Accidental paracetamol poisoning

Paracetamol toxicity is the most common cause of acute liver failure in Australia.3 A recent study of 662 patients from 22 tertiary care centres in the United States found that 48% of patients presenting with severe paracetamol hepatotoxicity had not intended to poison themselves, and took the drug for therapeutic purposes only. These patients tended to be older than patients who intentionally poison themselves.4 Paracetamol hepatotoxicity in those older than 40 years is associated with an increased risk of fulminant hepatic failure, death or liver transplantation.4,5 An analysis of 67 cases of “therapeutic misadventure” with paracetamol found that 60% of patients with accidental paracetamol poisoning had taken no more than 6 g paracetamol per day, and 40% had not exceeded the recommended maximum dose of 4 g per day.6 Risk factors for developing hepatic toxicity under these circumstances include prolonged fasting,7 regular excessive alcohol intake,6 or concurrent use of drugs that induce cytochrome P450 (CYP450), especially CYP450 2E1. Elderly patients with renal and cardiopulmonary insufficiency may also be at increased risk.8 Interestingly, there is little evidence that pre-existing liver disease increases the risk.1

The link between fasting or CYP450 induction and increased susceptibility to paracetamol toxicity can be readily explained by reviewing the metabolism of this drug. When paracetamol is taken in standard doses in healthy individuals, more than 90% is conjugated to form inactive metabolites, which are then excreted in the urine. A small proportion of the paracetamol is metabolised by the CYP450 system to N-acetyl-p-benzoquinone imine (NAPQI), which, if allowed to accumulate, is toxic to the liver. Normally, NAPQI is conjugated with glutathione and the harmless products excreted in the urine (Box 2). Prolonged starvation can severely deplete the cosubstrates required for paracetamol conjugation and reduce glutathione stores, so that even therapeutic doses of the drug can result in the accumulation of toxic amounts of NAPQI (Box 2). Regular and prolonged treatment with paracetamol may be particularly dangerous in fasting patients, as ongoing metabolism of the drug leads to further consumption of already depleted glutathione stores. Alcohol and other drugs capable of inducing CYP450 predispose patients to paracetamol toxicity by increasing the production of NAPQI. In addition, chronic alcohol misuse leads to depletion of glutathione.

Between 1989 and 2004, 42 patients were referred to the Victorian Liver Transplant Unit with paracetamol-induced acute liver failure.9 In 11 of these (26%), the poisoning was clearly accidental. Eight patients recovered spontaneously, one survived after undergoing liver transplantation, and two died — including the patient described in this report. Thus, in Australia, severe life-threatening liver injury from accidental paracetamol poisoning appears to be quite uncommon. Nevertheless, this is a readily preventable syndrome of which both patients and the medical profession should be made more aware. In particular, clinicians should be cautious about prescribing regular doses of paracetamol for pain control in malnourished or fasting patients, and need to appropriately counsel patients who are regular users of the drug.

Although many cases of accidental paracetamol poisoning at therapeutic dosage have been described, controversy surrounds the actual incidence and mechanism. Unfortunately, as with our patient, it is impossible to determine whether larger quantities of paracetamol had been ingested either accidentally or intentionally.2,10

1 Photomicrograph of the liver at autopsy

Massive panlobular necrosis with relative preservation of portal tracts (4 × objective). Inset: Hepatic necrosis with mild fatty changes (20 × objective).

2 Metabolism of paracetamol

A: In a healthy individual, about 95% of paracetamol is conjugated with glucuronide and excreted in the urine. Most of the remainder is conjugated with glutathione. B: In starvation, impaired conjugation and depletion of glutathione result in accumulation of hepatotoxic N-acetyl-p-benzoquinone imine (NAPQI).