Title: USE OF ORAL ENDOTHELIN-RECEPTOR ANTAGONIST BOSENTAN IN THE TREATMENT OF PORTOPULMONARY HYPERTENSION
Abstract: We report the successful treatment of portopulmonary hypertension (PPHT) with dual endothelin-receptor antagonist bosentan in a patient with liver cirrhosis of unknown origin and pulmonary arterial hypertension (PAH). A 66-year-old male with PPHT was admitted to our hospital with exertional dyspnea that markedly limited his physical activity (New York Heart Association class III). Portal hypertension with esophageal varices and hypertensive gastropathy have been previously diagnosed. On presentation, he showed no clinical signs of right heart or liver decompensation. International normalized ratio (INR), bilirubin, albumin, creatinine, and hepatic amino-transferase were all within normal range. Child-Pugh score revealed 5 points (Child A). He was able to walk 360 meters in 6 minutes. The peak oxygen uptake (VO2 peak) during exercise with a cycle ergometer was 14.1 ml/kg/min. The abdominal ultrasound showed clear evidence of liver cirrhosis and a dilatation of portal vein (15 mm) with a reduced portal venous flow of 10 cm/s. Echocardiography revealed no pulmonary shunting as a possible sign of hepatopulmonary syndrome and right ventricular systolic pressure was estimated at 85 mm Hg. Initial right-heart catheterization showed precapillary pulmonary hypertension with mean pulmonary artery pressure of 54 mm Hg, pulmonary vascular resistance of 741 dyn*s*cm−5, and cardiac index of 2.6 l/min/m2. The patient received 62.5 mg of bosentan twice daily for 4 weeks starting after initial right heart catheterization, followed by 125 mg of bosentan twice daily. After five months, repeated right-heart catheterization showed markedly improved hemodynamic characteristics at trough level (mean pulmonary artery pressure, 28 mm Hg; pulmonary vascular resistance, 215 dyn*s*cm−5; cardiac index, 4.3 l/min/m2). Distance in the 6-minute walk improved to 450 meters and VO2 peak increased to 18.2 ml/min/kg. These and other parameters at baseline and in the course of therapy are given in Table 1. The portal venous flow measured by duplex sonography was normalized with a flow of 20 cm/s. No change in liver function or hepatic aminotransferase levels was seen during therapy. Because of the age of our patient, no lung or lung-liver transplantation was planned.Table 1: Cardiopulmonary hemodynamics, six minute walk distance, and peak oxygen uptake during exercise at baseline and after five months of bosentan therapyBosentan has been proven effective in the treatment of disease-related symptoms and in slowing down disease progression. It was well tolerated in two placebo-controlled trials in patients with primary pulmonary hypertension (PPH) or with PAH associated with connective-tissue disease (CTD) (1, 2). Bosentan also decreased portal pressure in portal hypertensive animal models (3, 4). To our knowledge, this is the first report on its efficacy and safety in a patient with PPHT. One reason may be the theoretical danger of abnormal hepatic function. Abnormal hepatic function was found to be dose-dependent. In patients with PPH and patients with PAH associated with CTD, increases in hepatic aminotransferase levels to more than eight times the upper limit of normal occurred in 3 percent and 7 percent of those receiving 125 mg and 250 mg bosentan twice daily, respectively (2). We conclude that bosentan should be considered for treatment of portopulmonary hypertension, as well as a bridging strategy before liver or lung transplantation. A phase II trial with bosentan is warranted to establish its safety in patients with portopulmonary hypertension. Michael Halank Stephan Miehlke Gert Hoeffken Alexander Schmeisser Matthias Schulze Ruth H. Strasser