title: Macrophage migration inhibitory factor as a novel biomarker of portopulmonary hypertension.
abstract: Portopulmonary hypertension (POPH) is a poorly understood complication of liver disease associated with significant morbidity and mortality. We sought to identify novel biomarkers of POPH disease presence and severity. We performed a prospective, multicenter, case-control study involving patients with liver disease undergoing right heart catheterization. POPH cases were defined as a mean pulmonary arterial pressure (mPAP) ≥25 mmHg and pulmonary vascular resistance (PVR) >240 dynes˙s˙cm-5. Plasma samples were collected from the systemic and pulmonary circulation, and antibody microarray was used to identify biomarkers. Characterization and validation of a candidate cytokine, macrophage migration inhibitory factor (MIF), was performed using enzyme-linked immunosorbent assay. Continuous variables were compared using a Mann-WhitneyUtest and correlated with disease severity using Spearman correlation. MIF levels were elevated in both the systemic and pulmonary circulation in patients with POPH compared with controls (median MIF level [interquartile range] in systemic circulation: 46.68 ng/mL [32.31-76.04] vs. 31.19 ng/mL [26.92-42.17],P= 0.009; in pulmonary circulation: 49.59 ng/mL [35.90-108.80] vs. 37.78 [21.78-45.53],P= 0.002). In patients with POPH, MIF levels were positively correlated with PVR (r= 0.58,P= 0.006) and inversely correlated with cardiac output (r= -0.57,P= 0.007). MIF >60 ng/mL or tricuspid regurgitation gradient >50 mmHg had a 92% sensitivity and specificity for the diagnosis of POPH, with a positive predictive value of 86% and a negative predictive value of 96%. MIF is a promising novel biomarker of POPH disease presence and severity in patients with liver disease and portal hypertension.
authors.affiliation: Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.
authors.forename: Hilary M
authors.initials: HM
authors.lastname: DuBrock
authors.affiliation: Massachusetts General Hospital, Boston, Massachusetts, USA.
authors.forename: Josanna M
authors.initials: JM
authors.lastname: Rodriguez-Lopez
authors.affiliation: Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.
authors.forename: Barbara L
authors.initials: BL
authors.lastname: LeVarge
authors.affiliation: Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Curry
authors.affiliation: Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.
authors.forename: Paul A
authors.initials: PA
authors.lastname: VanderLaan
authors.affiliation: Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.
authors.forename: Zsuzsanna K
authors.initials: ZK
authors.lastname: Zsengeller
authors.affiliation: Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Pernicone
authors.affiliation: Tufts University Medical Center, Boston, Massachusetts, USA.
authors.forename: Ioana R
authors.initials: IR
authors.lastname: Preston
authors.affiliation: Brigham and Women's Hospital, Boston, Massachusetts, USA.
authors.forename: Paul B
authors.initials: PB
authors.lastname: Yu
authors.affiliation: Brigham and Women's Hospital, Boston, Massachusetts, USA.
authors.forename: Ivana
authors.initials: I
authors.lastname: Nikolic
authors.affiliation: Massachusetts General Hospital, Boston, Massachusetts, USA.
authors.forename: Dihua
authors.initials: D
authors.lastname: Xu
authors.affiliation: Massachusetts General Hospital, Boston, Massachusetts, USA.
authors.forename: Ravi I
authors.initials: RI
authors.lastname: Thadhani
authors.affiliation: Massachusetts General Hospital, Boston, Massachusetts, USA.
authors.forename: Richard N
authors.initials: RN
authors.lastname: Channick
authors.affiliation: Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.
authors.forename: S
authors.initials: S
authors.lastname: Ananth Karumanchi
keywords: biomarker; macrophage migration inhibitory factor; portopulmonary hypertension; pulmonary arterial hypertension; transpulmonary