Aetiology
Paracetamol 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 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 paracetamol to treat conditions such as pain or cough-and-cold illnesses.
Pathophysiology
Paracetamol metabolism is age- and dose-dependent. After ingestion of a therapeutic dose, paracetamol undergoes hepatic sulfation and glucuronidation, and the resulting non-toxic metabolites are excreted in the urine. About 4% of a therapeutic dose is metabolised by cytochrome P450 enzymes, mainly CYP2E1, to a potentially toxic intermediate metabolite N-acetyl-p-benzoquinone imine (NAPQI). The highest concentration of CYP2El is located in centrilobular hepatocytes around the central vein (i.e., perivenular or zone 3) and reflects the initial hepatic injury produced by paracetamol. Under normal conditions and therapeutic doses, NAPQI combines with intracellular glutathione to become a non-toxic mercapturate derivative with urinary excretion. However, after ingestion of an overdose, the normally minor CYP2E1 pathway becomes important. 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 paracetamol overdose.[15][16][17]
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