Portopulmonary Hypertension: Treatment

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.