Hepatotoxicity of acetaminophen

In therapeutic doses acetaminophen is predominantly metabolized in the liver, where 90 per cent of the drug undergoes either glucuronidation or sulfation to a non-toxic inactive compound which is excreted in the urine. The remainder of the drug is dealt with in two ways: 5 per cent is excreted unchanged in the urine, and the rest undergoes oxidation by the hepatic mixed-function oxidase system (cytochrome P-450 2E1) to the unstable toxic compound W-acetyl-p-benzoquine imine (NAPQI). NAPQI is rendered non-toxic by conjugation with hepatic intracellular glutathiones and is then excreted via the biliary system.

In acetaminophen poisoning there is saturation of the glucuronidation and sulfation pathways, which leads to an increase in the formation of the toxic NAPQI. The glutathione defense mechanism becomes depleted with even moderate doses of acetaminophen, and when it falls to less than 30 per cent of the normal level NAPQI is able to accumulate and bind covalently to the liver in a centrilobular fashion, causing hepatic necrosis via arylation and oxidation of key calcium-regulating proteins.

The minimum dose of acetaminophen believed to cause hepatic damage is 125 mg/kg (which is equivalent to 15 standard 500-mg tablets for a 60-kg person). Acetaminophen doses above 250 mg/kg produce hepatotoxicity in 60 per cent of cases, and severe liver damage (serum aspartate aminotransferase (AST) above 1000 IU/l) is inevitable when doses in excess of 350 mg/kg are absorbed. The most common method of predicting the potential risk of an overdose is through plasma levels and time from ingestion of tablets. These are plotted on a semilogarithmic graph ( Prescottetal 1979); 60 per cent of patients who lie above a line joining a plasma level of 200 mg/l at 4 h and 30 mg/l at 15 h will develop severe hepatic damage if untreated. A similar graph is used in the United States, except that the line is modified to be 25 per cent below the standard United Kingdom plot (Rumackefa/ 1981).

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