Acute and Chronic Hepatotoxicity: Pathologic Aspects

  • Florabel G. Mullick


Almost the entire morphologic spectrum of hepatic disorders may be produced by drug administration. Thus, the clinical history is crucial, because the diagnosis can seldom be made on the basis of histologic criteria alone. The methodology used for evaluation and validation of cases in which there is an alleged drug reaction has been discussed at length.1–4


Chronic Active Hepatitis Intrahepatic Cholestasis Hepatocellular Injury Contraceptive Steroid Sinusoidal Dilatation 
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.
    Irey NS: Tissue reaction to drugs. AM J Pathol 82:617–648, 1976.Google Scholar
  2. 2.
    Irey NS: Microscopic changes in adverse drug reactions, in Perper JA, Wecht CH (eds): Microscopic Diagnosis in Forensic Pathology. Charles C Thomas, Springfield, Illinois, 1980, pp. 67–148.Google Scholar
  3. 3.
    Irey NS; When is a disease drug-inducedS, in Riddell RH (ed): Pathology of Drug-Induced and Toxic Diseases. Churchill Livingstone, New York, 1982, pp. 1–18.Google Scholar
  4. 4.
    Ishak KG, Mullick, FG: Drug-induced and toxic liver injury, in Peters RL, Craig JR (eds): Liver Pathology. Churchill Livingstone, New York, 1986, pp. 221–254.Google Scholar
  5. 5.
    Black M, Mitchell JR, Zimmerman HJ, et al: Isoniazid hepatitis in 114 patients. Gastroenterology 69:289–301, 1975.PubMedGoogle Scholar
  6. 6.
    Scheuer PJ, Summerfield JA, Lal S, et al: Rifampicin hepatitis: A clinical and histological study. Lancet 1:421–425, 1974.PubMedCrossRefGoogle Scholar
  7. 7.
    Dujovne CA, Chan CH, Zimmerman HJ: Sulfonamide hepatic injury: Review of the literature and report of a case due to sulfamethazole. S Engl J Med 277:785–788, 1967.CrossRefGoogle Scholar
  8. 8.
    Fich A, Schwartz J, Braveman D, et al: Sulfasalazine hepatotoxicity. Am J Gastroenterol 79:401–402, 1984.PubMedGoogle Scholar
  9. 9.
    Hoyumpa AM Jr, Connell AM: Methyldopa hepatitis: Report of three cases. Am J Dig Dis 18:213–222, 1973.PubMedCrossRefGoogle Scholar
  10. 10.
    Peters RL, Edmondson HA, Reynolds TB, et al: Hepatic necrosis associated with halothane anesthesia. Am J Med 47:748–764, 1969.PubMedCrossRefGoogle Scholar
  11. 11.
    Benjamin SB, Ishak KG, Zimmerman HJ, et al: Phenylbutazone liver injury: A clinicopathologic survey of 23 cases and review of the literature. Hepatology 1:255–263, 1981.PubMedCrossRefGoogle Scholar
  12. 12.
    Kiaer HW, Olson S, Ronnov-Jessen V: Hepatotoxicity of papaverine. Arch Pathol Lab Med 98:292–296, 1974.Google Scholar
  13. 13.
    Fenech PF, Bannister WH, Gretch JL: Hepatitis with biliverdinaemia in association with indomethacin therapy. Br Med J 3:155–156, 1967.PubMedCrossRefGoogle Scholar
  14. 14.
    Nassberger L: Disulfiram-induced hepatitis—Report of a case and review of the literature. Postgrad Med J 60:639–641, 1984.PubMedCrossRefGoogle Scholar
  15. 15.
    Mullick FG, Ishak KG: Hepatic injury associated with diphenylhydantoin therapy: A clinicopathologic study of 20 cases. Am J Clin Pathol 74:442–452, 1980.PubMedGoogle Scholar
  16. 16.
    Lichtenstein MR, Cannemeyer W: Severe para-aminosalicylic acid hypersensitivity simulating mononucleosis or hepatitis. JAMA 152:606–607, 1953.CrossRefGoogle Scholar
  17. 17.
    Zimmerman HJ: Hepatotoxicity: The adverse effects of drugs and other chemicals on the liver. Appleton-Century-Crofts, New York, 1978, 481–482.Google Scholar
  18. 18.
    Gan TE, Van Der Weyden MB: Dapsone-induced infectious mononucleosis-like syndrome. Med J Aust 1:350–351, 1982.PubMedGoogle Scholar
  19. 19.
    Lewis JH, Zimmerman HJ, Ishak, KG, et al: Enflurane hepatoxicity: A clinicopathologic study of 24 cases. Ann Intern Med 98:984–992, 1983.PubMedGoogle Scholar
  20. 20.
    Lesna M, Watson AJ, Douglas AP, et al: Evaluation of paracetamol-induced damage in liver biopsies: Acute changes and follow-up findings. Virchows Arch 370:333–344, 1976.Google Scholar
  21. 21.
    Joshi PH, Conn HO: The syndrome of methoxyflurane-associated hepatitis. Ann Intern Med 80:395–401, 1974.PubMedGoogle Scholar
  22. 22.
    Lewis JH, Zimmerman HJ, Benson GD, et al: Hepatic injury associated with ketoconazole therapy: Analysis of 33 cases. Gastroenterology 96:503–513, 1984.Google Scholar
  23. 23.
    Kennedy S J: Metabolic and toxic effect of mithramycin tumor therapy. Am J Med 49:494–503, 1970.PubMedCrossRefGoogle Scholar
  24. 24.
    Zimmerman HJ: Hepatotoxicity: The adverse effects of drugs and other chemicals on the liver. Appleton-Century-Crofts, New York, 1978, 238–239.Google Scholar
  25. 25.
    Wepler W, Opitz S: Histologic change in the liver biopsy in Amanita phalloides intoxication. Hum Pathol 3:249–254, 1972.PubMedCrossRefGoogle Scholar
  26. 26.
    Ngindu A, Johnson BK, Kenya PR, et al: Outbreak of acute hepatitis caused by aflatoxln poisoning in Kenya. Lancet 1:1346–1348, 1982.PubMedCrossRefGoogle Scholar
  27. 27.
    Chuttani HK, Gupta PS, Gulati S, et al: Acute copper sulfate poisoning. Am J Med 39:849–852, 1964.CrossRefGoogle Scholar
  28. 28.
    Baerg RD, Kimberg DV: Centrilobular hepatic necrosis and acute renal failure in “solvent sniffers.” Ann Intern Med 73:713–720, 1970.PubMedGoogle Scholar
  29. 29.
    Luongo MA, Bjornson SS: The liver in ferrous sulfate poisoning: A report of three fatal cases and an experimental study. S Engl J Med 251:995–999, 1954.CrossRefGoogle Scholar
  30. 30.
    Diaz-Rivera RS, Collazo PJ, Pons ER, et al: Acute phosphorous poisoning in man: A study of 56 cases. Medicine (Baltimore) 29:269–298, 1950.Google Scholar
  31. 31.
    Zimmerman HJ, Ishak KG: Drug-induced and toxic liver injury, in MacSween RNM, Anthony PP, Scheuer S (eds): Pathology of the Liver. Churchill Livingstone, Edinburgh, 1979, pp. 335–386.Google Scholar
  32. 32.
    Ishak KG: The liver, in Riddell RH (ed): Pathology of Drug-Induced and Toxic Diseases, Churchill Livingstone, New York, 1982, pp. 457–513.Google Scholar
  33. 33.
    Ishak KG, Irey NS: Hepatic injury associated with phenothiazines. A clinicopathologic and follow-up study of 36 cases. Arch Pathol Lab Med 93:283–304, 1972.Google Scholar
  34. 34.
    Zafrani ES, Ishak KG, Rudzki C: Cholestatic and hepatocellular injury associated with erythromycin esters: Report of 9 cases. Am J Dig Dis 24:385–396, 1979.CrossRefGoogle Scholar
  35. 35.
    Baird RW, Hull JG: Cholestatic jaundice from tolbutamide. Ann Intern Med 53:194–196, 1960.PubMedGoogle Scholar
  36. 36.
    Reichel J, Goldberg SB, Ellenberg M, et al: Intrahepatic cholestasis following administration of chlorpropamide: Report of a case with electron microscopic observations. Am J Med 28:654–660, 1960.PubMedCrossRefGoogle Scholar
  37. 37.
    Reynolds TB: Laxative liver disease. In Gerok W, Sickinger S (eds): Drugs and the Liver. Schattauer Verlag, Stuttgart, 1975, pp. 319–325.Google Scholar
  38. 38.
    Einhorn M, Davidsohn I: Hepatotoxicity of mercaptopurine. JAMA 188:802–806, 1984.CrossRefGoogle Scholar
  39. 39.
    Mullick FG, Ishak KG, Mahabir R, et al: Hepatic injury with paraquat toxicity in humans. Liver 1:209–221, 1981.PubMedGoogle Scholar
  40. 40.
    Zelman S: Liver cell necrosis in chlorpromazine jaundice (allergic cholangiolitis). Am J Med 27:708–729, 1959.PubMedCrossRefGoogle Scholar
  41. 41.
    Al-Kawas FH, Seeff LB, Berendson RA, et al: Allopurinol hepatotoxicity: Report of two cases and review of the literature. Ann Intern Med 95:588–590, 1981.PubMedGoogle Scholar
  42. 42.
    Schneider HL, Hornbach KD, Kruaz JL, et al: Chlorpropamide hepatotoxicity: Report of a case and review of the literature. Am J Gastroenterol 79:721–724, 1984.PubMedGoogle Scholar
  43. 43.
    Myers JL, Augur NA: Hydralazine-induced cholangitis. Gastroenterology 87:1185–1188, 1984.PubMedGoogle Scholar
  44. 44.
    Mitchell JR, Zimmerman HJ, Ishak KG, et al: Isoniazid liver injury. Clinical spectrum, pathology and probable pathogenesis. Ann Intern Med 84:181–192, 1976.PubMedGoogle Scholar
  45. 45.
    Benjamin SB, Ishak KG, Zimmerman HJ, et al: Phenylbutazone liver injury: A clinicopathologic survey of 23 cases and review of the literature. Hepatology 1:255–263, 1981.PubMedCrossRefGoogle Scholar
  46. 46.
    Davion T, Capron JP, Andrejak M, et al: Hepatite aiguee a la carbamezepine (Tegretol): Etude d’un case et revue de la litterature. Gastroenterol Clin Biol 8:52, 1984.PubMedGoogle Scholar
  47. 47.
    Zimmerman HJ, Ishak KG: Valproate-induced hepatic injury: Analyses of 23 fatal cases. Hepatology 2:591–597, 1982.PubMedCrossRefGoogle Scholar
  48. 48.
    Starko KM, Mullick FG: Hepatic and cerebral pathology findings in children with fatal salicylate intoxication: Further evidence for a causal relation between salicylates and Reye’s syndrome. Lancet 1:326–329, 1983.PubMedCrossRefGoogle Scholar
  49. 49.
    Mullick FG, McAllister HA, Wagner BM, et al: Drug related vasculitis Hum Pathol 10:313–325, 1979.PubMedCrossRefGoogle Scholar
  50. 50.
    Lichtenstein L, Fox LJ: Necrotizing arterial lesions resembling those of periarteritis nodosa and focal necroses following administration of sulfathiazole. Am J Pathol 22:665–677, 1946.Google Scholar
  51. 51.
    Waugh D: Myocarditis, arteritis and focal hepatic, splenic and renal granulomas due to penicillin sensitivity. Am J Pathol 24:437–447, 1952.Google Scholar
  52. 52.
    Boyer TD, Sun N, Reynolds TB: Allopurinol—Hypersensitivity vasculitis and liver damage. West J Med 126:143–147, 1977.PubMedGoogle Scholar
  53. 53.
    Sharp JR, Ishak KG, Zimmerman HJ: Chronic active hepatitis and severe hepatic necrosis associated with nitrofurantoin. Ann Intern Med 92:14–19, 1980.PubMedGoogle Scholar
  54. 54.
    Goldstein GB, Lam KC, Mistilis SP: Drug-induced chronic active hepatitis. Am J Dig Dis 18:177–184, 1973.PubMedCrossRefGoogle Scholar
  55. 55.
    Seaman WE, Ishak KG, Plotz PH: Aspirin-induced hepatotoxicity in patients with lupus erythematosus. Ann Intern Med 80:1–8, 1974.PubMedGoogle Scholar
  56. 56.
    Glober GA, Wilkerson JA: Biliary cirrhosis following the administration of methyltestosterone. JAMA 204:170–173, 1968.PubMedCrossRefGoogle Scholar
  57. 57.
    Poucell S, Ireton J, Valencia-Mayoral P, et al: Amiodarone-associated phospholipidosis and fibrosis of the liver. Light, immunohistochemical and electron microscopic studies. Gastroenterology 86:926–936, 1984.PubMedGoogle Scholar
  58. 58.
    Oda T, Shikata S, Naito C, et al: Phospholipid fatty liver: A report of three cases with a new type of fatty liver. Jpn J Exp Med 40:127–140, 1970.PubMedGoogle Scholar
  59. 59.
    Paliard S, Vitrey D, Fournier G, et al: Perhexilene maleate-induced hepatitis. Digestion 17:419–427, 1978.PubMedCrossRefGoogle Scholar
  60. 60.
    Ishak KG: Granulomas of the liver, in Ioachim HL (ed): Pathology of Granulomas. Raven, New York, 1983, pp. 307–369.Google Scholar
  61. 61.
    Scheuer PJ: Hepatotoxicity of methotrexate and azathioprine, in Gerok W, Sickinger S (eds): Drugs and the Liver. Schattauer Verlag, Stuttgart, 1975, pp. 281–286.Google Scholar
  62. 62.
    Walker CO, Combes B: Biliary cirrhosis induced by chlorpromazine. Gastroenterology 51:631–640, 1966.PubMedGoogle Scholar
  63. 63.
    Boyer JL: Androgenic-anabolic steroid associated peliosis hepatis in man: A review of 38 reported cases. Adv Pharmacol Ther 8:175–185, 1979.Google Scholar
  64. 64.
    Okuda K, Omata M, Itoh Y, et al: Peliosis hepatis as a late and fatal complication of Thorotrast liver disease: Report of five cases. Liver 1:110–122, 1981.PubMedGoogle Scholar
  65. 65.
    Stillman AE, Huxtable R, Consaoe P, et al: Hepatic veno-occlusive disease due to pyrrolizidine (senecio) poisoning in Arizona. Gastroenterology 73:349–352, 1977.PubMedGoogle Scholar
  66. 66.
    Russell RM, Boyer JL, Bagheri SA, et al: Hepatic injury from chronic hypervitaminosis A resulting in portal hypertension and ascites. S Engl J Med 291:435–440, 1974.CrossRefGoogle Scholar
  67. 67.
    Marubbio AT, Danielson B: Hepatic veno-occlusive disease in a renal transplant patient receiving azathioprine. Gastroenterology 69:739–743, 1975.PubMedGoogle Scholar
  68. 68.
    Lewis JH, Tice H, Zimmerman HJ: Budd-Chiari syndrome associated with oral contraceptive steroids: Review of treatment of 47 cases. Dig Dis Sci 38:673–683, 1983.CrossRefGoogle Scholar
  69. 69.
    Rubel LR, Ishak KG: Thorotrast-associated cholangiocarcinoma: An epidemiologic and clinicopathologic study. Cancer 50:1408–1415, 1982.PubMedCrossRefGoogle Scholar
  70. 70.
    Goodman ZD, Ishak KG: Non-parenchymal and metastatic malignant tumors of the liver, in Berk JE (ed): Bockus Gastroenterology 4th ed. WB Sanders Company, Philadelphia, 1985, pp. 3377–3386.Google Scholar

Copyright information

© Plenum Publishing Corporation 1989

Authors and Affiliations

  • Florabel G. Mullick
    • 1
  1. 1.Department of Environmental and Drug-Induced PathologyArmed Forces Institute of PathologyUSA

Personalised recommendations