Cytokine and autoantibody patterns in acute liver failure

Abstract

The mechanisms of idiosyncratic drug-induced liver injury (IDILI) are still a matter of dispute. Some of the characteristics of reactions that have been classed as metabolic idiosyncrasy could also be those of an immune-mediated reaction with an autoimmune component. Many auto-immune reactions appear to be mediated by T_H17 cells, which are in part characterized by the production of interleukin (IL)-17. To test the involvement of T_H17 cells in IDILI, we quantified a number of cytokines, chemokines, and autoantibodies in the serum of 39 patients with acute liver failure (ALF) due to IDILI and compared the values with those from 21 patients with acetaminophen-induced ALF and 10 patients with viral hepatitis-induced ALF. The IL-17 levels were elevated in 60% of patients with IDILI, but also in a similar number of patients with acetaminophen-induced ALF and occasionally in patients with viral hepatitis. Levels of other cytokines, such as IL-21, that are also produced by T_H17 cells were higher in patients with IDILI, but again, there was overlap with acetaminophen DILI. Autoantibodies were more frequent in patients in the IDILI group but were absent in most patients. These data provide a picture of the cytokine/chemokine profile in patients with various types of ALF. The pattern varies from patient to patient and not specifically by etiology. This suggests that different underlying disease mechanisms may be at play in different individuals, even among those demonstrating injury from the same drug. Since cytokines may originate from more than one type of cell, interpretation of results of cytokine assays remains difficult in complex disease settings.

Keywords::

• Idiosyncratic drug reactions
• autoimmune
• Th17
• hepatotoxicity

Acknowledgements

The continued support of the coordinators and investigators participating in the ALF Study Group (ALFSG 1998–2006) has been essential to this work and is gratefully acknowledged: William M. Lee (PI), Julie Polson, Carla Pezzia, Ezmina Lalani, Linda S. Hynan, and Joan S. Reisch, University of Texas Southwestern Medical Center, Dallas, TX; Anne M. Larson, University of Washington, Seattle, WA; Jeffrey S. Crippin, Washington University School of Medicine, St. Louis, MO; Timothy J. Davern, University of California at San Francisco, CA; Sukru Emre, Mt Sinai Medical Center, New York, NY; Timothy M. McCashland, University of Nebraska, Omaha, NE; J. Eileen Hay, Mayo Clinic, Rochester, MN; Natalie Murray, Baylor University Medical Center, Dallas, TX; A. Obaid Shakil, University of Pittsburgh Medical Center, Pittsburgh, PA; Andres T. Blei, Northwestern University Medical School, Chicago, IL; Atif Zaman, Jonathan Schwartz, Oregon Health Sciences University, Portland, OR; Steven Han, University of California at Los Angeles, Los Angeles, CA; Robert J. Fontana, University of Michigan Medical Center, Ann Arbor, MI; Brendan McGuire, University of Alabama, Birmingham, AL; Raymond Chung, Massachusetts General Hospital, Boston, MA; Michael Schilsky, Columbia-Presbyterian Medical Center/Cornell-New York Hospital, New York, NY; M. Edwyn Harrison, Mayo Clinic, Scottsdale, Scottsdale, AZ; Adrian Reuben, Medical University of South Carolina, Charleston, SC; Santiago Munoz, Albert Einstein Medical Center, Philadelphia, PA; Todd Stravitz, Virginia Commonwealth University, Richmond, VA; Lorenzo Rossaro, University of California at Davis, Sacramento, CA; Raj Satyanarayana, Mayo Clinic, Jacksonville, FL; Raj Reddy, University of Pennsylvania, Philadelphia, PA; Tarek Hassanein, University of California at San Diego, San Diego, CA; and, Alistair Smith, Durham, NC.

Declaration of interest

J.U. holds a Canada Research Chair in Adverse Drug Reactions. The sample analysis was funded by grants from the Canadian Institutes of Health. Samples, clinical laboratory data, and information were obtained through the ALFSG which is funded by NIH Grant #DK U01-58369.