Etiology
Acetaminophen overdose usually occurs as a self-harm attempt or a therapeutic error. Self-harm involves the ingestion of a large amount, either at a single time point or over a longer time period. Therapeutic error involves the repeated ingestion of smaller amounts, and the cumulative dosage is much greater than the recommended maximum daily dosage. Therapeutic error may arise from the ingestion of multiple formulations that contain acetaminophen to treat conditions such as pain or cough-and-cold illnesses.[5] Pediatric poisoning mainly results from therapeutic mishaps and incorrect dosing by parents.[24][25][26][27]
Pathophysiology
Acetaminophen metabolism is age- and dose-dependent. After absorption of a therapeutic dose, approximately 90% of acetaminophen undergoes hepatic sulfation and glucuronidation, and the resulting nontoxic metabolites are excreted in the urine.[30] A further 2% to 5% of a therapeutic dose is eliminated as minor metabolites or unchanged acetaminophen (N-acetyl-para-aminophenol, APAP) in the urine, and the remainder is metabolized by cytochrome P450 enzymes, mainly CYP2E1, to a potentially toxic intermediate metabolite N-acetyl-p-benzoquinone imine (NAPQI).[31][32][33]
The highest concentration of CYP2E1 is located in centrilobular hepatocytes around the central vein (i.e., perivenular or zone 3); this reflects the initial hepatic injury produced by acetaminophen. Under normal conditions and therapeutic doses, NAPQI combines with intracellular glutathione to become a nontoxic mercapturate derivative, which is then excreted in the urine.[34] However, acetaminophen is a dose-related hepatotoxin. After an overdose, the normally minor CYP2E1 pathway can account for up to 50% of metabolism, resulting in a disproportionate amount of NAPQI production relative to the dose of acetaminophen in patients with severe liver damage.[31]
When the production of NAPQI exceeds the capacity to detoxify it, the excess NAPQI binds to cellular components, causing mitochondrial injury and ultimately the death of the hepatocyte. If a sufficient dose is taken, hepatocyte death may be massive and produce acute liver failure.
The presence of CYP2E1 in the kidney may be a factor in variable degrees of renal injury occasionally seen following acetaminophen overdose.[31][32][35]
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