Necrosis, liver, acetaminophen overdose

Figure 5. Acetaminophen overdose induces liver necrosis by formation of more hepatotoxin (metabolite A) than can be deactivated by glutathione conjugation (metabolite B). ...

Although considered safe at therapeutic doses, at higher doses, acetaminophen produces a centrilobular hepatic necrosis that can be fatal. Acetaminophen poisoning accounts for approximately one-half of all cases of acute liver failure in the United States and Great Britain today (Larson et al. 2005 Ostapowicz et al. 2002) Annually, it accounts for a very high percentage of inquiries to poison control centers and deaths (Litovitz et al. 2002). The direct costs of acetaminophen overdose have been estimated to be as high as US 87 million annually (Bond and Novak 1995). 

Grewal KK, Racz WJ (1993) Intracellular calcium disruption as a secondary event in acetaminophen-induced hepatotoxicity. Can J Physiol Pharmacol 71 26-33 Gujral JS, Knight TR, Earhood A, Bajt ML, Jaeschke H (2002) Mode of cell death after acetaminophen overdose in mice apoptosis or oncotic necrosis Toxicol Sci 67 322-328 Gujral JS, Hinson JA, Earhood A, Jaeschke H (2004) NADPH oxidase-derived oxidant stress is critical for neutrophil cytotoxicity during endotoxemia. Am J Physiol Gastrointest Liver Physiol 287 G243-252... 

Acute overdose with acetaminophen (>300 mg kg ) results in hepatotoxicity and/or nephrotoxicity. Although hepatotoxicity is frequently the predominant toxicity, acetaminophen nephrotoxicity can occur in the absence of marked hepatic toxicity. In these cases, liver function returns to normal or near normal levels before the onset of nephrotoxicity. Acute acetaminophen nephrotoxicity is generally characterized as oliguric acute renal failure with acute tubular necrosis. Acetaminophen can also induce acute nephrotoxicity in therapeutic doses, but chronic alcohol intake usually accompanies renal toxicity in these patients. 

Acetaminophen is metabolized mainly by liver glucuronyl transferase to form the inactive conjugate. A minor pathway (via P450) results in formation of a reactive metabolite (N-acetylbenzoquinoneimine) that is inactivated by glutathione (GSH). In overdose situations, the finite stores of GSH are depleted. Once this happens, the metabolite reacts with hepatocytes, causing nausea and vomiting, abdominal pain, and ultimately liver failure due to centrilobular necrosis. Chronic use of ethanol enhances liver toxicity via induction of P450. 

Dahlin DC, Miwa GT, Lu AY, Nelson SD (1984) N-acetyl-p-benzoquinone imine a cytochrome P-450-mediated oxidation product of acetaminophen. Proc Natl Acad Sci USA 81 1327-1331 Davem TJ 2nd, James LP, Hinson JA, Poison J, Larson AM, Fontana RJ, Lalani E, Munoz S, Shakil AO, Lee WM (2006) Measurement of serum acetaminophen-protein adducts in patients with acute liver failure. Gastroenterology 130 687-694 Davidson DG, Eastham WN (1966) Acute liver necrosis following overdose of paracetamol. Br Med J 5512 497 99... 

Hepatotoxicity does not occur at recommended doses of acetaminophen. Administration of 2 g, or twice the recommended dose, of intravenous paracetamol in healthy subjects has been shown to stay far below the threshold of hepatotoxicity. When ingested at high doses, acetaminophen is metabolized to JV-acetyl-p-benzoquinone-imine (NAPQI). NAPQI is rapidly conjugated with glutathione to a nontoxic compound. The depletion of glutathione results in the accumulation of NAPQI that is responsible for liver injury. Acetaminophen has a narrow therapeutic window and even minor overdoses may cause severe hepatic injury. Liver necrosis occurs at 7.5-10 g of acetaminophen. 

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