What is the role of acetaminophen toxicity in the pathogenesis of acute liver failure (ALF)?

Updated: Jun 13, 2019
  • Author: Gagan K Sood, MD; Chief Editor: BS Anand, MD  more...
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The development of liver failure represents the final common outcome of a wide variety of potential causes, as the broad differential diagnosis suggests (see Differential Diagnosis). As with many drugs that undergo hepatic metabolism (in this case, by cytochrome P-450), the oxidative metabolite of acetaminophen is more toxic than the drug. [13, 16, 17, 18] The highly reactive active metabolite N-acetyl-p-benzoquinone-imine (NAPQI) appears to mediate much of the acetaminophen-related damage to liver tissue by forming covalent bonds with cellular proteins.

Ordinarily, NAPQI is metabolized in the presence of glutathione to N-acetyl-p-aminophenol-mercaptopurine. Glutathione quenches this reactive metabolite and acts to prevent nonspecific oxidation of cellular structures, which might result in severe hepatocellular dysfunction.

This mechanism fails in two different yet equally important settings. The first is an overdose (accidental or intentional) of acetaminophen. Acetaminophen ingestion of more than 10 g simply overwhelms the normal hepatic stores of glutathione, allowing reactive metabolites to escape.

The second and less obvious scenario occurs in a patient who consumes alcohol regularly. This does not necessarily require a history of alcohol abuse or alcoholism. Even a moderate or social drinker who consistently consumes one to two drinks daily may sufficiently deplete intrahepatic glutathione reserves. This results in potentially lethal hepatotoxicity from what is otherwise a safe dose of acetaminophen (below the maximum total dose of 4 g/d) in an unsuspecting individual. Patients with acute liver failure may have unrecognized or uncertain acetaminophen toxicity. [19]

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