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.
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 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 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.