Acetaminophen hepatotoxicity: An update.
Acetaminophen is a widely used nonprescription analgesic and antipyretic agent. It is also a dose-related hepatotoxin that can cause fulminant liver failure when taken in massive overdoses or, much less commonly, at therapeutic doses in susceptible individuals. Persons who regularly consume alcohol or persons who have been fasting may be more susceptible to this hepatotoxicity. This liver injury is due not to the drug itself but to the formation of the toxic metabolite N-acetyl-p-benzoquinine imine generated through the cytochrome P-450 drug-metabolizing system. Normally, hepatic stores of glutathione combine with the toxic metabolite and prevent liver cell injury. When glutathione stores are depleted by overproduction of this metabolite, however, the reactive metabolite binds to liver cell proteins and causes hepatic necrosis. P-450 2E1 is induced by alcohol consumption and possibly starvation, and glutathione depletion can occur due to the inadequate nutrition occurring in chronic alcohol use or in starvation. Recent studies have shown that activated Kupffer cells and their secreted toxic agents such as cytokines may also play a role in this liver injury. This liver injury is characterized by extremely high levels of serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) (> 1000), and bad prognostic signs include severe prolongation of the prothrombin time, renal dysfunction, and, most importantly, acidosis. N-acetylcysteine is a highly effective antidote when given early (within 15 hours) of overdose. Some patients may develop such fulminant liver injury that they require transplantation. Unfortunately, many such patients have a course so rapid that a donor liver may not become available in time. Thus, both the medical community and the general public require a heightened understanding of this clinical problem in order to initiate prevention measures and to implement early therapeutic measures if an overdose situation occurs.
McClain
C J
CJ
Division of Digestive Diseases and Nutrition, University of Kentucky Medical Center, 800 Rose Street, Lexington, KY 40536-0084, USA.
Price
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Barve
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Devalarja
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Shedlofsky
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D000082:Acetaminophen / Q000008:administration & dosage / Q000009:adverse effects*; D018712:Analgesics, Non-Narcotic / Q000008:administration & dosage / Q000009:adverse effects*; D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008111:Liver Function Tests
D018712:Analgesics, Non-Narcotic; D000082:Acetaminophen