gastroenterol 2015; 110 (07) 985-992
    CrossrefPubMedSearch in Google Scholar
  • 88 Biecker E, Trebicka J, Kang A, Hennenberg M, Sauerbruch T, Heller J. Treatment of bile duct-ligated rats with the nitric oxide synthase transcription enhancer AVE 9488 ameliorates portal hypertension. Liver Int 2008; 28 (03) 331-338
    CrossrefPubMedSearch in Google Scholar
  • 89 Luna M, Karavitakis M. Treating portal hypertension in cirrhotic rats with AVE 9488. Liver Int 2009; 29 (09) 1448-1448 , author reply 1448–1449
    PubMedSearch in Google Scholar
  • 90 EU Clinical Trials Register (STOPP). https://www.clinicaltrialsregister.eu/ctr-search/trial/2015-004031-12/GB . Accessed April 19, 2019.
    PubMed
  • 91 Theilig F, Bostanjoglo M, Pavenstädt H. , et al. Cellular distribution and function of soluble guanylyl cyclase in rat kidney and liver. J Am Soc Nephrol 2001; 12 (11) 2209-2220
    PubMedSearch in Google Scholar
  • 92 Schwabl P, Brusilovskaya K, Supper P. , et al. The soluble guanylate cyclase stimulator riociguat reduces fibrogenesis and portal pressure in cirrhotic rats. Sci Rep 2018; 8 (01) 9372
    CrossrefPubMedSearch in Google Scholar
  • 93 Cichoż-Lach H, Michalak A. Oxidative stress as a crucial factor in liver diseases. World J Gastroenterol 2014; 20 (25) 8082-8091
    CrossrefPubMedSearch in Google Scholar
  • 94 Li S, Tan H-Y, Wang N. , et al. The role of oxidative stress and antioxidants in liver diseases. Int J Mol Sci 2015; 16 (11) 26087-26124
    CrossrefPubMedSearch in Google Scholar
  • 95 Xie G, Wang X, Wang L. , et al. Role of differentiation of liver sinusoidal endothelial cells in progression and regression of hepatic fibrosis in rats. Gastroenterology 2012; 142 (04) 918-927.e6
    CrossrefPubMedSearch in Google Scholar
  • 96 DeLeve LD. Liver sinusoidal endothelial cells in hepatic fibrosis. Hepatology 2015; 61 (05) 1740-1746
    CrossrefPubMedSearch in Google Scholar
  • 97 Deleve LD, Wang X, Guo Y. Sinusoidal endothelial cells prevent rat stellate cell activation and promote reversion to quiescence. Hepatology 2008; 48 (03) 920-930
    CrossrefPubMedSearch in Google Scholar
  • 98 Friedman SL. Liver fibrosis—from bench to bedside. J Hepatol 2003; 38 (Suppl. 01) S38-S53
    PubMedSearch in Google Scholar
  • 99 Sarno R. Expression of soluble guanylate cyclase in rat and human hepatocytes [master's thesis]. Cambridge, MA: Harvard Extension School; 2017
    PubMed
  • 100 Beyer C, Zenzmaier C, Palumbo-Zerr K. , et al. Stimulation of the soluble guanylate cyclase (sGC) inhibits fibrosis by blocking non-canonical TGFβ signalling. Ann Rheum Dis 2015; 74 (07) 1408-1416
    CrossrefPubMedSearch in Google Scholar
  • 101 Cohen JC, Horton JD, Hobbs HH. Human fatty liver disease: old questions and new insights. Science 2011; 332 (6037): 1519-1523
    CrossrefPubMedSearch in Google Scholar
  • 102 Curran RD, Billiar TR, Stuehr DJ. , et al. Multiple cytokines are required to induce hepatocyte nitric oxide production and inhibit total protein synthesis. Ann Surg 1990; 212 (04) 462-469 , discussion 470–471
    CrossrefPubMedSearch in Google Scholar
  • 103 Nussler AK, Billiar TR. Inflammation, immunoregulation, and inducible nitric oxide synthase. J Leukoc Biol 1993; 54 (02) 171-178
    CrossrefPubMedSearch in Google Scholar
  • 104 García-Pagán JC, Feu F, Navasa M. , et al. Long-term haemodynamic effects of isosorbide 5-mononitrate in patients with cirrhosis and portal hypertension. J Hepatol 1990; 11 (02) 189-195
    CrossrefPubMedSearch in Google Scholar
  • 105 Angelico M, Lionetti R. Long-acting nitrates in portal hypertension: to be or not to be?. Dig Liver Dis 2001; 33 (03) 205-211
    CrossrefPubMedSearch in Google Scholar
  • 106 Angelico M, Carli L, Piat C, Gentile S, Capocaccia L. Effects of isosorbide-5-mononitrate compared with propranolol on first bleeding and long-term survival in cirrhosis. Gastroenterology 1997; 113 (05) 1632-1639
    CrossrefPubMedSearch in Google Scholar
  • 107 Saleh S, Becker C, Frey R, Mück W. Population pharmacokinetics of single-dose riociguat in patients with renal or hepatic impairment. Pulm Circ 2016; 6 (Suppl. 01) S75-S85
    CrossrefPubMedSearch in Google Scholar
  • 108 Flores-Costa R, Alcaraz-Quiles J, Titos E. , et al. The soluble guanylate cyclase stimulator IW-1973 prevents inflammation and fibrosis in experimental non-alcoholic steatohepatitis. Br J Pharmacol 2018; 175 (06) 953-967
    CrossrefPubMedSearch in Google Scholar
  • 109 Flores-Costa R, Duran-Güell M, Casulleras M. , et al. FRI-296-Interaction between the soluble guanylate cyclase and the NLRP3 inflammasome in Kupffer cells: implications for the anti-inflammatory actions of sGC stimulation in liver. J Hepatol 2019; 70: e525
    PubMedSearch in Google Scholar
  • 110 Evgenov OV, Pacher P, Schmidt PM, Haskó G, Schmidt HH, Stasch JP. NO-independent stimulators and activators of soluble guanylate cyclase: discovery and therapeutic potential. Nat Rev Drug Discov 2006; 5 (09) 755-768
    CrossrefPubMedSearch in Google Scholar
  • 111 Dasgupta A, Bowman L, D'Arsigny CL, Archer SL. Soluble guanylate cyclase: a new therapeutic target for pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension. Clin Pharmacol Ther 2015; 97 (01) 88-102
    PubMedSearch in Google Scholar
  • 112 Nossaman B, Pankey E, Kadowitz P. Stimulators and activators of soluble guanylate cyclase: review and potential therapeutic indications. Crit Care Res Pract 2012; 2012: 290805
    PubMedSearch in Google Scholar
  • 113 Knorr A, Hirth-Dietrich C, Alonso-Alija C. , et al. Nitric oxide-independent activation of soluble guanylate cyclase by BAY 60-2770 in experimental liver fibrosis. Arzneimittelforschung 2008; 58 (02) 71-80
    Thieme ConnectPubMedSearch in Google Scholar
  • 114 Brusilovskaya K, Königshofer P, Lampach D. , et al. Targeting the nitric-oxide downstream pathway in bile-duct ligated rats to improve portal hypertension and liver fibrosis. J Hepatol 2018; 68: S9
    PubMedSearch in Google Scholar
  • 115 Lin CS. Tissue expression, distribution, and regulation of PDE5. Int J Impot Res 2004; 16 (Suppl. 01) S8-S10
    CrossrefPubMedSearch in Google Scholar
  • 116 Keravis T, Lugnier C. Cyclic nucleotide phosphodiesterase (PDE) isozymes as targets of the intracellular signalling network: benefits of PDE inhibitors in various diseases and perspectives for future therapeutic developments. Br J Pharmacol 2012; 165 (05) 1288-1305
    CrossrefPubMedSearch in Google Scholar
  • 117 Halverscheid L, Deibert P, Schmidt R. , et al. Phosphodiesterase-5 inhibitors have distinct effects on the hemodynamics of the liver. BMC Gastroenterol 2009; 9: 69
    CrossrefPubMedSearch in Google Scholar
  • 118 Colle I, De Vriese AS, Van Vlierberghe H, Lameire NH, DeVos M. Systemic and splanchnic haemodynamic effects of sildenafil in an in vivo animal model of cirrhosis support for a risk in cirrhotic patients. Liver Int 2004; 24 (01) 63-68
    CrossrefPubMedSearch in Google Scholar
  • 119 Choi SM, Shin JH, Kim JM. , et al. Effect of udenafil on portal venous pressure and hepatic fibrosis in rats. A novel therapeutic option for portal hypertension. Arzneimittelforschung 2009; 59 (12) 641-646
    Thieme ConnectPubMedSearch in Google Scholar
  • 120 Schaffner D, Lazaro A, Deibert P. , et al. Analysis of the nitric oxide-cyclic guanosine monophosphate pathway in experimental liver cirrhosis suggests phosphodiesterase-5 as potential target to treat portal hypertension. World J Gastroenterol 2018; 24 (38) 4356-4368
    CrossrefPubMedSearch in Google Scholar
  • 121 Lee KC, Yang YY, Wang YW. , et al. Acute administration of sildenafil enhances hepatic cyclic guanosine monophosphate production and reduces hepatic sinusoid resistance in cirrhotic patients. Hepatol Res 2008; 38 (12) 1186-1193
    PubMedSearch in Google Scholar
  • 122 Clemmesen JO, Giraldi A, Ott P, Dalhoff K, Hansen BA, Larsen FS. Sildenafil does not influence hepatic venous pressure gradient in patients with cirrhosis. World J Gastroenterol 2008; 14 (40) 6208-6212
    CrossrefPubMedSearch in Google Scholar
  • 123 Tandon P, Inayat I, Tal M. , et al. Sildenafil has no effect on portal pressure but lowers arterial pressure in patients with compensated cirrhosis. Clin Gastroenterol Hepatol 2010; 8 (06) 546-549
    CrossrefPubMedSearch in Google Scholar
  • 124 Kreisel W, Deibert P, Kupcinskas L. , et al. The phosphodiesterase-5-inhibitor udenafil lowers portal pressure in compensated preascitic liver cirrhosis. A dose-finding phase-II-study. Dig Liver Dis 2015; 47 (02) 144-150
    CrossrefPubMedSearch in Google Scholar
  • 125 Deibert P, Schumacher YO, Ruecker G. , et al. Effect of vardenafil, an inhibitor of phosphodiesterase-5, on portal haemodynamics in normal and cirrhotic liver —results of a pilot study. Aliment Pharmacol Ther 2006; 23 (01) 121-128
    CrossrefPubMedSearch in Google Scholar
  • 126 Bremer HC, Kreisel W, Roecker K. , et al. Phosphodiesterase 5 inhibitors lower both portal and pulmonary pressure in portopulmonary hypertension: a case report. J Med Case Reports 2007; 1: 46-46
    CrossrefPubMedSearch in Google Scholar
  • 127 Deibert P, Lazaro A, Stankovic Z, Schaffner D, Rössle M, Kreisel W. Beneficial long term effect of a phosphodiesterase-5-inhibitor in cirrhotic portal hypertension: a case report with 8 years follow-up. World J Gastroenterol 2018; 24 (03) 438-444
    CrossrefPubMedSearch in Google Scholar
  • 128 Higashiyama H, Kinoshita M, Asano S. Immunolocalization of farnesoid X receptor (FXR) in mouse tissues using tissue microarray. Acta Histochem 2008; 110 (01) 86-93
    CrossrefPubMedSearch in Google Scholar
  • 129 Fuchs CD, Schwabl P, Reiberger T, Trauner M. Liver capsule: FXR agonists against liver disease. Hepatology 2016; 64 (05) 1773
    CrossrefPubMedSearch in Google Scholar
  • 130 Halilbasic E, Fuchs C, Traussnigg S, Trauner M. Farnesoid X Receptor Agonists and Other Bile Acid Signaling Strategies for Treatment of Liver Disease. Dig Dis 2016; 34 (05) 580-588
    CrossrefPubMedSearch in Google Scholar
  • 131 Baghdasaryan A, Claudel T, Gumhold J. , et al. Dual farnesoid X receptor/TGR5 agonist INT-767 reduces liver injury in the Mdr2-/- (Abcb4-/-) mouse cholangiopathy model by promoting biliary HCO− 3 output. Hepatology 2011; 54 (04) 1303-1312
    CrossrefPubMedSearch in Google Scholar
  • 132 Comeglio P, Cellai I, Mello T. , et al. INT-767 prevents NASH and promotes visceral fat brown adipogenesis and mitochondrial function. J Endocrinol 2018; 238 (02) 107-127
    CrossrefPubMedSearch in Google Scholar
  • 133 Fiorucci S, Antonelli E, Rizzo G. , et al. The nuclear receptor SHP mediates inhibition of hepatic stellate cells by FXR and protects against liver fibrosis. Gastroenterology 2004; 127 (05) 1497-1512
    CrossrefPubMedSearch in Google Scholar
  • 134 Kong B, Luyendyk JP, Tawfik O, Guo GL. Farnesoid X receptor deficiency induces nonalcoholic steatohepatitis in low-density lipoprotein receptor-knockout mice fed a high-fat diet. J Pharmacol Exp Ther 2009; 328 (01) 116-122
    CrossrefPubMedSearch in Google Scholar
  • 135 Modica S, Petruzzelli M, Bellafante E. , et al. Selective activation of nuclear bile acid receptor FXR in the intestine protects mice against cholestasis. Gastroenterology 2012; 142 (02) 355-65.e1 , 4
    CrossrefPubMedSearch in Google Scholar
  • 136 Mookerjee RP, Mehta G, Balasubramaniyan V. , et al. Hepatic dimethylarginine-dimethylaminohydrolase1 is reduced in cirrhosis and is a target for therapy in portal hypertension. J Hepatol 2015; 62 (02) 325-331
    CrossrefPubMedSearch in Google Scholar
  • 137 Verbeke L, Farre R, Trebicka J. , et al. Obeticholic acid, a farnesoid X receptor agonist, improves portal hypertension by two distinct pathways in cirrhotic rats. Hepatology 2014; 59 (06) 2286-2298
    CrossrefPubMedSearch in Google Scholar
  • 138 Verbeke L, Mannaerts I, Schierwagen R. , et al. FXR agonist obeticholic acid reduces hepatic inflammation and fibrosis in a rat model of toxic cirrhosis. Sci Rep 2016; 6: 33453
    CrossrefPubMedSearch in Google Scholar
  • 139 Xu JY, Li ZP, Zhang L, Ji G. Recent insights into farnesoid X receptor in non-alcoholic fatty liver disease. World J Gastroenterol 2014; 20 (37) 13493-13500
    CrossrefPubMedSearch in Google Scholar
  • 140 Xu W, Lu C, Zhang F, Shao J, Yao S, Zheng S. Dihydroartemisinin counteracts fibrotic portal hypertension via farnesoid X receptor-dependent inhibition of hepatic stellate cell contraction. FEBS J 2017; 284 (01) 114-133
    CrossrefPubMedSearch in Google Scholar
  • 141 Zhang L, Wang YD, Chen WD. , et al. Promotion of liver regeneration/repair by farnesoid X receptor in both liver and intestine in mice. Hepatology 2012; 56 (06) 2336-2343
    CrossrefPubMedSearch in Google Scholar
  • 142 Zhang S, Wang J, Liu Q, Harnish DC. Farnesoid X receptor agonist WAY-362450 attenuates liver inflammation and fibrosis in murine model of non-alcoholic steatohepatitis. J Hepatol 2009; 51 (02) 380-388
    CrossrefPubMedSearch in Google Scholar
  • 143 Slater TF, Cheeseman KH, Ingold KU. Carbon tetrachloride toxicity as a model for studying free-radical mediated liver injury. Philos Trans R Soc Lond B Biol Sci 1985; 311 (1152): 633-645
    CrossrefPubMedSearch in Google Scholar
  • 144 He F, Li J, Mu Y. , et al. Downregulation of endothelin-1 by farnesoid X receptor in vascular endothelial cells. Circ Res 2006; 98 (02) 192-199
    CrossrefPubMedSearch in Google Scholar
  • 145 Schwabl P, Hambruch E, Seeland BA. , et al. The FXR agonist PX20606 ameliorates portal hypertension by targeting vascular remodelling and sinusoidal dysfunction. J Hepatol 2017; 66 (04) 724-733
    CrossrefPubMedSearch in Google Scholar
  • 146 Wang YD, Chen WD, Wang M, Yu D, Forman BM, Huang W. Farnesoid X receptor antagonizes nuclear factor kappaB in hepatic inflammatory response. Hepatology 2008; 48 (05) 1632-1643
    CrossrefPubMedSearch in Google Scholar
  • 147 Wirz W, Antoine M, Tag CG. , et al. Hepatic stellate cells display a functional vascular smooth muscle cell phenotype in a three-dimensional co-culture model with endothelial cells. Differentiation 2008; 76 (07) 784-794
    CrossrefPubMedSearch in Google Scholar
  • 148 Hellerbrand C. Hepatic stellate cells—the pericytes in the liver. Pflugers Arch 2013; 465 (06) 775-778
    CrossrefPubMedSearch in Google Scholar
  • 149 Iwakiri Y. Endothelial dysfunction in the regulation of cirrhosis and portal hypertension. Liver Int 2012; 32 (02) 199-213
    CrossrefPubMedSearch in Google Scholar
  • 150 Mookerjee RP, Malaki M, Davies NA. , et al. Increasing dimethylarginine levels are associated with adverse clinical outcome in severe alcoholic hepatitis. Hepatology 2007; 45 (01) 62-71
    CrossrefPubMedSearch in Google Scholar
  • 151 Vizzutti F, Romanelli RG, Arena U. , et al. ADMA correlates with portal pressure in patients with compensated cirrhosis. Eur J Clin Invest 2007; 37 (06) 509-515
    CrossrefPubMedSearch in Google Scholar
  • 152 Li J, Wilson A, Gao X. , et al. Coordinated regulation of dimethylarginine dimethylaminohydrolase-1 and cationic amino acid transporter-1 by farnesoid X receptor in mouse liver and kidney and its implication in the control of blood levels of asymmetric dimethylarginine. J Pharmacol Exp Ther 2009; 331 (01) 234-243
    CrossrefPubMedSearch in Google Scholar
  • 153 Rockey DC, Fouassier L, Chung JJ. , et al. Cellular localization of endothelin-1 and increased production in liver injury in the rat: potential for autocrine and paracrine effects on stellate cells. Hepatology 1998; 27 (02) 472-480
    CrossrefPubMedSearch in Google Scholar
  • 154 Rockey DC, Chung JJ. Endothelin antagonism in experimental hepatic fibrosis. Implications for endothelin in the pathogenesis of wound healing. J Clin Invest 1996; 98 (06) 1381-1388
    CrossrefPubMedSearch in Google Scholar
  • 155 Li J, Kuruba R, Wilson A, Gao X, Zhang Y, Li S. Inhibition of endothelin-1-mediated contraction of hepatic stellate cells by FXR ligand. PLoS One 2010; 5 (11) e13955
    CrossrefPubMedSearch in Google Scholar
  • 156 Wang C, Han J, Xiao L, Jin CE, Li DJ, Yang Z. Role of hydrogen sulfide in portal hypertension and esophagogastric junction vascular disease. World J Gastroenterol 2014; 20 (04) 1079-1087
    CrossrefPubMedSearch in Google Scholar
  • 157 Fiorucci S, Antonelli E, Mencarelli A. , et al. The third gas: H2S regulates perfusion pressure in both the isolated and perfused normal rat liver and in cirrhosis. Hepatology 2005; 42 (03) 539-548
    CrossrefPubMedSearch in Google Scholar
  • 158 Fan HN, Wang HJ, Yang-Dan CR. , et al. Protective effects of hydrogen sulfide on oxidative stress and fibrosis in hepatic stellate cells. Mol Med Rep 2013; 7 (01) 247-253
    CrossrefPubMedSearch in Google Scholar
  • 159 Renga B, Mencarelli A, Migliorati M, Distrutti E, Fiorucci S. Bile-acid-activated farnesoid X receptor regulates hydrogen sulfide production and hepatic microcirculation. World J Gastroenterol 2009; 15 (17) 2097-2108
    CrossrefPubMedSearch in Google Scholar
  • 160 Renga B, Bucci M, Cipriani S. , et al. Cystathionine γ-lyase, a H2S-generating enzyme, is a GPBAR1-regulated gene and contributes to vasodilation caused by secondary bile acids. Am J Physiol Heart Circ Physiol 2015; 309 (01) H114-H126
    CrossrefPubMedSearch in Google Scholar
  • 161 Di Leva FS, Festa C, Renga B. , et al. Structure-based drug design targeting the cell membrane receptor GPBAR1: exploiting the bile acid scaffold towards selective agonism. Sci Rep 2015; 5: 16605
    CrossrefPubMedSearch in Google Scholar
  • 162 Mehta G, Gustot T, Mookerjee RP. , et al. Inflammation and portal hypertension—the undiscovered country. J Hepatol 2014; 61 (01) 155-163
    CrossrefPubMedSearch in Google Scholar
  • 163 Schwabl P, Laleman W. Novel treatment options for portal hypertension. Gastroenterol Rep (Oxf) 2017; 5 (02) 90-103
    CrossrefPubMedSearch in Google Scholar
  • 164 Gai Z, Visentin M, Gui T. , et al. Effects of farnesoid X receptor activation on arachidonic acid metabolism, NF-kB signaling, and hepatic inflammation. Mol Pharmacol 2018; 94 (02) 802-811
    CrossrefPubMedSearch in Google Scholar
  • 165 Li YT, Swales KE, Thomas GJ, Warner TD, Bishop-Bailey D. Farnesoid X receptor ligands inhibit vascular smooth muscle cell inflammation and migration. Arterioscler Thromb Vasc Biol 2007; 27 (12) 2606-2611
    CrossrefPubMedSearch in Google Scholar
  • 166 Lee FY, Lee H, Hubbert ML, Edwards PA, Zhang Y. FXR, a multipurpose nuclear receptor. Trends Biochem Sci 2006; 31 (10) 572-580
    CrossrefPubMedSearch in Google Scholar
  • 167 Cariou B, Staels B. FXR: a promising target for the metabolic syndrome?. Trends Pharmacol Sci 2007; 28 (05) 236-243
    CrossrefPubMedSearch in Google Scholar
  • 168 Zhang Y, Edwards PA. FXR signaling in metabolic disease. FEBS Lett 2008; 582 (01) 10-18
    CrossrefPubMedSearch in Google Scholar
  • 169 Zou A, Magee N, Deng F, Lehn S, Zhong C, Zhang Y. Hepatocyte nuclear receptor SHP suppresses inflammation and fibrosis in a mouse model of nonalcoholic steatohepatitis. J Biol Chem 2018; 293 (22) 8656-8671
    CrossrefPubMedSearch in Google Scholar
  • 170 Maloney PR, Parks DJ, Haffner CD. , et al. Identification of a chemical tool for the orphan nuclear receptor FXR. J Med Chem 2000; 43 (16) 2971-2974
    CrossrefPubMedSearch in Google Scholar
  • 171 Kast HR, Nguyen CM, Sinal CJ. , et al. Farnesoid X-activated receptor induces apolipoprotein C-II transcription: a molecular mechanism linking plasma triglyceride levels to bile acids. Mol Endocrinol 2001; 15 (10) 1720-1728
    CrossrefPubMedSearch in Google Scholar
  • 172 Zhang Y, Castellani LW, Sinal CJ, Gonzalez FJ, Edwards PA. Peroxisome proliferator-activated receptor-gamma coactivator 1alpha (PGC-1alpha) regulates triglyceride metabolism by activation of the nuclear receptor FXR. Genes Dev 2004; 18 (02) 157-169
    CrossrefPubMedSearch in Google Scholar
  • 173 Watanabe M, Houten SM, Wang L. , et al. Bile acids lower triglyceride levels via a pathway involving FXR, SHP, and SREBP-1c. J Clin Invest 2004; 113 (10) 1408-1418
    CrossrefPubMedSearch in Google Scholar
  • 174 Pineda Torra I, Claudel T, Duval C, Kosykh V, Fruchart JC, Staels B. Bile acids induce the expression of the human peroxisome proliferator-activated receptor α gene via activation of the farnesoid X receptor. Mol Endocrinol 2003; 17 (02) 259-272
    CrossrefPubMedSearch in Google Scholar
  • 175 Wanless IR, Wong F, Blendis LM, Greig P, Heathcote EJ, Levy G. Hepatic and portal vein thrombosis in cirrhosis: possible role in development of parenchymal extinction and portal hypertension. Hepatology 1995; 21 (05) 1238-1247
    PubMedSearch in Google Scholar
  • 176 Unsworth AJ, Bye AP, Tannetta DS. , et al. Farnesoid X receptor and liver X receptor ligands initiate formation of coated platelets. Arterioscler Thromb Vasc Biol 2017; 37 (08) 1482-1493
    CrossrefPubMedSearch in Google Scholar
  • 177 Moraes LA, Unsworth AJ, Vaiyapuri S. , et al. Farnesoid X receptor and its ligands inhibit the function of platelets. Arterioscler Thromb Vasc Biol 2016; 36 (12) 2324-2333
    CrossrefPubMedSearch in Google Scholar
  • 178 Schwabl P, Hambruch E, Supper P. , et al. The non-steroidal Fxr agonist Gs-9674 reduces liver fibrosis and ameliorates portal hypertension in a rat NASH model. J Hepatol 2016; 64 (02) S165-S166
    PubMedSearch in Google Scholar
  • 179 Goto T, Itoh M, Suganami T. , et al. Obeticholic acid protects against hepatocyte death and liver fibrosis in a murine model of nonalcoholic steatohepatitis. Sci Rep 2018; 8 (01) 8157
    CrossrefPubMedSearch in Google Scholar
  • 180 Iracheta-Vellve A, Calenda CD, Petrasek J. , et al. FXR and TGR5 agonists ameliorate liver injury, steatosis, and inflammation after binge or prolonged alcohol feeding in mice. Hepatol Commun 2018; 2 (11) 1379-1391
    CrossrefPubMedSearch in Google Scholar
  • 181 Jiang LJ, Chau M, Li Y. , et al. EDP-305, a novel and highly potent farnesoid X receptor agonist, improves liver steatosis, ballooning and non-alcoholic fatty liver disease (NAFLD) activity score (NAS) in a diet-induced murine model of non-alcoholic steatohepatitis. J Hepatol 2017; 66: S434
    PubMedSearch in Google Scholar
  • 182 Jiang LBD, Yoon YJ, Chou H. , et al. Significant anti-fibrotic efficacy of EDP-305, a highly potent and selective farnesoid X receptor (FXR) agonist, in a rat model of thioacetamide-induced liver fibrosis and cirrhosis. 2017, Washington, DC: AASLD Annual Meeting; 2017
    PubMedSearch in Google Scholar
  • 183 Mookerjee R, Rosselli M, Pieri G. , et al. O15 effects of the Fxr agonist obeticholic acid on hepatic venous pressure gradient (HVPG) in alcoholic cirrhosis: a proof of concept phase 2A study. J Hepatol 2014; 60 (01) S7-S8
    CrossrefPubMedSearch in Google Scholar
  • 184 Hirschfield GM, Mason A, Luketic V. , et al. Efficacy of obeticholic acid in patients with primary biliary cirrhosis and inadequate response to ursodeoxycholic acid. Gastroenterology 2015; 148 (04) 751-61.e8
    CrossrefPubMedSearch in Google Scholar
  • 185 Neuschwander-Tetri BA, Loomba R, Sanyal AJ. , et al; NASH Clinical Research Network. Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial. Lancet 2015; 385 (9972): 956-965
    CrossrefPubMedSearch in Google Scholar
  • 186 Trauner M, Gulamhusein A, Hameed B. , et al. The nonsteroidal FXR agonist cilofexor (GS-9674) improves markers of cholestasis and liver injury in patients with PSC. Hepatology 2019 , in press
    PubMedSearch in Google Scholar
  • 187 U.S. National Library of Medicine (REVERSE). Available at: https://www.clinicaltrials.gov/ct2/show/NCT03439254?term=03439254&rank=1 . Accessed April 19, 2019
    PubMed
  • 188 U.S. National Library of Medicine (REGENERATE). Available at: https://www.clinicaltrials.gov/ct2/show/NCT02548351?term=02548351&rank=1 . Accessed April 19, 2019
    PubMed
  • 189 U.S. National Library of Medicine (COBALT). Available at: https://www.clinicaltrials.gov/ct2/show/NCT02308111?term=02308111&rank=1 . Accessed April 19, 2019
    PubMed
  • 190 U.S. National Library of Medicine (POISE) NCT01473524. Available at: https://www.clinicaltrials.gov/ct2/show/NCT01473524?term=01473524&rank=1 . Accessed April 19, 2019
    PubMed
  • 191 EU Clinical Trials Register (OCABILE). Available at: https://www.clinicaltrialsregister.eu/ctr-search/trial/2016-002965-67/NL . Assessed April 19, 2019
    PubMed
  • 192 Vargas JI, Arrese M, Shah VH, Arab JP. Use of statins in patients with chronic liver disease and cirrhosis: current views and prospects. Curr Gastroenterol Rep 2017; 19 (09) 43
    CrossrefPubMedSearch in Google Scholar
  • 193 Pose E, Trebicka J, Mookerjee RP, Angeli P, Ginès P. Statins: old drugs as new therapy for liver diseases?. J Hepatol 2019; 70 (01) 194-202
    CrossrefPubMedSearch in Google Scholar
  • 194 Ariza X, Angeli P, Barreto R. , et al. O74 urinary neutrophil gelatinase-associated lipocalin (NGAL) is a strong predictor of short-term outcome in patients with acute decompensation of cirrhosis. relationship with acute-on-chronic liver failure (ACLF). J Hepatol 2014; 60 (01) S30-S31
    PubMedSearch in Google Scholar
  • 195 Klein S, Klösel J, Schierwagen R. , et al. Atorvastatin inhibits proliferation and apoptosis, but induces senescence in hepatic myofibroblasts and thereby attenuates hepatic fibrosis in rats. Lab Invest 2012; 92 (10) 1440-1450
    CrossrefPubMedSearch in Google Scholar
  • 196 Klein S, Van Beuge MM, Granzow M. , et al. HSC-specific inhibition of Rho-kinase reduces portal pressure in cirrhotic rats without major systemic effects. J Hepatol 2012; 57 (06) 1220-1227
    CrossrefPubMedSearch in Google Scholar
  • 197 Trebicka J, Hennenberg M, Laleman W. , et al. Atorvastatin lowers portal pressure in cirrhotic rats by inhibition of RhoA/Rho-kinase and activation of endothelial nitric oxide synthase. Hepatology 2007; 46 (01) 242-253
    CrossrefPubMedSearch in Google Scholar
  • 198 Trebicka J, Hennenberg M, Odenthal M. , et al. Atorvastatin attenuates hepatic fibrosis in rats after bile duct ligation via decreased turnover of hepatic stellate cells. J Hepatol 2010; 53 (04) 702-712
    CrossrefPubMedSearch in Google Scholar
  • 199 Trebicka J, Schierwagen R. Statins, Rho GTPases and KLF2: new mechanistic insight into liver fibrosis and portal hypertension. Gut 2015; 64 (09) 1349-1350
    CrossrefPubMedSearch in Google Scholar
  • 200 Abraldes JG, Rodríguez-Vilarrupla A, Graupera M. , et al. Simvastatin treatment improves liver sinusoidal endothelial dysfunction in CCl4 cirrhotic rats. J Hepatol 2007; 46 (06) 1040-1046
    CrossrefPubMedSearch in Google Scholar
  • 201 Ascer E, Bertolami MC, Venturinelli ML. , et al. Atorvastatin reduces proinflammatory markers in hypercholesterolemic patients. Atherosclerosis 2004; 177 (01) 161-166
    CrossrefPubMedSearch in Google Scholar
  • 202 Bishnu S, Ahammed SM, Sarkar A. , et al. Effects of atorvastatin on portal hemodynamics and clinical outcomes in patients with cirrhosis with portal hypertension: a proof-of-concept study. Eur J Gastroenterol Hepatol 2018; 30 (01) 54-59
    CrossrefPubMedSearch in Google Scholar
  • 203 Tolman KG. The liver and lovastatin. Am J Cardiol 2002; 89 (12) 1374-1380
    CrossrefPubMedSearch in Google Scholar
  • 204 Calderon RM, Cubeddu LX, Goldberg RB, Schiff ER. Statins in the treatment of dyslipidemia in the presence of elevated liver aminotransferase levels: a therapeutic dilemma. Mayo Clin Proc 2010; 85 (04) 349-356
    CrossrefPubMedSearch in Google Scholar
  • 205 Bhardwaj SS, Chalasani N. Lipid-lowering agents that cause drug-induced hepatotoxicity. Clin Liver Dis 2007; 11 (03) 597-613 , vii
    CrossrefPubMedSearch in Google Scholar
  • 206 Chalasani N. Statins and hepatotoxicity: focus on patients with fatty liver. Hepatology 2005; 41 (04) 690-695
    CrossrefPubMedSearch in Google Scholar
  • 207 Khorashadi S, Hasson NK, Cheung RC. Incidence of statin hepatotoxicity in patients with hepatitis C. Clin Gastroenterol Hepatol 2006; 4 (07) 902-907 , quiz 806
    CrossrefPubMedSearch in Google Scholar
  • 208 Nseir W, Mahamid M. Statins in nonalcoholic fatty liver disease and steatohepatitis: updated review. Curr Atheroscler Rep 2013; 15 (03) 305
    CrossrefPubMedSearch in Google Scholar
  • 209 Avins AL, Manos MM, Ackerson L. , et al. Hepatic effects of lovastatin exposure in patients with liver disease: a retrospective cohort study. Drug Saf 2008; 31 (04) 325-334
    CrossrefPubMedSearch in Google Scholar
  • 210 Kim RG, Loomba R, Prokop LJ, Singh S. Statin use and risk of cirrhosis and related complications in patients with chronic liver diseases: a systematic review and meta-analysis. Clin Gastroenterol Hepatol 2017; 15 (10) 1521-1530.e8
    CrossrefPubMedSearch in Google Scholar
  • 211 Kaplan DE, Serper MA, Mehta R. , et al; VOCAL Study Group. Effects of hypercholesterolemia and statin exposure on survival in a large national cohort of patients with cirrhosis. Gastroenterology 2019; 156 (06) 1693-1706.e12
    CrossrefPubMedSearch in Google Scholar
  • 212 Kumar S, Grace ND, Qamar AA. Statin use in patients with cirrhosis: a retrospective cohort study. Dig Dis Sci 2014; 59 (08) 1958-1965
    CrossrefPubMedSearch in Google Scholar
  • 213 Kamath PS, Carpenter HA, Lloyd RV. , et al. Hepatic localization of endothelin-1 in patients with idiopathic portal hypertension and cirrhosis of the liver. Liver Transpl 2000; 6 (05) 596-602
    CrossrefPubMedSearch in Google Scholar
  • 214 Kawada N, Seki S, Kuroki T, Kaneda K. ROCK inhibitor Y-27632 attenuates stellate cell contraction and portal pressure increase induced by endothelin-1. Biochem Biophys Res Commun 1999; 266 (02) 296-300
    CrossrefPubMedSearch in Google Scholar
  • 215 Hernández-Perera O, Pérez-Sala D, Navarro-Antolín J. , et al. Effects of the 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors, atorvastatin and simvastatin, on the expression of endothelin-1 and endothelial nitric oxide synthase in vascular endothelial cells. J Clin Invest 1998; 101 (12) 2711-2719
    CrossrefPubMedSearch in Google Scholar
  • 216 Hernández-Perera O, Pérez-Sala D, Soria E, Lamas S. Involvement of Rho GTPases in the transcriptional inhibition of preproendothelin-1 gene expression by simvastatin in vascular endothelial cells. Circ Res 2000; 87 (07) 616-622
    CrossrefPubMedSearch in Google Scholar
  • 217 Hsu SJ, Wang SS, Hsin IF. , et al. Effects of simvastatin on the portal-systemic collateral vascular response to endothelin-1 and shunting degree in portal hypertensive rats. Scand J Gastroenterol 2013; 48 (07) 831-838
    CrossrefPubMedSearch in Google Scholar
  • 218 Morales-Ruiz M, Cejudo-Martín P, Fernández-Varo G. , et al. Transduction of the liver with activated Akt normalizes portal pressure in cirrhotic rats. Gastroenterology 2003; 125 (02) 522-531
    CrossrefPubMedSearch in Google Scholar
  • 219 Zafra C, Abraldes JG, Turnes J. , et al. Simvastatin enhances hepatic nitric oxide production and decreases the hepatic vascular tone in patients with cirrhosis. Gastroenterology 2004; 126 (03) 749-755
    CrossrefPubMedSearch in Google Scholar
  • 220 Rodríguez S, Raurell I, Torres-Arauz M, García-Lezana T, Genescà J, Martell M. A nitric oxide-donating statin decreases portal pressure with a better toxicity profile than conventional statins in cirrhotic rats. Sci Rep 2017; 7: 40461
    CrossrefPubMedSearch in Google Scholar
  • 221 Gracia-Sancho J, Russo L, García-Calderó H, García-Pagán JC, García-Cardeña G, Bosch J. Endothelial expression of transcription factor Kruppel-like factor 2 and its vasoprotective target genes in the normal and cirrhotic rat liver. Gut 2011; 60 (04) 517-524
    CrossrefPubMedSearch in Google Scholar
  • 222 Janicko M, Drazilova S, Pella D, Fedacko J, Jarcuska P. Pleiotropic effects of statins in the diseases of the liver. World J Gastroenterol 2016; 22 (27) 6201-6213
    CrossrefPubMedSearch in Google Scholar
  • 223 Sahebkar A, Serban C, Ursoniu S. , et al; Lipid and Blood Pressure Meta-analysis Collaboration (LBPMC) Group. The impact of statin therapy on plasma levels of von Willebrand factor antigen. Systematic review and meta-analysis of randomised placebo-controlled trials. Thromb Haemost 2016; 115 (03) 520-532
    Thieme ConnectPubMedSearch in Google Scholar
  • 224 Marrone G, Russo L, Rosado E. , et al. The transcription factor KLF2 mediates hepatic endothelial protection and paracrine endothelial-stellate cell deactivation induced by statins. J Hepatol 2013; 58 (01) 98-103
    CrossrefPubMedSearch in Google Scholar
  • 225 Russo L, Gracia-Sancho J, García-Calderó H. , et al. Addition of simvastatin to cold storage solution prevents endothelial dysfunction in explanted rat livers. Hepatology 2012; 55 (03) 921-930
    CrossrefPubMedSearch in Google Scholar
  • 226 Chong L-W, Hsu Y-C, Lee T-F. , et al. Fluvastatin attenuates hepatic steatosis-induced fibrogenesis in rats through inhibiting paracrine effect of hepatocyte on hepatic stellate cells. BMC Gastroenterol 2015; 15: 22
    CrossrefPubMedSearch in Google Scholar
  • 227 Marrone G, Maeso-Díaz R, García-Cardena G. , et al. KLF2 exerts antifibrotic and vasoprotective effects in cirrhotic rat livers: behind the molecular mechanisms of statins. Gut 2015; 64 (09) 1434-1443
    CrossrefPubMedSearch in Google Scholar
  • 228 Miao Q, Zeng X, Ma G. , et al. Simvastatin suppresses the proangiogenic microenvironment of human hepatic stellate cells via the Kruppel-like factor 2 pathway. Rev Esp Enferm Dig 2015; 107 (02) 63-71
    PubMedSearch in Google Scholar
  • 229 Shirin H, Sharvit E, Aeed H, Gavish D, Bruck R. Atorvastatin and rosuvastatin do not prevent thioacetamide induced liver cirrhosis in rats. World J Gastroenterol 2013; 19 (02) 241-248
    CrossrefPubMedSearch in Google Scholar
  • 230 Terui Y, Saito T, Watanabe H. , et al. Effect of angiotensin receptor antagonist on liver fibrosis in early stages of chronic hepatitis C. Hepatology 2002; 36 (4 Pt 1): 1022
    CrossrefPubMedSearch in Google Scholar
  • 231 Kurikawa N, Suga M, Kuroda S, Yamada K, Ishikawa H. An angiotensin II type 1 receptor antagonist, olmesartan medoxomil, improves experimental liver fibrosis by suppression of proliferation and collagen synthesis in activated hepatic stellate cells. Br J Pharmacol 2003; 139 (06) 1085-1094
    CrossrefPubMedSearch in Google Scholar
  • 232 Abbas G, Silveira MG, Lindor KD. Hepatic fibrosis and the renin-angiotensin system. Am J Ther 2011; 18 (06) e202-e208
    CrossrefPubMedSearch in Google Scholar
  • 233 Nie L, Imamura M, Itoh H, Ueno H. Pitavastatin enhances the anti-fibrogenesis effects of candesartan, an angiotensin II receptor blocker, on CCl4-induced liver fibrosis in rats. J UOEH 2004; 26 (02) 165-177
    CrossrefPubMedSearch in Google Scholar
  • 234 El-Ashmawy NE, El-Bahrawy HA, Shamloula MM, Ibrahim AO. Antifibrotic effect of AT-1 blocker and statin in rats with hepatic fibrosis. Clin Exp Pharmacol Physiol 2015; 42 (09) 979-987
    CrossrefPubMedSearch in Google Scholar
  • 235 Kleemann R, Verschuren L, de Rooij B-J. , et al. Evidence for anti-inflammatory activity of statins and PPARalpha activators in human C-reactive protein transgenic mice in vivo and in cultured human hepatocytes in vitro. Blood 2004; 103 (11) 4188-4194
    CrossrefPubMedSearch in Google Scholar
  • 236 Okada Y, Yamaguchi K, Nakajima T. , et al. Rosuvastatin ameliorates high-fat and high-cholesterol diet-induced nonalcoholic steatohepatitis in rats. Liver Int 2013; 33 (02) 301-311
    CrossrefPubMedSearch in Google Scholar
  • 237 Kamada Y, Kiso S, Yoshida Y. , et al. Pitavastatin ameliorated the progression of steatohepatitis in ovariectomized mice fed a high fat and high cholesterol diet. Hepatol Res 2013; 43 (04) 401-412
    CrossrefPubMedSearch in Google Scholar
  • 238 Meireles CZ, Pasarin M, Lozano JJ. , et al. Simvastatin attenuates liver injury in rodents with biliary cirrhosis submitted to hemorrhage/resuscitation. Shock 2017; 47 (03) 370-377
    CrossrefPubMedSearch in Google Scholar
  • 239 Wang J, Lu Z, Xu Z. , et al. Reduction of hepatic fibrosis by overexpression of von Hippel-Lindau protein in experimental models of chronic liver disease. Sci Rep 2017; 7: 41038-41038
    CrossrefPubMedSearch in Google Scholar
  • 240 Abraldes JG, Albillos A, Bañares R. , et al. Simvastatin lowers portal pressure in patients with cirrhosis and portal hypertension: a randomized controlled trial. Gastroenterology 2009; 136 (05) 1651-1658
    CrossrefPubMedSearch in Google Scholar
  • 241 Pollo-Flores P, Soldan M, Santos UC. , et al. Three months of simvastatin therapy vs. placebo for severe portal hypertension in cirrhosis: a randomized controlled trial. Dig Liver Dis 2015; 47 (11) 957-963
    CrossrefPubMedSearch in Google Scholar
  • 242 Abraldes JG, Villanueva C, Aracil C. , et al; BLEPS Study Group. Addition of simvastatin to standard therapy for the prevention of variceal rebleeding does not reduce rebleeding but increases survival in patients with cirrhosis. Gastroenterology 2016; 150 (05) 1160-1170.e3
    CrossrefPubMedSearch in Google Scholar
  • 243 Kamal S, Khan MA, Seth A. , et al. Beneficial effects of statins on the rates of hepatic fibrosis, hepatic decompensation, and mortality in chronic liver disease: a systematic review and meta-analysis. Am J Gastroenterol 2017; 112 (10) 1495-1505
    CrossrefPubMedSearch in Google Scholar
  • 244 Yang YH, Chen WC, Tsan YT. , et al. Statin use and the risk of cirrhosis development in patients with hepatitis C virus infection. J Hepatol 2015; 63 (05) 1111-1117
    CrossrefPubMedSearch in Google Scholar
  • 245 Chang FM, Wang YP, Lang HC. , et al. Statins decrease the risk of decompensation in hepatitis B virus- and hepatitis C virus-related cirrhosis: a population-based study. Hepatology 2017; 66 (03) 896-907
    CrossrefPubMedSearch in Google Scholar
  • 246 Bang UC, Benfield T, Bendtsen F. Reduced risk of decompensation and death associated with use of statins in patients with alcoholic cirrhosis. A nationwide case-cohort study. Aliment Pharmacol Ther 2017; 46 (07) 673-680
    CrossrefPubMedSearch in Google Scholar
  • 247 Mohanty A, Tate JP, Garcia-Tsao G. Statins are associated with a decreased risk of decompensation and death in veterans with hepatitis C-related compensated cirrhosis. Gastroenterology 2016; 150 (02) 430-40.e1
    CrossrefPubMedSearch in Google Scholar
  • 248 Huang YW, Lee CL, Yang SS. , et al. Statins reduce the risk of cirrhosis and its decompensation in chronic hepatitis B patients: a nationwide cohort study. Am J Gastroenterol 2016; 111 (07) 976-985
    CrossrefPubMedSearch in Google Scholar
  • 249 Simon TG, Bonilla H, Yan P, Chung RT, Butt AA. Atorvastatin and fluvastatin are associated with dose-dependent reductions in cirrhosis and hepatocellular carcinoma, among patients with hepatitis C virus: results from ERCHIVES. Hepatology 2016; 64 (01) 47-57
    CrossrefPubMedSearch in Google Scholar
  • 250 U.S. National Library of Medicine NCT02465645. Available at: https://www.clinicaltrials.gov/ct2/show/NCT02465645?term=02465645&rank=1 . Accessed April 19, 2019
    PubMed
  • 251 Pant A, Kopec AK, Luyendyk JP. Role of the blood coagulation cascade in hepatic fibrosis. Am J Physiol Gastrointest Liver Physiol 2018; 315 (02) G171-G176
    CrossrefPubMedSearch in Google Scholar
  • 252 Lisman T, Bongers TN, Adelmeijer J. , et al. Elevated levels of von Willebrand factor in cirrhosis support platelet adhesion despite reduced functional capacity. Hepatology 2006; 44 (01) 53-61
    CrossrefPubMedSearch in Google Scholar
  • 253 Lisman T, Leebeek FWG, de Groot PG. Haemostatic abnormalities in patients with liver disease. J Hepatol 2002; 37 (02) 280-287
    CrossrefPubMedSearch in Google Scholar
  • 254 Tacke F, Luedde T, Trautwein C. Inflammatory pathways in liver homeostasis and liver injury. Clin Rev Allergy Immunol 2009; 36 (01) 4-12
    CrossrefPubMedSearch in Google Scholar
  • 255 Gillibert-Duplantier J, Neaud V, Blanc JF, Bioulac-Sage P, Rosenbaum J. Thrombin inhibits migration of human hepatic myofibroblasts. Am J Physiol Gastrointest Liver Physiol 2007; 293 (01) G128-G136
    CrossrefPubMedSearch in Google Scholar
  • 256 Vu TK, Hung DT, Wheaton VI, Coughlin SR. Molecular cloning of a functional thrombin receptor reveals a novel proteolytic mechanism of receptor activation. Cell 1991; 64 (06) 1057-1068
    CrossrefPubMedSearch in Google Scholar
  • 257 Bitto N, Liguori E, La Mura V. Coagulation, microenvironment and liver fibrosis. Cells 2018; 7 (08) 7
    CrossrefPubMedSearch in Google Scholar
  • 258 Gaça MD, Zhou X, Benyon RC. Regulation of hepatic stellate cell proliferation and collagen synthesis by proteinase-activated receptors. J Hepatol 2002; 36 (03) 362-369
    CrossrefPubMedSearch in Google Scholar
  • 259 Anstee QM, Dhar A, Thursz MR. The role of hypercoagulability in liver fibrogenesis. Clin Res Hepatol Gastroenterol 2011; 35 (8-9): 526-533
    CrossrefPubMedSearch in Google Scholar
  • 260 Duplantier JG, Dubuisson L, Senant N. , et al. A role for thrombin in liver fibrosis. Gut 2004; 53 (11) 1682-1687
    CrossrefPubMedSearch in Google Scholar
  • 261 Knight V, Tchongue J, Lourensz D, Tipping P, Sievert W. Protease-activated receptor 2 promotes experimental liver fibrosis in mice and activates human hepatic stellate cells. Hepatology 2012; 55 (03) 879-887
    CrossrefPubMedSearch in Google Scholar
  • 262 Calvaruso V, Maimone S, Gatt A. , et al. Coagulation and fibrosis in chronic liver disease. Gut 2008; 57 (12) 1722-1727
    CrossrefPubMedSearch in Google Scholar
  • 263 Jairath V, Burroughs AK. Anticoagulation in patients with liver cirrhosis: complication or therapeutic opportunity?. Gut 2013; 62 (04) 479-482
    CrossrefPubMedSearch in Google Scholar
  • 264 Dhar A, Sadiq F, Anstee QM, Levene AP, Goldin RD, Thursz MR. Thrombin and factor Xa link the coagulation system with liver fibrosis. BMC Gastroenterol 2018; 18 (01) 60
    CrossrefPubMedSearch in Google Scholar
  • 265 Cerini F, Vilaseca M, Lafoz E. , et al. Enoxaparin reduces hepatic vascular resistance and portal pressure in cirrhotic rats. J Hepatol 2016; 64 (04) 834-842
    CrossrefPubMedSearch in Google Scholar
  • 266 Vilaseca M, García-Calderó H, Lafoz E. , et al. The anticoagulant rivaroxaban lowers portal hypertension in cirrhotic rats mainly by deactivating hepatic stellate cells. Hepatology 2017; 65 (06) 2031-2044
    CrossrefPubMedSearch in Google Scholar
  • 267 Villa E, Cammà C, Marietta M. , et al. Enoxaparin prevents portal vein thrombosis and liver decompensation in patients with advanced cirrhosis. Gastroenterology 2012; 143 (05) 1253-1260.e4
    CrossrefPubMedSearch in Google Scholar
  • 268 Delgado MG, Seijo S, Yepes I. , et al. Efficacy and safety of anticoagulation on patients with cirrhosis and portal vein thrombosis. Clin Gastroenterol Hepatol 2012; 10 (07) 776-783
    CrossrefPubMedSearch in Google Scholar
  • 269 Ageno W, Riva N, Schulman S. , et al. Long-term clinical outcomes of splanchnic vein thrombosis: results of an international registry. JAMA Intern Med 2015; 175 (09) 1474-1480
    CrossrefPubMedSearch in Google Scholar
  • 270 De Gottardi A, Trebicka J, Klinger C. , et al; VALDIG Investigators. Antithrombotic treatment with direct-acting oral anticoagulants in patients with splanchnic vein thrombosis and cirrhosis. Liver Int 2017; 37 (05) 694-699
    CrossrefPubMedSearch in Google Scholar
  • 271 EU Clinical Trials Register. Available at: https://www.clinicaltrialsregister.eu/ctr-search/trial/2014-005523-27/ES#P . Accessed April 19, 2019
    PubMed
  • 272 EU Clinical Trials Register. Available at: https://www.clinicaltrialsregister.eu/ctr-search/trial/2016-003240-37/ES . Accessed April 19, 2019
    PubMed