Pulmonary Hypertension Association

Medical Treatment Options / Advances in Portopulmonary Hypertension: How the Spectrum Is Expanding

Raymond L. Benza, MD
Department of Medicine–Cardiovascular Disease
University of Alabama at Birmingham
Birmingham, Alabama

[Editor's Note: This article is Part 2 of coverage that began in the last issue on pulmonary hypertension in the setting of liver disease. Whereas the first articles discussed pathophysiology and liver transplantation, this article reviews medical treatment and related options.]

Introduction
Portopulmonary hypertension is defined as the presence of an elevated pulmonary artery pressure (PAP; resting mean PAP >25 mm Hg or exercise PAP >30 mm Hg), with a normal pulmonary capillary wedge pressure in the presence of portal hypertension.¹ Portopulmonary hypertension is a recognized complication of end-stage liver disease that carries a high risk for orthotopic liver transplantation mortality.^2-4 The prevalence of significant pulmonary arterial hypertension in cirrhotic patients ranges from 2% to 20%, across studies that utilized different screening techniques (ie, Doppler echocardiography versus right heart catheterization).^5-7 A recent prospective analysis of Doppler echocardiographic measurements and pulmonary hemodynamics in cirrhotic patients awaiting transplant revealed a 6% incidence of portopulmonary hypertension.⁸ The actual prevalence may be greater in the cirrhotic population because patients are asymptomatic early in the disease. Sixmonth mortality in patients with portopulmonary hypertension is estimated to be 50%,⁹ emphasizing the need for appropriate medical therapy, especially for the transplantation candidate with

Table 1—Current and Potential Medical Treatment Options for Portopulmonary Hypertension.

Intravenous prostacyclin (epoprostenol)
Prostacyclin analogs (treprostinil, iloprost)
Inhaled nitric oxide
Phosphodiesterase inhibitors (sildenafil)
Endothelin antagonists (bosentan, sitaxsentan, ambrisentan)
L-arginine
? Combination therapy

portopulmonary hypertension.

Medical treatment of portopulmonary hypertension has typically been empirical and similar to that described for pulmonary arterial hypertension (Table 1). The numbers of reported portopulmonary hypertension patients treated with medical therapy are small, and long-term studies or consensus guidelines are lacking. This article focuses on the published data for the current medical management of portopulmonary hypertension as well as possible future treatments.

General Considerations For Treatment
Prior to the institution of pharmacologic therapy, the patient with portopulmonary hypertension should undergo a complete hemodynamic evaluation to determine the severity of pulmonary hypertension and right ventricular dysfunction. Exercise capacity and New York Heart Association (NYHA) functional class should also be documented prior to any therapeutic intervention. The clinician will also need to consider the potential orthotopic liver transplantation eligibility of each patient and the specific long-term treatment goals. Other factors of importance in this unique patient population would include, but not be limited to specific adverse effects of drug therapy (eg, thrombocytopenia); the potential for altered drug metabolism; drug-specific hepatic toxicity; the route of administration and technical considerations for drug administration; patients’ ability to use the prescribed drug correctly (presence or absence of encephalopathy); and any pertinent logistic considerations (eg, family support).

Therapeutic Options
Prostacyclin
Epoprostenol (prostacyclin) is a potent vasodilator produced by the endothelial and smooth-muscle cells of the vasculature. Prostacyclin also possesses antiproliferative and antiplatelet aggregating effects. The improvement in survival of pulmonary arterial hypertension patients treated with intravenous epoprostenol as compared to historical controls is well documented.^10,11 Intravenous epoprostenol also has proven efficacy in the treatment of portopulmonary hypertension and has been used as a therapeutic bridge to orthotopic liver transplantation.^12-15 Kuo et al¹³ observed a decrease in mean PAP and pulmonary vascular resistance (PVR) as well as an increase in cardiac output in 4 patients with portopulmonary hypertension treated for 6 to 14 months with intravenous epoprostenol (10 to 28 ng/kg/min). McLaughlin et al¹⁵ studied 7 patients with portopulmonary hypertension following an average of 12.7 months of treatment with continuous epoprostenol infusion. In this subgroup of pulmonary arterial hypertension patients, rightheart catheterization demonstrated a 33% decrease in mean PAP and a 68% decrease in PVR. Krowka et al¹⁴ confirmed the hemodynamic benefits of both acute and long-term intravenous epoprostenol in a study of 15 patients with moderate to severe portopulmonary hypertension (mean PAP 35 mm Hg).

Intravenous epoprostenol serves an important role in the perioperative period to decrease PVR in portopulmonary hypertension patients undergoing orthotopic liver transplantation. Published case reports have documented the efficacy of epoprostenol both prior to transplantation and in the treatment of portopulmonary hypertension that has progressed after transplantation.¹⁶

Commonly observed side effects of epoprostenol include flushing, headache, jaw pain, leg pain, diarrhea, and nausea. These adverse events are generally mild and dose-related. More serious complications are related to the delivery system for epoprostenol administration. Because of its short half-life (1 to 2 minutes) and chemical instability, epoprostenol must be administered via a central venous catheter and a portable infusion pump. This route of delivery exposes patients receiving long-term treatment to potential catheter-related complications such as sepsis and venous thromboembolism.

The inhaled route has been described in a single case report as a potential alternative delivery method for epoprostenol in the acute therapy of portopulmonary hypertension. ¹⁸ After 10 minutes of inhaled delivery, mean PAP decreased by 26%; cardiac output increased by 22%, and PVR decreased by 42%.

Prostacyclin Analogs
Treprostinil.This stable prostacyclin analog administered as a continuous subcutaneous infusion has documented clinical efficacy in pulmonary arterial hypertension.^19,20 Potential advantages of subcutaneous treprostinil administration compared with intravenous epoprostenol include lack of an indwelling catheter and stability of the medication at room temperature. The reduced infection risk with subcutaneous administration is significant in the potentially unstable post-orthotopic liver transplantation patient.

We recently reported the results of long-term subcutaneous treprostinil infusion in the treatment of portopulmonary hypertension.²¹ Thirty-seven portopulmonary hypertension patients (20 women, 17 men) received treprostinil for an average of 8.1 months. The dose of treprostinil increased over time with a mean maximum dose of 16.5± 12.6 ng/kg/min. Mean PVR index decreased by 18% compared to baseline. Prior to treprostinil treatment, 29 patients (78%) were classified as NYHA functional class III and 8 patients (22%) were classified as functional class II. Twenty-one patients had an assessment of functional class at both baseline and follow-up. Functional class at final assessment was improved or unchanged in 19 of 21 patients ( P= .031; Figure 1). Lifetime cumulative survival rates are shown in Figure 2. At 19 months the Kaplan-Meier survival estimate was 71%. This improvement in mortality, compared with historical control data, will need to be confirmed with long-term follow-up.

The most common drug-attributable adverse events were related to the infusion site and included site pain and reaction and bruising. Other common adverse events included diarrhea, headache, vasodilatation, and nausea. Importantly, there were no significant changes in platelet count, total bilirubin, alkaline phosphatase, AST, ALT, PT or PTT.

Iloprost. Inhaled iloprost, delivered via a hand-held nebulizer, is currently approved for pulmonary arterial hypertension treatment in Europe. A randomized trial of this stable prostacyclin analog in 203 patients with NYHA functional class III or IV disease demonstrated clinical efficacy compared with placebo.²² Secondary etiologies of pulmonary arterial hypertension in this trial did not include portopulmonary hypertension, so the efficacy of this agent for this particular patient subgroup is currently unknown. Inhaled iloprost has the disadvantage of a short duration of action and requires six to nine daily inhalations.

Inhaled Nitric Oxide
Nitric oxide is a potent, endogenous, endothelium-derived vasodilator that directly relaxes vascular smooth muscle by increasing cyclic guanosine monophosphate (cGMP). Inhaled nitric oxide, a pulmonary vasodilator, reduces PAP in some patients with primary pulmonary hypertension. The effect of this compound in patients with portopulmonary hypertension is controversial. In one series 5 of 6 patients responded to nitric oxide inhalation with decreases in PAP and PVR of greater than 10%; cardiac output did not significantly change.²³ These findings have not been consistently reproduced in other patient series and may be due to the increased levels of endogenous nitric oxide observed in patients with advanced liver disease.^24,25 The ability to predict hemodynamic responsiveness to inhaled nitric oxide would be clinically useful for the potential treatment of portopulmonary hypertension. It should be noted that this treatment requires a continuous inhalation device.

Phosphodiesterase Inhibitors
Phosphodiesterase (PDE) inhibitors have been suggested as potentially effective therapies for pulmonary arterial hypertension, but no PDE inhibitors are currently approved for this indication. PDE inhibitors presumably improve the hemodynamic abnormalities of pulmonary arterial hypertension by enhancement of endogenous nitric oxide effects (via inhibition of cGMP breakdown). Sildenafil, a PDE type-5 inhibitor, has been shown in uncontrolled, open-label studies to improve functional status and pulmonary hemodynamics. ^26,27 The European Commission recently granted orphan drug status to sildenafil citrate for possible use as a treatment of pulmonary arterial hypertension. This agent has not been studied for portopulmonary hypertension but may prove beneficial and should be evaluated in a placebo-controlled, randomized clinical trial. Dosage adjustments may be necessary in the cirrhotic patient as sildenafil undergoes extensive hepatic metabolism.

Endothelin Receptor Antagonists
Increased concentrations of endothelin-1 (ET-1), a potent vasoconstrictor, are found in the plasma and lung tissue of patients with pulmonary hypertension secondary to congenital heart disease and also in patients with liver disease. The involvement of ET-1 as a modulator of increased PVR in pulmonary arterial hypertension patients has led to the development of endothelin receptor antagonists as potential therapeutic agents. Bosentan is an orally active, nonpeptide, competitive antagonist of both ET-A and ET-B (endothelin type A and B) receptors, with a slightly higher affinity for the ET-A receptor. Bosentan is the only approved oral medication for the treatment of pulmonary arterial hypertension in the United States. The orally active selective ET-A receptor antagonist, sitaxsentan, is currently in clinical trials. The potential for hepatic toxicity with therapeutic doses of these agents precludes their use in the treatment of portopulmonary hypertension. Bosentan resulted in a threefold increase in aminotransferase enzymes in 11% of patients treated in the clinical development program.²⁸ Similar hepatotoxic findings have also been reported with sitaxsentan.²⁹ Another orally active selective ET-A receptor antagonist, ambrisentan, is currently entering phase 3 clinical trials. The potential for liver toxicity with this agent is currently unknown.

L-arginine
L-arginine is a substrate for the production of nitric oxide by the enzyme nitric oxide synthase. Oral supplementation of Larginine could possibly lead to an increase in endogenous nitric oxide production and subsequent pulmonary vascular dilation. Modest decreases in PVR and improved exercise capacity were noted in 10 patients with pulmonary arterial hypertension following 1 week of oral L-arginine supplementation. ³⁰ Additional studies will be necessary to confirm the potential role of L-arginine supplementation in the management of pulmonary arterial hypertension and portopulmonary hypertension. As with nitric oxide administration, increased levels of endogenous nitric oxide in patients with liver disease may blunt the therapeutic response observed with L-arginine.

Conclusions and Implications for Clinical Practice
The therapeutic agents available for the treatment of portopulmonary hypertension have been primarily used in the treatment of pulmonary arterial hypertension. Not all of the available pulmonary arterial hypertension treatments have been systematically evaluated in portopulmonary hypertension patients. Clinical experience is most extensive with intravenous epoprostenol for this patient population. Epoprostenol improves the hemodynamics of portopulmonary hypertension and can be used as a bridge to orthotopic liver transplantation. Recent data would suggest that continuous subcutaneous treprostinil infusion has a beneficial effect on portopulmonary hypertension patient functional class and overall mortality. Inhaled iloprost has not been adequately studied in this population and inhaled nitric oxide has pulmonary selectivity, but the data in portopulmonary hypertension patients have been conflicting. Bosentan, an orally active endothelin receptor antagonist, has demonstrated efficacy in pulmonary arterial hypertension but should be avoided in patients with portopulmonary hypertension because of its potential for liver toxicity. Because of altered hepatic metabolism in cirrhotic patients, therapeutic agents with extrahepatic mechanisms of excretion and without specific hepatic toxicity are preferred in the treatment of portopulmonary hypertension. Potentially useful agents for future study include phosphodiesterase inhibitors, “nonhepatotoxic” endothelin receptor antagonists, and L-arginine. Studies of combination therapy in pulmonary arterial hypertension, utilizing agents with differing mechanisms of action, are anxiously awaited and may also have application in portopulmonary hypertension.

References
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