Acetaminophen Overdose and Acute Liver Failure: Modern Management

  • A. J. Makin
  • R. Williams
Conference paper
Part of the Yearbook of Intensive Care and Emergency Medicine book series (YEARBOOK, volume 1996)


Acetaminophen (paracetamol; N-acetyl-p-aminophenol), a para-aminophenol derivative, was first introduced by von Mering in 1893 after acetanilide, the parent compound, had been withdrawn because of its toxicity. In the USA, acetaminophen has been available since 1952, and in the UK it steadily gained in popularity as an analgesic from 1956 onwards. It is available without prescription and, when used at the recommended dosage, has few side effects and is safer than aspirin [1]. Currently, in the UK and USA, there are over 100 proprietary preparations of acetaminophen, and well over 200 proprietary multi-ingredient preparations containing acetaminophen on sale. Hepatotoxicity from acetaminophen was first reported by Eder in 1964 during long-term toxicity studies in cats [2]. Two years later, Boyd and Bereczky [3] observed extensive centrilobular necrosis following ingestion of high doses of acetaminophen in rats, and the first cases of severe fatal and non-fatal hepatotoxicity in man were reported in the same year [4, 5].


Acute Liver Failure Fulminant Hepatic Failure Paracetamol Poisoning Severe Hepatotoxicity Acetaminophen Overdose 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Editorial (1981) Aspirin or paracetamol? Lancet 2: 287–289Google Scholar
  2. 2.
    Eder H (1964) Chronic toxicity studies on phenacitin, N-acetyl-p-aminophenol (NAPA) and acetylsalicylic acid on cats. Acta Pharmacol Toxicol 21: 197–204CrossRefGoogle Scholar
  3. 3.
    Boyd EM, Bereczky GM (1966) Liver necrosis from paracetamol. Br J Pharmacol 26: 606–614Google Scholar
  4. 4.
    Davidson DG, Eastham WN (1966) Acute liver necrosis following overdose of paracetamol. Br Med J 2: 497–499PubMedCrossRefGoogle Scholar
  5. 5.
    Thomson JS, Prescott LF (1966) Liver damage and impaired glucose tolerance after paracetamol overdosage. Br Med J 2: 506–507PubMedCrossRefGoogle Scholar
  6. 6.
    Smilkstein MJ, Knapp HL, Kulig KW, Rumack BH (1988) Efficacy of oral N-acetylcysteine in the treatment of acetaminophen overdose. New Engl J Med 319: 1557–1562PubMedCrossRefGoogle Scholar
  7. 7.
    Litovitz TL, Clark LR, Soloway RA (1994) 1993 Annual Report of the American Association of Poison Control Centers Toxic Exposure Surveillance System. Am J Emerg Med 12: 546–584PubMedCrossRefGoogle Scholar
  8. 8.
    Office of Population Censuses and Surveys (1994) Mortality statistics: Injury and poisoning 1992. London: HMSOGoogle Scholar
  9. 9.
    O’Grady JG, Alexander GJM, Hayllar KM, and Williams R (1989) Early indicators of prognosis in fulminant hepatic failure. Gastroenterology 97: 439–445PubMedGoogle Scholar
  10. 10.
    Benhamou JP (1990) Fulminant and subfulminant liver failure: Definitions and causes. In: Williams R, Hughes RD (eds). Acute Liver Failure. Improved understanding and better therapy. Proceedings of the eleventh BSG.SK&F International Workshop. SmithKline Beecham Pharmaceuticals, Welwyn Garden City, pp 6–10Google Scholar
  11. 11.
    Bernuau J, Durand F, Werner P, et al (1995) Management of patients with fulminant or subfulminant liver failure (FSLF) without intracranial pressure monitoring (ICPM): A 4-year prospective study. Joint Congress on Liver Transplantation, London, UK (Abst 1.4)Google Scholar
  12. 12.
    Ott P, Dalhoff K, Hansen PB, Loft S, Poulsen HE (1990) Consumption, overdose and death from analgesics during a period of over-the-counter availability of paracetamol in Denmark. J Int Med 227: 423–428CrossRefGoogle Scholar
  13. 13.
    Monteagudo FS, Folb PI (1987) Paracetamol poisoning at Groote Schuur Hospital. S Afr Med J 72: 773–776PubMedGoogle Scholar
  14. 14.
    Oren R, Levy M (1992) Paracetamol overdosage in Jerusalem, 1984–89. Isr J Med Sci 28: 795–796PubMedGoogle Scholar
  15. 15.
    Brotodihardjo AE, Batey RG, Farrell GC, Byth K (1992) Hepatotoxicity from paracetamol self-poisoning in western Sydney: A continuing challenge. Med J Aust 157: 382–385PubMedGoogle Scholar
  16. 16.
    Chan TYK, Chan AYW, Critchley JAJH (1993) Paracetamol poisoning and hepatotoxicity in Chinese: The Prince of Wales hospital (Hong-Kong) experience. Singapore Med J 34: 299–302PubMedGoogle Scholar
  17. 17.
    Hawton K, Ware C, Mistry H, et al (1995) Why patients choose paracetamol for self poisoning and their knowledge of its dangers. Br Med J 310: 164CrossRefGoogle Scholar
  18. 18.
    Prescott LF, Wright N (1973) The effects of hepatic and renal damage on paracetamol metabolism and excretion following overdosage. A pharmacokinetic study. Br J Pharmacol 43: 603–613Google Scholar
  19. 19.
    Prescott LF (1983) Paracetamol overdosage. Pharmacological considerations and clinical management. Drugs 25: 290–314PubMedCrossRefGoogle Scholar
  20. 20.
    Mitchell JR, Jollow DJ, Potter WZ, Gillette JR, Brodie BB (1973) Acetaminopheninducedhepatic necrosis IV: Protective role of glutathione. J Pharmacol Exp Ther 187: 211–217PubMedGoogle Scholar
  21. 21.
    Streeter AJ, Dahlin DC, Nelson SD, Baillie TA (1984) The covalent binding of acetaminophen to protein. Evidence for cysteine residues as major sites of arylation in vitro. Chern BioI Interact 48: 349–366CrossRefGoogle Scholar
  22. 22.
    Ray SD, Kamendulis LM, Gurule MW, Yorkin RD, Corcoran GB (1993) Ca2+ antagonists inhibit DNA fragmentation and toxic cell death induced by acetaminophen. FASEB J 7: 453–463PubMedGoogle Scholar
  23. 23.
    Glenney Jr JR, Kaulfus P, Weber KF (1981) Actin assembly modulated by villin: Ca2+dependent nucleation and capping of the barbed end. Cell 24: 471–480PubMedCrossRefGoogle Scholar
  24. 24.
    Placke ME, Ginsberg GL, Wyand DS, Cohen SD (1987) Ultrastructural changes during acute acetaminophen-induced hepatotoxicity in the mouse. A time and dose study. Toxicol PathoI 15: 431–438CrossRefGoogle Scholar
  25. 25.
    Donnelly pJ, Walker RM, Racz WJ (1994) Inhibition of mitochondrial respiration in vivo is an early event in acetaminophen-induced hepatotoxicity. Arch Toxicol 68: 110–118PubMedCrossRefGoogle Scholar
  26. 26.
    Nelson SD (1990) Molecular mechanisms of the hepatotoxicity caused by acetaminophen. Semin Liver Dis 10: 267–278PubMedCrossRefGoogle Scholar
  27. 27.
    Laskin DL, Gardner CR, Price VF, Jollow DJ (1995) Modulation of macrophage functioning abrogates the acute hepatotoxicity of acetaminophen. Hepatology 21: 1045–1050PubMedCrossRefGoogle Scholar
  28. 28.
    Prescott LF (1983) Paracetamol overdosage. Pharmacological considerations and clinical management. Drugs 25: 290–314PubMedCrossRefGoogle Scholar
  29. 29.
    Prescott LF, Illingworth RN, Critchley JAJH, Stewart MJ, Adam RD, Proudfoot AT (1979) Intravenous N-acetylcysteine: The treatment of choice for paracetamol poisoning. Br Med J 2: 1097–1100PubMedCrossRefGoogle Scholar
  30. 30.
    Rumack BH, RC, Koch GG, Amaral AI (1981) Acetaminophen overdose. 662 cases with evaluation of oral acetylcysteine treatment. Arch Intern Med 141: 380–385PubMedCrossRefGoogle Scholar
  31. 31.
    Makin AJ, Wendon J, Williams R (1995) A seven year experience of severe acetaminophen-induced hepatotoxicity (1987-1993). Gastroenterology (In Press)Google Scholar
  32. 32.
    Seeff LB, Cuccherini BA, Zimmerman HI, Adler E, Benjamin SB (1986) Acetaminophen hepatotoxicity in alcoholics: A therapeutic misadventure. Ann Intern Med 104: 399–404PubMedGoogle Scholar
  33. 33.
    Whitcomb DC, Block GD (1994) Association of acetaminophen hepatotoxicity with fasting and ethanol use. JAMA 272: 1845–1850PubMedCrossRefGoogle Scholar
  34. 34.
    Zimmerman HJ, Maddrey WC (1995) Acetaminophen (paracetamol) hepatotoxicity with regular intake of alcohol: Analysis of instances of therapeutic misadventure. Hepatology 22: 767–773PubMedCrossRefGoogle Scholar
  35. 35.
    Sato C, Matsuda Y, Lieber CS (1989) Increased hepatotoxicity of acetaminophen after chronic ethanol consumption in the rat. Gastroenterology 80: 140–148Google Scholar
  36. 36.
    Mitchell JR, Jollow DJ, Potter WZ, Davis DC, Gillette JR, Brodie BB (1973) Acetaminophen-induced hepatic necrosis. I. Role of drug metabolism. J Pharmacol Exp Ther 187: 185–194PubMedGoogle Scholar
  37. 37.
    Yang CS, Patten q, Ishizaki H, Yoo JH (1991) Induction, purification, and characterization of cytochrome P450 lIE. Methods Enzymol 206: 595–603PubMedCrossRefGoogle Scholar
  38. 38.
    Lauterburg BH, Velez ME (1988) Glutathione deficiency in alcoholics: Risk factor for paracetamol hepatotoxicity. Gut 29: 1153–1157PubMedCrossRefGoogle Scholar
  39. 39.
    Prescott LF (1986) Effects of non-narcotic analgesics on the liver. Drugs 32 (Suppl. 4): 129–147PubMedCrossRefGoogle Scholar
  40. 40.
    Lauterburg BH, Corcoran GB, Mitchell JR (1983) Mechanism of action of N-acetylcysteine in the protection against the hepatotoxicity of acetaminophen in rats in vivo. J Clin Invest 71: 980–991PubMedCrossRefGoogle Scholar
  41. 41.
    Parker D, White JP, Paton D, Routledge PA (1990) Safety of late acetylcysteine treatment in paracetamol poisoning. Hum Exp Toxicol 9: 25–27PubMedCrossRefGoogle Scholar
  42. 42.
    Harrison PM, Keays R, Bray GP, Alexander GJM, Williams R (1990) Improved outcome of paracetamol-induced fulminant hepatic failure by late administration of acetylcysteine. Lancet 335: 1572–1573PubMedCrossRefGoogle Scholar
  43. 43.
    Keays R, Harrison PM, Wendon J, et al (1991) Intravenous acetylcysteine in paracetamol- induced fulminant hepatic failure: A prospective controlled trial. Br Med J 303: 1026–1029CrossRefGoogle Scholar
  44. 44.
    O’Grady JG, Gimson AES, O’Brien q, Pucknell A, Hughes RD, Williams R (1988) Controlled trials of charcoal hemoperfusion and prognostic factors in fulminant hepatic failure. Gastroenterology 94: 1186–1192PubMedGoogle Scholar
  45. 45.
    Davenport A, Will EJ (1988) Hypophosphataemia in acute liver failure. Br Med J 296: 131CrossRefGoogle Scholar
  46. 46.
    Jones AF, Harvey JM, Vale JA (1989) Hypophosphataemia and phosphaturia in paracetamol poisoning. Lancet 2: 607–609Google Scholar
  47. 47.
    Gray TA, Buckley BM, Vale JA (1987) Hyperlactataemia and metabolic acidosis following paracetamol overdose. Q J Med 65: 811–821PubMedGoogle Scholar
  48. 48.
    Gimson AES, Waterson M, Williams R (1985) Tissue hypoxia during fulminant hepatic failure. Crit Care Med 13: 1034–1039PubMedCrossRefGoogle Scholar
  49. 49.
    Bihari D, Gimson AES, Williams R (1986) Cardiovascular, pulmonary and renal complications of fulminant hepatic failure. Semin Liv Dis 6: 119–128CrossRefGoogle Scholar
  50. 50.
    Harrison PM, O’Grady JG, Keays RT, Alexander GJM, Williams R (1990) Serial prothrombin time as prognostic indicator in paracetamol-induced fulminant hepatic failure. Br Med J 301: 964–966CrossRefGoogle Scholar
  51. 51.
    Rolando N, Harvey F, Brahm J, et al (1990) Prospective study of bacterial infection in acute liver failure: An analysis of fifty patients. Hepatology 11: 49–53PubMedCrossRefGoogle Scholar
  52. 52.
    Rolando N, Gimson A, Wade J, Philpott-Howard J, Casewell M, Williams R (1993) Prospective controlled trial of selective parenteral and enteral antimicrobial regimen in fulminant hepatic failure. Hepatology 17: 196–201PubMedCrossRefGoogle Scholar
  53. 53.
    Wendon JA, Harrison PM, Keays R, Gimson AES, Alexander GJM, Williams R (1992) The effects of vasopressor agents and prostacydin on systemic haemodynamics and oxygen transport in patients with fulminant hepatic failure. Hepatology 15: 1067–1071PubMedCrossRefGoogle Scholar
  54. 54.
    O’Grady JG, Wendon J, Tan KC, et al (1991) Liver transplantation after paracetamol overdose. Br Med J 303: 221–223CrossRefGoogle Scholar
  55. 55.
    Mutimer DJ, Ayres RCS, Neuberger JM, et al (1994) Serious paracetamol poisoning and the results of liver transplantation. Gut 35: 809–814PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 1996

Authors and Affiliations

  • A. J. Makin
  • R. Williams

There are no affiliations available

Personalised recommendations