Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Hepatopulmonary syndrome: update on pathogenesis and clinical features

Nature Reviews Gastroenterology & Hepatology volume 9, pages 539–549 (2012)Cite this article

Subjects

Abstract

Hepatopulmonary syndrome (HPS) is a serious vascular complication of liver disease that occurs in 5–32% of patients with cirrhosis. The presence of HPS markedly increases mortality. No effective medical therapies are currently available and liver transplantation is the only established treatment option for HPS. The definition and diagnosis of HPS are established by the presence of a triad of liver disease with intrapulmonary vascular dilation that causes abnormal arterial gas exchange. Experimental biliary cirrhosis induced by common bile duct ligation in the rat reproduces the pulmonary vascular and gas exchange abnormalities of human HPS and serves as a pertinent animal model. Pulmonary microvascular dilation and angiogenesis are two central pathogenic features that drive abnormal pulmonary gas exchange in experimental HPS, and thus might underlie HPS in humans. Defining the mechanisms involved in the microvascular alterations of HPS has the potential to lead to effective medical therapies. This Review focuses on the current understanding of the pathogenesis, clinical features and management of HPS.

Key Points

  • HPS is a common finding in patients with cirrhosis that increases mortality in this context

  • HPS is defined by the triad of liver disease with intrapulmonary vascular dilatation causing abnormal oxygenation

  • No effective medical therapies for HPS exist and liver transplantation is the only treatment option

  • Chronic common bile duct ligation in the rat is the only established experimental model of human HPS

  • Excess lung production of gaseous vasodilators, nitric oxide and carbon monoxide contributes to vasodilatation in human and experimental HPS

  • Pulmonary angiogenesis has an additive role in the development of experimental HPS

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Working model of pathogenic mechanisms in experimental HPS.

Similar content being viewed by others

References

  1. Rodriguez-Roisin, R. & Krowka, M. J. Hepatopulmonary syndrome—a liver-induced lung vascular disorder. N. Engl. J. Med. 358, 2378–2387 (2008).

    Article  CAS  PubMed  Google Scholar 

  2. Schenk, P. et al. Hepatopulmonary syndrome: prevalence and predictive value of various cut offs for arterial oxygenation and their clinical consequences. Gut 51, 853–859 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Swanson, K., Wiesner, R. & Krowka, M. Natural history of hepatopulmonary syndrome: impact of liver transplantation. Hepatology 41, 1122–1129 (2005).

    Article  PubMed  Google Scholar 

  4. Arguedas, M., Abrams, G. A., Krowka, M. J. & Fallon, M. B. Prospective evaluation of outcomes and predictors of mortality in patients with hepatopulmonary syndrome undergoing liver transplantation. Hepatology 37, 192–197 (2003).

    Article  PubMed  Google Scholar 

  5. Arguedas, M., Singh, H., Faulk, D. & Fallon, M. B. Utility of pulse oximetry screening for hepatopulmonary syndrome. Clin. Gastroenterol. Hepatol. 5, 749–754 (2007).

    Article  PubMed  Google Scholar 

  6. Fallon, M. B. et al. Impact of hepatopulmonary syndrome on quality of life and survival in liver transplant candidates. Gastroenterology 135, 1168–1175 (2008).

    Article  PubMed  Google Scholar 

  7. Krowka, M. J. & Cortese, D. A. Hepatopulmonary syndrome: an evolving perspective in the era of liver transplantation. Hepatology 11, 138–141 (1990).

    Article  CAS  PubMed  Google Scholar 

  8. Battaglia, S. E., Pretto, J. J., Irving, L. B., Jones, R. M. & Angus, P. W. Resolution of gas exchange abnormalities and intrapulmonary shunting following liver transplantation. Hepatology 25, 1228–1232 (1997).

    Article  CAS  PubMed  Google Scholar 

  9. Benjaminov, F. S. et al. Portopulmonary hypertension in decompensated cirrhosis with refractory ascites. Gut 52, 1355–1362 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Castro, M. et al. Frequency and clinical implications of increased pulmonary artery pressures in liver transplantation. Mayo Clin. Proc. 71, 543–551 (1996).

    Article  CAS  PubMed  Google Scholar 

  11. Hadengue, A., Benhayoun, M., Lebrec, D. & Benhamou, J. Pulmonary hypertension complicating portal hypertension: prevalence and relation to splanchnic hemodynamics. Gastroenterology 100, 520–528 (1991).

    Article  CAS  PubMed  Google Scholar 

  12. Hoeper, M. M., Krowka, M. J. & Strassburg, C. P. Portopulmonary hypertension and hepatopulmonary syndrome. Lancet 363, 1461–1468 (2004).

    Article  PubMed  Google Scholar 

  13. Mantz, F. & Craige, E. Portal axis thrombosis with spontaneous portocaval shunt and resultant cor pulmonale. AMA Arch. Pathol. 52, 91–97 (1951).

    PubMed  Google Scholar 

  14. McDonnell, P., Toye, P. & Hutchins, G. Primary pulmonary hypertension and cirrhosis: are they related? Am. Rev. Respir. Dis. 127, 437–441 (1983).

    Article  CAS  PubMed  Google Scholar 

  15. Plevak, D., Krowka, M., Rettke, S., Dunn, W. & Southorn, P. Successful liver transplantation in patients with mild to moderate pulmonary hypertension. Transplant. Proc. 25, 1840 (1993).

    CAS  PubMed  Google Scholar 

  16. Rodriguez-Roisin, R. et al. Pulmonary–hepatic vascular disorders (PHD). Eur. Respir. J. 24, 861–880 (2004).

    Article  CAS  PubMed  Google Scholar 

  17. Austin, M. J. et al. Safety and efficacy of combined use of sildenafil, bosentan, and iloprost before and after liver transplantation in severe portopulmonary hypertension. Liver Transpl. 14, 287–291 (2008).

    Article  PubMed  Google Scholar 

  18. Chua, R., Keogh, A. & Miyashita, M. Novel use of sildenafil in the treatment of portopulmonary hypertension. J. Heart Lung Transplant. 24, 498–500 (2005).

    Article  PubMed  Google Scholar 

  19. Halank, M. et al. Use of oral endothelin-receptor antagonist bosentan in the treatment of portopulmonary hypertension. Transplantation 77, 1775–1776 (2004).

    Article  PubMed  Google Scholar 

  20. Minder, S. et al. Intravenous iloprost bridging to orthotopic liver transplantation in portopulmonary hypertension. Eur. Respir. J. 24, 703–707 (2004).

    Article  CAS  PubMed  Google Scholar 

  21. Gough, M. S. & White, R. J. Sildenafil therapy is associated with improved hemodynamics in liver transplantation candidates with pulmonary arterial hypertension. Liver Transpl. 15, 30–36 (2009).

    Article  PubMed  Google Scholar 

  22. Ioachimescu, O. C., Mehta, A. C. & Stoller, J. K. Hepatopulmonary syndrome following portopulmonary hypertension. Eur. Respir. J. 29, 1277–1280 (2007).

    Article  CAS  PubMed  Google Scholar 

  23. Jones, F. D. et al. The coexistence of portopulmonary hypertension and hepatopulmonary syndrome. Anesthesiology 90, 626–629 (1999).

    Article  CAS  PubMed  Google Scholar 

  24. Aucejo, F. et al. Pulmonary hypertension after liver transplantation in patients with antecedent hepatopulmonary syndrome: a report of 2 cases and review of the literature. Liver Transpl. 12, 1278–1282 (2006).

    Article  PubMed  Google Scholar 

  25. Martinez-Palli, G. et al. Severe portopulmonary hypertension after liver transplantation in a patient with preexisting hepatopulmonary syndrome. J. Hepatol. 31, 1075–1079 (1999).

    Article  CAS  PubMed  Google Scholar 

  26. Mal, H. et al. Pulmonary hypertension following hepatopulmonary syndrome in a patient with cirrhosis. J. Hepatol. 31, 360–364 (1999).

    Article  CAS  PubMed  Google Scholar 

  27. Pham, D. M., Subramanian, R. & Parekh, S. Coexisting hepatopulmonary syndrome and portopulmonary hypertension: implications for liver transplantation. J. Clin. Gastroenterol. 44, e136–e140 (2010).

    Article  PubMed  Google Scholar 

  28. Abrams, G., Nanda, N., Dubovsky, E., Krowka, M. & Fallon, M. Use of macroaggregated albumin lung perfusion scan to diagnose hepatopulmonary syndrome: a new approach. Gastroenterology 114, 305–310 (1998).

    Article  CAS  PubMed  Google Scholar 

  29. Martinez, G. et al. Hepatopulmonary syndrome associated with cardiorespiratory disease. J. Hepatol. 30, 882–889 (1999).

    Article  CAS  PubMed  Google Scholar 

  30. Abrams, G. A., Jaffe, C. C., Hoffer, P. B., Binder, H. J. & Fallon, M. B. Diagnostic utility of contrast echocardiography and lung perfusion scan in patients with hepatopulmonary syndrome. Gastroenterology 109, 1283–1288 (1995).

    Article  CAS  PubMed  Google Scholar 

  31. Martinez, G. et al. Hepatopulmonary syndrome in candidates for liver transplantation. J. Hepatol. 34, 756–758 (2001).

    Article  Google Scholar 

  32. Abrams, G. & Fallon, M. The hepatopulmonary syndrome. Clin. Liver Dis. 1, 185–200 (1997).

    Article  CAS  PubMed  Google Scholar 

  33. Binay, K. et al. Hepatopulmonary syndrome in inferior vena cava obstruction responding to cavoplasty. Gastroenterology 118, 192–196 (2000).

    Article  Google Scholar 

  34. Gupta, D. et al. Prevalence of hepatopulmonary syndrome in cirrhosis and extrahepatic portal venous obstruction. Am. J. Gastroenterol. 96, 3395–3399 (2001).

    Article  CAS  PubMed  Google Scholar 

  35. Fuhrmann, V. et al. Hepatopulmonary syndrome in patients with hypoxic hepatitis. Gastroenterology 131, 69–75 (2006).

    Article  PubMed  Google Scholar 

  36. Regev, A. et al. Transient hepatopulmonary syndrome in a patient with acute hepatitis A. J. Viral Hep. 8, 83–86 (2001).

    Article  CAS  Google Scholar 

  37. Teuber, G. et al. Pulmonary dysfunction in non-cirrhotic patients with chronic viral hepatitis. Eur. J. Intern. Med. 13, 311–318 (2002).

    Article  PubMed  Google Scholar 

  38. Lee, D. & Lepler, L. Severe intrapulmonary shunting associated with metastatic carcinoid. Chest 115, 1203–1207 (1999).

    Article  CAS  PubMed  Google Scholar 

  39. Law, Y. M. et al. Cardiopulmonary manifestations of portovenous shunts from congenital absence of the portal vein: pulmonary hypertension and pulmonary vascular dilatation. Pediatr. Transplant. 15, E162–E168 (2011).

    Article  CAS  PubMed  Google Scholar 

  40. Gupta, N. A. et al. Pediatric hepatopulmonary syndrome is seen with polysplenia/interrupted inferior vena cava and without cirrhosis. Liver Transpl. 13, 680–686 (2007).

    Article  PubMed  Google Scholar 

  41. Kinane, T. B. & Westra, S. J. Case records of the Massachusetts General Hospital. Weekly clinicopathological exercises. Case 31–2004. A four-year-old boy with hypoxemia. N. Engl. J. Med. 351, 1667–1675 (2004).

    Article  CAS  PubMed  Google Scholar 

  42. O'Leary, J. G., Rees, C. R., Klintmalm, G. B. & Davis, G. L. Inferior vena cava stent resolves hepatopulmonary syndrome in an adult with a spontaneous inferior vena cava–portal vein shunt. Liver Transpl. 15, 1897–1900 (2009).

    Article  PubMed  Google Scholar 

  43. McFaul, R., Tajik, A., Mair, D., Danielson, G. & Seward, J. Development of pulmonary arteriovenous shunt after superior vena cava-right pulmonary artery (glenn) anastamosis. Report of four cases. Circulation 55, 212–216 (1977).

    Article  CAS  PubMed  Google Scholar 

  44. Srivastava, D. et al. Hepatic venous blood and the development of pulmonary arteriovenous malformations in congenital heart disease. Circulation 92, 1217–1222 (1995).

    Article  CAS  PubMed  Google Scholar 

  45. Duncan, B. W. & Desai, S. Pulmonary arteriovenous malformations after cavopulmonary anastomosis. Ann. Thorac. Surg. 76, 1759–1766 (2003).

    Article  PubMed  Google Scholar 

  46. Lee, J., Menkis, A. H. & Rosenberg, H. C. Reversal of pulmonary arteriovenous malformation after diversion of anomalous hepatic drainage. Ann. Thorac. Surg. 65, 848–849 (1998).

    Article  CAS  PubMed  Google Scholar 

  47. Rodriguez-Roison, R., Agusti, A. G. & Roca, J. The hepatopulmonary syndrome: new name, old complexities. Thorax 47, 897–902 (1992).

    Article  Google Scholar 

  48. Lange, P. A. & Stoller, J. K. The hepatopulmonary syndrome. Ann. Intern. Med. 122, 521–529 (1995).

    Article  CAS  PubMed  Google Scholar 

  49. Fallon, M., Mulligan, D., Gish, R. & Krowka, M. Model for end-stage liver disease (MELD) exception for hepatopulmonary syndrome. Liver Transpl. 12, s105–s107 (2006).

    Article  PubMed  Google Scholar 

  50. Krowka, M. J. et al. Hepatopulmonary syndrome and portopulmonary hypertension: a report of the multicenter liver transplant database. Liver Transpl. 10, 174–182 (2004).

    Article  PubMed  Google Scholar 

  51. Schenk, P. et al. Prognostic significance of the hepatopulmonary syndrome in patients with cirrhosis. Gastroenterology 125, 1042–1052 (2003).

    Article  PubMed  Google Scholar 

  52. Abrams, G. A., Sanders, M. K. & Fallon, M. B. Utility of pulse oximetry in the detection of arterial hypoxemia in liver transplant candidates. Liver Transpl. 8, 391–396 (2002).

    Article  PubMed  Google Scholar 

  53. Palma, D. T. & Fallon, M. B. The hepatopulmonary syndrome. J. Hepatol. 45, 617–625 (2006).

    Article  PubMed  Google Scholar 

  54. Crapo, R. O., Jensen, R. L., Hegewald, M. & Tashkin, D. P. Arterial blood gas reference values for sea level and an altitude of 1,400 meters. Am. J. Respir. Crit. Care Med. 160, 1525–1531 (1999).

    Article  CAS  PubMed  Google Scholar 

  55. Cardús, J. et al. Increase in pulmonary ventilation-perfusion inequality with age in healthy individuals. Am. J. Respir. Crit. Care Med. 156, 648–653 (1997).

    Article  PubMed  Google Scholar 

  56. Harris, E., Kenyon, A., Nisbet, H., Seelye, E. & Whitlock, R. The normal alveolar-arterial oxygen-tension gradient in man. Clin. Sci. Mol. Med. 46, 89–104 (1974).

    CAS  PubMed  Google Scholar 

  57. Krowka, M. J., Dickson, E. R. & Cortese, D. A. Hepatopulmonary syndrome. Clinical observations and lack of therapeutic response to somatostatin analogue. Chest 104, 515–521 (1993).

    Article  CAS  PubMed  Google Scholar 

  58. Anel, R. M. & Sheagren, J. N. Novel presentation and approach to management of hepatopulmonary syndrome with use of antimicrobial agents. Clin. Infect. Dis. 32, E131–E136 (2001).

    Article  CAS  PubMed  Google Scholar 

  59. Poterucha, J. J. et al. Failure of hepatopulmonary syndrome to resolve after liver transplantation and successful treatment with embolotherapy. Hepatology 21, 96–100 (1995).

    Article  CAS  PubMed  Google Scholar 

  60. Molleston, J. P. et al. Brain abscess in hepatopulmonary syndrome. J. Pediatr. Gastroenterol. Nutr. 29, 225–226 (1999).

    Article  CAS  PubMed  Google Scholar 

  61. Stickland, M. K. et al. Intra-pulmonary shunt and pulmonary gas exchange during exercise in humans. J. Physiol. 561, 321–329 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Berthelot, P., Walter, J. G., Sherlock, S. & Reid, L. Arterial changes in the lungs in cirrhosis of the liver-lung spider nevi. N. Engl. J. Med. 274, 291–298 (1966).

    Article  CAS  PubMed  Google Scholar 

  63. Herve, P. et al. Pulmonary vascular disorders in portal hypertension. Eur. Respir. J. 11, 1153–1166 (1998).

    Article  CAS  PubMed  Google Scholar 

  64. Roberts, D. N., Arguedas, M. R. & Fallon, M. B. Cost-effectiveness of screening for hepatopulmonary syndrome in liver transplant candidates. Liver Transpl. 13, 206–214 (2007).

    Article  PubMed  Google Scholar 

  65. Krowka, M. et al. Hepatopulmonary syndrome: a prospective study of relationships between severity of liver disease, pao2 response to 100% oxygen, and brain uptake after 99mTc MAA lung scanning. Chest 118, 615–624 (2000).

    Article  CAS  PubMed  Google Scholar 

  66. Krowka, M. J. & Cortese, D. A. Hepatopulmonary syndrome. Current concepts in diagnostic and therapeutic considerations. Chest 105, 1528–1537 (1994).

    Article  CAS  PubMed  Google Scholar 

  67. Sussman, N. L., Kochar, R. & Fallon, M. B. Pulmonary complications in cirrhosis. Curr. Opin. Organ Transplant. 16, 281–288 (2011).

    Article  CAS  PubMed  Google Scholar 

  68. Aller, R. et al. Diagnosis of hepatopulmonary syndrome with contrast transesophageal echocardiography: advantages over contrast transthoracic echocardiography. Dig. Dis. Sci. 44, 1243–1248 (1999).

    Article  CAS  PubMed  Google Scholar 

  69. Vedrinne, J. M. et al. Comparison of transesophageal and transthoracic contrast echocardiography for detection of an intrapulmonary shunt in liver disease. Chest 111, 1236–1240 (1997).

    Article  CAS  PubMed  Google Scholar 

  70. Fischer, C. H. et al. Role of contrast-enhanced transesophageal echocardiography for detection of and scoring intrapulmonary vascular dilatation. Echocardiography 27, 1233–1237 (2010).

    Article  PubMed  Google Scholar 

  71. Ryu, J. K. & Oh, J. H. Hepatopulmonary syndrome: angiography and therapeutic embolization. Clin. Imaging 27, 97–100 (2003).

    Article  PubMed  Google Scholar 

  72. Saad, N. E. A., Lee, D. E., Waldman, D. L. & Saad, W. E. A. Pulmonary arterial coil embolization for the management of persistent type I hepatopulmonary syndrome after liver transplantation. J. Vasc. Interv. Radiol. 18, 1576–1580 (2007).

    Article  PubMed  Google Scholar 

  73. Koksal, D. et al. Evaluation of intrapulmonary vascular dilatations with high-resolution computed thorax tomography in patients with hepatopulmonary syndrome. J. Clin. Gastroenterol. 40, 77–83 (2006).

    Article  PubMed  Google Scholar 

  74. Suga, K., Kawakami, Y., Iwanaga, H., Tokuda, O. & Matsunaga, N. Findings of hepatopulmonary syndrome on breath-hold perfusion spect-ct fusion images. Ann. Nucl. Med. 23, 413–419 (2009).

    Article  PubMed  Google Scholar 

  75. Schraufnagel, D., Malik, R., Goel, V., Ohara, N. & Chang, S. Lung capillary changes in hepatic cirrhosis in rats. Am. J. Physiol. 272, L139–L147 (1997).

    CAS  PubMed  Google Scholar 

  76. Schraufnagel, D. & Kay, J. Structural and pathologic changes in the lung vasculature in chronic liver disease. Clin. Chest Med. 17, 1–15 (1996).

    Article  CAS  PubMed  Google Scholar 

  77. Gómez, F. et al. Effects of nebulized ng-nitro-l-arginine methyl ester in patients with hepatopulmonary syndrome. Hepatology 43, 1084–1091 (2006).

    Article  PubMed  CAS  Google Scholar 

  78. Gómez, F. et al. Gas exchange mechanism of orthodeoxia in hepatopulmonary syndrome. Hepatology 40, 660–666 (2004).

    Article  PubMed  Google Scholar 

  79. Chang, S. W. & O'Hara, N. Increased pulmonary vascular permeability in rats with biliary cirrhosis: role of thomboxane A2. Am. J. Physiol. 264, L245–L252 (1993).

    Article  CAS  PubMed  Google Scholar 

  80. Chang, S. W. & O'Hara, N. Pulmonary circulatory dysfunction in rats with biliary cirrhosis. An animal model of the hepatopulmonary syndrome. Am. Rev. Respir. Dis. 145, 798–805 (1992).

    Article  CAS  PubMed  Google Scholar 

  81. Chang, S. W. & O'Hara, N. Chronic biliary obstruction induces pulmonary intravascular phagocytosis and endotoxin sensitivity in rats. J. Clin. Invest. 94, 2009–2019 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Chang, S. W. & O'Hara, N. Pulmonary circulatory dysfunction in rats with biliary cirrhosis. Am. Rev. Respir. Dis. 148, 798–805 (1992).

    Article  Google Scholar 

  83. Fallon, M. B. et al. The role of endothelial nitric oxide synthase in the pathogenesis of a rat model of hepatopulmonary syndrome. Gastroenterology 113, 606–614 (1997).

    Article  CAS  PubMed  Google Scholar 

  84. Fallon, M. B., Abrams, G. A., McGrath, J. W., Hou, Z. & Luo, B. Common bile duct ligation in the rat: a model of intrapulmonary vasodilatation and hepatopulmonary syndrome. Am. J. Physiol. 272, G779–G784 (1997).

    CAS  PubMed  Google Scholar 

  85. Luo, B., Abrams, G. A. & Fallon, M. B. Endothelin-1 in the rat bile duct ligation model of hepatopulmonary syndrome: correlation with pulmonary dysfunction. J. Hepatol. 29, 571–578 (1998).

    Article  CAS  PubMed  Google Scholar 

  86. Zhang, J. et al. Analysis of pulmonary heme oxygenase-1 and nitric oxide synthase alterations in experimental hepatopulmonary syndrome. Gastroenterology 125, 1441–1451 (2003).

    Article  CAS  PubMed  Google Scholar 

  87. Georgiev, P. et al. Characterization of time-related changes after experimental bile duct ligation. Br. J. Surg. 95, 646–656 (2008).

    Article  CAS  PubMed  Google Scholar 

  88. Groszmann, R. J., Vorobioff, J. & Riley, E. Splanchnic hemodynamics in portal-hypertensive rats: measurement with gamma-labeled microspheres. Am. J. Physiol. 242, G156–G160 (1982).

    CAS  PubMed  Google Scholar 

  89. Vorobioff, J., Bredfeldt, J. & Grosszmann, R. J. Hyperdynamic circulation in a portal hypertensive rat model: a primary factor for maintenance of chronic portal hypertension. Am. J. Physiol. 244, G52–G57 (1983).

    CAS  PubMed  Google Scholar 

  90. Abraldes, J. G. et al. 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. 290, G980–G987 (2006).

    Article  CAS  PubMed  Google Scholar 

  91. Luo, B. et al. ET-1 and TNF-α in HPS: analysis in prehepatic portal hypertension and biliary and nonbiliary cirrhosis in rats. Am. J. Physiol. Gastrointest. Liver Physiol. 286, G294–G303 (2004).

    Article  CAS  PubMed  Google Scholar 

  92. Luo, B. 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. 38, 556–563 (2003).

    Article  CAS  PubMed  Google Scholar 

  93. Geerts, A. et al. Comparison of three research models of portal hypertension in mice: Macroscopic, histological and portal pressure evaluation. Int. J. Exp. Pathol. 89, 251–263 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Mejias, M. et al. Beneficial effects of sorafenib on splanchnic, intrahepatic, and portocollateral circulations in portal hypertensive and cirrhotic rats. Hepatology 49, 1245–1256 (2009).

    Article  CAS  PubMed  Google Scholar 

  95. Laleman, W. et al. A stable model of cirrhotic portal hypertension in the rat: thioacetamide revisited. Eur. J. Clin. Invest. 36, 242–249 (2006).

    Article  CAS  PubMed  Google Scholar 

  96. Zhang, J. et al. Pulmonary angiogenesis in a rat model of hepatopulmonary syndrome. Gastroenterology 136, 1070–1080 (2009).

    Article  CAS  PubMed  Google Scholar 

  97. Zhang, M., Luo, B., Chen, S. J., Abrams, G. A. & Fallon, M. B. Endothelin-1 stimulation of endothelial nitric oxide synthase in the pathogenesis of hepatopulmonary syndrome. Am. J. Physiol. 277, G944–G952 (1999).

    CAS  PubMed  Google Scholar 

  98. Zhang, X.-J. et al. Intrapulmonary vascular dilatation and nitric oxide in hypoxemic rats with chronic bile duct ligation. J. Hepatol. 39, 724–730 (2003).

    Article  CAS  PubMed  Google Scholar 

  99. Miyamoto, A. et al. Effect of chronic methylene blue administration on hypoxemia in rats with common bile duct ligation. Hepatol. Res. 40, 622–632 (2010).

    Article  CAS  PubMed  Google Scholar 

  100. Nunes, H. et al. Role of nitric oxide in hepatopulmonary syndrome in cirrhotic rats. Am. J. Respir. Crit. Care Med. 164, 879–885 (2001).

    Article  CAS  PubMed  Google Scholar 

  101. Brussino, L. et al. Effect on dyspnoea and hypoxaemia of inhaled ng-nitro-l-arginine methyl ester in hepatopulmonary syndrome. Lancet 362, 43–44 (2003).

    Article  CAS  PubMed  Google Scholar 

  102. Luo, B. et al. Cholangiocyte endothelin-1 and transforming growth factor-beta1 production in rat experimental hepatopulmonary syndrome. Gastroenterology 129, 682–695 (2005).

    Article  CAS  PubMed  Google Scholar 

  103. Tang, L. et al. Modulation of pulmonary endothelial endothelin b receptor expression and signaling: Implications for experimental hepatopulmonary syndrome. Am. J. Physiol. Lung Cell. Mol. Physiol. 292, L1467–L1472 (2007).

    Article  CAS  PubMed  Google Scholar 

  104. Ling, Y. et al. The role of endothelin-1 and the endothelin b receptor in the pathogenesis of experimental hepatopulmonary syndrome. Hepatology 39, 1593–1602 (2004).

    Article  CAS  PubMed  Google Scholar 

  105. Zhang, J. et al. Attenuation of experimental hepatopulmonary syndrome in endothelin b receptor-deficient rats. Am. J. Physiol. Gastrointest. Liver Physiol. 296, G704–G708 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Schroeder, R. A., Ewing, C. A., Sitzmann, J. V. & Kuo, P. C. Pulmonary expression of inos and ho-1 protein is upregulated in a rat model of prehepatic portal hypertension. Dig. Dis. Sci. 45, 2405–2410 (2000).

    Article  CAS  PubMed  Google Scholar 

  107. Carter, E. P. et al. Regulation of heme oxygenase-1 by nitric oxide during hepatopulmonary syndrome. Am. J. Physiol. Lung Cell. Mol. Physiol. 283, L346–L353 (2002).

    Article  CAS  PubMed  Google Scholar 

  108. Roberts, K. E. et al. Genetic risk factors for hepatopulmonary syndrome in patients with advanced liver disease. Gastroenterology 139, 130–139e124 (2010).

    Article  CAS  PubMed  Google Scholar 

  109. Thenappan, T. et al. A central role for CD68+ macrophages in hepatopulmonary syndrome. Am. J. Respir. Crit. Care Med. 183, 1080–1091 (2011).

    Article  PubMed  Google Scholar 

  110. Bosch, J. Vascular deterioration in cirrhosis: the big picture. J. Clin. Gastroenterol. 41, S247–S253 (2007).

    Article  PubMed  Google Scholar 

  111. Dimmeler, S. et al. Activation of nitric oxide synthase in endothelial cells by akt-dependent phosphorylation. Nature 399, 601–605 (1999).

    Article  CAS  PubMed  Google Scholar 

  112. Dimmeler, S. & Zeiher, A. M. Akt takes center stage in angiogenesis signaling. Circ. Res. 86, 4–5 (2000).

    Article  CAS  PubMed  Google Scholar 

  113. Fernandez, M. et al. Reversal of portal hypertension and hyperdynamic splanchnic circulation by combined vascular endothelial growth factor and platelet-derived growth factor blockade in rats. Hepatology 46, 1208–1217 (2007).

    Article  CAS  PubMed  Google Scholar 

  114. Tugues, S. et al. Antiangiogenic treatment with sunitinib ameliorates inflammatory infiltrate, fibrosis, and portal pressure in cirrhotic rats. Hepatology 46, 1919–1926 (2007).

    Article  CAS  PubMed  Google Scholar 

  115. Lee, J., Semela, D., Iredale, J. & Shah, V. Sinusoidal remodeling and angiogenesis: a new function for the liver-specific pericyte? Hepatology 45, 817–825 (2007).

    Article  CAS  PubMed  Google Scholar 

  116. Fernandez, L. G. et al. Differential vascular growth in postpneumonectomy compensatory lung growth. J. Thorac. Cardiovasc. Surg. 133, 309–316 (2007).

    Article  CAS  PubMed  Google Scholar 

  117. Gill, S. et al. Role of pulmonary intravascular macrophages in endotoxin-induced lung inflammation and mortality in a rat model. Respir. Res. 9, 69 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  118. Zhang, J. et al. Pentoxifylline attenuation of experimental hepatopulmonary syndrome. J. Appl. Physiol. 102, 949–955 (2007).

    Article  CAS  PubMed  Google Scholar 

  119. Rabiller, A. et al. Prevention of gram-negative translocation reduces the severity of hepatopulmonary syndrome. Am. J. Respir. Crit. Care Med. 166, 514–517 (2002).

    Article  PubMed  Google Scholar 

  120. Sztrymf, B. et al. Prevention of hepatopulmonary syndrome by pentoxifylline in cirrhotic rats. Eur. Respir. J. 23, 752–758 (2004).

    Article  CAS  PubMed  Google Scholar 

  121. Hemprich, U., Papadakos, P. J. & Lachmann, B. Respiratory failure and hypoxemia in the cirrhotic patient including hepatopulmonary syndrome. Curr. Opin. Anaesthesiol. 23, 133–138 (2010).

    Article  PubMed  Google Scholar 

  122. Agusti, A. G. N., Roca, J. & Rodriguez-Roisin, R. Mechanisms of gas exchange impairment in patients with liver cirrhosis. Clin. Chest Med. 17, 49–66 (1996).

    Article  CAS  PubMed  Google Scholar 

  123. Krowka, M. J. et al. Hepatopulmonary syndrome: a prospective study of relationships between severity of liver disease, PaO2 response to 100% oxygen, and brain uptake after 99mTc MAA lung scanning. Chest 118, 615–624 (2000).

    Article  CAS  PubMed  Google Scholar 

  124. Cremona, G. et al. Elevated exhaled nitric oxide in patients with hepatopulmonary syndrome. Eur. Respir. J. 8, 1883–1885 (1995).

    Article  CAS  PubMed  Google Scholar 

  125. Rolla, G., Brussino, L. & Colagrande, P. Exhaled nitric oxide and impaired oxygenation in cirrhotic patients before and after liver transplantation. Ann. Intern. Med. 129, 375–378 (1998).

    Article  CAS  PubMed  Google Scholar 

  126. Rolla, G. et al. Exhaled nitric oxide and oxygenation abnormalities in hepatic cirrhosis. Hepatology 26, 842–847 (1997).

    Article  CAS  PubMed  Google Scholar 

  127. Arguedas, M. R., Drake, B. B., Kapoor, A. & Fallon, M. B. Carboxyhemoglobin levels in cirrhotic patients with and without hepatopulmonary syndrome. Gastroenterology 128, 328–333 (2005).

    Article  CAS  PubMed  Google Scholar 

  128. Sood, G. et al. Utility of a dyspnea–fatigue index for screening liver transplant candidates for hepatopulmonary syndrome. Hepatology 28, 2319 (1998).

    Google Scholar 

  129. Robin, E. D., Laman, D., Horn, B. R. & Theodore, J. Platypnea related to orthodeoxia caused by true vascular lung shunts. N. Engl. J. Med. 294, 941–943 (1976).

    Article  CAS  PubMed  Google Scholar 

  130. Martinez, G. P. et al. Hepatopulmonary syndrome in candidates for liver transplantation. J. Hepatol. 34, 651–657 (2001).

    Article  CAS  PubMed  Google Scholar 

  131. Palma, D. T., Philips, G. M., Arguedas, M. R., Harding, S. M. & Fallon, M. B. Oxygen desaturation during sleep in hepatopulmonary syndrome. Hepatology 47, 1257–1263 (2008).

    Article  PubMed  Google Scholar 

  132. McAdams, H. P. et al. The hepatopulmonary syndrome: radiologic findings in 10 patients. Am. J. Roentgenol. 166, 1379–1385 (1996).

    Article  CAS  Google Scholar 

  133. Fallon, M. & Abrams, G. Pulmonary dysfunction in chronic liver disease. Hepatology 32, 859–865 (2000).

    Article  CAS  PubMed  Google Scholar 

  134. Lima, B. et al. Frequency, clinical characteristics, and respiratory parameters of hepatopulmonary syndrome. Mayo Clin. Proc. 79, 42–48 (2004).

    Article  PubMed  Google Scholar 

  135. Yigit, I., Hacievliyagil, S., Seckin, Y., Öner, R. & Karincaoglu, M. The relationship between severity of liver cirrhosis and pulmonary function tests. Dig. Dis. Sci. 53, 1951–1956 (2008).

    Article  PubMed  Google Scholar 

  136. Møller, S., Krag, A., Madsen, J. L., Henriksen, J. H. & Bendtsen, F. Pulmonary dysfunction and hepatopulmonary syndrome in cirrhosis and portal hypertension. Liver Int. 29, 1528–1537 (2009).

    Article  PubMed  CAS  Google Scholar 

  137. Tumgor, G. et al. Childhood cirrhosis, hepatopulmonary syndrome and liver transplantation. Pediatr. Transplant. 12, 353–357 (2008).

    Article  PubMed  Google Scholar 

  138. Whitworth, J. R., Ivy, D. D., Gralla, J., Narkewicz, M. R. & Sokol, R. J. Pulmonary vascular complications in asymptomatic children with portal hypertension. J. Pediatr. Gastroenterol. Nutr. 49, 607–612 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  139. El-Shabrawi, M. H. et al. 99mTechnetium-macroaggregated albumin perfusion lung scan versus contrast enhanced echocardiography in the diagnosis of the hepatopulmonary syndrome in children with chronic liver disease. Eur. J. Gastroenterol. Hepatol. 22, 1006–1012 (2010).

    Article  CAS  PubMed  Google Scholar 

  140. Gupta, S. et al. Norfloxacin therapy for hepatopulmonary syndrome: a pilot randomized controlled trial. Clin. Gastroenterol. Hepatol. 8, 1095–1098 (2010).

    Article  CAS  PubMed  Google Scholar 

  141. Abrams, G. A. & Fallon, M. B. Treatment of hepatopulmonary syndrome with allium sativum l (garlic): a pilot trial. J. Clin. Gastroenterol. 27, 232–235 (1998).

    Article  CAS  PubMed  Google Scholar 

  142. Sani, M. N., Kianifar, H. R., Kianee, A. & Khatami, G. Effect of oral garlic on arterial oxygen pressure in children with hepatopulmonary syndrome. World J. Gastroenterol. 12, 2427–2431 (2006).

    Article  PubMed Central  Google Scholar 

  143. De, B. K. et al. The role of garlic in hepatopulmonary syndrome: a randomized controlled trial. Can. J. Gastroenterol. 24, 183–188 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  144. Akyüz, F. et al. Is there any medical therapeutic option in hepatopulmonary syndrome? A case report. Eur. J. Intern. Med. 16, 126–128 (2005).

    Article  PubMed  Google Scholar 

  145. Tanikella, R., Philips, G., Faulk, D., Kawut, S. & Fallon, M. Pilot study of pentoxifylline in hepatopulmonary syndrome. Liver Transpl. 14, 1199–1203 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  146. Gupta, L. B. et al. Pentoxifylline therapy for hepatopulmonary syndrome: a pilot study. Arch. Intern. Med. 168, 1820–1823 (2008).

    Article  PubMed  Google Scholar 

  147. Iqbal, C. W. et al. Liver transplantation for pulmonary vascular complications of pediatric end-stage liver disease. J. Pediatr. Surg. 43, 1813–1820 (2008).

    Article  PubMed  Google Scholar 

  148. Krug, S., Seyfarth, H.-J., Hagendorff, A. & Wirtz, H. Inhaled iloprost for hepatopulmonary syndrome: Improvement of hypoxemia. Eur. J. Gastroenterol. Hepatol. 19, 1140–1143 (2007).

    Article  PubMed  Google Scholar 

  149. Lau, E. M. T., McCaughan, G. & Torzillo, P. J. Improvement in hepatopulmonary syndrome after methadone withdrawal: a case report with implications for disease mechanism. Liver Transpl. 16, 870–873 (2010).

    Article  PubMed  Google Scholar 

  150. Reigler, J. L., Lang, K. A., Johnson, S. P. & Westerman, J. H. Transjugular intrahepatic portosystemic shunt improves oxygenation in hepatopulmonary syndrome. Gastroenterology 109, 978–983 (1995).

    Article  Google Scholar 

  151. Selim, K. M., Akriviadis, E. A., Zuckerman, E., Chen, D. & Reynolds, T. B. Transjugular intrahepatic portosystemic shunt: a successful treatment for hepatopulmonary syndrome. Am. J. Gastroenterol. 93, 455–458 (1998).

    Article  CAS  PubMed  Google Scholar 

  152. Allgaier, H. P. et al. Hepatopulmonary syndrome: Successful treatment by transjugular intrahepatic portosystemic stent-shunt (tips). J. Hepatol. 23, 102–105 (1995).

    Article  CAS  PubMed  Google Scholar 

  153. Paramesh, A. et al. Improvement of hepatopulmonary syndrome after transjugular intrahepatic portasystemic shunting: case report and review of literature. Pediatr. Transplant. 7, 157–162 (2003).

    Article  PubMed  Google Scholar 

  154. Corley, D. A., Scharschmidt, B., Bass, N., Somberg, K. & Gold, W. Lack of efficacy of tips for hepatopulmonary syndrome. Gastroenterology 113, 728–731 (1997).

    Article  CAS  PubMed  Google Scholar 

  155. Morikawa, N. et al. Resolution of hepatopulmonary syndrome after ligation of a portosystemic shunt in a pediatric patient with an abernethy malformation. J. Pediatr. Surg. 43, e35–e38 (2008).

    Article  PubMed  Google Scholar 

  156. Gupta, S. et al. Improved survival after liver transplantation in patients with hepatopulmonary syndrome. Am. J. Transplant. 10, 354–363 (2010).

    Article  CAS  PubMed  Google Scholar 

  157. Motomura, T. et al. Living donor liver transplantation for end-stage liver disease with severe hepatopulmonary syndrome: report of a case. Surg. Today 41, 436–440 (2011).

    Article  PubMed  Google Scholar 

  158. Chen, K. & Li, B. Reversal of severe hepatopulmonary syndrome in chronic hepatic cirrhosis by living donor liver transplantation: Report of two cases. Surg. Today 41, 441–443 (2011).

    Article  PubMed  Google Scholar 

  159. Schiller, O. et al. Nitric oxide for post-liver-transplantation hypoxemia in pediatric hepatopulmonary syndrome: case report and review. Pediatr. Transplant. 15, E130–E134 (2011).

    Article  PubMed  Google Scholar 

  160. Durand, P. et al. Reversal of hypoxemia by inhaled nitric oxide in children with severe hepatopulmonary syndrome, type 1, during and after liver transplantation. Transplantation 65, 437–439 (1998).

    Article  CAS  PubMed  Google Scholar 

  161. Taniai, N. et al. Reversal of hypoxemia by inhaled nitric oxide in a child with hepatopulmonary syndrome after living-related liver transplantation. Transplant. Proc. 34, 2791–2792 (2002).

    Article  CAS  PubMed  Google Scholar 

  162. Meyers, C., Low, L., Kaufman, L., Druger, G. & Wong, L. Trendelenburg positioning and continuous lateral rotation improve oxygenation in heaptopulmonary syndrome after liver transplantation. Liver Transpl. Surg. 6, 510–512 (1998).

    Article  Google Scholar 

  163. Taille, C. et al. Liver transplantation for hepatopulmonary syndrome: a ten-year experience in Paris, France. Transplantation 79, 1482–1489 (2003).

    Article  Google Scholar 

  164. Deberaldini, M. et al. Hepatopulmonary syndrome: morbidity and survival after liver transplantation. Transplant. Proc. 40, 3512–3516 (2008).

    Article  CAS  PubMed  Google Scholar 

  165. Schiffer, E. et al. Hepatopulmonary syndrome increases the postoperative mortality rate following liver transplantation: a prospective study in 90 patients. Am. J. Transplant. 6, 1430–1437 (2006).

    Article  CAS  PubMed  Google Scholar 

  166. De Palma, M., Murdoch, C., Venneri, M. A., Naldini, L. & Lewis, C. E. Tie2-expressing monocytes: regulation of tumor angiogenesis and therapeutic implications. Trends Immunol. 28, 545–550 (2007).

    Article  CAS  Google Scholar 

  167. Elsheikh, E. et al. Only a specific subset of human peripheral-blood monocytes has endothelial-like functional capacity. Blood 106, 2347–2355 (2005).

    Article  CAS  PubMed  Google Scholar 

  168. Venneri, M. A. et al. Identification of proangiogenic tie2-expressing monocytes (TEMS) in human peripheral blood and cancer. Blood 109, 5276–5285 (2007).

    Article  CAS  PubMed  Google Scholar 

  169. Schenk, P., Madl, C., Rezale-Majd, S., Lehr, S. & Muller, C. Methylene blue improves the hepatopulmonary syndrome. Ann. Intern. Med. 133, 701–706 (2000).

    Article  CAS  PubMed  Google Scholar 

  170. Rolla, G., Bucca, C. & Brussino, L. Methylene blue in the hepatopulmonary syndrome. N. Engl. J. Med. 331, 1098 (1994).

    Article  CAS  PubMed  Google Scholar 

  171. Almeida, J. A. et al. Deleterious effect of nitric oxide inhibition in chronic hepatopulmonary syndrome. Eur. J. Gastroenterol. Hepatol. 19, 341–346 (2007).

    Article  CAS  PubMed  Google Scholar 

  172. Tekin, A. et al. Effects of caffeic acid phenethyl ester (cape) on hepatopulmonary syndrome. Inflammation 34, 614–619 (2011).

    Article  CAS  PubMed  Google Scholar 

  173. Tieppo, J. et al. Quercetin administration ameliorates pulmonary complications of cirrhosis in rats. J. Nutr. 139, 1339–1346 (2009).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors acknowledge the support of NIH grant 5DKR01DK056804 (M. B. Fallon) and an award from the American Heart Association (J. Zhang).

Author information

Authors and Affiliations

  1. Division of Gastroenterology, Department of Internal Medicine, Hepatology and Nutrition, The University of Texas Health Science Center at Houston, 6431 Fannin Street, MSB 4.234, Houston, 77030-1501, TX, USA

    Junlan Zhang & Michael B. Fallon

Authors
  1. Junlan Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Michael B. Fallon
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Both authors contributed equally to all aspects of this article.

Corresponding author

Correspondence to Michael B. Fallon.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Zhang, J., Fallon, M. Hepatopulmonary syndrome: update on pathogenesis and clinical features. Nat Rev Gastroenterol Hepatol 9, 539–549 (2012). https://doi.org/10.1038/nrgastro.2012.123

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrgastro.2012.123

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing