Is paracetamol hepatotoxic at normal doses?
BMJ 2013; 346 doi: https://doi.org/10.1136/bmj.f1519 (Published 12 March 2013) Cite this as: BMJ 2013;346:f1519
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The question of chronic paracetamol use and hepatic toxicity is one that has been asked by hepatologists. Clearly, a prospective randomised trial is ethically questionable but a systematic review published in 2007 by Dart and Bailey (1) reviewed 791 articles and included 30,865 subjects in prospective studies and 9337 patients in retrospective reports. They reported that prospective studies demonstrated that repeated use of therapeutic paracetamol may slightly increase the level of serum aminotransferase activity, but hepatic failure or death was not reported. Retrospective reports indicated a higher rate of increased serum aminotransferase levels, and several reported associated liver injury and death.
Paracetamol is toxic in malnourished and underweight patients who take standard doses and has also been implicated in worsening liver failure from other causes (2). The data quoted in SALT is a series of case reports and is relatively small in comparison. While questions still remain over paracetamol, it is perhaps innocuous when dosed with respect.
1) Dart RC, Bailey E. Does therapeutic use of acetaminophen cause acute liver failure? Pharmacotherapy 2007; 27: 1219–30.
2) Yaghi C, Honein K, Boujaoude J, Slim R, Moucari R, Sayegh R. Infl uence of acetaminophen at therapeutic doses on surrogate markers of severity of acute viral hepatitis. Gastroenterol Clin Biol
2006; 30: 763–68
Competing interests: No competing interests
May I offer the anecdotal observation from a medico-legal perspective that iatrogenic liver failure caused by chronic paracetamol use at normal or slightly excessive dosage does from time to time reach the courts. In one recent Fatal Accident Inquiry the deceased was not eating and on a glucose and saline infusion for several days before liver failure became apparent. Paracetamol administration was IV and the overdose and its repitition may have been the result of over-familiarity with oral administration. Details are in the public domain and can be found at http://www.scotcourts.gov.uk/opinions/2011fai7.html
Competing interests: No competing interests
Re: Is paracetamol hepatotoxic at normal doses?
I thank Mr Whitehouse for his very insightful comment. I may just regret that he did not take the time to read or maybe understand the study he disparages. SALT considered every single liver transplantation in seven countries in Europe (including UK) and found 300 cases that had been exposed to nonoverdose medicinal drugs within 30 days before the first symptoms, out of almost ten thousand liver transplants studied. Of these, 81 had been exposed to paracetamol. The event rate per billion days of treatment sold or per million patient-years was three time higher than for NSAIDs. The background population was over 250 million persons over 3 years, i.e. 750 Million person-years. How this can be interpreted as "The data quoted in SALT is a series of case reports and is relatively small in comparison" to 30 000 pateints included in a meta-analysis is beyond me.
SALT is not a series of case reports, but a systematic epidemiological study, and I believe the largest study of drug-related liver failure in Europe to date.
Incidentally, the event rate for acute liver failure is around 0.5 per million persons per year, so that the numbers of patients cited by Mr Whitehouse are totally incapable of finding anything. The question of the toxicity at normal dose in patients with or without predisposing factors remains entirely open: is it a direct toxicity of paracetamol? Is paracetamol a favourizing factor for hepatic failure related to other drugs or to making those more severe. If Mr Whitehouse cannot obtain the original papers of SALT, I will be glad to provide them.
Competing interests: Author of the initial paper