Mechanistic biomarkers provide early and sensitive detection of acetaminophen‐induced acute liver injury at first presentation to hospital

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 ex...

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Veröffentlicht in:Hepatology (Baltimore, Md.) Jg. 58; H. 2; S. 777 - 787
Hauptverfasser: Antoine, Daniel J., Dear, James W., Lewis, Philip Starkey, Platt, Vivien, Coyle, Judy, Masson, Moyra, Thanacoody, Ruben H., Gray, Alasdair J., Webb, David J., Moggs, Jonathan G., Bateman, D. Nicholas, Goldring, Christopher E., Park, B. Kevin
Format: Journal Article
Sprache:Englisch
Veröffentlicht: United States Wolters Kluwer Health, Inc 01.08.2013
WILEY-VCH Verlag
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ISSN:0270-9139, 1527-3350, 1527-3350
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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. Conclusion: 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. (Hepatology 2013;58:777–787)
AbstractList 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. Conclusion: 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. (Hepatology 2013;58:777-787) [PUBLICATION 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. Conclusion: 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. (Hepatology 2013;58:777–787)
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. 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.
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. Conclusion: 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.
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.UNLABELLEDAcetaminophen 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.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.CONCLUSIONElevations 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.
Author Coyle, Judy
Masson, Moyra
Platt, Vivien
Park, B. Kevin
Goldring, Christopher E.
Antoine, Daniel J.
Moggs, Jonathan G.
Bateman, D. Nicholas
Thanacoody, Ruben H.
Webb, David J.
Gray, Alasdair J.
Dear, James W.
Lewis, Philip Starkey
Author_xml – sequence: 1
  givenname: Daniel J.
  surname: Antoine
  fullname: Antoine, Daniel J.
  organization: University of Liverpool
– sequence: 2
  givenname: James W.
  surname: Dear
  fullname: Dear, James W.
  organization: University of Edinburgh/British Heart Foundation Centre for Cardiovascular Science
– sequence: 3
  givenname: Philip Starkey
  surname: Lewis
  fullname: Lewis, Philip Starkey
  organization: University of Liverpool
– sequence: 4
  givenname: Vivien
  surname: Platt
  fullname: Platt, Vivien
  organization: University of Liverpool
– sequence: 5
  givenname: Judy
  surname: Coyle
  fullname: Coyle, Judy
  organization: Royal Infirmary of Edinburgh
– sequence: 6
  givenname: Moyra
  surname: Masson
  fullname: Masson, Moyra
  organization: Royal Infirmary of Edinburgh
– sequence: 7
  givenname: Ruben H.
  surname: Thanacoody
  fullname: Thanacoody, Ruben H.
  organization: University of Newcastle
– sequence: 8
  givenname: Alasdair J.
  surname: Gray
  fullname: Gray, Alasdair J.
  organization: Royal Infirmary of Edinburgh
– sequence: 9
  givenname: David J.
  surname: Webb
  fullname: Webb, David J.
  organization: University of Edinburgh/British Heart Foundation Centre for Cardiovascular Science
– sequence: 10
  givenname: Jonathan G.
  surname: Moggs
  fullname: Moggs, Jonathan G.
  organization: Novartis Institutes for Biomedical Research (NIBR)
– sequence: 11
  givenname: D. Nicholas
  surname: Bateman
  fullname: Bateman, D. Nicholas
  organization: Royal Infirmary of Edinburgh
– sequence: 12
  givenname: Christopher E.
  surname: Goldring
  fullname: Goldring, Christopher E.
  organization: University of Liverpool
– sequence: 13
  givenname: B. Kevin
  surname: Park
  fullname: Park, B. Kevin
  organization: University of Liverpool
BackLink https://www.ncbi.nlm.nih.gov/pubmed/23390034$$D View this record in MEDLINE/PubMed
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License Copyright © 2013 American Association for the Study of Liver Diseases.
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Notes These authors contributed equally to this work.
Supported by the Medical Research Council (via the Centre for Drug Safety Science, grant number G0700654), Chief Scientist's Office of Scotland, Mason Medical Research Foundation; D.J.A. received financial support from the Wellcome Trust; J.W.D. received a contribution from the British Heart Foundation Center of Research Excellence Award and financial support from the National Health Service (NHS) Research Scotland though NHS Lothian.
Potential conflict of interest: The authors have no conflict of interest to declare. J.G.M. is a full‐time employee of, consults for, and advises Novartis therapeutic targets or biomarkers were investigated in this study.
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Snippet Acetaminophen overdose is a common reason for hospital admission and the most frequent cause of hepatotoxicity in the Western world. Early identification would...
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SubjectTerms Acetaminophen - adverse effects
Adult
Alanine Transaminase - metabolism
Biomarkers
Biomarkers - blood
Chemical and Drug Induced Liver Injury - blood
Chemical and Drug Induced Liver Injury - diagnosis
Disease Management
Female
Glutamate Dehydrogenase - metabolism
Hepatology
HMGB1 Protein - blood
Hospitalization
Humans
Keratin-18 - blood
Liver
Liver - metabolism
Liver Injury/Regeneration
Male
MicroRNAs - blood
Middle Aged
Patients
Sensitivity and Specificity
Time Factors
Title Mechanistic biomarkers provide early and sensitive detection of acetaminophen‐induced acute liver injury at first presentation to hospital
URI https://onlinelibrary.wiley.com/doi/abs/10.1002%2Fhep.26294
https://www.ncbi.nlm.nih.gov/pubmed/23390034
https://www.proquest.com/docview/1414094713
https://www.proquest.com/docview/1416044268
https://www.proquest.com/docview/1492626611
https://pubmed.ncbi.nlm.nih.gov/PMC3842113
Volume 58
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