Serum mitochondrial biomarkers and damage-associated molecular patterns are higher in acetaminophen overdose patients with poor outcome

Acute Liver Failure Study Group

Research output: Contribution to journalArticle

67 Citations (Scopus)

Abstract

Acetaminophen (APAP) overdose is a major cause of acute liver failure (ALF). Numerous studies have shown that APAP hepatotoxicity in mice involves mitochondrial dysfunction, and recent data suggest that this is also the case in humans. We have previously shown that glutamate dehydrogenase (GDH), mitochondrial DNA (mtDNA), and nuclear DNA (nDNA) fragments can be measured in circulation of overdose patients as mechanistic biomarkers of mitochondrial damage and damage-associated molecular patterns. In the present study, our aim was to determine whether these biomarkers are higher in serum from nonsurvivors of APAP-induced ALF (AALF), compared to survivors. GDH, mtDNA, and nDNA fragments were measured in serum from AALF patients who did (n=34) or did not (n=35) recover. Importantly, all three were significantly increased in patients who died, compared to those who survived (GDH: 450±73 vs. 930±145 U/L; mtDNA: 21±6 vs. 48±13 and 33±10 vs. 43±7 ng/mL for two different genes; nDNA fragments: 148±13 vs. 210±13% of control). Receiver operating characteristic (ROC) curve analyses revealed that nDNA fragments, GDH, and mtDNA were predictive of outcome (area under the curve [AUC], study admission: 0.73, 0.70, and 0.71 or 0.76, respectively, P<0.05; AUC, time of peak ALT: 0.78, 0.71, and 0.71 or 0.76, respectively, P<0.05), and the results were similar to those from the Model for End-Stage Liver Disease (MELD; AUC, peak MELD: 0.77; P<0.05). Conclusions: Our data suggest that patients with more mitochondrial damage are less likely to survive, demonstrating that mitochondria are central in the mechanisms of APAP hepatotoxicity in humans. Clinically, serum nDNA fragments, GDH, and mtDNA could be useful as part of a panel of biomarkers to predict patient outcome. (Hepatology 2014;60:1336-1345)

Original languageEnglish (US)
Pages (from-to)1336-1345
Number of pages10
JournalHepatology
Volume60
Issue number4
DOIs
StatePublished - Oct 1 2014

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Acetaminophen
Glutamate Dehydrogenase
Biomarkers
Mitochondrial DNA
Serum
DNA
Area Under Curve
End Stage Liver Disease
Acute Liver Failure
Gastroenterology
ROC Curve
Survivors
Mitochondria
Genes

ASJC Scopus subject areas

  • Hepatology

Cite this

Serum mitochondrial biomarkers and damage-associated molecular patterns are higher in acetaminophen overdose patients with poor outcome. / Acute Liver Failure Study Group.

In: Hepatology, Vol. 60, No. 4, 01.10.2014, p. 1336-1345.

Research output: Contribution to journalArticle

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abstract = "Acetaminophen (APAP) overdose is a major cause of acute liver failure (ALF). Numerous studies have shown that APAP hepatotoxicity in mice involves mitochondrial dysfunction, and recent data suggest that this is also the case in humans. We have previously shown that glutamate dehydrogenase (GDH), mitochondrial DNA (mtDNA), and nuclear DNA (nDNA) fragments can be measured in circulation of overdose patients as mechanistic biomarkers of mitochondrial damage and damage-associated molecular patterns. In the present study, our aim was to determine whether these biomarkers are higher in serum from nonsurvivors of APAP-induced ALF (AALF), compared to survivors. GDH, mtDNA, and nDNA fragments were measured in serum from AALF patients who did (n=34) or did not (n=35) recover. Importantly, all three were significantly increased in patients who died, compared to those who survived (GDH: 450±73 vs. 930±145 U/L; mtDNA: 21±6 vs. 48±13 and 33±10 vs. 43±7 ng/mL for two different genes; nDNA fragments: 148±13 vs. 210±13{\%} of control). Receiver operating characteristic (ROC) curve analyses revealed that nDNA fragments, GDH, and mtDNA were predictive of outcome (area under the curve [AUC], study admission: 0.73, 0.70, and 0.71 or 0.76, respectively, P<0.05; AUC, time of peak ALT: 0.78, 0.71, and 0.71 or 0.76, respectively, P<0.05), and the results were similar to those from the Model for End-Stage Liver Disease (MELD; AUC, peak MELD: 0.77; P<0.05). Conclusions: Our data suggest that patients with more mitochondrial damage are less likely to survive, demonstrating that mitochondria are central in the mechanisms of APAP hepatotoxicity in humans. Clinically, serum nDNA fragments, GDH, and mtDNA could be useful as part of a panel of biomarkers to predict patient outcome. (Hepatology 2014;60:1336-1345)",
author = "{Acute Liver Failure Study Group} and Mcgill, {Mitchell R.} and Staggs, {Vincent S.} and Sharpe, {Matthew R.} and Lee, {William M.} and Hartmut Jaeschke",
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AU - Acute Liver Failure Study Group

AU - Mcgill, Mitchell R.

AU - Staggs, Vincent S.

AU - Sharpe, Matthew R.

AU - Lee, William M.

AU - Jaeschke, Hartmut

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N2 - Acetaminophen (APAP) overdose is a major cause of acute liver failure (ALF). Numerous studies have shown that APAP hepatotoxicity in mice involves mitochondrial dysfunction, and recent data suggest that this is also the case in humans. We have previously shown that glutamate dehydrogenase (GDH), mitochondrial DNA (mtDNA), and nuclear DNA (nDNA) fragments can be measured in circulation of overdose patients as mechanistic biomarkers of mitochondrial damage and damage-associated molecular patterns. In the present study, our aim was to determine whether these biomarkers are higher in serum from nonsurvivors of APAP-induced ALF (AALF), compared to survivors. GDH, mtDNA, and nDNA fragments were measured in serum from AALF patients who did (n=34) or did not (n=35) recover. Importantly, all three were significantly increased in patients who died, compared to those who survived (GDH: 450±73 vs. 930±145 U/L; mtDNA: 21±6 vs. 48±13 and 33±10 vs. 43±7 ng/mL for two different genes; nDNA fragments: 148±13 vs. 210±13% of control). Receiver operating characteristic (ROC) curve analyses revealed that nDNA fragments, GDH, and mtDNA were predictive of outcome (area under the curve [AUC], study admission: 0.73, 0.70, and 0.71 or 0.76, respectively, P<0.05; AUC, time of peak ALT: 0.78, 0.71, and 0.71 or 0.76, respectively, P<0.05), and the results were similar to those from the Model for End-Stage Liver Disease (MELD; AUC, peak MELD: 0.77; P<0.05). Conclusions: Our data suggest that patients with more mitochondrial damage are less likely to survive, demonstrating that mitochondria are central in the mechanisms of APAP hepatotoxicity in humans. Clinically, serum nDNA fragments, GDH, and mtDNA could be useful as part of a panel of biomarkers to predict patient outcome. (Hepatology 2014;60:1336-1345)

AB - Acetaminophen (APAP) overdose is a major cause of acute liver failure (ALF). Numerous studies have shown that APAP hepatotoxicity in mice involves mitochondrial dysfunction, and recent data suggest that this is also the case in humans. We have previously shown that glutamate dehydrogenase (GDH), mitochondrial DNA (mtDNA), and nuclear DNA (nDNA) fragments can be measured in circulation of overdose patients as mechanistic biomarkers of mitochondrial damage and damage-associated molecular patterns. In the present study, our aim was to determine whether these biomarkers are higher in serum from nonsurvivors of APAP-induced ALF (AALF), compared to survivors. GDH, mtDNA, and nDNA fragments were measured in serum from AALF patients who did (n=34) or did not (n=35) recover. Importantly, all three were significantly increased in patients who died, compared to those who survived (GDH: 450±73 vs. 930±145 U/L; mtDNA: 21±6 vs. 48±13 and 33±10 vs. 43±7 ng/mL for two different genes; nDNA fragments: 148±13 vs. 210±13% of control). Receiver operating characteristic (ROC) curve analyses revealed that nDNA fragments, GDH, and mtDNA were predictive of outcome (area under the curve [AUC], study admission: 0.73, 0.70, and 0.71 or 0.76, respectively, P<0.05; AUC, time of peak ALT: 0.78, 0.71, and 0.71 or 0.76, respectively, P<0.05), and the results were similar to those from the Model for End-Stage Liver Disease (MELD; AUC, peak MELD: 0.77; P<0.05). Conclusions: Our data suggest that patients with more mitochondrial damage are less likely to survive, demonstrating that mitochondria are central in the mechanisms of APAP hepatotoxicity in humans. Clinically, serum nDNA fragments, GDH, and mtDNA could be useful as part of a panel of biomarkers to predict patient outcome. (Hepatology 2014;60:1336-1345)

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