Department of Clinical Toxicology, Prince of Wales Hospital, Randwick, New South Wales, Australia.
Faculty of Medicine, The University of New South Wales, Sydney, New South Wales, Australia.
Clin Pharmacol Ther. 2023 Jun;113(6):1304-1314. doi: 10.1002/cpt.2888. Epub 2023 Apr 6.
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.
对乙酰氨基酚（APAP）在过量服用时很常见，可通过细胞色素（CYP）P450 途径形成的有毒代谢物 NAPQI 导致急性肝损伤。我们旨在评估急性 APAP 中毒后就诊时的 APAP 代谢物浓度，以及这些浓度是否预测随后发生的肝毒性（峰值丙氨酸氨基转移酶> 1000 U/L）。澳大利亚毒理学监测（ATOM）研究是一项前瞻性观察性研究，通过两个毒物信息中心和四个毒理学单位进行招募。招募了在摄入 APAP 后< 24 小时就诊的急性 APAP 摄入患者。对初始样本进行了 APAP 代谢物分析，测量的是无毒的葡糖醛酸（APAP-Glu）和硫酸盐（APAP-Sul）缀合物以及 NAPQI（有毒代谢物）缀合物 APAP-半胱氨酸（APAP-Cys）和 APAP-巯基尿酸（APAP-Mer）。主要结局是肝毒性。在这项研究中，纳入了 200 名患者，中位摄入剂量为 20 克，191 名患者在摄入后中位时间 5.8 小时内接受了乙酰半胱氨酸治疗。26 名患者发生了肝毒性，1 名患者在到达时就出现了肝毒性（被排除在分析之外）。发生肝毒性的患者总 CYP 代谢物浓度明显更高：（36.8 μmol/L 四分位间距（IQR）：27.8-51.7 与 10.8 μmol/L IQR：6.9-19.5），且这些代谢物占总代谢物的比例更大（5.4%，IQR：3.8-7.7 与 1.7%，IQR：1.3-2.6，P< 0.001）]。此外，发生肝毒性的患者 APAP-Sul 浓度较低（49.1 μmol/L，IQR：24.7-72.2 与 78.7 μmol/L，IQR：53.6-116.4），APAP-Sul 百分比较低（6.3%，IQR：4.6-10.9 与 13.1%，IQR：9.1-20.8，P< 0.001）]。这项研究发现，发生肝毒性的患者有更高的 CYP 途径衍生的 APAP 代谢物和较低的磺化代谢物。APAP 代谢物未来可能用于识别可能受益于增加乙酰半胱氨酸或新辅助或研究治疗的患者。
