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. 2022 Aug 4;60(2):2102304.
doi: 10.1183/13993003.02304-2021. Print 2022 Aug.

Impact of hepatopulmonary syndrome in liver transplantation candidates and the role of angiogenesis

Steven M Kawut  1   2 , Michael J Krowka  3 , Kimberly A Forde  4   2 , Nadine Al-Naamani  4 , Karen L Krok  5 , Mamta Patel  4   2 , Carlo R Bartoli  6   7 , Margaret Doyle  8 , Jude Moutchia  2 , Grace Lin  3 , Jae K Oh  3 , Carl D Mottram  3 , Paul D Scanlon  3 , Michael B Fallon  9 ; Pulmonary Vascular Complications of Liver Disease Study Group
Affiliations

Impact of hepatopulmonary syndrome in liver transplantation candidates and the role of angiogenesis

Steven M Kawut et al. Eur Respir J. .

Abstract

Background: Hepatopulmonary syndrome affects 10-30% of patients with cirrhosis and portal hypertension. We evaluated the serum angiogenic profile of hepatopulmonary syndrome and assessed the clinical impact of hepatopulmonary syndrome in patients evaluated for liver transplantation.

Methods: The Pulmonary Vascular Complications of Liver Disease 2 study was a multicentre, prospective cohort study of adults undergoing their first liver transplantation evaluation. Hepatopulmonary syndrome was defined as an alveolar-arterial oxygen gradient ≥15 mmHg (≥20 mmHg if age >64 years), positive contrast-enhanced transthoracic echocardiography and absence of lung disease.

Results: We included 85 patients with hepatopulmonary syndrome and 146 patients without hepatopulmonary syndrome. Patients with hepatopulmonary syndrome had more complications of portal hypertension and slightly higher Model for End-Stage Liver Disease-Na score compared to those without hepatopulmonary syndrome (median (interquartile range) 15 (12-19) versus 14 (10-17), p=0.006). Hepatopulmonary syndrome patients had significantly lower 6-min walk distance and worse functional class. Hepatopulmonary syndrome patients had higher circulating angiopoietin 2, Tie2, tenascin C, tyrosine protein kinase Kit (c-Kit), vascular cell adhesion molecule 1 and von Willebrand factor levels, and lower E-selectin levels. Patients with hepatopulmonary syndrome had an increased risk of death (hazard ratio 1.80, 95% CI 1.03-3.16, p=0.04), which persisted despite adjustment for covariates (hazard ratio 1.79, 95% CI 1.02-3.15, p=0.04). This association did not vary based on levels of oxygenation, reflecting the severity of hepatopulmonary syndrome.

Conclusion: Hepatopulmonary syndrome was associated with a profile of abnormal systemic angiogenesis, worse exercise and functional capacity, and an overall increased risk of death.

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Conflict of interest statement

Conflict of interest: None declared.

Figures

FIGURE 1
FIGURE 1
Least square means and 95% confidence intervals of 6-min walk test (6MWT) parameters. All values are adjusted for age, sex, Model for End-Stage Liver Disease (MELD)-Na and baseline values (other than distance). HPS: hepatopulmonary syndrome.
FIGURE 2
FIGURE 2
Violin plots of selected angiogenesis biomarkers. Boxes are interquartile ranges with median. Whiskers are observations within 1.5×interquartile range. Plots of platelet-derived growth factor (PDGF)-AB/BB, endostatin and angiostatin only show data that are within 1.5×interquartile range. p-values are from multivariable linear regression models adjusted for age and Model for End-Stage Liver Disease-Na score. HPS: hepatopulmonary syndrome; C-Kit: tyrosine protein kinase Kit; VCAM1: vascular cell adhesion molecule 1; Tie2: TEK tyrosine kinase, endothelial.
FIGURE 3
FIGURE 3
Violin plots of von Willebrand factor (vWF) biomarkers. Boxes are interquartile ranges with median. Whiskers are observations within 1.5×interquartile range. p-values are from multivariable linear regression models adjusted for age and Model for End-Stage Liver Disease-Na score. HPS: hepatopulmonary syndrome; HMW: high molecular weight; LMW: low molecular weight; ADAMTS13: ADAM metallopeptidase with thrombospondin type 1 motif 13.
FIGURE 4
FIGURE 4
Kaplan–Meier curves comparing patients with hepatopulmonary syndrome (HPS) and liver disease controls.
FIGURE 5
FIGURE 5
Predicted cumulative incidences of death and liver transplantation for patients with hepatopulmonary syndrome (HPS) and liver disease controls.
See this image and copyright information in PMC

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