title: Profiles of serum cytokines in acute drug-induced liver injury and their prognostic significance.
abstract: 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%)].
  
  
  CONCLUSIONS
  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.
authors.affiliation: 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.
authors.forename: Nury M
authors.initials: NM
authors.lastname: Steuerwald
authors.affiliation: 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.
authors.forename: David M
authors.initials: DM
authors.lastname: Foureau
authors.affiliation: 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.
authors.forename: H James
authors.initials: HJ
authors.lastname: Norton
authors.affiliation: 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.
authors.forename: Jie
authors.initials: J
authors.lastname: Zhou
authors.affiliation: 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.
authors.forename: Judith C
authors.initials: JC
authors.lastname: Parsons
authors.affiliation: Department of Internal Medicine, IUPUI, Indianapolis, Indiana, United States of America.
authors.forename: Naga
authors.initials: N
authors.lastname: Chalasani
authors.affiliation: Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, United States of America.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Fontana
authors.affiliation: Schools of Medicine and Pharmacy, University of North Carolina, Chapel Hill, North Carolina, United States of America.
authors.forename: Paul B
authors.initials: PB
authors.lastname: Watkins
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America.
authors.forename: William M
authors.initials: WM
authors.lastname: Lee
authors.affiliation: Department of Internal Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
authors.forename: K Rajender
authors.initials: KR
authors.lastname: Reddy
authors.affiliation: Department of Internal Medicine, University of Southern California, Los Angeles, California, United States of America.
authors.forename: Andrew
authors.initials: A
authors.lastname: Stolz
authors.affiliation: Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota, United States of America.
authors.forename: Jayant
authors.initials: J
authors.lastname: Talwalkar
authors.affiliation: Department of Internal Medicine, Pacific Medical Center, San Francisco, California, United States of America.
authors.forename: Timothy
authors.initials: T
authors.lastname: Davern
authors.affiliation: 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.
authors.forename: Dhanonjoy
authors.initials: D
authors.lastname: Saha
authors.affiliation: Department of Internal Medicine, IUPUI, Indianapolis, Indiana, United States of America.
authors.forename: Lauren N
authors.initials: LN
authors.lastname: Bell
authors.affiliation: Duke Clinical Research Institute, Durham, North Carolina, United States of America.
authors.forename: Huiman
authors.initials: H
authors.lastname: Barnhart
authors.affiliation: Duke Clinical Research Institute, Durham, North Carolina, United States of America.
authors.forename: Jiezhun
authors.initials: J
authors.lastname: Gu
authors.affiliation: National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland, United States of America.
authors.forename: Jose
authors.initials: J
authors.lastname: Serrano
authors.affiliation: 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.
authors.forename: Herbert L
authors.initials: HL
authors.lastname: Bonkovsky
mesh_terms: D000208:Acute Disease; D056486:Chemical and Drug Induced Liver Injury / Q000097:blood* / Q000175:diagnosis / Q000276:immunology; D015331:Cohort Studies; D016207:Cytokines / Q000097:blood*; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007113:Immunity, Innate; D018448:Models, Immunological; D011379:Prognosis
chemical_list: D016207:Cytokines