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Current Gastroenterology Reports

, Volume 13, Issue 1, pp 65–71 | Cite as

Idiosyncratic Drug-Induced Liver Injury: A Clinical Update

  • Haripriya Maddur
  • Naga ChalasaniEmail author
Article

Abstract

Drug-induced liver injury (DILI) is a rare but potentially devastating adverse drug reaction. Its presentation can range from asymptomatic elevation in liver biochemistries to fulminant liver failure. Over the past decade, clinical and research interest in the field of idiosyncratic DILI has been intense, and several new findings have been reported. In this article, we provide an update on implicated agents, clinical features, outcomes, and the results of recently reported genetic studies.

Keywords

Drug-induced liver injury (DILI) Genome-wide association studies Drug-Induced Liver Injury Network (DILIN) 

Notes

Disclosure

Conflicts of interest: H. Maddur—none; N. Chalasani—consulting fees from KaroBio, Amylin, Gilead, Genentech, Teva, Norgine, Ockham Development (general consulting related to clinical trials), Abbott, Salix, Phenomix, Medpace, AstraZeneca, Gilead, and Lilly.

References

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

  1. 1.
    Larson AM, Polson J, Fontana RJ, et al.: Acetaminophen-induced acute liver failure: results of a United States multi-center, prospective study. Hepatology 2005, 42:1364–1372.CrossRefPubMedGoogle Scholar
  2. 2.
    Larrey D: Epidemiology and individual susceptibility to adverse drug reactions affecting the liver. Semin Liver Dis 2002, 22:145–155.CrossRefPubMedGoogle Scholar
  3. 3.
    • Chalasani N, Fontana RJ, Herbert L, et al.: Causes, clinical features, and outcomes from a prospective study of drug-Induced liver injury in the United States. Gastroenterology 2008, 135:1924–1934. This paper reports preliminary findings of an ongoing study (nearly 800 patients enrolled) conducted in the United States. This study confirmed that DILI with jaundice carries high mortality. A surprising finding of this study is that about 0.5% of enrolled patients had unsuspected acute hepatitis C masquerading as DILI. CrossRefPubMedGoogle Scholar
  4. 4.
    Andrade RJ, Lucena I, Fernandez C, et al: Drug-induced liver injury: an analysis of 461 incidences submitted to the Spanish registry over a 10-year period. Gastroenterology 2005, 129:512–521.PubMedGoogle Scholar
  5. 5.
    Ibanez L, Perez E, Vidal X, Laporte JR: 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, 37:592–600.CrossRefPubMedGoogle Scholar
  6. 6.
    Alla V, Abraham J, Siddique J, et al.: Autoimmune liver disease triggered by statins: report of 3 instances and review of literature. J Clin Gastroenterol 2006, 40:757–761.CrossRefPubMedGoogle Scholar
  7. 7.
    Lim JR, Fraught PR, Chalasani N, Molleston J: Severe liver injury after starting atomoxetine (Strattera) in two children. J Pediatrics 2006, 148:831–834.CrossRefGoogle Scholar
  8. 8.
    Bjornsson E, Talwalkar J, Treeprasertsuk S, et al.: Drug induced Autoimmune Hepatitis: clinical characteristics and prognosis. Hepatology 2010, 51:2040–2048.PubMedGoogle Scholar
  9. 9.
    • Chalasani N, Bjornsson E: Risk factors for idiosyncratic drug-induced liver injury. Gastroenterology 2010, 138:2246–2259. This recently published review article summarizes nongenetic and genetic risk factors for developing idiosyncratic DILI. CrossRefPubMedGoogle Scholar
  10. 10.
    Chalasani N: Statin hepatotoxicity: focus on statin usage in nonalcoholic fatty liver disease. Hepatology 2005, 41:690–695.CrossRefPubMedGoogle Scholar
  11. 11.
    Cohen D, Anania F, Chalasani N: Report of the liver expert panel. Statin Safety Task Force, National Lipid Association. Am J Cardiol 2006, 97(Suppl):77C–81C.CrossRefPubMedGoogle Scholar
  12. 12.
    Chalasani N, Aljadhey H, Kesterson J, et al.: Patients with elevated liver enzymes are not at higher risk for statin hepatotoxicity. Gastroenterology 2004, 126:1287–1292.CrossRefPubMedGoogle Scholar
  13. 13.
    Vuppalanchi R, Teal E, Chalasani N: Patients with elevated baseline liver enzymes do not have higher frequency of hepatotoxicity from lovastatin than those with normal baseline liver enzymes. Am J Med Sci 2005, 329:62–65.CrossRefPubMedGoogle Scholar
  14. 14.
    Targher G, Day CP, Bonor E: Risk of cardiovascular disease in patients with nonalcoholic fatty liver disease. N Engl J Med 2010, 363:1341–1350.CrossRefPubMedGoogle Scholar
  15. 15.
    Browning JD: Statins and hepatic steatosis: perspectives from the Dallas Heart Study. Hepatology 2006, 44:466–471.CrossRefPubMedGoogle Scholar
  16. 16.
    Nunez M: Clinical syndromes and consequences of antiretroviral-related hepatotoxicity. Hepatology 2010, 52:1143–1155.CrossRefPubMedGoogle Scholar
  17. 17.
    Park WB, Kim W, Lee KL, et al.: Antituberculosis drug-induced liver injury in chronic hepatitis and cirrhosis. J Infect 2010, 61:323–329.CrossRefPubMedGoogle Scholar
  18. 18.
    Uetrecht J: Idiosyncratic drug reactions: current understanding. Annu Rev Pharmacol Toxicol 2007, 47:513–539.CrossRefPubMedGoogle Scholar
  19. 19.
    • Lammert C, Einarsson S, Saha C, et al.: Relationship between daily dose of oral medications and idiosyncratic drug induced liver injury (DILI): search for signals. Hepatology 2008, 47:2003–2009. This study showed that oral compounds administered at doses ≥50 mg/day are at higher risk to cause hepatotoxicity than those given at lower doses. This study consisted of several datasets that exhibited a similar pattern of dose-dependency. CrossRefPubMedGoogle Scholar
  20. 20.
    Lammert C, Niklasson A, Bjornsson E, Chalasani N: Oral medications with significant hepatic metabolism are at higher risk for hepatic adverse events. Hepatology 2010, 51:615–620.PubMedGoogle Scholar
  21. 21.
    Andrade JR, Lucena MI, Kaplowitz N, et al.: Outcome of acute idiosyncratic drug-induced liver injury: long-term follow-up in a hepatotoxicity registry. Hepatology 2006, 44:1581–1588.CrossRefPubMedGoogle Scholar
  22. 22.
    Fontana RJ, Watkins PB, Bonkovsky HL, et al.: Rationale, design and conduct of the drug induced liver injury network prospective study. Drug Safety 2009, 32:55–68.CrossRefPubMedGoogle Scholar
  23. 23.
    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, 25:1411–1421.CrossRefPubMedGoogle Scholar
  24. 24.
    Benichou C: Criteria of drug-induced liver disorders. Report of an international consensus meeting. J Hepatol 1990, 11:272–276.CrossRefPubMedGoogle Scholar
  25. 25.
    Benichou C, Danan G, Falhault A, et al.: Causality assessment of adverse reactions to drugs-II. An original model for validation of drug causality assessment methods: case reports with positive rechallenge. J Clin Epidemiol 1993, 45:1331–1336.CrossRefGoogle Scholar
  26. 26.
    Rockey DC, Seeff LB, Rochon J, et al. for the Drug-Induced Liver Injury Network: A structured assessment process to assign causality in drug induced liver injury. Hepatology 2010, 51:2117–2126.PubMedGoogle Scholar
  27. 27.
    Papay JI, Clines D, Rafi R, et al.: Drug-induced liver injury following positive drug rechallenge. Regul Toxicol Pharmacol 2009, 54: 84–90.CrossRefPubMedGoogle Scholar
  28. 28.
    Dalton HR, Fellows HJ, Stableforth W, et al.: The role of hepatitis E virus testing in drug-induced liver injury. Aliment Pharmacol Ther 2007, 26:1429–1435.CrossRefPubMedGoogle Scholar
  29. 29.
    Kaplowitz N: Idiosyncratic drug hepatotoxicity. Nat Rev Drug Discov 2005, 4:489–499.CrossRefPubMedGoogle Scholar
  30. 30.
    •• Kindmark A, Jawaid A, Harbron CG, et al.: Genome-wide pharmacogenetic investigation of a hepatic adverse event without clinical signs of immunopathology suggests an underlying immune pathogenesis. Pharmacogenomics J 2008, 8:186–195. This article describes the first genome-wide association study conducted to explore the genetic basis of DILI in humans. Ximelagatran, a compound with great promise, was abandoned because of idiosyncratic DILI. This study showed a strong relationship between HLA DRB1*07 and HLA DQA1*02 and liver injury from ximelagatran. CrossRefPubMedGoogle Scholar
  31. 31.
    •• Daly AK, Donaldson PT, Bhatnagar P, et al.: HLA-B*5701 genotype is a major determinant of drug-induced liver injury due to flucloxacillin. Nat Genet 2009, 41:816–821. A landmark article published by the International SAE consortium showed an exceptionally strong relationship between HLA B*5701 and flucloxacillin hepatotoxicity. This compound is not available in the United States. CrossRefPubMedGoogle Scholar
  32. 32.
    The International Serious Adverse Events Consortium DILI Genetics Research Update: Drug-induced liver injury getting the medicine and science together. Presented at the Food and Drug Administration/American Association for the Study of Liver Diseases/Pharmaceutical Research and Manufacturers of America (FDA/AASLD/PhRMA) meeting. Silver Spring, MD; March 24, 2010. Available at http://www.aasld.org/conferences/Documents/PresentationLibrary/2010Hepatoxicity_SessionII_Nelson.pdf. Accessed October 2010.
  33. 33.
    US Department of Health and Human Services, Food and Drug Administration: Guidance for industry: drug-induced liver injury: premarketing clinical evaluation. Available at http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM174090.pdf. Accessed October 2010.
  34. 34.
    Bjornsson E: Drug induced liver injury: Hy’s rule revisited. Clin Pharmacol Ther 2006, 79:521–528.CrossRefPubMedGoogle Scholar
  35. 35.
    Lewis JH: Hy’s law, the “rezulin rule,” and other predictors of severe drug-induced hepatotoxicity; putting risk-benefit into perspective. Pharmacoepidemiol Drug Saf 2006, 15:221–229.CrossRefPubMedGoogle Scholar
  36. 36.
    Lee WM, Hynan LS, Rossaro L, et al.: Intravenous N-acetylcysteine improves transplant-free survival in early stage non-acetaminophen acute liver failure. Gastroenterology 2009, 137:856–864.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  1. 1.Division of Gastroenterology and HepatologyIndiana University School of MedicineIndianapolisUSA

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