Skip to main content

Advertisement

Log in

Uncommon Presentations of Idiosyncratic Drug-Induced Liver Injury

  • Drug-Induced Liver Injury (NP Chalasani and MS Ghabril, Section Editors)
  • Published:
Current Hepatology Reports Aims and scope Submit manuscript

Abstract

Purpose of Review

Idiosyncratic drug-induced liver injury (DILI) typically presents acutely with liver test abnormalities, sometimes with associated symptoms of abdominal pain, nausea, vomiting, jaundice, fevers, and rash. Histologic abnormalities in such cases of DILI typically range from lobular or portal hepatitis to hepatocyte necrosis. However, sometimes the drug-related liver injuries present with clinical and/or histological features atypical of garden variety DILI and they may be related to uncommon mechanisms of injury, histologic features, or clinical presentation.

Recent Findings

Multiple agents or classes of agents can result in uncommon forms of liver injury that are phenotypically unique and differ from commonly recognized acute DILI. These include unusual presentations of drugs commonly associated with typical acute DILI, such as drug-induced autoimmune hepatitis. Atypical DILI also includes histologically atypical manifestations of DILI, such as nodular regenerative hyperplasia, sinusoidal obstruction syndrome, granulomatous hepatitis, and steatosis/steatohepatitis.

Summary

Atypical DILI encompasses recognized patterns of injury associated with specific agents or drug classes. These can manifest by atypical biochemical, clinical, and histopathological signatures. An understanding of these types of liver injury is important for the timely recognition of such atypical DILI.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

Abbreviations

DILI:

Drug-induced liver injury

DILIN:

Drug-Induced Liver Injury Network

NRH:

Nodular regenerative hyperplasia

SOS:

Sinusoidal obstruction syndrome

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major Importance

  1. Chalasani N, Bonkovsky HL, Fontana R, Lee W, Stolz A, Talwalkar J, Reddy KR, Watkins PB, Navarro V, Barnhart H, Gu J, Serrano J, Ahmad J, Bach N, Bansal M, Barnhart HX, Beavers K, Bonkovsky H, Calvo FO, Chalasani N, Chang C, Conjeevaram H, Conner G, Darling J, de Boer Y, Dieterich D, DiPaola F, Durazo FA, (Jay) Everhart JE, Fontana RJ, Ghabril MS, Goldstein D, Gopalreddy V, Grewal P, Hayashi PH, Hoofnagle J, Kaplowitz N, Liangpunsakul S, Lichtman S, Liu L, Navarro VJ, Odin J, Rossi S, Russo M, Schiano T, Serrano J, Sherker AH, Stolz A, Vuppalanchi R, Watkins P, Zacks S, Balasco A, Chesney K, Corne A, Cummings S, Groseclose G, Hammett A, Hooker J, Kesar V, Mao S, Marks K, McFadden R, Melgoza Y, Mikhail S, Milstein S, Morlan W, Peacock V, Rosado N, Russell T, Vega M, Verma M, Walker P, Yalamanchili R, McClanahan-Crowder M, Galan K, (Sherry) Gu J, Chau T, Ragavan K, Rostami H, Puglisi-Scharenbroich C, Torrance RJ, van Raaphorst R Features and outcomes of 899 patients with drug-induced liver injury: the DILIN prospective study. Gastroenterology 2015;148:1340–1352 e7.

    Article  Google Scholar 

  2. Chalasani N, Fontana RJ, Bonkovsky HL, Watkins PB, Davern T, Serrano J, Yang H, Rochon J, Drug Induced Liver Injury Network (DILIN) Causes, clinical features, and outcomes from a prospective study of drug-induced liver injury in the United States. Gastroenterology 2008;135:1924–34, 1934 e1–4, 1934.e4.

    Article  Google Scholar 

  3. Chalasani NP, Hayashi PH, Bonkovsky HL, et al. ACG clinical guideline: the diagnosis and management of idiosyncratic drug-induced liver injury. Am J Gastroenterol 2014;109:950–66; quiz 967, 966.

    Article  Google Scholar 

  4. Haque T, Sasatomi E, Hayashi PH. Drug-induced liver injury: pattern recognition and future directions. Gut Liver. 2016;10:27–36.

    Article  Google Scholar 

  5. Padda MS, Sanchez M, Akhtar AJ, Boyer JL. Drug-induced cholestasis. Hepatology. 2011;53:1377–87.

    Article  CAS  Google Scholar 

  6. Martinez MA, Vuppalanchi R, Fontana RJ, Stolz A, Kleiner DE, Hayashi PH, Gu J, Hoofnagle JH, Chalasani N Clinical and histologic features of azithromycin-induced liver injury. Clin Gastroenterol Hepatol 2015;13:369–376 e3, 376.e3.

    Article  Google Scholar 

  7. Vuppalanchi R, Hayashi PH, Chalasani N, Fontana RJ, Bonkovsky H, Saxena R, et al. Duloxetine hepatotoxicity: a case-series from the drug-induced liver injury network. Aliment Pharmacol Ther. 2010;32:1174–83.

    Article  CAS  Google Scholar 

  8. Kleiner DECN, Conjeevaram HS, Bonkovsky H, Russo M, Davern T, McHutchison JG, et al. B for the drug-induced liver injury network (DILIN). Relationship of biochemical variables to histologic findings and the pathological pattern of injury among cases identified in the NIH DILIN study. Gastroenterology. 2007;132

  9. • 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;59:661–70. This paper summarized the myriad hisotologic presentations of DILI as seen in the course of prospective study.

    Article  Google Scholar 

  10. Rochon J, Protiva P, Seeff LB, Fontana RJ, Liangpunsakul S, Watkins PB, et al. Reliability of the Roussel Uclaf causality assessment method for assessing causality in drug-induced liver injury. Hepatology. 2008;48:1175–83.

    Article  Google Scholar 

  11. Fontana RJ, Hayashi PH, Barnhart H, et al. Persistent liver biochemistry abnormalities are more common in older patients and those with cholestatic drug induced liver injury. Am J Gastroenterol. 2015;110:1450–9.

    Article  CAS  Google Scholar 

  12. Elsharkawy AM, McPherson S, Masson S, Burt AD, Dawson RT, Hudson M. Cholestasis secondary to anabolic steroid use in young men. BMJ. 2012;344:e468.

    Article  Google Scholar 

  13. Robles-Diaz M, Gonzalez-Jimenez A, Medina-Caliz I, Stephens C, García-Cortes M, García-Muñoz B, et al. Distinct phenotype of hepatotoxicity associated with illicit use of anabolic androgenic steroids. Aliment Pharmacol Ther. 2015;41:116–25.

    Article  CAS  Google Scholar 

  14. Czaja AJ. Drug-induced autoimmune-like hepatitis. Dig Dis Sci. 2011;56:958–76.

    Article  CAS  Google Scholar 

  15. Czaja AJ. Acute and acute severe (fulminant) autoimmune hepatitis. Dig Dis Sci. 2013;58:897–914.

    Article  CAS  Google Scholar 

  16. Czaja AJ. Review article: the management of autoimmune hepatitis beyond consensus guidelines. Aliment Pharmacol Ther. 2013;38:343–64.

    Article  CAS  Google Scholar 

  17. Czaja AJ, Carpenter HA. Progressive fibrosis during corticosteroid therapy of autoimmune hepatitis. Hepatology. 2004;39:1631–8.

    Article  Google Scholar 

  18. Iqbal U, Siddiqui HU, Anwar H, et al. Allopurinol-induced granulomatous hepatitis: a case report and review of literature. J Investig Med High Impact Case Rep. 2017;5:2324709617728302.

    PubMed  PubMed Central  Google Scholar 

  19. Marin Zuluaga JI, Marin Castro AE, Perez Cadavid JC, Restrepo Gutierrez JC. Albendazole-induced granulomatous hepatitis: a case report. J Med Case Rep. 2013;7:201.

    Article  Google Scholar 

  20. Adike A, Smith ML, Chervenak A, Vargas HE. Hydroxycut-related vanishing bile duct syndrome. Clin Gastroenterol Hepatol. 2017;15:142–4.

    Article  Google Scholar 

  21. Balakrishnan A, Ledford R, Jaglal M. Temozolomide-induced biliary ductopenia: a case report. J Med Case Rep. 2016;10:33.

    Article  Google Scholar 

  22. Bhayana H, Appasani S, Thapa BR, Das A, Singh K. Lamotrigine-induced vanishing bile duct syndrome in a child. J Pediatr Gastroenterol Nutr. 2012;55:e147–8.

    Article  Google Scholar 

  23. Bjornsson ES, Jonasson JG. Idiosyncratic drug-induced liver injury associated with bile duct loss and vanishing bile duct syndrome: rare but has severe consequences. Hepatology. 2017;65:1091–3.

    Article  Google Scholar 

  24. • Bonkovsky HL, Kleiner DE, Gu J, Odin JA, Russo MW, Navarro VM, et al. Clinical presentations and outcomes of bile duct loss caused by drugs and herbal and dietary supplements. Hepatology. 2017;65:1267–77. This recent study describes the evolution of vanishing bile duct syndrome in the ourse of drug-induced liver injury and highlights the prognostic impact of the degree of ductpenia.

    Article  CAS  Google Scholar 

  25. Robinson W, Habr F, Manlolo J, Bhattacharya B. Moxifloxacin associated vanishing bile duct syndrome. J Clin Gastroenterol. 2010;44:72–3.

    Article  Google Scholar 

  26. Schumaker AL, Okulicz JF. Meropenem-induced vanishing bile duct syndrome. Pharmacotherapy. 2010;30:953.

    Article  Google Scholar 

  27. Tekin F, Celik F, Nart D, Akarca U. The first report of oxcarbazepine-induced vanishing bile duct syndrome. J Gastrointestin Liver Dis. 2014;23:222–3.

    PubMed  Google Scholar 

  28. Vuppalanchi R, Chalasani N, Saxena R. Restoration of bile ducts in drug-induced vanishing bile duct syndrome due to zonisamide. Am J Surg Pathol. 2006;30:1619–23.

    Article  Google Scholar 

  29. Nijhawan R, Wierzbicki AS, Tozer R, Lascelles PT, Patsalos PN. Antiepileptic drugs, hepatic enzyme induction and raised serum alkaline phosphatase isoenzymes. Int J Clin Pharmacol Res. 1990;10:319–23.

    CAS  PubMed  Google Scholar 

  30. Murphy JV. Valproate-induced hyperammonemic encephalopathy. Epilepsia. 2003;44:268. author reply 268

    Article  Google Scholar 

  31. Satapathy SK, Kuwajima V, Nadelson J, Atiq O, Sanyal A. Drug-induced fatty liver disease: an overview of pathogenesis and management. Ann Hepatol. 2015;14:789–806.

    Article  CAS  Google Scholar 

  32. Amacher DE, Chalasani N. Drug-induced hepatic steatosis. Semin Liver Dis. 2014;34:205–14.

    Article  CAS  Google Scholar 

  33. Ryan P, Nanji S, Pollett A, Moore M, Moulton CA, Gallinger S, et al. Chemotherapy-induced liver injury in metastatic colorectal cancer: semiquantitative histologic analysis of 334 resected liver specimens shows that vascular injury but not steatohepatitis is associated with preoperative chemotherapy. Am J Surg Pathol. 2010;34:784–91.

    Article  Google Scholar 

  34. Dash A, Figler RA, Sanyal AJ, Wamhoff BR. Drug-induced steatohepatitis. Expert Opin Drug Metab Toxicol. 2017;13:193–204.

    Article  CAS  Google Scholar 

  35. Cupido AJ, Reeskamp LF, Kastelein JJP. Novel lipid modifying drugs to lower LDL cholesterol. Curr Opin Lipidol. 2017;28:367–73.

    Article  CAS  Google Scholar 

  36. Gouni-Berthold I, Berthold HK. Mipomersen and lomitapide: two new drugs for the treatment of homozygous familial hypercholesterolemia. Atheroscler Suppl. 2015;18:28–34.

    Article  Google Scholar 

  37. Miyares MA. Progression to hepatitis and fibrosis secondary to lomitapide use: selecting the next course of action. JAMA Intern Med. 2014;174:1522.

    Article  Google Scholar 

  38. Rader DJ, Kastelein JJ. Lomitapide and mipomersen: two first-in-class drugs for reducing low-density lipoprotein cholesterol in patients with homozygous familial hypercholesterolemia. Circulation. 2014;129:1022–32.

    Article  Google Scholar 

  39. Ishak KG. Hepatic lesions caused by anabolic and contraceptive steroids. Semin Liver Dis. 1981;1:116–28.

    Article  CAS  Google Scholar 

  40. Laurent A, Dokmak S, Nault JC, Pruvot FR, Fabre JM, Letoublon C, et al. European experience of 573 liver resections for hepatocellular adenoma: a cross-sectional study by the AFC-HCA-2013 study group. HPB (Oxford). 2016;18:748–55.

    Article  Google Scholar 

  41. Nault JC, Bioulac-Sage P, Zucman-Rossi J. Hepatocellular benign tumors-from molecular classification to personalized clinical care. Gastroenterology. 2013;144:888–902.

    Article  CAS  Google Scholar 

  42. Nault JC, Paradis V, Cherqui D, Vilgrain V, Zucman-Rossi J. Molecular classification of hepatocellular adenoma in clinical practice. J Hepatol. 2017;67:1074–83.

    Article  CAS  Google Scholar 

  43. Mays ET, Christopherson W. Hepatic tumors induced by sex steroids. Semin Liver Dis. 1984;4:147–57.

    Article  CAS  Google Scholar 

  44. van Aalten SM, de Man RA, JN IJ, et al. Systematic review of haemorrhage and rupture of hepatocellular adenomas. Br J Surg. 2012;99:911–6.

    Article  Google Scholar 

  45. Kudo M. Malignant transformation of hepatocellular adenoma: how frequently does it happen? Liver Cancer. 2015;4:1–5.

    Article  CAS  Google Scholar 

  46. Kwok WY, Hagiwara S, Nishida N, Watanabe T, Sakurai T, Ida H, et al. Malignant transformation of hepatocellular adenoma. Oncology. 2017;92(Suppl 1):16–28.

    Article  Google Scholar 

  47. Torbenson M. Hepatic adenomas: classification, controversies, and consensus. Surg Pathol Clin. 2018;11:351–66.

    Article  Google Scholar 

  48. Shapiro P, Ikeda RM, Ruebner BH, Connors MH, Halsted CC, Abildgaard CF. Multiple hepatic tumors and peliosis hepatis in Fanconi's anemia treated with androgens. Am J Dis Child. 1977;131:1104–6.

    CAS  PubMed  Google Scholar 

  49. https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm279174.htm. Volume 2017: FDA, 2017.

  50. 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:e9–e12.

    Article  Google Scholar 

  51. Vuppalanchi R, Saxena R, Storniolo AMV, Chalasani N. Pseudocirrhosis and liver failure in patients with metastatic breast cancer after treatment with palbociclib. Hepatology. 2017;65:1762–4.

    Article  Google Scholar 

  52. Hillaire S, Bonte E, Denninger MH, Casadevall N, Cadranel JF, Lebrec D, et al. Idiopathic non-cirrhotic intrahepatic portal hypertension in the west: a re-evaluation in 28 patients. Gut. 2002;51:275–80.

    Article  CAS  Google Scholar 

  53. Steiner PE. Nodular regenerative hyperplasia of the liver. Am J Pathol. 1959;35:943–53.

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Nakanuma Y, Hoso M, Sasaki M, et al. Histopathology of the liver in non-cirrhotic portal hypertension of unknown aetiology. Histopathology. 1996;28:195–204.

    Article  CAS  Google Scholar 

  55. Shastri S, Dubinsky MC, Fred Poordad F, Vasiliauskas EA, Geller SA. Early nodular hyperplasia of the liver occurring with inflammatory bowel diseases in association with thioguanine therapy. Arch Pathol Lab Med. 2004;128:49–53.

    PubMed  Google Scholar 

  56. Hartleb M, Gutkowski K, Milkiewicz P. Nodular regenerative hyperplasia: evolving concepts on underdiagnosed cause of portal hypertension. World J Gastroenterol. 2011;17:1400–9.

    Article  Google Scholar 

  57. Naber AH, Van Haelst U, Yap SH. Nodular regenerative hyperplasia of the liver: an important cause of portal hypertension in non-cirrhotic patients. J Hepatol. 1991;12:94–9.

    Article  CAS  Google Scholar 

  58. • Ghabril M, Vuppalanchi R. Drug-induced nodular regenerative hyperplasia. Semin Liver Dis 2014;34:240–5. The broad range of agents associated with nodular regenerative hyperplasia are described

    Article  CAS  Google Scholar 

  59. • DeLeve LD, Shulman HM, McDonald GB. Toxic injury to hepatic sinusoids: sinusoidal obstruction syndrome (veno-occlusive disease). Semin Liver Dis. 2002;22:27–42. This increasingly recognized form of drug-induced liver injury is unusual in its presentation and is well summarized in this review paper.

    Article  Google Scholar 

  60. Kumar S, DeLeve LD, Kamath PS, et al. Hepatic veno-occlusive disease (sinusoidal obstruction syndrome) after hematopoietic stem cell transplantation. Mayo Clin Proc. 2003;78:589–98.

    Article  Google Scholar 

  61. DeLeve LD, Valla DC, Garcia-Tsao G. Vascular disorders of the liver. Hepatology. 2009;49:1729–64.

    Article  CAS  Google Scholar 

  62. Hoofnagle JH, Serrano J, Knoben JE, Navarro VJ. LiverTox: a website on drug-induced liver injury. Hepatology. 2013;57:873–4.

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Raj Vuppalanchi.

Ethics declarations

Conflict of Interest

Raj Vuppalanchi and Marwan Ghabril declare no conflicts of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Additional information

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

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Vuppalanchi, R., Ghabril, M. Uncommon Presentations of Idiosyncratic Drug-Induced Liver Injury. Curr Hepatology Rep 17, 254–259 (2018). https://doi.org/10.1007/s11901-018-0417-7

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11901-018-0417-7

Keywords

Navigation