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Acetaminophen hepatotoxicity: An update

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Abstract

Acetaminophen is a widely used nonprescription analgesic and antipyretic agent. It is also a dose-related hepatotoxin that can cause fulminant liver failure when taken in massive overdoses or, much less commonly, at therapeutic doses in susceptible individuals. Persons who regularly consume alcohol or persons who have been fasting may be more susceptible to this hepatotoxicity. This liver injury is due not to the drug itself but to the formation of the toxic metabolite N-acetyl-p-benzoquinine imine generated through the cytochrome P-450 drug-metabolizing system. Normally, hepatic stores of glutathione combine with the toxic metabolite and prevent liver cell injury. When glutathione stores are depleted by overproduction of this metabolite, however, the reactive metabolite binds to liver cell proteins and causes hepatic necrosis. P-450 2E1 is induced by alcohol consumption and possibly starvation, and glutathione depletion can occur due to the inadequate nutrition occurring in chronic alcohol use or in starvation. Recent studies have shown that activated Kupffer cells and their secreted toxic agents such as cytokines may also play a role in this liver injury. This liver injury is characterized by extremely high levels of serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) (> 1000), and bad prognostic signs include severe prolongation of the prothrombin time, renal dysfunction, and, most importantly, acidosis. Nacetylcysteine is a highly effective antidote when given early (within 15 hours) of overdose. Some patients may develop such fulminant liver injury that they require transplantation. Unfortunately, many such patients have a course so rapid that a donor liver may not become available in time. Thus, both the medical community and the general public require a heightened understanding of this clinical problem in order to initiate prevention measures and to implement early therapeutic measures if an overdose situation occurs.

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References

  1. McClain CJ, Holtzman J, Allen J, et al.: Clinical features of acetaminophen toxicity. J Clin Gastroenterol 1988, 10:76–80.

    Article  PubMed  CAS  Google Scholar 

  2. Schiodt FV, Rochling FA, Casey DL, et al.: Acetaminophen toxicity in an urban county hospital. N Engl J Med 1997, 337:1112–1117. This paper evaluates patients hospitalized with acetaminophen hepatotoxicity in an urban county hospital and highlights the importance of this type of liver injury as a major cause of fulminant liver failure and the importance of chronic alcohol abuse among patients with accidental overdose.

    Article  PubMed  CAS  Google Scholar 

  3. Makin AJ, Wendon J, Williams R: A 7-year experience of severe acetaminophen-induced hepatotoxicity (1987-1993). Gastroenterology 1995, 109:1907–1916.

    Article  PubMed  CAS  Google Scholar 

  4. Black M: Acetaminophen toxicity. Annu Rev Med 1984, 35:577–593.

    Article  PubMed  CAS  Google Scholar 

  5. Cohen SD, Khairallah EA. Selective protein arylation and acetaminophen-induced hepatotoxicity. Drug Metab Rev 1997, 29:59–77.

    PubMed  CAS  Google Scholar 

  6. Pumford NR, Hinson JA, Benson RW. Immunoblot analysis of protein containing 3-(Cystein-S-yl)acetaminophen adducts in serum and subcellular liver fractions from acetaminophentreated mice. Toxicol Appl Pharmacol 1990, 104:521–532.

    Article  PubMed  CAS  Google Scholar 

  7. Birge RB, Bartolone JB, Emeigh Hart SG. Acetaminophen hepatotoxicity: correspondence of selective protein arylation in human and mouse liver in vitro, in culture, and in vivo. Toxicol Appl Pharmacol 1990, 105:472–482.

    Article  PubMed  CAS  Google Scholar 

  8. Rex DK, Kumar S. Recognizing acetaminophen hepatotoxicity in chronic alcoholics Postgrad Med 1992, 91:241–245.

    PubMed  CAS  Google Scholar 

  9. Nelson DR, Koymans L, Kamataki T, et al.: P-450 superfamily: update on news sequences, gene mapping, accession numbers and nomenclature. Pharmacogenetic 1996, 6:1–42.

    Article  CAS  Google Scholar 

  10. Raucy JL, Lasker JM, Lieber CS, et al.: Acetaminophen activation by human liver cytochromes P-450IIEI and P-450IA2. Arch Biochem Biophys 1989, 271:270–283.

    Article  PubMed  CAS  Google Scholar 

  11. Thummel KE, Lee CA, Kunzel KL, et al.: Oxidation of acetaminophen to N-acetyl-p-aminobenzoquinone imine by human CYP3A4. Biochem Pharmacol 1993, 45:1563 1569.

    Article  PubMed  Google Scholar 

  12. Patten CJ, Thomas PE, Guy RL, et al.: Cytochrome P-450 enzymes involved in acetaminophen activation by rat and human liver microsomes and their kinetics. Chem Res Toxicol 1993, 6:511–518.

    Article  PubMed  CAS  Google Scholar 

  13. Diaz D, Fabre I, Daujat M, et al.: Omeprazole is an aryl hydrocarbon-like inducer of human hepatic cytochrome P-450. Gastro 1990, 99:737–747.

    CAS  Google Scholar 

  14. Sarich T, Kalhorn T, Al Sayegh F, et al.: The effect of omeprazole pretreatment on acetaminophen metabolism in rapid and slow metabolizers of S-mephenytoin. Clin Pharmacol Ther 1997, 62:21–28.

    Article  PubMed  CAS  Google Scholar 

  15. Tonge RP, Bruschi SA, Kelly EJ, et al.: Role of CYP1A2 in the hepatotoxicity of acetaminophen (abstract). ISSX Proc 1997, 12:59.

    Google Scholar 

  16. Thomsen MS, Loft S, Roberts DW, et al.: Cytochrome 2E1 inhibitor by propylene glycol prevents acetaminophen hepatotoxicity in mice without cytochrome 1A2 inhibition. Pharmacol Toxicol 1995, 76:395–399.

    PubMed  CAS  Google Scholar 

  17. Lee SST, Buters JTM, Pineau T, et al.: Role of CYP2E1 in the hepatotoxicity of acetaminophen. J Biol Chem 1996, 271:12063–12067. This article unequivocally defines the role of cytochrome P-450 2E1 in acetaminophen hepatotoxicity using knockout mice.

    Article  PubMed  CAS  Google Scholar 

  18. Dai Y, Cederbaum AI: Cytotoxicity of acetaminophen in human cytochrome P-4502E1-transfected Hep G2 cells. J Pharmacol Exp Ther 1995, 273:1497–1505.

    PubMed  CAS  Google Scholar 

  19. Shimada T, Yamazaki H, Mimura M, et al.: Interindividual variations in human liver cytochrome P-450 enzymes involved in the oxidation of drugs. J Pharmacol Exp Ther 1994, 270:414–423.

    PubMed  CAS  Google Scholar 

  20. Hill D, Diehl AM, Tsukamoto H, et al.: Cytokines and liver disease. In Cytokines in Health and Disease, 2nd ed. Edited by Remick and Friedland. New York:Marcel Dekker; 1997 401–425.

    Google Scholar 

  21. Laskin DL, Pilaro AM. Potential role of activated macrophages in acetaminophen hepatotoxicity: I. Isolation and characterization of activated macrophages. Toxicol Appl Pharmacol 1986, 86:204–215.

    Article  PubMed  CAS  Google Scholar 

  22. Laskin DL, Pilaro AM, Ji S. Potential role of activated macrophages in acetaminophen hepatotoxicity: II. mechanism of macrophage accumulation and cativation. . Toxicol Appl Pharmacol 1986, 86:216–226.

    Article  PubMed  CAS  Google Scholar 

  23. Blazka ME, Wilmer JL, Holladay SD, et al.: Role of proinflammatory cytokines in acetaminophen hepatotoxicity. Toxicol Appl Pharmacol 1995, 133:43–52.

    Article  PubMed  CAS  Google Scholar 

  24. Goldin RD, Ratnayaka ID, Breach CS, et al.: Acetaminophen and macrophage activation. Int Hepatol Commum 1995, 4:16–18.

    Article  Google Scholar 

  25. Laskin DL, Gardner CR, Price VF et al.: Modulation of macrophage functioning abrogates the acute hepatotoxicity of acetaminophen. Hepatology 1995, 21:1045–1050. This article highlights the role of macrophages/Kupffer cells in acetaminophen hepatotoxicity.

    PubMed  CAS  Google Scholar 

  26. Goldin RD, Ratnayaka ID, Breach CS, et al.: Role of macrophages in acetaminophen (Paracetamol)-induced hepatotoxicity.

  27. Boess F, Bopst M, Althaus R, et al.: Acetaminophen hepatotoxicity in tumor necrosis factor/lymphotoxin-(gene knockout mice. Hepatology 1998, 27:1021–1029.

    Article  PubMed  CAS  Google Scholar 

  28. Black M: Acetaminophen hepatotoxicity. Annu Rev Med 1984, 35:577–593.

    Article  PubMed  CAS  Google Scholar 

  29. Seef LB, Cuccherini BA, Zimmerman HJ, et al: Acetaminophen hepatotoxicity in alcoholics:A therapeutic misadventure. Ann Intern Med 1986, 104(3):399–404.

    Google Scholar 

  30. McClain CJ, Kromhout JP, Peterson FJ, et al.: Potentiation of acetaminophen hepatotoxicity by alcohol. JAMA 1980, 244:251–253.

    Article  PubMed  CAS  Google Scholar 

  31. Lauterburg BH, Velez ME. Glutathione deficiency in alcoholics: Risk factor for paracetamol hepatotoxicity Gut 1988, 29:1153–1157.

    PubMed  CAS  Google Scholar 

  32. Sinclair J, Jeffrey E, Wrighton S, et al.: Alcohol-mediated increases in acetaminophen hepatotoxicity -Role of CYP2E and CYP3A.. Biochem Pharmacol 1998, 55:1557–1565.

    Article  PubMed  CAS  Google Scholar 

  33. Kostrubsky VE, Wood SG, Bush MD, et al.: Acute hepatotoxicity of acetaminophen in rats treated with ethanol plus isopentenyl. Biochem Pharmacol 1995, 50:1743–1748.

    Article  PubMed  CAS  Google Scholar 

  34. Kostrubsky VE, Szakacs JG, Jeffrey EH, et al.: Protection of ethanolmediated acetaminophen hepatotoxicity by triacetyloleandomycin, a specific inhibitor of CYP3A.. Ann Clin Lab 1997, 27:57–62.

    CAS  Google Scholar 

  35. Hoshino U, Kawasaki H. Urinary 6(-hydroxycortisol excretion in patients with alcoholic liver disease. Res Commun Alcohol Sub Abuse 1995, 16:116–124.

    Google Scholar 

  36. Seifret CF, Lucas DS, Vondracek TG, et al.: Patterns of acetaminophen use in alcoholic patients. Pharmacotherapy 1993, 13:391–395.

    Google Scholar 

  37. Eriksson LS, Broome U, Kalin M, et al.: Case Report: Hepatotoxicity due to repeated intake of low doses of paracetamol. J Int Med 1992, 231:567–570.

    Article  CAS  Google Scholar 

  38. Whitcom DC, Block GD: Association of acetaminophen hepatotoxicity with fasting and ethanol use JAMA 1994, 272:1845–1850.

    Article  Google Scholar 

  39. Critchley JAHJ, Nimmo GR, Gregson CA, et al.: Inter-subject and ethnic differences in paracetamol metabolism. Br J Clin Pharmacol 1986, 22:649–657.

    PubMed  CAS  Google Scholar 

  40. Zimmerman HJ, Maddrey WC. Acetaminophen (Paracetamol) hepatotoxicity with regular intake of alcohol: Analysis of instances of therapeutic misadventure. Hepatology 1995, 22:767–773. This article describes 67 patients who developed hepatic injury after ingestion of acetaminophen for therapeutic reasons. It stresses the importance of alcohol intake in enhancing therapeutic misadventures. It also stresses the unique nature of the markedly elevated AST levels in acetaminophen overdose.

    PubMed  CAS  Google Scholar 

  41. Baudouin SV, Howdle P, O‘Grady JG, et al.: Acute lung injury in fulminant hepatic failure following paracetamol poisoning. Thorax 1995, 50:399–402.

    PubMed  CAS  Google Scholar 

  42. Yip L, Dart R, Hurlbut K. Intravenous administration of oral N-acetylcysteine. Crit Care Med 1998, 26:40–43.

    Article  PubMed  CAS  Google Scholar 

  43. Falk JL. Oral N-acetylcysteine given intravenously for acetaminophen overdose: We shouldn‘t have to but we must. Crit Care Med 1998, 26:7.

    Article  PubMed  CAS  Google Scholar 

  44. Jones AL. Mechanism of action and value of N-acetylcysteine in the treatment of early and late acetaminophen poisoning: A critical review. Clin Toxicol 1998, 36(4):277–285. This article reviews the role of NAC therapy in acetaminophen overdose and focuses on the utilization of this treatment late in the course of acetaminophen poisoning.

    CAS  Google Scholar 

  45. Rumack BH, Matthew H. Acetaminophen poisoning and toxicity. Pediatrics 1975, 55:871–876.

    PubMed  CAS  Google Scholar 

  46. Speeg KV, Patwardhan RV, Avant GR, et al.: Inhibition of microsomal drug metabolism by histamine H2-receptor antagonists studied in vivo and in vitro in rodents. Gastroenterology 1982, 82:89–96.

    PubMed  CAS  Google Scholar 

  47. Speeg KV, Mitchell MC, Maldonado AL. Additive protection of cimetidine and N-acetylcysteine treatment against acetaminophen-induced hepatic necrosis in the rat. J Pharm and Exp Therap 1984, 234:550–554.

    Google Scholar 

  48. Burkhart KK, Janco N, Kulig KW, et al.: Cimetidine as adjunctive treatment for acetaminophen overdose. Human & Exp Toxicol 1995, 14:299–304.

    CAS  Google Scholar 

  49. Bernal W, Wendon J, Rela M, et al.: Use and outcome of liver transplantation in acetaminophen-induced liver failure. Hepatology 1998, 27:1050–1055. This article reviews the use of liver transplantation in acute acetaminophen-induced liver failure. Patients frequently deteriorated so rapidly that donor organs were not available. In the patients who underwent liver transplantation, 75% survived to leave the hospital. Poor prognostic indicators in acetaminophen overdose were considered to be markedly elevated prothrombin times, renal failure, hepatic encephalopathy, and acidosis. This is an excellent review of the role of liver transplantation in this form of hepatotoxicity.

    Article  PubMed  CAS  Google Scholar 

  50. Devlin J, Wendon J, Heaton N, et al.: Pretransplantation clinical status and outcome of emergency transplantation for acute liver failure. Hepatology 1995, 21:1018–1024.

    Article  PubMed  CAS  Google Scholar 

  51. Watanabe F-D, Shackleton CR, Cohen SM, et al.: Treatment of acetaminophen-induced fulminant hepatic failure with a bioartificial liver. Transplant Proceed 1997, 29:487–488.

    Article  CAS  Google Scholar 

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McClain, C.J., Price, S., Barve, S. et al. Acetaminophen hepatotoxicity: An update. Curr Gastroenterol Rep 1, 42–49 (1999). https://doi.org/10.1007/s11894-999-0086-3

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