Top

Current Hepatology Reports

Published in:

01-09-2018 | Drug-Induced Liver Injury (NP Chalasani and MS Ghabril, Section Editors)

Drug-Induced Liver Injury: Understanding the Different Immune-Mediated Phenotypes and Clinical Management

Authors: Ben L. Da, Gil Ben-Yakov, David Kleiner, Christopher Koh

Published in: Current Hepatology Reports | Issue 3/2018

Abstract

Purpose of Review

The aim of this manuscript is to review two immune-mediated drug-induced liver injury (DILI) phenotypes, immune-allergic DILI (IA-DILI) and DILI with autoimmune hepatitis features (DILI-AIH), which are poorly defined and can lead to significant morbidity and mortality.

Recent Findings

Recent information on this topic improves the understanding of IA-DILI and DILI-AIH regarding risk factors, associated medications, clinical presentations, histopathologic findings, and management strategies.

Summary

Although the pathogenesis and specific mechanisms remain elusive, clinical and pathological advancements in our understanding of IA-DILI and DILI-AIH have provided clinicians with added tools for the diagnosis and management of these diseases. Further studies are needed to improve our understanding of immune-mediated DILI.

Bjornsson ES, Bergmann OM, Bjornsson HK, Kvaran RB, Olafsson S. Incidence, presentation, and outcomes in patients with drug-induced liver injury in the general population of Iceland. Gastroenterology. 2013;144(7):1419–25. https://doi.org/10.1053/j.gastro.2013.02.006. 25 e1-3; quiz e19-20CrossRefPubMed

Sgro C, Clinard F, Ouazir K, Chanay H, Allard C, Guilleminet C, et al. Incidence of drug-induced hepatic injuries: a French population-based study. Hepatology. 2002;36(2):451–5. https://doi.org/10.1053/jhep.2002.34857.CrossRefPubMed

Reuben A, Koch DG, Lee WM, Acute Liver Failure Study G. Drug-induced acute liver failure: results of a U.S. multicenter, prospective study. Hepatology. 2010;52(6):2065–76. https://doi.org/10.1002/hep.23937. CrossRefPubMedPubMedCentral

Fontana RJ. Pathogenesis of idiosyncratic drug-induced liver injury and clinical perspectives. Gastroenterology. 2014;146(4):914–28. https://doi.org/10.1053/j.gastro.2013.12.032.CrossRefPubMed

•• Kullak-Ublick GA, Andrade RJ, Merz M, End P, Benesic A, Gerbes AL, et al. Drug-induced liver injury: recent advances in diagnosis and risk assessment. Gut. 2017;66(6):1154–64. https://doi.org/10.1136/gutjnl-2016-313369. An article highlighting recent advances in idiosyncratic drug-induced liver injury covering topics such as genetic risk assessment, new emerging biomarkers, and in vitro test systems. CrossRefPubMedPubMedCentral

Kaplowitz N. Idiosyncratic drug hepatotoxicity. Nat Rev Drug Discov. 2005;4(6):489–99. https://doi.org/10.1038/nrd1750.CrossRefPubMed

Verma S, Kaplowitz N. Diagnosis, management and prevention of drug-induced liver injury. Gut. 2009;58(11):1555–64. https://doi.org/10.1136/gut.2008.163675.CrossRefPubMed

Gunawan BK, Kaplowitz N. Mechanisms of drug-induced liver disease. Clin Liver Dis. 2007;11(3):459–75. https://doi.org/10.1016/j.cld.2007.06.001. vCrossRefPubMed

•• deLemos AS, Foureau DM, Jacobs C, Ahrens W, Russo MW, Bonkovsky HL. Drug-induced liver injury with autoimmune features. Semin Liver Dis. 2014;34(2):194–204. https://doi.org/10.1055/s-0034-1375959. A review focusing on drug-induced liver injury with features of autoimmunity. CrossRefPubMed

10.

Castiella A, Zapata E, Lucena MI, Andrade RJ. Drug-induced autoimmune liver disease: a diagnostic dilemma of an increasingly reported disease. World J Hepatol. 2014;6(4):160–8. https://doi.org/10.4254/wjh.v6.i4.160.CrossRefPubMedPubMedCentral

11.

Russmann S, Kullak-Ublick GA, Grattagliano I. Current concepts of mechanisms in drug-induced hepatotoxicity. Curr Med Chem. 2009;16(23):3041–53.CrossRef

12.

Liu ZX, Kaplowitz N. Immune-mediated drug-induced liver disease. Clin Liver Dis. 2002;6(3):755–74.CrossRef

13.

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. https://doi.org/10.1021/tx980249i.CrossRefPubMed

14.

Vergani D, Mieli-Vergani G, Alberti A, Neuberger J, Eddleston AL, Davis M, et al. Antibodies to the surface of halothane-altered rabbit hepatocytes in patients with severe halothane-associated hepatitis. N Engl J Med. 1980;303(2):66–71. https://doi.org/10.1056/NEJM198007103030202.CrossRefPubMed

15.

Ju C, Reilly T. Role of immune reactions in drug-induced liver injury (DILI). Drug Metab Rev. 2012;44(1):107–15. https://doi.org/10.3109/03602532.2011.645579.CrossRefPubMed

16.

Pichler WJ. Direct T-cell stimulations by drugs—bypassing the innate immune system. Toxicology. 2005;209(2):95–100. https://doi.org/10.1016/j.tox.2004.12.014.CrossRefPubMed

17.

Schnyder B, Burkhart C, Schnyder-Frutig K, von Greyerz S, Naisbitt DJ, Pirmohamed M, et al. Recognition of sulfamethoxazole and its reactive metabolites by drug-specific CD4+ T cells from allergic individuals. J Immunol. 2000;164(12):6647–54.CrossRef

18.

Naisbitt DJ, Britschgi M, Wong G, Farrell J, Depta JP, Chadwick DW, et al. Hypersensitivity reactions to carbamazepine: characterization of the specificity, phenotype, and cytokine profile of drug-specific T cell clones. Mol Pharmacol. 2003;63(3):732–41.CrossRef

19.

• Selvaraj S, Oh JH, Spanel R, Langer F, Han HY, Lee EH, et al. The pathogenesis of diclofenac induced immunoallergic hepatitis in a canine model of liver injury. Oncotarget. 2017;8(64):107763–824. https://doi.org/10.18632/oncotarget.21201. A canine pathogenesis model of diclofenac-induced immunoallergic hepatitis. CrossRefPubMedPubMedCentral

20.

•• Foureau DM, Walling TL, Maddukuri V, Anderson W, Culbreath K, Kleiner DE, et al. Comparative analysis of portal hepatic infiltrating leucocytes in acute drug-induced liver injury, idiopathic autoimmune and viral hepatitis. Clin Exp Immunol. 2015;180(1):40–51. https://doi.org/10.1111/cei.12558. A study characterizing the inflammatory infiltrate in patients with immune-allergic and autoimmune drug-induced liver injury. CrossRefPubMedPubMedCentral

21.

Chakraborty M, Fullerton AM, Semple K, Chea LS, Proctor WR, Bourdi M, et al. Drug-induced allergic hepatitis develops in mice when myeloid-derived suppressor cells are depleted prior to halothane treatment. Hepatology. 2015;62(2):546–57. https://doi.org/10.1002/hep.27764.CrossRefPubMed

22.

Sebode M, Schulz L, Lohse AW. “Autoimmune(-like)” drug and herb induced liver injury: new insights into molecular pathogenesis. Int J Mol Sci. 2017;18(9) https://doi.org/10.3390/ijms18091954.

23.

•• Chalasani NP, Hayashi PH, Bonkovsky HL, Navarro VJ, Lee WM, Fontana RJ et al. ACG clinical guideline: the diagnosis and management of idiosyncratic drug-induced liver injury. Am J Gastroenterol 2014;109(7):950–966; quiz 67. https://doi.org/10.1038/ajg.2014.131. American college of gastroenterology guidelines on the diagnosis and management of idiosyncratic drug-induced liver injury. CrossRef

24.

Czaja AJ. Drug-induced autoimmune-like hepatitis. Dig Dis Sci. 2011;56(4):958–76. https://doi.org/10.1007/s10620-011-1611-4.CrossRefPubMed

25.

Aithal GP. Pharmacogenetic testing in idiosyncratic drug-induced liver injury: current role in clinical practice. Liver Int. 2015;35(7):1801–8. https://doi.org/10.1111/liv.12836.CrossRefPubMed

26.

Rieder MJ, Shear NH, Kanee A, Tang BK, Spielberg SP. Prominence of slow acetylator phenotype among patients with sulfonamide hypersensitivity reactions. Clin Pharmacol Ther. 1991;49(1):13–7.CrossRef

27.

Beaune PH, Lecoeur S. Immunotoxicology of the liver: adverse reactions to drugs. J Hepatol. 1997;26(Suppl 2):37–42.CrossRef

28.

Neuberger J, Williams R. Immune mechanisms in tienilic acid associated hepatotoxicity. Gut. 1989;30(4):515–9.CrossRef

29.

Mallal S, Nolan D, Witt C, Masel G, Martin AM, Moore C, et al. Association between presence of HLA-B*5701, HLA-DR7, and HLA-DQ3 and hypersensitivity to HIV-1 reverse-transcriptase inhibitor abacavir. Lancet. 2002;359(9308):727–32.CrossRef

30.

Mallal S, Phillips E, Carosi G, Molina JM, Workman C, Tomazic J, et al. HLA-B*5701 screening for hypersensitivity to abacavir. N Engl J Med. 2008;358(6):568–79. https://doi.org/10.1056/NEJMoa0706135.CrossRefPubMed

31.

Alfirevic A, Park BK, Pirmohamed M, Naisbitt DJ. Explanation for HLA-B*57:01-linked immune-mediated abacavir-induced hypersensitivity. Pharmacogenomics. 2012;13(14):1567–9. https://doi.org/10.2217/pgs.12.146. CrossRefPubMed

32.

Alfirevic A, Pirmohamed M. Predictive genetic testing for drug-induced liver injury: considerations of clinical utility. Clin Pharmacol Ther. 2012;92(3):376–80. https://doi.org/10.1038/clpt.2012.107.CrossRefPubMed

33.

•• Hisamochi A, Kage M, Ide T, Arinaga-Hino T, Amano K, Kuwahara R, et al. An analysis of drug-induced liver injury, which showed histological findings similar to autoimmune hepatitis. J Gastroenterol. 2016;51(6):597–607. https://doi.org/10.1007/s00535-015-1131-7. An analysis of histological findings of drug-induced liver injury with and without autoimmune hepatitis features. CrossRefPubMed

34.

•• de Boer YS, Kosinski AS, Urban TJ, Zhao Z, Long N, Chalasani N, et al. Features of autoimmune hepatitis in patients with drug-induced liver injury. Clin Gastroenterol Hepatol. 2017;15(1):103–12 e2. https://doi.org/10.1016/j.cgh.2016.05.043. An in-depth analysis of DILI attributed to nitrofurantoin, minocycline, methyldopa, and hydralazine with special focus on autoimmunity CrossRefPubMed

35.

Bjornsson E, Aithal G. Immune-mediated drug-induced liver injury. Liver Immunology. Springer International Publishing; 2014.

36.

Ghabril M, Bonkovsky HL, Kum C, Davern T, Hayashi PH, Kleiner DE, et al. Liver injury from tumor necrosis factor-alpha antagonists: analysis of thirty-four cases. Clin Gastroenterol Hepatol. 2013;11(5):558–64 e3. https://doi.org/10.1016/j.cgh.2012.12.025.CrossRefPubMed

37.

• Russo MW, Hoofnagle JH, Gu J, Fontana RJ, Barnhart H, Kleiner DE, et al. Spectrum of statin hepatotoxicity: experience of the drug-induced liver injury network. Hepatology. 2014;60(2):679–86. https://doi.org/10.1002/hep.27157. An article reviewing the spectrum of drug-induced liver injury from statins. CrossRefPubMedPubMedCentral

38.

• Fujii Y, Uchida Y, Mochida S. Drug-induced immunoallergic hepatitis during combination therapy with daclatasvir and asunaprevir. Hepatology. 2015;61(1):400–1. https://doi.org/10.1002/hep.27559. A first-case report on immunoallergic drug-induced liver injury by the hepatitis C combination treatment with daclatasvir and asunaprevir. CrossRefPubMed

39.

Mirza S, Hill E, Ludlow SP, Nanjappa S. Checkpoint inhibitor-associated drug reaction with eosinophilia and systemic symptom syndrome. Melanoma Res. 2017;27(3):271–3. https://doi.org/10.1097/CMR.0000000000000326. CrossRefPubMed

40.

Diseases NIoDaDaK. LiverTox: clinical and research information on drug-induced liver injury. http://www.livertox.nih.gov/. Accessed May 16, 2018.

41.

Bjornsson E, Talwalkar J, Treeprasertsuk S, Kamath PS, Takahashi N, Sanderson S, et al. Drug-induced autoimmune hepatitis: clinical characteristics and prognosis. Hepatology. 2010;51(6):2040–8. https://doi.org/10.1002/hep.23588.CrossRefPubMed

42.

Schneider JS, Montani M, Stickel F. Drug-induced autoimmune hepatitis following treatment with zoledronic acid. Case Rep Gastroenterol. 2017;11(2):440–5. https://doi.org/10.1159/000479314.CrossRefPubMedPubMedCentral

43.

De Martin E, Michot JM, Papouin B, Champiat S, Mateus C, Lambotte O, et al. Characterization of liver injury induced by cancer immunotherapy using immune checkpoint inhibitors. J Hepatol. 2018;68:1181–90. https://doi.org/10.1016/j.jhep.2018.01.033.CrossRefPubMed

44.

Oh HJ, Mok YM, Baek MS, Lee JK, Seo BS, Kim TH, et al. Co-development of autoimmune hepatitis and Sjogren’s syndrome triggered by the administration of herbal medicines. Clin Mol Hepatol. 2013;19(3):305–8. https://doi.org/10.3350/cmh.2013.19.3.305.CrossRefPubMedPubMedCentral

45.

von Felden J, Montani M, Kessebohm K, Stickel F. Drug-induced acute liver injury mimicking autoimmune hepatitis after intake of dietary supplements containing glucosamine and chondroitin sulfate. Int J Clin Pharmacol Ther. 2013;51(3):219–23. https://doi.org/10.5414/CP201835.CrossRef

46.

Franco DL, Kale S, Lam-Himlin DM, Harrison ME. Black cohosh hepatotoxicity with autoimmune hepatitis presentation. Case Rep Gastroenterol. 2017;11(1):23–8. https://doi.org/10.1159/000452735.CrossRefPubMedPubMedCentral

47.

Castell JV, Castell M. Allergic hepatitis induced by drugs. Curr Opin Allergy Clin Immunol. 2006;6(4):258–65. https://doi.org/10.1097/01.all.0000235898.80052.80.CrossRefPubMed

48.

•• Chalasani N, Bonkovsky HL, Fontana R, Lee W, Stolz A, Talwalkar J, et al. Features and outcomes of 899 patients with drug-induced liver injury: the DILIN Prospective Study. Gastroenterology. 2015;148(7):1340–52 e7. https://doi.org/10.1053/j.gastro.2015.03.006. A prospective study from the DILI network that highlights features and outcomes of patients with drug-induced liver injury. CrossRefPubMedPubMedCentral

49.

Lee WM. Drug-induced hepatotoxicity. N Engl J Med. 1995;333(17):1118–27. https://doi.org/10.1056/NEJM199510263331706.CrossRefPubMed

50.

Chang CY, Schiano TD. Review article: drug hepatotoxicity. Aliment Pharmacol Ther. 2007;25(10):1135–51. https://doi.org/10.1111/j.1365-2036.2007.03307.x.CrossRefPubMed

51.

Andrade RJ, Lucena MI, Kaplowitz N, Garcia-Munoz 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. https://doi.org/10.1002/hep.21424.CrossRefPubMed

52.

Hussaini SH, Farrington EA. Idiosyncratic drug-induced liver injury: an update on the 2007 overview. Expert Opin Drug Saf. 2014;13(1):67–81. https://doi.org/10.1517/14740338.2013.828032.CrossRefPubMed

53.

Bjornsson ES, Bergmann O, Jonasson JG, Grondal G, Gudbjornsson B, Olafsson S. Drug-induced autoimmune hepatitis: response to corticosteroids and lack of relapse after cessation of steroids. Clin Gastroenterol Hepatol. 2017;15(10):1635–6. https://doi.org/10.1016/j.cgh.2017.05.027.CrossRefPubMed

54.

Hisamochi A, Kage M, Arinaga T, Ide T, Miyajima I, Ogata K, et al. Drug-induced liver injury associated with Agaricus blazei Murill which is very similar to autoimmune hepatitis. Clin J Gastroenterol. 2013;6(2):139–44. https://doi.org/10.1007/s12328-013-0359-0.CrossRefPubMed

55.

• Kleiner DE. Histopathological challenges in suspected drug-induced liver injury. Liver Int. 2018;38(2):198–209. https://doi.org/10.1111/liv.13584. A review on the histopathological challenges in suspected drug-induced liver injury. CrossRefPubMed

56.

Ramachandran R, Kakar S. Histological patterns in drug-induced liver disease. J Clin Pathol. 2009;62(6):481–92. https://doi.org/10.1136/jcp.2008.058248.CrossRefPubMed

57.

Kleiner DE. The histopathological evaluation of drug-induced liver injury. Histopathology. 2017;70(1):81–93. https://doi.org/10.1111/his.13082.CrossRefPubMed

58.

Khoury T, Rmeileh AA, Yosha L, Benson AA, Daher S, Mizrahi M. Drug induced liver injury: review with a focus on genetic factors, tissue diagnosis, and treatment options. J Clin Transl Hepatol. 2015;3(2):99–108. https://doi.org/10.14218/JCTH.2015.00007.CrossRefPubMedPubMedCentral

59.

Suzuki A, Brunt EM, Kleiner DE, Miquel R, Smyrk TC, Andrade RJ, et al. The use of liver biopsy evaluation in discrimination of idiopathic autoimmune hepatitis versus drug-induced liver injury. Hepatology. 2011;54(3):931–9. https://doi.org/10.1002/hep.24481.CrossRefPubMedPubMedCentral

60.

Kleiner DE, Chalasani NP, Lee WM, Fontana RJ, Bonkovsky HL, Watkins PB, et al. 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.CrossRefPubMed

61.

Navarro VJ, Senior JR. Drug-related hepatotoxicity. N Engl J Med. 2006;354(7):731–9. https://doi.org/10.1056/NEJMra052270.CrossRefPubMed

62.

Ahmad J, Odin JA, Hayashi PH, Chalasani N, Fontana RJ, Barnhart H, et al. Identification and characterization of fenofibrate-induced liver injury. Dig Dis Sci. 2017;62(12):3596–604. https://doi.org/10.1007/s10620-017-4812-7.CrossRefPubMed

63.

Chalasani N, Fontana RJ, Bonkovsky HL, Watkins PB, Davern T, Serrano J, et al. Causes, clinical features, and outcomes from a prospective study of drug-induced liver injury in the United States. Gastroenterology. 2008;135(6):1924–34. https://doi.org/10.1053/j.gastro.2008.09.011. 34 e1-4CrossRefPubMedPubMedCentral

64.

Hunt CM, Papay JI, Stanulovic V, Regev A. Drug rechallenge following drug-induced liver injury. Hepatology. 2017;66(2):646–54. https://doi.org/10.1002/hep.29152.CrossRefPubMed

65.

Paiva LA, Wright PJ, Koff RS. Long-term hepatic memory for hypersensitivity to nitrofurantoin. Am J Gastroenterol. 1992;87(7):891–3.PubMed

66.

Giannattasio A, D’Ambrosi M, Volpicelli M, Iorio R. Steroid therapy for a case of severe drug-induced cholestasis. Ann Pharmacother. 2006;40(6):1196–9. https://doi.org/10.1345/aph.1G345.CrossRefPubMed

67.

• Goldstein NS, Bayati N, Silverman AL, Gordon SC. Minocycline as a cause of drug-induced autoimmune hepatitis. Report of four cases and comparison with autoimmune hepatitis. Am J Clin Pathol. 2000;114(4):591–8. https://doi.org/10.1309/KV2J-VX6Q-L95V-VDE4. Case series of minocycline-induced autoimmune hepatitis. CrossRefPubMed

Title: Drug-Induced Liver Injury: Understanding the Different Immune-Mediated Phenotypes and Clinical Management
Authors: Ben L. Da
Gil Ben-Yakov
David Kleiner
Christopher Koh
Publication date: 01-09-2018
Publisher: Springer US
Published in: Current Hepatology Reports / Issue 3/2018
Electronic ISSN: 2195-9595
DOI: https://doi.org/10.1007/s11901-018-0407-9

ACC 2024 Congress Coverage

Heart Failure Video

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Drug-Induced Liver Injury: Understanding the Different Immune-Mediated Phenotypes and Clinical Management

Abstract

Purpose of Review

Recent Findings

Summary

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Purpose of Review

Recent Findings

Summary

Please log in to get access to this content

Other articles of this Issue 3/2018

Knowns and Unknowns: the Safety and Efficacy of Cancer Immunotherapy in Chronic Liver Disease

Long-Term Outcomes After Drug-Induced Liver Injury

Is Exercise Beneficial and Safe in Patients with Cirrhosis and Portal Hypertension?

The Role of Anticoagulation in Treating Portal Hypertension

DILI Associated with Skin Reactions

Extrahepatic Manifestations of Chronic Hepatitis B Infection

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page