Hepatotoxicity: Mechanisms of Liver Injury

  • Manuela G. NeumanEmail author


Toxic liver disease, hepatotoxicity, encompasses numerous different individual diseases that ultimately lead to progressive damage of the liver, to liver malfunction and death. Environmental toxicity, alcoholic and non-alcoholic steatohepatitis, viral hepatitis, and cirrhosis are examples of liver diseases, though not reciprocally exclusive, that can ultimately lead to fatal liver disease. In young adults, there are several factors associated with risk of liver damage, including rising rates of obesity, excessive alcohol consumption, drugs of misuse alone or in combination with drugs of use. There is an urgent need to better understand the causes of this recent rise in fatal liver disease in a population that has not been at great risk previously.

Aims: The purpose of this chapter is to provide guidance to detection and assessment of hepatotoxicity induced by human health products, toxic environmental pollutants and plant and animal toxins. This paper is promoting the safe and effective use of therapeutic products by physicians, other health care professionals as well as patients. The knowledge is applicable to pharmaceutical products for human use, natural health products and biological drugs.

This chapter is intended to provide basic considerations for the detection requirements of hepatotoxicity caused by natural health products and pharmaceutical, both alone and in the presence of other health products, foods or xenobiotics.

The investigational approach used for a particular product will depend on multiple factors, including the pharmacodynamic and pharmacokinetic characteristics of the product, the indications, the dosages and routes of administration.


Hepatocytotoxicity Drug induced liver injury DILI Herb induced liver injury HILI Occupational and environmental liver injury Hy’s law 



Alkaline phosphatase


Alanine aminotransferase (glutamic-pyruvic transaminase, SGPT)


Aspartate aminotransferase (glutamic-oxaloacetic aminotransferases, SGOT)


Conjugated (direct) bilirubin


γ-Glutamyltransferase (γ-glutamyltranspeptidase, GGTP)


International Conference on Harmonisation


International Normalized Ratio


Total bilirubin (sum of conjugated and non-conjugated serum bilirubin)


Upper limit of the normal reference range (or N)



All the micrographs presented are cases that consulted Dr. Neuman and belong to In Vitro Drug Safety and Biotechnology.


  1. 1.
    Ch R. Experimental toxic injury of the liver. In: Ch R, editor. The liver. New York: Academic; 1964. p. 335–476.Google Scholar
  2. 2.
    Benhamou JP. Drug-induced hepatitis: clinical aspects. In: Fillastre JP, editor. Hepatotoxicity of drugs. Rouen: Universite de Rouen; 1986. p. 26–30.Google Scholar
  3. 3.
    Zimmerman HJ. The spectrum of hepatotoxicity. Perspect Biol Med. 1968;12:135–61.PubMedCrossRefPubMedCentralGoogle Scholar
  4. 4.
    Zimmerman HJ, Maddrey WC. Toxic and drug-induced hepatitis. In: Schiff L, Schiff ER, editors. Diseases of the liver. Philadelphia: JB Lippincott Company; 1993. p. 707–69.Google Scholar
  5. 5.
    Zimmerman HJ. Hepatotoxicity: the adverse effects of drug and other chemicals on the liver. 2nd ed. Philadelphia: Lippincott Williams and Wilkins; 1999. Chapters 4, 5 and 16Google Scholar
  6. 6.
    McCuskey RS, Earnest DL. Hepatic and gastrointestinal toxicology, vol 9. In: Sipes IG, CA MQ, Gandolfi AJ, editors. Comprehensive toxicology. Cambridge: Pergamen Press; 1997.Google Scholar
  7. 7.
    Wieland T. Poisonous principles of mushrooms of the genus Amanita. Science. 1968;159:946.PubMedCrossRefPubMedCentralGoogle Scholar
  8. 8.
    Goldblatt LA. Aflatoxins—scientific background control and implications. New York: Academic; 1969.Google Scholar
  9. 9.
    Neuman MG, Eshchar J, Cotariu D, Ishay J, Barr-Nea L. Hepatotoxicity of Hornet’s venom sac extract, after repeated in vivo and in vitro envenomation. Acta Pharmacol Toxicol Scand. 1983;53:314–9.CrossRefGoogle Scholar
  10. 10.
    Neuman MG, Ishay J, Zimmerman HJ, Eshchar J. Hepatotoxicity of the oriental hornet venom. Harefuah. 1990;118(2):78–80.PubMedPubMedCentralGoogle Scholar
  11. 11.
    Teschke R, Danan G. Review: drug induced liver injury with analysis of alternative causes as confounding variables. Br J Clin Pharmacol. 2018;84:1467–77.PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    Chuttani HK, Gupta PS, Gulati S, Gupta DN. Acute copper sulfate poisoning. Am J Med. 1965;39:849.PubMedCrossRefPubMedCentralGoogle Scholar
  13. 13.
    Goldstein BD, Witz G. Benzene. In: Lippman M, editor. Environmental toxicants: human exposures and their health effects. 2nd ed. New York: Wiley Interscience; 2000. p. 121–51.Google Scholar
  14. 14.
    Kenna JG. Immunological allergic drug-induced hepatitis. Lessons from halothane. J Hepatol. 1997;26(Suppl):5.PubMedCrossRefPubMedCentralGoogle Scholar
  15. 15.
    Ludwig J, Kim CH, Wiesner RH, Krom RI. Floxuridine-induced sclerosing cholangitis. An ischemic cholangiopathy? Hepatology. 1989;9:215–8.PubMedCrossRefPubMedCentralGoogle Scholar
  16. 16.
    Neuman MG, French SW, Zakhari S, Malnick S, Seitz HK, Cohen LB, Salaspuro M, Voinea-Griffin A, Barasch A, Kirpich IA, Thomes PS, Schrum LW, Donohue TM Jr, Kharbanda K, Cruz M, Opris M. Alcohol, microbiome, life style influence alcohol and non-alcoholic organ damage. Exp Mol Pathol. 2017;102(1):162–80. Scholar
  17. 17.
    Navarro VJ, Senior JR. Drug-related hepatotoxicity. N Engl J Med. 2006;354(7):731–9.PubMedCrossRefPubMedCentralGoogle Scholar
  18. 18.
    Hoofnagle JH, Carithers RL, Shapiro C, Ascher N. Fulminant hepatic failure. Summary of a workshop. Hepatology. 1995;21:240–52.PubMedPubMedCentralGoogle Scholar
  19. 19.
    Zafrani E, Pinaudeau Y, Dhumeaux D. Drug-induced vascular lesions of the liver. Arch Intern Med. 1983;143:195–200.CrossRefGoogle Scholar
  20. 20.
    Daly A. Drug-induced liver injury: past, present and future. Pharmacogenomics. 2010;11:607–11.PubMedCrossRefPubMedCentralGoogle Scholar
  21. 21.
    Lee WM, Senior JR. Recognizing drug-induced liver injury: current problems, possible solutions. Toxicol Pathol. 2005;33(1):155–64.PubMedCrossRefPubMedCentralGoogle Scholar
  22. 22.
    Rappaport AM. Acinar units and pathophysiology of the liver. In: Rouiller C, editor. The liver, vol. I. New York: Academic; 1963. p. 265–328.Google Scholar
  23. 23.
    Zimmerman HJ, Ishak KG. Hepatic injury due to drugs and toxins. In: MacSween RNM, Anthony PP, Scheuer PJ, Burt AD, Portman BC, editors. Pathology of the liver. 3rd ed. Edinburgh: Churchill- Livingstone; 1994. p. 563–634.Google Scholar
  24. 24.
    Ishak KG, Mullick FG. Drug-induced and toxic injury. In: Peters RL, Craig JR, editors. Liver pathology. New York: Churchill-Livingstone; 1986. p. 221–54.Google Scholar
  25. 25.
    Neuman MG, Winkler R. Veno-occlusive disease of the liver induced by traditional herbal medicine Roumanian. J Rev Hepatol. 2008;4(2):3, 7-9.Google Scholar
  26. 26.
    Loyke HF. Experimental hypertension treated with CCl4: measurement of adrenal function, vascular responsiveness, and angiotensinase converting enzyme. Proc Soc Exp Biol Med. 1964;115:1035.PubMedCrossRefPubMedCentralGoogle Scholar
  27. 27.
    Andrade RJ, Robles M, Lucena MI. Rechallenge in drug-induced liver injury: the attractive hazard. Expert Opin Drug Saf. 2009;8(6):709–14.PubMedCrossRefPubMedCentralGoogle Scholar
  28. 28.
    Watkins PB. Role of cytochrome P450 in drug metabolism and hepatotoxicity. Semin Liver Dis. 1990;10:235–50.PubMedCrossRefPubMedCentralGoogle Scholar
  29. 29.
    Plaa GL, Hewitt WR. Quantitative evaluation of indices of hepatotoxicity. In: Plaa GL, Hewitt WR, editors. Toxicology of the liver. New York: Raven Press; 1982. p. 103–20.Google Scholar
  30. 30.
    Ishak KG, Zimmerman HJ. Morphologic spectrum of drug-induced hepatic disease. Gastroenterol Clin No Am. 1995;24:759–78.Google Scholar
  31. 31.
    Wilke RA, Reif DM, Moore JH. Combinatorial pharmacogenetics. Nature Rev Drug Discov. 2005;4:911–8.CrossRefGoogle Scholar
  32. 32.
    Pirmohamed M, Park BK. Genetic susceptibility to adverse drug reactions. Trends Pharmacol Sci. 2001;22:298–305.PubMedCrossRefPubMedCentralGoogle Scholar
  33. 33.
    Severino G, Del Zompo M. Adverse drug reactions: role of pharmacogenomics. Pharmacol Res. 2004;49:363–73.PubMedCrossRefPubMedCentralGoogle Scholar
  34. 34.
    Lazarou J, Pomeranz BH, Corey PN. Incidence of adverse drug reactions in hospitalized patients: a meta-analysis of prospective studies. JAMA. 1998;279:1200–5.PubMedCrossRefPubMedCentralGoogle Scholar
  35. 35.
    Pasanen MK, Neuvonen M, Neuvonen PJ, Niemi M. SLCO1B1 polymorphism markedly affects the pharmacokinetics of simvastatin acid. Pharmacogenet Gen. 2006;16:873–9.CrossRefGoogle Scholar
  36. 36.
    Bissell DM, Gores GJ, Laskin DL, Hoofnagle JH. Drug-induced liver injury: mechanisms and test systems. Hepatology. 2001;33:1009–13.PubMedCrossRefPubMedCentralGoogle Scholar
  37. 37.
    Neuman MG. Apoptosis in liver disease. Rom J Gastroenterol. 2002;11(1):3–7.PubMedPubMedCentralGoogle Scholar
  38. 38.
    Phillips MJ, Latham PS, Poucell-Halton S. Electron microscopy of human liver disease. In: Schiff L, Schiff ER, editors. Diseases of the liver. 7th ed. Philadelphia: J.B. Lippincott; 1993. p. 189–216.Google Scholar
  39. 39.
    Apostolova N, Lj G-S, Moran A, Alvarez A, Blas-Garcia A, Esplugues J. Enhanced oxidative stress and increased mitochondrial mass during Efavirenz-induced apoptosis in human hepatic cells. Br J Pharmacol. 2010;160(8):2069–84.PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    Assis DN, Navarro VJ. Human drug hepatotoxicity: a contemporary clinical perspective. Expert Opin Drug Metab Toxicol. 2009;5(5):463–73.PubMedCrossRefPubMedCentralGoogle Scholar
  41. 41.
    De Bus L, Depuydt P, Libbrecht L, Vandekerckhove L, Nollet J, Benoit D, Vogelaers D, Van Vlierberghe H. Severe drug-induced liver injury associated with prolonged use of linezolid. J Med Toxicol. 2010;6(3):322–6.PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    Jones DP, Lemasters JJ, Han D, Boelsterli UA, Kaplowitz N. Mechanisms of pathogenesis in drug hepatotoxicity putting the stress on mitochondria. Mol Interv. 2010;10(2):98–111.PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    Kaplowitz N, LD DL. Drug-induced hepatic disease. New York: Marcel Decker Inc; 2003.Google Scholar
  44. 44.
    Lucena MI, Garca-Martín E, Andrade RJ, Martínez C, Stephens C, Ruiz JD, Ulzurrun E, Fernandez MC, Romero-Gomez M, Castiella A, Planas R, Durán JA, De Dios AM, Guarner C, Soriano G, Borraz Y, Agundez JA. Mitochondrial superoxide dismutase and glutathione peroxidase in idiosyncratic drug-induced liver injury. Hepatology. 2010;52(1):303–12.PubMedCrossRefPubMedCentralGoogle Scholar
  45. 45.
    Neuman MG. Cytokines and Inflamed Liver. Clin Biochem. 1999;33:601–5.Google Scholar
  46. 46.
    Lewis J. ‘Hy’s law’, the ‘Rezulin Rule’ and other predictors of severe drug-induced hepatotoxicity; putting risk-benefit into perspective. Pharmacoepiol Drug Safety. 2006;15:221–9.CrossRefGoogle Scholar
  47. 47.
    Neuman MG, Malkiewicz IM, Shear NH. A novel lymphocyte toxicity assay to assess drug hypersensitivity syndromes. Clin Biochem. 2000;33(7):517–24.PubMedCrossRefPubMedCentralGoogle Scholar
  48. 48.
    Neuman MG, Shear NH, Jacobson-Brown PM, Katz GG, Neilson HK, Malkiewicz IM, Cameron RG, Abbott F. CYP2E1-mediated modulation of valproic acid-induced hepatocytotoxicity. Clin Biochem. 2001;34(3):211–8.PubMedCrossRefPubMedCentralGoogle Scholar
  49. 49.
    Krivoy N, Taeri M, Neuman MG. Antiepileptic drug-induced hypersensitivity syndrome reactions mechanisms. Curr Drug Safety. 2006;1(3):289–99.CrossRefGoogle Scholar
  50. 50.
    Aithal GP, Rawlins MD, Day CP. Clinical diagnostic scale: a useful tool in the evaluation of suspected hepatotoxic adverse drug reactions. J Hepatol. 2000;33(6):949–52.PubMedCrossRefPubMedCentralGoogle Scholar
  51. 51.
    Danan G, Benichou C. Causality assessment of adverse reactions to drugs—I. A novel method based on the conclusions of international consensus meetings: application to drug-induced liver injuries. J Clin Epidemiol. 1993;46(11):1323–30.PubMedCrossRefPubMedCentralGoogle Scholar
  52. 52.
    Fontana RJ, Seeff LB, Andrade RJ, Björnsson E, Day CP, Serrano J, Hoofnagle JH. Standardization of nomenclature and causality assessment in drug-induced liver injury: summary of a clinical research workshop. Hepatology. 2010;52(2):730–42.PubMedPubMedCentralCrossRefGoogle Scholar
  53. 53.
    Food and Drug Administration Warning Working Group. Nonclinical assessment of potential hepatotoxicity in man. p. 1–12, appendix, November 2000. Food and Drug Administration Warning Working Group. Clinical white paper. November 2000.Google Scholar
  54. 54.
    Lee WM. Drug-induced hepatotoxicity. N Engl J Med. 2003;349:474–85.PubMedCrossRefPubMedCentralGoogle Scholar
  55. 55.
    Maria VA, Victorino RM. Development and validation of a clinical scale for the diagnosis of drug-induced hepatitis. Hepatology. 1997;26(3):664–9.PubMedCrossRefPubMedCentralGoogle Scholar
  56. 56.
    Naranjo CA, Busto U, Sellers EM, Sandor P, Ruiz I, Roberts EA, Janecek E, Domecq C, Greenblatt DJ. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther. 1981;30(2):239–45.PubMedCrossRefPubMedCentralGoogle Scholar
  57. 57.
    European Medicines Agency, Committee for Medicinal Products for Human Use, Draft Guideline on Detection of Early Signals of Drug-induced Hepatotoxicity in Non-clinical Studies. Doc. Ref. EMEA/CHMP/SWP/150115/2006. 2006.Google Scholar
  58. 58.
    Food and Drug Administration Warning. 2004.
  59. 59.
    Food and Drug Administration. Warning concept paper. Premarketing evaluation of drug-induced liver injury. 2007.Google Scholar
  60. 60.
    Food and Drug Administration. Guidance for industry, drug-induced liver injury: premarketing clinical evaluation. 2009.Google Scholar
  61. 61.
    McLean EK. The toxic actions of pyrrolizidine (Senecio) alkaloids. Pharmacol Rev. 1970;22:429–83.PubMedPubMedCentralGoogle Scholar
  62. 62.
    Neuman MG, Cameron RG, Shear NH, Feuer G. Drug-induced apoptosis of skin cells and liver. In: Cameron RG, Fauer G, editors. Handbook of experimental pharmacology: apoptosis modulation by drugs. Vol. 142, Chapter 13. Heidelberg: Springer Verlag Publishers; 1999. p. 344–55.Google Scholar
  63. 63.
    Neuman MG, Cohen L, Opris M, Nanau RM, Jeong H. Hepatotoxicity of pyrrolizidine alkaloids. J Pharm Pharm Sci. 2015;18(4):825–43.PubMedCrossRefPubMedCentralGoogle Scholar
  64. 64.
    Neuman MG, Ishay J, Zimmerman HJ, Eshchar J. Hepatotoxicity of Vespa orientalis venom sac extract. Pharmacol Toxicol. 1991;69(1):1–36.PubMedCrossRefPubMedCentralGoogle Scholar
  65. 65.
    Schoepfer AM, Engel A, Fattinger K, Marbet UA, Criblez D, Reichen J, Zimmermann A, Oneta CM. Herbal does not mean innocuous: ten cases of severe hepatotoxicity associated with dietary supplements from Herbalife products. J Hepatol. 2007;47(4):521–6.PubMedCrossRefPubMedCentralGoogle Scholar
  66. 66.
    Fischl J. Aminoaciduria in thallium poisoning. Am J Med Sci. 1966;251:40.PubMedCrossRefPubMedCentralGoogle Scholar
  67. 67.
    Luongo MA, Bjornson SS. The liver in ferrous sulfate poisoning. A report of three fatal cases in children and an experimental study. N Engl J Med. 1954;251:995.PubMedCrossRefPubMedCentralGoogle Scholar
  68. 68.
    Bagberi SA, Boyer JL. Peliosis hepatis associated with androgen-anabolic steroid therapy. A severe form of hepatic injury. Ann Intern Med. 1974;81:6100618.Google Scholar
  69. 69.
    Benjamin SB, Ishak KG, Zimmerman H, Agron M. Phenylbutazone liver injury: a clinical pathologic survey of 23 cases and review of the of the literature. Hepatology. 1981;1:255–63.PubMedCrossRefPubMedCentralGoogle Scholar
  70. 70.
    McLean AEM, McLean ER, Judah JD. Cellular necrosis in the liver induced and modified by drugs. Internat Rev Exp Pathol. 1965;4:127.Google Scholar
  71. 71.
    Schiodt FV, Rochling FA, Casey DL, Lee WM. Acetaminophen toxicity in a urban county hospital. N Engl J Med. 1997;337:112–7.CrossRefGoogle Scholar
  72. 72.
    Vale JA, Proudfoot AT. Paracetamol (acetaminophen) poisoning. Lancet. 1995;346:547–52.PubMedCrossRefPubMedCentralGoogle Scholar
  73. 73.
    Wendel A, Feuerstein S, Konz KH. Acute paracetamol intoxication of starved mice leads to lipid peroxidation in vivo. Biochem Pharmacol. 1979;28:2051.PubMedCrossRefPubMedCentralGoogle Scholar
  74. 74.
    Artwohl JE, Henne-Bruns O, Carter E, Cara LM. Acetaminophen toxicosis: a potential model for liver failure in swine. Vet Hum Toxicol. 1988;30:324.PubMedPubMedCentralGoogle Scholar
  75. 75.
    Zimmerman HJ. Effects of aspirin and acetaminophen on the liver. Arch Intern Med. 1981;141:333–8.PubMedCrossRefPubMedCentralGoogle Scholar
  76. 76.
    Zimmmerman HJ, Maddrey WC. Acetaminophen (paracetamol) hepatotoxicity with regular intake of alcohol. Analysis of instances of a therapeutic misadventure. Hepatology. 1995;22:767–2.CrossRefGoogle Scholar
  77. 77.
    Schiano TD. Liver injury from herbs and other botanicals. Clin Liver Dis. 1998;2:607–36.CrossRefGoogle Scholar
  78. 78.
    Javaid A, Bonkovsky HL. Hepatotoxicity due to extracts of Chinese green tea (Camellia sinensis): a growing concern. J Hepatol. 2006;45(2):334–5.PubMedCrossRefPubMedCentralGoogle Scholar
  79. 79.
    Jimenez-Saenz M, Martinez-Sanchez MC. Acute hepatitis associated with the use of green tea infusions. J Hepatol. 2006;44(3):616–7.PubMedCrossRefPubMedCentralGoogle Scholar
  80. 80.
    Molinari M, Watt KD, Kruszyna T, Nelson R, Walsh M, Huang WY, Nashan B, Peltekian K. Acute liver failure induced by green tea extracts: case report and review of the literature. Liver Transpl. 2006;12(12):1892–5.PubMedCrossRefPubMedCentralGoogle Scholar
  81. 81.
    Teschke R, Andrade RJ. Special Issue “Drug, Herb, and Dietary Supplement Hepatotoxicity”. Int J Mol Sci. 2016;17(9):1488. Scholar
  82. 82.
    Cornish HM, Block WD. A study of carbon tetrachloride. II. The effect of carbon tetrachloride on serum and tissue enzymes. Arch Environ Hlth. 1960;1:96.CrossRefGoogle Scholar
  83. 83.
    Kosrud GO, Price HG, McLaughlin JM. Sensitivity of several serum enzymes in detecting carbon tetrachloride-induced liver damage in rats. Toxicol Appl Pharmacol. 1972;22:474.CrossRefGoogle Scholar
  84. 84.
    Fox CF, Dinman BD, Frajola WJ. CCl4 poisoning. II. Serum enzymes, free fatty acids and liver pathology: effects of phenoxybenzamine and phenergan. Proc Soc Exp Biol Med. 1962;111:731.PubMedCrossRefPubMedCentralGoogle Scholar
  85. 85.
    Recknagel RO. Carbon tetrachloride hepatotoxicity. Pharmacol Rev. 1967;19:145.PubMedPubMedCentralGoogle Scholar
  86. 86.
    Recknagel RO, Glende EA Jr. Carbon tetrachloride hepatotoxicity: an example of lethal cleavage. CRC Crit Rev Toxicol. 1973;2:263.CrossRefGoogle Scholar
  87. 87.
    Lai KK, Gang DL, Zawacki JK, Cooley TP. Fulminant hepatic failure associated with 2′3'dideoxyinosine (ddI). Ann Intern Med. 1991;165:382–284.Google Scholar
  88. 88.
    Davis DC, Hashimoto M, Gillette JR. Effects of bromobenzene and carbon tetrachloride on the synthesis and release of proteins by the perfused rat liver. Biochem Pharmacol. 1973;22:1989.PubMedCrossRefPubMedCentralGoogle Scholar
  89. 89.
    Althausen TL, Thoenes E. Influence on carbohydrate metabolism of experimentally induced hepatic changes in phosphorus poisoning. Arch Intern Med. 1932;50:58.CrossRefGoogle Scholar
  90. 90.
    Suzuki S, Ogawa W, Shibata KL, Tsuzuki H. Changes in Zn and Fe metabolism and carbonic anhydrase and catalase activity in animals with liver damage by carbon tetrachloride or ethionine. Jpn J Pharmacol. 1967;17:393.PubMedCrossRefPubMedCentralGoogle Scholar
  91. 91.
    Gumucio JJ, Katz ME, Miller DL, et al. Bile salt transport after selective damage to acinar zone 3 hepatocytes by bromobenzene in the rat. Toxicol Appl Pharmacol. 1979;50:77.PubMedCrossRefPubMedCentralGoogle Scholar
  92. 92.
    Haddad P, Gascon-Barr M, Dumont A. Comparative hepatic response to bromobenzene and allyl alcohol in the vitamin D-replete and vitamin D depleted rat. J Pharmacol Exp Ther. 1985;233:499.PubMedPubMedCentralGoogle Scholar
  93. 93.
    Mallory FB. Phosphorous poisoning and alcoholic cirrhosis. Am J Pathol. 1933;9:557.PubMedPubMedCentralGoogle Scholar
  94. 94.
    Rojkind A. Collagen metabolism in the liver. In: Hall P, editor. Alcoholic liver disease pathobiology, epidemiology and clinical aspects. London: Edward Arnold; 1985. p. 90–112.Google Scholar
  95. 95.
    Maker JJ, Friedman SL. Pathogenesis of hepatic fibrosis. In: Hall P, editor. Alcoholic liver disease. 2nd ed. London: Edward Arnold; 1995. p. 71–8.Google Scholar
  96. 96.
    Seeff LB, Cuccherini BA, Zimmerman HJ, Adler E, Benjamin SB. Acetaminophen hepatotoxicity in alcoholics: a therapeutic misadventure. Ann Intern Med. 1986;104:399–404.PubMedCrossRefPubMedCentralGoogle Scholar
  97. 97.
    Neuman MG, Cohen LB, Steenkamp V. Pyrrolizidine alkaloids enhance alcohol-induced hepatocytotoxicity in vitro in normal human hepatocytes. Eur Rev Med Pharmacol Sci. 2017;21(1 Suppl):53–68.PubMedPubMedCentralGoogle Scholar
  98. 98.
    Katz GG, Shear NH, Malkiewicz IM, Valentino K, Neuman MG. Signaling for ethanol-induced apoptosis and repair in vitro. Clin Biochem. 2001;34:219–27.PubMedCrossRefPubMedCentralGoogle Scholar
  99. 99.
    Malnick S, Maor Y, Melzer E, Ziv-Sokolowskaia N, Neuman MG. Severe hepatotoxicity link to denosumab. Eur Rev Med Pharmacol Sci. 2017;21(1):78–85.PubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2020

Authors and Affiliations

  1. 1.In Vitro Drug Safety and Biotechnology, Department of Pharmacology and ToxicologyBanting Institute, University of TorontoTorontoCanada

Personalised recommendations