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Hepatology International
Published in: Hepatology International 1/2018

01-02-2018 | Special Issue - Portal Hypertension

Novelties in the pathophysiology and management of portal hypertension: new treatments on the horizon

Authors: Seong Hee Kang, Moon Young Kim, Soon Koo Baik

Published in: Hepatology International | Special Issue 1/2018

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Abstract

Portal hypertension (PH) is responsible for the most severe complications of cirrhosis and leading cause of death and liver transplantation. The standard pharmacological treatment available for PH currently consists of the use of a non-selective beta-blocker. However, a significant proportion of patients do not respond to pharmacological treatment. This has led to the development of identifiable targets for the discovery of new horizons in PH treatment. Recently, there has been significant progress in understanding the mechanism behind PH, which is a product of increased hepatic vascular resistance including structural changes and functional change due to endothelial dysfunction. Moreover, increased portal inflow is the outcome of dilation of splanchnic vessels and hyperdynamic circulation. Here, challenges in formulating potential pharmacological treatment as well as current potential targets for PH will be reviewed. During the past decades, there have been many efforts to explore new techniques to stimulate liver regeneration in addition to pharmacological treatment. The bone marrow (BM) stem cells which differentiate into mature hepatocytes are thought to contribute to liver regeneration and have been found to demonstrate great potential as regenerative medicine in different therapeutic applications. Based on these insights, we explore the current and potential novel therapeutic uses of BM stem cell therapy in PH.
Literature
1.
Kim MY, Suk KT, Baik SK, et al. Hepatic vein arrival time as assessed by contrast-enhanced ultrasonography is useful for the assessment of portal hypertension in compensated cirrhosis. Hepatology 2012;56:1053–62CrossRefPubMed
2.
Kim G, Lee SS, Baik SK, et al. The need for histological subclassification of cirrhosis: a systematic review and meta-analysis. Liver Int 2016;36:847–55CrossRefPubMed
3.
Baik SK. Haemodynamic evaluation by Doppler ultrasonography in patients with portal hypertension: a review. Liver Int 2010;30:1403–13CrossRefPubMed
4.
5.
Lo GH, Chen WC, Lin CK, et al. Improved survival in patients receiving medical therapy as compared with banding ligation for the prevention of esophageal variceal rebleeding. Hepatology 2008;48:580–7CrossRefPubMed
6.
Kim G, Shim KY, Baik SK. Diagnostic accuracy of hepatic vein arrival time performed with contrast-enhanced ultrasonography for cirrhosis: a systematic review and meta-analysis. Gut Liver 2017;11:93–101CrossRefPubMed
7.
Kim G, Kim MY, Baik SK. Transient elastography versus hepatic venous pressure gradient for diagnosing portal hypertension: a systematic review and meta-analysis. Clin Mol Hepatol 2017;23:34–41CrossRefPubMedPubMedCentral
8.
Kim MY, Baik SK, Yea CJ, et al. Hepatic venous pressure gradient can predict the development of hepatocellular carcinoma and hyponatremia in decompensated alcoholic cirrhosis. Eur J Gastroenterol Hepatol 2009;21:1241–6CrossRefPubMed
9.
Garcia-Pagan JC, Gracia-Sancho J, Bosch J. Functional aspects on the pathophysiology of portal hypertension in cirrhosis. J Hepatol 2012;57:458–61CrossRefPubMed
10.
Bhathal PS, Grossman HJ. Reduction of the increased portal vascular resistance of the isolated perfused cirrhotic rat liver by vasodilators. J Hepatol 1985;1:325–37CrossRefPubMed
11.
Jun JH, Choi JH, Bae SH, Oh SH, Kim GJ. Decreased C-reactive protein induces abnormal vascular structure in a rat model of liver dysfunction induced by bile duct ligation. Clin Mol Hepatol 2016;22:372–81CrossRefPubMedPubMedCentral
12.
13.
Iwakiri Y, Groszmann RJ. The hyperdynamic circulation of chronic liver diseases: from the patient to the molecule. Hepatology 2006;43:S121–31CrossRefPubMed
14.
de Franchis R, Baveno VIF. Expanding consensus in portal hypertension: report of the Baveno VI Consensus Workshop: Stratifying risk and individualizing care for portal hypertension. J Hepatol 2015;63:743–52CrossRefPubMed
15.
Kong DR, Wang JG, Sun B, et al. beta-2 Adrenergic receptor gene polymorphism and response to propranolol in cirrhosis. World J Gastroenterol 2015;21:7191–6CrossRefPubMedPubMedCentral
16.
Kallis YN, Robson AJ, Fallowfield JA, et al. Remodelling of extracellular matrix is a requirement for the hepatic progenitor cell response. Gut 2011;60:525–33CrossRefPubMed
17.
Jang YO, Cho MY, Yun CO, et al. Effect of function-enhanced mesenchymal stem cells infected with decorin-expressing adenovirus on hepatic fibrosis. Stem Cells Transl Med 2016;5:1247–56CrossRefPubMedPubMedCentral
18.
19.
20.
Kim MY, Cho MY, Baik SK, et al. Beneficial effects of candesartan, an angiotensin-blocking agent, on compensated alcoholic liver fibrosis—a randomized open-label controlled study. Liver Int 2012;32:977–87CrossRefPubMed
21.
Kim G, Kim J, Lim YL, Kim MY, Baik SK. Renin-angiotensin system inhibitors and fibrosis in chronic liver disease: a systematic review. Hepatol Int 2016;10:819–28CrossRefPubMed
22.
Lan T, Kisseleva T, Brenner DA. Deficiency of NOX1 or NOX4 prevents liver inflammation and fibrosis in mice through inhibition of hepatic stellate cell activation. PLoS ONE 2015;10:e0129743CrossRefPubMedPubMedCentral
23.
Barry-Hamilton V, Spangler R, Marshall D, et al. Allosteric inhibition of lysyl oxidase-like-2 impedes the development of a pathologic microenvironment. Nat Med 2010;16:1009–17CrossRefPubMed
24.
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;53:702–12CrossRefPubMed
25.
Wanless IR, Liu JJ, Butany J. Role of thrombosis in the pathogenesis of congestive hepatic fibrosis (cardiac cirrhosis). Hepatology 1995;21:1232–7PubMed
26.
Cerini F, Vilaseca M, Lafoz E, et al. Enoxaparin reduces hepatic vascular resistance and portal pressure in cirrhotic rats. J Hepatol 2016;64:834–42CrossRefPubMed
27.
Vilaseca M, Garcia-Caldero H, Lafoz E, et al. The anticoagulant rivaroxaban lowers portal hypertension in cirrhotic rats mainly by deactivating hepatic stellate cells. Hepatology 2017;65(6):2031–2044CrossRefPubMed
28.
Villa E, Camma C, Marietta M, et al. Enoxaparin prevents portal vein thrombosis and liver decompensation in patients with advanced cirrhosis. Gastroenterology 2012;143(1253–1260):e1251–4
29.
Khoury T, Ayman AR, Cohen J, Daher S, Shmuel C, Mizrahi M. The complex role of anticoagulation in cirrhosis: an updated review of where we are and where we are going. Digestion 2016;93:149–59CrossRefPubMed
30.
Iwakiri Y, Shah V, Rockey DC. Vascular pathobiology in chronic liver disease and cirrhosis—current status and future directions. J Hepatol 2014;61:912–24CrossRefPubMedPubMedCentral
31.
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;46:242–53CrossRefPubMed
32.
Abraldes JG, Albillos A, Banares R, et al. Simvastatin lowers portal pressure in patients with cirrhosis and portal hypertension: a randomized controlled trial. Gastroenterology 2009;136:1651–8CrossRefPubMed
33.
Abraldes JG, Villanueva C, Aracil C, et al. 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(1160–1170):e1163
34.
Lefebvre P, Cariou B, Lien F, Kuipers F, Staels B. Role of bile acids and bile acid receptors in metabolic regulation. Physiol Rev 2009;89:147–91CrossRefPubMed
35.
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;127:1497–512CrossRefPubMed
36.
Li J, Wilson A, Kuruba R, et al. FXR-mediated regulation of eNOS expression in vascular endothelial cells. Cardiovasc Res 2008;77:169–77CrossRefPubMed
37.
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;66:724–33CrossRefPubMed
38.
Davies NA, Hodges SJ, Pitsillides AA, Mookerjee RP, Jalan R, Mehdizadeh S. Hepatic guanylate cyclase activity is decreased in a model of cirrhosis: a quantitative cytochemistry study. FEBS Lett 2006;580:2123–8CrossRefPubMed
39.
Loureiro-Silva MR, Iwakiri Y, Abraldes JG, Haq O, Groszmann RJ. Increased phosphodiesterase-5 expression is involved in the decreased vasodilator response to nitric oxide in cirrhotic rat livers. J Hepatol 2006;44:886–93CrossRefPubMed
40.
Murad F. Shattuck lecture. Nitric oxide and cyclic GMP in cell signaling and drug development. N Engl J Med 2006;355:2003–11CrossRefPubMed
41.
Lee KC, Yang YY, Huang YT, et al. Administration of a low dose of sildenafil for 1 week decreases intrahepatic resistance in rats with biliary cirrhosis: the role of NO bioavailability. Clin Sci (Lond) 2010;119:45–55CrossRef
42.
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;47:144–50CrossRefPubMed
43.
Kalambokis GN, Kosta P, Pappas K, Tsianos EV. Haemodynamic and renal effects of tadalafil in patients with cirrhosis. World J Gastroenterol 2010;16:5009–10CrossRefPubMedPubMedCentral
44.
45.
Matei V, Rodriguez-Vilarrupla A, Deulofeu R, et al. The eNOS cofactor tetrahydrobiopterin improves endothelial dysfunction in livers of rats with CCl4 cirrhosis. Hepatology 2006;44:44–52CrossRefPubMed
46.
Matei V, Rodriguez-Vilarrupla A, Deulofeu R, et al. Three-day tetrahydrobiopterin therapy increases in vivo hepatic NOS activity and reduces portal pressure in CCl4 cirrhotic rats. J Hepatol 2008;49:192–7CrossRefPubMed
47.
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;110:985–92CrossRefPubMed
48.
Hong WK, Shim KY, Baik SK, et al. Relationship between tetrahydrobiopterin and portal hypertension in patients with chronic liver disease. J Korean Med Sci 2014;29:392–9CrossRefPubMedPubMedCentral
49.
Zima T, Kalousova M. Oxidative stress and signal transduction pathways in alcoholic liver disease. Alcohol Clin Exp Res 2005;29:110S–5SCrossRefPubMed
50.
Taddei S, Virdis A, Ghiadoni L, Magagna A, Salvetti A. Vitamin C improves endothelium-dependent vasodilation by restoring nitric oxide activity in essential hypertension. Circulation 1998;97:2222–9CrossRefPubMed
51.
Ting HH, Timimi FK, Boles KS, Creager SJ, Ganz P, Creager MA. Vitamin C improves endothelium-dependent vasodilation in patients with non-insulin-dependent diabetes mellitus. J Clin Invest 1996;97:22–8CrossRefPubMedPubMedCentral
52.
Hernandez-Guerra M, Garcia-Pagan JC, Turnes J, et al. Ascorbic acid improves the intrahepatic endothelial dysfunction of patients with cirrhosis and portal hypertension. Hepatology 2006;43:485–91CrossRefPubMed
53.
Gracia-Sancho J, Lavina B, Rodriguez-Vilarrupla A, et al. Increased oxidative stress in cirrhotic rat livers: a potential mechanism contributing to reduced nitric oxide bioavailability. Hepatology 2008;47:1248–56CrossRefPubMed
54.
Guillaume M, Rodriguez-Vilarrupla A, Gracia-Sancho J, et al. Recombinant human manganese superoxide dismutase reduces liver fibrosis and portal pressure in CCl4-cirrhotic rats. J Hepatol 2013;58:240–6CrossRefPubMed
55.
Bataller R, Gines P, Nicolas JM, et al. Angiotensin II induces contraction and proliferation of human hepatic stellate cells. Gastroenterology 2000;118:1149–56CrossRefPubMed
56.
Kim MY, Baik SK, Park DH, et al. Angiotensin receptor blockers are superior to angiotensin-converting enzyme inhibitors in the suppression of hepatic fibrosis in a bile duct-ligated rat model. J Gastroenterol 2008;43:889–96CrossRefPubMed
57.
Schepke M, Wiest R, Flacke S, et al. Irbesartan plus low-dose propranolol versus low-dose propranolol alone in cirrhosis: a placebo-controlled, double-blind study. Am J Gastroenterol 2008;103:1152–8CrossRefPubMed
58.
Gonzalez-Abraldes J, Albillos A, Banares R, et al. Randomized comparison of long-term losartan versus propranolol in lowering portal pressure in cirrhosis. Gastroenterology 2001;121:382–8CrossRefPubMed
59.
Baik SK, Park DH, Kim MY, et al. Captopril reduces portal pressure effectively in portal hypertensive patients with low portal venous velocity. J Gastroenterol 2003;38:1150–4CrossRefPubMed
60.
Kim JH, Kim JM, Cho YZ, et al. Effects of candesartan and propranolol combination therapy versus propranolol monotherapy in reducing portal hypertension. Clin Mol Hepatol 2014;20:376–83CrossRefPubMedPubMedCentral
61.
Tandon P, Abraldes JG, Berzigotti A, Garcia-Pagan JC, Bosch J. Renin-angiotensin-aldosterone inhibitors in the reduction of portal pressure: a systematic review and meta-analysis. J Hepatol 2010;53:273–82CrossRefPubMed
62.
Lubel JS, Herath CB, Tchongue J, et al. Angiotensin-(1–7), an alternative metabolite of the renin-angiotensin system, is up-regulated in human liver disease and has antifibrotic activity in the bile-duct-ligated rat. Clin Sci (Lond) 2009;117:375–86CrossRef
63.
Klein S, Herath CB, Schierwagen R, et al. Hemodynamic effects of the non-peptidic angiotensin-(1–7) agonist AVE0991 in liver cirrhosis. PLoS ONE 2015;10:e0138732CrossRefPubMedPubMedCentral
64.
Granzow M, Schierwagen R, Klein S, et al. Angiotensin-II type 1 receptor-mediated Janus kinase 2 activation induces liver fibrosis. Hepatology 2014;60:334–48CrossRefPubMedPubMedCentral
65.
Klein S, Rick J, Lehmann J, et al. Janus-kinase-2 relates directly to portal hypertension and to complications in rodent and human cirrhosis. Gut 2017;66:145–55CrossRefPubMed
66.
Graupera M, Garcia-Pagan JC, Abraldes JG, et al. Cyclooxygenase-derived products modulate the increased intrahepatic resistance of cirrhotic rat livers. Hepatology 2003;37:172–81CrossRefPubMed
67.
Rosado E, Rodriguez-Vilarrupla A, Gracia-Sancho J, et al. Terutroban, a TP-receptor antagonist, reduces portal pressure in cirrhotic rats. Hepatology 2013;58:1424–35CrossRefPubMed
68.
Suk KT, Kim MY, Park DH, et al. Effect of propranolol on portal pressure and systemic hemodynamics in patients with liver cirrhosis and portal hypertension: a prospective study. Gut Liver 2007;1:159–64CrossRefPubMedPubMedCentral
69.
Fernandez M, Semela D, Bruix J, Colle I, Pinzani M, Bosch J. Angiogenesis in liver disease. J Hepatol 2009;50:604–20CrossRefPubMed
70.
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;49:1245–56CrossRefPubMed
71.
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;35:83–91CrossRefPubMed
72.
Chen Y, Yang F, Lu H, et al. Characterization of fecal microbial communities in patients with liver cirrhosis. Hepatology 2011;54:562–72CrossRefPubMed
73.
74.
Vlachogiannakos J, Saveriadis AS, Viazis N, et al. Intestinal decontamination improves liver haemodynamics in patients with alcohol-related decompensated cirrhosis. Aliment Pharmacol Ther 2009;29:992–9CrossRefPubMed
75.
Vlachogiannakos J, Viazis N, Vasianopoulou P, Vafiadis I, Karamanolis DG, Ladas SD. Long-term administration of rifaximin improves the prognosis of patients with decompensated alcoholic cirrhosis. J Gastroenterol Hepatol 2013;28:450–5CrossRefPubMed
76.
Baik SK, Lim YL, Kim MY, et al. Rifaximin and propranolol combination therapy is more effective than propranolol monotherapy in the hepatic venous pressure gradient response and propranolol dose reduction—a pilot study. J Hepatology 2015;62:S187–212
77.
Kimer N, Pedersen JS, Busk TM, et al. Rifaximin has no effect on hemodynamics in decompensated cirrhosis: a randomized, double-blind, placebo-controlled trial. Hepatology 2017;65:592–603CrossRefPubMed
78.
Gupta N, Kumar A, Sharma P, Garg V, Sharma BC, Sarin SK. Effects of the adjunctive probiotic VSL#3 on portal haemodynamics in patients with cirrhosis and large varices: a randomized trial. Liver Int 2013;33:1148–57CrossRefPubMed
79.
Jayakumar S, Carbonneau M, Hotte N, et al. VSL#3 (R) probiotic therapy does not reduce portal pressures in patients with decompensated cirrhosis. Liver Int 2013;33:1470–7PubMed
80.
Forbes SJ, Russo FP, Rey V, et al. A significant proportion of myofibroblasts are of bone marrow origin in human liver fibrosis. Gastroenterology 2004;126:955–63CrossRefPubMed
81.
82.
83.
Lyra AC, Soares MB, da Silva LF, et al. Infusion of autologous bone marrow mononuclear cells through hepatic artery results in a short-term improvement of liver function in patients with chronic liver disease: a pilot randomized controlled study. Eur J Gastroenterol Hepatol 2010;22:33–42CrossRefPubMed
84.
Jang YO, Kim MY, Cho MY, Baik SK, Cho YZ, Kwon SO. Effect of bone marrow-derived mesenchymal stem cells on hepatic fibrosis in a thioacetamide-induced cirrhotic rat model. BMC Gastroenterol 2014;14:198CrossRefPubMedPubMedCentral
85.
Jang YO, Jun BG, Baik SK, Kim MY, Kwon SO. Inhibition of hepatic stellate cells by bone marrow-derived mesenchymal stem cells in hepatic fibrosis. Clin Mol Hepatol 2015;21:141–9CrossRefPubMedPubMedCentral
86.
Kim G, Eom YW, Baik SK, et al. Therapeutic effects of mesenchymal stem cells for patients with chronic liver diseases: systematic review and meta-analysis. J Korean Med Sci 2015;30:1405–15CrossRefPubMedPubMedCentral
87.
Jang YO, Kim YJ, Baik SK, et al. Histological improvement following administration of autologous bone marrow-derived mesenchymal stem cells for alcoholic cirrhosis: a pilot study. Liver Int 2014;34:33–41CrossRefPubMed
88.
89.
Lalu MM, McIntyre L, Pugliese C, et al. Safety of cell therapy with mesenchymal stromal cells (SafeCell): a systematic review and meta-analysis of clinical trials. PLoS ONE 2012;7:e47559CrossRefPubMedPubMedCentral
90.
Suk KT, Yoon JH, Kim MY, et al. Transplantation with autologous bone marrow-derived mesenchymal stem cells for alcoholic cirrhosis: phase 2 trial. Hepatology 2016;64:2185–97CrossRefPubMed
Metadata
Title
Novelties in the pathophysiology and management of portal hypertension: new treatments on the horizon
Authors
Seong Hee Kang
Moon Young Kim
Soon Koo Baik
Publication date
01-02-2018
Publisher
Springer India
Published in
Hepatology International / Issue Special Issue 1/2018
Print ISSN: 1936-0533
Electronic ISSN: 1936-0541
DOI
https://doi.org/10.1007/s12072-017-9806-1

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