Acetaminophen Metabolites on Presentation Following an Acute Acetaminophen Overdose (ATOM‐7)

Abstract

Acetaminophen (APAP) is commonly taken in overdose and can cause acute liver injury via the toxic metabolite NAPQI formed by cytochrome (CYP) P450 pathway. We aimed to evaluate the concentrations of APAP metabolites on presentation following an acute APAP poisoning and whether these predicted the subsequent onset of hepatotoxicity (peak alanine aminotransferase > 1,000 U/L). The Australian Toxicology Monitoring (ATOM) study is a prospective observational study, recruiting via two poison information centers and four toxicology units. Patients following an acute APAP ingestion presenting < 24 hours post-ingestion were recruited. Initial samples were analyzed for APAP metabolites, those measured were the nontoxic glucuronide (APAP-Glu) and sulfate (APAP-Sul) conjugates and NAPQI (toxic metabolite) conjugates APAP-cysteine (APAP-Cys) and APAPmercapturate (APAP-Mer). The primary outcome was hepatotoxicity. In this study, 200 patients were included, with a median ingested dose of 20 g, 191 received acetylcysteine at median time of 5.8 hours post-ingestion. Twenty-six patients developed hepatotoxicity, one had hepatotoxicity on arrival (excluded from analysis). Those who developed hepatotoxicity had significantly higher total CYP metabolite concentrations: (36.8 μmol/L

The chemokine CXCL14 is a novel early prognostic biomarker for poor outcome in acetaminophen-induced acute liver failure

“…[26] More recent work found that APAP metabolites generated by cytochrome P450-mediated metabolism (APAP-cysteine) had a stronger association with hepatotoxicity than sulfation-related metabolites. [27] Collectively, these advances in delineating the timing of the APAP overdose will aid in assisting the prognostic value of CXCL14.…”

“…However, APAP-protein adducts have been found to have an elimination half-life of 42 hours, 25 and APAP-cysteine concentrations of 0.58 nmol/ml can identify patients who later develop hepatotoxicity 26 . More recent work found that APAP metabolites generated by cytochrome P450-mediated metabolism (APAP-cysteine) had a stronger association with hepatotoxicity than sulfation-related metabolites 27 . Collectively, these advances in delineating the timing of the APAP overdose will aid in assisting the prognostic value of CXCL14.…”