The Liver-Lung Connection in Portopulmonary Hypertension

Abstract

Portopulmonary hypertension, a subtype of World Health Organization Group 1 pulmonary arterial hypertension (PAH) that develops in the setting of portal hypertension, is the third most common cause of associated PAH and affects approximately 5-6% of patients evaluated for liver transplant. POPH is pathologically indistinct from idiopathic PAH(1), but is associated with a significantly lower 5-year survival of 40%(2).

POPH can complicate or preclude liver transplantation due to an elevated risk of perioperative death(8). Because of this increased risk, patients on the liver transplant list undergo yearly echocardiograms to screen for POPH, and patients with a known diagnosis of POPH undergo repeated right heart catheterizations every 3 months to ensure hemodynamics are acceptable for transplant(9, 10). Since 2006, patients with treated POPH who meet certain hemodynamic criteria have been eligible to receive MELD exception points, or waitlist priority upgrades, in order to expedite liver transplant(10, 11), but potentially important factors, such as severity of liver disease and POPH, are not included in the score and may affect survival.

The pathogenesis of POPH, characterized by pulmonary vasoconstriction and vascular remodeling, is poorly understood. There is no association between the presence of POPH and severity of liver disease or portal hypertension(3-5), but an increased prevalence of spontaneous portosystemic shunts in patients with POPH(6) as well as the development of POPH in patients with congenital portosystemic shunts with normal liver function(7) suggests that vasoactive factors from the splanchnic circulation contribute to disease pathogenesis. Identification of these factors and improved understanding of the role of the liver in the pathogenesis of POPH could lead to novel targeted therapies for this disease.

The overall goal of my research is to define the liver-lung connection in POPH and to determine the role of the portal circulation in disease pathogenesis and the role of liver transplant in the management of POPH. To address these goals, we have performed two studies. First, we performed a prospective multicenter case-control study in patients with liver disease to identify novel biomarkers of POPH and to compare biomarker gradients across the systemic and pulmonary circulation. We identified higher levels of macrophage migration inhibitory factor (MIF), a pleiotropic inflammatory cytokine, in both the systemic and pulmonary circulation of patients with POPH and found that MIF was correlated with POPH disease severity. Additionally, MIF in conjunction with echocardiogram could improve the screening of patients with liver disease for POPH. In the second study, we performed a retrospective analysis of the United Network for Organ Sharing (UNOS) national database to identify significant predictors of waitlist mortality in patients with POPH. We characterized waitlist and post-transplant outcomes in patients with POPH and identified both initial MELD score and pulmonary vascular resistance as significant predictors of waitlist mortality. Future directions will include prospective study to identify the short-term and long-term effects of liver transplant on pulmonary hemodynamics in patients with POPH.