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Portopulmonary hypertension (POPH) is a form of group 1 pulmonary arterial hypertension. When treating patients with POPH, baseline assessment is necessary so that response to therapy can be measured as the change from baseline. Patients should undergo echocardiography and right heart catheterization, and their exercise capacity and NYHA functional class should be determined. Patients with POPH should be considered for treatment if they are NYHA functional class II or above and/or their mean pulmonary artery pressure (MPAP) is greater than 35 mm Hg in transplant candidates. The goal in the treatment and management of POPH is to improve pulmonary hemodynamics by reducing the obstruction to pulmonary arterial flow and to preserve right ventricular function (Table). This article, the second in a 2-part review of POPH in patients with liver disease, reviews the role of medical therapy and liver transplantation in treatment. Evaluation and diagnosis of POPH are discussed in a separate article.
Medical Therapy
Prostanoids
Although prostacyclin and prostaglandin analogs entered routine clinical practice for POPH in the 1990s, reports of investigational use date back to the 1980s. Prostanoids are potent vasodilators with antiplatelet aggregation and antiproliferative properties. Prostacyclin synthase is reduced in patients with PAH, resulting in decreased concentration of prostacyclin with vasoconstriction and proliferative changes in the pulmonary vasculature.1
Epoprostenol
Epoprostenol is also known as synthetic prostaglandin I2 or prostacyclin. It was the first therapy approved for the treatment of PAH in 1995 by the US Food and Drug Administration (FDA) as a continuous intravenous infusion.2,3 It also inhibits platelet aggregation and may help modulate pulmonary vascular remodeling.4,5 Epoprostenol is derived from the metabolism of arachidonic acid and is a potent pulmonary and systemic vasodilator. One study reported an immediate 11.8% decrease in MPAP, 24% decrease in pulmonary vascular resistance (PVR) and 28% drop in systemic vascular resistance (SVR) during an epoprostenol infusion.6 The authors reported that epoprostenol was a more potent vasodilator than nitric oxide and may have a role in predicting the reversibility of POPH. In a case series of 33 patients with secondary pulmonary hypertension (including 7 patients with POPH) treated with continuous intravenous prostacyclin for approximately 1 year, exercise tolerance, NYHA functional class, and pulmonary hemodynamics improved in each patient compared to baseline.7 Krowka et al studied 14 patients with moderate to severe POPH treated with intravenous epoprostenol.8 No significant side effects were noted and treatment resulted in significant improvements in PVR, MPAP, and cardiac output. In 2007, Fix et al published a large retrospective cohort of patients with moderate to severe POPH.9 Nineteen patients treated with epoprostenol were compared to 17 patients with no treatment. After a median treatment period of 15.4 months, the epoprostenol group showed significant improvement in MPAP, PVR and cardiac output, but survival did not differ between the 2 groups.
Epoprostenol has often been considered a bridge to transplant in patients with POPH. Sussman et al described 8 consecutive patients with POPH who were treated with intravenous epoprostenol (2 to 8 ng/kg/min dose).10 Liver transplant was considered in 7 of the 8 patients when MPAP decreased to less than 35 mm Hg. Six patients were eventually listed for liver transplant, but 2 died waiting on the list. Long-term outcomes in the group of transplanted recipients were excellent. They remained alive and well at least 9 to 18 months post-transplant, and half did not require long-term vasodilator therapy post-orthotopic liver transplant. Similarly, Ashfaq et al published their data on 16 patients with moderate-to-severe POPH who were treated with vasodilator therapy.11 MPAP decreased to acceptable levels in 75% of the treated patients, and 11 went on to liver transplantation. Rates of 1- and 5-year survival in the transplanted patients were 91% and 67% respectively. None of the patients who failed vasodilator therapy survived.
Epoprostenol has a short half-life (3 to 5 minutes) and requires continuous infusion through central access via an infusion pump. Aseptic technique must be maintained to avoid blood stream infections. Pump failure or loss of vascular access can result in rebound pulmonary vasoconstriction that can be life-threatening and requires immediate attention. Side effects associated with epoprostenol include flushing, headache, nausea/vomiting, bradycardia, chest pain, jaw pain, diarrhea, and musculoskeletal pain.
Patients on epoprostenol should be monitored for prostanoid overdose. In the case of patients with chronic liver disease, epoprostenol increases systemic vasodilation in patients with already low systemic vascular tone. As a result, cardiac output may increase to the point of high cardiac output failure. MPAP will remain elevated secondary to high cardiac output rather than high PVR. In these patients, right heart catheterization will show an elevated MPAP in the setting of normal to low PVR/transpulmonary gradient (TPG) values. Lowering the epoprostenol dose will successfully reduce both cardiac output and MPAP.
Treprostinil
Treprostinil is a prostacyclin analog that is available in intravenous, inhalational, and subcutaneous form, although subcutaneous dosing may be limited by pain. Sakai et al published a small case series of 3 patients with PAH and end-stage liver disease treated with intravenous treprostinil.12 Pulmonary hemodynamics improved in all patients, and 2 patients went on to an uneventful liver transplantation. More than 10 years later, data were published on 255 patients with PAH on therapy with bosentan or sildenafil randomized to additional inhaled treprostinil.13 Treprostinil proved to be safe and well tolerated, with improvement in quality of life measures but no improvement in other secondary endpoints.
Iloprost
Inhaled iloprost is another prostacyclin that has a short therapeutic half-life of 20 to 30 minutes and requires frequent administration (6 to 9 times daily). In study in which patients with severe POPH were treated for up to 3 years with inhaled iloprost,14 survival rates at 1, 2, and 3 years were 77%, 62%, and 46%, respectively. A second study published in 2010 was designed to assess the acute effects of inhaled iloprost on pulmonary hemodynamics and evaluate the clinical outcome after 12 months of treatment.15 Iloprost was found to rapidly reduce pulmonary arterial pressure and PVR. In the long-term evaluation, inhaled iloprost increased the 6-minute walk distance (6MWD) and functional class, but no change was noted in the systolic pulmonary artery pressure. The authors concluded that iloprost might provide symptomatic improvement and improvement in exercise capacity.
Selexipag
Selexipag is an oral selective IP prostacyclin receptor agonist that is structurally distinct from other prostacyclins.16 In a phase 3 randomized double blind clinical trial, PAH patients treated with selexipag had lower composite of death or complication of PAH to the end of the study period.17 This effect was consistent across all dose ranges, but POPH patients were excluded from this study. Safety and efficacy of selexipag has not been evaluated in POPH patients.
Endothelin Receptor Antagonists
Endothelin receptor antagonists block the production of endothelin-1 (ET-1), a potent vasoconstrictor and smooth muscle mitogen that may contribute to the development of PAH. Three different receptors have been described: endothelin A, endothelin B, and endothelin B2. Elevated ET-1 levels have been reported in patients with chronic liver disease and may originate from hepatosplanchnic circulation.18
Bosentan
Bosentan is an oral, nonspecific, ET-1A and ET-1B receptor antagonist. Initial use of bosentan in patients with POPH was limited because of concern for hepatotoxicity. Approximately 10% of patients on bosentan were reported to have mild hepatic side effects in the form of elevated aminotransferases, but severe injury has been reported.19 One of the first clinical experiences of bosentan in patients with POPH was published in 2005. Hoeper et al followed 11 patients with Child A cirrhosis and severe POPH.20 All patients included were in NYHA functional class III or IV and were treated with bosentan for over 1 year. Exercise capacity and symptoms improved in all treated patients. The medication was tolerated well and there was no evidence of drug-induced liver injury. A single case report showed the effectiveness of bosentan in a 43-year-old man with alcohol-related liver disease (Child-Pugh A) and right ventricular enlargement and dysfunction secondary to POPH.21 Pulmonary arterial pressure decreased, exercise capacity increased, and improvement was maintained over 2 years.
In a group of 31 patients with Child A or B cirrhosis and severe POPH, bosentan had significantly better effects than inhaled iloprost on exercise capacity, hemodynamics, and survival.14 One, 2, and 3-year survival rates in the bosentan group were 94%, 89%, and 89% (compared to 77%, 62%, and 46% in the iloprost group). Both drugs were considered safe with no reported hepatotoxicity. In 2013, Savale et al published data on 34 patients with POPH, Child-Pugh A and/or B who were treated with bosentan for a median of 43 months.22 The authors reported significant improvements in hemodynamics, NYHA functional class, and 6WMD. Event-free survival rates at 1, 2, and 3 years were 82%, 63%, and 47%, respectively.
Ambrisentan
Ambrisentan is a highly selective ET-1A receptor antagonist with once daily dosing and a lower risk of hepatotoxicity compared to bosentan. Fourteen patients with moderate to severe POPH treated with ambrisentan in 4 German hospitals were retrospectively analyzed.23 Median follow-up was 16 months, and the study demonstrated significant improvement in exercise capacity and clinical symptoms without significant change in liver function tests. Cartin-Ceba et al published their experience of 13 patients with moderate to severe POPH treated with ambrisentan monotherapy.24 Patients were followed for a median of 613 days and on treatment for a median time of 390 days. Significant improvements were shown in pulmonary arterial pressure and PVR without adverse effect on hepatic function. Over 270 patients with PAH (6% with POPH) received ambrisentan from March 2009 through June 2013 at a large United Kingdom portal hypertension referral center.25 Discontinuation due to side effects was higher than previously reported. Discontinuation due to abnormal transaminases was uncommon.
Macitentan
Macitentan is a dual endothelin-receptor antagonist developed by modifying the structure of bosentan to increase efficacy and safety. The SERAPHIN trial compared oral macitentan to placebo in 250 patients with moderate to severe PAH, some of whom were also on a stable dose of oral or inhaled therapy for PAH.26 Over a 2-year period, patients treated with macitentan were less likely to have progression of their disease or die on therapy (38% and 31% versus 46%), regardless of if they were receiving additional oral therapy and more likely to have improvement of their exercise capacity and WHO functional class. Nasopharyngitis and significant anemia were more common in the macitentan group, but there was no difference in the rate of liver function test abnormalities compared to placebo. Trials with macitentan are currently ongoing in patients with POPH.
Phosphodiesterase-5 Inhibitors
Cyclic guanosine monophosphate (cGMP) is the mediator of nitric oxide–induced vasodilation. Phosphodiesterase-5 (PDE-5) inhibitors prolong the vasodilatory effects of cyclic guanosine monophosphate by preventing its hydrolysis, thereby reducing the pulmonary arterial pressure.
Sildenafil
Sildenafil is the most widely accepted PDE-5 inhibitor for POPH. Fourteen patients with moderate to severe POPH were treated with sildenafil (50 mg 3 times per day) in an observational study published by Reichenberger et al in 2006.27 Eight patients were newly started on sildenafil, whereas sildenafil was added to inhaled prostanoids in the remaining 6x patients. Sildenafil significantly decreased 66MWD, MPAP, PVR, and cardiac index alone or in combination with inhaled prostanoids.
Sildenafil has also been used as a bridge to transplant in liver transplant candidates with POPH. Ten patients with POPH treated with sildenafil monotherapy were followed for a 21±16 months.28 Patients improved symptomatically and increased their 6MWD at 1 year by 30 meters or more. Three patients became transplant eligible and another 3 patients were stable, without progression of their liver disease or POPH. Four patients were not considered transplant candidates, 2 because of refractory POPH and 2 for other comorbidities. The authors concluded that sildenafil monotherapy could stabilize or improve pulmonary hemodynamics in patients with POPH and eventually lead to liver transplantation. Gough et al took a similar look at 9 patients with POPH treated with sildenafil.29 All patients had initial and follow-up right heart catheterizations within a period of 3 years. Mean PVR improved in all patients, decreasing from 575 to 375 dynes/s/cm–5. MPAP decreased to ≤ 35 mmHg in 4 patients, 1 of whom went on to receive a liver transplant. Overall sildenafil improved pulmonary hemodynamics in this small cohort of POPH patients.
Tadalafil
Tadalafil is another oral PDE-5 inhibitor but with a longer half-life than sildenafil. Unlike sildenafil, which requires 3 times daily dosing, tadalafil requires once daily administration. A few case reports have demonstrated tadalafil’s effectiveness for POPH in combination with other medical therapy (eg, sildenafil, ambrisentan).30,31
Guanylate Cyclase Stimulator
Riociguat
Riociguat is a first-in-class activator of soluble form of guanylate cyclase that increases levels of cyclic GMP. Two randomized clinical trials, PATENT, a study in PAH patients, and CHEST, a study in patients with chronic thromboembolic pulmonary hypertension showed improvement in 6MWD at 12 weeks (PATENT) or 16 weeks (CHEST), with improvement in secondary endpoints such as PVR, N-terminal pro b-type natriuretic peptide and WHO functional class.32,33 Riociguat may have potential advantages in patients with POPH given that it has a favorable liver safety profile. A subgroup analysis of patients enrolled in the PATENT study showed that 13 had POPH and 11 were randomized to receive riociguat 2.5 mg 3 times daily dose and 2 received placebo.34 Riociguat was well tolerated and improved 6MWD that was maintained over 2 years in the open label extension.
Medications to Avoid
Nonselective beta-blockers are commonly recommended in patients with portal hypertension to help prevent variceal hemorrhage. However, in patients with POPH, beta-blockers have been shown to decrease exercise capacity and worsen pulmonary hemodynamics. A study of 10 patients with moderate to severe POPH who were receiving beta-blockers for variceal bleeding prophylaxis showed that 6MWD improved in almost all of the patients, cardiac output increased by 28%, and PVR decreased by 19% when beta-blockers were discontinued.35 The authors concluded that the use of beta-blockers should be avoided in this patient population.
Calcium channel blockers should not be used in patients with POPH because they can cause significant hypotension due to systemic vasodilatation and decreased right ventricular filling. Patients with portal hypertension and chronic liver disease commonly have low systemic vascular resistance and are particularly susceptible to the deleterious effects of calcium channel blockers.
Transplantation
Liver transplantation is a potential cure for POPH and its role in POPH has evolved over the past 2 decades. In 1997, Ramsay et al published their review of 1205 consecutive liver transplants at Baylor University Medical Center (BUMC) in Texas.36 The incidence of POPH in this group was 8.5%, with the majority of patients having mild POPH. Liver transplant outcomes were not affected by mild and moderate pulmonary hypertension. However, patients with severe POPH (n = 7, systolic pulmonary artery pressure > 60 mm Hg) had a mortality rate of 42% at 9 months post-transplantation and 71% at 36 months post-transplant. The surviving patients continued to deteriorate with progressive right heart failure and no improvement in POPH.
To understand the effect of liver transplantation on POPH, one must understand the hemodynamic changes that occur with POPH and during liver transplant. The right ventricle is able to manage the same volume as the left ventricle under normal circumstances, but is unable to pump against a significant pressure gradient.37 In the setting of POPH, right ventricular hypertrophy occurs and RV output remains stable for some time. With time, pulmonary artery pressure increases secondary to pulmonary arteriolar vasoconstriction, intimal thickening, and progressive occlusion of the pulmonary vascular bed. Right ventricular failure may occur as a result. Cardiac output increases significantly at the time of reperfusion during liver transplant (up to 3-fold in 15 minutes),38 and in the setting of a noncompliant vascular bed, the patient is at risk for right heart failure. This is the likely explanation to such high perioperative mortality rates in patients with uncontrolled POPH. Failure to decrease MPAP to less than 50 mm Hg is considered a complete contraindication to liver transplant at most institutions. Many transplant centers will list patients for liver transplant if MPAP can be decreased to less than 35 mm Hg and PVR < 400 dynes/s/cm–5. These parameters are thought to represent an adequate right ventricular reserve and a compliant pulmonary vascular bed.37 However, even with good pressure control, the anesthesiology and critical care teams must be prepared to deal with acute right heart failure peri-operatively. Intraoperative transesophageal echocardiography has been recommended to closely follow right ventricular function.38 Inhaled or intravenous dilators are the most effective agents in the event of a pulmonary hypertensive crisis.
Review of Outcomes
A retrospective review evaluated 43 patients with untreated POPH who underwent attempted liver transplantation.39 Data were collected from 18 peer-reviewed studies and 7 patients at the authors’ institution. Overall mortality was 35% (15 patients), with almost all of the deaths secondary to cardiac dysfunction. Two deaths occurred intraoperatively and 8 deaths occurred during the transplant hospitalization. The transplant could not be successfully completed in 4 of the patients. MPAP > 50 mm Hg was associated with 100% mortality, whereas patients with MPAP between 35 mm Hg and 50 mm Hg had a 50% mortality. No mortality was noted in patients with MPAP < 35 mm Hg.
Liver transplantation has been shown to be successful in patients with controlled POPH. Sussman et al published their data on 8 patients with severe POPH in 2006. In this prospective study, all patients were treated with sequential epoprostenol infusions and 7 of the 8 patients experienced a significant reduction in MPAP and PVR. Six patients were listed for liver transplant, 4 of who were transplanted successfully and alive up to 5 years later.
The Baylor University Medical Center published their data on POPH patients who received liver transplants in 2007.11 POPH was confirmed by right heart catheterization in 30 patients evaluated for liver transplant. Sixteen patients were considered to be suitable candidates for transplant and MPAP was decreased to less than 35 mmHg in 12 patients with vasodilator therapy. Eleven patients eventually underwent liver transplant and 1- and 5-year survival rates were 91% and 67%.
Compared to medical therapy or liver transplant alone, patients who receive medical therapy followed by liver transplantation have the best survival. The Mayo Clinic retrospectively reviewed 74 POPH patients identified between 1994 and 2007.40 Patients were categorized in 1 of 3 categories: no medical therapy, medical therapy alone for POPH, or medical therapy for POPH followed by liver transplantation. Patients who received no medical therapy for POPH and no liver transplant had the worst outcomes, with a dismal 5-year survival of only 14% with over 50% deceased at 1 year of diagnosis. Five-year survival was 45% in patients who received medical therapy only. Patients who received medical therapy with prostacyclin followed by liver transplantation had the best outcomes, with a 5-year survival of 67% versus 25% in those who were transplanted without prior prostacyclin therapy.
We reported the longest follow-up study for patients undergoing liver transplantation with POPH in 2014.41 Seven patients with moderate to severe POPH received a liver transplant at our institution between June 2004 and January 2011. Mean pulmonary artery pressure was reduced to < 35 mm Hg, with appropriate POPH therapy in all of the patients. Both the graft and patient survival rates were 85.7% after a median follow-up of 7.8 years. The 1 patient who did not survive died from complications related to recurrent hepatitis C and cirrhosis, not from POPH-related issues. Four of the remaining 6 patients continue to require oral vasodilator therapy post-transplant, suggesting irreversible remodeling of the pulmonary vasculature. Two patients (4.4 and 8.5 years post-transplant) have no evidence of pulmonary hypertension post-transplant and therefore do not require medical treatment for pulmonary hypertension. We concluded that POPH responsive to vasodilator therapy is an appropriate indication for liver transplant, with excellent long-term survival.
Hollatz et al published their data on 11 patients with moderate to severe POPH who were successfully treated (mostly with oral sildenafil and subcutaneous treprostinil) as a bridge to liver transplant.42 The mortality rate was 0, with a follow-up duration of 7 to 60 months. Interestingly, 7 of the 11 patients (64%) were off all pulmonary vasodilators post-transplant. Ashfaq et al reported similar results.11 Nine of 11 patients with treated moderate to severe POPH who received liver transplants stopped vasodilator therapy at a median period of 9.2 months post-transplant. Raevens et al described a group of 3 patients with POPH who went on to liver transplant after their pulmonary pressures were decreased with combined oral vasodilator therapy: 1 required continued long-term vasodilator therapy, another was weaned off medications after transplant, and the third patient died during the liver transplant from perioperative complications that induced uncontrolled pulmonary hypertension.43
Patient Selection
In 2006, the United Network for Organ Sharing (UNOS) initiated a policy whereby a higher priority for liver transplantation was granted for highly selected patients in the United States.44 UNOS policy 3.6.4.5.6 upgraded POPH patients to a MELD score of 22, with an increase in MELD every 3 months as long as MPAP remained < 35 mm Hg and PVR remained < 400 dynes/s/cm–5. One hundred fifty-five patients were granted MELD exception points for POPH between 2002 and 2010 and went on to receive liver transplants.45 Goldberg et al collected data from the Organ Procurement and Transplantation Network (OPTN) and compared outcomes of patients with approved POPH MELD exception points versus waitlist candidates with no exception points.46 One hundred fifty-five waitlisted patients received POPH MELD exception points, with only 43.1% meeting OPTN exception requirements. One-third did not fulfill hemodynamic criteria consistent with POPH or had missing data, and 80% went on to receive a liver transplant. Waitlist candidates receiving POPH MELD exception points also had increased waitlist mortality and several early post-transplant deaths. The authors felt these data highlighted the need for OPTN/UNOS to revise their policy for POPH MELD exceptions points, revise how points are rewarded, and continue research to help risk stratify these patients to minimize perioperative complications.
Conclusion
Several effective medical treatment regimens are available, including prostanoids, endothelin receptor antagonists, and PDE-5 inhibitors. Liver transplantation is a potential cure but is only recommended if MPAP can be decreased to ≤ 35 mmHg. Long-term follow-up studies have shown these patients do well several years post-transplant but may continue to require oral therapy for their POPH.
1. Tuder RM, Cool CD, Geraci MW, et al. Prostacyclin synthase expression is decreased in lungs from patients with severe pulmonary hypertension. Am J Respir Crit Care Med. 1999;159:1925-1932.
2. Chin K, Rubin L. Pulmonary arterial hypertension. Am Coll Cardiol. 2008;51:1527-1538.
3. Doran A, Harris S, Goetz B. Advances in prostanoid infusion therapy for pulmonary arterial hypertension. J Infus Nurs. 2008;31:336-345.
4. Chin KM, Channick RN, De Lemos JA, ET AL. Hemodynamics and epoprostenol use are associated with thrombocytopenia in pulmonary arterial hypertension. Chest. 2009;135:130-136.
5. Hoshikawa Y, Voelkel NF, Gesell TL, et al. Prostacyclin receptor-dependent modulation of pulmonary vascular remodeling. Am J Respir Crit Care Med. 2001;164:314-318.
6. Ricci GL, Melgosa MT, Burgos F, et al. Assessment of acute pulmonary vascular reactivity in portopulmonary hypertension. Liver Transplant. 2007;13:1506-1514.
7. McLaughlin V V, Genthner DE, Panella MM, et al. Compassionate use of continuous prostacyclin in the management of secondary pulmonary hypertension: a case series. Ann Intern Med. 1999;130:740-743.
8. Krowka MJ, Frantz RP, McGoon MD, et al. Improvement in pulmonary hemodynamics during intravenous epoprostenol (prostacyclin): A study of 15 patients with moderate to severe portopulmonary hypertension. Hepatology. 1999;30:641-648.
9. Fix OK, Bass NM, De Morco T, Merriman RB. Long-term follow-up of portopulmonary hypertension: Effect of treatment with epoprostenol. Liver Transplant. 2007;13:875-885.
10. Sussman N, Kaza V, Barshes N, et al. Successful liver transplantation following medical management of portopulmonary hypertension: a single-center series. Am J Transplant. 2006;6:2177-2182.
11. Ashfaq M, Chinnakotla S, Rogers L, et al. The impact of treatment of portopulmonary hypertension on survival following liver transplantation. Am J Transplant. 2007;7:1258-1264.
12. Sakai T, Planinsic RM, Mathier MA, et al. initial experience using continuous intravenous treprostinil to manage pulmonary arterial hypertension in patients with end-stage liver disease. Transpl Int. 2009;22:554-561.
13. McLaughlin VV, Benza RL, Rubin LJ, et al. Addition of inhaled treprostinil to oral therapy for pulmonary arterial hypertension: A randomized controlled clinical trial. J Am Coll Cardiol. 2010;55:1915-1922.
14. Hoeper MM, Seyfarth HJ, Hoeffken G, et al. Experience with inhaled iloprost and bosentan in portopulmonary hypertension. Eur Respir J. 2007;30:1096-1102.
15. Melgosa MT, Ricci GL, Garcia-Pagan JC et al. Acute and long-term effects of inhaled iloprost in portopulmonary hypertension. Liver Transplant. 2010;16:348-356.
16. Simonneau G, Torbicki A, Hoeper MM, et al. Selexipag: an oral, selective prostacyclin receptor agonist for the treatment of pulmonary arterial hypertension. Eur Respir J. 2012;40:874-880
17. Sitbon O, Channick R, Chin, KM, et al. Selexipag for the treatment of pulmonary arterial hypertension. N Engl J Med. 2015;373:2522-2533.
18. Moller S, Gulberg V, Henriksen JH, Gerbes AL. Endothelin-1 and endothelin-3 in cirrhosis: Relations to systemic and splanchnic haemodynamics. J Hepatol. 1995;23:135-144.
19. Eriksson C, Gustavsson A, Kronvall T, Tysk C. Hepatotoxicity by bosentan in a patient with portopulmonary hypertension : a case-report and review of the literature. J Gastrointestin Liver Dis. 2011;20:77-80.
20. Hoeper MM, Halank M, Marx C, et al. Bosentan therapy for portopulmonary hypertension. Eur Respir J. 2005;25:502-508.
21. Stähler G, Von Hunnius P. Successful treatment of portopulmonary hypertension with bosentan: Case report.: Eur J Clin Investig. 2006;36:62-66.
22. Savale L, Magnier R, Le Pavec J, et al. Efficacy, safety and pharmacokinetics of bosentan in portopulmonary hypertension. Eur. 2013;41:96-103.
23. Halank M, Knudsen L, Seyfarth H, et al. Ambrisentan improves exercise capacity and symptoms in patients with portopulmonary hypertension. Z Gastroenterol. 2011;49:1258-1262.
24. Cartin-Ceba R, Swanson K, Iyer V, et al. Safety and efficacy of ambrisentan for the treatment of portopulmonary hypertension. Chest. 2011;139:109-114.
25. Condliffe R, Elliot C, Hurdman J, et al. Ambrisentan therapy in pulmonary hypertension: clinical use and tolerability in a referral centre. Ther Adv Respir Dis. 2014;8:71-77.
26. Pulido T, Adzerikho I, Channick RN, et al. Macitentan and morbidity and mortality in pulmonary arterial hypertension. N Engl J Med. 2013;369:809-818.
27. Reichenberger F, Voswinckel R, Steveling E, et al. Sildenafil treatment for portopulmonary hypertension. Eur Respir J. 2006;28:563-567.
28. Hemnes AR RI. Sildenafil monotherapy in portopulmonary hypertension can facilitate liver transplantation. Liver Transplant. 2009;15:15-19.
29. Gough WR. Sildenafil therapy is associated with improved hemodynamics in liver transplantation candidates with pulmonary arterial hypertension. Liver Transplant. 2009;15:30-36.
30. Yamashita Y. Hemodynamic effects of ambrisentan-tadalafil combination therapy on progressive portopulmonary hypertension. World J Hepatol. 2014;6:825.
31. Bremer HC, Kreisel W, Roecker K, et al. Phosphodiesterase 5 inhibitors lower both portal and pulmonary pressure in portopulmonary hypertension: a case report. J Med Case Rep. 2007;1:46.
32. Ghofrani HA, Galie N, Grimminger F, et al. Riociguat for the treatment of pulmonary arterial hypertension. N Engl J Med. 2013:369;330-340.
33. Ghofrani HA, Galie N, Grimminger F, et al. Riociguat for the treatment of chronic thromboembolic pulmonary hypertension. N Engl J Med. 2013:369;319-329
34. Cartin-Ceba R, Halank M, Ghofrani HA, et al. Riociguat treatment for portopulmonary hypertension: a subgroup analysis from the PATENT-1/-2 studies. Pulm Circ. 2018: 8:2045894018769305.
35. Provencher S, Herve P, Jais X, et al. Deleterious effects of beta-blockers on exercise capacity and hemodynamics in patients with portopulmonary hypertension. 2006. Gastroenterology. 2006;130:120-126.
36. Ramsay M a, Simpson BR, Nguyen T, et al. Severe pulmonary hypertension in liver transplant candidates. Liver Transpl Surg. 1997;3:494-500.
37. Safdar Z, Bartolome S, Sussman N. Portopulmonary hypertension : an update. Liver Tranpl. 2012;18:881-891.
38. Ramsay M. Portopulmonary hypertension and right heart failure in patients with cirrhosis. Curr Opin Anaesthesiol. 2010;23:145-150.
39. Krowka MJ, Plevak DJ, Findlay JY, et al. Pulmonary hemodynamics and perioperative cardiopulmonary-related mortality in patients with portopulmonary hypertension undergoing liver transplantation. Liver Transpl. 2000;6:443-450.
40. Swanson KL, Wiesner RH, Nyberg SL, et al. Survival in portopulmonary hypertension: Mayo Clinic experience categorized by treatment subgroups. Am J Transplant. 2008;8:2445-2453.
41. Khaderi S, Khan R, Safdar Z, et al. Long-term follow-up of portopulmonary hypertension patients after liver transplantation. Liver Transplant. 2014;20:724-727.
42. Hollatz TJ, Musat A, Westphal S, et al. Treatment with sildenafil and treprostinil allows successful liver transplantation of patients with moderate to severe portopulmonary hypertension. Liver Transpl. 2012:686-695.
43. Raevens S, De Pauw M, Reyntjens K, et al. Oral vasodilator therapy in patients with moderate to severe portopulmonary hypertension as a bridge to liver transplantation. Eur J Gastroenterol Hepatol. 2012:1-8.
44. Krowka M, Fallon M, Mulligan D. Model for end-stage liver disease (MELD) exception for portopulmonary hypertension. Liver Transplant. 2006;12:S114-S116.
45. Krowka M, Wiesner R, Rosen C. Portopulmonary hypertension outcomes in the era of MELD exception. Liver Transplant. 2012;18:S259.
46. Goldberg DS, Batra S, Sahay S, et al. MELD Exceptions for portopulmonary hypertension: current policy and future implementation. Am J Transplant. 2014;14:2081-2087.
Portopulmonary hypertension (POPH) is a form of group 1 pulmonary arterial hypertension. When treating patients with POPH, baseline assessment is necessary so that response to therapy can be measured as the change from baseline. Patients should undergo echocardiography and right heart catheterization, and their exercise capacity and NYHA functional class should be determined. Patients with POPH should be considered for treatment if they are NYHA functional class II or above and/or their mean pulmonary artery pressure (MPAP) is greater than 35 mm Hg in transplant candidates. The goal in the treatment and management of POPH is to improve pulmonary hemodynamics by reducing the obstruction to pulmonary arterial flow and to preserve right ventricular function (Table). This article, the second in a 2-part review of POPH in patients with liver disease, reviews the role of medical therapy and liver transplantation in treatment. Evaluation and diagnosis of POPH are discussed in a separate article.
Medical Therapy
Prostanoids
Although prostacyclin and prostaglandin analogs entered routine clinical practice for POPH in the 1990s, reports of investigational use date back to the 1980s. Prostanoids are potent vasodilators with antiplatelet aggregation and antiproliferative properties. Prostacyclin synthase is reduced in patients with PAH, resulting in decreased concentration of prostacyclin with vasoconstriction and proliferative changes in the pulmonary vasculature.1
Epoprostenol
Epoprostenol is also known as synthetic prostaglandin I2 or prostacyclin. It was the first therapy approved for the treatment of PAH in 1995 by the US Food and Drug Administration (FDA) as a continuous intravenous infusion.2,3 It also inhibits platelet aggregation and may help modulate pulmonary vascular remodeling.4,5 Epoprostenol is derived from the metabolism of arachidonic acid and is a potent pulmonary and systemic vasodilator. One study reported an immediate 11.8% decrease in MPAP, 24% decrease in pulmonary vascular resistance (PVR) and 28% drop in systemic vascular resistance (SVR) during an epoprostenol infusion.6 The authors reported that epoprostenol was a more potent vasodilator than nitric oxide and may have a role in predicting the reversibility of POPH. In a case series of 33 patients with secondary pulmonary hypertension (including 7 patients with POPH) treated with continuous intravenous prostacyclin for approximately 1 year, exercise tolerance, NYHA functional class, and pulmonary hemodynamics improved in each patient compared to baseline.7 Krowka et al studied 14 patients with moderate to severe POPH treated with intravenous epoprostenol.8 No significant side effects were noted and treatment resulted in significant improvements in PVR, MPAP, and cardiac output. In 2007, Fix et al published a large retrospective cohort of patients with moderate to severe POPH.9 Nineteen patients treated with epoprostenol were compared to 17 patients with no treatment. After a median treatment period of 15.4 months, the epoprostenol group showed significant improvement in MPAP, PVR and cardiac output, but survival did not differ between the 2 groups.
Epoprostenol has often been considered a bridge to transplant in patients with POPH. Sussman et al described 8 consecutive patients with POPH who were treated with intravenous epoprostenol (2 to 8 ng/kg/min dose).10 Liver transplant was considered in 7 of the 8 patients when MPAP decreased to less than 35 mm Hg. Six patients were eventually listed for liver transplant, but 2 died waiting on the list. Long-term outcomes in the group of transplanted recipients were excellent. They remained alive and well at least 9 to 18 months post-transplant, and half did not require long-term vasodilator therapy post-orthotopic liver transplant. Similarly, Ashfaq et al published their data on 16 patients with moderate-to-severe POPH who were treated with vasodilator therapy.11 MPAP decreased to acceptable levels in 75% of the treated patients, and 11 went on to liver transplantation. Rates of 1- and 5-year survival in the transplanted patients were 91% and 67% respectively. None of the patients who failed vasodilator therapy survived.
Epoprostenol has a short half-life (3 to 5 minutes) and requires continuous infusion through central access via an infusion pump. Aseptic technique must be maintained to avoid blood stream infections. Pump failure or loss of vascular access can result in rebound pulmonary vasoconstriction that can be life-threatening and requires immediate attention. Side effects associated with epoprostenol include flushing, headache, nausea/vomiting, bradycardia, chest pain, jaw pain, diarrhea, and musculoskeletal pain.
Patients on epoprostenol should be monitored for prostanoid overdose. In the case of patients with chronic liver disease, epoprostenol increases systemic vasodilation in patients with already low systemic vascular tone. As a result, cardiac output may increase to the point of high cardiac output failure. MPAP will remain elevated secondary to high cardiac output rather than high PVR. In these patients, right heart catheterization will show an elevated MPAP in the setting of normal to low PVR/transpulmonary gradient (TPG) values. Lowering the epoprostenol dose will successfully reduce both cardiac output and MPAP.
Treprostinil
Treprostinil is a prostacyclin analog that is available in intravenous, inhalational, and subcutaneous form, although subcutaneous dosing may be limited by pain. Sakai et al published a small case series of 3 patients with PAH and end-stage liver disease treated with intravenous treprostinil.12 Pulmonary hemodynamics improved in all patients, and 2 patients went on to an uneventful liver transplantation. More than 10 years later, data were published on 255 patients with PAH on therapy with bosentan or sildenafil randomized to additional inhaled treprostinil.13 Treprostinil proved to be safe and well tolerated, with improvement in quality of life measures but no improvement in other secondary endpoints.
Iloprost
Inhaled iloprost is another prostacyclin that has a short therapeutic half-life of 20 to 30 minutes and requires frequent administration (6 to 9 times daily). In study in which patients with severe POPH were treated for up to 3 years with inhaled iloprost,14 survival rates at 1, 2, and 3 years were 77%, 62%, and 46%, respectively. A second study published in 2010 was designed to assess the acute effects of inhaled iloprost on pulmonary hemodynamics and evaluate the clinical outcome after 12 months of treatment.15 Iloprost was found to rapidly reduce pulmonary arterial pressure and PVR. In the long-term evaluation, inhaled iloprost increased the 6-minute walk distance (6MWD) and functional class, but no change was noted in the systolic pulmonary artery pressure. The authors concluded that iloprost might provide symptomatic improvement and improvement in exercise capacity.
Selexipag
Selexipag is an oral selective IP prostacyclin receptor agonist that is structurally distinct from other prostacyclins.16 In a phase 3 randomized double blind clinical trial, PAH patients treated with selexipag had lower composite of death or complication of PAH to the end of the study period.17 This effect was consistent across all dose ranges, but POPH patients were excluded from this study. Safety and efficacy of selexipag has not been evaluated in POPH patients.
Endothelin Receptor Antagonists
Endothelin receptor antagonists block the production of endothelin-1 (ET-1), a potent vasoconstrictor and smooth muscle mitogen that may contribute to the development of PAH. Three different receptors have been described: endothelin A, endothelin B, and endothelin B2. Elevated ET-1 levels have been reported in patients with chronic liver disease and may originate from hepatosplanchnic circulation.18
Bosentan
Bosentan is an oral, nonspecific, ET-1A and ET-1B receptor antagonist. Initial use of bosentan in patients with POPH was limited because of concern for hepatotoxicity. Approximately 10% of patients on bosentan were reported to have mild hepatic side effects in the form of elevated aminotransferases, but severe injury has been reported.19 One of the first clinical experiences of bosentan in patients with POPH was published in 2005. Hoeper et al followed 11 patients with Child A cirrhosis and severe POPH.20 All patients included were in NYHA functional class III or IV and were treated with bosentan for over 1 year. Exercise capacity and symptoms improved in all treated patients. The medication was tolerated well and there was no evidence of drug-induced liver injury. A single case report showed the effectiveness of bosentan in a 43-year-old man with alcohol-related liver disease (Child-Pugh A) and right ventricular enlargement and dysfunction secondary to POPH.21 Pulmonary arterial pressure decreased, exercise capacity increased, and improvement was maintained over 2 years.
In a group of 31 patients with Child A or B cirrhosis and severe POPH, bosentan had significantly better effects than inhaled iloprost on exercise capacity, hemodynamics, and survival.14 One, 2, and 3-year survival rates in the bosentan group were 94%, 89%, and 89% (compared to 77%, 62%, and 46% in the iloprost group). Both drugs were considered safe with no reported hepatotoxicity. In 2013, Savale et al published data on 34 patients with POPH, Child-Pugh A and/or B who were treated with bosentan for a median of 43 months.22 The authors reported significant improvements in hemodynamics, NYHA functional class, and 6WMD. Event-free survival rates at 1, 2, and 3 years were 82%, 63%, and 47%, respectively.
Ambrisentan
Ambrisentan is a highly selective ET-1A receptor antagonist with once daily dosing and a lower risk of hepatotoxicity compared to bosentan. Fourteen patients with moderate to severe POPH treated with ambrisentan in 4 German hospitals were retrospectively analyzed.23 Median follow-up was 16 months, and the study demonstrated significant improvement in exercise capacity and clinical symptoms without significant change in liver function tests. Cartin-Ceba et al published their experience of 13 patients with moderate to severe POPH treated with ambrisentan monotherapy.24 Patients were followed for a median of 613 days and on treatment for a median time of 390 days. Significant improvements were shown in pulmonary arterial pressure and PVR without adverse effect on hepatic function. Over 270 patients with PAH (6% with POPH) received ambrisentan from March 2009 through June 2013 at a large United Kingdom portal hypertension referral center.25 Discontinuation due to side effects was higher than previously reported. Discontinuation due to abnormal transaminases was uncommon.
Macitentan
Macitentan is a dual endothelin-receptor antagonist developed by modifying the structure of bosentan to increase efficacy and safety. The SERAPHIN trial compared oral macitentan to placebo in 250 patients with moderate to severe PAH, some of whom were also on a stable dose of oral or inhaled therapy for PAH.26 Over a 2-year period, patients treated with macitentan were less likely to have progression of their disease or die on therapy (38% and 31% versus 46%), regardless of if they were receiving additional oral therapy and more likely to have improvement of their exercise capacity and WHO functional class. Nasopharyngitis and significant anemia were more common in the macitentan group, but there was no difference in the rate of liver function test abnormalities compared to placebo. Trials with macitentan are currently ongoing in patients with POPH.
Phosphodiesterase-5 Inhibitors
Cyclic guanosine monophosphate (cGMP) is the mediator of nitric oxide–induced vasodilation. Phosphodiesterase-5 (PDE-5) inhibitors prolong the vasodilatory effects of cyclic guanosine monophosphate by preventing its hydrolysis, thereby reducing the pulmonary arterial pressure.
Sildenafil
Sildenafil is the most widely accepted PDE-5 inhibitor for POPH. Fourteen patients with moderate to severe POPH were treated with sildenafil (50 mg 3 times per day) in an observational study published by Reichenberger et al in 2006.27 Eight patients were newly started on sildenafil, whereas sildenafil was added to inhaled prostanoids in the remaining 6x patients. Sildenafil significantly decreased 66MWD, MPAP, PVR, and cardiac index alone or in combination with inhaled prostanoids.
Sildenafil has also been used as a bridge to transplant in liver transplant candidates with POPH. Ten patients with POPH treated with sildenafil monotherapy were followed for a 21±16 months.28 Patients improved symptomatically and increased their 6MWD at 1 year by 30 meters or more. Three patients became transplant eligible and another 3 patients were stable, without progression of their liver disease or POPH. Four patients were not considered transplant candidates, 2 because of refractory POPH and 2 for other comorbidities. The authors concluded that sildenafil monotherapy could stabilize or improve pulmonary hemodynamics in patients with POPH and eventually lead to liver transplantation. Gough et al took a similar look at 9 patients with POPH treated with sildenafil.29 All patients had initial and follow-up right heart catheterizations within a period of 3 years. Mean PVR improved in all patients, decreasing from 575 to 375 dynes/s/cm–5. MPAP decreased to ≤ 35 mmHg in 4 patients, 1 of whom went on to receive a liver transplant. Overall sildenafil improved pulmonary hemodynamics in this small cohort of POPH patients.
Tadalafil
Tadalafil is another oral PDE-5 inhibitor but with a longer half-life than sildenafil. Unlike sildenafil, which requires 3 times daily dosing, tadalafil requires once daily administration. A few case reports have demonstrated tadalafil’s effectiveness for POPH in combination with other medical therapy (eg, sildenafil, ambrisentan).30,31
Guanylate Cyclase Stimulator
Riociguat
Riociguat is a first-in-class activator of soluble form of guanylate cyclase that increases levels of cyclic GMP. Two randomized clinical trials, PATENT, a study in PAH patients, and CHEST, a study in patients with chronic thromboembolic pulmonary hypertension showed improvement in 6MWD at 12 weeks (PATENT) or 16 weeks (CHEST), with improvement in secondary endpoints such as PVR, N-terminal pro b-type natriuretic peptide and WHO functional class.32,33 Riociguat may have potential advantages in patients with POPH given that it has a favorable liver safety profile. A subgroup analysis of patients enrolled in the PATENT study showed that 13 had POPH and 11 were randomized to receive riociguat 2.5 mg 3 times daily dose and 2 received placebo.34 Riociguat was well tolerated and improved 6MWD that was maintained over 2 years in the open label extension.
Medications to Avoid
Nonselective beta-blockers are commonly recommended in patients with portal hypertension to help prevent variceal hemorrhage. However, in patients with POPH, beta-blockers have been shown to decrease exercise capacity and worsen pulmonary hemodynamics. A study of 10 patients with moderate to severe POPH who were receiving beta-blockers for variceal bleeding prophylaxis showed that 6MWD improved in almost all of the patients, cardiac output increased by 28%, and PVR decreased by 19% when beta-blockers were discontinued.35 The authors concluded that the use of beta-blockers should be avoided in this patient population.
Calcium channel blockers should not be used in patients with POPH because they can cause significant hypotension due to systemic vasodilatation and decreased right ventricular filling. Patients with portal hypertension and chronic liver disease commonly have low systemic vascular resistance and are particularly susceptible to the deleterious effects of calcium channel blockers.
Transplantation
Liver transplantation is a potential cure for POPH and its role in POPH has evolved over the past 2 decades. In 1997, Ramsay et al published their review of 1205 consecutive liver transplants at Baylor University Medical Center (BUMC) in Texas.36 The incidence of POPH in this group was 8.5%, with the majority of patients having mild POPH. Liver transplant outcomes were not affected by mild and moderate pulmonary hypertension. However, patients with severe POPH (n = 7, systolic pulmonary artery pressure > 60 mm Hg) had a mortality rate of 42% at 9 months post-transplantation and 71% at 36 months post-transplant. The surviving patients continued to deteriorate with progressive right heart failure and no improvement in POPH.
To understand the effect of liver transplantation on POPH, one must understand the hemodynamic changes that occur with POPH and during liver transplant. The right ventricle is able to manage the same volume as the left ventricle under normal circumstances, but is unable to pump against a significant pressure gradient.37 In the setting of POPH, right ventricular hypertrophy occurs and RV output remains stable for some time. With time, pulmonary artery pressure increases secondary to pulmonary arteriolar vasoconstriction, intimal thickening, and progressive occlusion of the pulmonary vascular bed. Right ventricular failure may occur as a result. Cardiac output increases significantly at the time of reperfusion during liver transplant (up to 3-fold in 15 minutes),38 and in the setting of a noncompliant vascular bed, the patient is at risk for right heart failure. This is the likely explanation to such high perioperative mortality rates in patients with uncontrolled POPH. Failure to decrease MPAP to less than 50 mm Hg is considered a complete contraindication to liver transplant at most institutions. Many transplant centers will list patients for liver transplant if MPAP can be decreased to less than 35 mm Hg and PVR < 400 dynes/s/cm–5. These parameters are thought to represent an adequate right ventricular reserve and a compliant pulmonary vascular bed.37 However, even with good pressure control, the anesthesiology and critical care teams must be prepared to deal with acute right heart failure peri-operatively. Intraoperative transesophageal echocardiography has been recommended to closely follow right ventricular function.38 Inhaled or intravenous dilators are the most effective agents in the event of a pulmonary hypertensive crisis.
Review of Outcomes
A retrospective review evaluated 43 patients with untreated POPH who underwent attempted liver transplantation.39 Data were collected from 18 peer-reviewed studies and 7 patients at the authors’ institution. Overall mortality was 35% (15 patients), with almost all of the deaths secondary to cardiac dysfunction. Two deaths occurred intraoperatively and 8 deaths occurred during the transplant hospitalization. The transplant could not be successfully completed in 4 of the patients. MPAP > 50 mm Hg was associated with 100% mortality, whereas patients with MPAP between 35 mm Hg and 50 mm Hg had a 50% mortality. No mortality was noted in patients with MPAP < 35 mm Hg.
Liver transplantation has been shown to be successful in patients with controlled POPH. Sussman et al published their data on 8 patients with severe POPH in 2006. In this prospective study, all patients were treated with sequential epoprostenol infusions and 7 of the 8 patients experienced a significant reduction in MPAP and PVR. Six patients were listed for liver transplant, 4 of who were transplanted successfully and alive up to 5 years later.
The Baylor University Medical Center published their data on POPH patients who received liver transplants in 2007.11 POPH was confirmed by right heart catheterization in 30 patients evaluated for liver transplant. Sixteen patients were considered to be suitable candidates for transplant and MPAP was decreased to less than 35 mmHg in 12 patients with vasodilator therapy. Eleven patients eventually underwent liver transplant and 1- and 5-year survival rates were 91% and 67%.
Compared to medical therapy or liver transplant alone, patients who receive medical therapy followed by liver transplantation have the best survival. The Mayo Clinic retrospectively reviewed 74 POPH patients identified between 1994 and 2007.40 Patients were categorized in 1 of 3 categories: no medical therapy, medical therapy alone for POPH, or medical therapy for POPH followed by liver transplantation. Patients who received no medical therapy for POPH and no liver transplant had the worst outcomes, with a dismal 5-year survival of only 14% with over 50% deceased at 1 year of diagnosis. Five-year survival was 45% in patients who received medical therapy only. Patients who received medical therapy with prostacyclin followed by liver transplantation had the best outcomes, with a 5-year survival of 67% versus 25% in those who were transplanted without prior prostacyclin therapy.
We reported the longest follow-up study for patients undergoing liver transplantation with POPH in 2014.41 Seven patients with moderate to severe POPH received a liver transplant at our institution between June 2004 and January 2011. Mean pulmonary artery pressure was reduced to < 35 mm Hg, with appropriate POPH therapy in all of the patients. Both the graft and patient survival rates were 85.7% after a median follow-up of 7.8 years. The 1 patient who did not survive died from complications related to recurrent hepatitis C and cirrhosis, not from POPH-related issues. Four of the remaining 6 patients continue to require oral vasodilator therapy post-transplant, suggesting irreversible remodeling of the pulmonary vasculature. Two patients (4.4 and 8.5 years post-transplant) have no evidence of pulmonary hypertension post-transplant and therefore do not require medical treatment for pulmonary hypertension. We concluded that POPH responsive to vasodilator therapy is an appropriate indication for liver transplant, with excellent long-term survival.
Hollatz et al published their data on 11 patients with moderate to severe POPH who were successfully treated (mostly with oral sildenafil and subcutaneous treprostinil) as a bridge to liver transplant.42 The mortality rate was 0, with a follow-up duration of 7 to 60 months. Interestingly, 7 of the 11 patients (64%) were off all pulmonary vasodilators post-transplant. Ashfaq et al reported similar results.11 Nine of 11 patients with treated moderate to severe POPH who received liver transplants stopped vasodilator therapy at a median period of 9.2 months post-transplant. Raevens et al described a group of 3 patients with POPH who went on to liver transplant after their pulmonary pressures were decreased with combined oral vasodilator therapy: 1 required continued long-term vasodilator therapy, another was weaned off medications after transplant, and the third patient died during the liver transplant from perioperative complications that induced uncontrolled pulmonary hypertension.43
Patient Selection
In 2006, the United Network for Organ Sharing (UNOS) initiated a policy whereby a higher priority for liver transplantation was granted for highly selected patients in the United States.44 UNOS policy 3.6.4.5.6 upgraded POPH patients to a MELD score of 22, with an increase in MELD every 3 months as long as MPAP remained < 35 mm Hg and PVR remained < 400 dynes/s/cm–5. One hundred fifty-five patients were granted MELD exception points for POPH between 2002 and 2010 and went on to receive liver transplants.45 Goldberg et al collected data from the Organ Procurement and Transplantation Network (OPTN) and compared outcomes of patients with approved POPH MELD exception points versus waitlist candidates with no exception points.46 One hundred fifty-five waitlisted patients received POPH MELD exception points, with only 43.1% meeting OPTN exception requirements. One-third did not fulfill hemodynamic criteria consistent with POPH or had missing data, and 80% went on to receive a liver transplant. Waitlist candidates receiving POPH MELD exception points also had increased waitlist mortality and several early post-transplant deaths. The authors felt these data highlighted the need for OPTN/UNOS to revise their policy for POPH MELD exceptions points, revise how points are rewarded, and continue research to help risk stratify these patients to minimize perioperative complications.
Conclusion
Several effective medical treatment regimens are available, including prostanoids, endothelin receptor antagonists, and PDE-5 inhibitors. Liver transplantation is a potential cure but is only recommended if MPAP can be decreased to ≤ 35 mmHg. Long-term follow-up studies have shown these patients do well several years post-transplant but may continue to require oral therapy for their POPH.
Portopulmonary hypertension (POPH) is a form of group 1 pulmonary arterial hypertension. When treating patients with POPH, baseline assessment is necessary so that response to therapy can be measured as the change from baseline. Patients should undergo echocardiography and right heart catheterization, and their exercise capacity and NYHA functional class should be determined. Patients with POPH should be considered for treatment if they are NYHA functional class II or above and/or their mean pulmonary artery pressure (MPAP) is greater than 35 mm Hg in transplant candidates. The goal in the treatment and management of POPH is to improve pulmonary hemodynamics by reducing the obstruction to pulmonary arterial flow and to preserve right ventricular function (Table). This article, the second in a 2-part review of POPH in patients with liver disease, reviews the role of medical therapy and liver transplantation in treatment. Evaluation and diagnosis of POPH are discussed in a separate article.
Medical Therapy
Prostanoids
Although prostacyclin and prostaglandin analogs entered routine clinical practice for POPH in the 1990s, reports of investigational use date back to the 1980s. Prostanoids are potent vasodilators with antiplatelet aggregation and antiproliferative properties. Prostacyclin synthase is reduced in patients with PAH, resulting in decreased concentration of prostacyclin with vasoconstriction and proliferative changes in the pulmonary vasculature.1
Epoprostenol
Epoprostenol is also known as synthetic prostaglandin I2 or prostacyclin. It was the first therapy approved for the treatment of PAH in 1995 by the US Food and Drug Administration (FDA) as a continuous intravenous infusion.2,3 It also inhibits platelet aggregation and may help modulate pulmonary vascular remodeling.4,5 Epoprostenol is derived from the metabolism of arachidonic acid and is a potent pulmonary and systemic vasodilator. One study reported an immediate 11.8% decrease in MPAP, 24% decrease in pulmonary vascular resistance (PVR) and 28% drop in systemic vascular resistance (SVR) during an epoprostenol infusion.6 The authors reported that epoprostenol was a more potent vasodilator than nitric oxide and may have a role in predicting the reversibility of POPH. In a case series of 33 patients with secondary pulmonary hypertension (including 7 patients with POPH) treated with continuous intravenous prostacyclin for approximately 1 year, exercise tolerance, NYHA functional class, and pulmonary hemodynamics improved in each patient compared to baseline.7 Krowka et al studied 14 patients with moderate to severe POPH treated with intravenous epoprostenol.8 No significant side effects were noted and treatment resulted in significant improvements in PVR, MPAP, and cardiac output. In 2007, Fix et al published a large retrospective cohort of patients with moderate to severe POPH.9 Nineteen patients treated with epoprostenol were compared to 17 patients with no treatment. After a median treatment period of 15.4 months, the epoprostenol group showed significant improvement in MPAP, PVR and cardiac output, but survival did not differ between the 2 groups.
Epoprostenol has often been considered a bridge to transplant in patients with POPH. Sussman et al described 8 consecutive patients with POPH who were treated with intravenous epoprostenol (2 to 8 ng/kg/min dose).10 Liver transplant was considered in 7 of the 8 patients when MPAP decreased to less than 35 mm Hg. Six patients were eventually listed for liver transplant, but 2 died waiting on the list. Long-term outcomes in the group of transplanted recipients were excellent. They remained alive and well at least 9 to 18 months post-transplant, and half did not require long-term vasodilator therapy post-orthotopic liver transplant. Similarly, Ashfaq et al published their data on 16 patients with moderate-to-severe POPH who were treated with vasodilator therapy.11 MPAP decreased to acceptable levels in 75% of the treated patients, and 11 went on to liver transplantation. Rates of 1- and 5-year survival in the transplanted patients were 91% and 67% respectively. None of the patients who failed vasodilator therapy survived.
Epoprostenol has a short half-life (3 to 5 minutes) and requires continuous infusion through central access via an infusion pump. Aseptic technique must be maintained to avoid blood stream infections. Pump failure or loss of vascular access can result in rebound pulmonary vasoconstriction that can be life-threatening and requires immediate attention. Side effects associated with epoprostenol include flushing, headache, nausea/vomiting, bradycardia, chest pain, jaw pain, diarrhea, and musculoskeletal pain.
Patients on epoprostenol should be monitored for prostanoid overdose. In the case of patients with chronic liver disease, epoprostenol increases systemic vasodilation in patients with already low systemic vascular tone. As a result, cardiac output may increase to the point of high cardiac output failure. MPAP will remain elevated secondary to high cardiac output rather than high PVR. In these patients, right heart catheterization will show an elevated MPAP in the setting of normal to low PVR/transpulmonary gradient (TPG) values. Lowering the epoprostenol dose will successfully reduce both cardiac output and MPAP.
Treprostinil
Treprostinil is a prostacyclin analog that is available in intravenous, inhalational, and subcutaneous form, although subcutaneous dosing may be limited by pain. Sakai et al published a small case series of 3 patients with PAH and end-stage liver disease treated with intravenous treprostinil.12 Pulmonary hemodynamics improved in all patients, and 2 patients went on to an uneventful liver transplantation. More than 10 years later, data were published on 255 patients with PAH on therapy with bosentan or sildenafil randomized to additional inhaled treprostinil.13 Treprostinil proved to be safe and well tolerated, with improvement in quality of life measures but no improvement in other secondary endpoints.
Iloprost
Inhaled iloprost is another prostacyclin that has a short therapeutic half-life of 20 to 30 minutes and requires frequent administration (6 to 9 times daily). In study in which patients with severe POPH were treated for up to 3 years with inhaled iloprost,14 survival rates at 1, 2, and 3 years were 77%, 62%, and 46%, respectively. A second study published in 2010 was designed to assess the acute effects of inhaled iloprost on pulmonary hemodynamics and evaluate the clinical outcome after 12 months of treatment.15 Iloprost was found to rapidly reduce pulmonary arterial pressure and PVR. In the long-term evaluation, inhaled iloprost increased the 6-minute walk distance (6MWD) and functional class, but no change was noted in the systolic pulmonary artery pressure. The authors concluded that iloprost might provide symptomatic improvement and improvement in exercise capacity.
Selexipag
Selexipag is an oral selective IP prostacyclin receptor agonist that is structurally distinct from other prostacyclins.16 In a phase 3 randomized double blind clinical trial, PAH patients treated with selexipag had lower composite of death or complication of PAH to the end of the study period.17 This effect was consistent across all dose ranges, but POPH patients were excluded from this study. Safety and efficacy of selexipag has not been evaluated in POPH patients.
Endothelin Receptor Antagonists
Endothelin receptor antagonists block the production of endothelin-1 (ET-1), a potent vasoconstrictor and smooth muscle mitogen that may contribute to the development of PAH. Three different receptors have been described: endothelin A, endothelin B, and endothelin B2. Elevated ET-1 levels have been reported in patients with chronic liver disease and may originate from hepatosplanchnic circulation.18
Bosentan
Bosentan is an oral, nonspecific, ET-1A and ET-1B receptor antagonist. Initial use of bosentan in patients with POPH was limited because of concern for hepatotoxicity. Approximately 10% of patients on bosentan were reported to have mild hepatic side effects in the form of elevated aminotransferases, but severe injury has been reported.19 One of the first clinical experiences of bosentan in patients with POPH was published in 2005. Hoeper et al followed 11 patients with Child A cirrhosis and severe POPH.20 All patients included were in NYHA functional class III or IV and were treated with bosentan for over 1 year. Exercise capacity and symptoms improved in all treated patients. The medication was tolerated well and there was no evidence of drug-induced liver injury. A single case report showed the effectiveness of bosentan in a 43-year-old man with alcohol-related liver disease (Child-Pugh A) and right ventricular enlargement and dysfunction secondary to POPH.21 Pulmonary arterial pressure decreased, exercise capacity increased, and improvement was maintained over 2 years.
In a group of 31 patients with Child A or B cirrhosis and severe POPH, bosentan had significantly better effects than inhaled iloprost on exercise capacity, hemodynamics, and survival.14 One, 2, and 3-year survival rates in the bosentan group were 94%, 89%, and 89% (compared to 77%, 62%, and 46% in the iloprost group). Both drugs were considered safe with no reported hepatotoxicity. In 2013, Savale et al published data on 34 patients with POPH, Child-Pugh A and/or B who were treated with bosentan for a median of 43 months.22 The authors reported significant improvements in hemodynamics, NYHA functional class, and 6WMD. Event-free survival rates at 1, 2, and 3 years were 82%, 63%, and 47%, respectively.
Ambrisentan
Ambrisentan is a highly selective ET-1A receptor antagonist with once daily dosing and a lower risk of hepatotoxicity compared to bosentan. Fourteen patients with moderate to severe POPH treated with ambrisentan in 4 German hospitals were retrospectively analyzed.23 Median follow-up was 16 months, and the study demonstrated significant improvement in exercise capacity and clinical symptoms without significant change in liver function tests. Cartin-Ceba et al published their experience of 13 patients with moderate to severe POPH treated with ambrisentan monotherapy.24 Patients were followed for a median of 613 days and on treatment for a median time of 390 days. Significant improvements were shown in pulmonary arterial pressure and PVR without adverse effect on hepatic function. Over 270 patients with PAH (6% with POPH) received ambrisentan from March 2009 through June 2013 at a large United Kingdom portal hypertension referral center.25 Discontinuation due to side effects was higher than previously reported. Discontinuation due to abnormal transaminases was uncommon.
Macitentan
Macitentan is a dual endothelin-receptor antagonist developed by modifying the structure of bosentan to increase efficacy and safety. The SERAPHIN trial compared oral macitentan to placebo in 250 patients with moderate to severe PAH, some of whom were also on a stable dose of oral or inhaled therapy for PAH.26 Over a 2-year period, patients treated with macitentan were less likely to have progression of their disease or die on therapy (38% and 31% versus 46%), regardless of if they were receiving additional oral therapy and more likely to have improvement of their exercise capacity and WHO functional class. Nasopharyngitis and significant anemia were more common in the macitentan group, but there was no difference in the rate of liver function test abnormalities compared to placebo. Trials with macitentan are currently ongoing in patients with POPH.
Phosphodiesterase-5 Inhibitors
Cyclic guanosine monophosphate (cGMP) is the mediator of nitric oxide–induced vasodilation. Phosphodiesterase-5 (PDE-5) inhibitors prolong the vasodilatory effects of cyclic guanosine monophosphate by preventing its hydrolysis, thereby reducing the pulmonary arterial pressure.
Sildenafil
Sildenafil is the most widely accepted PDE-5 inhibitor for POPH. Fourteen patients with moderate to severe POPH were treated with sildenafil (50 mg 3 times per day) in an observational study published by Reichenberger et al in 2006.27 Eight patients were newly started on sildenafil, whereas sildenafil was added to inhaled prostanoids in the remaining 6x patients. Sildenafil significantly decreased 66MWD, MPAP, PVR, and cardiac index alone or in combination with inhaled prostanoids.
Sildenafil has also been used as a bridge to transplant in liver transplant candidates with POPH. Ten patients with POPH treated with sildenafil monotherapy were followed for a 21±16 months.28 Patients improved symptomatically and increased their 6MWD at 1 year by 30 meters or more. Three patients became transplant eligible and another 3 patients were stable, without progression of their liver disease or POPH. Four patients were not considered transplant candidates, 2 because of refractory POPH and 2 for other comorbidities. The authors concluded that sildenafil monotherapy could stabilize or improve pulmonary hemodynamics in patients with POPH and eventually lead to liver transplantation. Gough et al took a similar look at 9 patients with POPH treated with sildenafil.29 All patients had initial and follow-up right heart catheterizations within a period of 3 years. Mean PVR improved in all patients, decreasing from 575 to 375 dynes/s/cm–5. MPAP decreased to ≤ 35 mmHg in 4 patients, 1 of whom went on to receive a liver transplant. Overall sildenafil improved pulmonary hemodynamics in this small cohort of POPH patients.
Tadalafil
Tadalafil is another oral PDE-5 inhibitor but with a longer half-life than sildenafil. Unlike sildenafil, which requires 3 times daily dosing, tadalafil requires once daily administration. A few case reports have demonstrated tadalafil’s effectiveness for POPH in combination with other medical therapy (eg, sildenafil, ambrisentan).30,31
Guanylate Cyclase Stimulator
Riociguat
Riociguat is a first-in-class activator of soluble form of guanylate cyclase that increases levels of cyclic GMP. Two randomized clinical trials, PATENT, a study in PAH patients, and CHEST, a study in patients with chronic thromboembolic pulmonary hypertension showed improvement in 6MWD at 12 weeks (PATENT) or 16 weeks (CHEST), with improvement in secondary endpoints such as PVR, N-terminal pro b-type natriuretic peptide and WHO functional class.32,33 Riociguat may have potential advantages in patients with POPH given that it has a favorable liver safety profile. A subgroup analysis of patients enrolled in the PATENT study showed that 13 had POPH and 11 were randomized to receive riociguat 2.5 mg 3 times daily dose and 2 received placebo.34 Riociguat was well tolerated and improved 6MWD that was maintained over 2 years in the open label extension.
Medications to Avoid
Nonselective beta-blockers are commonly recommended in patients with portal hypertension to help prevent variceal hemorrhage. However, in patients with POPH, beta-blockers have been shown to decrease exercise capacity and worsen pulmonary hemodynamics. A study of 10 patients with moderate to severe POPH who were receiving beta-blockers for variceal bleeding prophylaxis showed that 6MWD improved in almost all of the patients, cardiac output increased by 28%, and PVR decreased by 19% when beta-blockers were discontinued.35 The authors concluded that the use of beta-blockers should be avoided in this patient population.
Calcium channel blockers should not be used in patients with POPH because they can cause significant hypotension due to systemic vasodilatation and decreased right ventricular filling. Patients with portal hypertension and chronic liver disease commonly have low systemic vascular resistance and are particularly susceptible to the deleterious effects of calcium channel blockers.
Transplantation
Liver transplantation is a potential cure for POPH and its role in POPH has evolved over the past 2 decades. In 1997, Ramsay et al published their review of 1205 consecutive liver transplants at Baylor University Medical Center (BUMC) in Texas.36 The incidence of POPH in this group was 8.5%, with the majority of patients having mild POPH. Liver transplant outcomes were not affected by mild and moderate pulmonary hypertension. However, patients with severe POPH (n = 7, systolic pulmonary artery pressure > 60 mm Hg) had a mortality rate of 42% at 9 months post-transplantation and 71% at 36 months post-transplant. The surviving patients continued to deteriorate with progressive right heart failure and no improvement in POPH.
To understand the effect of liver transplantation on POPH, one must understand the hemodynamic changes that occur with POPH and during liver transplant. The right ventricle is able to manage the same volume as the left ventricle under normal circumstances, but is unable to pump against a significant pressure gradient.37 In the setting of POPH, right ventricular hypertrophy occurs and RV output remains stable for some time. With time, pulmonary artery pressure increases secondary to pulmonary arteriolar vasoconstriction, intimal thickening, and progressive occlusion of the pulmonary vascular bed. Right ventricular failure may occur as a result. Cardiac output increases significantly at the time of reperfusion during liver transplant (up to 3-fold in 15 minutes),38 and in the setting of a noncompliant vascular bed, the patient is at risk for right heart failure. This is the likely explanation to such high perioperative mortality rates in patients with uncontrolled POPH. Failure to decrease MPAP to less than 50 mm Hg is considered a complete contraindication to liver transplant at most institutions. Many transplant centers will list patients for liver transplant if MPAP can be decreased to less than 35 mm Hg and PVR < 400 dynes/s/cm–5. These parameters are thought to represent an adequate right ventricular reserve and a compliant pulmonary vascular bed.37 However, even with good pressure control, the anesthesiology and critical care teams must be prepared to deal with acute right heart failure peri-operatively. Intraoperative transesophageal echocardiography has been recommended to closely follow right ventricular function.38 Inhaled or intravenous dilators are the most effective agents in the event of a pulmonary hypertensive crisis.
Review of Outcomes
A retrospective review evaluated 43 patients with untreated POPH who underwent attempted liver transplantation.39 Data were collected from 18 peer-reviewed studies and 7 patients at the authors’ institution. Overall mortality was 35% (15 patients), with almost all of the deaths secondary to cardiac dysfunction. Two deaths occurred intraoperatively and 8 deaths occurred during the transplant hospitalization. The transplant could not be successfully completed in 4 of the patients. MPAP > 50 mm Hg was associated with 100% mortality, whereas patients with MPAP between 35 mm Hg and 50 mm Hg had a 50% mortality. No mortality was noted in patients with MPAP < 35 mm Hg.
Liver transplantation has been shown to be successful in patients with controlled POPH. Sussman et al published their data on 8 patients with severe POPH in 2006. In this prospective study, all patients were treated with sequential epoprostenol infusions and 7 of the 8 patients experienced a significant reduction in MPAP and PVR. Six patients were listed for liver transplant, 4 of who were transplanted successfully and alive up to 5 years later.
The Baylor University Medical Center published their data on POPH patients who received liver transplants in 2007.11 POPH was confirmed by right heart catheterization in 30 patients evaluated for liver transplant. Sixteen patients were considered to be suitable candidates for transplant and MPAP was decreased to less than 35 mmHg in 12 patients with vasodilator therapy. Eleven patients eventually underwent liver transplant and 1- and 5-year survival rates were 91% and 67%.
Compared to medical therapy or liver transplant alone, patients who receive medical therapy followed by liver transplantation have the best survival. The Mayo Clinic retrospectively reviewed 74 POPH patients identified between 1994 and 2007.40 Patients were categorized in 1 of 3 categories: no medical therapy, medical therapy alone for POPH, or medical therapy for POPH followed by liver transplantation. Patients who received no medical therapy for POPH and no liver transplant had the worst outcomes, with a dismal 5-year survival of only 14% with over 50% deceased at 1 year of diagnosis. Five-year survival was 45% in patients who received medical therapy only. Patients who received medical therapy with prostacyclin followed by liver transplantation had the best outcomes, with a 5-year survival of 67% versus 25% in those who were transplanted without prior prostacyclin therapy.
We reported the longest follow-up study for patients undergoing liver transplantation with POPH in 2014.41 Seven patients with moderate to severe POPH received a liver transplant at our institution between June 2004 and January 2011. Mean pulmonary artery pressure was reduced to < 35 mm Hg, with appropriate POPH therapy in all of the patients. Both the graft and patient survival rates were 85.7% after a median follow-up of 7.8 years. The 1 patient who did not survive died from complications related to recurrent hepatitis C and cirrhosis, not from POPH-related issues. Four of the remaining 6 patients continue to require oral vasodilator therapy post-transplant, suggesting irreversible remodeling of the pulmonary vasculature. Two patients (4.4 and 8.5 years post-transplant) have no evidence of pulmonary hypertension post-transplant and therefore do not require medical treatment for pulmonary hypertension. We concluded that POPH responsive to vasodilator therapy is an appropriate indication for liver transplant, with excellent long-term survival.
Hollatz et al published their data on 11 patients with moderate to severe POPH who were successfully treated (mostly with oral sildenafil and subcutaneous treprostinil) as a bridge to liver transplant.42 The mortality rate was 0, with a follow-up duration of 7 to 60 months. Interestingly, 7 of the 11 patients (64%) were off all pulmonary vasodilators post-transplant. Ashfaq et al reported similar results.11 Nine of 11 patients with treated moderate to severe POPH who received liver transplants stopped vasodilator therapy at a median period of 9.2 months post-transplant. Raevens et al described a group of 3 patients with POPH who went on to liver transplant after their pulmonary pressures were decreased with combined oral vasodilator therapy: 1 required continued long-term vasodilator therapy, another was weaned off medications after transplant, and the third patient died during the liver transplant from perioperative complications that induced uncontrolled pulmonary hypertension.43
Patient Selection
In 2006, the United Network for Organ Sharing (UNOS) initiated a policy whereby a higher priority for liver transplantation was granted for highly selected patients in the United States.44 UNOS policy 3.6.4.5.6 upgraded POPH patients to a MELD score of 22, with an increase in MELD every 3 months as long as MPAP remained < 35 mm Hg and PVR remained < 400 dynes/s/cm–5. One hundred fifty-five patients were granted MELD exception points for POPH between 2002 and 2010 and went on to receive liver transplants.45 Goldberg et al collected data from the Organ Procurement and Transplantation Network (OPTN) and compared outcomes of patients with approved POPH MELD exception points versus waitlist candidates with no exception points.46 One hundred fifty-five waitlisted patients received POPH MELD exception points, with only 43.1% meeting OPTN exception requirements. One-third did not fulfill hemodynamic criteria consistent with POPH or had missing data, and 80% went on to receive a liver transplant. Waitlist candidates receiving POPH MELD exception points also had increased waitlist mortality and several early post-transplant deaths. The authors felt these data highlighted the need for OPTN/UNOS to revise their policy for POPH MELD exceptions points, revise how points are rewarded, and continue research to help risk stratify these patients to minimize perioperative complications.
Conclusion
Several effective medical treatment regimens are available, including prostanoids, endothelin receptor antagonists, and PDE-5 inhibitors. Liver transplantation is a potential cure but is only recommended if MPAP can be decreased to ≤ 35 mmHg. Long-term follow-up studies have shown these patients do well several years post-transplant but may continue to require oral therapy for their POPH.
1. Tuder RM, Cool CD, Geraci MW, et al. Prostacyclin synthase expression is decreased in lungs from patients with severe pulmonary hypertension. Am J Respir Crit Care Med. 1999;159:1925-1932.
2. Chin K, Rubin L. Pulmonary arterial hypertension. Am Coll Cardiol. 2008;51:1527-1538.
3. Doran A, Harris S, Goetz B. Advances in prostanoid infusion therapy for pulmonary arterial hypertension. J Infus Nurs. 2008;31:336-345.
4. Chin KM, Channick RN, De Lemos JA, ET AL. Hemodynamics and epoprostenol use are associated with thrombocytopenia in pulmonary arterial hypertension. Chest. 2009;135:130-136.
5. Hoshikawa Y, Voelkel NF, Gesell TL, et al. Prostacyclin receptor-dependent modulation of pulmonary vascular remodeling. Am J Respir Crit Care Med. 2001;164:314-318.
6. Ricci GL, Melgosa MT, Burgos F, et al. Assessment of acute pulmonary vascular reactivity in portopulmonary hypertension. Liver Transplant. 2007;13:1506-1514.
7. McLaughlin V V, Genthner DE, Panella MM, et al. Compassionate use of continuous prostacyclin in the management of secondary pulmonary hypertension: a case series. Ann Intern Med. 1999;130:740-743.
8. Krowka MJ, Frantz RP, McGoon MD, et al. Improvement in pulmonary hemodynamics during intravenous epoprostenol (prostacyclin): A study of 15 patients with moderate to severe portopulmonary hypertension. Hepatology. 1999;30:641-648.
9. Fix OK, Bass NM, De Morco T, Merriman RB. Long-term follow-up of portopulmonary hypertension: Effect of treatment with epoprostenol. Liver Transplant. 2007;13:875-885.
10. Sussman N, Kaza V, Barshes N, et al. Successful liver transplantation following medical management of portopulmonary hypertension: a single-center series. Am J Transplant. 2006;6:2177-2182.
11. Ashfaq M, Chinnakotla S, Rogers L, et al. The impact of treatment of portopulmonary hypertension on survival following liver transplantation. Am J Transplant. 2007;7:1258-1264.
12. Sakai T, Planinsic RM, Mathier MA, et al. initial experience using continuous intravenous treprostinil to manage pulmonary arterial hypertension in patients with end-stage liver disease. Transpl Int. 2009;22:554-561.
13. McLaughlin VV, Benza RL, Rubin LJ, et al. Addition of inhaled treprostinil to oral therapy for pulmonary arterial hypertension: A randomized controlled clinical trial. J Am Coll Cardiol. 2010;55:1915-1922.
14. Hoeper MM, Seyfarth HJ, Hoeffken G, et al. Experience with inhaled iloprost and bosentan in portopulmonary hypertension. Eur Respir J. 2007;30:1096-1102.
15. Melgosa MT, Ricci GL, Garcia-Pagan JC et al. Acute and long-term effects of inhaled iloprost in portopulmonary hypertension. Liver Transplant. 2010;16:348-356.
16. Simonneau G, Torbicki A, Hoeper MM, et al. Selexipag: an oral, selective prostacyclin receptor agonist for the treatment of pulmonary arterial hypertension. Eur Respir J. 2012;40:874-880
17. Sitbon O, Channick R, Chin, KM, et al. Selexipag for the treatment of pulmonary arterial hypertension. N Engl J Med. 2015;373:2522-2533.
18. Moller S, Gulberg V, Henriksen JH, Gerbes AL. Endothelin-1 and endothelin-3 in cirrhosis: Relations to systemic and splanchnic haemodynamics. J Hepatol. 1995;23:135-144.
19. Eriksson C, Gustavsson A, Kronvall T, Tysk C. Hepatotoxicity by bosentan in a patient with portopulmonary hypertension : a case-report and review of the literature. J Gastrointestin Liver Dis. 2011;20:77-80.
20. Hoeper MM, Halank M, Marx C, et al. Bosentan therapy for portopulmonary hypertension. Eur Respir J. 2005;25:502-508.
21. Stähler G, Von Hunnius P. Successful treatment of portopulmonary hypertension with bosentan: Case report.: Eur J Clin Investig. 2006;36:62-66.
22. Savale L, Magnier R, Le Pavec J, et al. Efficacy, safety and pharmacokinetics of bosentan in portopulmonary hypertension. Eur. 2013;41:96-103.
23. Halank M, Knudsen L, Seyfarth H, et al. Ambrisentan improves exercise capacity and symptoms in patients with portopulmonary hypertension. Z Gastroenterol. 2011;49:1258-1262.
24. Cartin-Ceba R, Swanson K, Iyer V, et al. Safety and efficacy of ambrisentan for the treatment of portopulmonary hypertension. Chest. 2011;139:109-114.
25. Condliffe R, Elliot C, Hurdman J, et al. Ambrisentan therapy in pulmonary hypertension: clinical use and tolerability in a referral centre. Ther Adv Respir Dis. 2014;8:71-77.
26. Pulido T, Adzerikho I, Channick RN, et al. Macitentan and morbidity and mortality in pulmonary arterial hypertension. N Engl J Med. 2013;369:809-818.
27. Reichenberger F, Voswinckel R, Steveling E, et al. Sildenafil treatment for portopulmonary hypertension. Eur Respir J. 2006;28:563-567.
28. Hemnes AR RI. Sildenafil monotherapy in portopulmonary hypertension can facilitate liver transplantation. Liver Transplant. 2009;15:15-19.
29. Gough WR. Sildenafil therapy is associated with improved hemodynamics in liver transplantation candidates with pulmonary arterial hypertension. Liver Transplant. 2009;15:30-36.
30. Yamashita Y. Hemodynamic effects of ambrisentan-tadalafil combination therapy on progressive portopulmonary hypertension. World J Hepatol. 2014;6:825.
31. Bremer HC, Kreisel W, Roecker K, et al. Phosphodiesterase 5 inhibitors lower both portal and pulmonary pressure in portopulmonary hypertension: a case report. J Med Case Rep. 2007;1:46.
32. Ghofrani HA, Galie N, Grimminger F, et al. Riociguat for the treatment of pulmonary arterial hypertension. N Engl J Med. 2013:369;330-340.
33. Ghofrani HA, Galie N, Grimminger F, et al. Riociguat for the treatment of chronic thromboembolic pulmonary hypertension. N Engl J Med. 2013:369;319-329
34. Cartin-Ceba R, Halank M, Ghofrani HA, et al. Riociguat treatment for portopulmonary hypertension: a subgroup analysis from the PATENT-1/-2 studies. Pulm Circ. 2018: 8:2045894018769305.
35. Provencher S, Herve P, Jais X, et al. Deleterious effects of beta-blockers on exercise capacity and hemodynamics in patients with portopulmonary hypertension. 2006. Gastroenterology. 2006;130:120-126.
36. Ramsay M a, Simpson BR, Nguyen T, et al. Severe pulmonary hypertension in liver transplant candidates. Liver Transpl Surg. 1997;3:494-500.
37. Safdar Z, Bartolome S, Sussman N. Portopulmonary hypertension : an update. Liver Tranpl. 2012;18:881-891.
38. Ramsay M. Portopulmonary hypertension and right heart failure in patients with cirrhosis. Curr Opin Anaesthesiol. 2010;23:145-150.
39. Krowka MJ, Plevak DJ, Findlay JY, et al. Pulmonary hemodynamics and perioperative cardiopulmonary-related mortality in patients with portopulmonary hypertension undergoing liver transplantation. Liver Transpl. 2000;6:443-450.
40. Swanson KL, Wiesner RH, Nyberg SL, et al. Survival in portopulmonary hypertension: Mayo Clinic experience categorized by treatment subgroups. Am J Transplant. 2008;8:2445-2453.
41. Khaderi S, Khan R, Safdar Z, et al. Long-term follow-up of portopulmonary hypertension patients after liver transplantation. Liver Transplant. 2014;20:724-727.
42. Hollatz TJ, Musat A, Westphal S, et al. Treatment with sildenafil and treprostinil allows successful liver transplantation of patients with moderate to severe portopulmonary hypertension. Liver Transpl. 2012:686-695.
43. Raevens S, De Pauw M, Reyntjens K, et al. Oral vasodilator therapy in patients with moderate to severe portopulmonary hypertension as a bridge to liver transplantation. Eur J Gastroenterol Hepatol. 2012:1-8.
44. Krowka M, Fallon M, Mulligan D. Model for end-stage liver disease (MELD) exception for portopulmonary hypertension. Liver Transplant. 2006;12:S114-S116.
45. Krowka M, Wiesner R, Rosen C. Portopulmonary hypertension outcomes in the era of MELD exception. Liver Transplant. 2012;18:S259.
46. Goldberg DS, Batra S, Sahay S, et al. MELD Exceptions for portopulmonary hypertension: current policy and future implementation. Am J Transplant. 2014;14:2081-2087.
1. Tuder RM, Cool CD, Geraci MW, et al. Prostacyclin synthase expression is decreased in lungs from patients with severe pulmonary hypertension. Am J Respir Crit Care Med. 1999;159:1925-1932.
2. Chin K, Rubin L. Pulmonary arterial hypertension. Am Coll Cardiol. 2008;51:1527-1538.
3. Doran A, Harris S, Goetz B. Advances in prostanoid infusion therapy for pulmonary arterial hypertension. J Infus Nurs. 2008;31:336-345.
4. Chin KM, Channick RN, De Lemos JA, ET AL. Hemodynamics and epoprostenol use are associated with thrombocytopenia in pulmonary arterial hypertension. Chest. 2009;135:130-136.
5. Hoshikawa Y, Voelkel NF, Gesell TL, et al. Prostacyclin receptor-dependent modulation of pulmonary vascular remodeling. Am J Respir Crit Care Med. 2001;164:314-318.
6. Ricci GL, Melgosa MT, Burgos F, et al. Assessment of acute pulmonary vascular reactivity in portopulmonary hypertension. Liver Transplant. 2007;13:1506-1514.
7. McLaughlin V V, Genthner DE, Panella MM, et al. Compassionate use of continuous prostacyclin in the management of secondary pulmonary hypertension: a case series. Ann Intern Med. 1999;130:740-743.
8. Krowka MJ, Frantz RP, McGoon MD, et al. Improvement in pulmonary hemodynamics during intravenous epoprostenol (prostacyclin): A study of 15 patients with moderate to severe portopulmonary hypertension. Hepatology. 1999;30:641-648.
9. Fix OK, Bass NM, De Morco T, Merriman RB. Long-term follow-up of portopulmonary hypertension: Effect of treatment with epoprostenol. Liver Transplant. 2007;13:875-885.
10. Sussman N, Kaza V, Barshes N, et al. Successful liver transplantation following medical management of portopulmonary hypertension: a single-center series. Am J Transplant. 2006;6:2177-2182.
11. Ashfaq M, Chinnakotla S, Rogers L, et al. The impact of treatment of portopulmonary hypertension on survival following liver transplantation. Am J Transplant. 2007;7:1258-1264.
12. Sakai T, Planinsic RM, Mathier MA, et al. initial experience using continuous intravenous treprostinil to manage pulmonary arterial hypertension in patients with end-stage liver disease. Transpl Int. 2009;22:554-561.
13. McLaughlin VV, Benza RL, Rubin LJ, et al. Addition of inhaled treprostinil to oral therapy for pulmonary arterial hypertension: A randomized controlled clinical trial. J Am Coll Cardiol. 2010;55:1915-1922.
14. Hoeper MM, Seyfarth HJ, Hoeffken G, et al. Experience with inhaled iloprost and bosentan in portopulmonary hypertension. Eur Respir J. 2007;30:1096-1102.
15. Melgosa MT, Ricci GL, Garcia-Pagan JC et al. Acute and long-term effects of inhaled iloprost in portopulmonary hypertension. Liver Transplant. 2010;16:348-356.
16. Simonneau G, Torbicki A, Hoeper MM, et al. Selexipag: an oral, selective prostacyclin receptor agonist for the treatment of pulmonary arterial hypertension. Eur Respir J. 2012;40:874-880
17. Sitbon O, Channick R, Chin, KM, et al. Selexipag for the treatment of pulmonary arterial hypertension. N Engl J Med. 2015;373:2522-2533.
18. Moller S, Gulberg V, Henriksen JH, Gerbes AL. Endothelin-1 and endothelin-3 in cirrhosis: Relations to systemic and splanchnic haemodynamics. J Hepatol. 1995;23:135-144.
19. Eriksson C, Gustavsson A, Kronvall T, Tysk C. Hepatotoxicity by bosentan in a patient with portopulmonary hypertension : a case-report and review of the literature. J Gastrointestin Liver Dis. 2011;20:77-80.
20. Hoeper MM, Halank M, Marx C, et al. Bosentan therapy for portopulmonary hypertension. Eur Respir J. 2005;25:502-508.
21. Stähler G, Von Hunnius P. Successful treatment of portopulmonary hypertension with bosentan: Case report.: Eur J Clin Investig. 2006;36:62-66.
22. Savale L, Magnier R, Le Pavec J, et al. Efficacy, safety and pharmacokinetics of bosentan in portopulmonary hypertension. Eur. 2013;41:96-103.
23. Halank M, Knudsen L, Seyfarth H, et al. Ambrisentan improves exercise capacity and symptoms in patients with portopulmonary hypertension. Z Gastroenterol. 2011;49:1258-1262.
24. Cartin-Ceba R, Swanson K, Iyer V, et al. Safety and efficacy of ambrisentan for the treatment of portopulmonary hypertension. Chest. 2011;139:109-114.
25. Condliffe R, Elliot C, Hurdman J, et al. Ambrisentan therapy in pulmonary hypertension: clinical use and tolerability in a referral centre. Ther Adv Respir Dis. 2014;8:71-77.
26. Pulido T, Adzerikho I, Channick RN, et al. Macitentan and morbidity and mortality in pulmonary arterial hypertension. N Engl J Med. 2013;369:809-818.
27. Reichenberger F, Voswinckel R, Steveling E, et al. Sildenafil treatment for portopulmonary hypertension. Eur Respir J. 2006;28:563-567.
28. Hemnes AR RI. Sildenafil monotherapy in portopulmonary hypertension can facilitate liver transplantation. Liver Transplant. 2009;15:15-19.
29. Gough WR. Sildenafil therapy is associated with improved hemodynamics in liver transplantation candidates with pulmonary arterial hypertension. Liver Transplant. 2009;15:30-36.
30. Yamashita Y. Hemodynamic effects of ambrisentan-tadalafil combination therapy on progressive portopulmonary hypertension. World J Hepatol. 2014;6:825.
31. Bremer HC, Kreisel W, Roecker K, et al. Phosphodiesterase 5 inhibitors lower both portal and pulmonary pressure in portopulmonary hypertension: a case report. J Med Case Rep. 2007;1:46.
32. Ghofrani HA, Galie N, Grimminger F, et al. Riociguat for the treatment of pulmonary arterial hypertension. N Engl J Med. 2013:369;330-340.
33. Ghofrani HA, Galie N, Grimminger F, et al. Riociguat for the treatment of chronic thromboembolic pulmonary hypertension. N Engl J Med. 2013:369;319-329
34. Cartin-Ceba R, Halank M, Ghofrani HA, et al. Riociguat treatment for portopulmonary hypertension: a subgroup analysis from the PATENT-1/-2 studies. Pulm Circ. 2018: 8:2045894018769305.
35. Provencher S, Herve P, Jais X, et al. Deleterious effects of beta-blockers on exercise capacity and hemodynamics in patients with portopulmonary hypertension. 2006. Gastroenterology. 2006;130:120-126.
36. Ramsay M a, Simpson BR, Nguyen T, et al. Severe pulmonary hypertension in liver transplant candidates. Liver Transpl Surg. 1997;3:494-500.
37. Safdar Z, Bartolome S, Sussman N. Portopulmonary hypertension : an update. Liver Tranpl. 2012;18:881-891.
38. Ramsay M. Portopulmonary hypertension and right heart failure in patients with cirrhosis. Curr Opin Anaesthesiol. 2010;23:145-150.
39. Krowka MJ, Plevak DJ, Findlay JY, et al. Pulmonary hemodynamics and perioperative cardiopulmonary-related mortality in patients with portopulmonary hypertension undergoing liver transplantation. Liver Transpl. 2000;6:443-450.
40. Swanson KL, Wiesner RH, Nyberg SL, et al. Survival in portopulmonary hypertension: Mayo Clinic experience categorized by treatment subgroups. Am J Transplant. 2008;8:2445-2453.
41. Khaderi S, Khan R, Safdar Z, et al. Long-term follow-up of portopulmonary hypertension patients after liver transplantation. Liver Transplant. 2014;20:724-727.
42. Hollatz TJ, Musat A, Westphal S, et al. Treatment with sildenafil and treprostinil allows successful liver transplantation of patients with moderate to severe portopulmonary hypertension. Liver Transpl. 2012:686-695.
43. Raevens S, De Pauw M, Reyntjens K, et al. Oral vasodilator therapy in patients with moderate to severe portopulmonary hypertension as a bridge to liver transplantation. Eur J Gastroenterol Hepatol. 2012:1-8.
44. Krowka M, Fallon M, Mulligan D. Model for end-stage liver disease (MELD) exception for portopulmonary hypertension. Liver Transplant. 2006;12:S114-S116.
45. Krowka M, Wiesner R, Rosen C. Portopulmonary hypertension outcomes in the era of MELD exception. Liver Transplant. 2012;18:S259.
46. Goldberg DS, Batra S, Sahay S, et al. MELD Exceptions for portopulmonary hypertension: current policy and future implementation. Am J Transplant. 2014;14:2081-2087.