Liver and intrahepatic bile ducts - nontumor
Hepatitis (drug / toxin induced)

Topic Completed: 1 February 2016

Revised: 23 January 2019, last major update February 2016

Copyright: (c) 2002-2017,, Inc.

PubMed Search: Hepatitis[TI] acetaminophen[TI]

Anthony W.H. Chan, F.R.C.P.A.
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Cite this page: Chan A. Drug / toxin induced hepatitis - acetaminophen. website. Accessed September 22nd, 2019.
Definition / general
  • Acetaminophen, also known as paracetamol and N-acetyl-p-aminophenol, is one of most commonly used analgesic and antipyretic drugs, either as a stand alone medication or combined with other medications (prescription or over the counter)
  • Maximal recommended dosage is 4 g/day (adult) or 50 - 75 mg/kg/day (children) (Cleve Clin J Med 2010;77:19)
  • In the United States, 43 million adults take some form of acetaminophen
  • Acetaminophen overdose may lead to hepatotoxicity and annually accounts for > 80,000 emergency department visits, > 30,000 hospitalizations and 42% of all cases of acute liver failure in the U.S. (Arch Toxicol 2015;89:193)
  • 61.8% of overdose were unintentional but 30.5% were associated with a suicidal attempt (J Clin Gastroenterol 2016;50:85)
  • For acetaminophen overdoses, 30.3% were with this drug only, 14.1% were with a combination containing diphenhydramine and 56.6% were with a combination containing an opioid (J Clin Gastroenterol 2016;50:85)
  • Normally, < 10% of acetaminophen is metabolized by the cytochrome p450 system in the liver to generate N-acetyl-p-benzoquinone imine (NAPQI)
  • NAPQI is then quickly metabolized to nontoxic metabolites by glutathione
  • NAPQI may accumulate, secondary to acetaminophen overdose, due to upregulation of the cytochrome p450 system (through chronic use of alcohol, isoniazid, rifampicin or phenobarbital) or depletion of glutathione (due to malnutrition or chronic liver disease), which leads to hepatotoxicity through mitochondrial dysfunction, cell death and modulation of the innate immune system (Arch Toxicol 2015;89:193)
Clinical features
  • Most overdose patients are asymptomatic initially but progress to acute liver failure if untreated
  • Initial presentation of acute liver failure includes abdominal pain, fatigue, anorexia and fever
  • Later presentation includes jaundice, coagulopathy and encephalopathy, which may be complicated by shock, pulmonary edema and acute renal failure (Arch Toxicol 2015;89:193)
  • Of those who developed acute liver failure, 7.1% required liver transplantation, 29.3% required hemodialysis and 16.7% died (J Clin Gastroenterol 2016;50:85)
  • Serum acetaminophen level is useful
Prognostic factors
  • Associated with poor clinical outcome: older age, unintentional overdose, repeated supratherapeutic doses, alcoholism, chronic liver disease (Arch Toxicol 2015;89:193)
Case reports
  • 29 year old woman with paracetamol induced Stevens-Johnson syndrome and cholestatic hepatitis (Curr Drug Saf 2015;10:187)
  • 44 year old woman with acetaminophen induced acute hepatitis during febrile reactivation of systemic lupus erythematosus (J Clin Rheumatol 2014;20:349)
  • 45 year old man with severe hepatotoxicity after therapeutic doses of acetaminophen (Clin Ther 2006;28:755)
  • Activated charcoal minimizes GI absorption of acetaminophen if administered within 4 hours of an acute overdose (Arch Toxicol 2015;89:193)
  • N-acetylcysteine minimizes hepatotoxicity by replenishing glutathione stores (Arch Toxicol 2015;89:193)
  • Liver transplantation is the last resort for patients progressing to acute liver failure despite N-acetylcysteine
Microscopic (histologic) description
  • Extensive zone 3 or panacinar necrosis with minimal inflammatory infiltrate
Microscopic (histologic) images

Images hosted on PathOut server:

Images contributed by Dr. Anthony Chan:
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Acetaminophen toxicity

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Centrilobular pattern

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