title: Serum proteomic profiling in patients with drug-induced liver injury.
abstract: BACKGROUND
  Idiosyncratic drug-induced liver injury (DILI) is a complex disorder that is difficult to predict, diagnose and treat.
  
  
  OBJECTIVE
  To describe the global serum proteome of patients with DILI and controls.
  
  
  METHODS
  A label-free, mass spectrometry-based quantitative proteomic approach was used to explore protein expression in serum samples from 74 DILI patients (collected within 14 days of DILI onset) and 40 controls. A longitudinal analysis was conducted in a subset of 21 DILI patients with available 6-month follow-up serum samples.
  
  
  RESULTS
  Comparison of DILI patients based on pattern, severity and causality assessment of liver injury revealed many differentially expressed priority 1 proteins among groups. Expression of fumarylacetoacetase was correlated with alanine aminotransferase (ALT; r = 0.237; P = 0.047), aspartate aminotransferase (AST; r = 0.389; P = 0.001) and alkaline phosphatase (r = -0.240; P = 0.043), and this was the only protein with significant differential expression when comparing patients with hepatocellular vs. cholestatic or mixed injury. In the longitudinal analysis, expression of 53 priority 1 proteins changed significantly from onset of DILI to 6-month follow-up, and nearly all proteins returned to expression levels comparable to control subjects. Ninety-two serum priority 1 proteins with significant differential expression were identified when comparing the DILI and control groups. Pattern analysis revealed proteins that are components of inflammation, immune system activation and several hepatotoxicity-specific pathways. Apolipoprotein E expression had the greatest power to differentiate DILI patients from controls (89% correct classification; AUROC = 0.97).
  
  
  CONCLUSIONS
  This proteomic analysis identified differentially expressed proteins that are components of pathways previously implicated in the pathogenesis of idiosyncratic drug-induced liver injury.
authors.affiliation: Division of Gastroenterology/Hepatology, Indiana University, Indianapolis, USA.
authors.forename: L N
authors.initials: LN
authors.lastname: Bell
authors.forename: R
authors.initials: R
authors.lastname: Vuppalanchi
authors.forename: P B
authors.initials: PB
authors.lastname: Watkins
authors.forename: H L
authors.initials: HL
authors.lastname: Bonkovsky
authors.forename: J
authors.initials: J
authors.lastname: Serrano
authors.forename: R J
authors.initials: RJ
authors.lastname: Fontana
authors.forename: M
authors.initials: M
authors.lastname: Wang
authors.forename: J
authors.initials: J
authors.lastname: Rochon
authors.forename: N
authors.initials: N
authors.lastname: Chalasani
mesh_terms: D000368:Aged; D015415:Biomarkers / Q000097:blood; D001798:Blood Proteins / Q000032:analysis; D016022:Case-Control Studies; D056486:Chemical and Drug Induced Liver Injury / Q000097:blood* / Q000503:physiopathology; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008099:Liver / Q000187:drug effects*; D008137:Longitudinal Studies; D008297:Male; D013058:Mass Spectrometry / Q000379:methods; D008875:Middle Aged; D020543:Proteome / Q000032:analysis*; D040901:Proteomics / Q000379:methods*; D012720:Severity of Illness Index
chemical_list: D015415:Biomarkers; D001798:Blood Proteins; D020543:Proteome