Survival in portopulmonary hypertension: Outcomes of the United Kingdom National Pulmonary Arterial Hypertension Registry

doi:10.1016/j.healun.2016.12.014

The Journal of Heart and Lung Transplantation

Volume 36, Issue 7, July 2017, Pages 770-779

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https://doi.org/10.1016/j.healun.2016.12.014 Get rights and content

Background

Portopulmonary hypertension (PoPH) is a rare condition associated with poor survival, and the effect of modern therapies that target pulmonary arterial hypertension (PAH) on long-term outcome is unknown. This study investigated the baseline characteristics and survival in the cohort of patients diagnosed with PoPH in the United Kingdom National Pulmonary Hypertension Service.

Methods

A retrospective review was conducted of all incident treatment-naïve patients with PoPH within the United Kingdom national registry diagnosed between January 2001 and December 2010.

Results

Patients with PoPH (n = 110) had survival rates of 85%, 60%, and 35% at 1, 3, and 5 years. The prevalence of PoPH was 0.85 cases/1 million. Mean age at diagnosis was 53 ± 12 years, with a balanced distribution in gender. Alcohol (n = 57) and hepatitis C (n = 10) were the most common causes of portal hypertension. Phosphodiesterase V inhibitors were the most frequently used targeted therapy, in 63.6% (n = 70) of patients, endothelin receptor antagonists were used in 10% (n = 11) and prostacyclin analogs in 12.7% (n = 14). Univariate and multivariate analysis of baseline characteristics did not demonstrate a significant influence of severity of portal hypertension or liver cirrhosis, World Health Organization Functional Class, cardiopulmonary hemodynamics, or year of diagnosis on survival.

Conclusions

Survival of patients with PoPH remains poor despite targeted therapy and worse than patients with idiopathic PAH. The benefit of PAH therapies in PoPH on long-term morbidity and mortality outcomes needs further consideration and study.

Section snippets

Methods

Permission was obtained for the conduct of this study from the National Information Governance Board for the UK and National Health Service Health Research Authority Confidentiality Advisory Group (reference: ECC 7–05(j)/2011). Permission was also obtained from individual PH centers for investigator visitation with Caldicott approval. The Patient Information Advisory Group was fully informed regarding the use of the patient data.

Incidence and prevalence

The population of the UK in 2001 to 2003, 2004 to 2007, and 2008 to 2010 was estimated (http://www.statistics.gov.uk) to be 59.38, 60.63, and 62.26 million, respectively. This gave a rising incidence (in million per year) of PoPH in the United Kingdom of 0.06, 0.17, and 0.32 in 2001 to 2003, 2004 to 2007, and 2008 to 2010, respectively. The prevalence of PoPH in 2010 was 0.85 cases/million population.

Baseline characteristics at the time of diagnosis

A total of 110 patients fulfilled the inclusion criteria. Baseline characteristics of the

Discussion

This national study describes a large cohort of incident treatment-naïve PoPH patients in the UK. The number of incident cases of PoPH diagnosed at PAH specialist centers has increased during the study interval and in the modern era of PH. Patients with PoPH have a poor prognosis, with a 5-year survival rate of 35%. There was no clear evidence of survival benefit in treating these patients and no significant difference in survival between cirrhotic and non-cirrhotic causes of portal

Disclosure statement

S.S. and L.T. report an educational grant from Actelion outside the submitted work. J.G.C. has received speaker fees, honoraria, consultancy, advisory board fees, or investigator, committee member from Actelion, GSK, Bayer, Endotronix, United Therapeutics, and Pfizer, and has also received unrestricted grants from Actelion and GSK. R.C. reports personal fees from Actelion, Bayer, and GSK outside the submitted work. C.A.E. reports personal fees from Actelion and from GSK, grants from Pfizer,

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Portopulmonary hypertension (POPH) is a complication of cirrhosis that results in right ventricular failure and death. The objective of this autopsy investigation was to compare pulmonary arterial receptors in subjects with cirrhosis and histopathologic evidence of pulmonary vascular disease (PVD) and control group subjects with cirrhosis lacking evidence of PVD. Autopsy records of 824 subjects with cirrhosis were reviewed to identify pulmonary arterial vasculopathy. Lung sections from paraffin embedded blocks were immunostained for endothelin A (ET-A), endothelin B (ET- B), estrogen α (ER-α), estrogen β (ER-β), and vascular endothelial growth factor (VEGF). Subjects with cirrhosis and histopathologic evidence of PVD included 27 individuals with intimal hyperplasia (93%), medial hypertrophy (96%), and plexiform lesions (78%). Immunohistochemical staining for ET-A revealed positive reactivity in 40% of the group with cirrhosis and histopathologic evidence of PVD and 13% of the control group (NS). ET-B reactivity in the pulmonary endothelium and smooth muscle was identified in all subjects with cirrhosis and histopathologic evidence of PVD and control group. VEGF reactivity was identified in the endothelium in all subjects with cirrhosis and histopathologic evidence of PVD compared with 33% of the control group (p = 0.0002). ER-β reactivity was observed in four subjects (26.6%) with cirrhosis and histopathologic evidence of PVD while none in the control group (NS). Cirrhosis and histopathologic evidence of PVD was found in 3.3% of autopsies with the pulmonary vasculature immunohistochemical profile demonstrating endothelial and smooth muscle reactivity for endothelin, VEGF and ER-β.
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Portopulmonary hypertension is defined as the development of pulmonary arterial hypertension in the setting of portal hypertension with or without liver cirrhosis. Portal hypertension-associated haemodynamic changes, including hyperdynamic state, portosystemic shunts and splanchnic vasodilation, induce significant alterations in pulmonary vascular bed and play a pivotal role in the pathogenesis of the disease. If left untreated, portopulmonary hypertension results in progressive right heart failure, with a poor prognosis. Although Doppler echocardiography is the best initial screening tool for symptomatic patients and liver transplantation candidates, right heart catheterisation remains the gold standard for the diagnosis of the disease. Severe portopulmonary hypertension exerts a prohibitive risk to liver transplantation by conferring an elevated perioperative mortality risk. It is important for haemodynamic parameters to correspond with non-severe portopulmonary hypertension before patients can proceed with the liver transplantation. Small uncontrolled studies and a recent randomised controlled trial have reported promising results with vasodilatory therapies in clinical and haemodynamic improvement of patients, allowing a proportion of patients to undergo liver transplantation. In this review, the epidemiology, pathogenesis, diagnostic approach and management of portopulmonary hypertension are discussed. We also highlight fields of ongoing investigation pertinent to risk stratification and optimal patient selection to maximise long-term benefit from currently available treatments.
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Porto-pulmonary arterial hypertension (PoPAH) is a form of pulmonary arterial hypertension (PAH) that affects patients with cirrhosis, and — to a lesser extent — patients with non-cirrhotic liver diseases. Compared with other forms of PAH, PoPAH is more prevalent in male, in older subjects, and is characterized by lower mean pulmonary arterial pressure (mPAP) and lower pulmonary vascular resistance (PVR) with higher cardiac output. Despite more favorable hemodynamics and functional class, patients with PoPAH have a significantly worse survival than patients with other forms of PAH, likely because of liver-related events and therapeutic barriers to PAH-specific therapy. Furthermore, here cardiopulmonary and hepatic complications may affect treatment efficacy. These patients have been excluded from most randomized clinical trials testing PAH-specific treatments. To date, there is only one study investigating efficacy, safety, tolerability and pharmacokinetics of PAH-specific therapy in patients with PoPAH in a randomized placebo-controlled setting. In this trial the use of the endothelin-1 receptor antagonist macitentan showed clear hemodynamic benefit without safety concerns. However, the drug effects on functional capacity and mortality remain unclear. Here we review the current knowledge on the pathophysiology and management of PoPAH and report a case vignette of a patient with PoPAH due to hepatorenal polycystic disease.

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Survival in portopulmonary hypertension: Outcomes of the United Kingdom National Pulmonary Arterial Hypertension Registry

Background

Methods

Results

Conclusions

Section snippets

Methods

Incidence and prevalence

Baseline characteristics at the time of diagnosis

Discussion

Disclosure statement

Chest

Mayo Clin Proc

Gastroenterology

Liver Transpl

Liver Transpl

Chest

Chest

Gastroenterology

Am J Transplant

Am J Transplant

Portopulmonary hypertension: survival and prognostic factors

Am J Respir Crit Care Med

Hemodynamics and survival of patients with portopulmonary hypertension

Liver Transpl

Portopulmonary hypertension

Semin Respir Crit Care Med

Bosentan therapy for portopulmonary hypertension

Eur Respir J

Sildenafil monotherapy in portopulmonary hypertension can facilitate liver transplantation

Liver Transpl