title: Noninvasive markers of liver fibrosis: on-treatment changes of serum markers predict the outcome of antifibrotic therapy.
abstract: OBJECTIVE
  The utility of noninvasive serum markers to longitudinally monitor liver fibrosis is not established.
  
  
  METHODS
  A total of 70 patients with chronic hepatitis C who had previously failed antiviral therapy were randomized to receive pegylated interferon with or without silymarin for 24 months. Enhanced Liver Fibrosis (ELF) tests (hyularonic acid, terminal peptide of procollagen III, tissue inhibitor of matrix metaloproteinase-1) were performed on patient sera obtained before, during and at the end of the study (0, 12, 24 months) and liver histology obtained before and at the end of the study.
  
  
  RESULTS
  At 24 months, absolute changes in Ishak fibrosis stage and ELF ranged from -4 to +4 and from -2.41 to +2.68, respectively. Absolute changes in ELF at 12 months were significantly associated with changes in both ELF and histology at 24 months. A model combining both baseline ELF and change of ELF at 12 months could predict the 24-month ELF (R=0.609, P<1×10), a decrease in ELF at 24 months [area under the curve (AUC): 0.80-0.85] and an increase in ELF at 24 months (AUC: 0.81-0.85). Furthermore, a model combining both baseline histologic stage and ELF together with the change of ELF at 12 months could predict 24-month histology (R=0.601, P<1×10, AUC: 0.88-0.92), histologic fibrosis regression (AUC: 0.81-0.84) and progression (AUC: 0.86-0.91).
  
  
  CONCLUSIONS
  Our observations suggest that a change in the serum marker ELF predicts changes in liver fibrosis over a longer period. These data support the use of ELF as a surrogate marker of liver fibrosis evolution in monitoring antifibrotic treatments, thus permitting 'response-guided' therapy by the early identification of patients who will benefit from prolonged treatment.
authors.affiliation: aDivision of Medicine, Institute for Liver and Digestive Health, University College London bDepartment of Clinical Microbiology and Virology, University College London Hospitals NHS Foundation Trust, London cDepartment of Public Health Sciences and Medical Statistics, Faculty of Medicine, University of Southampton, Southampton, UK dDepartment of Medicine 1, University of Erlangen, Erlangen eInstitute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry fDepartment of Medicine, Research Center for Immunology (FZI), University of Mainz, Mainz, Germany gInstitute of Pathology, Paracelsus Medical University/Salzburger Landeskliniken (SALK), Salzburg, Austria hDivision of Gastroenterology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Sudeep
authors.initials: S
authors.lastname: Tanwar
authors.forename: Paul M
authors.initials: PM
authors.lastname: Trembling
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Hogan
authors.forename: Ankur
authors.initials: A
authors.lastname: Srivastava
authors.forename: Julie
authors.initials: J
authors.lastname: Parkes
authors.forename: Scott
authors.initials: S
authors.lastname: Harris
authors.forename: Paul
authors.initials: P
authors.lastname: Grant
authors.forename: Eleni
authors.initials: E
authors.lastname: Nastouli
authors.forename: Mathias
authors.initials: M
authors.lastname: Ocker
authors.forename: Klaus
authors.initials: K
authors.lastname: Wehr
authors.forename: Christoph
authors.initials: C
authors.lastname: Herold
authors.forename: Daniel
authors.initials: D
authors.lastname: Neureiter
authors.forename: Detlef
authors.initials: D
authors.lastname: Schuppan
authors.forename: William M
authors.initials: WM
authors.lastname: Rosenberg
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000998:Antiviral Agents / Q000009:adverse effects / Q000627:therapeutic use*; D019540:Area Under Curve; D001317:Austria; D015415:Biomarkers / Q000097:blood; D001706:Biopsy; D004359:Drug Therapy, Combination; D005260:Female; D005838:Genotype; D005858:Germany; D016174:Hepacivirus / Q000187:drug effects / Q000235:genetics; D019698:Hepatitis C, Chronic / Q000097:blood / Q000175:diagnosis / Q000188:drug therapy*; D006801:Humans; D006820:Hyaluronic Acid / Q000097:blood; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000009:adverse effects / Q000627:therapeutic use*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000821:virology; D008103:Liver Cirrhosis / Q000097:blood / Q000175:diagnosis / Q000188:drug therapy* / Q000821:virology; D008297:Male; D008875:Middle Aged; D010446:Peptide Fragments / Q000097:blood; D011092:Polyethylene Glycols / Q000009:adverse effects / Q000627:therapeutic use*; D011237:Predictive Value of Tests; D011347:Procollagen / Q000097:blood; D011446:Prospective Studies; D012367:RNA, Viral / Q000097:blood; D012372:ROC Curve; D011994:Recombinant Proteins / Q000009:adverse effects / Q000627:therapeutic use; D012838:Silymarin / Q000009:adverse effects / Q000627:therapeutic use*; D013997:Time Factors; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000097:blood; D016896:Treatment Outcome; D019562:Viral Load; D055815:Young Adult
chemical_list: D000998:Antiviral Agents; D015415:Biomarkers; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D010446:Peptide Fragments; D011347:Procollagen; D012367:RNA, Viral; D011994:Recombinant Proteins; D012838:Silymarin; C560822:TIMP1 protein, human; D019715:Tissue Inhibitor of Metalloproteinase-1; C041876:procollagen Type III-N-terminal peptide; D011092:Polyethylene Glycols; D006820:Hyaluronic Acid; C417083:peginterferon alfa-2b