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Hepatotoxicity and Hepatic Dysfunction

  • Ahmet Taner Sümbül
  • Özgür Özyılkan
Chapter

Abstract

Cancer is a multisystemic disease, and every patient needs detailed evaluation before building a treatment plan. In the setting of multiple therapeutic modalities, chemotherapy which consists of conventional and novel therapeutics (tyrosine kinase inhibitors, monoclonal antibodies, immunotherapies, etc.) is the most widely used one. The metabolism and clearance of these drugs are mostly dependent on a normally functioning kidney and liver. Monitoring the liver function tests during the treatment period is crucial for preventing permanent harmful and fatal outcomes.

Especially, the liver is the keystone for the metabolism (i.e., inactivation or activation) and clearance of anticancer agents which are commonly used in different types of cancers. In most cases it is impossible to distinguish the cause of liver dysfunction from cause as compared to other comorbid conditions, and this makes the clinicians job much more complicated before deciding about therapy. Assessment of liver function and uncovering of preexisting liver diseases should be the approach before starting and also during therapy for the optimal management.

Keywords

Cancer Hepatic dysfunction Hepatotoxicity Conventional and targeted therapies Management 

References

  1. 1.
    Swick RW, Barnstein PL, Stange JL. The metabolism of mitochondrial proteins. I. Distributrion adn characterization of the isozymes of alanine aminotransferase in rat liver. J Biol Chem. 1965;240:3334–41.PubMedGoogle Scholar
  2. 2.
    Superfin D, Iannucci AA, Davies AM. Commentary: oncologic drugs in patients with organ dysfunction: a summary. Oncologist. 2007;12(9):1070–83.CrossRefPubMedGoogle Scholar
  3. 3.
    Mano MS, Cassidy J, Canney P. Liver metastases from breast cancer: man- agement of patients with significant liver dysfunction. Cancer Treat Rev. 2005;31:35–48.CrossRefPubMedGoogle Scholar
  4. 4.
    Thatishetty AV, Agresti N, O'Brien CB. Chemotherapy-induced hepatotoxicity. Clin Liver Dis. 2013;17(4):671–86.CrossRefPubMedGoogle Scholar
  5. 5.
    Hamilton M, Wolf JL, Rusk J, et al. Effects of smoking on the pharmacokinetics of erlotinib. Clin Cancer Res. 2006;12:2166–71.CrossRefPubMedGoogle Scholar
  6. 6.
    Farrell GC. Drug induced liver disease. J Hepatol. 2000;32:77–88.Google Scholar
  7. 7.
    Giannini EG, Testa R, Savarino V. Liver enzyme alteration: a guide for clinicians. CMAJ. 2005;172:367–79.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Karczmarek-Borowska B, Sałek-Zań A. Hepatotoxicity of molecular targeted therapy. Contemp Oncol (Pozn). 2015;19(2):87–92.Google Scholar
  9. 9.
    Gholson CF, Morgan K, Catinis G, et al. Chronic hepatitis C with normal aminotransferase levels: a clinical histologic study. Am J Gastroenterol. 1997;92:1788–92.PubMedGoogle Scholar
  10. 10.
    Mofrad P, Contos MJ, Haque M, et al. Clinical and histologic spectrum of nonalcoholic fatty liver disease associated with normal ALT values. Hepatology. 2003;37:1286–92.CrossRefPubMedGoogle Scholar
  11. 11.
    Bahirwani R, Reddy KR. Drug-induced liver injury due to cancer chemotherapeutic agents. Semin Liver Dis. 2014;34(2):162–71.CrossRefPubMedGoogle Scholar
  12. 12.
    Low JK, Hojin K, Hoskins PJ, et al. Fatal reactivation of hepatitis B post chemotherapy for lymphoma in a hepatitis B surface antigen negative hepatitis B core antibody positive patient. Leuk Lymphoma. 2005;46:1085–9.CrossRefGoogle Scholar
  13. 13.
    Markovic S, Drozina G, Vovk M, Fidler-Jenko M. Reactivation of hepatitis B but not hepatitis C in patients with malignant lymphoma and immunosuppressive therapy. A prospective study in 305 patients. Hepatogastroenterology. 1999;46:2925.PubMedGoogle Scholar
  14. 14.
    Kawatani T, Suou T, Tajima F, et al. Incidence of hepatitis virus infection and severe liver dysfunction in patients receiving chemotherapy for hematologic malignancies. Eur J Haematol. 2001;67:45.CrossRefPubMedGoogle Scholar
  15. 15.
    Wai CT, Tan BH, Chan CL, et al. Drug-induced liver injury at an Asian center: a prospective study. Liver Int. 2007;27:465.CrossRefPubMedGoogle Scholar
  16. 16.
    Norris W, Paredes AH, Lewis JH. Drug-induced liver injury in 2007. Curr Opin Gastroenterol. 2008;24:287.CrossRefPubMedGoogle Scholar
  17. 17.
    Navarro VJ, Senior JR. Drug-related hepatotoxicity. N Engl J Med. 2006;354:731.CrossRefPubMedGoogle Scholar
  18. 18.
    Andrade RJ, Lucena MI, Fernandez MC, et al. Drug-induced liver injury: an analysis of 461 incidences submitted to the spanish registry over a 10-year period. Gastroenterology. 2005;129:512.CrossRefPubMedGoogle Scholar
  19. 19.
    De Pree C, Giastro E, Galatto A, et al. Hepatitis C virus acute exacerbation during chemotherapy and radiotherapy for oesaphageal carcinoma. Ann Oncol. 1994;5:861–2.CrossRefPubMedGoogle Scholar
  20. 20.
    Santini D, Picardi A, Vincenci B, et al. Severe liver dysfunction after ralitrexed administration in a HCV positive colorectal cancer patient. Cancer Invest. 2003;21:162–3.CrossRefPubMedGoogle Scholar
  21. 21.
    Salt WB II. Nonalcoholic fatty liver disease (NAFLD) a comprehensive review. J Insur Med. 2004;36:27–41.Google Scholar
  22. 22.
    Zeiss J, Merrick HW, Savolaine ER, Woldenberg LS, Kim K, Schlembach PJ. Fatty liver change as a result of hepatic artery infusion chemotherapy. Am J Clin Oncol. 1990;13:156–60.CrossRefPubMedGoogle Scholar
  23. 23.
    Zorzi D, Laurent A, Pawlik TM, Lauwers GY, Vauthey J-N, Abdalla EK. Chemotherapy-associated hepatotoxicity and surgery for colorectal liver metastases. Br J Surg. 2007;94:274–86.CrossRefGoogle Scholar
  24. 24.
    Grigorian A, O'Brien CB. Hepatotoxicity secondary to chemotherapy. J Clin Transl Hepatol. 2014;2(2):95–102.PubMedPubMedCentralGoogle Scholar
  25. 25.
    Watkins PB, Seeff LB. Drug-induced liver injury: summary of a single topic clinical research conference. Hepatology. 2006;43:618.CrossRefPubMedGoogle Scholar
  26. 26.
    Lee WM. Drug-induced hepatotoxicity. N Engl J Med. 1995;333:1118.CrossRefPubMedGoogle Scholar
  27. 27.
    Snyder LS, Heigh RI, Anderson ML. Cyclophosphamide-induced hepatotoxicity in a patient with Wegener’s granulomatosis. Mayo Clin Proc. 1993;68:1203.CrossRefPubMedGoogle Scholar
  28. 28.
    Shaunak S, Munro JM, Weinbren K, et al. Cyclophosphamide induced liver necrosis: a possible interaction with azathioprine. Q J Med. 1988;252:309–17.Google Scholar
  29. 29.
    King PD, Perry MC. Hepatotoxicity of chemotherapeutic agents. In: Perry MC, editor. The chemotherapy source book. 3rd ed. Philadelphia, PA: Lippincott, Williams and Wilkins; 2001. p. 487.Google Scholar
  30. 30.
    Paschke R, Worst P, Brust J, Queisser W. Hepatotoxicity with etoposide-ifosfamide combination therapy. Onkologie. 1988;11:273.PubMedGoogle Scholar
  31. 31.
    Donelli MG, Zucchetti M, Munzone E, et al. Pharmacokinetics of anticancer agents in patients with impaired liver function. Eur J Cancer. 1998;34:33–46.CrossRefPubMedGoogle Scholar
  32. 32.
    Ayash LJ, Elias A, Wheeler C, et al. Double dose-intensive chemotherapy with autologous marrow and peripheral-blood progenitor-cell support for metastatic breast cancer: a feasibility study. J Clin Oncol. 1994;12:37–44.CrossRefPubMedGoogle Scholar
  33. 33.
    Amromin GD, Delman RM, Shanbran E. Liver damage after chemotherapy for leukemia and lymphoma. Gastroenterology. 1962;42:401–10.PubMedGoogle Scholar
  34. 34.
    Koler RD, Forsgren AL. Hepatotoxicity due to chlorambucil; report of a case. J Am Med Assoc. 1958;167:316.CrossRefPubMedGoogle Scholar
  35. 35.
    Peters WP, Henner WD, Grochow LB, et al. Clinical and pharmacological effects of high-dose single-agent busulfan with autologous bone marrow support in the treatment of solid tumors. Cancer Res. 1987;47:6402–6.PubMedGoogle Scholar
  36. 36.
  37. 37.
    Koren G, Beatty K, Seto A, et al. The effects of impaired liver function on the elimination of antineoplastic agents. Ann Pharmacother. 1992;26:363.CrossRefPubMedGoogle Scholar
  38. 38.
    Pizzuto J, Aviles A, Ramos E, et al. Cytosine arabinoside induced liver damage: histopathologic demonstration. Med Pediatr Oncol. 1983;11:287.CrossRefPubMedGoogle Scholar
  39. 39.
    George CB, Mansour RP, Redmond J 3rd, Gandara DR. Hepatic dysfunction and jaundice following high-dose cytosine arabinoside. Cancer. 1984;54:2360.CrossRefGoogle Scholar
  40. 40.
    Donehower RC, Karp JE, Burke PJ. Pharmacology and toxicity of high-dose cytarabine by 72-hour continuous infusion. Cancer Treat Rep. 1986;70:1059.PubMedGoogle Scholar
  41. 41.
    Bateman JR, Pugh RP, Cassidy FR, et al. 5-fluorouracil given once weekly: comparison of intravenous and oral administration. Cancer. 1971;28:907.CrossRefPubMedGoogle Scholar
  42. 42.
    Hohn D, Melnick J, Stagg R, et al. Biliary sclerosis in patients receiving hepatic arterial infusions of floxuridine. J Clin Oncol. 1985;3:98.CrossRefPubMedGoogle Scholar
  43. 43.
    Yildirim Y, Ozyilkan O, Akcali Z, Basturk B. Drug interaction between capecitabine and warfarin: a case report and review of the literature. Int J Clin Pharmacol Ther. 2006;44(2):80–2.CrossRefPubMedGoogle Scholar
  44. 44.
    Aki Z, Kotiloğlu G, Ozyilkan O. A patient with a prolonged prothrombin time due to an adverse interaction between 5-fluorouracil and warfarin. Am J Gastroenterol. 2000;95(4):1093–4.CrossRefPubMedGoogle Scholar
  45. 45.
    Twelves C, Glynne-Jones R, Cassidy J, et al. Effectofhepaticdysfunction due to liver metastases on the pharmacokinetics of capecitabine and its me- tabolites. Clin Cancer Res. 1999;5:1696–702.PubMedGoogle Scholar
  46. 46.
    Robinson K, Lambiase L, Li J, Monteiro C, Schiff M. Fatal cholestatic liver failure associated with gemcitabine therapy. Dig Dis Sci. 2003;48:1804–8.CrossRefPubMedGoogle Scholar
  47. 47.
    Saif MW, Shahrokni A, Cornfeld D. Gemcitabine-induced liver fi brosis in a patient with pancreatic cancer. JOP. 2007;8:460–7.PubMedGoogle Scholar
  48. 48.
    Venook AP, Egorin MJ, Rosner GL, et al. Phase I and pharmacokinetic trial of gemcitabine in patients with hepatic or renal dysfunction: Cancer and Leukemia Group B 9565. J Clin Oncol. 2000;18:2780–7.CrossRefPubMedGoogle Scholar
  49. 49.
    McIlvanie SK, MacCarthy JD. Hepatitis in association with prolonged 6-mercaptopurine therapy. Blood. 1959;14:80–90.PubMedGoogle Scholar
  50. 50.
    Romagnuolo J, Sadowski DC, Lalor E, et al. Cholestatic hepatocellular injury with azathioprine: a case report and review of the mechanisms of hepatotoxicity. Can J Gastroenterol. 1998;12:479.CrossRefPubMedGoogle Scholar
  51. 51.
    Griner PF, Elbadawi A, Packman CH. Veno-occlusive disease of the liver after chemotherapy of acute leukemia. Report of two cases. Ann Intern Med. 1976;85:578.CrossRefPubMedGoogle Scholar
  52. 52.
    Leme PR, Creaven PJ, Allen LM, Berman M. Kinetic model for the disposition and metabolism of moderate and high-dose methotrexate (NSC-740) in man. Cancer Chemother Rep. 1975;59:811.PubMedGoogle Scholar
  53. 53.
    Evans WE, Pratt CB. Effect of pleural effusion on high-dose methotrexate kinetics. Clin Pharmacol Ther. 1978;23:68.CrossRefPubMedGoogle Scholar
  54. 54.
    Farrell GC. Drug-induced liver disease. New York: Churchill Livingstone; 1994.Google Scholar
  55. 55.
    Buroker TR, Kim PN, Baker LH, et al. Mitomycin-C alone and in combination with infused 5-fluorouracil to the treatment of disseminated gastrointestinal carcinomas. Med Pediatr Oncol. 1978;4:35.CrossRefPubMedGoogle Scholar
  56. 56.
    Twelves C, Glynne-Jones R, Cassidy J, et al. Effect of hepatic dysfunction due to liver metastases on the pharmacokinetics of capecitabine and its metabolites. Clin Cancer Res. 1999;5:1696.PubMedGoogle Scholar
  57. 57.
    Huizing MT, Misser VH, Pieters RC, et al. Taxanes: a new class of antitumor agents. Cancer Invest. 1995;13:381.CrossRefPubMedGoogle Scholar
  58. 58.
    Francis P, et al. Pharmacodynamics of docetaxel in patients with liver metastases. Proc Am Soc Clin Oncol. 1994;13:138.Google Scholar
  59. 59.
    Burris HA. Optimaluseofdocetaxel(Taxotere):Maximizingitspotential. Anticancer Drugs. 1996;7(suppl 2):25–8.CrossRefPubMedGoogle Scholar
  60. 60.
    Takimoto CH, Liu PY, Lenz H, et al. A phase I pharmacokinetic (PK) study of the epothilone B analogue, ixabepilone (BMS-247550) in patients with advanced malignancies and varying degrees of hepatic impairment. A SWOG Early Therapeutics Committee and NCI Organ Dysfunction Work- ing Group trial. Proc Am Soc Clin Oncol. 2006;24:2004.Google Scholar
  61. 61.
    Hirth J, Watkins PB, Strawderman M, et al. The effect of an individual’s cytochrome CYP3A4 activity on docetaxel clearance. Clin Cancer Res. 2000;6:1255.PubMedGoogle Scholar
  62. 62.
    Shah RR, Morganroth J, Shah DR. Hepatotoxicity of tyrosine kinase inhibitors: clinical and regulatory perspectives. Drug Saf. 2013;36(7):491–503.CrossRefPubMedGoogle Scholar
  63. 63.
    Kikuchi S, Muroi K, Takahashi S, et al. Severe hepatitis and complete molecular response caused by imatinib mesylate: possible association of its serum concentration with clinical outcomes. Leuk Lymphoma. 2004;45(11):2349–51.CrossRefPubMedGoogle Scholar
  64. 64.
    Reuben A. Hy’s law. Hepatology. 2004;39:574–8.CrossRefPubMedGoogle Scholar
  65. 65.
    Castellino S, O’Mara M, Koch K, Borts DJ, Bowers GD, MacLauchlin C. Human metabolism of lapatinib, a dual kinase inhibitor: impli- cations for hepatotoxicity. Drug Metab Dispos. 2012;40:139–50.CrossRefPubMedGoogle Scholar
  66. 66.
    Teng WC, Oh JW, New LS, Wahlin MD, Nelson SD, Ho HK, Chan EC. Mechanism-based inactivation of cytochrome P450 3A4 by lapa- tinib. Mol Pharmacol. 2010;78:693–703.CrossRefPubMedGoogle Scholar
  67. 67.
    Mathijssen RH, van Alphen RJ, Verweij J, et al. Clinical pharmacokinetics and metabolism of irinotecan (CPT-11). Clin Cancer Res. 2182;2001:7.Google Scholar
  68. 68.
    Gupta-Abramson V, Troxel AB, Nellore A, et al. Phase II trial of sorafenib in advanced thyroid cancer. J Clin Oncol. 2008;26:4714–9.CrossRefPubMedPubMedCentralGoogle Scholar
  69. 69.
    Miller AA, Murry DJ, Owzar K, et al. Phase I and pharmacokinetic study of sorafenib in patients with hepatic or renal dysfunction: CALGB 60301. J Clin Oncol. 2009;27:1800.CrossRefPubMedPubMedCentralGoogle Scholar
  70. 70.
    Meza-Junco J, Chu QS, Christensen O, et al. UGT1A1 polymorphism and hyperbilirubinemia in a patient who received sorafenib. Cancer Chemother Pharmacol. 2009;65(1):1–4.CrossRefPubMedGoogle Scholar
  71. 71.
    Ramanathan RK, Egorin MJ, Takimoto CH, et al. Phase I and pharmacokinetic study of imatinib mesylate in patients with advanced malignancies and varying degrees of liver dysfunction: a study by the National Cancer Institute Organ Dysfunction Working Group. J Clin Oncol. 2008;26:563.CrossRefPubMedGoogle Scholar
  72. 72.
    Shepherd F, Rodrigues Pereira J, Ciuleanu T, et al. National Cancer Institute of Canada Clinical Trials Group. Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med. 2005;353:123–32.CrossRefGoogle Scholar
  73. 73.
    Moore M, Goldstein D, Hamm J, et al. Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 2007;25:1960–6.CrossRefPubMedGoogle Scholar
  74. 74.
    US Food and Drug Administration (FDA). http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/125477lbl.pdf. Accessed 25 Apr 2014.
  75. 75.
    European Medicines Agency. http://www.ema.europa.eu/ema/.
  76. 76.
    Frampton J, Keating G. Bevacizumab: in first-line treatment of ad- vanced and/or metastatic renal cell carcinoma. BioDrugs. 2008;22:113–20.CrossRefPubMedGoogle Scholar
  77. 77.
    Zalinski S, Bigourdan J, Vauthey J. Does bevacizumab have a pro- tective effect on hepatotoxicity induced by chemotherapy? J Chir. 2010;47(Supp 1):18–24.Google Scholar
  78. 78.
    Srinivasan S, Parsa V, Liu C, Fontana J. Trastuzumab-induced hep- atotoxicity. Ann Pharmacother. 2008;42:1497–501.CrossRefPubMedGoogle Scholar
  79. 79.
  80. 80.
    Kim YH, Mio T, Mishima M. Gefitinib for non-small cell lung cancer patients with liver cirrhosis. Intern Med. 2009;48:1677.CrossRefPubMedGoogle Scholar
  81. 81.
    Wolchok JD, Neyns B, Linette G, et al. Ipilimumab monotherapy in patients with pretreated advanced melanoma: a randomised, double-blind, multicentre, phase 2, dose-ranging study. Lancet Oncol. 2010;11(2):155–64.CrossRefPubMedGoogle Scholar
  82. 82.
    Robert C, Thomas L, Bondarenko I, et al. Ipilimumab plus dacar- bazine for previously untreated metastatic melanoma. N Engl J Med. 2011;364(26):2517–26.CrossRefPubMedGoogle Scholar
  83. 83.
    Weber JS, Kähler KC, Hauschild A. Management of immune- related adverse events and kinetics of response with ipilimumab. J Clin Oncol. 2012;30(21):2691–7.CrossRefPubMedGoogle Scholar
  84. 84.
    Naidoo J, Page DB, Li BT, et al. Toxicities of the anti-PD-1 and anti-PD-L1 immune checkpoint antibodies. Ann Oncol. 2015;26:2375.Google Scholar
  85. 85.
  86. 86.
    Champiat S, Lambotte O, Barreau E, et al. Management of immune checkpoint blockade dysimmune toxicities: a collaborative position paper. Ann Oncol. 2016;27:559.CrossRefPubMedGoogle Scholar
  87. 87.
    Suzuki A, Andrade RJ, Bjornsson E, et al. Drugs associated with hepatotoxicity and their reporting frequency of liver adverse events in VigiBase: unified list based on international collaborative work. Drug Saf. 2010;33:503.CrossRefPubMedGoogle Scholar
  88. 88.
    Chen M, Zhang J, Wang Y, et al. The liver toxicity knowledge base: a systems approach to a complex end point. Clin Pharmacol Ther. 2013;93:409.CrossRefPubMedGoogle Scholar
  89. 89.
    Kirkwood JM, Ernstoff MS. Interferons in the treatment of human cancer. J Clin Oncol. 1984;2:336.CrossRefPubMedGoogle Scholar
  90. 90.
    Rollins BJ. Hepatic veno-occlusive disease. Am J Med. 1986;81:297–306.CrossRefPubMedGoogle Scholar
  91. 91.
    Carreras E. Veno-occlusive disease of the liver after hemopoietic cell transplantation. Eur J Haematol. 2000;64:281–91.CrossRefPubMedGoogle Scholar
  92. 92.
    Wanless IR, Godwin TA, Allen F, et al. Nodular regenerative hyperplasia of the liver in hematological disorders: a possible response to obliterative portal venopathy. A morphometric study of nine cases with a hypothesis on the pathogenesis. Medicine. 1980;59:367.CrossRefPubMedGoogle Scholar
  93. 93.
    Fleming DR, Wolff SN, Fay JW, et al. Protracted results of dose-intensive therapy using cyclophosphamide, carmustine, and continuous infusion etoposide with autologous stem cell support in patients with relapse or refractory Hodgkin’s disease: a phase II study from the North American Marrow Transplant Group. Leuk Lymphoma. 1999;35:91.CrossRefPubMedGoogle Scholar

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© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  • Ahmet Taner Sümbül
    • 1
  • Özgür Özyılkan
    • 1
  1. 1.Department of Medical OncologyBaskent University School of Medicine, Baskent Universitesi Adana Hastanesi Kisla Yerleskesi Tibbi Onkoloji BD Kazim Karabekir cadYuregirAdanaTurkey

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