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Presentation and Outcomes with Clinically Apparent Interferon Beta Hepatotoxicity

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Abstract

Aims

The aim of this study was to describe the presenting features and outcomes of consecutive patients with liver injury attributed to interferon beta.

Methods

The presenting features of eight subjects with clinically apparent liver injury attributed to interferon beta enrolled in the U.S. Drug-Induced Liver Injury Network (DILIN) prospective registry between 2004 and 2010 were reviewed and compared to 11 published reports of symptomatic hepatotoxicity.

Results

All eight of the DILIN patients were women, 75 % were Caucasian and the mean age was 49 years. Most subjects presented with an acute hepatocellular injury pattern and mean serum alanine aminotransferase (ALT) levels were 725 ± 593 U/L. The median duration of interferon beta use before injury onset was 462 days, and four patients had been treated for more than a year. No patient had detectable antinuclear or smooth muscle antibodies. One patient died of acute liver failure and the remaining patients usually recovered within 2–3 months. Causality assessment scored three cases as definite, three highly likely, one probable and one possible. Eleven additional published cases were all women, mean age was 40 years, mean ALT at onset 840 U/L, and 7 (63 %) had autoantibodies. Liver histology in three cases from DILIN and nine from the literature commented upon centrilobular (zone 3) necrosis and infiltrates with lymphocytes and plasma cells.

Conclusions

Interferon beta hepatotoxicity occurs mostly in women and has a variable, but often prolonged time to onset. Most patients have self-limited acute hepatocellular liver injury but several have required liver transplantation or died of acute liver failure. Liver histology available in three cases demonstrated zone 3 necrosis and autoimmune features suggestive of an immunologic basis to this adverse drug reaction.

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Abbreviations

ALT:

Alanine aminotransferase

AST:

Aspartate aminotransferase

Alk P:

Alkaline phosphatase

DILI:

Drug-induced liver injury

DILIN:

Drug-Induced Liver Injury Network

IFN:

Interferon

MS:

Multiple sclerosis

ULN:

Upper limit of the normal range

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Acknowledgments

The website http://dilin.dcri.duke.edu/publications-1 provides a complete listing of DILIN funding sources, DILIN sites, investigators, co-investigators, coordinators, and staff funded by cooperative agreements with the National Institute of Diabetes and Digestive and Kidney Diseases, Grants No. U01DK065184 (University of Michigan, Ann Arbor, MI), U01DK065201 (University of North Carolina, Chapel Hill, NC; Carolinas Medical Center), U01DK065211 (Indiana University, Indianapolis, IN), U01DK065176 (Duke Clinical Research Institute, Durham, NC). This work was also supported in part by the Intramural Research Program of the National Cancer Institute.

Conflict of interest

Drs. Kleiner, Kochar, Gu, Hayashi, and Barnhart have no conflicts. Dr. Ghabril has received research support from Salix Pharmaceuticals. Dr. Fontana has been a consultant with Merck, Medtronic, Tibotec, and GlaxoSmithkline and also received grant/research support from Vertex and Gilead Sciences. Dr. Bonkovsky has provided consulting to Novartis Pharmaceuticals, Boehringer-Ingelheim, Lundbeck Pharmaceuticals and Clinuvel, Inc. He has also received Grant/Research Support from Vertex, Clinuvel, Inc, and Novartis Pharmaceuticals.

Author information

Authors and Affiliations

  1. Division of Gastroenterology, Department of Internal Medicine, University of Michigan Medical School, University of Michigan Medical Center, 3912 Taubman Center, Ann Arbor, MI, 48109-0362, USA

    Robert J. Fontana & Sweta Kochhar

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

    Paul Hayashi & Herbert L. Bonkovsky

  3. Departments of Medicine and Research, Carolinas Medical Center, Charlotte, NC, USA

    Herbert L. Bonkovsky

  4. National Cancer Institute, National Institutes of Health, Bethesda, MD, USA

    David E. Kleiner

  5. Duke Clinical Research Institute, Durham, NC, USA

    Jiezhun Gu

  6. Department of Internal Medicine, Indiana University, Indianapolis, IN, USA

    Marwan Ghabril

Authors
  1. Robert J. Fontana
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  2. Paul Hayashi
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  3. Herbert L. Bonkovsky
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  4. David E. Kleiner
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  5. Sweta Kochhar
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  6. Jiezhun Gu
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  7. Marwan Ghabril
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Corresponding author

Correspondence to Robert J. Fontana.

Additional information

This study was conducted for the Drug Induced Liver Injury Network (DILIN).

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Fontana, R.J., Hayashi, P., Bonkovsky, H.L. et al. Presentation and Outcomes with Clinically Apparent Interferon Beta Hepatotoxicity. Dig Dis Sci 58, 1766–1775 (2013). https://doi.org/10.1007/s10620-012-2553-1

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  • DOI: https://doi.org/10.1007/s10620-012-2553-1

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