Gastroenterology
Volume 135, Issue 6 , Pages 1924-1934.e4 , December 2008

Causes, Clinical Features, and Outcomes From a Prospective Study of Drug-Induced Liver Injury in the United States

  • Naga Chalasani

      Affiliations

    • Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana
    • Clarian/Indiana University Digestive Diseases Center, Indianapolis, Indiana
    • Corresponding Author InformationAddress requests for reprints to: Naga Chalasani, MD, Indiana University School of Medicine, RG 4100, 1050 Wishard Boulevard, Indianapolis, Indiana 46202. fax: (317) 278-1949
    • ,
  • Robert J. Fontana

      Affiliations

    • Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan
    • ,
  • Herbert L. Bonkovsky

      Affiliations

    • Cannon Research Center and Center for Liver and Digestive Diseases, Carolinas Medical Center, Charlotte, North Carolina
    • Department of Internal Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
    • Department of Internal Medicine, University of Connecticut, Farmington, Connecticut
    • ,
  • Paul B. Watkins

      Affiliations

    • Department of Internal Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
    • ,
  • Timothy Davern

      Affiliations

    • Department of Internal Medicine, University of California, San Francisco, San Francisco, California
    • ,
  • Jose Serrano

      Affiliations

    • Liver Disease Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland
    • ,
  • Hongqiu Yang

      Affiliations

    • Duke Clinical Research Institute, Durham, North Carolina
    • ,
  • James Rochon

      Affiliations

    • Duke Clinical Research Institute, Durham, North Carolina
    • ,
  • Drug Induced Liver Injury Network (DILIN)

Received 4 August 2008 ,Accepted 8 September 2008.

References 

  1. Watkins PB, Seeff LB. Drug-induced liver injury: summary of a single topic clinical research conference. Hepatology. 2006;43:618–631
  2. Navarro VJ, Senior JR. Drug-related hepatotoxicity. N Engl J Med. 2006;35:731–739
  3. Abboud G, Kaplowitz N. Drug-induced liver injury. Drug Saf. 2007;30:277–294
  4. Ostapowicz G, Fontana RJ, Schiødt FV, et al. U.S. Acute Liver Failure Study Group Results of a prospective study of acute liver failure at 17 tertiary care centers in the United States. Ann Intern Med. 2002;137:947–954
  5. Uetrecht J. Idiosyncratic drug reactions: current understanding. Annu Rev Pharmacol Toxicol. 2007;47:513–539
  6. Wilkes RA, Lin DW, Roden DM, et al. Identifying genetic risk factors for serious adverse drug reactions: current progress and challenges. Nat Rev Drug Discov. 2007;6:904–916
  7. Lammert C, Einarsson S, Saha C, et al. Relationship between daily dose of oral medications and idiosyncratic drug-induced liver injury: search for signals. Hepatology. 2008;47:2003–2007
  8. Senior JR. What is idiosyncratic hepatotoxicity? (What is not?). Hepatology. 2008;47:1813–1815
  9. Seeff LB. Herbal hepatotoxicity. Clin Liver Dis. 2007;11:577–596
  10. Strader DB, Seeff LB. Hepatotoxicity of herbal preparation. Chapter 37 In:  Boyer TD,  Wright TL,  Manns MP editor. Zakim and Boyer's hepatology, a textbook of liver disease. 5th ed.. Philadelphia, PA: Saunders-Elsevier; 2006;p. 551–560
  11. Elinav E, Pinsker G, Safadi R, et al. Association between consumption of Herbalife® nutritional supplements and acute hepatotoxicity. J Hepatol. 2007;47:514–520
  12. Schoepfer AM, Engel A, Fattinger K, et al. Herbal does not mean innocuous: ten cases of severe hepatotoxicity associated with dietary supplements from Herbalife® products. J Hepatol. 2007;47:521–526
  13. Sarma DN, Barrett ML, Chavez ML, et al. Safety of green tea extracts: a systematic review by the US Pharmacopeia. Drug Saf. 2008;31:469–484
  14. Bonkovsky HL. Hepatotoxicity associated with supplements containing Chinese Green Tea (Camellia sinensis). (letter) Ann Intern Med. 2006;144:68–70
  15. Javaid A, Bonkovsky HL. Hepatotoxicity due to extracts of Chinese green tea (Camellia sinensis): a growing concern. (letter) J Hepatol. 2006;45:334–336
  16. Gardiner P, Graham R, Legedza AT, et al. Factors associated with herbal therapy use by adults in the United States. Altern Ther Health Med. 2007;13:22–29
  17. Uetrecht J. Idiosyncratic drug reactions: past, present, and future. Chem Res Toxicol. 2008;21:84–92
  18. Ingelman-Sundberg M. Pharmacogenomic biomarkers for prediction of severe adverse drug reactions. N Engl J Med. 2008;358:637–639
  19. Eichelbaum M, Ingelman-Sundberg M, Evans WE. Pharmacogenomics and individualized drug therapy. Annu Rev Med. 2006;57:119–137
  20. Hoofnagle JH. Drug-Induced Liver Injury Network (DILIN). Hepatology. 2004;40:773
  21. Fontana RJ, Watkins PB, Bonkovsky HL, et al. Rationale, design and conduct of the Drug-Induced Liver Injury Network (DILIN) prospective study. Drug Saf (in press).
  22. Rockey DC, Seeff LB, Freston JW, et al. Comparison between expert opinion and RUCAM for assignment of causality in drug induced liver injury. (abstr M1777) Gastroenterology. 2007;132(suppl 2):A-773
  23. Benichou C. Criteria of drug induced liver disorders: report of an international consensus meeting. J Hepatol. 1990;11:272–276
  24. Danan G, Benichou C. Causality assessment of adverse reactions to drugs - I (A novel method based on the conclusions of international consensus meeting). J Clin Epidemiol. 1993;46:1323–1330
  25. Benichou C, Danan G, Flahault A. 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;46:1331–1336
  26. 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;129:512–521
  27. De Valle MB, Klinteberg VA, Alem N, et al. Drug induced liver injury in a Swedish University Hospital out-patient hepatology clinic. Aliment Pharmacol Ther. 2006;24:1187–1195
  28. Pillans PI. Drug associated hepatic reactions in New Zealand: 21 years experience. N Z Med J. 1996;109:315–319
  29. Björnsson E, Olsson R. Outcome and prognostic markers in severe drug-induced liver disease. Hepatology. 2005;42:481–489
  30. Ganey PE, Luyendyk JP, Maddox JF, et al. Adverse hepatic drug reactions: inflammatory episodes as consequence and contributor. Chem Biol Interact. 2004;150:35–51
  31. 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
  32. El-Serag HB, Everhart JE. Diabetes increases the risk of acute hepatic failure. Gastroenterology. 2002;122:1822–1828
  33. Wang T, Shankar K, Ronis MJ, et al. Mechanisms and outcomes of drug-and toxicant-induced liver toxicity in diabetes. Clin Rev Toxicol. 2007;37:413–459
  34. Mehendale HM. Role of tissue repair in liver injury. In:  Kaplowitz N,  Delve L editor. Drug induced liver injury. 2nd ed.. Philadelphia, PA: Informa Health Care; 2007;
  35. Björnsson E, Kalaitzakis E, Olsson R. The impact of eosinophilia and hepatic necrosis on prognosis in patients with drug-induced liver injury. Aliment Pharmcol Ther. 2007;25:1411–1421
  36. Ohmori S, Shiraki K, Inoue H, et al. Clinical characteristics and prognostic indicators of drug-induced fulminant hepatic failure. Hepatogastroenterology. 2003;50:1531–1534
  37. Zimmerman HJ. Drug-induced liver disease (Chapter 16. Hepatotoxicity: the adverse effects of drugs and other chemicals on the liver). 2nd ed.. Philadelphia, PA: Lippincott, Williams and Wilkins; 1999;427–456
  38. Björnsson E. Drug-induced liver injury: Hy's rule revisited. Clin Pharmacol Ther. 2006;79:521–528
  39. Sgro C, Clinard F, Ouazir K, et al. Incidence of drug-induced hepatic injuries: a French population-based study. Hepatology. 2002;36:451–455

 DILIN is supported by the National Institute of Diabetes and Digestive and Kidney Diseases under the following cooperative agreements: 1U01DK065201, 1U01DK065193, 1U01DK065184, 1U01DK065211, 1U01DK065238, and 1U01DK065176.

 The authors disclose the following: N.C. served as a paid consultant in the preceding 12 months to Takeda Pharmaceuticals, AtheroGenics, Advanced Life Sciences, Kari Bio, Metabasis, Pfizer, and Eli Lilly. He received research grant support from Debiovision and Sanofi-Aventis. On his behalf, his institution has initiated contract negotiations with Gilead Sciences and Pfizer for conducting clinical trials unrelated to drug-induced liver injury. He served as an expert witness for a product liability litigation involving suspected drug-induced liver injury.

 R.J.F. has served on the speakers' bureau or as a paid consultant during the past 12 months to Roche, Bristol-Myers Squibb, Vertex Pharmaceuticals, and Gilead Sciences.

 H.L.B. served as a paid advisor to InfaCare Pharmaceuticals, Novartis Pharmaceuticals, and Ovation Pharmaceuticals. He is on the speakers' bureau of Ovation Pharmaceuticals. He receives support for research studies from the American Porphyria Foundation, Merck, Novartis, Roche, and Vertex. During the past 12 months, he has served as an expert witness for plaintiffs in litigation regarding suspected drug-induced liver injury.

 P.B.W. served as a paid consultant in the preceding 12 months to the following pharmaceutical companies: Actelion, Aldus, Astellas, Bristol-Myers Squibb, Boehringer-Ingleheim, Danube, Endo, FibroGen, GlaxoSmithKline, Hoffmann-La Roche, Imtech, King, Millennium, Merck, Novartis, Nuon, Orion, Pfizer, Pharmasset, Schering Plough, TAP, Valiant, VIA, and Wyeth. He served as both a plaintiff and a defense expert in litigation involving suspected drug-induced liver injury.

 T.D. served as a paid consultant to Entelos and FibroGen. He served as both a plaintiff and a defense expert in litigation involving suspected drug-induced liver injury.

 J.S., H.Y., and J.R. have no potential conflicts of interest to report.

 Members of DILIN include the following: Clinical Centers—Indiana University: Naga Chalasani, MD (primary investigator), Raj Vuppalanchi, MD (coinvestigator), Jean Molleston, MD (coinvestigator), Lawrence Lumeng, MD (coinvestigator), Audrey Corne (research coordinator), Angie Plummer (research coordinator); University of Connecticut: Herbert Bonkovsky, MD (primary investigator), Petr Protiva, MD (coinvestigator), James Freston, MD, PhD (coinvestigator), Robert Rosson, MD (coinvestigator), Robert A. Levine, MD (satellite site investigator), Benedict Maliakkal, MD (satellite site investigator), Paul Appleton, MD (research coordinator), Mariola Smialek, RN (research coordinator); University of Michigan: Robert J. Fontana, MD (primary investigator), Hari Conjeevaram, MD (coinvestigator), Stuart Gordon, MD (satellite site investigator), Suzanne Welch (research coordinator), Jessica Worley (research coordinator), Jordan Kridler (research coordinator); University of North Carolina: Paul Watkins, MD (primary investigator), Paul Hayashi, MD (coinvestigator), Mark Russo, MD (coinvestigator), the late Harry Guess, MD, PhD (coinvestigator), Kimberly Beaver, MD (satellite site investigator), Alastair Smith, MD (satellite site investigator), James Lewis, MD (satellite site investigator), Susan Pusek (research coordinator); University of California, San Francisco: Tim Davern, MD (primary investigator), Maurizo Bonacini, MD (coinvestigator), Kristine Partovi (research coordinator). Data Coordinating Center—Duke Clinical Research Institute: James Rochon, MD (primary investigator), John McHutchison, MD (coinvestigator), Don Rockey, MD (coinvestigator), Mary Maggio (project manager), Hongqiu Yang, PhD (biostatistician); National Institute of Diabetes and Digestive and Kidney Diseases Scientists: Jose Serrano, MD (project officer), Leonard Seeff, MD, Jay Hoofnagle, MD, Mark Avigan, MD, and John Senior, MD, employees of the US Food and Drug Administration, have participated in selected aspects of DILIN activities.

PII: S0016-5085(08)01674-0

doi: 10.1053/j.gastro.2008.09.011

Gastroenterology
Volume 135, Issue 6 , Pages 1924-1934.e4 , December 2008

Article Tools