Hepatology International

, Volume 12, Supplement 1, pp 112–121 | Cite as

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

Special Issue - Portal Hypertension

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.

Keywords

Portal hypertension Hepatic vascular resistance Portal pressure Pharmacological treatment Bone marrow stem cell 

Abbreviations

ARB

Angiotensin-II receptor blockade

BH4

Tetrahydrobiopterin

BM

Bone marrow

BM-MSC

Bone marrow-derived mesenchymal stem/stromal cells

COX

Cyclooxygenase

eNOS

Endothelial NO synthase

FXR

Farnesoid X receptor

HCC

Hepatocellular carcinoma

HSC

Hematopoietic stem cells

HStCs

Hepatic stellate cells

HVR

Hepatic vascular resistance

HVPG

Hepatic venous pressure gradient

JAK2

Janus-kinase-2

LOXL2

Lysyloxidase-like-2

MSC

Mesenchymal stem/stromal cells

NO

Nitric oxide

NSBB

Non-selective beta-blocker

OCA

Obeticholic acid

PDE-5

Phosphodiesterase-5

PDGF

Platelet-derived growth factor

PH

Portal hypertension

RAAS

Renin–angiotensin–aldosterone system

RCT

Randomized control trial

rMnSOD

Recombinant human manganese superoxide dismutase

SOD

Superoxide dismutase

TGF

Transforming growth factor receptor

TXA2

Thromboxane A2

VEGF

Vascular endothelial growth factor

Notes

Compliance with ethical standards

Conflict of interest

Soon Koo Baik has received research grants of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI) and the Ministry of Health & Welfare, Republic of Korea (HI15C2364). Moon Young Kim declares that he has no conflict of interest. Seong Hee Kang declares that she has no conflict of interest.

Informed consent in studies with human subjects

This article does not contain any studies with human or animal subjects.

References

  1. 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;56:1053–62CrossRefPubMedGoogle Scholar
  2. 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;36:847–55CrossRefPubMedGoogle Scholar
  3. 3.
    Baik SK. Haemodynamic evaluation by Doppler ultrasonography in patients with portal hypertension: a review. Liver Int 2010;30:1403–13CrossRefPubMedGoogle Scholar
  4. 4.
    Guan R, Lui HF. Treatment of hepatitis B in decompensated liver cirrhosis. Int J Hepatol 2011;2011:918017CrossRefPubMedPubMedCentralGoogle Scholar
  5. 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;48:580–7CrossRefPubMedGoogle Scholar
  6. 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;11:93–101CrossRefPubMedGoogle Scholar
  7. 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;23:34–41CrossRefPubMedPubMedCentralGoogle Scholar
  8. 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;21:1241–6CrossRefPubMedGoogle Scholar
  9. 9.
    Garcia-Pagan JC, Gracia-Sancho J, Bosch J. Functional aspects on the pathophysiology of portal hypertension in cirrhosis. J Hepatol 2012;57:458–61CrossRefPubMedGoogle Scholar
  10. 10.
    Bhathal PS, Grossman HJ. Reduction of the increased portal vascular resistance of the isolated perfused cirrhotic rat liver by vasodilators. J Hepatol 1985;1:325–37CrossRefPubMedGoogle Scholar
  11. 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;22:372–81CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Wong F. Acute kidney injury in liver cirrhosis: new definition and application. Clin Mol Hepatol 2016;22:415–22CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Iwakiri Y, Groszmann RJ. The hyperdynamic circulation of chronic liver diseases: from the patient to the molecule. Hepatology 2006;43:S121–31CrossRefPubMedGoogle Scholar
  14. 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;63:743–52CrossRefPubMedGoogle Scholar
  15. 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;21:7191–6CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Kallis YN, Robson AJ, Fallowfield JA, et al. Remodelling of extracellular matrix is a requirement for the hepatic progenitor cell response. Gut 2011;60:525–33CrossRefPubMedGoogle Scholar
  17. 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;5:1247–56CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Friedman SL. Mechanisms of hepatic fibrogenesis. Gastroenterology 2008;134:1655–69CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Fan X, Zhang Q, Li S, et al. Attenuation of CCl4-induced hepatic fibrosis in mice by vaccinating against TGF-beta1. PLoS ONE 2013;8:e82190CrossRefPubMedPubMedCentralGoogle Scholar
  20. 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;32:977–87CrossRefPubMedGoogle Scholar
  21. 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;10:819–28CrossRefPubMedGoogle Scholar
  22. 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:e0129743CrossRefPubMedPubMedCentralGoogle Scholar
  23. 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;16:1009–17CrossRefPubMedGoogle Scholar
  24. 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;53:702–12CrossRefPubMedGoogle Scholar
  25. 25.
    Wanless IR, Liu JJ, Butany J. Role of thrombosis in the pathogenesis of congestive hepatic fibrosis (cardiac cirrhosis). Hepatology 1995;21:1232–7PubMedGoogle Scholar
  26. 26.
    Cerini F, Vilaseca M, Lafoz E, et al. Enoxaparin reduces hepatic vascular resistance and portal pressure in cirrhotic rats. J Hepatol 2016;64:834–42CrossRefPubMedGoogle Scholar
  27. 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):2031–2044CrossRefPubMedGoogle Scholar
  28. 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):e1251–4Google Scholar
  29. 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;93:149–59CrossRefPubMedGoogle Scholar
  30. 30.
    Iwakiri Y, Shah V, Rockey DC. Vascular pathobiology in chronic liver disease and cirrhosis—current status and future directions. J Hepatol 2014;61:912–24CrossRefPubMedPubMedCentralGoogle Scholar
  31. 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;46:242–53CrossRefPubMedGoogle Scholar
  32. 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;136:1651–8CrossRefPubMedGoogle Scholar
  33. 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):e1163Google Scholar
  34. 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;89:147–91CrossRefPubMedGoogle Scholar
  35. 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;127:1497–512CrossRefPubMedGoogle Scholar
  36. 36.
    Li J, Wilson A, Kuruba R, et al. FXR-mediated regulation of eNOS expression in vascular endothelial cells. Cardiovasc Res 2008;77:169–77CrossRefPubMedGoogle Scholar
  37. 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;66:724–33CrossRefPubMedGoogle Scholar
  38. 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;580:2123–8CrossRefPubMedGoogle Scholar
  39. 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;44:886–93CrossRefPubMedGoogle Scholar
  40. 40.
    Murad F. Shattuck lecture. Nitric oxide and cyclic GMP in cell signaling and drug development. N Engl J Med 2006;355:2003–11CrossRefPubMedGoogle Scholar
  41. 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;119:45–55CrossRefGoogle Scholar
  42. 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;47:144–50CrossRefPubMedGoogle Scholar
  43. 43.
    Kalambokis GN, Kosta P, Pappas K, Tsianos EV. Haemodynamic and renal effects of tadalafil in patients with cirrhosis. World J Gastroenterol 2010;16:5009–10CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Sasaki H, Nagayama T, Blanton RM, et al. PDE5 inhibitor efficacy is estrogen dependent in female heart disease. J Clin Invest 2014;124:2464–71CrossRefPubMedPubMedCentralGoogle Scholar
  45. 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;44:44–52CrossRefPubMedGoogle Scholar
  46. 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;49:192–7CrossRefPubMedGoogle Scholar
  47. 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;110:985–92CrossRefPubMedGoogle Scholar
  48. 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;29:392–9CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Zima T, Kalousova M. Oxidative stress and signal transduction pathways in alcoholic liver disease. Alcohol Clin Exp Res 2005;29:110S–5SCrossRefPubMedGoogle Scholar
  50. 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;97:2222–9CrossRefPubMedGoogle Scholar
  51. 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;97:22–8CrossRefPubMedPubMedCentralGoogle Scholar
  52. 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;43:485–91CrossRefPubMedGoogle Scholar
  53. 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;47:1248–56CrossRefPubMedGoogle Scholar
  54. 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;58:240–6CrossRefPubMedGoogle Scholar
  55. 55.
    Bataller R, Gines P, Nicolas JM, et al. Angiotensin II induces contraction and proliferation of human hepatic stellate cells. Gastroenterology 2000;118:1149–56CrossRefPubMedGoogle Scholar
  56. 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;43:889–96CrossRefPubMedGoogle Scholar
  57. 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;103:1152–8CrossRefPubMedGoogle Scholar
  58. 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;121:382–8CrossRefPubMedGoogle Scholar
  59. 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;38:1150–4CrossRefPubMedGoogle Scholar
  60. 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;20:376–83CrossRefPubMedPubMedCentralGoogle Scholar
  61. 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;53:273–82CrossRefPubMedGoogle Scholar
  62. 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;117:375–86CrossRefGoogle Scholar
  63. 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:e0138732CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Granzow M, Schierwagen R, Klein S, et al. Angiotensin-II type 1 receptor-mediated Janus kinase 2 activation induces liver fibrosis. Hepatology 2014;60:334–48CrossRefPubMedPubMedCentralGoogle Scholar
  65. 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;66:145–55CrossRefPubMedGoogle Scholar
  66. 66.
    Graupera M, Garcia-Pagan JC, Abraldes JG, et al. Cyclooxygenase-derived products modulate the increased intrahepatic resistance of cirrhotic rat livers. Hepatology 2003;37:172–81CrossRefPubMedGoogle Scholar
  67. 67.
    Rosado E, Rodriguez-Vilarrupla A, Gracia-Sancho J, et al. Terutroban, a TP-receptor antagonist, reduces portal pressure in cirrhotic rats. Hepatology 2013;58:1424–35CrossRefPubMedGoogle Scholar
  68. 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;1:159–64CrossRefPubMedPubMedCentralGoogle Scholar
  69. 69.
    Fernandez M, Semela D, Bruix J, Colle I, Pinzani M, Bosch J. Angiogenesis in liver disease. J Hepatol 2009;50:604–20CrossRefPubMedGoogle Scholar
  70. 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;49:1245–56CrossRefPubMedGoogle Scholar
  71. 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;35:83–91CrossRefPubMedGoogle Scholar
  72. 72.
    Chen Y, Yang F, Lu H, et al. Characterization of fecal microbial communities in patients with liver cirrhosis. Hepatology 2011;54:562–72CrossRefPubMedGoogle Scholar
  73. 73.
    Wiest R, Garcia-Tsao G. Bacterial translocation (BT) in cirrhosis. Hepatology 2005;41:422–33CrossRefPubMedGoogle Scholar
  74. 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;29:992–9CrossRefPubMedGoogle Scholar
  75. 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;28:450–5CrossRefPubMedGoogle Scholar
  76. 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:S187–212Google Scholar
  77. 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;65:592–603CrossRefPubMedGoogle Scholar
  78. 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;33:1148–57CrossRefPubMedGoogle Scholar
  79. 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;33:1470–7PubMedGoogle Scholar
  80. 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;126:955–63CrossRefPubMedGoogle Scholar
  81. 81.
    Eom YW, Kim G, Baik SK. Mesenchymal stem cell therapy for cirrhosis: present and future perspectives. World J Gastroenterol 2015;21:10253–61CrossRefPubMedPubMedCentralGoogle Scholar
  82. 82.
    Bryder D, Rossi DJ, Weissman IL. Hematopoietic stem cells: the paradigmatic tissue-specific stem cell. Am J Pathol 2006;169:338–46CrossRefPubMedPubMedCentralGoogle Scholar
  83. 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;22:33–42CrossRefPubMedGoogle Scholar
  84. 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;14:198CrossRefPubMedPubMedCentralGoogle Scholar
  85. 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;21:141–9CrossRefPubMedPubMedCentralGoogle Scholar
  86. 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;30:1405–15CrossRefPubMedPubMedCentralGoogle Scholar
  87. 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;34:33–41CrossRefPubMedGoogle Scholar
  88. 88.
    Eom YW, Shim KY, Baik SK. Mesenchymal stem cell therapy for liver fibrosis. Korean J Intern Med 2015;30:580–9CrossRefPubMedPubMedCentralGoogle Scholar
  89. 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:e47559CrossRefPubMedPubMedCentralGoogle Scholar
  90. 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;64:2185–97CrossRefPubMedGoogle Scholar

Copyright information

© Asian Pacific Association for the Study of the Liver 2017

Authors and Affiliations

  • Seong Hee Kang
    • 1
  • Moon Young Kim
    • 1
    • 2
  • Soon Koo Baik
    • 1
    • 2
    • 3
  1. 1.Department of Internal MedicineYonsei University Wonju College of MedicineWonjuKorea
  2. 2.Cell Therapy and Tissue Engineering CenterYonsei University Wonju College of MedicineWonjuKorea
  3. 3.Institute of Evidence Based MedicineYonsei University Wonju College of MedicineWonjuKorea

Personalised recommendations