Serum mitochondrial biomarkers and damage-associated... : Hepatology (original) (raw)

Liver Failure/Cirrhosis/Portal Hypertension

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

McGill, Mitchell R.1; Staggs, Vincent S.2; Sharpe, Matthew R.3; Lee, William M.4; Jaeschke, Hartmut1 Acute Liver Failure Study Group

From the 1 Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, KS; 2Department of Biostatistics, University of Kansas Medical Center, Kansas City, KS; 3Department of Internal Medicine, University of Kansas Hospital, Kansas City, KS; 4Division of Digestive and Liver Diseases, University of Texas Southwestern Medical Center, Dallas, TX.

Received 3 March 2014; accepted 7 June 2014

Published online 25 August 2014.

Address reprint requests to: Hartmut Jaeschke, Ph.D., Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Boulevard, MS 1018, Kansas City, KS 66160. E-mail:[email protected]; fax: 913–588–7501.

Potential conflict of interest: Dr. Lee received grants from Boehringer Ingelheim, Bristol-Myers Squibb, Gilead, Merck, Novartis, and GlaxoSmithKline.

The Acute Liver Failure Study Group was supported by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK; grant no.: U-01–58369). The data and samples reported here were supplied by the NIDDK Central Repositories. This article does not necessarily reflect the opinions or views of the NIDDK Central Repositories or the NIDDK. This work was also supported, in part, by grants from the University of Kansas Medical Center Liver Center (to H.J.), from the National Institutes of Health (R01 DK070195 and R01 AA12916; to H.J.), and from the National Center for Research Resources (5P20RR021940–07) and the National Institute of General Medical Sciences (8 P20 GM103549–07) of the National Institutes of Health. Additional support came from the Training Program in Environmental Toxicology (T32 ES007079–26A2; to M.R.M.) from the National Institute of Environmental Health Sciences.

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)