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Drug-Induced Liver Injury—Perspectives from Pathology

  • Drug-induced Liver Injury (X Ma, Section Editor)
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Abstract

Purpose of Review

Drug-induced liver injury (DILI) may be caused by prescription or over-the-counter medications, herbals and nutritional supplements, or environmental agents. This review provides an overview of (1) pathogenetic mechanisms and risk factors, (2) biochemical classification, (3) diagnostic approach, (4) role of liver biopsy, and (5) narratives on commoner agents that cause DILI.

Recent Findings

DILI is increasingly seen in contemporary practice due to increased usage of medications in general, introduction of newer agents for treatment of cancers and autoimmune diseases, and increasing consumption of herbals and nutritional supplements.

Summary

Drug-induced liver injury is a significant cause of liver disease worldwide. No clinical, biochemical, or histological feature is specific for the diagnosis of DILI, which can mimic every pattern of liver injury and is in the differential diagnosis of every patient with liver disease. The diagnosis of DILI relies on (1) establishing a temporal association between clinical disease and initiation of the suspected drug, followed in the majority of cases by clinical improvement and disease resolution on its withdrawal and (2) exclusion of competing causes of liver injury. Herbals and nutritional supplements are particularly interesting as these are generally regarded as “safe, natural” compounds by an increasingly health-conscious population. Establishing a temporal relationship is often challenging as the patient may be taking multiple supplements simultaneously and is usually unclear about timing of initiation and withdrawal of the agents. Additionally, these agents change in potency and composition depending on the harvest conditions of the constituent botanicals.

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References

  1. Fenkel JM, Navarro VJ. Herbal and dietary supplement-induced liver injury. Gastroenterol Hepatol (N Y). 2011;7(10):695–6.

    Google Scholar 

  2. Stournaras E, Tziomalos K. Herbal medicine-related hepatotoxicity. World J Hepatol. 2015 Sep 8;7(19):2189–93. https://doi.org/10.4254/wjh.v7.i19.2189.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Ostapowicz G, Fontana RJ, Schiodt FV, Larson A, Davern TJ, Han SH, et al. Results of a prospective study of acute liver failure at 17 tertiary care centers in the United States. Ann Intern Med. 2002;137(12):947–54.

    Article  Google Scholar 

  4. Bower WA, Johns M, Margolis HS, Williams IT, Bell BP. Population-based surveillance for acute liver failure. Am J Gastroenterol. 2007 Nov;102(11):2459–63.

    Article  Google Scholar 

  5. Lasser KE, Allen PD, Woolhandler SJ, Himmelstein DU, Wolfe SM, Bor DH. Timing of new black box warnings and withdrawals for prescription medications. JAMA. 2002;287(17):2215–20.

    Article  Google Scholar 

  6. Wysowski DK, Swartz L. Adverse drug event surveillance and drug withdrawals in the United States, 1969-2002: the importance of reporting suspected reactions. Arch Intern Med. 2005;165(12):1363–9.

    Article  Google Scholar 

  7. Vuppalanchi R, Gotur R, Reddy KR, Fontana RJ, Ghabril M, Kosinski AS, et al. Relationship between characteristics of medications and drug-induced liver disease phenotype and outcome. Clin Gastroenterol Hepatol. 2014;12(9):1550–5. https://doi.org/10.1016/j.cgh.2013.12.016.

    Article  PubMed  Google Scholar 

  8. Williams R. Changing clinical patterns in acute liver failure. J Hepatol. 2003;39(4):660–1.

    Article  Google Scholar 

  9. Russo MW, Galanko JA, Shrestha R, Fried MW, Watkins P. Liver transplantation for acute liver failure from drug induced liver injury in the United States. Liver Transpl. 2004;10(8):1018–23.

    Article  Google Scholar 

  10. Hanje AJ, Chalasani N. How common is chronic liver disease from acute drug-induced liver injury? Gastroenterology. 2007;132(5):2067–8. discussion 2068-9

    Article  Google Scholar 

  11. Lefkowitch JH. The pathology of acute liver failure. Adv Anat Pathol. 2016;23(3):144–58. https://doi.org/10.1097/PAP.0000000000000112.

    Article  CAS  PubMed  Google Scholar 

  12. Mitchell JR, Jollow DJ, Potter WZ, Gillette JR, Brodie BB. Acetaminophen-induced hepatic necrosis. IV. Protective role of glutathione. J Pharmacol Exp Ther. 1973;187(1):211–7.

    CAS  PubMed  Google Scholar 

  13. Hinson JA, Roberts DW, James LP. Mechanisms of acetaminophen-induced liver necrosis. Handb Exp Pharmacol. 2010;196:369–405. https://doi.org/10.1007/978-3-642-00663-0_12.

    Article  CAS  Google Scholar 

  14. Peterson RG, Rumack BH. Toxicity of acetaminophen overdose. JACEP. 1978;7(5):202–5.

    Article  CAS  Google Scholar 

  15. Williamson K, Wahl MS, Mycyk MB. Direct comparison of 20-hour IV, 36-hour oral, and 72-hour oral acetylcysteine for treatment of acute acetaminophen poisoning. Am J Ther. 2013;20(1):37–40. https://doi.org/10.1097/MJT.0b013e318250f829.

    Article  PubMed  Google Scholar 

  16. Urban TJ, Shen Y, Stolz A, Chalasani N, Fontana RJ, Rochon J. Limited contribution of common genetic variants to risk for liver injury due to a variety of drugs. Pharmacogenet Genomics. 2012;22(11):784–95. https://doi.org/10.1097/FPC.0b013e3283589a76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Lammert C, Einarsson S, Saha C, Niklasson A, Bjornsson E, Chalasani N. Relationship between daily dose of oral medications and idiosyncratic drug-induced liver injury: search for signals. Hepatology. 2008;47(6):2003–9. https://doi.org/10.1002/hep.22272.

    Article  CAS  PubMed  Google Scholar 

  18. Lammert C, Bjornsson E, Niklasson A, Chalasani N. Oral medications with significant hepatic metabolism at higher risk for hepatic adverse events. Hepatology. 2010;51(2):615–20. https://doi.org/10.1002/hep.23317.

    Article  CAS  PubMed  Google Scholar 

  19. Chen M, Borlak J, Tong W. High lipophilicity and high daily dose of oral medications are associated with significant risk for drug-induced liver injury. Hepatology. 2013;58(1):388–96. https://doi.org/10.1002/hep.26208.

    Article  CAS  PubMed  Google Scholar 

  20. Ibáñez L, Pérez E, Vidal X, Laporte JR, Grup d’Estudi Multicènteric d’Hepatotoxicitat Aguda de Barcelona (GEMHAB). Prospective surveillance of acute serious liver disease unrelated to infectious, obstructive, or metabolic diseases: epidemiological and clinical features, and exposure to drugs. J Hepatol. 2002;37(5):592–600.

    Article  Google Scholar 

  21. Björnsson E, Kalaitzakis E, Olsson R. The impact of eosinophilia and hepatic necrosis on prognosis in patients with drug-induced liver injury. Aliment Pharmacol Ther. 2007;25(12):1411–21.

    Article  Google Scholar 

  22. Larrey D. Epidemiology and individual susceptibility to adverse drug reactions affecting the liver. Semin Liver Dis. 2002;22(2):145–55.

    Article  CAS  Google Scholar 

  23. Bell LN, Chalasani N. Epidemiology of idiosyncratic drug-induced liver injury. Semin Liver Dis. 2009;29(4):337–47. https://doi.org/10.1055/s-0029-1240002.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Lucena MI, Andrade RJ, Fernández MC, Pachkoria K, Pelaez G, Durán JA, et al. Determinants of the clinical expression of amoxicillin-clavulanate hepatotoxicity a prospective series from Spain. Hepatology. 2006;44(4):850–6.

    Article  CAS  Google Scholar 

  25. Jinjuvadia K, Kwan W, Fontana RJ. Searching for a needle in a haystack: use of ICD-9-CM codes in drug-induced liver injury. Am J Gastroenterol. 2007;102(11):2437–43.

    Article  Google Scholar 

  26. Andrade RJ, Lucena MI, Fernández MC, Pelaez G, Pachkoria K, García-Ruiz E. Drug-induced liver injury: an analysis of 461 incidences submitted to the Spanish registry over a 10-year period. Gastroenterology. 2005;129(2):512–21.

    Article  Google Scholar 

  27. Cotreau MM, von Moltke LL, Greenblatt DJ. The influence of age and sex on the clearance of cytochrome P450 3A substrates. Clin Pharmacokinet. 2005;44(1):33–60.

    Article  CAS  Google Scholar 

  28. Wynne HA, Cope LH, Mutch E, Rawlins MD, Woodhouse KW, James OF. The effect of age upon liver volume and apparent liver blood flow in healthy man. Hepatology. 1989;9(2):297–301.

    Article  CAS  Google Scholar 

  29. Sgro C, Clinard F, Ouazir K, Chanay H, Allard C, Guilleminet C. Incidence of drug-induced hepatic injuries: a French population-based study. Hepatology. 2002;36(2):451–5.

    Article  Google Scholar 

  30. Uetrecht J. Idiosyncratic drug reactions: current understanding. Annu Rev Pharmacol Toxicol. 2007;47:513–39.

    Article  CAS  Google Scholar 

  31. Uetrecht JP. New concepts in immunology relevant to idiosyncratic drug reactions: the “danger hypothesis” and innate immune system. Chem Res Toxicol. 1999;12(5):387–95.

    Article  CAS  Google Scholar 

  32. Pessayre D. Role of reactive metabolites in drug-induced hepatitis. J Hepatol. 1995;23(Suppl 1):16–24.

    CAS  PubMed  Google Scholar 

  33. Knowles SR, Uetrecht J, Shear NH. Idiosyncratic drug reactions: the reactive metabolite syndromes. Lancet. 2000;356(9241):1587–91.

    Article  CAS  Google Scholar 

  34. Lewis JH. The rational use of potentially hepatotoxic medications in patients with underlying liver disease. Expert Opin Drug Saf. 2002;1(2):159–72.

    Article  CAS  Google Scholar 

  35. Russo MW, Watkins PB. Are patients with elevated liver tests at increased risk of drug-induced liver injury? Gastroenterology. 2004;126(5):1477–80.

    Article  Google Scholar 

  36. Stewart JD, Horvath R, Baruffini E, Ferrero I, Bulst S, Watkins PB, et al. Polymerase γ gene POLG determines the risk of sodium valproate-induced liver toxicity. Hepatology. 2010;52(5):1791–6. https://doi.org/10.1002/hep.23891.

    Article  CAS  PubMed  Google Scholar 

  37. Daly AK, Day CP. Genetic association studies in drug-induced liver injury. Drug Metab Rev. 2012;44(1):116–26. https://doi.org/10.3109/03602532.2011.605790.

    Article  CAS  PubMed  Google Scholar 

  38. Berson A, Fréneaux E, Larrey D, Lepage V, Douay C, Mallet C, et al. Possible role of HLA in hepatotoxicity. An exploratory study in 71 patients with drug-induced idiosyncratic hepatitis. J Hepatol. 1994;20(3):336–42.

    Article  CAS  Google Scholar 

  39. Andrade RJ, Lucena MI, Alonso A, García-Cortes M, García-Ruiz E, Benitez R. HLA class II genotype influences the type of liver injury in drug-induced idiosyncratic liver disease. Hepatology. 2004;39(6):1603–12.

    Article  CAS  Google Scholar 

  40. Lucena MI, Molokhia M, Shen Y, Urban TJ, Aithal GP, Andrade RJ. Susceptibility to amoxicillin-clavulanate-induced liver injury is influenced by multiple HLA class I and II alleles. Gastroenterology. 2011;141(1):338–47. https://doi.org/10.1053/j.gastro.2011.04.001.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Kleiner DE, Chalasani NP, Lee WM, Fontana RJ, Bonkovsky HL, Watkins PB. Hepatic histological findings in suspected drug-induced liver injury: systematic evaluation and clinical associations. Hepatology. 2014;59(2):661–70. https://doi.org/10.1002/hep.26709.

    Article  PubMed  Google Scholar 

  42. Lucena MI, Camargo R, Andrade RJ, Perez-Sanchez CJ, Sanchez De La Cuesta F. Comparison of two clinical scales for causality assessment in hepatotoxicity. Hepatology. 2001;33(1):123–30.

    Article  CAS  Google Scholar 

  43. García-Cortés M, Lucena MI, Pachkoria K, Borraz Y, Hidalgo R, Andrade RJ, et al. Evaluation of naranjo adverse drug reactions probability scale in causality assessment of drug-induced liver injury. Aliment Pharmacol Ther. 2008;27(9):780–9. https://doi.org/10.1111/j.1365-2036.2008.03655.x.

    Article  PubMed  Google Scholar 

  44. Navarro V, Khan I, Björnsson E, Seeff LB, Serrano J, Hoofnagle JH. Liver injury from herbal and dietary supplements. Hepatology. 2017;65(1):363–73. https://doi.org/10.1002/hep.28813.

    Article  CAS  PubMed  Google Scholar 

  45. Andrade RJ, Lucena MI, Kaplowitz N, García-Muņoz B, Borraz Y, Pachkoria K, et al. Outcome of acute idiosyncratic drug-induced liver injury: long-term follow-up in a hepatotoxicity registry. Hepatology. 2006;44(6):1581–8.

    Article  CAS  Google Scholar 

  46. Kleiner DE. The pathology of drug-induced liver injury. Semin Liver Dis. 2009;29(4):364–72. https://doi.org/10.1055/s-0029-1240005.

    Article  PubMed  Google Scholar 

  47. Fontana RJ, Shakil AO, Greenson JK, Boyd I, Lee WM. Acute liver failure due to amoxicillin and amoxicillin/clavulanate. Dig Dis Sci. 2005;50(10):1785–90.

    Article  Google Scholar 

  48. Orman ES, Conjeevaram HS, Raj Vuppalanchi MD, Freston JW, Rochon J, Kleiner DE, et al. Clinical and histopathologic features of fluoroquinolone-induced liver injury. Clin Gastroenterol Hepatol. 2011;9(6):517–523.e3. https://doi.org/10.1016/j.cgh.2011.02.019.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Alqahtani SA, Kleiner DE, Ghabril M, Gu J, Hoofnagle JH, Rockey DC. Identification and characterization of cefazolin-induced liver injury. Clin Gastroenterol Hepatol. 2015;13(7):1328–1336.e2. https://doi.org/10.1016/j.cgh.2014.11.036.

    Article  CAS  PubMed  Google Scholar 

  50. Björnsson ES, Gunnarsson BI, Gröndal G, Jonasson JG, Einarsdottir R, Ludviksson BR, et al. Risk of drug-induced liver injury from tumor necrosis factor antagonists. Clin Gastroenterol Hepatol. 2015;13(3):602–8. https://doi.org/10.1016/j.cgh.2014.07.062.

    Article  CAS  PubMed  Google Scholar 

  51. Ghabril M, Bonkovsky HL, Kum C, Davern T, Hayashi PH, Kleiner DE. Liver injury from tumor necrosis factor-α antagonists: analysis of thirty-four cases. Clin Gastroenterol Hepatol. 2013;11(5):558–564.e3. https://doi.org/10.1016/j.cgh.2012.12.025.

    Article  CAS  PubMed  Google Scholar 

  52. Diallo A, Mekinian A, Boukari L, Mouas H, Zamy M, Nahon P. Severe hepatitis in a patient with adult-onset Still’s disease treated with anakinra. Rev Med Interne. 2013 Mar;34(3):168–70. https://doi.org/10.1016/j.revmed.2012.10.372.

    Article  CAS  PubMed  Google Scholar 

  53. Alfreijat M, Habibi M, Bhatia P, Bhatia A. Severe hepatitis associated with tocilizumab in a patient with rheumatoid arthritis. Rheumatology (Oxford). 2013;52:1340–1.

    Article  Google Scholar 

  54. Shah RR, Morganroth J, Shah DR. Hepatotoxicity of tyrosine kinase inhibitors: clinical and regulatory perspectives. Drug Saf. 2013;36(7):491–503. https://doi.org/10.1007/s40264-013-0048-4.

    Article  CAS  PubMed  Google Scholar 

  55. Al Sobhi E, Zahrani Z, Zevallos E, Zuraiki A. Imatinib-induced immune hepatitis: case report and literature review. Hematology. 2007;12(1):49–53.

    Article  Google Scholar 

  56. Seidel C, Fenner M, Länger F, Bantel H, Ganser A, Grünwald V. Imatinib-induced liver cirrhosis in a patient with advanced gastrointestinal stroma tumor (GIST). BMC Cancer. 2012;12:186. https://doi.org/10.1186/1471-2407-12-186.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Suzuki R, Kobayashi C, Sakai A, Fukushima H, Tagawa M, Satomi K, et al. Imatinib-induced severe hepatitis in a 9-year-old girl with Philadelphia chromosome-positive acute lymphoblastic leukemia. J Pediatr Hematol Oncol. 2015;37(6):e368–71. https://doi.org/10.1097/MPH.0000000000000337.

    Article  PubMed  Google Scholar 

  58. Cross TJ, Bagot C, Portmann B, Wendon J, Gillett D. Imatinib mesylate as a cause of acute liver failure. Am J Hematol. 2006;81(3):189–92.

    Article  Google Scholar 

  59. James C, Trouette H, Marit G, Cony-Makhoul P, Mahon FX. Histological features of acute hepatitis after imatinib mesylate treatment. Leukemia. 2003;17:978–9.

    Article  CAS  Google Scholar 

  60. Kikuchi S, Muroi K, Takahashi S, Kawano-Yamamoto C, Takatoku M, Miyazato A, et al. Severe hepatitis and complete molecular response caused by Imatinib mesylate: possible association of its serum concentration and clinical outcomes. Leuk Lymphoma. 2004;45:2349–51.

    Article  Google Scholar 

  61. Lin NU, Sarantopoulos S, Stone JR, Galinsky I, Stone RM, Deangelo DJ, et al. Fatal hepatic necrosis following imatinib mesylate therapy. Blood. 2003;102:3455–6.

    Article  CAS  Google Scholar 

  62. Ohyashiki K, Kuriyama Y, Nakajima A, Tauchi T, Ito Y, Miyazawa H, et al. Imatinib mesylate-induced hepato-toxicity in chronic myeloid leukemia demonstrated focal necrosis resembling acute viral hepatitis. Leukemia. 2002;16:2160–1.

    Article  CAS  Google Scholar 

  63. Fairfax BP, Pratap S, Roberts IS, Collier J, Kaplan R, Meade AM, et al. Fatal case of sorafenib-associated idiosyncratic hepatotoxicity in the adjuvant treatment of a patient with renal cell carcinoma. BMC Cancer. 2012;12:590. https://doi.org/10.1186/1471-2407-12-590.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Herden U, Fischer L, Schäfer H, Nashan B, von Baehr V, Sterneck M. Sorafenib-induced severe acute hepatitis in a stable liver transplant recipient. Transplantation. 2010;90(1):98–9. https://doi.org/10.1097/TP.0b013e3181daac69.

    Article  PubMed  Google Scholar 

  65. Karoui M, Penna C, Amin-Hashem M, Mitry E, Benoist S, Franc B, et al. Influence of preoperative chemotherapy on the risk of major hepatectomy for colorectal liver metastases. Ann Surg. 2006;243(1):1–7.

    Article  Google Scholar 

  66. Nordlinger B, Benoist S. Benefits and risks of neoadjuvant therapy for liver metastases. J Clin Oncol. 2006;24(31):4954–5.

    Article  Google Scholar 

  67. Kandutsch S, Klinger M, Hacker S, Wrba F, Gruenberger B, Gruenberger T. Patterns of hepatotoxicity after chemotherapy for colorectal cancer liver metastases. Eur J Surg Oncol. 2008;34(11):1231–6. https://doi.org/10.1016/j.ejso.2008.01.001.

    Article  CAS  PubMed  Google Scholar 

  68. Nalbantoglu IL, Tan BR Jr, Linehan DC, Gao F, Brunt EM. Histological features and severity of oxaliplatin-induced liver injury and clinical associations. J Dig Dis. 2014;15(10):553–60. https://doi.org/10.1111/1751-2980.

    Article  CAS  PubMed  Google Scholar 

  69. Vuppalanchi R, Saxena R, Storniolo AMV, Chalasani N. Pseudocirrhosis and liver failure in patients with metastatic breast cancer after treatment with palbociclib. Hepatology. 2017;65(5):1762–4. https://doi.org/10.1002/hep.28720.

    Article  PubMed  Google Scholar 

  70. Tallman MS, McDonald GB, DeLeve LD, Baer MR, Cook MN, Graepel GJ, et al. Incidence of sinusoidal obstruction syndrome following Mylotarg (gemtuzumab ozogamicin): a prospective observational study of 482 patients in routine clinical practice. Int J Hematol. 2013;97(4):456–64. https://doi.org/10.1007/s12185-013-1275-2.

    Article  PubMed  Google Scholar 

  71. Giles FJ, Kantarjian HM, Kornblau SM, Thomas DA, Garcia-Manero G, Waddelow TA. Mylotarg (gemtuzumab ozogamicin) therapy is associated with hepatic venoocclusive disease in patients who have not received stem cell transplantation. Cancer. 2001;92(2):406–13.

    Article  CAS  Google Scholar 

  72. Gordon LI. Gemtuzumab ozogamicin (Mylotarg) and hepatic veno-occlusive disease: take two acetaminophen, and. Bone Marrow Transplant. 2001;28(9):811–2.

    Article  CAS  Google Scholar 

  73. Neumeister P, Eibl M, Zinke-Cerwenka W, Scarpatetti M, Sill H, Linkesch W. Hepatic veno-occlusive disease in two patients with relapsed acute myeloid leukemia treated with anti-CD33 calicheamicin(CMA-676) immunoconjugate. Ann Hematol. 2001;80:119–20.

    Article  CAS  Google Scholar 

  74. Force J, Saxena R, Schneider BP, Storniolo AM, Sledge GW Jr, Chalasani N, et al. Nodular regenerative hyperplasia after treatment with trastuzumab emtansine. J Clin Oncol. 2016;34(3):e9–12. https://doi.org/10.1200/JCO.2013.49.8543.

    Article  PubMed  Google Scholar 

  75. Kleiner DE, Berman D. Pathologic changes in ipilimumab-related hepatitis in patients with metastatic melanoma. Dig Dis Sci. 2012;57:2233–40.

    Article  Google Scholar 

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Correspondence to Shefali Chopra.

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This article is part of the Topical Collection on Drug-induced Liver Injury

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Chopra, S., Saxena, R. Drug-Induced Liver Injury—Perspectives from Pathology. Curr Pharmacol Rep 4, 182–192 (2018). https://doi.org/10.1007/s40495-018-0136-3

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