Epidemiology
Acetaminophen is responsible for over half of all cases of acute liver failure in the US and is the second most common cause of liver transplant worldwide.[11] The 2022 Annual Report of the National Poison Data System in the US reported 94,782 single substance exposures to acetaminophen alone, representing a 42% increase when compared with the previous year. In the same report, acetaminophen-containing combination product exposures totaled 27,432 during 2022, an 8.9% decrease from the previous year.[12] Exposure cases are defined as actual or suspected contact (for example, ingestion, inhalation, absorption) reported with a substance.
Although a leading cause of liver failure worldwide, acetaminophen is one of the most widely used analgesic and antipyretic drugs.[13] Toxicity may occur during self-treatment for pain where unintentional “double-dipping” with two acetaminophen-containing products, and misunderstanding the instructions for proper nonprescription use, are common.[14] The potential for errors and subsequent adverse events from unintentional misuse is higher among frequent acetaminophen users, those with limited literacy, and patients with dental pain.[14][15][16][17] Reports suggest that approximately 6% of frequent acetaminophen users unintentionally take more than the recommended dose of 4 g/day at least once a week.[18]
Acetaminophen-opioid combination products increase the risk of hepatotoxicity, both from double-dipping and substance misuse. This finding led the Food and Drug Administration (FDA) to limit the doses of acetaminophen found in combination products, and the Drug Enforcement Administration to change hydrocodone/acetaminophen from Schedule III to Schedule II. Subsequent to these changes, the rates of combination product overdoses may be declining.[12][19][20]
Acetaminophen is one of the most frequently used drugs in intentional overdose, particularly in young people, and has historically accounted for similar proportions of acetaminophen-induced liver failure cases as unintentional chronic poisoning.[21][22][23]
Pediatric patients may be at unique risk for therapeutic excess of acetaminophen due to miscommunication among caregivers (e.g., timing of last dose or number of doses in a day), discomfort with the recommended exclusive dosing for pediatric liquid formulations (which is typically dosed in milliliters rather than milligrams), and use of nonstandard tools (e.g., kitchen spoons) for drug administration.[24][25][26][27]
There are rare case reports relating to iatrogenic acetaminophen poisoning following intravenous administration of acetaminophen in both the adult and the pediatric population.[28][29]
Risk factors
Acetaminophen is present either alone or in combination with other drugs in many nonprescription formulations. The use of multiple brand-name products containing acetaminophen in varying doses can lead to unintended overdose.[5] A clinically significant proportion of emergency department patients overuse nonprescription analgesics, with dental pain appearing to be a particular risk factor.[15][16][17]
Retrospective studies suggest that patients who have a frequent or repeated supratherapeutic ingestion pattern of misuse for pain relief have a disproportionate incidence of severe hepatotoxicity and the most deaths.[5][37]
Patients who have relatively low levels of glutathione may be more at risk of liver damage following acetaminophen overdose.[38] Those at greatest risk appear to have therapeutic excess as opposed to acute ingestions. There is no reliable method to assess glutathione stores in patients. Susceptible groups may include children with febrile illness who may not have eaten for a few days, those with malnourishment, nutritional deficiencies, and eating disorders (e.g., anorexia nervosa or bulimia).[5][38] Patients with chronic debilitating illnesses (e.g., cystic fibrosis, AIDS, alcohol dependence, or hepatitis C) may also have glutathione deficiency.[38]
Long-term treatment with cytochrome P450 2E1 (CYP2E1) inducers (e.g., carbamazepine, phenytoin, phenobarbital, isoniazid, rifampin) or long-standing misuse of alcohol may increase the risk of liver damage following acetaminophen overdose.[38] St. John’s wort is postulated to exacerbate acetaminophen-induced liver injury via multiple mechanisms, including enhanced CYP2E1 activity.[39] Clinicians should ask specifically about herbal supplement use when taking a drug history, as patients often do not disclose their use to their physician.[40]
Malnutrition and a period of fasting may increase risk of hepatotoxicity via multiple mechanisms, including decreased hepatic glucuronidation (resulting in increased CYP450 metabolism and N-acetyl-p-benzoquinone imine production) and depletion of hepatic glutathione stores. Both prolonged and short-term fasting may increase risk of hepatotoxicity. Short-term fasting was defined as 36 hours in one study.[41]
Susceptible groups may include children with febrile illness who may not have eaten for a few days, and those with malnourishment, nutritional deficiencies, or eating disorders (e.g., anorexia nervosa or bulimia).[5][38]
A recent Health Services Safety investigation found that adults with low body weight (<50 kg) may be at increased risk of acetaminophen overdose even with standard doses.[42]
The impact of ethanol use on acetaminophen toxicity is complex.[43] Chronic consumption of alcohol may place patients at increased risk of toxicity after therapeutic excess via multiple mechanisms, including enhanced CYP450 activity, depletion of glutathione stores, and reduced glutathione synthesis.[44][45][46] Other factors that may increase risk in this population include delayed recognition, concomitant malnutrition, and a period of recent fasting.
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