title: Angiopoietin-2 in acute liver failure.
abstract: OBJECTIVE
  Angiopoietin-2, an antagonistic ligand of the endothelial Tie2 receptor, has been identified as a gatekeeper of endothelial activation. We examined whether the release of Angiopoietin-2 correlates with surrogates of organ dysfunction and outcome in patients with acute liver failure.
  
  
  METHODS
  Retrospective clinical and immunohistological study.
  
  
  METHODS
  Intensive care unit of a university hospital.
  
  
  METHODS
  Thirty-seven patients with acute liver failure and 20 healthy control subjects.
  
  
  METHODS
  None.
  
  
  RESULTS
  Angiopoietin-2 levels were measured in sera from 37 patients with acute liver failure on admission and from 20 healthy control subjects. Median age of patients with acute liver failure was 34 yrs, 29 were female, and 21 developed encephalopathy grade 3 or greater. Nine patients survived to day 28 without transplantation, five died without transplantation, and 23 received a transplant. Median (interquartile range) Angiopoietin-2 serum concentrations steadily increased across the following groups: healthy control subjects (1.4 [0.9-1.7] ng/mL), patients with transplant-free recovery (10.0 [4.7-12.1] ng/mL), and patients who reached the composite end point of death or emergency liver transplantation (16.8 [11.3-39.5] ng/mL). Angiopoietin-2 release correlated strongly with surrogate markers of organ dysfunction and disease severity measures (lactate, platelet count, Sequential Organ Failure Assessment score, and Simplified Acute Physiology Score III). Angiopoietin-2 levels were higher in patients with acute kidney injury and patients on mechanical ventilation. Furthermore, Angiopoietin-2 levels were closely associated with Bilirubin-Lactate-Etiology score but not with other liver-specific markers. Unadjusted and adjusted Cox's proportional hazards analyses identified Angiopoietin-2 as a predictor of the composite end point of death or transplantation. Finally, immunohistological studies showed that Angiopoietin-2 protein was upregulated in acute liver failure explants compared with matched liver biopsies obtained at baseline.
  
  
  CONCLUSIONS
  Collectively, our data show that circulating Angiopoietin-2, which potentially originates from the injured liver, correlates with several features of multiple organ dysfunction syndrome and independently predicts outcome. Tie2 agonists may have potential as an endothelium-targeted therapy to ameliorate multiple organ dysfunction syndrome and improve outcome in acute liver failure.
authors.affiliation: Department of Gastroenterology, Hepatology, and Endocrinology, the Institute of Pathology, Hannover Medical School, Hannover, Germany. hadem.johannes@mh-hannover.de
authors.forename: Johannes
authors.initials: J
authors.lastname: Hadem
authors.forename: Clemens L
authors.initials: CL
authors.lastname: Bockmeyer
authors.forename: Alexander
authors.initials: A
authors.lastname: Lukasz
authors.forename: Sven
authors.initials: S
authors.lastname: Pischke
authors.forename: Andrea S
authors.initials: AS
authors.lastname: Schneider
authors.forename: Heiner
authors.initials: H
authors.lastname: Wedemeyer
authors.forename: Danny
authors.initials: D
authors.lastname: Jonigk
authors.forename: Michael P
authors.initials: MP
authors.lastname: Manns
authors.forename: Philipp
authors.initials: P
authors.lastname: Kümpers
mesh_terms: D000328:Adult; D042702:Angiopoietin-2 / Q000097:blood* / Q000502:physiology; D015415:Biomarkers / Q000097:blood; D016022:Case-Control Studies; D016009:Chi-Square Distribution; D005260:Female; D006801:Humans; D008099:Liver / Q000378:metabolism; D017114:Liver Failure, Acute / Q000097:blood* / Q000503:physiopathology; D008297:Male; D009102:Multiple Organ Failure / Q000097:blood / Q000503:physiopathology; D012189:Retrospective Studies; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018709:Statistics, Nonparametric
chemical_list: D042702:Angiopoietin-2; D015415:Biomarkers