McGill 2014

Serum biomarkers of mitochondrial damage are higher in acetaminophen overdose patients with poor outcome

Mitchell R. McGill1, Vincent S. Staggs2, Matthew R. Sharpe3, William M. Lee4, Hartmut Jaeschke1

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

Acetaminophen (APAP) overdose is a major problem. Although most patients survive, the large number of cases makes it the most common cause of acute liver failure (ALF) and ALF-related deaths in the US. We are just beginning to translate the mechanisms of hepatotoxicity from rodents to humans. Our group recently reported evidence of mitochondrial dysfunction in APAP overdose patients using biomarkers of mitochondrial damage (mitochondrial DNA [mtDNA], glutamate dehydrogenase [GDH], and nuclear DNA [nDNA] fragments). In this study, we wanted to determine if these markers correlate with death or survival. We measured mtDNA by qPCR, GDH activity by kinetic assay and nDNA fragments by ELISA in serum from APAP-induced ALF patients who did (n = 34) or did not (n = 35) survive. All three parameters were elevated at or near the time of peak ALT, a standard liver injury marker, in patients with APAP-induced liver injury. Unlike ALT, peak levels of these mitochondrial damage biomarkers were higher in serum from non-survivors than survivors. Importantly, receiver operating characteristic (ROC) curve analyses revealed that higher peak levels of serum nDNA fragments, GDH and mtDNA could predict death (AUC=0.78, 0.71 and 0.76, respectively; p<0.05) while ALT could not (AUC=0.61, p=0.11). Conclusions: Biomarkers of mitochondrial damage are higher in non-survivors of APAP-induced ALF. This indicates that patients with more mitochondrial damage are less likely to survive, and suggests that mitochondria are critical in the mechanisms of hepatotoxicity. These biomarkers may also be useful clinically.