Abstract
Background/AimAcetaminophen (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.MethodsSerum 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).ResultsSurvivors 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).ConclusionOA 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.
Highlights
Acute liver failure (ALF) is defined by the occurrence of encephalopathy and synthetic dysfunction within 8 weeks of the first symptoms of liver disease [1, 2]
Ophthalmic Acid in Acute Liver Failure for a copy of the database may be made through the NIDDK webpage:
Ophthalmic acid (OA) was detectable more frequently in APAP-ALF non-survivors but mean OA levels were not associated with survival
Summary
Acute liver failure (ALF) is defined by the occurrence of encephalopathy and synthetic dysfunction within 8 weeks of the first symptoms of liver disease [1, 2]. APAP metabolism occurs in the liver, predominantly through glucuronide and sulfate conjugation. A small amount of the APAP dose is catalyzed by cytochrome P450 2E1 (CYP2E1) to form the reactive intermediate species, N-acetyl-p-benzoquinone imine (NAPQI), which can be detoxified by glutathione (GSH) conjugation. If APAP doses are excessive, rapid depletion of GSH from the liver will occur. Treatment of APAP-induced ALF is through the administration of N-acetyl cysteine (NAC) therapy. This elevates cellular cysteine levels, allowing for GSH synthesis [5]. Metabolomics studies of mice undergoing APAP induced ALF have identified OA as a marker for oxidative stress and hepatic GSH depletion [6]. The aim of this study was to determine firstly whether the human serum concentrations of OA were detectable in patients with APAP-ALF and secondly whether OA levels were associated with subsequent clinically relevant outcomes (21-day survival) and be a potential biomarker in APAP-ALF
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
