- Title
- Early acetaminophen-protein adducts predict hepatotoxicity following overdose (ATOM-5)
- Creator
- Chiew, Angela L.; James, Laura P.; Isbister, Geoffrey K.; Pickering, John W.; McArdle, Kylie; Chan, Betty S. H.; Buckley, Nicholas A.
- Relation
- NHMRC.1061041 http://purl.org/au-research/grants/nhmrc/1061041
- Relation
- Journal of Hepatology Vol. 72, Issue 3, p. 450-462
- Publisher Link
- http://dx.doi.org/10.1016/j.jhep.2019.10.030
- Publisher
- Elsevier
- Resource Type
- journal article
- Date
- 2020
- Description
- Background & Aims: Acetaminophen-protein adducts are specific biomarkers of toxic acetaminophen (paracetamol) metabolite exposure. In patients with hepatotoxicity (alanine aminotransferase [ALT] >1,000 U/L), an adduct concentration ≥1.0 nmol/ml is sensitive and specific for identifying cases secondary to acetaminophen. Our aim was to characterise acetaminophen-protein adduct concentrations in patients following acetaminophen overdose and determine if they predict toxicity. Methods: We performed a multicentre prospective observational study, recruiting patients 14 years of age or older with acetaminophen overdose regardless of intent or formulation. Three serum samples were obtained within the first 24 h of presentation and analysed for acetaminophen-protein adducts. Acetaminophen-protein adduct concentrations were compared to ALT and other indicators of toxicity. Results: Of the 240 patients who participated, 204 (85%) presented following acute ingestions, with a median ingested dose of 20 g (IQR 10–40), and 228 (95%) were treated with intravenous acetylcysteine at a median time of 6 h (IQR 3.5–10.5) post-ingestion. Thirty-six (15%) patients developed hepatotoxicity, of whom 22 had an ALT ≤1,000 U/L at the time of initial acetaminophen-protein adduct measurement. Those who developed hepatotoxicity had a higher initial acetaminophen-protein adduct concentration compared to those who did not, 1.63 nmol/ml (IQR 0.76–2.02, n = 22) vs. 0.26 nmol/ml (IQR 0.15–0.41; n = 204; p <0.0001), respectively. The AUROC for hepatotoxicity was 0.98 (95% CI 0.96–1.00; n = 226; p <0.0001) with acetaminophen-protein adduct concentration and 0.89 (95% CI 0.82–0.96; n = 219; p <0.0001) with ALT. An acetaminophen-protein adduct concentration of 0.58 nmol/ml was 100% sensitive and 91% specific for identifying patients with an initial ALT ≤1,000 U/L who would develop hepatotoxicity. Adding acetaminophen-protein adduct concentrations to risk prediction models improved prediction of hepatotoxicity to a level similar to that obtained by more complex models. Conclusion: Acetaminophen-protein adduct concentration on presentation predicted which patients with acetaminophen overdose subsequently developed hepatotoxicity, regardless of time of ingestion. An adduct threshold of 0.58 nmol/L was required for optimal prediction. Lay summary: Acetaminophen poisoning is one of the most common causes of liver injury. This study examined a new biomarker of acetaminophen toxicity, which measures the amount of toxic metabolite exposure called acetaminophen-protein adduct. We found that those who developed liver injury had a higher initial level of acetaminophen-protein adducts than those who did not. Clinical Trial registration: Australian Toxicology Monitoring (ATOM) Study–Australian Paracetamol Project: ACTRN12612001240831 (ANZCTR) Date of registration: 23/11/2012.
- Subject
- hepatotoxicity; poisoning; biomarker; acute liver injury; paracetamol poisoning; SDG 3; Sustainable Development Goals
- Identifier
- http://hdl.handle.net/1959.13/1459345
- Identifier
- uon:45649
- Identifier
- ISSN:0168-8278
- Language
- eng
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