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 APAP-mercapturate (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 interquartile range (IQR): 27.8-51.7 vs. 10.8 μmol/L IQR: 6.9-19.5) and these were a greater proportion of total metabolites (5.4%, IQR: 3.8-7.7) vs. 1.7%, IQR: 1.3-2.6, P < 0.001)]. Furthermore, those who developed hepatotoxicity had lower APAP-Sul concentrations (49.1 μmol/L, IQR: 24.7-72.2 vs. 78.7 μmol/L, IQR: 53.6-116.4) and lower percentage of APAP-Sul (6.3%, IQR: 4.6-10.9 vs. 13.1%, IQR, 9.1-20.8, P < 0.001)]. This study found that those who developed hepatotoxicity had higher APAP metabolites derived from CYP pathway and lower sulfation metabolite on presentation. APAP metabolites may be utilized in the future to identify patients who could benefit from increased acetylcysteine or newer adjunct or research therapies.

Figure 1

Box and whiskers plot of initial acetaminophen metabolite concentrations stratified according to outcome ALT > 1,000 U/L. (a) APAP‐Glu, (b) APAP‐Sul, (c) APAP‐Cys, (d) APAP‐Mer. Only including those patients with an initial ALT < 1,000 U/L. Box and whiskers plot the midline bar represents the median value, box represents the first and third quartile, bars the 10th and 90th centiles. ALT, alanine aminotransferase; APAP, acetaminophen; APAP‐Cys, acetaminophen‐cysteine; APAP‐Glu, acetaminophen‐glucuronide; APAP‐Mer, acetaminophen‐mercapturate; APAP‐Sul, acetaminophen‐sulfate.

Figure 2

ROC analysis of the ability of APAP metabolite concentration, ALT and metabolite ratios to predict hepatotoxicity. ROC analysis of the ability of (a) initial APAP metabolite concentrations (b) ALT, APAP‐Cys/APAP‐Sul and APAP‐Cys/APAP‐Sul*ALT (c) Forest plot of AUC‐ROC to predict hepatotoxicity (ALT >1,000 U/L) (squares) and ALT >100 U/L (open circles). ALT, alanine aminotransferase; APAP, acetaminophen; APAP‐Cys, acetaminophen‐cysteine; APAP‐Glu, acetaminophen‐glucuronide; APAP‐Mer, acetaminophen‐mercapturate; APAP‐Sul, acetaminophen‐sulfate; AUC, area under the curve; CI, confidence interval; ROC, receiver operating characteristic curve.

Figure 3

Correlation among: (a) APAP‐Cys and acetaminophen ratio (n = 200). (b) APAP‐Cys and peak INR (n = 165). (c) Percentage of CYP metabolites of total metabolites and paracetamol ratio (n = 200). (d) Percentage of CYP metabolites of total metabolites and peak INR (n = 165). APAP, acetaminophen; APAP‐Cys, acetaminophen‐cysteine; INR, international normalized ratio; IR, immediate release; MR, modified release.