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PLoS One. 2013 Dec 27;8(12):e81974. doi: 10.1371/journal.pone.0081974. eCollection 2013.

Profiles of serum cytokines in acute drug-induced liver injury and their prognostic significance.

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The Liver-Biliary-Pancreatic Center and Departments of Internal Medicine, General Surgery, Research, and Dickson Advanced Analytics, Carolinas Medical Center, Charlotte, North Carolina, United States of America.
Department of Internal Medicine, IUPUI, Indianapolis, Indiana, United States of America.
Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, United States of America.
Schools of Medicine and Pharmacy, University of North Carolina, Chapel Hill, North Carolina, United States of America.
Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America.
Department of Internal Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
Department of Internal Medicine, University of Southern California, Los Angeles, California, United States of America.
Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota, United States of America.
Department of Internal Medicine, Pacific Medical Center, San Francisco, California, United States of America.
Duke Clinical Research Institute, Durham, North Carolina, United States of America.
National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland, United States of America.


Drug-induced liver injury (DILI) is the most common cause of acute liver failure in the United-States. The aim of the study was to describe serum immune profiles associated with acute DILI, to investigate whether there are profiles associated with clinical features or types of DILI and/or with prognosis, and to assess temporal changes in levels. Twenty-seven immune analytes were measured in the sera of 78 DILI subjects in the Drug-Induced Liver Injury Network (DILIN) and compared with 40 healthy controls. Immune analytes (14 cytokines, 7 chemokines and 6 growth factors) were measured by BioPlex multiplex ELISA at DILI onset and after 6 months. A modeling process utilizing immune principles was used to select a final set of variables among 27 immune analytes and several additional clinical lab values for prediction of early death (within 6 months of DILI onset). Nineteen of the 27 immune analytes were differentially expressed among healthy control, DILI onset and 6-month cohorts. Disparate patterns of immune responses, especially innate and adaptive cellular (mostly TH17) immunity were evident. Low values of four immune analytes (IL-9, IL-17, PDGF-bb and RANTES) and serum albumin are predictive of early death [PPV = 88% (95% CI, 65%-100%), NPV = 97% (95% CI, 93%-100%), accuracy = 96% (95% CI, 92%-100%)].


Acute DILI is associated with robust and varying immune responses. High levels of expression of cytokines associated with innate immunity are associated with a poor prognosis, whereas high levels of expression of adaptive cytokines are associated with good long-term prognosis and eventual recovery. Serum immune analyte profiles at DILI onset appear to be of prognostic, and perhaps, diagnostic significance.

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