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Accidental paracetamol overdosing and fulminant hepatic failure in children
Fiona K Miles, Ramananda Kamath, Stuart F A Dorney, Kevin J Gaskin and Edward V O'Loughlin
MJA 1999; 171: 472-475
See also Hynson
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More articles on Pathology
| Abstract |
Objective: To delineate clinical characteristics
useful for identifying children with liver failure due to accidental
paracetamol overdose. Design: Retrospective review of medical records of all patients admitted from 1985 to 1998 with fulminant hepatic failure. Setting: Royal Alexandra Hospital for Children, a tertiary referral centre for paediatric liver transplantation. Main outcome measures: Contribution of paracetamol to liver failure; other risk factors for liver failure; comparison of clinical features of paracetamol group and others. Results: 18 patients were identified. Eight were considered to have accidental paracetamol hepatotoxicity. In a further three, other risk factors were present but paracetamol was considered a major contributor to liver failure. The seven remaining patients had other risk factors for liver failure. Patients with paracetamol-induced liver failure usually had an acute prodromal illness with prolonged fasting and, at presentation, had encephalopathy, coagulopathy, very high transaminase levels, but disproportionately low total bilirubin levels. Five patients had hypoglycaemia. End-stage liver failure occurred in 4/11 of the paracetamol group compared with 7/7 of the others. Conclusion: Accidental paracetamol overdose is associated with fulminant hepatic failure in infants and children. Patients present with high transaminase levels and liver synthetic failure out of proportion to the level of serum bilirubin. Prompt identification of such patients is important as many recover with supportive therapy. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Introduction |
Paracetamol is a commonly used antipyretic and analgesic
medication; in 1996, it was the second most common drug used in
Australia, with 4.75 million units dispensed.1 There is a large
range in the preparations of doses available, and the potential for
accidental overdose due to confusion over concentration and
frequency of dosing is high.2
Intentional paracetamol overdose is a well-recognised cause of fulminant liver failure.2 However, there are few reports of accidental overdose due to recurrent ingestion of high therapeutic doses in children.3-6 Alonso et al reported seven children with fulminant liver failure without obvious cause.5 All patients had ingested paracetamol, but serum paracetamol levels were not in the toxic range. The authors postulated that, although paracetamol may have contributed to the liver injury, it was not causative. Two other reports describe accidental multiple dosing causing liver failure in children, with many patients receiving doses in the recommended therapeutic range.3,6 Prodromal illness associated with prolonged fasting was also recognised as potentially important in the development of liver injury.4,5 Since 1985, the Royal Alexandra Hospital for Children has been a tertiary referral centre for paediatric liver transplantation. Over this period, 19 patients have presented with acute liver failure. Our aims were to review all cases of acute liver failure, to identify patients with accidental (overdose with therapeutic intent) paracetamol-induced liver failure, and to define clinical features which may be useful in identifying such cases. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Methods |
All patients at the Royal Alexandra Hospital with fulminant hepatic
failure -- severe acute liver injury with no pre-existing liver
disease resulting in encephalopathy within eight weeks of onset --
are managed by members of the liver transplant service. We reviewed
case records of such patients for a history of liver disease,
presenting symptoms, pre-existing history of paracetamol
ingestion, clinical status at presentation, laboratory
investigations and outcome.
Paracetamol hepatotoxicity was considered likely if patients with liver failure had:
Approval for our study was obtained from the hospital's institutional ethics committee. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Results | Ninteen patients were identified, aged 6-165 months. One adolescent developed liver failure from suicidal overdose (30 g), and made a complete recovery with conservative treatment; this patient was excluded from the study. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Paracetamol hepatotoxicity | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Eleven of the remaining 18 patients had presumed paracetamol
hepatotoxicity. The patient data shown in the Table represent peak
levels of study parameters or stage of encephalopathy. All patients
had coagulopathy, elevated transaminase levels, and abnormal total
serum bilirubin.
Eight patients (numbers 1-8, Table) were identified as having paracetamol overdose as the only risk factor for liver failure. All eight patients had a history of a prodromal illness for which they received paracetamol for 4-21 days prior to the identification of liver disease. Reported paracetamol intakes ranged from 20 to 200 mg/kg per day. Paracetamol was detected in the blood of all eight patients, and all were encephalopathic (stage I-III) at presentation. Patients 1, 2, 3, 5 and 7 were hypoglycaemic (blood glucose levels < 3 mmol/L) at admission. Liver failure resolved with supportive treatment in six of these patients; Patients 2 and 6 died while awaiting liver transplants. Patient 5 survived, but had severe neurological sequelae as a result of protracted hypoglycaemia and stage IV encephalopathy. Patient 4 was admitted to the intensive care unit, but was not initially recognised as having liver failure. Patients 9, 10 and 11 had probable paracetamol hepatotoxicity, but also had other risk factors for liver injury. Patient 9 had Ewing's sarcoma and had been receiving chemotherapy. Multiple doses of paracetamol had been administered in hospital before the onset of liver failure. At postmortem, hepatic centrilobular necrosis consistent with paracetamol hepatotoxicity was found. Patient 10 also had a history of paracetamol ingestion, although the quantity could not be determined from the history. However, a high level of paracetamol was detected in the blood. The patient had had one previous admission with mumps encephalitis, which resulted in epilepsy and mental retardation. He had also been taking sodium valproate for seizures for several years, with no evidence of liver abnormalities. The patient died of end-stage liver failure and post-mortem revealed severe centrilobular necrosis consistent with paracetamol- rather than valproate-induced liver injury. Patient 11 had a mild prodromal illness due to Epstein-Barr virus infection, but ingested large quantities of paracetamol and presented with the clinical picture as described for Patients 1-8. Coagulopathy precluded liver biopsy in this group of patients. Metabolic studies: Urinary metabolic studies failed to reveal abnormal metabolites indicative of fatty acid oxidation defects in Patients 1, 2, 5, 6, 7 and 8, and skin fibroblast assays for fatty acid oxidation defects were normal in Patients 3, 6, 7 and 8. For Patient 4, no metabolic studies were performed. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Other causes of liver failure | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Seven patients presented with fulminating liver failure from other causes, including Wilson's disease (1), cytomegalovirus infection (1), hepatitis B virus infection (1), presumed viral hepatitis (3), and an adverse reaction to dapsone (1). All patients presented with evidence of severe synthetic failure (coagulopathy and hypoalbuminaemia) and hepatic encephalopathy. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Distinguishing paracetamol hepatotoxicity | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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The Figure compares the serum bilirubin levels plotted against
alanine transaminase levels in both groups of patients. In contrast
to patients with other causes of acute liver failure, patients with
presumed paracetamol hepatotoxicity all had serum bilirubin levels
less than 200 µmol/L, and most had alanine transaminase levels
greater than 4000 IU/L.
Hypoglycaemia was not detected in any of the patients with liver failure from causes other than paracetamol, and all patients in this group either died or received transplants. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Discussion | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Clinical features | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Accidental paracetamol overdose was the likely cause of acute liver
failure in most children in this series presenting to a single
paediatric institution. Eight of the 18 patients had likely
paracetamol-induced liver failure due to accidental overdose, and
in a further three paracetamol was a major risk factor. A distinct
clinical pattern emerges when the patients with definite or presumed
paracetamol toxicity are compared with patients with other causes of
fulminant hepatic failure. Patients with paracetamol toxicity
presented with a non-specific prodromal illness, often with fasting
and/or vomiting. At the time of hospitalisation they had evidence of
severe synthetic failure, often with associated hypoglycaemia,
coagulopathy and mild encephalopathy, but with disproportionately
low bilirubin levels. Moreover, most patients recovered with
supportive therapy.
A history of paracetamol ingestion over several days is important in establishing the diagnosis of paracetamol toxicity. In our study, reported ingestion of as little as 20 mg/kg per day over a protracted period was associated with liver failure. Similar toxic dosage ranges have been reported in other studies of children,3,5 raising the question of whether some susceptible children could suffer acute liver failure as a result of therapeutic doses of paracetamol ingested over several days. However, it is important to emphasise that the paracetamol intake data reported in this study, as in previous published reports, rely on history alone. The dosages reported by parents could not be verified by other means. Whether therapeutic doses of paracetamol could result in liver failure in susceptible children remains unresolved owing to the poor quality of the existing paediatric data. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Serum paracetamol levels | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Paracetamol was detected in the serum of patients with presumed
paracetamol hepatotoxicity. Although other investigators have
used a level of 0.04 mmol/L3,4 as indicative of
toxicity, it is not clear that this is a meaningful level in an
individual with repeated ingestions over several days. A level of 40
µmol/L or greater at 24 hours after the ingested dose is thought
to predict the likely development of liver failure, as portrayed in
the nomogram adapted by Rumack and Matthews.7 However, this nomogram was
derived from adult patients presenting with liver failure from a
single suicidal overdose. No studies have addressed the question of
serum levels likely to predict hepatic failure after repeated doses.
We observed that the possible role of paracetamol was, on occasion,
discounted because paracetamol levels were lower than those
predictive of the development of liver failure from the nomogram.
Poor correlation between paracetamol levels and liver toxicity with
accidental overdose has been observed in a large series of adult
patients in whom less than 50% had peak serum levels greater than 10
µg/mL (40 µmol/L).4 Similarly, low levels were
reported in a small series of children.5 Nevertheless, serum
paracetamol levels should be measured routinely in the
investigation of children presenting with acute liver failure as
soon as possible after assessment, but should be interpreted with
caution.
A recent study of paracetamol toxicity in adults by Schiodt et al identified a distinct group of patients who developed liver dysfunction after accidental poisoning with therapeutic intent.4 This group of 21 patients had ingested frequent doses of paracetamol for pain relief. Toxicity may have been compounded by prior starvation.2 Mortality in that study (4/21) was similar to ours, but was substantially higher than in a group of adult patients with non-accidental overdose. Some doubts about the role of paracetamol in causing fulminant hepatic failure in the study by Schiodt et al have been raised, as a high proportion of patients had a history of concurrent alcohol abuse and dosage levels were considered by some to be too low to cause toxicity.8-11 In contrast to that study of adults, studies in children raise considerable concern that accidental paracetamol overdose causes liver failure in this age group.3,5 However, it is important to note that all the reported series in children (including our own) are anecdotal reports. No studies have included a control group or undertaken a case-control study design, although liver biopsies were performed in six of seven patients in one series.5 While one could argue that the association between accidental overdose and liver failure in children is speculative, several arguments support the likely association with paracetamol:
Recent in-vitro and animal studies indicate that paracetamol or its metabolites impair mitochondrial metabolism, and this effect occurs before hepatocyte necrosis.13-15 In this regard, paracetamol hepatotoxicity demonstrates some remarkable clinical and biochemical similarities to some inborn errors of fatty acid oxidation which can present with fulminant liver failure.16 Despite several attempts to define a safe therapeutic regimen, there is still no consensus as to the appropriate dose, or even efficacy, in children. One report recommended single doses of 10-15 mg/kg four-hourly as a "safe maximum".17 However, Nahata et al demonstrated that paracetamol may accumulate substantially, with raised concentrations after therapeutic doses for two to three days, even with doses of 13 mg/kg 24-hourly.18 One study which did review the potential for chronic overdose in children was done by Penna et al,19 in which 190 of 299 paediatric inpatients received paracetamol for indications of fever and postoperative pain. Most were prescribed four-hourly doses, with potential for greater than 90 mg/kg per day. Nearly a quarter of the high doses were for children under 12 months of age. Although it can be argued that paracetamol "is commonly administered to children . . . for most febrile illnesses",5 and thus can be a frequent coincidental association, there is evidence that accidental overdose while ingesting high therapeutic doses of paracetamol for pain and fever relief may cause fulminating liver failure in children. Clinicians should be alerted to the possibility of paracetamol toxicity in an infant or child presenting with a prodromal illness associated with fasting and the regular ingestion of paracetamol over several days. Hypoglycaemia, severe synthetic failure and encephalopathy with very high transaminase levels (above 4000 IU/L) and a serum bilirubin level less than 200 µmol/L would support the diagnosis. It is important to distinguish this group of patients, as the prognosis for recovery is good with conservative therapy. If N-acetylcysteine is instituted early, liver transplantation may be avoided. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| References |
(Received 25 Jun, accepted 2 Sep, 1999) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Authors' details |
The Royal Alexandra Hospital for Children, Sydney, NSW.
Fiona K Miles, MB ChB, Fellow in Intensive Care; Ramananda Kamath, MD, FRACP, Associate Professor and Staff Specialist, Department of Gastroenterology; Stuart F A Dorney, MB BS, FRACP, Staff Specialist, Department of Gastroenterology; Kevin J Gaskin, MD, FRACP, Professor and Staff Specialist, Department of Gastroenterology; Edward V O'Loughlin, MD, FRACP, Staff Specialist, Department of Gastroenterology. Reprints: Dr E V O'Loughlin, Department of Gastroenterology, The Royal Alexandra Hospital for Children, PO Box 3515, Parramatta, NSW 2124. tedoATnch.edu.au ©MJA 1999
Readers may print a single copy for personal use. No further reproduction or distribution of the articles should proceed without the permission of the publisher. For permission, contact the Australasian Medical Publishing Company. Journalists are welcome to write news stories based on what they read here, but should acknowledge their source as "an article published on the Internet by The Medical Journal of Australia <http://www.mja.com.au>". <URL: http://www.mja.com.au/> © 1999 Medical Journal of Australia. We appreciate your comments. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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1-antitrypsin deficiency, and
fatty acid oxidation abnormalities).
