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Acetaminophen (APAP), a widely available antipyretic and analgesic, is the leading worldwide cause of drug overdose and acute liver failure (ALF).
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Single overdose ingestion and therapeutic misadventure may cause hepatotoxicity.
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Several factors, such as concomitant alcohol use or abuse, concurrent medications, genetic factors, and nutritional status, can influence the susceptibility and severity of APAP hepatotoxicity.
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Early manifestations of APAP hepatotoxicity are nonspecific, but require prompt
Acetaminophen-related Hepatotoxicity
Section snippets
Key points
Epidemiology
APAP has been a major cause of overdose and overdose-related ALF (∼50% of cases) and death in the United States and in many other countries.3, 4, 5, 6 In the United States, APAP overdose is the leading reason for calls to the Poison Control Centers (>100,000 per year) and accounts annually for more than 56,000 emergency room visits, 2600 hospitalizations, and an approximate 450 deaths caused by ALF.3 In the US ALF Multicenter Prospective Study, APAP accounted for 42% (275 of 662) of ALF cases;
Pharmacology and hepatotoxicity
The therapeutic dose of APAP is 325 to 1000 mg/dose (10–15 mg/kg/dose in children), given every 4 to 6 hours, with a maximum recommended daily dose of 4 g (80 mg/kg in children). Although the US Food and Drug Administration (FDA) Advisory Committee proposed a decrease in the maximum daily dose from 4000 to 3250 mg, this recommendation has not been implemented.10 After oral ingestion, APAP is rapidly absorbed from the gastrointestinal tract with peak concentrations being achieved within
Factors influencing APAP-related hepatotoxicity
The ingested dose of APAP seems to be the most important factor determining the development and severity of APAP hepatotoxicity. In addition, the pattern of use and various factors (eg, age, concurrent use of alcohol and certain medications, genetic factors, pre-existing liver disease, and nutritional status) can also influence the susceptibility to APAP hepatotoxicity through several mechanisms including decreased capacity for glucuronidation or sulfation, excessive CYP activity, and depletion
Clinical manifestations
Early recognition of APAP overdose is likely to prevent subsequent morbidity and mortality. The early manifestations of APAP overdose are frequent, mild, and nonspecific, and include nausea, vomiting, malaise, and abdominal pain. In general, these symptoms do not reliably predict subsequent hepatotoxicity. However, a study of 291 patients suggested that an increase in episodes of vomiting at first presentation seems to be a risk marker of subsequent hepatotoxicity.54 The clinical course of APAP
General approach and diagnostic tools
General approach promptly begins with careful history taking and physical examination. The precise time and amount of APAP intake, and 4-hour APAP level, or as soon thereafter as feasible, should be obtained. Other tests, such as hepatic biochemical tests, creatinine, and electrolytes, may also be useful, particularly in patients with repeated overdoses and those who present more than 8 hours after ingestion. Investigations for possible coingested substances and other causes of hepatitis may be
Gastrointestinal Decontamination
Activated charcoal is effective at limiting the absorption of APAP when given within 4 hours after overdose and is recommended in all patients who present early after APAP ingestion, unless there are contraindications (eg, unsecured airway or gastrointestinal tract injury).94, 95, 96, 97 Patients who present 4 hours after ingestion are unlikely to benefit from activated charcoal, except in those who ingested extended-release APAP preparations or coingested drugs that delayed gastric emptying
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Conflict of Interest: The authors have nothing to disclose.