title: Mechanistic biomarkers provide early and sensitive detection of acetaminophen-induced acute liver injury at first presentation to hospital.
abstract: Acetaminophen overdose is a common reason for hospital admission and the most frequent cause of hepatotoxicity in the Western world. Early identification would facilitate patient-individualized treatment strategies. We investigated the potential of a panel of novel biomarkers (with enhanced liver expression or linked to the mechanisms of toxicity) to identify patients with acetaminophen-induced acute liver injury (ALI) at first presentation to the hospital when currently used markers are within the normal range. In the first hospital presentation plasma sample from patients (n = 129), we measured microRNA-122 (miR-122; high liver specificity), high mobility group box-1 (HMGB1; marker of necrosis), full-length and caspase-cleaved keratin-18 (K18; markers of necrosis and apoptosis), and glutamate dehydrogenase (GLDH; marker of mitochondrial dysfunction). Receiver operator characteristic curve analysis and positive/negative predictive values were used to compare sensitivity to report liver injury versus alanine transaminase (ALT) and International Normalized Ratio (INR). In all patients, biomarkers at first presentation significantly correlated with peak ALT or INR. In patients presenting with normal ALT or INR, miR-122, HMGB1, and necrosis K18 identified the development of liver injury (n = 15) or not (n = 84) with a high degree of accuracy and significantly outperformed ALT, INR, and plasma acetaminophen concentration for the prediction of subsequent ALI (n = 11) compared with no ALI (n = 52) in patients presenting within 8 hours of overdose.
  
  
  CONCLUSIONS
  Elevations in plasma miR-122, HMGB1, and necrosis K18 identified subsequent ALI development in patients on admission to the hospital, soon after acetaminophen overdose, and in patients with ALTs in the normal range. The application of such a biomarker panel could improve the speed of clinical decision-making, both in the treatment of ALI and the design/execution of patient-individualized treatment strategies.
authors: MRC Centre for Drug Safety Science, Department of Molecular & Clinical Pharmacology, University of Liverpool, Liverpool, UK.
authors: Daniel J
authors: DJ
authors: Antoine
authors: James W
authors: JW
authors: Dear
authors: Philip Starkey
authors: PS
authors: Lewis
authors: Vivien
authors: V
authors: Platt
authors: Judy
authors: J
authors: Coyle
authors: Moyra
authors: M
authors: Masson
authors: Ruben H
authors: RH
authors: Thanacoody
authors: Alasdair J
authors: AJ
authors: Gray
authors: David J
authors: DJ
authors: Webb
authors: Jonathan G
authors: JG
authors: Moggs
authors: D Nicholas
authors: DN
authors: Bateman
authors: Christopher E
authors: CE
authors: Goldring
authors: B Kevin
authors: BK
authors: Park
mesh_terms: D000082:Acetaminophen / Q000009:adverse effects*; D000328:Adult; D000410:Alanine Transaminase / Q000378:metabolism; D015415:Biomarkers / Q000097:blood; D056486:Chemical and Drug Induced Liver Injury / Q000097:blood* / Q000175:diagnosis*; D019468:Disease Management; D005260:Female; D005969:Glutamate Dehydrogenase / Q000378:metabolism; D024243:HMGB1 Protein / Q000097:blood*; D006760:Hospitalization; D006801:Humans; D053538:Keratin-18 / Q000097:blood*; D008099:Liver / Q000378:metabolism; D008297:Male; D035683:MicroRNAs / Q000097:blood*; D008875:Middle Aged; D012680:Sensitivity and Specificity; D013997:Time Factors
chemical_list: D015415:Biomarkers; D024243:HMGB1 Protein; D053538:Keratin-18; C531907:MIRN122 microRNA, human; D035683:MicroRNAs; D000082:Acetaminophen; D005969:Glutamate Dehydrogenase; D000410:Alanine Transaminase
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