title: Markers of Collagen Remodeling Detect Clinically Significant Fibrosis in Chronic Hepatitis C Patients.
abstract: OBJECTIVE
  Detection of advanced fibrosis (Metavir F≥3) is important to identify patients with a high urgency of antiviral treatments vs. those whose treatment could be deferred (F≤2). The aim was to assess the diagnostic value of novel serological extracellular matrix protein fragments as potential biomarkers for clinically significant and advanced fibrosis.
  
  
  METHODS
  Specific protein fragments of matrix metalloprotease degraded type I, III, IV and VI collagen (C1M, C3M, C4M, C6M) and type III and IV collagen formation (Pro-C3 and P4NP7S) were assessed in plasma from 403 chronic hepatitis C patients by specific ELISAs. Patients were stratified according to Metavir Fibrosis stage; F0 (n = 46), F1 (n = 161), F2 (n = 95), F3 (n = 44) and F4 (n = 33) based on liver biopsy.
  
  
  RESULTS
  Pro-C3 was significantly elevated in patients with significant fibrosis (≥F2) compared to F0-F1 (p<0.05), while the markers C3M, C4M, C6M and P4NP7S were significantly elevated in patients with advanced fibrosis (≥F3) compared to F0-F2 (p<0.05). C1M showed no difference between fibrosis stages. Using Receiver Operating Characteristics analysis, the best marker for detecting ≥F2 and ≥F3 was Pro-C3 with AUC = 0.75 and AUC = 0.86. Combination of Pro-C3 and C4M with age, BMI and gender in a multiple ordered logistic regression model improved the diagnostic value for detecting ≥F2 and ≥F3 with AUC = 0.80 and AUC = 0.88.
  
  
  CONCLUSIONS
  The Pro-C3 protein fragment provided clinically relevant diagnostic accuracy as a single marker of liver fibrosis. A model combining Pro-C3 and C4M along with patient's age, body mass index and gender increased the diagnostic power for identifying clinically significant fibrosis.
authors.affiliation: Nordic Bioscience A/S, Fibrosis Biology and Biomarkers, Herlev, Denmark; Department of Gastroenterology and Hepatology, Odense University Hospital, University of Southern Denmark, Faculty of Health Science, Odense, Denmark.
authors.forename: Mette J
authors.initials: MJ
authors.lastname: Nielsen
authors.affiliation: Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Konstantin
authors.initials: K
authors.lastname: Kazankov
authors.affiliation: Nordic Bioscience A/S, Fibrosis Biology and Biomarkers, Herlev, Denmark.
authors.forename: Diana J
authors.initials: DJ
authors.lastname: Leeming
authors.affiliation: Nordic Bioscience A/S, Fibrosis Biology and Biomarkers, Herlev, Denmark.
authors.forename: Morten A
authors.initials: MA
authors.lastname: Karsdal
authors.affiliation: Department of Gastroenterology and Hepatology, Odense University Hospital, University of Southern Denmark, Faculty of Health Science, Odense, Denmark.
authors.forename: Aleksander
authors.initials: A
authors.lastname: Krag
authors.affiliation: Storr Liver Unit, Westmead Millennium Institute, Westmead Hospital and University of Sydney, Sydney, Australia.
authors.forename: Francisco
authors.initials: F
authors.lastname: Barrera
authors.affiliation: Department of Anatomical Pathology, Institute of Clinical Pathology and Medical Research, Westmead Hospital, Sydney, Australia.
authors.forename: Duncan
authors.initials: D
authors.lastname: McLeod
authors.affiliation: Storr Liver Unit, Westmead Millennium Institute, Westmead Hospital and University of Sydney, Sydney, Australia.
authors.forename: Jacob
authors.initials: J
authors.lastname: George
authors.affiliation: Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Henning
authors.initials: H
authors.lastname: Grønbæk
mesh_terms: D000328:Adult; D015415:Biomarkers / Q000378:metabolism; D003094:Collagen / Q000378:metabolism*; D005260:Female; D019698:Hepatitis C, Chronic / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D006801:Humans; D008103:Liver Cirrhosis / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies
chemical_list: D015415:Biomarkers; D003094:Collagen