Advertisement

Vascular syndromes in liver cirrhosis

  • Botros Shenoda
  • Joseph BoselliEmail author
Clinical Review
  • 40 Downloads

Abstract

Liver cirrhosis is associated with multiple vascular syndromes affecting almost all body systems. Many of these syndromes are directly related to impaired liver function and sometimes reversible after liver transplantation while others arise secondary to portal hypertension and ascites. Altered expression of angiogenic and vasoactive compounds (most importantly nitric oxide), endothelial dysfunction, dysregulated neurohormonal control, and systemic inflammatory state play differential roles in mediating homeostatic instability and abnormal vasogenic response. Important vascular features encountered in liver disease include portal hypertension, splanchnic overflow, abnormal angiogenesis and shunts, portopulmonary syndrome, hepatopulmonary syndrome, and systemic hyperdynamic circulation. Redistribution of effective circulatory volume deviating from vital organs and pooling in splanchnic circulation is also encountered in liver patients which may lead to devastating outcomes as hepatorenal syndrome. Etiologically, vascular syndromes are not isolated phenomena and vascular dysfunction in one system may lead to the development of another in a different system. This review focuses on understanding the pathophysiological factors underlying vascular syndromes related to chronic liver disease and the potential links among them. Many of these syndromes are associated with high mortality, thus it is crucial to look for early biomarkers for these syndromes and develop novel preventive and therapeutic strategies.

Keywords

Liver cirrhosis Portal hypertension Portopulmonary hypertension Hepatopulmonary syndrome Hepatorenal syndrome 

Notes

Compliance with ethical standards

Conflict of interest

The authors have no conflict of interest.

Human rights

All procedures followed have been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments.

Informed consent

For this type of study, informed consent is not required.

References

  1. 1.
    Moller S, Henriksen JH, Bendtsen F. Extrahepatic complications to cirrhosis and portal hypertension: haemodynamic and homeostatic aspects. World J Gastroenterol. 2014;20:15499–517.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Gines P, Cardenas A. The management of ascites and hyponatremia in cirrhosis. Semin Liver Dis. 2008;28:43–58.CrossRefPubMedGoogle Scholar
  3. 3.
    Nunes H, Lebrec D, Mazmanian M, et al. Role of nitric oxide in hepatopulmonary syndrome in cirrhotic rats. Am J Respir Crit Care Med. 2001;164:879–85.CrossRefPubMedGoogle Scholar
  4. 4.
    Carter EP, Hartsfield CL, Miyazono M, et al. Regulation of heme oxygenase-1 by nitric oxide during hepatopulmonary syndrome. Am J Physiol Lung Cell Mol Physiol. 2002;283:L346-53.CrossRefPubMedGoogle Scholar
  5. 5.
    Zhang HY, Han DW, Wang XG, et al. Experimental study on the role of endotoxin in the development of hepatopulmonary syndrome. World J Gastroenterol. 2005;11:567–72.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Zhang HY, Han DW, Zhao ZF, et al. Multiple pathogenic factor-induced complications of cirrhosis in rats: a new model of hepatopulmonary syndrome with intestinal endotoxemia. World J Gastroenterol. 2007;13:3500–7.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Henriksen JH, Bendtsen F, Sorensen TI, et al. Reduced central blood volume in cirrhosis. Gastroenterology. 1989;97:1506–13.CrossRefPubMedGoogle Scholar
  8. 8.
    Gatta A, Bolognesi M, Merkel C. Vasoactive factors and hemodynamic mechanisms in the pathophysiology of portal hypertension in cirrhosis. Mol Aspects Med. 2008;29:119–29.CrossRefPubMedGoogle Scholar
  9. 9.
    Gines P, Fernandez J, Durand F, et al. Management of critically-ill cirrhotic patients. J Hepatol. 2012;56(Suppl 1):13–24.CrossRefGoogle Scholar
  10. 10.
    Zheng Y, Song WP, Zhao YY, et al. A new strategy to establish a hepatopulmonary syndrome model in rats by inducing abdominal compartment syndrome in the presence of cirrhosis. Zhonghua Gan Zang Bing Za Zhi. 2013;21:138–41.PubMedGoogle Scholar
  11. 11.
    Roberts KE, Fallon MB, Krowka MJ, et al. Genetic risk factors for portopulmonary hypertension in patients with advanced liver disease. Am J Respir Crit Care Med. 2009;179:835–42.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Moller S, Henriksen JH. Cardiovascular complications of cirrhosis. Postgrad Med J. 2009;85:44–54.PubMedGoogle Scholar
  13. 13.
    Angeli P, Volpin R, Gerunda G, et al. Reversal of type 1 hepatorenal syndrome with the administration of midodrine and octreotide. Hepatology. 1999;29:1690–7.CrossRefPubMedGoogle Scholar
  14. 14.
    Gracia-Sancho J, Lavina B, Rodriguez-Vilarrupla A, et al. Enhanced vasoconstrictor prostanoid production by sinusoidal endothelial cells increases portal perfusion pressure in cirrhotic rat livers. J Hepatol. 2007;47:220–7.CrossRefPubMedGoogle Scholar
  15. 15.
    Carrion JA, Navasa M, Bosch J, et al. Transient elastography for diagnosis of advanced fibrosis and portal hypertension in patients with hepatitis C recurrence after liver transplantation. Liver Transpl. 2006;12:1791–8.CrossRefPubMedGoogle Scholar
  16. 16.
    Nagula S, Jain D, Groszmann RJ, et al. Histological-hemodynamic correlation in cirrhosis-a histological classification of the severity of cirrhosis. J Hepatol. 2006;44:111–7.CrossRefPubMedGoogle Scholar
  17. 17.
    Garcia-Tsao G. Portal hypertension. Curr Opin Gastroenterol. 2006;22:254–62.PubMedGoogle Scholar
  18. 18.
    Rockey D. The cellular pathogenesis of portal hypertension: stellate cell contractility, endothelin, and nitric oxide. Hepatology. 1997;25:2–5.CrossRefPubMedGoogle Scholar
  19. 19.
    Bhathal PS, Grossman HJ. Reduction of the increased portal vascular resistance of the isolated perfused cirrhotic rat liver by vasodilators. J Hepatol. 1985;1:325–37.CrossRefPubMedGoogle Scholar
  20. 20.
    Rockey DC. Vasoactive agents in intrahepatic portal hypertension and fibrogenesis: implications for therapy. Gastroenterology. 2000;118:1261–5.CrossRefPubMedGoogle Scholar
  21. 21.
    Garcia-Pagan JC, Bosch J, Rodes J. The role of vasoactive mediators in portal hypertension. Semin Gastrointest Dis. 1995;6:140–7.PubMedGoogle Scholar
  22. 22.
    Jimenez W, Rodes J. Impaired responsiveness to endogenous vasoconstrictors and endothelium-derived vasoactive factors in cirrhosis. Gastroenterology. 1994;107:1201–3.CrossRefPubMedGoogle Scholar
  23. 23.
    Gabbiani G. The myofibroblast in wound healing and fibrocontractive diseases. J Pathol. 2003;200:500–3.CrossRefPubMedGoogle Scholar
  24. 24.
    Pinzani M, Failli P, Ruocco C, et al. Fat-storing cells as liver-specific pericytes. Spatial dynamics of agonist-stimulated intracellular calcium transients. J Clin Invest. 1992;90:642–6.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Laragh JH, Angers M, Kelly WG, et al. Hypotensive agents and pressor substances. The effect of epinephrine, norepinephrine, angiotensin II, and others on the secretory rate of aldosterone in man. JAMA. 1960;174:234–40.CrossRefPubMedGoogle Scholar
  26. 26.
    Schneider AW, Kalk JF, Klein CP. Effect of losartan, an angiotensin II receptor antagonist, on portal pressure in cirrhosis. Hepatology. 1999;29:334–9.CrossRefPubMedGoogle Scholar
  27. 27.
    Bhunchet E, Fujieda K. Capillarization and venularization of hepatic sinusoids in porcine serum-induced rat liver fibrosis: a mechanism to maintain liver blood flow. Hepatology. 1993;18:1450–8.CrossRefPubMedGoogle Scholar
  28. 28.
    Iwakiri Y, Shah V, Rockey DC. Vascular pathobiology in chronic liver disease and cirrhosis—current status and future directions. J Hepatol. 2014;61:912–24.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Gupta TK, Toruner M, Chung MK, et al. Endothelial dysfunction and decreased production of nitric oxide in the intrahepatic microcirculation of cirrhotic rats. Hepatology. 1998;28:926–31.CrossRefPubMedGoogle Scholar
  30. 30.
    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;44:44–52.CrossRefPubMedGoogle Scholar
  31. 31.
    Ding BS, Nolan DJ, Butler JM, et al. Inductive angiocrine signals from sinusoidal endothelium are required for liver regeneration. Nature. 2010;468:310–5.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Wang L, Wang X, Xie G, et al. Liver sinusoidal endothelial cell progenitor cells promote liver regeneration in rats. J Clin Invest. 2012;122:1567–73.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Sarela AI, Mihaimeed FM, Batten JJ, et al. Hepatic and splanchnic nitric oxide activity in patients with cirrhosis. Gut. 1999;44:749–53.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Hou MC, Cahill PA, Zhang S, et al. Enhanced cyclooxygenase-1 expression within the superior mesenteric artery of portal hypertensive rats: role in the hyperdynamic circulation. Hepatology. 1998;27:20–7.CrossRefPubMedGoogle Scholar
  35. 35.
    Benzel I, Bansal A, Browning BL, et al. Interactions among genes in the ErbB-Neuregulin signalling network are associated with increased susceptibility to schizophrenia. Behav Brain Funct. 2007;3:31.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Graupera M, Garcia-Pagan JC, Pares M, et al. Cyclooxygenase-1 inhibition corrects endothelial dysfunction in cirrhotic rat livers. J Hepatol. 2003;39:515–21.CrossRefPubMedGoogle Scholar
  37. 37.
    Rockey DC, Chung JJ. Reduced nitric oxide production by endothelial cells in cirrhotic rat liver: endothelial dysfunction in portal hypertension. Gastroenterology. 1998;114:344–51.CrossRefPubMedGoogle Scholar
  38. 38.
    Shah V, Toruner M, Haddad F, et al. Impaired endothelial nitric oxide synthase activity associated with enhanced caveolin binding in experimental cirrhosis in the rat. Gastroenterology. 1999;117:1222–8.CrossRefPubMedGoogle Scholar
  39. 39.
    Clemens MG. Does altered regulation of ecNOS in sinusoidal endothelial cells determine increased intrahepatic resistance leading to portal hypertension? Hepatology. 1998;27:1745–7.CrossRefPubMedGoogle Scholar
  40. 40.
    Thabut D, Shah V. Intrahepatic angiogenesis and sinusoidal remodeling in chronic liver disease: new targets for the treatment of portal hypertension? J Hepatol. 2010;53:976–80.CrossRefPubMedGoogle Scholar
  41. 41.
    Taura K, De Minicis S, Seki E, et al. Hepatic stellate cells secrete angiopoietin 1 that induces angiogenesis in liver fibrosis. Gastroenterology. 2008;135:1729–38.CrossRefPubMedGoogle Scholar
  42. 42.
    De Spiegelaere W, Cornillie P, Van den Broeck W, et al. Angiopoietins differentially influence in vitro angiogenesis by endothelial cells of different origin. Clin Hemorheol Microcirc. 2011;48:15–27.PubMedGoogle Scholar
  43. 43.
    Moreno AH, Burchell AR, Rousselot LM, et al. Portal blood flow in cirrhosis of the liver. J Clin Invest. 1967;46:436–45.CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Bolognesi M, Di Pascoli M, Verardo A, et al. Splanchnic vasodilation and hyperdynamic circulatory syndrome in cirrhosis. World J Gastroenterol. 2014;20:2555–63.CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Vorobioff J, Bredfeldt JE, Groszmann RJ. Hyperdynamic circulation in portal-hypertensive rat model: a primary factor for maintenance of chronic portal hypertension. Am J Physiol. 1983;244:G52–7.PubMedGoogle Scholar
  46. 46.
    Fernandez M, Mejias M, Angermayr B, et al. Inhibition of VEGF receptor-2 decreases the development of hyperdynamic splanchnic circulation and portal-systemic collateral vessels in portal hypertensive rats. J Hepatol. 2005;43:98–103.CrossRefPubMedGoogle Scholar
  47. 47.
    Sherwin R, Joshi P, Hendler R, et al. Hyperglucagonemia in Laennec’s cirrhosis. The role of portal-systemic shunting. N Engl J Med. 1974;290:239–42.CrossRefPubMedGoogle Scholar
  48. 48.
    Sogni P, Moreau R, Gadano A, et al. The role of nitric oxide in the hyperdynamic circulatory syndrome associated with portal hypertension. J Hepatol. 1995;23:218–24.CrossRefPubMedGoogle Scholar
  49. 49.
    Hori N, Okanoue T, Sawa Y, et al. Role of calcitonin gene-related peptide in the vascular system on the development of the hyperdynamic circulation in conscious cirrhotic rats. J Hepatol. 1997;26:1111–9.CrossRefPubMedGoogle Scholar
  50. 50.
    Fernandez-Rodriguez CM, Prada IR, Prieto J, et al. Circulating adrenomedullin in cirrhosis: relationship to hyperdynamic circulation. J Hepatol. 1998;29:250–6.CrossRefPubMedGoogle Scholar
  51. 51.
    Perez-Ruiz M, Ros J, Morales-Ruiz M, et al. Vascular endothelial growth factor production in peritoneal macrophages of cirrhotic patients: regulation by cytokines and bacterial lipopolysaccharide. Hepatology. 1999;29:1057–63.CrossRefPubMedGoogle Scholar
  52. 52.
    Bolognesi M, Sacerdoti D, Di Pascoli M, et al. Haeme oxygenase mediates hyporeactivity to phenylephrine in the mesenteric vessels of cirrhotic rats with ascites. Gut. 2005;54:1630–6.CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Parfieniuk A, Flisiak R. Role of cannabinoids in chronic liver diseases. World J Gastroenterol. 2008;14:6109–14.CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Grace JA, Klein S, Herath CB, et al. Activation of the MAS receptor by angiotensin-(1–7) in the renin-angiotensin system mediates mesenteric vasodilatation in cirrhosis. Gastroenterology. 2013;145:874–84 e5.CrossRefPubMedGoogle Scholar
  55. 55.
    Atucha NM, Shah V, Garcia-Cardena G, et al. Role of endothelium in the abnormal response of mesenteric vessels in rats with portal hypertension and liver cirrhosis. Gastroenterology. 1996;111:1627–32.CrossRefPubMedGoogle Scholar
  56. 56.
    Cahill PA, Redmond EM, Hodges R, et al. Increased endothelial nitric oxide synthase activity in the hyperemic vessels of portal hypertensive rats. J Hepatol. 1996;25:370–8.CrossRefPubMedGoogle Scholar
  57. 57.
    Dimmeler S, Fleming I, Fisslthaler B, et al. Activation of nitric oxide synthase in endothelial cells by Akt-dependent phosphorylation. Nature. 1999;399:601–5.CrossRefPubMedGoogle Scholar
  58. 58.
    Wiest R, Das S, Cadelina G, et al. Bacterial translocation in cirrhotic rats stimulates eNOS-derived NO production and impairs mesenteric vascular contractility. J Clin Invest. 1999;104:1223–33.CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    Hamilton G, Phing RC, Hutton RA, et al. The relationship between prostacyclin activity and pressure in the portal vein. Hepatology. 1982;2:236–42.CrossRefPubMedGoogle Scholar
  60. 60.
    Bruix J, Bosch J, Kravetz D, et al. Effects of prostaglandin inhibition on systemic and hepatic hemodynamics in patients with cirrhosis of the liver. Gastroenterology. 1985;88:430–5.CrossRefPubMedGoogle Scholar
  61. 61.
    Cahill PA, Redmond EM, Sitzmann JV. Endothelial dysfunction in cirrhosis and portal hypertension. Pharmacol Ther. 2001;89:273–93.CrossRefPubMedGoogle Scholar
  62. 62.
    Barriere E, Tazi KA, Rona JP, et al. Evidence for an endothelium-derived hyperpolarizing factor in the superior mesenteric artery from rats with cirrhosis. Hepatology. 2000;32:935–41.CrossRefPubMedGoogle Scholar
  63. 63.
    Iwakiri Y, Groszmann RJ. The hyperdynamic circulation of chronic liver diseases: from the patient to the molecule. Hepatology. 2006;43:121-31.CrossRefGoogle Scholar
  64. 64.
    Chen YC, Gines P, Yang J, et al. Increased vascular heme oxygenase-1 expression contributes to arterial vasodilation in experimental cirrhosis in rats. Hepatology. 2004;39:1075–87.CrossRefPubMedGoogle Scholar
  65. 65.
    Bolognesi M, Sacerdoti D, Piva A, et al. Carbon monoxide-mediated activation of large-conductance calcium-activated potassium channels contributes to mesenteric vasodilatation in cirrhotic rats. J Pharmacol Exp Ther. 2007;321:187–94.CrossRefPubMedGoogle Scholar
  66. 66.
    Batkai S, Jarai Z, Wagner JA, et al. Endocannabinoids acting at vascular CB1 receptors mediate the vasodilated state in advanced liver cirrhosis. Nat Med. 2001;7:827–32.CrossRefPubMedGoogle Scholar
  67. 67.
    Moezi L, Gaskari SA, Liu H, et al. Anandamide mediates hyperdynamic circulation in cirrhotic rats via CB(1) and VR(1) receptors. Br J Pharmacol. 2006;149:898–908.CrossRefPubMedPubMedCentralGoogle Scholar
  68. 68.
    Ros J, Claria J, To-Figueras J, et al. Endogenous cannabinoids: a new system involved in the homeostasis of arterial pressure in experimental cirrhosis in the rat. Gastroenterology. 2002;122:85–93.CrossRefPubMedGoogle Scholar
  69. 69.
    Moleda L, Trebicka J, Dietrich P, et al. Amelioration of portal hypertension and the hyperdynamic circulatory syndrome in cirrhotic rats by neuropeptide Y via pronounced splanchnic vasoaction. Gut. 2011;60:1122–32.CrossRefPubMedGoogle Scholar
  70. 70.
    Trebicka J, Leifeld L, Hennenberg M, et al. Hemodynamic effects of urotensin II and its specific receptor antagonist palosuran in cirrhotic rats. Hepatology. 2008;47:1264–76.CrossRefPubMedGoogle Scholar
  71. 71.
    Acosta F, Sansano T, Palenciano CG, et al. Differential response of the systemic and pulmonary circulation related to disease severity of cirrhosis. Transplant Proc. 2005;37:3889–3890.Google Scholar
  72. 72.
    Blendis L, Wong F. The hyperdynamic circulation in cirrhosis: an overview. Pharmacol Ther. 2001;89:221–31.CrossRefPubMedGoogle Scholar
  73. 73.
    Bosch J, Arroyo V, Betriu A, et al. Hepatic hemodynamics and the renin-angiotensin-aldosterone system in cirrhosis. Gastroenterology. 1980;78:92–9.PubMedGoogle Scholar
  74. 74.
    Fernandez-Seara J, Prieto J, Quiroga J, et al. Systemic and regional hemodynamics in patients with liver cirrhosis and ascites with and without functional renal failure. Gastroenterology. 1989;97:1304–12.CrossRefPubMedGoogle Scholar
  75. 75.
    Schrier RW, Arroyo V, Bernardi M, et al. Peripheral arterial vasodilation hypothesis: a proposal for the initiation of renal sodium and water retention in cirrhosis. Hepatology. 1988;8:1151–7.CrossRefPubMedGoogle Scholar
  76. 76.
    Claria J, Jimenez W, Arroyo V, et al. Effect of V1-vasopressin receptor blockade on arterial pressure in conscious rats with cirrhosis and ascites. Gastroenterology. 1991;100:494–501.CrossRefPubMedGoogle Scholar
  77. 77.
    Bernardi M, Moreau R, Angeli P, et al. Mechanisms of decompensation and organ failure in cirrhosis: from peripheral arterial vasodilation to systemic inflammation hypothesis. J Hepatol. 2015;63:1272–84.CrossRefPubMedGoogle Scholar
  78. 78.
    Tazi KA, Barriere E, Moreau R, et al. Role of shear stress in aortic eNOS up-regulation in rats with biliary cirrhosis. Gastroenterology. 2002;122:1869–77.CrossRefPubMedGoogle Scholar
  79. 79.
    Wiest R, Lawson M, Geuking M. Pathological bacterial translocation in liver cirrhosis. J Hepatol. 2014;60:197–209.CrossRefPubMedGoogle Scholar
  80. 80.
    Miele L, Valenza V, La Torre G, et al. Increased intestinal permeability and tight junction alterations in nonalcoholic fatty liver disease. Hepatology. 2009;49:1877–87.CrossRefPubMedGoogle Scholar
  81. 81.
    Bauer TM, Schwacha H, Steinbruckner B, et al. Small intestinal bacterial overgrowth in human cirrhosis is associated with systemic endotoxemia. Am J Gastroenterol. 2002;97:2364–70.CrossRefPubMedGoogle Scholar
  82. 82.
    Gandoura S, Weiss E, Rautou PE, et al. Gene- and exon-expression profiling reveals an extensive LPS-induced response in immune cells in patients with cirrhosis. J Hepatol. 2013;58:936–48.CrossRefPubMedGoogle Scholar
  83. 83.
    Wiest R, Cadelina G, Milstien S, et al. Bacterial translocation up-regulates GTP-cyclohydrolase I in mesenteric vasculature of cirrhotic rats. Hepatology. 2003;38:1508–15.CrossRefPubMedGoogle Scholar
  84. 84.
    Ohta M, Tarnawski AS, Itani R, et al. Tumor necrosis factor alpha regulates nitric oxide synthase expression in portal hypertensive gastric mucosa of rats. Hepatology. 1998;27:906–13.CrossRefPubMedGoogle Scholar
  85. 85.
    Riordan SM, Skinner N, Nagree A, et al. Peripheral blood mononuclear cell expression of toll-like receptors and relation to cytokine levels in cirrhosis. Hepatology. 2003;37:1154–64.CrossRefPubMedGoogle Scholar
  86. 86.
    Tazi KA, Moreau R, Herve P, et al. Norfloxacin reduces aortic NO synthases and proinflammatory cytokine up-regulation in cirrhotic rats: role of Akt signaling. Gastroenterology. 2005;129:303–14.CrossRefPubMedGoogle Scholar
  87. 87.
    Chin-Dusting JP, Rasaratnam B, Jennings GL, et al. Effect of fluoroquinolone on the enhanced nitric oxide-induced peripheral vasodilation seen in cirrhosis. Ann Intern Med. 1997;127:985–8.CrossRefPubMedGoogle Scholar
  88. 88.
    Lopez-Talavera JC, Merrill WW, Groszmann RJ. Tumor necrosis factor alpha: a major contributor to the hyperdynamic circulation in prehepatic portal-hypertensive rats. Gastroenterology. 1995;108:761–7.CrossRefPubMedGoogle Scholar
  89. 89.
    Munoz J, Albillos A, Perez-Paramo M, et al. Factors mediating the hemodynamic effects of tumor necrosis factor-alpha in portal hypertensive rats. Am J Physiol. 1999;276:G687-93.PubMedGoogle Scholar
  90. 90.
    Lopez-Talavera JC, Cadelina G, Olchowski J, et al. Thalidomide inhibits tumor necrosis factor alpha, decreases nitric oxide synthesis, and ameliorates the hyperdynamic circulatory syndrome in portal-hypertensive rats. Hepatology. 1996;23:1616–21.PubMedGoogle Scholar
  91. 91.
    Lopez-Talavera JC, Levitzki A, Martinez M, et al. Tyrosine kinase inhibition ameliorates the hyperdynamic state and decreases nitric oxide production in cirrhotic rats with portal hypertension and ascites. J Clin Invest. 1997;100:664–70.CrossRefPubMedPubMedCentralGoogle Scholar
  92. 92.
    Niederberger M, Martin PY, Gines P, et al. Normalization of nitric oxide production corrects arterial vasodilation and hyperdynamic circulation in cirrhotic rats. Gastroenterology. 1995;109:1624–30.CrossRefPubMedGoogle Scholar
  93. 93.
    Newby DE, Hayes PC. Hyperdynamic circulation in liver cirrhosis: not peripheral vasodilatation but ‘splanchnic steal’. QJM. 2002;95:827–30.CrossRefPubMedGoogle Scholar
  94. 94.
    Ruiz-del-Arbol L, Monescillo A, Arocena C, et al. Circulatory function and hepatorenal syndrome in cirrhosis. Hepatology. 2005;42:439–47.CrossRefPubMedGoogle Scholar
  95. 95.
    Wiese S, Hove JD, Bendtsen F, et al. Cirrhotic cardiomyopathy: pathogenesis and clinical relevance. Nat Rev Gastroenterol Hepatol. 2014;11:177–86.CrossRefPubMedGoogle Scholar
  96. 96.
    Merkel C, Gatta A, Milani L, et al. Intrarenal blood flow, circulation time, and cortical vascular volume in patients with cirrhosis. Scand J Gastroenterol. 1981;16:775–80.CrossRefPubMedGoogle Scholar
  97. 97.
    Almdal T, Schroeder T, Ranek L. Cerebral blood flow and liver function in patients with encephalopathy due to acute and chronic liver diseases. Scand J Gastroenterol. 1989;24:299–303.CrossRefPubMedGoogle Scholar
  98. 98.
    Maroto A, Gines P, Arroyo V, et al. Brachial and femoral artery blood flow in cirrhosis: relationship to kidney dysfunction. Hepatology. 1993;17:788–93.PubMedGoogle Scholar
  99. 99.
    Rajekar H, Chawla Y. Terlipressin in hepatorenal syndrome: evidence for present indications. J Gastroenterol Hepatol. 2011;26(Suppl 1):109–14.CrossRefPubMedGoogle Scholar
  100. 100.
    Groszmann RJ, Abraldes JG. Portal hypertension: from bedside to bench. J Clin Gastroenterol. 2005;39:125-30.CrossRefGoogle Scholar
  101. 101.
    Bosch J. Vascular deterioration in cirrhosis: the big picture. J Clin Gastroenterol. 2007;41(Suppl 3):247-53.Google Scholar
  102. 102.
    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;16:1125–33.CrossRefPubMedPubMedCentralGoogle Scholar
  103. 103.
    Fernandez M, Vizzutti F, Garcia-Pagan JC, et al. Anti-VEGF receptor-2 monoclonal antibody prevents portal-systemic collateral vessel formation in portal hypertensive mice. Gastroenterology. 2004;126:886–94.CrossRefPubMedGoogle Scholar
  104. 104.
    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;137:2112-24 e1–6.Google Scholar
  105. 105.
    Gines A, Escorsell A, Gines P, et al. Incidence, predictive factors, and prognosis of the hepatorenal syndrome in cirrhosis with ascites. Gastroenterology. 1993;105:229–36.CrossRefPubMedGoogle Scholar
  106. 106.
    Arroyo V, Gines P, Gerbes AL, et al. Definition and diagnostic criteria of refractory ascites and hepatorenal syndrome in cirrhosis. Int Ascites Club Hepatol. 1996;23:164–76.Google Scholar
  107. 107.
    Durand F, Graupera I, Gines P, et al. Pathogenesis of hepatorenal syndrome: implications for therapy. Am J Kidney Dis. 2016;67:318–28.CrossRefPubMedGoogle Scholar
  108. 108.
    Epstein M, Berk DP, Hollenberg NK, et al. Renal failure in the patient with cirrhosis. The role of active vasoconstriction. Am J Med. 1970;49:175–85.CrossRefPubMedGoogle Scholar
  109. 109.
    Stadlbauer V, Wright GA, Banaji M, et al. Relationship between activation of the sympathetic nervous system and renal blood flow autoregulation in cirrhosis. Gastroenterology. 2008;134:111–9.CrossRefPubMedGoogle Scholar
  110. 110.
    Moore K, Wendon J, Frazer M, et al. Plasma endothelin immunoreactivity in liver disease and the hepatorenal syndrome. N Engl J Med. 1992;327:1774–8.CrossRefPubMedGoogle Scholar
  111. 111.
    Asbert M, Gines A, Gines P, et al. Circulating levels of endothelin in cirrhosis. Gastroenterology. 1993;104:1485–91.CrossRefPubMedGoogle Scholar
  112. 112.
    Wong F, Moore K, Dingemanse J, et al. Lack of renal improvement with nonselective endothelin antagonism with tezosentan in type 2 hepatorenal syndrome. Hepatology. 2008;47:160–8.CrossRefPubMedGoogle Scholar
  113. 113.
    La Villa G, Romanelli RG, Casini Raggi V, et al. Plasma levels of brain natriuretic peptide in patients with cirrhosis. Hepatology. 1992;16:156–61.CrossRefPubMedGoogle Scholar
  114. 114.
    Gines P, Jimenez W, Arroyo V, et al. Atrial natriuretic factor in cirrhosis with ascites: plasma levels, cardiac release and splanchnic extraction. Hepatology. 1988;8:636–42.CrossRefPubMedGoogle Scholar
  115. 115.
    Elia C, Graupera I, Barreto R, et al. Severe acute kidney injury associated with non-steroidal anti-inflammatory drugs in cirrhosis: a case-control study. J Hepatol. 2015;63:593–600.CrossRefPubMedGoogle Scholar
  116. 116.
    Adebayo D, Morabito V, Davenport A, et al. Renal dysfunction in cirrhosis is not just a vasomotor nephropathy. Kidney Int. 2015;87:509–15.CrossRefPubMedGoogle Scholar
  117. 117.
    Tumgor G. Cirrhosis and hepatopulmonary syndrome. World J Gastroenterol. 2014;20:2586–94.CrossRefPubMedPubMedCentralGoogle Scholar
  118. 118.
    Schraufnagel DE, Kay JM. Structural and pathologic changes in the lung vasculature in chronic liver disease. Clin Chest Med. 1996;17:1–15.CrossRefPubMedGoogle Scholar
  119. 119.
    Lange PA, Stoller JK. The hepatopulmonary syndrome. Ann Intern Med. 1995;122:521–9.CrossRefPubMedGoogle Scholar
  120. 120.
    Rodriguez-Roisin R, Krowka MJ. Hepatopulmonary syndrome–a liver-induced lung vascular disorder. N Engl J Med. 2008;358:2378–87.CrossRefPubMedGoogle Scholar
  121. 121.
    Rolla G, Brussino L, Colagrande P, et al. Exhaled nitric oxide and impaired oxygenation in cirrhotic patients before and after liver transplantation. Ann Intern Med. 1998;129:375–8.CrossRefPubMedGoogle Scholar
  122. 122.
    Tumgor G, Arikan C, Yuksekkaya HA, et al. Childhood cirrhosis, hepatopulmonary syndrome and liver transplantation. Pediatr Transplant. 2008;12:353–7.CrossRefPubMedGoogle Scholar
  123. 123.
    Rovin BH, Yoshiumura T, Tan L. Cytokine-induced production of monocyte chemoattractant protein-1 by cultured human mesangial cells. J Immunol. 1992;148:2148–53.PubMedGoogle Scholar
  124. 124.
    Carter D, Douglass JF, Cornellison CD, et al. Purification and characterization of the mammaglobin/lipophilin B complex, a promising diagnostic marker for breast cancer. Biochemistry. 2002;41:6714–22.CrossRefPubMedGoogle Scholar
  125. 125.
    Arguedas MR, Drake BB, Kapoor A, et al. Carboxyhemoglobin levels in cirrhotic patients with and without hepatopulmonary syndrome. Gastroenterology. 2005;128:328–33.CrossRefPubMedGoogle Scholar
  126. 126.
    Ebeid AM, Escourrou J, Soeters PB, et al. Hepatic inactivation of vasoactive intestinal peptide in man and dog. Ann Surg. 1978;188:28–33.CrossRefPubMedPubMedCentralGoogle Scholar
  127. 127.
    Hortnagl H, Singer EA, Lenz K, et al. Substance P is markedly increased in plasma of patients with hepatic coma. Lancet. 1984;1:480–3.CrossRefPubMedGoogle Scholar
  128. 128.
    Caramelo C, Fernandez-Gallardo S, Santos JC, et al. Increased levels of platelet-activating factor in blood from patients with cirrhosis of the liver. Eur J Clin Invest. 1987;17:7–11.CrossRefPubMedGoogle Scholar
  129. 129.
    Panos RJ, Baker SK. Mediators, cytokines, and growth factors in liver-lung interactions. Clin Chest Med. 1996;17:151–69.CrossRefPubMedGoogle Scholar
  130. 130.
    Song JY, Choi JY, Ko JT, et al. Long-term aspirin therapy for hepatopulmonary syndrome. Pediatrics. 1996;97:917–20.PubMedGoogle Scholar
  131. 131.
    Zhang J, Luo B, Tang L, et al. Pulmonary angiogenesis in a rat model of hepatopulmonary syndrome. Gastroenterology. 2009;136:1070–80.CrossRefPubMedGoogle Scholar
  132. 132.
    Roberts KE, Kawut SM, Krowka MJ, et al. Genetic risk factors for hepatopulmonary syndrome in patients with advanced liver disease. Gastroenterology. 2010;139:130-9 e24.CrossRefPubMedPubMedCentralGoogle Scholar
  133. 133.
    Sussman NL, Kochar R, Fallon MB. Pulmonary complications in cirrhosis. Curr Opin Organ Transplant. 2011;16:281–8.CrossRefPubMedGoogle Scholar
  134. 134.
    Dickinson MG, Bartelds B, Borgdorff MA, et al. The role of disturbed blood flow in the development of pulmonary arterial hypertension: lessons from preclinical animal models. Am J Physiol Lung Cell Mol Physiol. 2013;305:L1–14.CrossRefPubMedGoogle Scholar
  135. 135.
    Machicao VI, Balakrishnan M, Fallon MB. Pulmonary complications in chronic liver disease. Hepatology. 2014;59:1627–37.CrossRefPubMedGoogle Scholar
  136. 136.
    Talwalkar JA, Swanson KL, Krowka MJ, et al. Prevalence of spontaneous portosystemic shunts in patients with portopulmonary hypertension and effect on treatment. Gastroenterology. 2011;141:1673–9.CrossRefPubMedGoogle Scholar
  137. 137.
    Mancuso L, Scordato F, Pieri M, et al. Management of portopulmonary hypertension: new perspectives. World J Gastroenterol. 2013;19:8252–7.CrossRefPubMedPubMedCentralGoogle Scholar
  138. 138.
    Tuder RM, Cool CD, Geraci MW, et al. Prostacyclin synthase expression is decreased in lungs from patients with severe pulmonary hypertension. Am J Respir Crit Care Med. 1999;159:1925–32.CrossRefPubMedGoogle Scholar
  139. 139.
    Battistini B, Dussault P. Biosynthesis, distribution and metabolism of endothelins in the pulmonary system. Pulm Pharmacol Ther. 1998;11:79–88.CrossRefPubMedGoogle Scholar
  140. 140.
    Luo B, Liu L, Tang L, et al. Increased pulmonary vascular endothelin B receptor expression and responsiveness to endothelin-1 in cirrhotic and portal hypertensive rats: a potential mechanism in experimental hepatopulmonary syndrome. J Hepatol. 2003;38:556–63.CrossRefPubMedGoogle Scholar

Copyright information

© Japanese Society of Gastroenterology 2019

Authors and Affiliations

  1. 1.Department of MedicineDrexel University College of MedicinePhiladelphiaUSA
  2. 2.Drexel Internal MedicinePhiladelphiaUSA

Personalised recommendations