JOURNAL OF THE ROYAL SOCIETY OF MEDICINE. Volume 90. July 1 997. Paracetamol hepatotoxicity: how to prevent. John G O'Grady MD FRCPI. J R Soc ...
JOURNAL OF THE ROYAL SOCIETY OF MEDICINE
Volume 90
July 1 997
Paracetamol hepatotoxicity: how to prevent John G O'Grady MD FRCPI J R Soc Med 1997;90:368-370
Paracetamol is the drug most commonly taken as an overdose and the main cause of acute liver failure in the UK. The estimates of the number of overdoses including paracetamol range up to 70000 per annuml. The great majority of these patients show no sign of important liver or kidney damage and are discharged from hospital within a few days of presentation. The percentage who receive Nacetylcysteine is unknown, but this treatment would represent the main cost difference in the management of paracetamol and other ultimately innocuous drug overdoses. However, resource implications are vastly greater for the 400-500 patients per year who develop severe liver damage and require management in specialist liver centres. The guidelines for transfer to a specialist unit after a paracetamol overdose are outlined in Table 1. About 38% of patients transferred to specialist liver units do not deteriorate significantly after arrival and are fit to return to the referring hospital within 3-4 days2. A small group of patients develop renal failure as the dominant manifestation of the paracetamol overdose and these may require renal support for up to 6 weeks. The correlation between disorders of coagulation [prothrombin time or international normalized ratio (INR)] and outcome is imprecise and there is considerable overlap between the derangements seen in this group and those who progress to grade 3-4 encephalopathy. Metabolic acidosis is the only early prognostic indicator that is strongly indicative of a poor outcome, but this lacks sensitivity and was present in only about a third of patients who ultimately died3. The lack of precision in predicting outcome, combined with the potential for rapid progression to advanced encephalopathy and its associated complications, makes this level of 'unnecessary transfer' unavoidable, especially if the potential for transplantation is to be fully realized; these patients have a very short window period during which they are suitable candidates for liver transplantation4. The typical patient transferred to a specialist unit is young (average age 29 years), single (57%), female (56%), and taking the first overdose (62%)2. Of those who develop advanced encephalopathy (grades 3 and 4) 50-55% will survive with medical management, 35% will die, and 10-15% will undergo emergency liver transplantation2'5.
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Institute of Liver Studies, King's College Hospital, Denmark Hill, London SE5 9PJ, England
The survivors with medical management typically spend 710 days in intensive care and a further 2-4 weeks in hospital, before ultimately regaining full physical health without sequelae or the need for drug therapy. The number of patients undergoing transplantation represents 41-43% of those listed for transplantation because they meet the criteria in Table 2 and lack medical or psychosocial contraindications4'6. The remaining patients die or develop contraindications to transplantation before an organ becomes available4'6. The survival rates in those receiving liver grafts have ranged between 66% and 76%2,4,6. These patients do not return to normality but must adapt to the discipline and constraints common to liver transplant recipients. They will probably require anti-rejection medication for the remainder of their lives and the cost of this and the attendant monitoring is great. The cost to the National Health Service (NHS) of treating the cohort who develop severe liver damage is £6-8 million a year and the cost of maintaining a liver transplant recipient is between £3000 and £5000 a year. Auxiliary liver transplantation has the potential to confer the benefits of transplantation without the need for longterm maintenance of the graft once the native organ has regenerated. This approach is in theory ideal for paracetamol-induced acute liver failure because the native liver regenerates to completely normal morphology, but the Table 1 Guidelines for referral of patients to specialist centres following paracetamol overdose 24-48h
49-72 h
73+ h
Arterial pH 3.0 or prothrombin time (PT) 40s Hypoglycaemia
Encephalopathy* Arterial pH< 7.30
Encephalopathy* INR>6 or PT>80s
INR>4.5 or PT > 60s
Creatinine > 2009mol/L Severe thrombocytopenia
Creatinine > 200 ,mol/L
Progressive rise in PT irrespective of value Creatinine > 250 mol/L
*Any grade
JOURNAL OF THE ROYAL SOCIETY OF MEDICINE
Table 2 Selection criteria for liver transplantation following paracetamol overdose Arterial pH < 7.30* or
All three of the following occurring concomitantly: Prothrombin time >100s Creatinine >300 umol/L Grade 3-4 encephalopathy
*Unless rapidly corrected by rehydration
optimum role for auxiliary transplantation has yet to be defined7. Patients with severe neurological and haemodynamic complications benefit substantially from removal of the necrotic liver and thus do best with standard wholeorgan transplants. Ultimately, auxiliary liver transplantation may be most useful for pre-empting the development of severe complications in cases where the prognosis is uncertain. However, this is a function for which the emerging extracorporeal liver assist devices may prove
useful8. Prevention of paracetamol hepatotoxicity has the potential to save lives, make more organs available for elective transplantation and reduce demands on valuable intensive care resources. The dose-dependent nature of the hepatotoxicity and the parasuicidal, rather than suicidal, intent in the majority of cases suggest that a considerable proportion could be prevented. Since paracetamol is marketed in the UK as an inexpensive analgesic in quantities of up to 50 g it is widely, available when parasuicidal gestures are contemplated, and this may contribute to its prominent profile in this regard. Half of all cases of severe paracetamol hepatotoxicity were impulsive or reactive to life-events, and only 4% of these patients left suicide notes2. However, even amongst the patients taking overdoses against a background of depression, only 8% left suicide notes, so there may also be an impulsive element to the overdose in these cases2. Preventive strategies could address the ease of access to paracetamol, the way it is packaged, or the availability of methionine as a hepatoprotective agent. Paracetamol hepatotoxicity could be largely abolished by an Act of Parliament making the drug available only on prescription. However, this would deprive the general population of easy access to a cheap, effective and safe analgesic. The late UK Government consulted on a proposal to restrict the sale of paracetamol to quantities of 6 g in general outlets and 15 g in pharmacies, while multiple packs would be available at a pharmacist's discretion for chronic and recurrent illnesses9. These quantities overlap with the range of observed toxic doses (5-210 g), although in one study only 8% of patients with severe liver damage had taken less than 12 g2. This would suggest that restriction of the quantities easily available could reduce the incidence of hepatotoxicity. The
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impulsiveness typical of many overdoses may be obstructed by presenting the tablets in blister packs so that the time needed to punch them out allows the implications of the act to register. An alternative approach is the addition of methionine to paracetamol tablets to reduce the toxicity in overdose. Methionine has a similar function to N-acetylcysteine: it is a substrate that allows glutathione repletion, thus protecting against the hepatotoxicity caused by an unstable metabolite of paracetamol. Such preparations are available but they represent a tiny proportion of the total sales of paracetamol and are used mainly in controlled environments. This approach cannot be expected to have an impact on the burden of overdoses unless inclusion of methionine in all paracetamol preparations becomes obligatory. Early problems with palatability and inflated cost are said to have been overcome, although the existing preparations are considerably more expensive than simple paracetamol. However, it must be conceded that the efficacy of this approach has not yet been demonstrated and there is considerable opposition to the imposition of obligatory paracetamol/methionine combinations. Given the scale of the problem caused by paracetamol toxicity and the availability of preventive measures, it is hard to resist the conclusion that the status quo is unsustainable. Unfortunates intent on committing suicide are not going to benefit from change, nor is the number of parasuicidal gestures likely to fall substantially. However, few of the alternative methods favoured for parasuicides possess the 'sting in the tail' so characteristic of paracetamol self-poisoning. Thus, even if the parasuicide burden is merely shifted to another aspect of healthcare, the overall benefit to a young population and to the NHS could be enormous. Inadvertent paracetamol-induced hepatotoxicity accounted for 8% of cases admitted to the Liver Unit at King's College Hospital between 1987 and 19932. This may result from excessive dosing through lack of realization of the maximum recommended dose (despite explicit labelling) or lack of awareness of the presence of paracetamol in multiple drug combinations. Educational initiatives to promote awareness of these issues are necessary if the explicit advice on drug packaging and information sheets is to be effective. Chronic alcohol consumers, malnourished individuals and patients with enzyme induction secondary to antiepileptic therapy are also at risk from paracetamol taken with therapeutic intent1I 12. In one series of 67 patients with liver damage attributed to therapeutic usage, 64% were considered to be alcohol abusers12. This observation has resulted in a modification of the treatment nomogram widely used to determine the need for N-acetylcysteine, so that the threshold has been halved for these cases.
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REFERENCES 1 Fagan EA. Reducing paracetamol overdoses. BMJ 1996;313: 1417-18 2 Makin AJ, Wendon J, Williams R. A 7-year experience of severe acetaminophen-induced hepatotoxicity (1987-1993). Gastroenterology 1995; 109: 1907-16 3 O'Grady JG, Alexander GJM, Hayllar KM, Williams R. Early indicators of prognosis in acute liver failure and their application to selection of patients for orthotopic liver transplantation. Gastroenterology 1989;97:439-45 4 O'Grady JG, Wendon J, Tan KC, Potter D, Cottam S, Cohen AT, Gimson AES, Williams R. Liver transplantation after paracetamol
overdose. BMJ 1991;303:221-3 5 Anand AC, Nightingale P, Neuberger JM. Early indicators of prognosis in fulminant hepatic failure: an assessment of the King's criteria. J Hepatol 1997;26:62-8 6 Mutimer DJ, Ayres RCS, Neuberger JM, et al. Serious paracetamol poisoning and the results of liver transplantation. Gut 1994;35: 809-814
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7 Heaton ND, Corbally MT, Rela M, Tan KC. Surgical techniques of segmental reduction, split and auxiliary liver transplantation. In: Williams R, Portmann B, Tan KC, eds The Practice of Liver Transplantation, London: Churchill Livingstone, 1995:143-51 8 Ellis AJ, Wendon JA, Hughes RD, et a). The extracorporeal liver assist device in acute liver failure: Design and testing of a controlled trial protocol. Hepatology 1996;24:1446-51 9 Consultation Letter: Analgesic Medicines Available Without Prescription: Proposed Changes To Product Information and Sale Or Supply Of Paracetamol. Medicines Control Agency, November, 1996 10 Whitcomb DC, Block GD. Association of acetaminophen hepatotoxicity with fasting and ethanol use. JAMA 1994;23:1845-50 11 Zimmerman HJ, Maddrey WC. Acetaminophen (paracetamol) hepatotoxicity with regular intake of alcohol: Analysis of instances of therapeutic misadventure. Hepatology 1995;22:767-73 12 Bray GP, Harrison PM, O'Grady JG, Tredger JM, Williams R. Long-term anticonvulsant therapy worsens outcome in paracetamol-induced fulminant hepatic failure. Hum Exp Toxicol 1992;11:265-70
