Paracetamol hepatic necrosis

Paracetamol overdose is most likely to cause hepatic necrosis and to a lesser extent renal necrosis. Hepatic necrosis is maximal within 3-4 hours of ingestion and may lead to encephalopathy, haemorrhage, hypoglycaemia, cerebral oedema and death. Acetylcysteine tends to protect the liver if given within 10-12 hours of paracetamol poisoning. The maximum adult dose of paracetamol is 4 g in 24 hours. 

Paracetamol (acetaminophen) is a widely used analgesic and antipyretic drug that is relatively safe when taken at prescribed therapeutic doses. However, it has become increasingly common for overdoses of paracetamol to be taken for suicidal intent. In the United Kingdom, for example, around 200 deaths a year result from overdoses of paracetamol. This has prompted some to call for changes in its availability, with newspaper headlines such as "Doctors demand curbs on killer paracetamol" (Sunday Times, London, 14th November, 1993). When taken in overdoses, paracetamol causes primarily centrilobular hepatic necrosis, but this may also be accompanied by renal damage and failure. 

Table 7.4 The Effect of Various Pretreatments on the Severity of Hepatic Necrosis and Covalent Binding of Paracetamol to Mouse Tissue Protein...

Acetaminophen (paracetamol, 4-hydroxyacetanilide, APAP), a commonly used analgesic drug, causes centrilobular hepatic necrosis upon overdosage. APAP displays toxicity characteristics that demonstrate, very clearly, dependence upon GSH for protection. Hepatotoxicity, including liver failure, often occurs when APAP is... 

Toxicity. The minimum lethal dose is about 10 g. Symptoms of hepatic damage do not occur for at least 12 hours after overdosage but may not appear until 4 to 6 days later. Plasma concentrations have been used to indicate possible hepatic necrosis at 4 hours, hepatic necrosis is possible at concentrations of paracetamol of 120 to 300 pg/ml, probable at concentrations above 300pg/ml, and unlikely at concentrations below 120pg/ ml. Similarly, at 12 hours, concentrations above 120pg/ml indicate the probability of necrosis, concentrations of 50 to 120 pg/ml indicate that it is possible, and concentrations below 50 pg/ml indicate that it is unlikely. 

The binding of drug to tissue is usually reversible. In some cases, however, there is covalent binding, which by definition is not reversible. This applies to drug or metabolite and could be important because it could be related to toxicity. " A good correlation has been reported in animals between the degree of covalent binding to hepatic protein and the severity of hepatic necrosis of paracetamol, isoniazid, adriamycin, and furosemide. " ... 

Prescott LF, Roscoe P, Wright N, Brown SS. Plasma-paracetamol half-hfe and hepatic necrosis in patients with paracetamol overdose. Lancet 1971 1 519-22. 

Paracetamol causes centrilobular hepatic necrosis in various species, although there are substantial species differences in susceptibility (figure 7,9). Experimental animal species susceptible to paracetamol have been used to study the mechanism underlying the hepatotoxicity. It was found that the degree of hepatic necrosis caused by paracetamol was markedly increased by pretreatment of animals with microsomal enzyme inducers and, conversely,... 

TABLE 7.3 The effect of various pretreatments on the severity of hepatic necrosis from and covalent binding of paracetamol to mouse tissue protein... 

Simpson KJ, Lukacs NW, McGregor AH, Harrison DJ, Strieter RM, Kimkel SL (2000) Inhibition of tumour necrosis factor alpha does not prevent experimental paracetamol-induced hepatic necrosis. J Pathol 190 489-494... 

Dimova S, Koleva M, Rangelova D, Stoythchev T (1995) Effect of nifedipine, verapamil, diltiazem and trifluoperazine on acetaminophen toxicity in mice. Arch Toxicol 70 112-118 Dixon MF, Nimmo J, Prescott LF (1971) Experimental paracetamol-induced hepatic necrosis a histopathological study. J Pathol 103 225-229... 

Acetaminophen (APAP, N-acetyl-p-aminophenol, paracetamol) is a widely used over-the-counter analgesic. At erapeutic doses it is a safe drug. However, at high doses it may produce severe hepatic necrosis and has also been reported in some individuals to be nephrotoxic (1-3). Available evidence indicates that acetaminophen hepatotoxicity is not a result of the parent compound but is mediated by a reactive metabolite N-acetyl-g-benzoquinone imine (NAPQI). This metabolite is the two-electron oxidation product of acetaminophen and is formed by the microsomal cytochrome P-450 mixed function oxidase system (4-8). Following a therapeutic dose of acetaminophen the reactive metabolite is detoxified Current address National Institutes of Health, Bethesda, MD 20892 Current address Rohm and Haas Company, Spring House, PA 19477... 

Many hepatotoxic reactions result from a common initiating event - the metabolic activation in the body of drugs that are chemically stable to potent alkylating or arylating agents. Paracetamol may be used as an example of this type of reaction (Prescott et al. 1974) if it is taken in excess (more than 15 g) with suicidal intent, it produces a clinical, laboratory and pathologic syndrome of severe, acute, and usually fatal hepatic necrosis. 

Paracetamol is a remarkably safe drug and serious toxicity is almost unheard of following therapeutic doses. However, acute hepatic necrosis is a serious complication of overdosage. 

Paracetamol overdosage is an increasing problem in some countries and is often complicated by acute centrilobular hepatic necrosis which may be fatal (215 —224, 225, 226 —230, 257 ). The current importance of the phenomenon naturally results from the trend to replace other simple analgesics by paracetamol, especially in Britain. 

Dixon, M. F., Dixon, B., Aparicio, S. R. and Loney,D. P. (1975) Experimental paracetamol-induced hepatic necrosis A light and electron-microscope, and histochemical study. J. Path., 116, 17. 

Dixon, M. F., Fulker, M. J., Walker, B. E Kelleher, J. and Losowsky, M. S. (1975) Serum transaminase levels after experimental paracetamol-induced hepatic necrosis. Gut, 16, 800. 

Overdoses of paracetamol can be very dangerous, as the drug has a narrow therapeutic index and may cause hepatic and renal necrosis. Nausea, vomiting, lethargy, and sweating are the early overdose symptoms. Paracetamol must be given with caution in alcoholics and patients with liver and kidney damage. 

Isolated cases of chronic paracetamol toxicity have been reported, such as hepatocellular necrosis, hepatic inflammation and fibrosis. These cases occurred in patients taking 2-6 g of paracetamol daily for months... 

Apart from renal tubular necrosis, which is usually associated with hepatic toxicity, but is occasionally seen without hepatic damage, there have been reports of a nephropathy similar to that seen with phenacetin, after prolonged use of paracetamol alone or in combination with other NSAIDs (22-27). 

Paracetamol is metabolised in the liver, where it is converted to a highly toxic intermediate that is normally detoxified by conjugation with glutathione. In overdose, this detoxification mechanism is overwhelmed and the free toxic metabolite causes hepatitis and necrosis, which can prove fatal. 

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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