title: Plasma biomarkers to study mechanisms of liver injury in patients with hypoxic hepatitis.
abstract: Hypoxic hepatitis is a clinical condition precipitated by prolonged periods of oxygen deprivation to the liver. It can have several underlying causes. Despite its prevalence in critically ill patients, which can reach upwards of 10%, very little is known about the mechanisms of injury. Thus, we set out to measure previously identified circulating biomarkers in an attempt to describe mechanisms of injury following hypoxic hepatitis.
  
  
  
  Plasma from patients diagnosed with hypoxic hepatitis was collected for this study. Biomarkers of hepatocellular injury, mitochondrial damage and cell death were measured. These results were compared against results obtained from well-characterized acetaminophen overdose patients.
  
  
  
  At peak injury, ALT measured 4082±606 U/L and gradually decreased over 5 days, corresponding to the clinically observed pattern of hypoxic hepatitis. Levels of GDH showed a similar pattern, but neither ALT nor GDH were significantly higher in these patients than in acetaminophen patients. Plasma levels of DNA fragments mimicked hepatocellular injury as measured by ALT and miRNA-122. Interestingly, we found a significant increase in caspase-cleaved cytokeratin-18; however, the full-length form greatly exceeded the cleaved form at the time of maximum injury (45837±12085 vs 2528±1074 U/L). We also found an increase in acHMGB1 at later time points indicating a possible role of inflammation, but cytokine levels at these times were actually decreased relative to early time points.
  
  
  
  The mechanism of injury following hypoxic hepatitis involves mitochondrial damage and DNA fragmentation. Importantly, necrosis, rather than apoptosis, is the main mode of cell death.
authors.affiliation: Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA.
authors.forename: James L
authors.initials: JL
authors.lastname: Weemhoff
authors.affiliation: Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA.
authors.forename: Benjamin L
authors.initials: BL
authors.lastname: Woolbright
authors.affiliation: MRC Centre for Drug Safety Science, Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool, UK.
authors.forename: Rosalind E
authors.initials: RE
authors.lastname: Jenkins
authors.affiliation: Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA.
authors.forename: Mitchell R
authors.initials: MR
authors.lastname: McGill
authors.affiliation: Department of Internal Medicine, University of Kansas Medical Center, Kansas City, KS, USA.
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Sharpe
authors.affiliation: Department of Internal Medicine, University of Kansas Medical Center, Kansas City, KS, USA.
authors.forename: Jody C
authors.initials: JC
authors.lastname: Olson
authors.affiliation: MRC Centre for Drug Safety Science, Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool, UK.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Antoine
authors.affiliation: Department of Medical Toxicology, Banner -University Medical Center Phoenix, Phoenix, AZ, USA.|Department of Medicine, and the Center for Toxicology and Pharmacology Education and Research, University of Arizona College of Medicine, Phoenix, AZ, USA.
authors.forename: Steven C
authors.initials: SC
authors.lastname: Curry
authors.affiliation: Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA.
authors.forename: Hartmut
authors.initials: H
authors.lastname: Jaeschke
mesh_terms: D000082:Acetaminophen / Q000633:toxicity; D000293:Adolescent; D000328:Adult; D000410:Alanine Transaminase / Q000097:blood; D017209:Apoptosis; D015415:Biomarkers / Q000097:blood; D053938:DNA Fragmentation; D004272:DNA, Mitochondrial / Q000097:blood; D005260:Female; D024243:HMGB1 Protein / Q000097:blood; D006505:Hepatitis / Q000097:blood*; D006801:Humans; D000860:Hypoxia / Q000097:blood*; D007511:Ischemia / Q000097:blood* / Q000209:etiology; D053538:Keratin-18 / Q000097:blood; D016014:Linear Models; D008099:Liver / Q000098:blood supply / Q000503:physiopathology*; D008297:Male; D035683:MicroRNAs / Q000097:blood; D008875:Middle Aged; D008928:Mitochondria / Q000473:pathology; D009336:Necrosis / Q000209:etiology; D014481:United States; D055815:Young Adult
chemical_list: D015415:Biomarkers; D004272:DNA, Mitochondrial; D024243:HMGB1 Protein; D053538:Keratin-18; C531907:MIRN122 microRNA, human; D035683:MicroRNAs; D000082:Acetaminophen; D000410:Alanine Transaminase
keywords: Hypoxic hepatitis; acetaminophen; apoptosis; biomarkers; ischaemic hepatitis; miRNA-122; necrosis