Detection of ophthalmic acid in serum from acetaminophen-induced acute liver failure patients is more frequent in non-survivors

Gurnit Kaur, Elaine M. Leslie, Holly Tillman, William M. Lee, Diane P. Swanlund, Constantine J. Karvellas, Anne M. Larson, Iris Liou, Oren Fix, Michael Schilsky, Daniel Ganger, Steven H B Han, Robert Fontana, Brendan McGuire, Adrian Reuben, David Koch, Rajender Reddy, R. Todd Stravitz, James Hanje, Jody OlsonRam Subramanian, Grace Samuel, Ezmina Lalani, Carla Pezzia, Corron Sanders, Nahid Attar, Linda S. Hynan, Valerie Durkalski, Wenle Zhao, Jaime Speiser, Catherine Dillon, Holly Battenhouse, Michelle Gottfried

Research output: Contribution to journalArticle

9 Scopus citations

Abstract

Background/Aim: Acetaminophen (APAP) hepatotoxicity is related to the formation of N-acetyl-p-benzoquinone imine (NAPQI), which is detoxified through conjugation with reduced glutathione (GSH). Ophthalmic acid (OA) is an analogue of GSH in which cysteine is replaced with 2-aminobutyrate. Metabolomics studies of mice with APAP-induced acute liver failure (APAPALF) identified OA as a marker of oxidative stress and hepatic GSH consumption. The aim of the current study was to determine whether OA is detectable in APAP-ALF human patients either early (day 2) or late (day 4) and whether OA levels were associated with inhospital survival in the absence of liver transplant. Methods: Serum samples from 130 APAP-ALF patients (82 survivors, 48 non-survivors) were analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS) and correlated with clinical data from the United States Acute Liver Failure Study Group (US ALFSG) Registry (2004-2011). Results: Survivors had significantly lower admission bilirubin (4.2 vs. 5.7 mg/dl) and lactate levels (3.3 vs. 6.5 μmol/l, p<0.05 for all). During the first 7 days of the study, survivors were less likely to require mechanical ventilation (55% vs. 88%), vasopressor support (9.8% vs. 67%) or renal replacement therapy (26% vs. 63%, p<0.001 for all). Non-survivors were more likely to have detectable OA levels early (31% vs. 15%, p = 0.034) and late (27% vs. 11%, p = 0.02). However there were no significant differences in mean OA levels between non-survivors and survivors (early 0.48 vs. 0.36, late 0.43 vs. 0.37, P > 0.5 for all). Conclusion: OA was detectable more frequently in APAP-ALF non-survivors but mean OA levels were not associated with survival. The routine clinical administration of N-acetyl cysteine could replenish GSH levels and prevent OA production.

Original languageEnglish (US)
Article numbere0139299
JournalPloS one
Volume10
Issue number9
DOIs
StatePublished - Sep 25 2015

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

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    Kaur, G., Leslie, E. M., Tillman, H., Lee, W. M., Swanlund, D. P., Karvellas, C. J., Larson, A. M., Liou, I., Fix, O., Schilsky, M., Ganger, D., Han, S. H. B., Fontana, R., McGuire, B., Reuben, A., Koch, D., Reddy, R., Stravitz, R. T., Hanje, J., ... Gottfried, M. (2015). Detection of ophthalmic acid in serum from acetaminophen-induced acute liver failure patients is more frequent in non-survivors. PloS one, 10(9), [e0139299]. https://doi.org/10.1371/journal.pone.0139299