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==Clinical Characteristics==
==Clinical Characteristics==


PPH  presents roughly equally in male and female cirrhotics; 71% female in an American series and 57% male in a larger French series.<ref name=LePavec> Le Pavec et al. Portopulmonary Hypertension: Survival and Prognostic Factors. Am J Respir Crit Care Med Vol 178. pp 637–643, 2008</ref><ref name=Kawut>Kawut SM et al. Clinical Risk Factors for Portopulmonary Hypertension. Hepatology 2008;48</ref> Typically, patients present in their fifth decade, aged 49 +/- 11 years in one series.<ref name=LePavec><ref> Bejaminov et al. Portopulmonary hypertension in decompensated cirrhosis with refractory ascites. Gut 2003; 52:1355-1362</ref> On average, PPH is diagnosed 4-7 years after the patient is diagnosed with portal hypertension<ref> Hadengue et al. PH complicating portal hypertension: prevalence and relation to splanchnic hemodynamics. Gastroenterology 1991;100:520-528</ref> and in roughly 65% of cases, the diagnosis is actually made at the time of invasive hemodynamic monitoring following anesthesia induction prior to liver transplantation.<ref> Hadengue et al. Pulmonary hypertension complicating portal hypertension: prevalence and relation to splanchnic hemodynamics. Gastroenterology 1991;100:520-528</ref>  
PPH  presents roughly equally in male and female cirrhotics; 71% female in an American series and 57% male in a larger French series.<ref name=LePavec> Le Pavec et al. Portopulmonary Hypertension: Survival and Prognostic Factors. Am J Respir Crit Care Med Vol 178. pp 637–643, 2008</ref><ref name=Kawut>Kawut SM et al. Clinical Risk Factors for Portopulmonary Hypertension. Hepatology 2008;48</ref> Typically, patients present in their fifth decade, aged 49 +/- 11 years in one series.<ref name=LePavec> Le Pavec et al. Portopulmonary Hypertension: Survival and Prognostic Factors. Am J Respir Crit Care Med Vol 178. pp 637–643, 2008</ref><ref> Bejaminov et al. Portopulmonary hypertension in decompensated cirrhosis with refractory ascites. Gut 2003; 52:1355-1362</ref> On average, PPH is diagnosed 4-7 years after the patient is diagnosed with portal hypertension<ref> Hadengue et al. PH complicating portal hypertension: prevalence and relation to splanchnic hemodynamics. Gastroenterology 1991;100:520-528</ref> and in roughly 65% of cases, the diagnosis is actually made at the time of invasive hemodynamic monitoring following anesthesia induction prior to liver transplantation.<ref> Hadengue et al. Pulmonary hypertension complicating portal hypertension: prevalence and relation to splanchnic hemodynamics. Gastroenterology 1991;100:520-528</ref>  


Once patients are symptomatic, they present with right heart dysfunction secondary to pulmonary hypertension and its consequent dyspnea, fatigue, chest pain and syncope.<ref> Martinex-Palli et al. Liver Transplant in High Risk Patients. Transplant Proceedings 2005;37:3861-3864</ref> Patients tend to have a poor cardiac status, with 60% having stage III-IV NYHA heart failure.<ref name=LePavec> PPH is not related to the severity of cirrhosis but may be more common in specific types of cirrhosis, in one series moreso in Autoimmune Hepatitis and less in Hepatitis C cirrhosis,<ref name=Kawut> while in another it was equally distributed throughout the diagnoses.<ref name=Tapper>.
Once patients are symptomatic, they present with right heart dysfunction secondary to pulmonary hypertension and its consequent dyspnea, fatigue, chest pain and syncope.<ref> Martinex-Palli et al. Liver Transplant in High Risk Patients. Transplant Proceedings 2005;37:3861-3864</ref> Patients tend to have a poor cardiac status, with 60% having stage III-IV NYHA heart failure.<ref name=LePavec> PPH is not related to the severity of cirrhosis but may be more common in specific types of cirrhosis, in one series moreso in Autoimmune Hepatitis and less in Hepatitis C cirrhosis,<ref name=Kawut>Kawut SM et al. Clinical Risk Factors for Portopulmonary Hypertension. Hepatology 2008;48</ref> while in another it was equally distributed throughout the diagnoses.<ref name=Tapper>Tapper EB, Knowles D, Heffron T, Lawrence EC, Csete M. Portopulmonary hypertension: imatinib as a novel treatment and the Emory experience with this condition. Transplant Proc. 2009 Jun;41(5):1969-71.</ref>.


==Natural History==
==Natural History==
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Following diagnosis, mean survival of patients with PPH is 15 months.<ref> Ramsay et al. Severed PHTN in liver Transplant candidates. Liver Transplant Surg 1997 3:494</ref> Indeed, the survival of those with cirrhosis is sharply curtailed by PPH but can be significantly extended by both medical therapy and liver transplantation, provided they remain eligible.  
Following diagnosis, mean survival of patients with PPH is 15 months.<ref> Ramsay et al. Severed PHTN in liver Transplant candidates. Liver Transplant Surg 1997 3:494</ref> Indeed, the survival of those with cirrhosis is sharply curtailed by PPH but can be significantly extended by both medical therapy and liver transplantation, provided they remain eligible.  


Given the fear that those PPH patients with high pulmonary artery pressures (PAP) will suffer right heart failure following the stress of post-transplant reperfusion or in the immediate perioperative period, patients are typically risk-stratified based on mean PAP. The operation-related mortality rate is greater than 50% when pre-operative mean PAP values lie between 35 and 50 mm Hg; if mean PAP exceeds 40-45, transplantation is associated with a perioperative mortality of 70-80% (in those cases without preoperative treatment).<ref> Csete M. Intraoperative management of liver transplant patients with PHTN. Liver Transplant Surg 1997:3:454-55</ref><ref name=Kim> Kim et al. Accuracy of Doppler Echos in the assessment of PTHN in liver transplant candidates. Liver Transplant. 6:453, 2000</ref> Patients, then, are considered to have a high risk of perioperative death once their mean PAP exceeds 35 mm_Hg.<ref> Krowka et al. Pulm Hemodynamics and perioperative cardiopulmonary-related mortality in patients with portopulmonary hypertension undergoing liver Transplant. Liver Transpl 2000;6:443-450</ref> The focus on mean PAP values as a chief prognostic index has achieved an apparent consensus according to a recent multicenter study: 45% of patients with PPH were denied OLT candidacy based on the degree of their pulmonary hypertension, while no patient with mPAP < 35 mm_Hg was denied (Between those accepted and those denied, there was no significant difference in cardiac output or right atrial pressure).<ref> Krowka et al. Hepatopulmonary syndrom and portopulmonary hypertension: A report of the multicenter Liver transplant database. Liver Transplant. 2004;10:174-182</ref>
Given the fear that those PPH patients with high pulmonary artery pressures (PAP) will suffer right heart failure following the stress of post-transplant reperfusion or in the immediate perioperative period, patients are typically risk-stratified based on mean PAP. The operation-related mortality rate is greater than 50% when pre-operative mean PAP values lie between 35 and 50 mm Hg; if mean PAP exceeds 40-45, transplantation is associated with a perioperative mortality of 70-80% (in those cases without preoperative treatment).<ref> Csete M. Intraoperative management of liver transplant patients with pulmonary hypertension. Liver Transplant Surg 1997:3:454-55</ref><ref name=Kim> Kim et al. Accuracy of Doppler Echos in the assessment of PTHN in liver transplant candidates. Liver Transplant. 6:453, 2000</ref> Patients, then, are considered to have a high risk of perioperative death once their mean PAP exceeds 35 mm_Hg.<ref> Krowka et al. Pulm Hemodynamics and perioperative cardiopulmonary-related mortality in patients with portopulmonary hypertension undergoing liver Transplant. Liver Transpl 2000;6:443-450</ref> The focus on mean PAP values as a chief prognostic index has achieved an apparent consensus according to a recent multicenter study: 45% of patients with PPH were denied OLT candidacy based on the degree of their pulmonary hypertension, while no patient with mPAP < 35 mm_Hg was denied (Between those accepted and those denied, there was no significant difference in cardiac output or right atrial pressure).<ref>Krowka et al. Hepatopulmonary syndrome and portopulmonary hypertension: A report of the multicenter Liver transplant database. Liver Transplant. 2004;10:174-182</ref>


Survival is best inferred from institutional experience. At one instituation, without treatment, 1-year survival was 46% and 5-year survival was 14%. With medical therapy, 1-year survival was 88% and 5-year survival was 55%. Survival at 5 years with medical therapy followed by liver transplantation was 67%. <ref name=swanson>Swanson KL et al. Survival in Portopulmonary Hypertension: Mayo Clinic Experience Categorized by Treatment Subgroups. Am J Transpl 2008; 8: 2445–2453</ref> At another institution, of the 67 patients with PPH from 1652 total cirrhotics evaluated for transplant, half (34) were placed on the waiting list. Of these, 16 (48%) were transplanted at a time when 25% of all patients who underwent full evaluation received new livers, meaning the diagnosis of PPH made a patient twice as likely to be transplanted, once on the waiting list. Of those listed for transplant with PPH, 11 (33%) were eventually removed because of PPH, and 5 (15%) died on the waitlist. Of the 16 transplanted patients with PPH, 11 (69%) survived for more than a year after transplant, at a time when overall one-year survival in that center was 86.4%. The three year post-transplant survival for patients with PPH was 62.5% when it was 81.02% overall.<ref name=Tapper>
Survival is best inferred from institutional experience. At one instituation, without treatment, 1-year survival was 46% and 5-year survival was 14%. With medical therapy, 1-year survival was 88% and 5-year survival was 55%. Survival at 5 years with medical therapy followed by liver transplantation was 67%.<ref name=swanson>Swanson KL et al. Survival in Portopulmonary Hypertension: Mayo Clinic Experience Categorized by Treatment Subgroups. Am J Transpl 2008; 8: 2445–2453</ref> At another institution, of the 67 patients with PPH from 1652 total cirrhotics evaluated for transplant, half (34) were placed on the waiting list. Of these, 16 (48%) were transplanted at a time when 25% of all patients who underwent full evaluation received new livers, meaning the diagnosis of PPH made a patient twice as likely to be transplanted, once on the waiting list. Of those listed for transplant with PPH, 11 (33%) were eventually removed because of PPH, and 5 (15%) died on the waitlist. Of the 16 transplanted patients with PPH, 11 (69%) survived for more than a year after transplant, at a time when overall one-year survival in that center was 86.4%. The three year post-transplant survival for patients with PPH was 62.5% when it was 81.02% overall.<ref>Tapper EB, Knowles D, Heffron T, Lawrence EC, Csete M. Portopulmonary hypertension: imatinib as a novel treatment and the Emory experience with this condition. Transplant Proc. 2009 Jun;41(5):1969-71.</ref>


==Diagnosis==
==Diagnosis==
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As above, the diagnosis of portopulmonary hypertension is based on hemodynamic criteria:
As above, the diagnosis of portopulmonary hypertension is based on hemodynamic criteria:


1. Portal hypertension and/or liver disease (clinical diagnosis—ascites/varices/splenomagly)
#. Portal hypertension and/or liver disease (clinical diagnosis—ascites/varices/splenomegaly)
2. Mean pulmonary artery pressure—MPAP > 25 mmHg at rest
#. Mean pulmonary artery pressure—MPAP > 25 mmHg at rest
3. Pulmonary vascular resistance—PVR > 240 dynes s cm−5
#. Pulmonary vascular resistance—PVR > 240 dynes s cm−5
4. Pulmonary artery occlusion pressure—PAOP < 15 mmHg or transpulmonary gradient—TPG > 12 mmHg
#. Pulmonary artery occlusion pressure— PAOP < 15mmHg or transpulmonary gradient—TPG > 12 mmHg where TPG = MPAP − PAOP.<ref name=swanson>Swanson KL et al. Survival in Portopulmonary Hypertension: Mayo Clinic Experience Categorized by Treatment Subgroups. Am J Transpl 2008; 8: 2445–2453</ref>
where TPG = MPAP − PAOP.<ref name=Swanson>


The diagnosis is usually first suggested by a transthoracic echocardiogram, part of the standard pre-transplantation work-up. Echocardiogram estimated pulmonary artery systolic pressures of 40 to 50 mm Hg are used as a screening cutoff for PPH diagnosis,<ref> Torregosa et al. Role of Doppler echos in the assessment of PPHTN in liver transplant candidates. Transplantation 2001;71:572-574</ref> with a sensitivity of 100% and a specificity as high as 96%.<ref name=Kim>  The negative predictive value of this method is 100% but the positive predictive value is 60%.<ref name=Colle> Colle et al. Diagnosis of portopulmonary hypertension in candidates for liver transplant: a prospective study. Hepatology 2003;37:401-209</ref>  
The diagnosis is usually first suggested by a transthoracic echocardiogram, part of the standard pre-transplantation work-up. Echocardiogram estimated pulmonary artery systolic pressures of 40 to 50 mm Hg are used as a screening cutoff for PPH diagnosis,<ref>Torregosa et al. Role of Doppler echos in the assessment of PPHTN in liver transplant candidates. Transplantation 2001;71:572-574</ref> with a sensitivity of 100% and a specificity as high as 96%.<ref name=Kim>  The negative predictive value of this method is 100% but the positive predictive value is 60%.<ref name=Colle> Colle et al. Diagnosis of portopulmonary hypertension in candidates for liver transplant: a prospective study. Hepatology 2003;37:401-209</ref>  


The measurement of PAP by Echocardiogram is made using a simplified Bernoulli equation. The speed of a fluid through a narrow orifice is proportional to the difference of the pressures on either side – in this case, the right atrium and ventricle. Therefore the velocity of tricuspid regurgitation (which occurs at a measurable but normal level in the vast majority of humans) is squared, multiplied by four and added to the estimated right atrial pressure. Right atrial pressure is a derivative value, found by examining the inferior vena cava in the following sense: If, on inspiration, it should collapse roughly 50%, then the right atrial pressure is roughly 5mm_Hg; some collapse gives a right atrial pressure of 10 mm_Hg and no collapse, pressure of 15 mm_Hg. High cardiac index and pulmonary capillary wedge pressures, however, may lead to false positives by this standard. By one institution’s evaluation, the correlation (simple linear regression) between estimated systolic PAP and directly measured PAP was poor, 0.49.<ref> Tapper EB, unpublished data</ref> For these reasons, right heart catheterization is needed to confirm the diagnosis.<ref name=Colle>
The measurement of PAP by echocardiogram is made using a simplified Bernoulli equation. The speed of a fluid through a narrow orifice is proportional to the difference of the pressures on either side – in this case, the right atrium and ventricle. Therefore the velocity of tricuspid regurgitation (which occurs at a measurable but normal level in the vast majority of humans) is squared, multiplied by four and added to the estimated right atrial pressure. Right atrial pressure is a derivative value, found by examining the inferior vena cava in the following sense: If, on inspiration, it should collapse roughly 50%, then the right atrial pressure is roughly 5mm_Hg; some collapse gives a right atrial pressure of 10 mm_Hg and no collapse, pressure of 15 mm_Hg. High cardiac index and pulmonary capillary wedge pressures, however, may lead to false positives by this standard. By one institution’s evaluation, the correlation (simple linear regression) between estimated systolic PAP and directly measured PAP was poor, 0.49.<ref> Tapper EB, unpublished data</ref> For these reasons, right heart catheterization is needed to confirm the diagnosis.<Colle>


==Pathophysiology==
==Pathophysiology==


PPH pathology arises both from the humoral consequences of cirrhosis and the mechanical obstruction of the portal vein.<ref> Budhiraja et al. Portopulmonary Hypertension: A Tale of Two Circulations. Chest. 2003;123:562-576.</ref> A central paradigm holds responsible an excess local pulmonary production of vasoconstrictors that occurs while vasodilatation predominates systemically<ref> Moller et al. Cardiopulmonary complications in chronic liver disease. World J Gastroenterol 2006;12;526-538</ref>. Key here are imbalances between vasodilating and vasoconstricting molecules; endogenous prostacyclin and thromboxane (from Kuppfer Cells) <ref> Christman et al. An imbalance between the excretion of thromboxane and prostacyclin metabolites in pulmonary hypertension. N Engl J Med 1992;327:1774-78</ref><ref> Maruyama et al. Thromboxane-dependent portopulmonary hypertension. Am J Med. 2005;118:93-94</ref> or nitrous oxide (NO) and endothelin-1 (ET-1).<ref> Bejaminov et al. Portopulmonary hypertension in decompensated cirrhosis with refractory ascites. Gut 2003; 52:1355-1362</ref> ET-1 is the most potent vasoconstrictor under investigation<ref> Giaid A. Nitrous oxide and endothelin-1 in pulmonary hypertension. Chest. 1998;114;208-12S </ref> and it has been found to be increased in both cirrhosis<ref> Gerbes. ET1 and 3 plasma conc in patients with cirrhosis: role of splanchnic and renal passage and liver function. Hepatology 1995;21:735-9</ref> and pulmonary hypertension. <ref> Stewart. Increase plasma endothelin-1 in pulmonary hypertension: marker or mediator of disease? Ann Intern Med 1991;114:464-9</ref>  Endothelin-1 has two receptors in the pulmonary arterial tree, ET-A which mediates vasoconstriction and ET-B which mediates vasodilation. Rat models have shown decreased ET-B receptor expression in pulmonary arteries of cirrhotic and portal hypertensive animals, leading to a predominant vasoconstricting response to endothelin-1. <ref> Luo et al. Increase pulmonary vascular ETb receptor expression and responsiveness to ET-1 in cirrhotive and portal hypertensive rats. J Hepatol 2003;38:556-63</ref>
PPH pathology arises both from the humoral consequences of cirrhosis and the mechanical obstruction of the portal vein.<ref>Budhiraja et al. Portopulmonary Hypertension: A Tale of Two Circulations. Chest. 2003;123:562-576.</ref> A central paradigm holds responsible an excess local pulmonary production of vasoconstrictors that occurs while vasodilatation predominates systemically<ref> Moller et al. Cardiopulmonary complications in chronic liver disease. World J Gastroenterol 2006;12;526-538</ref>. Key here are imbalances between vasodilating and vasoconstricting molecules; endogenous prostacyclin and thromboxane (from Kuppfer Cells) <ref> Christman et al. An imbalance between the excretion of thromboxane and prostacyclin metabolites in pulmonary hypertension. N Engl J Med 1992;327:1774-78</ref><ref>Maruyama et al. Thromboxane-dependent portopulmonary hypertension. Am J Med. 2005;118:93-94</ref> or nitrous oxide (NO) and endothelin-1 (ET-1).<ref> Bejaminov et al. Portopulmonary hypertension in decompensated cirrhosis with refractory ascites. Gut 2003; 52:1355-1362</ref> ET-1 is the most potent vasoconstrictor under investigation<ref> Giaid A. Nitrous oxide and endothelin-1 in pulmonary hypertension. Chest. 1998;114;208-12S </ref> and it has been found to be increased in both cirrhosis<ref> Gerbes. ET1 and 3 plasma conc in patients with cirrhosis: role of splanchnic and renal passage and liver function. Hepatology 1995;21:735-9</ref> and pulmonary hypertension. <ref> Stewart. Increase plasma endothelin-1 in pulmonary hypertension: marker or mediator of disease? Ann Intern Med 1991;114:464-9</ref>  Endothelin-1 has two receptors in the pulmonary arterial tree, ET-A which mediates vasoconstriction and ET-B which mediates vasodilation. Rat models have shown decreased ET-B receptor expression in pulmonary arteries of cirrhotic and portal hypertensive animals, leading to a predominant vasoconstricting response to endothelin-1. <ref> Luo et al. Increase pulmonary vascular ETb receptor expression and responsiveness to ET-1 in cirrhotive and portal hypertensive rats. J Hepatol 2003;38:556-63</ref>


In portal hypertension, blood will shunt from portal to systemic circulation, bypassing the liver. This leaves unmetabolized potentially toxic or vasoconstricting substances to reach and attack the pulmonary circulation. Serotonin, normally metabolized by the liver, is returned to the lung instead where it mediates a smooth muscle hyperplasia and hypertrophy. <ref> Egermayer et al. Role of serotonin in the pathogenesis of acute and chronic pulmonary hypertension. Thorax 1999;54:161-168</ref>.Moreover, a key pathogenic factor in the decline in status of PPH patients related to this shunting is the cirrhotic cardiomyopathy with myocardial thickening and diastolic dysfunction.  
In portal hypertension, blood will shunt from portal to systemic circulation, bypassing the liver. This leaves unmetabolized potentially toxic or vasoconstricting substances to reach and attack the pulmonary circulation. Serotonin, normally metabolized by the liver, is returned to the lung instead where it mediates a smooth muscle hyperplasia and hypertrophy. <ref> Egermayer et al. Role of serotonin in the pathogenesis of acute and chronic pulmonary hypertension. Thorax 1999;54:161-168</ref>.Moreover, a key pathogenic factor in the decline in status of PPH patients related to this shunting is the cirrhotic cardiomyopathy with myocardial thickening and diastolic dysfunction.  
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Finally, the pulmonary pathology of PPH is very similar to that of primary pulmonary hypertension.<ref> Schraufnagel DE, Kay JM. Structural and pathologic changes in lung vasculature in chronic liver disease. Clin Chest Med 1996; 17: 1</ref> The muscular pulmonary arteries fibrose and hypertrophy while the smaller arteries lose smooth muscle cells and their elastic intima. One study found at autopsy significant thickening of pulmonary arteries in cirrhotic patients.<ref> Matsubara O, Nakamura T, Uehara T, Kasuga T. Histometrical investigations of the pulmonary artery in severe hepatic disease. J Pathol 1984; 143: 31. </ref> This thickening and remodeling forms a positive feedback loop that serves to increase PAP and induce right heart hypertrophy.
Finally, the pulmonary pathology of PPH is very similar to that of primary pulmonary hypertension.<ref> Schraufnagel DE, Kay JM. Structural and pathologic changes in lung vasculature in chronic liver disease. Clin Chest Med 1996; 17: 1</ref> The muscular pulmonary arteries fibrose and hypertrophy while the smaller arteries lose smooth muscle cells and their elastic intima. One study found at autopsy significant thickening of pulmonary arteries in cirrhotic patients.<ref> Matsubara O, Nakamura T, Uehara T, Kasuga T. Histometrical investigations of the pulmonary artery in severe hepatic disease. J Pathol 1984; 143: 31. </ref> This thickening and remodeling forms a positive feedback loop that serves to increase PAP and induce right heart hypertrophy.


==Treatment ==
==Treatment==


In general, the treatment of PPH is derived from the pulmonary hypertension experience and literature. Though, the best treatment available is the combination of medical therapy and orthotopic liver transplantation. This review will focus on medical therapy.
In general, the treatment of PPH is derived from the pulmonary hypertension experience and literature. Though, the best treatment available is the combination of medical therapy and orthotopic liver transplantation. This review will focus on medical therapy.
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The newest generation in PPH pharmacy shows great promise. Bosentan is a nonspecific endothelin-receptor antagonist capable of neutralizing the most identifiable cirrhosis associated vasoconstrictor,<ref> Rubin et al. Bosentan therapy for Pulmonary arterial hypertension. N Engl J Med 2002;346:896-903</ref> safely and efficaciously improving oxygenation and PVR,<ref> Hoeper et al. Bosentan therapy for portopulmonary hypertension. Eur Respir J. 2005;25:502-8</ref><ref> Kuntzen. Use of a mixed endothelin receptor antagonist in portopulmonary hypertension: a safe and effective therapy? Gastroenterology. 2005;128:164-8</ref> especially in conjunction with sildenafil. <ref> Wilkins et al.Sildenafil versus Endothelin Receptor Antagonist for Pulmonary Hypertension (SERAPH) study. Am J Respir Crit Care Med. 2005;171:1292-7</ref> Finally, where the high pressures and pulmonary tree irritations of PPH cause a medial thickening of the vessels (smooth muscle migration and hyperplasia), one can remove the cause –control the pressure, transplant the liver – yet those morphological changes persist, sometimes necessitating lung transplantation. Imantib, designed to treat chronic myeloid leukemia, has been shown to reverse the pulmonary remodeling associated with PPH. <ref> Schermuly et al. Reversal of experimental pulmonary hypertension by PDGF inhibition. J. Clin. Invest. 115:2811-2821 (2005).</ref><ref> Ghofrani et al. Imatinib for the Treatment of Pulmonary Arterial Hypertension. N Engl J Med 2005; 353:1412-1413</ref><ref name=Tapper>
The newest generation in PPH pharmacy shows great promise. Bosentan is a nonspecific endothelin-receptor antagonist capable of neutralizing the most identifiable cirrhosis associated vasoconstrictor,<ref> Rubin et al. Bosentan therapy for Pulmonary arterial hypertension. N Engl J Med 2002;346:896-903</ref> safely and efficaciously improving oxygenation and PVR,<ref> Hoeper et al. Bosentan therapy for portopulmonary hypertension. Eur Respir J. 2005;25:502-8</ref><ref> Kuntzen. Use of a mixed endothelin receptor antagonist in portopulmonary hypertension: a safe and effective therapy? Gastroenterology. 2005;128:164-8</ref> especially in conjunction with sildenafil. <ref> Wilkins et al.Sildenafil versus Endothelin Receptor Antagonist for Pulmonary Hypertension (SERAPH) study. Am J Respir Crit Care Med. 2005;171:1292-7</ref> Finally, where the high pressures and pulmonary tree irritations of PPH cause a medial thickening of the vessels (smooth muscle migration and hyperplasia), one can remove the cause –control the pressure, transplant the liver – yet those morphological changes persist, sometimes necessitating lung transplantation. Imantib, designed to treat chronic myeloid leukemia, has been shown to reverse the pulmonary remodeling associated with PPH. <ref> Schermuly et al. Reversal of experimental pulmonary hypertension by PDGF inhibition. J. Clin. Invest. 115:2811-2821 (2005).</ref><ref> Ghofrani et al. Imatinib for the Treatment of Pulmonary Arterial Hypertension. N Engl J Med 2005; 353:1412-1413</ref><ref name=Tapper>


==External links==
<references/>
* [http://www.phassociation.org/Medical/Advances_in_PH/Summer_2004/porto.asp Portopulmonary Hypertension: Understanding Pulmonary Hypertension in the Setting of Liver Disease]


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Introduction and Overview

Portopulmonary hypertension (PPH) is defined by the coexistence of portal and pulmonary hypertension. PPH is a serious complication of liver disease, present in 0.25 to 4% of all patients suffering from cirrhosis. Once an absolute contraindication to liver transplantation, it is no longer, thanks to rapid advances in the treatment of this condition.[1] Today, PPH is comorbid in 4-6% of those referred for a liver transplant.[2][3]

Clinical Characteristics

PPH presents roughly equally in male and female cirrhotics; 71% female in an American series and 57% male in a larger French series.[4][5] Typically, patients present in their fifth decade, aged 49 +/- 11 years in one series.[4][6] On average, PPH is diagnosed 4-7 years after the patient is diagnosed with portal hypertension[7] and in roughly 65% of cases, the diagnosis is actually made at the time of invasive hemodynamic monitoring following anesthesia induction prior to liver transplantation.[8]

Once patients are symptomatic, they present with right heart dysfunction secondary to pulmonary hypertension and its consequent dyspnea, fatigue, chest pain and syncope.[9] Patients tend to have a poor cardiac status, with 60% having stage III-IV NYHA heart failure. while in another it was equally distributed throughout the diagnoses.[3].

Natural History

Following diagnosis, mean survival of patients with PPH is 15 months.[10] Indeed, the survival of those with cirrhosis is sharply curtailed by PPH but can be significantly extended by both medical therapy and liver transplantation, provided they remain eligible.

Given the fear that those PPH patients with high pulmonary artery pressures (PAP) will suffer right heart failure following the stress of post-transplant reperfusion or in the immediate perioperative period, patients are typically risk-stratified based on mean PAP. The operation-related mortality rate is greater than 50% when pre-operative mean PAP values lie between 35 and 50 mm Hg; if mean PAP exceeds 40-45, transplantation is associated with a perioperative mortality of 70-80% (in those cases without preoperative treatment).[11][12] Patients, then, are considered to have a high risk of perioperative death once their mean PAP exceeds 35 mm_Hg.[13] The focus on mean PAP values as a chief prognostic index has achieved an apparent consensus according to a recent multicenter study: 45% of patients with PPH were denied OLT candidacy based on the degree of their pulmonary hypertension, while no patient with mPAP < 35 mm_Hg was denied (Between those accepted and those denied, there was no significant difference in cardiac output or right atrial pressure).[14]

Survival is best inferred from institutional experience. At one instituation, without treatment, 1-year survival was 46% and 5-year survival was 14%. With medical therapy, 1-year survival was 88% and 5-year survival was 55%. Survival at 5 years with medical therapy followed by liver transplantation was 67%.[15] At another institution, of the 67 patients with PPH from 1652 total cirrhotics evaluated for transplant, half (34) were placed on the waiting list. Of these, 16 (48%) were transplanted at a time when 25% of all patients who underwent full evaluation received new livers, meaning the diagnosis of PPH made a patient twice as likely to be transplanted, once on the waiting list. Of those listed for transplant with PPH, 11 (33%) were eventually removed because of PPH, and 5 (15%) died on the waitlist. Of the 16 transplanted patients with PPH, 11 (69%) survived for more than a year after transplant, at a time when overall one-year survival in that center was 86.4%. The three year post-transplant survival for patients with PPH was 62.5% when it was 81.02% overall.[16]

Diagnosis

As above, the diagnosis of portopulmonary hypertension is based on hemodynamic criteria:

  1. . Portal hypertension and/or liver disease (clinical diagnosis—ascites/varices/splenomegaly)
  2. . Mean pulmonary artery pressure—MPAP > 25 mmHg at rest
  3. . Pulmonary vascular resistance—PVR > 240 dynes s cm−5
  4. . Pulmonary artery occlusion pressure— PAOP < 15mmHg or transpulmonary gradient—TPG > 12 mmHg where TPG = MPAP − PAOP.[15]

The diagnosis is usually first suggested by a transthoracic echocardiogram, part of the standard pre-transplantation work-up. Echocardiogram estimated pulmonary artery systolic pressures of 40 to 50 mm Hg are used as a screening cutoff for PPH diagnosis,[17] with a sensitivity of 100% and a specificity as high as 96%.

The measurement of PAP by echocardiogram is made using a simplified Bernoulli equation. The speed of a fluid through a narrow orifice is proportional to the difference of the pressures on either side – in this case, the right atrium and ventricle. Therefore the velocity of tricuspid regurgitation (which occurs at a measurable but normal level in the vast majority of humans) is squared, multiplied by four and added to the estimated right atrial pressure. Right atrial pressure is a derivative value, found by examining the inferior vena cava in the following sense: If, on inspiration, it should collapse roughly 50%, then the right atrial pressure is roughly 5mm_Hg; some collapse gives a right atrial pressure of 10 mm_Hg and no collapse, pressure of 15 mm_Hg. High cardiac index and pulmonary capillary wedge pressures, however, may lead to false positives by this standard. By one institution’s evaluation, the correlation (simple linear regression) between estimated systolic PAP and directly measured PAP was poor, 0.49.[18] For these reasons, right heart catheterization is needed to confirm the diagnosis.<Colle>

Pathophysiology

PPH pathology arises both from the humoral consequences of cirrhosis and the mechanical obstruction of the portal vein.[19] A central paradigm holds responsible an excess local pulmonary production of vasoconstrictors that occurs while vasodilatation predominates systemically[20]. Key here are imbalances between vasodilating and vasoconstricting molecules; endogenous prostacyclin and thromboxane (from Kuppfer Cells) [21][22] or nitrous oxide (NO) and endothelin-1 (ET-1).[23] ET-1 is the most potent vasoconstrictor under investigation[24] and it has been found to be increased in both cirrhosis[25] and pulmonary hypertension. [26] Endothelin-1 has two receptors in the pulmonary arterial tree, ET-A which mediates vasoconstriction and ET-B which mediates vasodilation. Rat models have shown decreased ET-B receptor expression in pulmonary arteries of cirrhotic and portal hypertensive animals, leading to a predominant vasoconstricting response to endothelin-1. [27]

In portal hypertension, blood will shunt from portal to systemic circulation, bypassing the liver. This leaves unmetabolized potentially toxic or vasoconstricting substances to reach and attack the pulmonary circulation. Serotonin, normally metabolized by the liver, is returned to the lung instead where it mediates a smooth muscle hyperplasia and hypertrophy. [28].Moreover, a key pathogenic factor in the decline in status of PPH patients related to this shunting is the cirrhotic cardiomyopathy with myocardial thickening and diastolic dysfunction.

Finally, the pulmonary pathology of PPH is very similar to that of primary pulmonary hypertension.[29] The muscular pulmonary arteries fibrose and hypertrophy while the smaller arteries lose smooth muscle cells and their elastic intima. One study found at autopsy significant thickening of pulmonary arteries in cirrhotic patients.[30] This thickening and remodeling forms a positive feedback loop that serves to increase PAP and induce right heart hypertrophy.

Treatment

In general, the treatment of PPH is derived from the pulmonary hypertension experience and literature. Though, the best treatment available is the combination of medical therapy and orthotopic liver transplantation. This review will focus on medical therapy.

The ideal treatment for PPH management is that which can achieve pulmonary vasodilatation and smooth muscle relaxation without exacerbating systemic hypotension. Most of the therapies for PPH have been adapted from the primary pulmonary hypertension literature. Calcium channel blockers, b-blockers and nitrates have all been used – but the most potent and widely used aids are prostaglandin (and prostacyclin) analogs, phosphodiesterase inhibitors, nitrous oxide and, most recently, endothelin receptor antagonists and agents capable of reversing the remodeling of pulmonary vasculature.

Inhaled nitrous oxide vasodilates by increasing intracellular cGMP in endothelial cells. It decreases pulmonary arterial pressure (PAP) and pulmonary vascular resistance (PVR) without affecting systemic artery pressure because it is rapidly inactivated by hemoglobin,[31] and improves oxygenation by redistributing pulmonary blood flow to ventilated areas of lung.[32] Inhaled nitrous oxide has been used successfully to bridge patients through liver transplantation and the immediate perioperative period, but there are two significant drawbacks: it requires intubation and cannot be used for long periods of time due to methemoglobinemia.

Prostaglandin PGE1 (Alprostadil) binds G-protein linked cell surface receptors that activate adenylate cyclase to relax vascular smooth muscle. [33] Prostacyclin – PGI2, an arachadonic acid derived lipid mediator (Epoprostenol, Flolan, Treprostenil) – is a vasodilator and, at the same time, the most potent inhibitor of platelet aggregation.[34] More importantly, PGI2 (and not nitrous oxide) is also associated with an improvement in splanchnic perfusion and oxygenation. [35] Epoprostenol and ilioprost (a more stable, longer acting variation[36]) can and does successfully bridge for patients to transplant.[37] Epoprostenol therapy can lower PAP by 29-46% and PVR by 21-71%.,[38] Ilioprost shows no evidence of generating tolerance, increases cardiac output and improves gas exchange while lowering PAP and PVR.[39] A subset of patients does not respond to any therapy, likely having fixed vascular anatomic changes.

Phosphodiesterase inhibitors (PDE-i) have been employed with excellent results. Sildenafil (Viagra) increases intracellular cGMP by inhibiting PDE-type 5, which is abundant in pulmonary artery smooth muscle cells.[40]. It has been shown to reduce mean PAP by as much as 50%,[41] though it prolongs bleeding time by inhibiting collagen-induced platelet aggregation.[42] Another drug, Milrinone, a Type 3 PDE-i increases vascular smooth muscle adenosine-3,5-cyclic monophosphate concentrations to cause selective pulmonary vasodilation.[43]Also, by causing the buildup of cAMP in the myocardium, Milrinone increases contractile force, heart rate and the extent of relaxation.

The newest generation in PPH pharmacy shows great promise. Bosentan is a nonspecific endothelin-receptor antagonist capable of neutralizing the most identifiable cirrhosis associated vasoconstrictor,[44] safely and efficaciously improving oxygenation and PVR,[45][46] especially in conjunction with sildenafil. [47] Finally, where the high pressures and pulmonary tree irritations of PPH cause a medial thickening of the vessels (smooth muscle migration and hyperplasia), one can remove the cause –control the pressure, transplant the liver – yet those morphological changes persist, sometimes necessitating lung transplantation. Imantib, designed to treat chronic myeloid leukemia, has been shown to reverse the pulmonary remodeling associated with PPH. [48][49]<ref name=Tapper>

  1. ↑ Kuo PC et al. Portopulmonary Hypertension and the Liver Transplant Candidate. Transplantation 1999;67(8):1087-1093
  2. ↑ Torregosa et al. Role of Doppler echos in the assessment of PPHTN in liver transplant candidates. Transplantation 2001;71:572-574
  3. ↑ 3.0 3.1 Tapper EB, Knowles D, Heffron T, Lawrence EC, Csete M. Portopulmonary hypertension: imatinib as a novel treatment and the Emory experience with this condition. Transplant Proc. 2009 Jun;41(5):1969-71.
  4. ↑ 4.0 4.1 Le Pavec et al. Portopulmonary Hypertension: Survival and Prognostic Factors. Am J Respir Crit Care Med Vol 178. pp 637–643, 2008
  5. ↑ Kawut SM et al. Clinical Risk Factors for Portopulmonary Hypertension. Hepatology 2008;48
  6. ↑ Bejaminov et al. Portopulmonary hypertension in decompensated cirrhosis with refractory ascites. Gut 2003; 52:1355-1362
  7. ↑ Hadengue et al. PH complicating portal hypertension: prevalence and relation to splanchnic hemodynamics. Gastroenterology 1991;100:520-528
  8. ↑ Hadengue et al. Pulmonary hypertension complicating portal hypertension: prevalence and relation to splanchnic hemodynamics. Gastroenterology 1991;100:520-528
  9. ↑ Martinex-Palli et al. Liver Transplant in High Risk Patients. Transplant Proceedings 2005;37:3861-3864
  10. ↑ Ramsay et al. Severed PHTN in liver Transplant candidates. Liver Transplant Surg 1997 3:494
  11. ↑ Csete M. Intraoperative management of liver transplant patients with pulmonary hypertension. Liver Transplant Surg 1997:3:454-55
  12. ↑ Kim et al. Accuracy of Doppler Echos in the assessment of PTHN in liver transplant candidates. Liver Transplant. 6:453, 2000
  13. ↑ Krowka et al. Pulm Hemodynamics and perioperative cardiopulmonary-related mortality in patients with portopulmonary hypertension undergoing liver Transplant. Liver Transpl 2000;6:443-450
  14. ↑ Krowka et al. Hepatopulmonary syndrome and portopulmonary hypertension: A report of the multicenter Liver transplant database. Liver Transplant. 2004;10:174-182
  15. ↑ 15.0 15.1 Swanson KL et al. Survival in Portopulmonary Hypertension: Mayo Clinic Experience Categorized by Treatment Subgroups. Am J Transpl 2008; 8: 2445–2453
  16. ↑ Tapper EB, Knowles D, Heffron T, Lawrence EC, Csete M. Portopulmonary hypertension: imatinib as a novel treatment and the Emory experience with this condition. Transplant Proc. 2009 Jun;41(5):1969-71.
  17. ↑ Torregosa et al. Role of Doppler echos in the assessment of PPHTN in liver transplant candidates. Transplantation 2001;71:572-574
  18. ↑ Tapper EB, unpublished data
  19. ↑ Budhiraja et al. Portopulmonary Hypertension: A Tale of Two Circulations. Chest. 2003;123:562-576.
  20. ↑ Moller et al. Cardiopulmonary complications in chronic liver disease. World J Gastroenterol 2006;12;526-538
  21. ↑ Christman et al. An imbalance between the excretion of thromboxane and prostacyclin metabolites in pulmonary hypertension. N Engl J Med 1992;327:1774-78
  22. ↑ Maruyama et al. Thromboxane-dependent portopulmonary hypertension. Am J Med. 2005;118:93-94
  23. ↑ Bejaminov et al. Portopulmonary hypertension in decompensated cirrhosis with refractory ascites. Gut 2003; 52:1355-1362
  24. ↑ Giaid A. Nitrous oxide and endothelin-1 in pulmonary hypertension. Chest. 1998;114;208-12S
  25. ↑ Gerbes. ET1 and 3 plasma conc in patients with cirrhosis: role of splanchnic and renal passage and liver function. Hepatology 1995;21:735-9
  26. ↑ Stewart. Increase plasma endothelin-1 in pulmonary hypertension: marker or mediator of disease? Ann Intern Med 1991;114:464-9
  27. ↑ Luo et al. Increase pulmonary vascular ETb receptor expression and responsiveness to ET-1 in cirrhotive and portal hypertensive rats. J Hepatol 2003;38:556-63
  28. ↑ Egermayer et al. Role of serotonin in the pathogenesis of acute and chronic pulmonary hypertension. Thorax 1999;54:161-168
  29. ↑ Schraufnagel DE, Kay JM. Structural and pathologic changes in lung vasculature in chronic liver disease. Clin Chest Med 1996; 17: 1
  30. ↑ Matsubara O, Nakamura T, Uehara T, Kasuga T. Histometrical investigations of the pulmonary artery in severe hepatic disease. J Pathol 1984; 143: 31.
  31. ↑ Steudel et al. Inhaled nitrous oxide: Basic biology and clinical applications. Anesthesiology 1999;91:1090-121
  32. ↑ Lowson. Inhaled alternative to nitrous oxide. Anesthesiology 2002;96:1504-13
  33. ↑ Kerins et al. Prostacyclin and Prostaglandin E1: Molecular mechanisms and therapeutic utility. Prog Hemostasis Thrombosis 1991;10:307-37
  34. ↑ Vane et al. Pharmacodynamic profile of prostacyclin. Am J Cardiol 1995;75:3A-10A
  35. ↑ Eichelbronner et al. Aerosolized prostacyclin and INO in septic shock: Different effects on splanchnic oxygenation. Intensive Care Med 1996;22:880-7
  36. ↑ Minder et al. Intravenous ilioprost bridging to orthotopic liver transplant in portopulmonary hypertension. Eur Respir J 2004;24:703-707
  37. ↑ et al. Successful use of chronic epoprostenol as a bridge to liver transplant in severe PPHTN. Transplant 1998 4:457
  38. ↑ Kuo PC, Johnson LB, Plotkin JS, Howell CD, Bartlett ST, Rubin LJ. Continuous intravenous infusion of epoprostenol for the treatment of portopulmonary hypertension. Transplantation 1997; 63: 604
  39. ↑ Lowson. Inhaled alternative to nitrous oxide. Anesthesiology 2002;96:1504-13
  40. ↑ Evangelos D et al. Long-term treatment with oral sildenafil is safe and improves functional capacity and hemodynamics in patients with pulmonary arterial hypertension. Circulation 2003;108:2066-2069
  41. ↑ Makisalo et al. Sildenafil for portopulmonary hypertension in a patient undergoing liver Transplant. Liver Transplant. 2004;10:945-950
  42. ↑ Berkels et al. Modulation of human platelet aggregation by the phosphodiesterase type 5 inhibitor sildenafil. J Cardiovasc Pharmacolo 2001;37:413-421
  43. ↑ Haraldsson et al. The additive pulmonary vasodilatory effect of inhaled prostacyclin and inhaled milrinone in postcardiac surgical patients with pulmonary hypertension. Aesth Analg 2001;93:1439-45
  44. ↑ Rubin et al. Bosentan therapy for Pulmonary arterial hypertension. N Engl J Med 2002;346:896-903
  45. ↑ Hoeper et al. Bosentan therapy for portopulmonary hypertension. Eur Respir J. 2005;25:502-8
  46. ↑ Kuntzen. Use of a mixed endothelin receptor antagonist in portopulmonary hypertension: a safe and effective therapy? Gastroenterology. 2005;128:164-8
  47. ↑ Wilkins et al.Sildenafil versus Endothelin Receptor Antagonist for Pulmonary Hypertension (SERAPH) study. Am J Respir Crit Care Med. 2005;171:1292-7
  48. ↑ Schermuly et al. Reversal of experimental pulmonary hypertension by PDGF inhibition. J. Clin. Invest. 115:2811-2821 (2005).
  49. ↑ Ghofrani et al. Imatinib for the Treatment of Pulmonary Arterial Hypertension. N Engl J Med 2005; 353:1412-1413

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