Liver paracetamol poisoning

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. 

As discussed in Chapter 2, after a drug (or other chemical) is taken by mouth, it first reaches the stomach and then the small intestine. It is most likely to be absorbed from the small intestine, where it enters the bloodstream which will transport it directly to the liver (see Figure 3, p. 15). In the liver paracetamol is changed into two other substances, which are relatively harmless but another metabolite, which is produced in only small amounts, is potentially poisonous. This metabolite is normally safely removed by further metabolism, which employs the substance glutathione (see box, p. 24). After a large overdose, however, this process of detoxication is overwhelmed and the poisonous substance attacks the liver. 

Drugs that induce liver microsomal enzymes, such as phenobarbital, phenytoin, carbamazepine, rifampicin, and isoniazid, can make paracetamol poisoning more severe (104,105). In patients taking such drugs the serum paracetamol concentration should be doubled before consulting the usual treatment nomogram. 

Paracetamol poisoning provides a useful human model to compare the effectiveness of plasma GST with aminotransferase measurements because in such patients there is often a wide spectrum of the severity of liver damage encountered. In addition, damage to the liver initially occurs in the centrilobular hepatocytes, where phase I drug metabolizing enzymes produce the toxic metabolite (J3). 

This is used as a sulphydryl donor in the treatment of paracetamol poisoning. It has side effects of its own which include nausea, vomiting and drowsiness. It must be given early, otherwise it is ineffective since paracetamol oxidation to toxic metabolic products will already have occurred. In addition, cysteamine itself, or any sulphydryl donor, could precipitate hepatic coma in a patient with overt liver damage (21 ). 

By measurement of the blood level of paracetamol in overdose cases, it is possible to estimate the likely outcome of the poisoning, and hence determine the type of treatment. Measurement of the blood level of paracetamol and its various metabolites at various times after the overdose showed that the half-life was increased several folds (Table 7.3), and the patients who sustained liver damage had an impaired ability to metabolize paracetamol to conjugates (Fig. 7.16). 

Why does a drug that is safe when taken at the recommended dose become potentially lethal The answer lies in the metabolism. The toxicity of paracetamol is not due to the drug itself, nor is it related to the therapeutic effect it has on the body at low doses (lowering of temperature and reduction of pain). Paracetamol becomes poisonous to the liver after large doses and may cause liver failure. 

Except for the treatment of, for example, paracetamol intoxication and Amanita phalloides poisoning, there is no causal therapy for liver insufficiency. All conservative treatment measures are based on four principles ... 

Antidotes e. g. silibinin against Amanita poisoning or N-acetylcysteine in paracetamol intoxication, haemarginate in acute porphyria Primary iiver therapeutics e. g. penicillamine, glucocorticoids, azathioprine, interferon-a, aimed at primary intervention in the aetiology or pathomechanism of liver disease. 

The tiiost well-documented poisons which affect the liver are paracetamol and carbon tetrachloride. These are metabolized by the intact liver in small amounts, but when present at high concentrations they give rise to toxic metaboUtes, leading to destruction of hepatocytes with massive release of enzymes. The capacity of the liver to withstand an insult is reduced if there is underlying liver damage due to alcohol, malnutrition or other chronic disease. 

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... 

---