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Hepatopulmonary Disorders: Gas Exchange and Vascular Manifestations in Chronic Liver Disease

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ABSTRACT

This review concentrates on the determinants of gas exchange abnormalities in liver‐induced pulmonary vascular disorders, more specifically in the hepatopulmonary syndrome. Increased alveolar‐arterial O2 difference, with or without different levels of arterial hypoxemia, and reduced diffusing capacity represent the most characteristic gas exchange disturbances in the absence of cardiac and pulmonary comorbidities. Pulmonary gas exchange abnormalities in the hepatopulmonary syndrome are unique encompassing all three pulmonary factors determining arterial PO2, that is, ventilation‐perfusion imbalance, increased intrapulmonary shunt and oxygen diffusion limitation that, combined, interplay with two relevant nonpulmonary determinants, that is, increased total ventilation and high cardiac output. Behind the complexity of this lung‐liver association there is an abnormal pulmonary vascular tone that combines inhibition of hypoxic pulmonary vasoconstriction with a reduced (or blunted) hypoxic vascular response. The pathology and pathobiology include the presence of intrapulmonary vascular dilatations with or without pulmonary vascular remodeling, i.e. angiogenesis. Liver transplantation, the only effective therapeutic approach to successfully improve and resolve the vast majority of complications induced by the hepatopulmonary syndrome, along with a large list of frustrating pharmacologic interventions, are also reviewed. Another liver‐induced pulmonary vascular disorder with less gas exchange involvement, such as portopulmonary hypertension, is also considered. © 2018 American Physiological Society. Compr Physiol 8:711‐729, 2018.

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Figure 1. Figure 1. (A) Mechanisms of gas exchange, namely, ventilation‐perfusion matching with absence of intrapulmonary shunt and of oxygen diffusion limitation, under normal conditions. (B) Mechanisms of arterial hypoxemia in the hepatopulmonary syndrome that illustrate intrapulmonary vascular dilatations inducing ventilation‐perfusion imbalance, the main pulmonary determinant, perhaps with mild increased intrapulmonary shunt, with or without diffusion limitation to oxygen [reproduced with permission from Ref. ()].
Figure 2. Figure 2. Pulmonary vascular resistance (expressed in mmHg/L/min) (top) and ventilation‐perfusion imbalance (as assessed by the dispersion of pulmonary blood flow—dimensionless) (bottom) responses to three inspired oxygen fractions breathing in subjects with liver cirrhosis (). Compared to ambient air, pulmonary vascular resistance increases significantly as opposed to unchanged ventilation‐perfusion inequalities during hypoxic breathing; by contrast, pulmonary vascular resistance remains unaltered with further ventilation‐perfusion worsening during hyperoxic breathing.
Figure 3. Figure 3. Pulmonary vascular resistance (expressed in mmHg/L/min) (top) and ventilation‐perfusion imbalance (as assessed by the dispersion of pulmonary blood flow—dimensionless) (bottom) responses to the breathing of different inspired oxygen fractions in subjects with liver cirrhosis without and with spiders (). Compared to ambient air, individuals without spiders (left) increase pulmonary vascular resistance whereas ventilation‐perfusion imbalance remains unchanged during 11% oxygen (hypoxic) breathing (left); by contrast, in subjects with spiders (right) pulmonary vascular resistance remains unaltered while ventilation‐perfusion worsens, that is, the dispersion of pulmonary blood flow, during 100% oxygen (hyperoxic) breathing (right), overall reinforcing the view of a paradoxical behavior of the pulmonary vasculature in those with worse liver dysfunction (i.e., with spiders).
Figure 4. Figure 4. Lineal carbon monoxide diffusing capacity (DLCO) (as % predicted) and inverse (left) intrapulmonary shunt negative associations (right) (y‐axes), respectively, with arterial PO2 (x‐axis) in subjects with hepatopulmonary syndrome, candidates to liver transplantation [reproduced with permission from Ref. ()].
Figure 5. Figure 5. Both a descriptor of ventilation‐perfusion imbalance (intrapulmonary shunt and areas with low ventilation‐perfusion ratios) (left) and the inert gas diffusion component of arterial hypoxemia, expressed as the difference between the predicted inert and measured (actual) arterial PO2, (right) (y‐axes) correlate inversely with carbon monoxide diffusing capacity (DLCO) (as % predicted) (x‐axis) in subjects with hepatopulmonary syndrome, candidates for liver transplantation [reproduced with permission from Ref. ()].
Figure 6. Figure 6. Alveolar‐arterial O2 difference (top) and carbon monoxide diffusing capacity (DLCO) (as % predicted) (bottom) values in individuals with hepatopulmonary syndrome, before and after liver transplantation, assessed at mid‐term (median, 15 months) and at long‐term (median, 86 months) (bars indicate mean values). While each value of alveolar‐arterial O2 difference decrease, that reflect individual respective increases in arterial PO2, diffusing capacity values remain unaltered [reproduced with permission from Ref. ()].
Figure 7. Figure 7. Postural‐induced major differences (bars) on arterial blood gases, ventilation‐perfusion imbalance, cardiac output ( ), and total ventilation in individuals with the hepatopulmonary syndrome with (solid bars) and without (gray bars) orthodeoxia (from top to bottom) (DISP R‐E* represents an overall index of ventilation‐perfusion heterogeneity—dimensionless; ns, not significant) [reproduced with permission from Ref. ()]. For further explanation, see text.
Figure 8. Figure 8. Arterial PO2, AaPO2 (alveolar‐arterial PO2 difference), intrapulmonary shunt (expressed as percentage of cardiac output), and an overall index of ventilation‐perfusion imbalance (DISP R‐E*) values, before and after acute nebulization of NG‐nitro‐l‐arginine methyl ester (L‐NAME) (arrows), in subjects with hepatopulmonary syndrome (bars indicate mean values) [reproduced with permission from Ref. ()].


Figure 1. (A) Mechanisms of gas exchange, namely, ventilation‐perfusion matching with absence of intrapulmonary shunt and of oxygen diffusion limitation, under normal conditions. (B) Mechanisms of arterial hypoxemia in the hepatopulmonary syndrome that illustrate intrapulmonary vascular dilatations inducing ventilation‐perfusion imbalance, the main pulmonary determinant, perhaps with mild increased intrapulmonary shunt, with or without diffusion limitation to oxygen [reproduced with permission from Ref. ()].


Figure 2. Pulmonary vascular resistance (expressed in mmHg/L/min) (top) and ventilation‐perfusion imbalance (as assessed by the dispersion of pulmonary blood flow—dimensionless) (bottom) responses to three inspired oxygen fractions breathing in subjects with liver cirrhosis (). Compared to ambient air, pulmonary vascular resistance increases significantly as opposed to unchanged ventilation‐perfusion inequalities during hypoxic breathing; by contrast, pulmonary vascular resistance remains unaltered with further ventilation‐perfusion worsening during hyperoxic breathing.


Figure 3. Pulmonary vascular resistance (expressed in mmHg/L/min) (top) and ventilation‐perfusion imbalance (as assessed by the dispersion of pulmonary blood flow—dimensionless) (bottom) responses to the breathing of different inspired oxygen fractions in subjects with liver cirrhosis without and with spiders (). Compared to ambient air, individuals without spiders (left) increase pulmonary vascular resistance whereas ventilation‐perfusion imbalance remains unchanged during 11% oxygen (hypoxic) breathing (left); by contrast, in subjects with spiders (right) pulmonary vascular resistance remains unaltered while ventilation‐perfusion worsens, that is, the dispersion of pulmonary blood flow, during 100% oxygen (hyperoxic) breathing (right), overall reinforcing the view of a paradoxical behavior of the pulmonary vasculature in those with worse liver dysfunction (i.e., with spiders).


Figure 4. Lineal carbon monoxide diffusing capacity (DLCO) (as % predicted) and inverse (left) intrapulmonary shunt negative associations (right) (y‐axes), respectively, with arterial PO2 (x‐axis) in subjects with hepatopulmonary syndrome, candidates to liver transplantation [reproduced with permission from Ref. ()].


Figure 5. Both a descriptor of ventilation‐perfusion imbalance (intrapulmonary shunt and areas with low ventilation‐perfusion ratios) (left) and the inert gas diffusion component of arterial hypoxemia, expressed as the difference between the predicted inert and measured (actual) arterial PO2, (right) (y‐axes) correlate inversely with carbon monoxide diffusing capacity (DLCO) (as % predicted) (x‐axis) in subjects with hepatopulmonary syndrome, candidates for liver transplantation [reproduced with permission from Ref. ()].


Figure 6. Alveolar‐arterial O2 difference (top) and carbon monoxide diffusing capacity (DLCO) (as % predicted) (bottom) values in individuals with hepatopulmonary syndrome, before and after liver transplantation, assessed at mid‐term (median, 15 months) and at long‐term (median, 86 months) (bars indicate mean values). While each value of alveolar‐arterial O2 difference decrease, that reflect individual respective increases in arterial PO2, diffusing capacity values remain unaltered [reproduced with permission from Ref. ()].


Figure 7. Postural‐induced major differences (bars) on arterial blood gases, ventilation‐perfusion imbalance, cardiac output ( ), and total ventilation in individuals with the hepatopulmonary syndrome with (solid bars) and without (gray bars) orthodeoxia (from top to bottom) (DISP R‐E* represents an overall index of ventilation‐perfusion heterogeneity—dimensionless; ns, not significant) [reproduced with permission from Ref. ()]. For further explanation, see text.


Figure 8. Arterial PO2, AaPO2 (alveolar‐arterial PO2 difference), intrapulmonary shunt (expressed as percentage of cardiac output), and an overall index of ventilation‐perfusion imbalance (DISP R‐E*) values, before and after acute nebulization of NG‐nitro‐l‐arginine methyl ester (L‐NAME) (arrows), in subjects with hepatopulmonary syndrome (bars indicate mean values) [reproduced with permission from Ref. ()].
References
 1.Abrams GA, Nanda NC, Dubovsky EV, Krowka MJ, Fallon MB. Use of macroaggregated albumin lung perfusion scan to diagnose hepatopulmonary syndrome: A new approach. Gastroenterology 114: 305‐310, 1998.
 2.Abrams GA, Sanders MK, Fallon MB. Utility of pulse oximetry in the detection of arterial hypoxemia in liver transplant candidates. Liver Transpl 8: 391‐396, 2002.
 3.Agusti AG, Roca J, Bosch J, Garcia‐Pagan JC, Wagner PD, Rodriguez‐Roisin R. Effects of propranolol on arterial oxygenation and oxygen transport to tissues in patients with cirrhosis. Am Rev Respir Dis 142: 306‐310, 1990.
 4.Agusti AG, Roca J, Bosch J, Rodriguez‐Roisin R. The lung in patients with cirrhosis. J Hepatol 10: 251‐257, 1990.
 5.Agusti AG, Roca J, Rodriguez‐Roisin R. Mechanisms of gas exchange impairment in patients with liver cirrhosis. Clin Chest Med 17: 49‐66, 1996.
 6.Agusti AG, Roca J, Rodriguez‐Roisin R, Mastai R, Wagner PD, Bosch J. Pulmonary hemodynamics and gas exchange during exercise in liver cirrhosis. Am Rev Respir Dis 139: 485‐491, 1989.
 7.Aller R, Moya JL, Avila S, Villa J, Moreira V, Barcena R, Boxeida D, de Luis DA. Implications of estradiol and progesterone in pulmonary vasodilatation in cirrhotic patients. J Endocrinol Invest 25: 4‐10, 2002.
 8.Arguedas MR, Abrams GA, Krowka MJ, Fallon MB. Prospective evaluation of outcomes and predictors of mortality in patients with hepatopulmonary syndrome undergoing liver transplantation. Hepatology 37: 192‐197, 2003.
 9.Arguedas MR, Drake BB, Kapoor A, Fallon MB. Carboxyhemoglobin levels in cirrhotic patients with and without hepatopulmonary syndrome. Gastroenterology 128: 328‐333, 2005.
 10.Arguedas MR, Singh H, Faulk DK, Fallon MB. Utility of pulse oximetry screening for hepatopulmonary syndrome. Clin Gastroenterol Hepatol 5: 749‐754, 2007.
 11.Arismendi E, Rivas E, Agusti A, Rios J, Barreiro E, Vidal J, Rodriguez‐Roisin R. The systemic inflammome of severe obesity before and after bariatric surgery. PLoS One 9: e107859, 2014.
 12.Bashour FA, Cochran P. Alveolar‐arterial oxygen tension gradients in cirrhosis of the liver. Further evidence of existing pulmonary arteriovenous shunting. Am Heart J 71: 734‐740, 1966.
 13.Battaglia SE, Pretto JJ, Irving LB, Jones RM, Angus PW. Resolution of gas exchange abnormalities and intrapulmonary shunting following liver transplantation. Hepatology 25: 1228‐1232, 1997.
 14.Berthelot P, Walker JG, 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.
 15.Cadranel JL, Milleron BJ, Cadranel JF, Fermand JP, Andrivet P, Brouet JC, Adnot S, Akoun GM. Severe hypoxemia‐associated intrapulmonary shunt in a patient with chronic liver disease: Improvement after medical treatment. Am Rev Respir Dis 146: 526‐527, 1992.
 16.Calabresi P, Belmann WH. Porto‐caval and porto‐pulmonary anastomoses in Laennec's cirrhosis and in heart failure. J Clin Invest 36: 1257‐1265, 1957.
 17.Caldwell SH, Brantley K, Dent J, Keeley RC, Pruett T, Angle JF, Gaffey M, Waldron P. The hepatopulmonary syndrome masquerading as pulmonary Langerhans‐cell histiocytosis. Hepatopulmonary Syndrome Study Group. Ann Intern Med 121: 34‐36, 1994.
 18.Caldwell SH, Jeffers LJ, Narula OS, Lang EA, Reddy KR, Schiff ER. Ancient remedies revisited: Does Allium sativum (garlic) palliate the hepatopulmonary syndrome? J Clin Gastroenterol 15: 248‐250, 1992.
 19.Carter EP, Hartsfield CL, Miyazono M, Jakkula M, Morris KG, Jr., McMurtry IF. Regulation of heme oxygenase‐1 by nitric oxide during hepatopulmonary syndrome. Am J Physiol Lung Cell Mol Physiol 283: L346‐L353, 2002.
 20.Carter EP, Sato K, Morio Y, McMurtry IF. Inhibition of K(Ca) channels restores blunted hypoxic pulmonary vasoconstriction in rats with cirrhosis. Am J Physiol Lung Cell Mol Physiol 279: L903‐L910, 2000.
 21.Cartin‐Ceba R, Krowka MJ. Portopulmonary hypertension. Clin Liver Dis 18: 421‐438, 2014.
 22.Castaing Y, Manier G. Hemodynamic disturbances and VA/Q matching in hypoxemic cirrhotic patients. Chest 96: 1064‐1069, 1989.
 23.Chemla D, Castelain V, Herve P, Lecarpentier Y, Brimioulle S. Haemodynamic evaluation of pulmonary hypertension. Eur Respir J 20: 1314‐1331, 2002.
 24.Craig DB, Wahba WM, Don HF, Couture JG, Becklake MR. “Closing volume” and its relationship to gas exchange in seated and supine positions. J Appl Physiol 31: 717‐721, 1971.
 25.Cremona G, Higenbottam TW, Mayoral V, Alexander G, Demoncheaux E, Borland C, Roe P, Jones GJ. Elevated exhaled nitric oxide in patients with hepatopulmonary syndrome. Eur Respir J 8: 1883‐1885, 1995.
 26.Dantzker DR. The influence of cardiovascular function on gas exchange. Clin Chest Med 4: 149‐159, 1983.
 27.Dantzker DR, D'Alonzo GE. Pulmonary gas exchange and exercise performance in pulmonary hypertension. Chest 88: 255S‐257S, 1985.
 28.Daoud FS, Reeves JT, Schaefer JW. Failure of hypoxic pulmonary vasoconstriction in patients with liver cirrhosis. J Clin Invest 51: 1076‐1080, 1972.
 29.Davis HH, Schwartz DJ, Lefrak SS, Susman N, Schainker BA. Alveolar‐capillary oxygen disequilibrium in hepatic cirrhosis. Chest 73: 507‐511, 1978.
 30.Degano B, Mittaine M, Guenard H, Rami J, Garcia G, Kamar N, Bureau C, Peron JM, Rostaing L, Riviere D. Nitric oxide and carbon monoxide lung transfer in patients with advanced liver cirrhosis. J Appl Physiol 107: 139‐143, 2009.
 31.Duncan BW, Desai S. Pulmonary arteriovenous malformations after cavopulmonary anastomosis. Ann Thorac Surg 76: 1759‐1766, 2003.
 32.Edell ES, Cortese DA, Krowka MJ, Rehder K. Severe hypoxemia and liver disease. Am Rev Respir Dis 140: 1631‐1635, 1989.
 33.Edwards BS, Weir EK, Edwards WD, Ludwig J, Dykoski RK, Edwards JE. Coexistent pulmonary and portal hypertension: Morphologic and clinical features. J Am Coll Cardiol 10: 1233‐1238, 1987.
 34.Fallon MB, Abrams GA, Luo B, Hou Z, Dai J, Ku DD. The role of endothelial nitric oxide synthase in the pathogenesis of a rat model of hepatopulmonary syndrome. Gastroenterology 113: 606‐614, 1997.
 35.Farhi LE, Rahn H. A theoretical analysis of the alveolar‐arterial O2 difference with special reference to the distribution effect. J Appl Physiol 7: 699‐703, 1955.
 36.Faughnan ME, Granton JT, Young LH. The pulmonary vascular complications of hereditary haemorrhagic telangiectasia. Eur Respir J 33: 1186‐1194, 2009.
 37.Fritz JS, Fallon MB, Kawut SM. Pulmonary vascular complications of liver disease. Am J Respir Crit Care Med 187: 133‐143, 2013.
 38.Fuhrmann V, Madl C, Mueller C, Holzinger U, Kitzberger R, Funk GC, Schenk P. Hepatopulmonary syndrome in patients with hypoxic hepatitis. Gastroenterology 131: 69‐75, 2006.
 39.Fussner LA, Iyer VN, Cartin‐Ceba R, Lin G, Watt KD, Krowka MJ. Intrapulmonary vascular dilatations are common in portopulmonary hypertension and may be associated with decreased survival. Liver Transpl 21: 1355‐1364, 2015.
 40.Gadre A, Highland KB, Mehta A. Reversible platypnea‐orthodeoxia syndrome from ventilation‐perfusion mismatch in interstitial lung disease: A novel etiology. Ann Am Thorac Soc 13: 137‐138, 2016.
 41.Galie N, Hoeper MM, Humbert M, Torbicki A, Vachiery JL, Barbera JA, Beghetti M, Corris P, Gaine S, Gibbs JS, Gomez‐Sanchez MA, Jondeau G, Klepetko W, Opitz C, Peacock A, Rubin L, Zellweger M, Simonneau G. Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Respir J 34: 1219‐1263, 2009.
 42.Genovesi MG, Tierney DF, Taplin GV, Eisenberg H. An intravenous radionuclide method to evaluate hypoxemia caused by abnormal alveolar vessels. Limitation of conventional techniques. Am Rev Respir Dis 114: 59‐65, 1976.
 43.Georg J, Tygstrup N, Mellemgaard K, Winkler K. Venoarterial shunts in cirrhosis of the liver. Lancet 1: 852‐854, 1960.
 44.Glazier JB, Hughes JM, Maloney JE, West JB. Measurements of capillary dimensions and blood volume in rapidly frozen lungs. J Appl Physiol 26: 65‐76, 1969.
 45.Goldberg DS, Krok K, Batra S, Trotter JF, Kawut SM, Fallon MB. Impact of the hepatopulmonary syndrome MELD exception policy on outcomes of patients after liver transplantation: an analysis of the UNOS database. Gastroenterology 146: 1256‐1265 e1251, 2014.
 46.Gomez FP, Barbera JA, Roca J, Burgos F, Gistau C, Rodriguez‐Roisin R. Effects of nebulized N(G)‐nitro‐L‐arginine methyl ester in patients with hepatopulmonary syndrome. Hepatology 43: 1084‐1091, 2006.
 47.Gomez FP, Martinez‐Palli G, Barbera JA, Roca J, Navasa M, Rodriguez‐Roisin R. Gas exchange mechanism of orthodeoxia in hepatopulmonary syndrome. Hepatology 40: 660‐666, 2004.
 48.Gupta LB, Kumar A, Jaiswal AK, Yusuf J, Mehta V, Tyagi S, Tempe DK, Sharma BC, Sarin SK. Pentoxifylline therapy for hepatopulmonary syndrome: A pilot study. Arch Intern Med 168: 1820‐1823, 2008.
 49.Hedenstierna G, Soderman C, Eriksson LS, Wahren J. Ventilation‐perfusion inequality in patients with non‐alcoholic liver cirrhosis. Eur Respir J 4: 711‐717, 1991.
 50.Herve P, Le Pavec J, Sztrymf B, Decante B, Savale L, Sitbon O. Pulmonary vascular abnormalities in cirrhosis. Best Pract Res Clin Gastroenterol 21: 141‐159, 2007.
 51.Hourani JM, Bellamy PE, Tashkin DP, Batra P, Simmons MS. Pulmonary dysfunction in advanced liver disease: Frequent occurrence of an abnormal diffusing capacity. Am J Med 90: 693‐700, 1991.
 52.Hughes JM, van der Lee I. The TL,NO/TL,CO ratio in pulmonary function test interpretation. Eur Respir J 41: 453‐461, 2013.
 53.Humbert M, Lau EM, Montani D, Jais X, Sitbon O, Simonneau G. Advances in therapeutic interventions for patients with pulmonary arterial hypertension. Circulation 130: 2189‐2208, 2014.
 54.Iyer VN, Swanson KL, Cartin‐Ceba R, Dierkhising RA, Rosen CB, Heimbach JK, Wiesner RH, Krowka MJ. Hepatopulmonary syndrome: Favorable outcomes in the MELD exception era. Hepatology 57: 2427‐2435, 2013.
 55.Kennedy TC, Knudson RJ. Exercise‐aggravated hypoxemia and orthodeoxia in cirrhosis. Chest 72: 305‐309, 1977.
 56.Knapper JT, Schultz J, Das G, Sperling LS. Cardiac platypnea‐orthodeoxia syndrome: An often unrecognized malady. Clin Cardiol 37: 645‐649, 2014.
 57.Krowka MJ. Hepatopulmonary syndrome versus portopulmonary hypertension: Distinctions and dilemmas. Hepatology 25: 1282‐1284, 1997.
 58.Krowka MJ. The lung‐liver connection. BRN Rev 3: 204‐219, 2017.
 59.Krowka MJ. Portopulmonary hypertension: Diagnostic advances and caveats. Liver Transpl 9: 1336‐1337, 2003.
 60.Krowka MJ, Cortese DA. Hepatopulmonary syndrome: An evolving perspective in the era of liver transplantation. Hepatology 11: 138‐142, 1990.
 61.Krowka MJ, Cortese DA. Severe hypoxemia associated with liver disease: Mayo Clinic experience and the experimental use of almitrine bismesylate. Mayo Clin Proc 62: 164‐173, 1987.
 62.Krowka MJ, Dickson ER, Cortese DA. Hepatopulmonary syndrome. Clinical observations and lack of therapeutic response to somatostatin analogue. Chest 104: 515‐521, 1993.
 63.Krowka MJ, Edwards WD. A spectrum of pulmonary vascular pathology in portopulmonary hypertension. Liver Transpl 6: 241‐242, 2000.
 64.Krowka MJ, Fallon MB, Kawut SM, Fuhrmann V, Heimbach JK, Ramsay MA, Sitbon O, Sokol RJ. International Liver Transplant Society Practice Guidelines: Diagnosis and management of hepatopulmonary syndrome and portopulmonary hypertension. Transplantation 100: 1440‐1452, 2016.
 65.Krowka MJ, Mandell MS, Ramsay MA, Kawut SM, Fallon MB, Manzarbeitia C, Pardo M, Jr., Marotta P, Uemoto S, Stoffel MP, Benson JT. Hepatopulmonary syndrome and portopulmonary hypertension: A report of the multicenter liver transplant database. Liver Transpl 10: 174‐182, 2004.
 66.Krowka MJ, Porayko MK, Plevak DJ, Pappas SC, Steers JL, Krom RA, Wiesner RH. Hepatopulmonary syndrome with progressive hypoxemia as an indication for liver transplantation: Case reports and literature review. Mayo Clin Proc 72: 44‐53, 1997.
 67.Krowka MJ, Tajik AJ, Dickson ER, Wiesner RH, Cortese DA. Intrapulmonary vascular dilatations (IPVD) in liver transplant candidates. Screening by two‐dimensional contrast‐enhanced echocardiography. Chest 97: 1165‐1170, 1990.
 68.Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, de Oliveira AC, Santoro A, Raoul JL, Forner A, Schwartz M, Porta C, Zeuzem S, Bolondi L, Greten TF, Galle PR, Seitz JF, Borbath I, Haussinger D, Giannaris T, Shan M, Moscovici M, Voliotis D, Bruix J, Group SIS. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 359: 378‐390, 2008.
 69.MacNee W, Buist TA, Finlayson ND, Lamb D, Miller HC, Muir AL, Douglas AC. Multiple microscopic pulmonary arteriovenous connections in the lungs presenting as cyanosis. Thorax 40: 316‐318, 1985.
 70.Martinez‐Palli G, Barbera JA, Taura P, Cirera I, Visa J, Rodriguez‐Roisin R. Severe portopulmonary hypertension after liver transplantation in a patient with preexisting hepatopulmonary syndrome. J Hepatol 31: 1075‐1079, 1999.
 71.Martinez‐Palli G, Drake BB, Garcia‐Pagan JC, Barbera JA, Arguedas MR, Rodriguez‐Roisin R, Bosch J, Fallon MB. Effect of transjugular intrahepatic portosystemic shunt on pulmonary gas exchange in patients with portal hypertension and hepatopulmonary syndrome. World J Gastroenterol 11: 6858‐6862, 2005.
 72.Martinez‐Palli G, Gomez FP, Barbera JA, Navasa M, Roca J, Rodriguez‐Roisin R, Burgos F, Gistau C. Sustained low diffusing capacity in hepatopulmonary syndrome after liver transplantation. World J Gastroenterol 12: 5878‐5883, 2006.
 73.Martinez G, Barbera JA, Navasa M, Roca J, Visa J, Rodriguez‐Roisin R. Hepatopulmonary syndrome associated with cardiorespiratory disease. J Hepatol 30: 882‐889, 1999.
 74.Martinez GP, Barbera JA, Visa J, Rimola A, Pare JC, Roca J, Navasa M, Rodes J, Rodriguez‐Roisin R. Hepatopulmonary syndrome in candidates for liver transplantation. J Hepatol 34: 651‐657, 2001.
 75.Martini GA, Baltzer G, Arndt H. Some aspects of circulatory disturbances in cirrhosis of the liver. Prog Liver Dis 4: 231‐250, 1972.
 76.McAdams HP, Erasmus J, Crockett R, Mitchell J, Godwin JD, McDermott VG. The hepatopulmonary syndrome: Radiologic findings in 10 patients. AJR Am J Roentgenol 166: 1379‐1385, 1996.
 77.Melot C, Naeije R, Dechamps P, Hallemans R, Lejeune P. Pulmonary and extrapulmonary contributors to hypoxemia in liver cirrhosis. Am Rev Respir Dis 139: 632‐640, 1989.
 78.Mithoefer JC, Ramirez C, Cook W. The effect of mixed venous oxygenation on arterial blood in chronic obstructive pulmonary disease: The basis for a classification. Am Rev Respir Dis 117: 259‐264, 1978.
 79.Naeije R. [Hypoxic pulmonary vasoconstriction. What clinical importance?]. Presse Med 14: 1359‐1361, 1985.
 80.Naeije R, Hallemans R, Mols P, Melot C. Hypoxic pulmonary vasoconstriction in liver cirrhosis. Chest 80: 570‐574, 1981.
 81.Nunes H, Lebrec D, Mazmanian M, Capron F, Heller J, Tazi KA, Zerbib E, Dulmet E, Moreau R, Dinh‐Xuan AT, Simonneau G, Herve P. Role of nitric oxide in hepatopulmonary syndrome in cirrhotic rats. Am J Respir Crit Care Med 164: 879‐885, 2001.
 82.Poterucha JJ, Krowka MJ, Dickson ER, Cortese DA, Stanson AW, Krom RA. Failure of hepatopulmonary syndrome to resolve after liver transplantation and successful treatment with embolotherapy. Hepatology 21: 96‐100, 1995.
 83.Rabiller A, Nunes H, Lebrec D, Tazi KA, Wartski M, Dulmet E, Libert JM, Mougeot C, Moreau R, Mazmanian M, Humbert M, Herve P. Prevention of gram‐negative translocation reduces the severity of hepatopulmonary syndrome. Am J Respir Crit Care Med 166: 514‐517, 2002.
 84.Rivas E, Arismendi E, Agusti A, Gistau C, Wagner PD, Rodriguez‐Roisin R. Postural effects on pulmonary gas exchange abnormalities in severe obesity before and after bariatric surgery. Minerva Anestesiol 82: 403‐410, 2016.
 85.Rivas E, Arismendi E, Agusti A, Sanchez M, Delgado S, Gistau C, Wagner PD, Rodriguez‐Roisin R. Ventilation/perfusion distribution abnormalities in morbidly obese subjects before and after bariatric surgery. Chest 147: 1127‐1134, 2015.
 86.Roberts KE, Fallon MB, Krowka MJ, Brown RS, Trotter JF, Peter I, Tighiouart H, Knowles JA, Rabinowitz D, Benza RL, Badesch DB, Taichman DB, Horn EM, Zacks S, Kaplowitz N, Kawut SM. Genetic risk factors for portopulmonary hypertension in patients with advanced liver disease. Am J Respir Crit Care Med 179: 835‐842, 2009.
 87.Robin ED, Laman D, Horn BR, Theodore J. Platypnea related to orthodeoxia caused by true vascular lung shunts. N Engl J Med 294: 941‐943, 1976.
 88.Rodriguez‐Roisin R. Nonpulmonary influences on gas exchange. Compr Physiol 4: 1455‐1494, 2014.
 89.Rodriguez‐Roisin R, Agusti AG, Roca J. The hepatopulmonary syndrome: New name, old complexities. Thorax 47: 897‐902, 1992.
 90.Rodriguez‐Roisin R, Bartolome SD, Huchon G, Krowka MJ. Inflammatory bowel diseases, chronic liver diseases and the lung. Eur Respir J 47: 638‐650, 2016.
 91.Rodriguez‐Roisin R, Krowka MJ. Hepatopulmonary syndrome‐‐‐a liver‐induced lung vascular disorder. N Engl J Med 358: 2378‐2387, 2008.
 92.Rodriguez‐Roisin R, Krowka MJ. Is severe arterial hypoxaemia due to hepatic disease an indication for liver transplantation? A new therapeutic approach. Eur Respir J 7: 839‐842, 1994.
 93.Rodriguez‐Roisin R, Krowka MJ, Herve P, Fallon MB. Pulmonary‐hepatic vascular disorders (PHD). Eur Respir J 24: 861‐880, 2004.
 94.Rodriguez‐Roisin R, Roca J, Agusti AG, Mastai R, Wagner PD, Bosch J. Gas exchange and pulmonary vascular reactivity in patients with liver cirrhosis. Am Rev Respir Dis 135: 1085‐1092, 1987.
 95.Rodriguez‐Roisin R, Wagner PD. Clinical relevance of ventilation‐perfusion inequality determined by inert gas elimination. Eur Respir J 3: 469‐482, 1990.
 96.Rolla G, Brussino L, Colagrande P, Scappaticci E, Morello M, Bergerone S, Ottobrelli A, Cerutti E, Polizzi S, Bucca C. Exhaled nitric oxide and impaired oxygenation in cirrhotic patients before and after liver transplantation. Ann Intern Med 129: 375‐378, 1998.
 97.Ruff F, Hughes JM, Stanley N, McCarthy D, Greene R, Aronoff A, Clayton L, Milic‐Emili J. Regional lung function in patients with hepatic cirrhosis. J Clin Invest 50: 2403‐2413, 1971.
 98.Ruttner JR, Bartschi JP, Niedermann R, Schneider J. Plexogenic pulmonary arteriopathy and liver cirrhosis. Thorax 35: 133‐136, 1980.
 99.Rydell R, Hoffbauer FW. Multiple pulmonary arteriovenous fistulas in juvenile cirrhosis. Am J Med 21: 450‐460, 1956.
 100.Santos A, Rivas E, Rodriguez‐Roisin R, Sanchez M, Ruiz‐Cabello J, Arismendi E, Venegas JG. Lung tissue volume is elevated in obesity and reduced by bariatric surgery. Obes Surg 26: 2475‐2482, 2016.
 101.Schenk P, Madl C, Rezaie‐Majd S, Lehr S, Muller C. Methylene blue improves the hepatopulmonary syndrome. Ann Intern Med 133: 701‐706, 2000.
 102.Schenk P, Schoniger‐Hekele M, Fuhrmann V, Madl C, Silberhumer G, Muller C. Prognostic significance of the hepatopulmonary syndrome in patients with cirrhosis. Gastroenterology 125: 1042‐1052, 2003.
 103.Schraufnagel DE, Malik R, Goel V, Ohara N, Chang SW. Lung capillary changes in hepatic cirrhosis in rats. Am J Physiol 272: L139‐L147, 1997.
 104.Shijo H, Sasaki H, Miyajima Y, Okumura M. Prostaglandin F2 alpha and indomethacin in hepatogenic pulmonary angiodysplasia. Effects on pulmonary hemodynamics and gas exchange. Chest 100: 873‐875, 1991.
 105.Shijo H, Sasaki H, Yuh K, Sakaguchi S, Okumura M. Effects of indomethacin on hepatogenic pulmonary angiodysplasia. Chest 99: 1027‐1029, 1991.
 106.Stanley NN, Williams AJ, Dewar CA, Blendis LM, Reid L. Hypoxia and hydrothoraces in a case of liver cirrhosis: Correlation of physiological, radiographic, scintigraphic, and pathological findings. Thorax 32: 457‐471, 1977.
 107.Swanson KL, Krowka MJ. Arterial oxygenation associated with portopulmonary hypertension. Chest 121: 1869‐1875, 2002.
 108.Sztrymf B, Rabiller A, Nunes H, Savale L, Lebrec D, Le Pape A, de Montpreville V, Mazmanian M, Humbert M, Herve P. Prevention of hepatopulmonary syndrome and hyperdynamic state by pentoxifylline in cirrhotic rats. Eur Respir J 23: 752‐758, 2004.
 109.Taille C, Cadranel J, Bellocq A, Thabut G, Soubrane O, Durand F, Ichai P, Duvoux C, Belghiti J, Calmus Y, Mal H. Liver transplantation for hepatopulmonary syndrome: A ten‐year experience in Paris, France. Transplantation 75: 1482‐1489, 2003.
 110.Talwalkar JA, Swanson KL, Krowka MJ, Andrews JC, Kamath PS. Prevalence of spontaneous portosystemic shunts in patients with portopulmonary hypertension and effect on treatment. Gastroenterology 141: 1673‐1679, 2011.
 111.Tang L, Luo B, Patel RP, Ling Y, Zhang J, Fallon MB. 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.
 112.Trembath RC, Thomson JR, Machado RD, Morgan NV, Atkinson C, Winship I, Simonneau G, Galie N, Loyd JE, Humbert M, Nichols WC, Morrell NW, Berg J, Manes A, McGaughran J, Pauciulo M, Wheeler L. Clinical and molecular genetic features of pulmonary hypertension in patients with hereditary hemorrhagic telangiectasia. N Engl J Med 345: 325‐334, 2001.
 113.Vachiery F, Moreau R, Hadengue A, Gadano A, Soupison T, Valla D, Lebrec D. Hypoxemia in patients with cirrhosis: Relationship with liver failure and hemodynamic alterations. J Hepatol 27: 492‐495, 1997.
 114.Wagner PD. The physiological basis of pulmonary gas exchange: Implications for clinical interpretation of arterial blood gases. Eur Respir J 45: 227‐243, 2015.
 115.Wagner PD, Rodriguez‐Roisin R. Clinical advances in pulmonary gas exchange. Am Rev Respir Dis 143: 883‐888, 1991.
 116.Wagner PD, Saltzman HA, West JB. Measurement of continuous distributions of ventilation‐perfusion ratios: Theory. J Appl Physiol 36: 588‐599, 1974.
 117.Williams MH, Jr. Hypoxemia due to venous admixture in cirrhosis of the liver. J Appl Physiol 15: 253‐254, 1960.
 118.Zhang J, Fallon MB. Hepatopulmonary syndrome: Update on pathogenesis and clinical features. Nat Rev Gastroenterol Hepatol 9: 539‐549, 2012.
 119.Zhang J, Ling Y, Luo B, Tang L, Ryter SW, Stockard CR, Grizzle WE, Fallon MB. Analysis of pulmonary heme oxygenase‐1 and nitric oxide synthase alterations in experimental hepatopulmonary syndrome. Gastroenterology 125: 1441‐1451, 2003.
 120.Zhang J, Ling Y, Tang L, Luo B, Chacko BK, Patel RP, Fallon MB. Pentoxifylline attenuation of experimental hepatopulmonary syndrome. J Appl Physiol 102: 949‐955, 2007.
 121.Zhang J, Luo B, Tang L, Wang Y, Stockard CR, Kadish I, Van GT, Grizzle WE, Ponnazhagan S, Fallon MB. Pulmonary angiogenesis in a rat model of hepatopulmonary syndrome. Gastroenterology 136: 1070‐1080, 2009.
 122.Zhang J, Yang W, Hu B, Wu W, Fallon MB. Endothelin‐1 activation of the endothelin B receptor modulates pulmonary endothelial CX3CL1 and contributes to pulmonary angiogenesis in experimental hepatopulmonary syndrome. Am J Pathol 184: 1706‐1714, 2014.
 123.Zhang XJ, Katsuta Y, Akimoto T, Ohsuga M, Aramaki T, Takano T. Intrapulmonary vascular dilatation and nitric oxide in hypoxemic rats with chronic bile duct ligation. J Hepatol 39: 724‐730, 2003.

Further Reading

Fritz JS, Fallon MB and Kawut SM. Pulmonary Vascular Complications of Liver Disease. American Journal of Respiratory and Critical Care Medicine 187: 133-143, 2013.

Krowka MJ, Fallon MB, Kawut SM, Fuhrmann V, Heimbach JK, Ramsay MA, Sitbon O and Sokol RJ. International Liver Transplant Society Practice Guidelines: Diagnosis and Management of Hepatopulmonary Syndrome and Portopulmonary Hypertension. Transplantation 100: 1440-1452, 2016.

Rodriguez-Roisin R, Krowka MJ, Herve P and Fallon MB. Pulmonary-Hepatic vascular Disorders (PHD). Eur Respir J 24: 861-880, 2004.

Rodriguez-Roisin R and Krowka MJ. Hepatopulmonary syndrome--a liver-induced lung vascular disorder. N Engl J Med 358: 2378-2387, 2008.

Wagner PD. The physiological basis of pulmonary gas exchange: implications for clinical interpretation of arterial blood gases. Eur Respir J 45: 227-243, 2015.

Teaching Material

R. Rodríguez-Roisin, M. J. Krowka, A. Agustí. Hepatopulmonary Disorders: Gas Exchange and Vascular Manifestations in Chronic Liver Disease. Compr Physiol. 8: 2018, 711-729.

Didactic Synopsis

Major Teaching Points:

  • The paradigm of liver-induced vascular diseases is the hepatopulmonary syndrome, a triad characterized by arterial deoxygenation, intrapulmonary vascular dilatations and hepatic disorder.
  • The key criterion of arterial deoxygenation encompasses an increased alveolar-arterial O2 difference, with or without arterial hypoxemia, arterial hypocapnia, and reduced diffusing capacity.
  • These gas exchange disturbances are essentially induced by ventilation-perfusion imbalance that can be associated with mild-to-moderate increases in intrapulmonary shunt and some diffusion limitation to oxygen transfer.
  • The gas exchange response to 100% oxygen is characterized by ventilation-perfusion worsening without changes in intrapulmonary shunt suggesting inhibition of hypoxic pulmonary vasoconstriction.
  • The hypoxic vascular response can be reduced or abolished pointing to a paradoxical behavior of the underlying pulmonary vascular bed.
  • Portopulmonary hypertension, the other relevant liver-induced pulmonary vascular disorder, is dominated by the hemodynamic hallmarks of the abnormal pulmonary circulatory state with little gas exchange impairment.

Didactic Legends

The figures—in a freely downloadable PowerPoint format—can be found on the Images tab along with the formal legends published in the article. The following legends to the same figures are written to be useful for teaching.

Figure 1. Teaching points: (A) This figure illustrates the three pulmonary factors governing pulmonary gas exchange, namely ventilation-perfusion matching with absence of intrapulmonary shunt and of oxygen diffusion limitation, under normal, healthy conditions while breathing ambient air using the simile of a two-compartmental lung model. (B) Abnormal mechanisms of arterial hypoxemia in the hepatopulmonary syndrome encompassing ventilation-perfusion imbalance, the main pulmonary determinant, that can associate mild increased intrapulmonary shunt, with or without diffusion limitation to oxygen, in the most advances severe conditions [reproduced with permission from Ref. (91)].

Figure 3. Pulmonary vascular resistance (expressed in mmHg/L/min) (top) and ventilation-perfusion imbalance (as assessed by the dispersion of pulmonary blood flow—dimensionless) (bottom) responses to the breathing of different inspired oxygen fractions in subjects with liver cirrhosis without and with spiders (94). Compared to ambient air, individuals without spiders increase pulmonary vascular resistance whereas ventilation-perfusion imbalance remains unchanged during 11% oxygen (hypoxic) breathing (left); by contrast, in subjects with spiders pulmonary vascular resistance remains unaltered while ventilation-perfusion worsens, that is, the dispersion of pulmonary blood flow, during 100% oxygen (hyperoxic) breathing (right), overall reinforcing the view of a paradoxical behavior of the pulmonary vasculature in those with worse liver dysfunction (i.e., with spiders) (see Figure 2).

Figure 4. Teaching points: The lineal correlation between diffusing capacity for carbon monoxide (DLCO) (as % predicted) (left) combined with the negative association with intrapulmonary shunt (right) in subjects with hepatopulmonary syndrome, candidates to liver transplantation [reproduced with permission from Ref. (74)], indicate the close interaction between the three components of gas exchange abnormalities (physiologic and inert gases and carbon monoxide transfer factor).

Figure 5. Both a descriptor of ventilation-perfusion imbalance (intrapulmonary shunt and areas with low ventilation-perfusion ratios) (left) and the inert gas diffusion component of arterial hypoxemia, expressed as the difference between the predicted inert and measured (actual) arterial PO2, (right) (y-axes) correlate inversely with carbon monoxide diffusing capacity (DLCO) (as % predicted) (x-axis) in subjects with hepatopulmonary syndrome, candidates for liver transplantation.

Figure 6. Alveolar-arterial O2 difference (top) and carbon monoxide diffusing capacity (DLCO) (as % predicted) (bottom) values in individuals with hepatopulmonary syndrome, before and after liver transplantation, assessed at mid-term (median,15 months) and at long-term (median, 86 months). While each value of alveolar-arterial O2 difference decrease, that reflect individual respective increases in arterial PO2, diffusing capacity values remain unaltered.

Figure 7. Teaching points: Bars represent changes that reflect measured differences between upright and supine postures in arterial and mixed venous PO2, and their pulmonary (shunt + low VA/Q [ventilation-perfusion]) and DISP R-E* (an overall index of ventilation-perfusion heterogeneity—dimensionless) and nonpulmonary determinants (minute ventilation and cardiac output) of gas exchange in individuals with hepatopulmonary syndrome with (solid bars) and without orthodeoxia (gray bars). Of note that, in individuals who develop orthodeoxia, there is more arterial deoxygenation (decreases in arterial and mixed venous PO2) induced by higher intrapulmonary shunt and areas with low ventilation-perfusion ratios, without changes in the nonpulmonary determinants (ns, not significant) [reproduced with permission from Ref. (47)]. For further explanation, see text.

Figure 8. Arterial PO2, alveolar-arterial PO2, intrapulmonary shunt and an overall index of ventilation-perfusion imbalance (DISP R-E*) values, before and after acute nebulization of NG-nitro-l-arginine methyl ester (L-NAME) (arrows), in subjects with hepatopulmonary syndrome.


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How to Cite

Robert Rodríguez‐Roisin, Michael J. Krowka, Alvar Agustí. Hepatopulmonary Disorders: Gas Exchange and Vascular Manifestations in Chronic Liver Disease. Compr Physiol 2018, 8: 711-729. doi: 10.1002/cphy.c170020