been associated with low morbidity, although occasional cases of hepatotoxicity occur, particularly in the context of inadvertent repetitive overdosing The primary toxicity of APAP is hepatocellular damage Acetaminophen is metabolized in three ways by the liver: (i) glucuronidation, (ii) sulfation, and (iii) metabolism through the cytochrome P-450 pathway to form a potentially toxic intermediate, which conjugates with glutathione In a massive overdose, glutathione becomes depleted, thus allowing the undetoxified intermediate to bind to hepatocytes, leading to cellular necrosis This damage is reflected by rising levels of liver enzymes, by hepatic dysfunction, and in severe poisonings, by hepatic failure and death The use of N -acetylcysteine as an antidote relates in part to this molecule’s ability to act as a glutathione precursor Clinical Considerations Initially, the signs and symptoms of APAP ingestion are vague and nonspecific but can include nausea and vomiting, anorexia, pallor, and diaphoresis These manifestations usually resolve within 12 to 24 hours, and the patient appears well for to days During this latent period, levels of liver enzymes may rise, and jaundice with liver tenderness may ensue Most patients have a gradual resolution of their hepatic dysfunction, although without antidotal treatment about 2% to 4% of intoxications that develop toxic plasma levels will go on to hepatic failure and death Such patients with severe toxicity develop further clinical evidence of hepatic disease at to days after ingestion, and some develop renal damage Anorexia, malaise, and abdominal pain may progress to signs of fulminant liver failure with hepatic encephalopathy, coagulopathy, and multisystem organ dysfunction Key components of the history include estimated amount ingested, formulation ingested, time of ingestion, and the presence of coingestants The potential severity of an acute intoxication may be predicted by the amount ingested, if accurately known, and the plasma level of APAP A single acute overdose of less than 200 mg/kg of APAP in young children is unlikely to cause significant toxicity Severe toxicity in adolescents or adults usually occurs with overdoses of at least 7.5 to 10 g Initial GI symptoms, although vague, are generally more pronounced when the overdose is large, and with massive ingestions patients may demonstrate altered mental status and metabolic acidosis soon after ingestion However, the only reliable indication of the potential severity of the hepatic damage is the plasma APAP level, taken at least hours after ingestion Basic toxicologic principles of preventing absorption apply to APAP overdoses, and it is important to note that there are both immediate- and