Acute liver failure after administration of paracetamol at the maximum recommended daily dose in adults
BMJ 2010; 341 doi: https://doi.org/10.1136/bmj.c6764 (Published 02 December 2010) Cite this as: BMJ 2010;341:c6764
- Lee C Claridge, Wellcome Trust clinical research fellow and specialist registrar in hepatology12,
- Bertus Eksteen, MRC clinician scientist and honorary consultant hepatologist12,
- Amanda Smith, lead pharmacist in liver and solid organ transplantation1,
- Tahir Shah, consultant hepatologist1,
- Andrew P Holt, consultant hepatologist1
- 1Liver Unit, Queen Elizabeth Hospital, Birmingham B15 2TH, UK
- 2Centre for Liver Research, Institute of Biomedical Research, University of Birmingham, Birmingham B15 2TT
- Correspondence to: L C Claridge l.c.claridge{at}bham.ac.uk
- Accepted 12 October 2010
Paracetamol is the most commonly used analgesic and antipyretic in the world; it can be bought without prescription in most countries despite being the commonest cause of acute liver failure in western Europe. Prescribing information suggests that it is safe to use in adults in divided doses that total 4 g daily. Malnutrition, starvation, chronic alcohol misuse, and concomitant use of drugs that induce cytochrome P450 enzymes increase the risk of hepatotoxicity induced by paracetamol. Nevertheless, doctors commonly regard paracetamol 4 g daily as being safe as well as an effective analgesic. We describe two cases (one fatal) of acute liver failure secondary to maximum dose oral paracetamol; these highlight the importance of considering dose reduction in those with low body weight and/or other risk factors for hepatotoxicity.
Case reports
Case 1
A 43 year old man was admitted with an exacerbation of Crohn’s colitis. His nutritional status was poor, with an admission weight of 30 kg and a body mass index (weight (kg)/(height (m)2)) of 12. He received intravenous hydrocortisone and metronidazole along with oral paracetamol at a total dose of 4 g daily. Four days later he became confused and tachypnoeic and was found to have developed acute liver failure with an aspartate aminotransferase of 12 769 IU/l, international normalised ratio of 9.1 (figure⇓), and severe lactic acidosis. Liver function tests were normal at the time of his admission. His paracetamol concentration was raised (92 mg/l) despite him having received the standard maximum adult dose under direct supervision. No other cause of liver failure could be identified; he was never hypotensive, and serological studies for acute viral infection were negative. He was transferred to the regional liver failure service, but despite treatment with N-acetylcysteine and supportive care on the liver intensive care unit he died 12 days later of multiorgan failure.
Dynamic changes in aspartate aminotransferase (left axis) and international normalised ratio (right axis) for each patient. Both patients received oral paracetamol, each at a total dose of 4 g daily from the time of admission to hospital (day 0)
Case 2
A 32 year old woman with a history of chronic alcoholism was admitted with acute alcohol withdrawal and abdominal pain secondary to alcoholic gastritis. She was prescribed vitamin supplements, chlordiazepoxide, and oral paracetamol (total 4 g daily). She weighed 44 kg on admission (body mass index 17). Blood tests and abdominal ultrasound on admission were unremarkable (aspartate aminotransferase 56 IU/l). Three days later she became increasingly agitated and complained of nausea. She was found to be in acute liver failure with a peak aspartate aminotransferase of 7116 IU/l and international normalised ratio of 3.2 (figure⇑). Her paracetamol concentration was raised (105 mg/l). She was transferred to the liver intensive care unit and received full supportive care including N-acetylcysteine. Her liver function gradually recovered and she was discharged 15 days later.
Discussion
Paracetamol is metabolised in the liver by processes of glucuronidation and sulfation. Most of the drug is metabolised into non-toxic metabolites, but 5-10% is converted by the cytochrome P450 system into the reactive toxic intermediate N-acetyl-p-benzoquinoneimine (NAPQI).1 In healthy individuals taking therapeutic doses of paracetamol this metabolite is usually rendered non-toxic by binding to glutathione.2 Overdose of paracetamol, induction of cytochrome P450 enzymes, or glutathione deficiency may result in the metabolic pathway becoming overwhelmed, producing an excess of NAPQI, which binds to hepatocyte macromolecules causing enzymatic dysfunction, structural and metabolic disarray, and eventually necrotic cell death. Hepatocytes are increasingly susceptible to oxidative stress when glutathione is depleted.3
Glutathione is synthesised from glutamate, cysteine, and glycine by two cytosolic enzymes (γ-glutamylcysteine synthetase and glutathione synthetase).4 Thus protein or amino acid deficiency secondary to malnutrition, malabsorption, or synthetic failure leads to glutathione deficiency. Alcoholics have low serum and intrahepatic glutathione concentrations, and chronic illness and fasting are risk factors for glutathione deficiency.5
Paracetamol has a narrow therapeutic index, and severe hepatocellular necrosis may follow the oral ingestion of a single dose of 150 mg/kg. Both of the patients we describe were underweight and had additional factors that made them at increased risk of hepatotoxicity. Patient 1 weighed 30 kg and his daily dose of 4 g was therefore 133 mg/kg. The daily dose received by patient 2 was 91 mg/kg. Doses of this magnitude repeated daily in individuals with inadequate metabolic capacity may lead to liver injury, which in severe cases may result in acute liver failure.
Several cases of acute liver failure secondary to oral paracetamol at the maximum recommended daily dose have been reported, and in all these cases the patients had identifiable risk factors for hepatotoxicity.6 7 8 9 10 Although these cases are rare, it is likely that they are an under-representation of the true incidence as some practitioners may not identify the correct cause of liver injury owing to a low index of suspicion. Patients who develop milder hepatic impairment may not be identified at all if liver function tests are not measured. A prospective study of acute liver failure at 17 tertiary care centres in the United States identified 21 patients with acute liver failure secondary to paracetamol at doses of ≤4 g daily over a 41 month period.11
The widespread use of paracetamol in hospitals and in the community, coupled with the high prevalence of chronic alcoholism and malnutrition, particularly in hospital inpatients, means that more cases will probably occur. However, if awareness is raised, further cases of acute liver failure may be preventable through reduced doses in those who are most at risk.
Intravenous paracetamol is now increasingly used in secondary care; at our hospital the annual number of prescriptions for intravenous paracetamol rose by 30% between 2007 and 2009 (from 2438 to 3174). The bioavailability of intravenous paracetamol (1.0) is higher than that of oral paracetamol, which is dose dependent and ranges from 0.7 to 0.9.12 Thus, there may be a greater potential for liver injury if a total of 4 g daily intravenous paracetamol is prescribed to malnourished patients with low body weight.
The British National Formulary (BNF) states that the daily dose of intravenous paracetamol should not exceed 60 mg/kg when prescribed for adults weighing <50 kg.13 The latest edition also cautions for the first time that the maximum daily dose of infusions should be reduced to 3 g for patients with hepatocellular insufficiency, chronic alcoholism, chronic malnutrition, or dehydration. However, it contains no recommendations to reduce the dose of oral paracetamol for adults weighing <50 kg or in the presence of other risk factors. This disparity between the maximum recommended dose of oral and intravenous paracetamol for adults with low body weight and/or other risk factors for hepatotoxicity is surprising, given that the systemic bioavailability of oral paracetamol may be as high as 90%.
We reviewed oral and intravenous paracetamol prescriptions issued at our hospital to adults weighing <50 kg over eight weeks. Eighty two per cent (47/57) of patients were prescribed oral paracetamol at the maximum recommended daily dose. Two of these patients had a transient rise in aspartate aminotransferase during treatment (from 29 IU/l to a peak of 526 IU/l over four days in a patient weighing 39 kg, and from 29 IU/l to 138 IU/l over three days in a patient weighing 40 kg). Moreover, in 17 of the 18 patients given intravenous paracetamol, the dose was not reduced as recommended by the British National Formulary. This shows that few practitioners in secondary care reduce the dose of either oral or intravenous paracetamol in adults with a low body weight and confirms that many patients are potentially at risk. The fact that we were able to identify two susceptible adults with evidence of liver injury secondary to maximum dose paracetamol at a single centre in a period as short as eight weeks suggests that these cases may be under-recognised.
We have raised awareness of this matter locally via email bulletins, pharmacists, and the introduction of an alert message on our electronic prescribing system recommending the reduction of the daily dose of paracetamol (oral and intravenous) to 2 g for adults weighing <50 kg.
Notes
Cite this as: BMJ 2010;341:c6764
Footnotes
Contributors: LCC wrote the first draft of the article and finalised subsequent revisions. LCC and AS performed the prescribing audit. BE and TS supervised the hepatological management of patient 1. APH supervised the hepatological management of patient 2. All authors critically appraised the manuscript and approved the final version. APH is the guarantor.
Funding: None.
Competing interests: All authors have completed the Unified Competing Interest form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare: no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous 3 years; no other relationships or activities that could appear to have influenced the submitted work
Provenance and peer review: Not commissioned; externally peer reviewed.
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