Safety and efficacy of combined use of sildenafil, bosentan, and iloprost before and after liver transplantation in severe portopulmonary hypertension

Abstract

Portopulmonary hypertension (PPHTN) represents a constrictive pulmonary vasculopathy in patients with portal hypertension. Liver transplantation (LT) may be curative and is usually restricted to patients with mild-to-moderate disease severity characterized by a mean pulmonary artery pressure (mPAP Ͻ 35 mm Hg). Patients with severe disease (mPAP Ͼ 50 mm Hg) are usually excluded from transplantation. We describe a patient with severe PPHTN, initiated on sequential and ultimately combination therapy of prostacyclin, sildenafil, and bosentan (PSB) pretransplantation and continued for 2 years posttransplantation. Peak mPAP on PSB therapy was dramatically reduced from 70 mm Hg to 32 mm Hg pretransplantation, and continued therapy facilitated a further fall in mPAP to 28 mm Hg posttransplantation. The pulmonary vascular resistance index fell from 604 to 291 dyne second Ϫ1 cm Ϫ5 . The perioperative mPAP rose to 100 mm Hg following an episode of sepsis and fell with optimization of PSB therapy. In conclusion, this is the first reported patient with severe PPHTN using this combination of vasodilator therapy as a bridge to LT and then as maintenance in the posttransplantation phase. This regimen may enable LT in similar patients in the future, without long-term consequences. Liver Transpl 14: [287][288][289][290][291] 2008. See Editorial on Page 270Portopulmonary hypertension (PPHTN) is defined as the development of pulmonary arterial hypertension associated with liver disease or portal hypertension. 1 The diagnostic criteria for PPHTN are a mean pulmonary artery pressure (mPAP) Ͼ 25 mm Hg at rest, mPAP Ͼ 30 mm Hg during exercise, a normal capillary wedge pressure (Ͻ15 mm Hg), and an elevated pulmonary vascular resistance index (Ͼ240 dyne/second/cm Ϫ5 ) alongside portal hypertension (with or without cirrhosis). [2][3][4][5] The recognized noncirrhotic causes of portal hypertension associated with PPHTN include extrahepatic portal vein obstruction, congenital hepatic fibrosis, nodular regenerative hyperplasia, and hepatoportal sclerosis. [5][6][7] Patients with PPHTN have nonspecific symptoms such as worsening fatigue, dyspnea, and peripheral edema. Men and women are equally affected. 7 No clear relationship exists between severity of liver disease, degree of portal hypertension, and severity of PPHTN. 8,9 Treatment of PPHTN is currently limited by lack of randomized controlled trials, concerns related to drug delivery, safety profiles, and failure of reversibility of the pulmonary disease. 10,11 Vasodilators, in particular, Abbreviations: LT, liver transplantation; mPAP, mean pulmonary artery pressure; NR, normal range; PPHTN, portopulmonary hypertension; PSB, prostacyclin, sildenafil, and bosentan.

2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension

“…In the past, significant PAH was considered a contraindication for liver transplantation, but anecdotal reports suggest that pretreating these patients with [46] RHC is recommended in all cases of suspected PAH associated with CTD C I [46,327] Resting echocardiography is recommended as a screening test in asymptomatic patients with SSc, followed by annual screening with echocardiography, DLCO and biomarkers C I [46] Oral anticoagulation may be considered on an individual basis and in the presence of thrombophilic predisposition C IIb [175,339] CTD: connective tissue disease; DLCO: diffusing capacity of the lung for carbon monoxide; IPAH: idiopathic pulmonary arterial hypertension; PAH: pulmonary arterial hypertension; RHC: right heart catheterization; SSc: systemic sclerosis. PAH drugs might improve the outcome after liver transplantation [360][361][362][363]. There is not yet sufficient evidence to allow general recommendations and the transplant decision should be made by multidisciplinary teams in expert centres.…”

“…The absence of viral particles in the complex plexiform lesions found from these patients suggests that an indirect action of viral infection on inflammation and growth factors may act as a trigger in a predisposed patient. [344] It is recommended that the treatment algorithm for patients with other forms of PAH should be applied to patients with PAH associated with portal hypertension, taking into account the severity of liver disease C I [214,[350][351][352][353][354][355][356] Liver transplantation may be considered in selected patients responding well to PAH therapy C IIb [361][362][363] It is recommended that patients affected by PAH associated with portal hypertension should be referred to centres with expertise in managing both conditions C I [344] Anticoagulation is not recommended in patients with PH associated with portal hypertension C III [365] Liver transplantation is contraindicated in patients with severe and uncontrolled PAH C III [361][362][363] PAH: pulmonary arterial hypertension; PH: pulmonary hypertension. with other risk factors for PAH, such as liver disease (chronic hepatitis B or C), exposure to drugs or toxins or PE due to i.v.…”

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“…It usually is used in combination with other medications. [30][31] Use of the endothelin A/B receptor antagonist bosentan currently is under investigation. Hoeper and associates showed the effectiveness of bosentan as monotherapy 32 and in combination with inhaled iloprost 33 for the treatment of POPH.…”

Treatment with a combination of bosentan and sildenafil allows for successful liver transplantation in a patient with portopulmonary hypertension

“…Phosphodiesterase inhibitors have been successfully applied for the reduction of pulmonary arterial hypertension (8). They are well-tolerated and have a relatively mild adverse effect profile.…”

“…Primary pulmonary hypertension has been managed more successfully since the introduction of endothelin receptor antagonists (8,11). These drugs target endothelin-1, a strong vasoconstrictor.…”