Description

• A disorder characterized by hepatic necrosis following large acetaminophen ingestions. Clinical manifestations of acetaminophen toxicity vary with time of ingestion and are generally classified into four stages.
• Single, large ingestions of acetaminophen account for a majority of poisonings. Toxicity can also occur with ingestions of lesser amounts in individuals who regularly abuse alcohol, are chronically malnourished, or take medications impacting hepatic metabolism. Ingestions >12 g in adults and >250 mg/kg in children are likely to cause toxicity.

Epidemiology

• Two-thirds of hospitalizations due to acetaminophen toxicity are due to intentional ingestion. Most (80%) are adults, and 70% are women. 50% of poison control calls related to acetaminophen are related to unintentional ingestions in children <5 years old.
• The second leading factor associated with liver transplantation worldwide
• >50,000 emergency department visits, >2,500 hospitalizations, and nearly 500 deaths annually in the United States are associated with acetaminophen ingestion.

Etiology and Pathophysiology

• Pharmacokinetics
  • With oral therapeutic ingestion, acetaminophen is entirely absorbed from the duodenum and reaches peak serum concentrations of 10 to 20 μg/mL after up to 2 hours. This peak may be delayed with toxic ingestions.
  • Therapeutic adult doses of acetaminophen are 325 to 1,000 mg q4–6h to a maximum dose of 4 g/day. Therapeutic pediatric doses are 10 to 15 mg/kg q4–6h, not to exceed 5 doses in 24 hours or 75 g/kg/day.
  • The elimination half-life of acetaminophen ranges from 2 to 4 hours but may be delayed in extended-release formulation.
• Pathophysiology
  • Ingestion of supratherapeutic doses of acetaminophen or subtherapeutic ingestions in individuals with compromised liver function can cause acetaminophen poisoning and result in hepatocellular damage. The liver metabolizes 96% of ingested acetaminophen and 2–4% is excreted in urine. Therapeutic doses break down into 90–95% benign metabolites and 5–10% of the toxic metabolite, N-acetyl-p-benzoquinone imine (NAPQI). NAPQI is rapidly conjugated with hepatic stores of glutathione to form a nontoxic metabolite to be excreted in the urine. Toxic ingestions of acetaminophen saturate the glucuronidation and sulfation pathways, depleting glutathione stores and result in accumulations of NAPQI that cause hepatocellular damage.

Risk Factors

Concurrent poisoning with other hepatotoxic substances; psychiatric illness or history of suicide attempts; ingestion of large amounts of alcohol; chronic malnutrition and risk related to previous weight loss surgery

General Prevention

• Poison Control: 800-222-1222 for consultations and management guidance
• U.S. Food and Drug Administration labeling guidance: https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidance...

Geriatric Considerations
There is an increased risk of hepatic damage in elderly patients due to decreased hepatic metabolism and coingestion of other hepatotoxic medications. Recommendation is to limit acetaminophen to ≤3,000 mg/day in seniors and in patients with liver disease and/or alcohol abuse disorders.Pediatric Considerations
Hepatic damage after ingestion of toxic acetaminophen doses can be less severe in young children, potentially because they have more stores of glutathione.Pregnancy Considerations
There is an increased incidence of spontaneous abortion in pregnant patients with acetaminophen poisoning. Abortion incidence and possible fetal death is increased if N-acetylcysteine (NAC) treatment is delayed. IV NAC is generally preferred in pregnancy due to greater bioavailability.