Acetaminophen Toxicity in Children: Diagnostic Confirmation Using a Specific Antigenic Biomarker

Abstract

Chronic acetaminophen (APAP) toxicity poses a difficult diagnostic challenge to the clinician. Signs and symptoms are nonspecific and no currently available laboratory study can confirm APAP as the causative agent of hepatic injury. In this study an antigenic biomarker for APAP toxicity was used to confirm the diagnosis of APAP-induced hepatic failure in two children with chronic APAP toxicity. APAP that has been metabolized to N-acetyl-benzoquinone imine (NAPQI) reacts with cellular proteins to form 3-(cystein-S-yl)-APAP protein adducts (3-Cys-A). Serum from both patients was submitted for quantitation of 3-Cys-A by a competitive inhibition enzyme-linked immunosorbent assay (ELISA). Concentrations of 3-Cys-A in the two patients were 1.97 and 2.77 nmol/mg protein, which are similar to concentrations found in adults with hepatic injury secondary to an overdose of APAP. Individuals with no exposure to APAP have no detectable 3-Cys-A in serum. It was concluded that 3-Cys-A is a useful marker of APAP intoxication after long-term ingestion of APAP when total dose and time course of ingestion are uncertain, and may prove to be a useful clinical and investigative tool in the study of APAP intoxication.

Quantification of a biomarker of acetaminophen protein adducts in human serum by high-performance liquid chromatography-electrospray ionization-tandem mass spectrometry: Clinical and animal model applications

“…Early studies of APAP protein adducts relied on radiometric [24,34] and immunochemical [26,[35][36][37][38][39] methods for qualitative and quantitative detection. Muldrew et al later developed a sensitive high-performance liquid chromatography-electrochemical detection (HPLC-ECD) assay that obviated the use of radiolabeled drug or antibodies [27,30].…”

Hepatoprotective activity of Uvaria chamae root bark methanol extract against acetaminophen-induced liver lesions in rats

“…At therapeutic doses AA is considered a safe drug. However, it can cause hepatic necrosis, nephrotoxicity, extra hepatic lesions, and even death in humans and experimental animals when taken in overdoses (Ray et al 1966;Webster et al 1996). Lipid peroxidation resulting from oxidative stress contributes to the initiation and progress of liver damage (Albano et al 1985;Kyle et al 1987) and suggesting that AA hepatotoxicity is mediated by an initial metabolic oxidation, covalent binding, and subsequent activation of macrophages to form reactive oxygen and nitrogen species.…”

Protective effect of Moutan Cortex extract on acetaminophen-induced hepatotoxicity in mice

“…At the therapeutic doses, AAP is considered a safe drug. However, it can cause hepatic necrosis, nephrotoxicity, extrahepatic lesions, and even death in humans and experimental animals when taken in overdoses (Ray et al, 1996;Webster et al, 1996). AAP is metabolized by a cytochrome P450-dependent pathway to an electrophilic metabolite, N-acetyl-p-benzoquinone imine (NAPQI) (Lee et al, 1996).…”