title: Detection of Ophthalmic Acid in Serum from Acetaminophen-Induced Acute Liver Failure Patients Is More Frequent in Non-Survivors.
abstract: OBJECTIVE
  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 (APAP-ALF) 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 in-hospital 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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Laboratory Medicine, Pathology, University of Alberta, Edmonton, Canada.
authors.forename: Gurnit
authors.initials: G
authors.lastname: Kaur
authors.affiliation: Department of Laboratory Medicine, Pathology, University of Alberta, Edmonton, Canada; Department of Physiology, University of Alberta, Edmonton, Canada.
authors.forename: Elaine M
authors.initials: EM
authors.lastname: Leslie
authors.affiliation: Department of Public Health Sciences, Medical University of South Carolina, Charleston, South Carolina, United States of America.
authors.forename: Holly
authors.initials: H
authors.lastname: Tillman
authors.affiliation: Division of Digestive and Liver Diseases, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America.
authors.forename: William M
authors.initials: WM
authors.lastname: Lee
authors.affiliation: Department of Physiology, University of Alberta, Edmonton, Canada.
authors.forename: Diane P
authors.initials: DP
authors.lastname: Swanlund
authors.affiliation: Divisions of Hepatology and Critical Care Medicine, University of Alberta, Edmonton, Canada.
authors.forename: Constantine J
authors.initials: CJ
authors.lastname: Karvellas
mesh_terms: D000082:Acetaminophen / Q000009:adverse effects*; D000328:Adult; D016022:Case-Control Studies; D003710:Demography; D005260:Female; D006801:Humans; D017114:Liver Failure, Acute / Q000097:blood* / Q000139:chemically induced*; D008297:Male; D009842:Oligopeptides / Q000097:blood*; D017741:Survivors
chemical_list: D009842:Oligopeptides; D000082:Acetaminophen; C016632:ophthalmic acid