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Drug-Induced Liver Injury Network (DILIN) Prospective Study

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Abstract

Background: Drug-induced liver injury (DILI) is an uncommon adverse drug reaction of increasing importance to the medical community, pharmaceutical industry, regulatory agencies and the general public.

Objectives: The Drug-Induced Liver Injury Network (DILIN) was established to advance understanding and research into DILI by initiating a prospective registry of patients with bona fide DILI for future studies of host clinical, genetic, environmental and immunological risk factors. The DILIN was also charged with developing standardized nomenclature, terminology and causality assessment instruments.

Methods: Five clinical sites, a data coordinating centre and senior scientists from the National Institute of Diabetes and Digestive and Kidney Diseases initiated the DILIN prospective study in September 2004. Eligible patients are required to meet minimal laboratory or histological criteria within 6 months of DILI onset and have other competing causes of liver injury excluded. Patients in the general community setting with pre-existing HIV, hepatitis B virus or hepatitis C virus infections and/or abnormal baseline liver biochemistries are eligible for enrolment. In addition, subjects with liver injury due to herbal products are eligible to participate. Control patients without DILI are also to be recruited in the future.

Results: All referred subjects undergo an extensive review of available laboratory, pathology and imaging studies. Subjects who meet pre-defined eligibility criteria at the 6-month study visit are followed for 2 years to better define the natural history of chronic DILI. Causality assessment is determined by a panel of three hepatologists who independently assign a causality score ranging from 1 (definite) to 5 (unlikely) as well as a severity score ranging from 1 (mild) to 5 (fatal). During the first 3 years, 367 subjects were enrolled into the DILIN prospective study. Conclusion: DILIN is a multicentre research network charged with improving our understanding of the aetiologies, risk factors and outcomes of DILI in the US. The network is meeting the targeted enrolment of ten patients per month and is developing a repository of clinical data and biological samples for future studies of DILI pathogenesis and outcome.

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Acknowledgements

Funding for the DILIN is provided by the NIDDK under cooperative agreements: 1U01DK065201, 1U01DK065193, 1U01DK065184, 1U01DK065211, 1U01DK065238 and 1U01DK065176.

The authors have the following disclosures: Robert J. Fontana: Speaker’s Bureau for Roche Laboratories, Bristol-Meyers Squibb, consultant for Vertex Pharmaceuticals; Naga Chalasani: consultant for or grant funding from Takeda, Atherogenics, Eli-Lilly Company, Merck, Abbott, Ortho-McNeill, Metabasis Advanced Life Sciences, Sanof-Aventis, Deviousion; Herbert L. Bonkovsky: served as a paid advisor to Infracare, Novartis and Ovation Pharmaceuticals and is on the Speaker’s Bureau for Ovation Pharmaceuticals, grant support from Merck, Novartis, Roche and Vertex, during the past 12 months he served as an expert witness for plaintiffs in litigation regarding potential DILI; Paul B. Watkins: served as a paid consultant in the preceding 12 months to the following pharmaceutical companies: Actellion, Aldus, Astellas, Bristol-Myers Squibb, Boerringer-Ingleheim, Danube, Endo, Fibrogen, GlaxoSmithKline, Hoffman-LaRoche, Imtech, King, Mellenium, Merck, Novartis, Nuon, Orion, Pfizer, Pharmasset, Schering Plough, TAP, Valiant, VIA and Wyeth, he served as both a plaintiff and defence expert in litigation involving suspected DILI involving some of these companies. Drs Rochon, Davern and Serrano have no financial disclosures relating to this work.

The following is a list of the principal investigators (co-investigators) and [study coordinators] participating in the DILIN: University of North Carolina at Chapel Hill: Paul Watkins, Chair of DILIN Steering Committee (Paul Hayashi, Mark Russo) [Anne Criss, Susan Pusek, Gale Groseclose]; University of Connecticut Health Center: Herbert Bonkovsky (James Freston, Robert Levine, Benedict Maliakkal, Petr Protiva, Robert Rosson) [Jane Bulger, Mariola Smialek, Paul Appleton]; Indiana University School of Medicine: Naga Chalasani (Lawrence Lumeng, Raj Vuppalanchi) [Audrey Corne]; University of California San Francisco: Tim Davern (Maurizio Bonacini) [Dalia Moawad, Kristine Partovi]; University of Michigan: Robert Fontana (Hari Conjeeveram) [Suzanne Welch, Jordan Kridler]; Data Coordinating Center, Duke Clinical Research Institute: James Rochon (John McHutchison, Don C. Rockey) [Carla Ange, Katherine Berezny, Michelle Crowder, Satarah Latiker, Mary Moggio, Lauren Ruffrage, Carmel Scharenbroich, June Wampole]; NIDDK: José Serrano, Leonard Seeff, Jay Hoofnagle; NIDDK Biosample Repository: David Toke (Dana Witt), Rutgers University; Rich Frome, Fisher BioServices; Liver Histopathology Review Center: David Kleiner, National Cancer Institute.

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Authors and Affiliations

  1. Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, USA

    Robert J. Fontana

  2. Department of Internal Medicine, University of North Carolina, Chapel Hill, North Carolina, USA

    Paul B. Watkins

  3. Department of Internal Medicine, Center for Liver and Digestive Diseases, Charlotte, North Carolina, USA

    Herbert L. Bonkovsky

  4. Department of Medicine and Cannon Research Center, Carolinas Medical Center, Charlotte, North Carolina, USA

    Herbert L. Bonkovsky

  5. Department of Medicine, University of Connecticut Health Center, Farmington, Connecticut, USA

    Herbert L. Bonkovsky

  6. Department of Medicine, University of North Carolina, Chapel Hill, North Carolina, USA

    Herbert L. Bonkovsky

  7. Department of Internal Medicine, Indiana University, Indianapolis, Indiana, USA

    Naga Chalasani

  8. Department of Internal Medicine, University of California, San Francisco, California, USA

    Timothy Davern

  9. Liver Disease Research Branch, National Institutes of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA

    Jose Serrano

  10. Duke Clinical Research Institute, Durham, North Carolina, USA

    James Rochon

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Correspondence to Robert J. Fontana.

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Fontana, R.J., Watkins, P.B., Bonkovsky, H.L. et al. Drug-Induced Liver Injury Network (DILIN) Prospective Study. Drug-Safety 32, 55–68 (2009). https://doi.org/10.2165/00002018-200932010-00005

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