BACKGROUND AND AIMS Acetaminophen-protein adducts are a specific biomarker of toxic acetaminophen (paracetamol) metabolite exposure. In patients with hepatotoxicity (ALT>1000U/L), a concentration >1.0nmol/mL is sensitive and specific in 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 A multi-centre prospective observational study, recruiting patients ≥14 years with acetaminophen overdose regardless of intent or formulation. Three serum samples were obtained within the first 24h of presentation and analysed for acetaminophen-protein adducts. Acetaminophen-protein adduct concentrations were compared to ALT and other indicators of toxicity. RESULTS 240 patients participated, and 1009 samples were analysed. 204(85%) were acute ingestions with a median ingested dose of 20g(IQR:10-40). 228(95%) were treated with intravenous acetylcysteine at a median time of 6h(IQR:3.5-10.5) post-ingestion. 36(15%) patients developed hepatotoxicity, of which 22 had an ALT≤1000 U/L at the time of initial acetaminophen-protein adduct measurement. Those who developed hepatotoxicity had a higher initial acetaminophen-protein adduct concentration vs those who didn't, 1.63nmol/mL (IQR:0.76-2.02, n=22) vs. 0.26nmol/mL (IQR:0.15-0.41, n=204)(p<0.0001), respectively. The ROCAUC for acetaminophen-protein adducts and ALT for prediction of hepatotoxicity in these patients was 0.98 (95%CI:0.96-1.00, n = 226, p<0.0001) and 0.89 (95%CI:0.82 - 0.96, n=219, p<0.0001) respectively. An acetaminophen-protein adduct concentration of 0.58nmol/mL was 100% sensitive and 91% specific for identifying patients that would develop hepatotoxicity, who presented with an initial ALT<1000U/L. When utilised in risk prediction models the addition of acetaminophen-protein adducts to initial ALT and time to presentation improved prediction of hepatotoxicity. The improvement was similar to that obtained from more complex prediction models including time adjusted acetaminophen concentrations. CONCLUSION Acetaminophen-protein adduct concentration on presentation predicted which patients with acetaminophen overdose subsequently developed hepatotoxicity, regardless of time of ingestion, or intent. An adduct threshold of 0.58nmol/L was required for optimal prediction.

中文翻译：

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早期对乙酰氨基酚-蛋白质加合物可预测过量服用后的肝毒性

背景和目的 对乙酰氨基酚-蛋白质加合物是毒性对乙酰氨基酚（扑热息痛）代谢物暴露的特定生物标志物。在有肝毒性（ALT>1000U/L）的患者中，浓度>1.0nmol/mL 对识别继发于对乙酰氨基酚的病例具有敏感性和特异性。我们的目的是表征对乙酰氨基酚过量后患者的对乙酰氨基酚-蛋白质加合物浓度，并确定它们是否能预测毒性。方法 一项多中心前瞻性观察性研究，招募≥14 岁对乙酰氨基酚过量的患者，无论其意图或配方如何。在出现的第一个 24 小时内获得了三个血清样本，并分析了对乙酰氨基酚-蛋白质加合物。对乙酰氨基酚-蛋白质加合物浓度与 ALT 和其他毒性指标进行比较。结果 240 名患者参与，并分析了 1009 个样品。204 (85%) 次是急性摄入，中位摄入剂量为 20 克（IQR：10-40）。228 (95%) 名患者在摄入后 6 小时（IQR：3.5-10.5）的中位时间接受了静脉内乙酰半胱氨酸治疗。36 (15%) 名患者出现肝毒性，其中 22 名患者在初始对乙酰氨基酚-蛋白质加合物测量时 ALT ≤ 1000 U/L。发生肝毒性的患者与未发生肝毒性的患者相比，初始对乙酰氨基酚-蛋白质加合物浓度更高，分别为 1.63nmol/mL (IQR:0.76-2.02, n=22) vs. 0.26nmol/mL (IQR:0.15-0.41, n= 204)(p<0.0001)，分别。对乙酰氨基酚蛋白加合物的 ROCAUC 和用于预测这些患者肝毒性的 ALT 的 ROCAUC 为 0.98 (95%CI:0.96-1.00, n = 226, p<0.0001) 和 0.89 (95%CI:0.82 - 0.96, n=219, p<0.0001) 分别。对乙酰氨基酚-蛋白质加合物浓度为 0。58nmol/mL 的敏感性为 100%，特异性为 91%，可用于识别初始 ALT<1000U/L 的会发生肝毒性的患者。当用于风险预测模型时，将乙酰氨基酚-蛋白质加合物添加到初始 ALT 和出现时间可改善肝毒性的预测。这种改进类似于从更复杂的预测模型中获得的改进，包括时间调整的对乙酰氨基酚浓度。结论 就诊时的对乙酰氨基酚-蛋白质加合物浓度可预测哪些对乙酰氨基酚过量的患者随后发生肝毒性，无论摄入时间或意图如何。最佳预测需要 0.58nmol/L 的加合物阈值。初始ALT<1000U/L。当用于风险预测模型时，将乙酰氨基酚-蛋白质加合物添加到初始 ALT 和出现时间可改善肝毒性的预测。这种改进类似于从更复杂的预测模型中获得的改进，包括时间调整的对乙酰氨基酚浓度。结论 就诊时的对乙酰氨基酚-蛋白质加合物浓度可预测哪些对乙酰氨基酚过量的患者随后发生肝毒性，无论摄入时间或意图如何。最佳预测需要 0.58nmol/L 的加合物阈值。初始 ALT<1000U/L。当用于风险预测模型时，将乙酰氨基酚-蛋白质加合物添加到初始 ALT 和出现时间可改善肝毒性的预测。这种改进类似于从更复杂的预测模型中获得的改进，包括时间调整的对乙酰氨基酚浓度。结论 就诊时的对乙酰氨基酚-蛋白质加合物浓度可预测哪些对乙酰氨基酚过量的患者随后发生肝毒性，无论摄入时间或意图如何。最佳预测需要 0.58nmol/L 的加合物阈值。这种改进类似于从更复杂的预测模型中获得的改进，包括时间调整的对乙酰氨基酚浓度。结论 就诊时的对乙酰氨基酚-蛋白质加合物浓度可预测哪些对乙酰氨基酚过量的患者随后发生肝毒性，无论摄入时间或意图如何。最佳预测需要 0.58nmol/L 的加合物阈值。这种改进类似于从更复杂的预测模型中获得的改进，包括时间调整的对乙酰氨基酚浓度。结论 就诊时的对乙酰氨基酚-蛋白质加合物浓度可预测哪些对乙酰氨基酚过量的患者随后发生肝毒性，无论摄入时间或意图如何。最佳预测需要 0.58nmol/L 的加合物阈值。