Poster ()- #SCSOT12 - KEYWORDS: ALF Biomarkers MELD Proteomics Hepatotoxicity DILI APAP

Untargeted Proteomics Reveals Regeneration-associated Serum Biomarkers that can Predict Death in Acute Liver Failure Patients

Joel H. Vazquez1,2, Jonathan A. Dranoff3, D. Keith Williams4, William M. Lee, Mitchell R. McGill1,2 and the Acute Liver Failure Study Group
1Dept. of Pharmacology and Toxicology, College of Medicine; 2Dept. of Environmental and Occupational Health, College of Public Health; 3Dept. of Internal Medicine, College of Medicine; 4Dept. of Biostatistics, College of Medicine; University of Arkansas for Medical Sciences, Little Rock, AR USA. 5Dept. of Internal Medicine, University of Texas – Southwestern, Dallas, TX USA.

ABSTRACT:
Acute liver failure (ALF) is a rare yet serious condition with a high rate of mortality (~30%). Unfortunately, there are currently no biomarkers that have sufficient prognostic value to determine if a patient is unlikely to survive without a liver transplant. We obtained early and later serum samples (study days 1s and 3, respectively) from patients with Acetaminophen (APAP)-induced ALF in the Acute Liver Failure Study Group biorepository, divided into transplant-free survivor (n=28) and non-survivor (n=30) groups, and from volunteer controls. We then selected samples (n=10/group) from patients for whom ALT was lower on day 1 than day 3, indicating an early timepoint in injury, and ran untargeted proteomics on their day 1 samples. We could quantify 1,682 proteins across all 30 samples, with 79 of those proteins elevated ≥4-fold in ALF patients vs. control and 23 further elevated ≥4-fold in non-survivors vs. survivors. Among the latter 23, lactate dehydrogenase (LDH) appeared to have the highest prognostic value. We then tested LDH in all day 1, day 3, and control samples from our subjects. LDH was significantly elevated in non-survivors compared to survivors on both day 1 and day 3, and receiver operator characteristic (ROC) curve analysis showed that LDH performs similar to the model for end-stage liver disease (MELD) score, while a combination of LDH and MELD derived from multiple logistic regression outperforms either one alone. An upstream analysis of our proteomics data also revealed that LKB1-AMPK signaling is important in liver regeneration, which we confirmed using a mouse model of APAP overdose. We conclude that LDH can predict death in APAP-induced ALF, and that LKB1-AMPK signaling may be a valuable target for therapy in ALF patients.