title: Serum fibrosis markers are associated with liver disease progression in non-responder patients with chronic hepatitis C.
abstract: OBJECTIVE
  The aim of this study was to explore the association of serum fibrosis marker levels with the risk of clinical and histological disease progression in a large cohort of patients with chronic hepatitis C (CHC).
  
  
  METHODS
  462 prior non-responders to peginterferon and ribavirin enrolled in the randomised phase of the Hepatitis C Antiviral Long-term Treatment against Cirrhosis (HALT-C) Trial had baseline and annual serum samples tested for hyaluronic acid (HA), N-terminal peptide of procollagen type 3, tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) and YKL-40. All patients underwent a pretreatment liver biopsy and follow-up biopsies at years 2 and 4. Histological progression was defined as a ≥2 point increase in Ishak fibrosis score in patients without cirrhosis. Clinical outcomes included development of decompensation, hepatocellular cancer, death or an increase in the CTP (Child-Turcotte-Pugh) score to ≥7.
  
  
  RESULTS
  Mean patient age was 49.5 years and 39% had histological cirrhosis at entry. Baseline HA, YKL-40 and TIMP-1 levels combined with other laboratory parameters were all significantly associated with clinical outcomes in the 69 (15%) patients with disease progression (p<0.0001). The best multivariate model to predict clinical outcomes included baseline bilirubin, albumin, international normalised ratio (INR) and YKL-40 levels. All of the baseline serum fibrosis marker levels were also significantly associated with histological fibrosis progression that developed in 70 (33%) of the 209 patients with cirrhosis (p <0.0001). However, baseline HA and platelet counts were best at predicting histological progression (area under the curve (AUC)=0.663).
  
  
  CONCLUSIONS
  Pretreatment serum fibrosis marker levels are significantly increased in patients with CHC at risk of clinical and histological disease progression. If validated in additional cohorts, measurement of these markers could help identify patients with CHC who would benefit from more frequent and intensive monitoring.
authors.affiliation: Department of Internal Medicine, University of Michigan, 3912 Taubman Center, Ann Arbor, Michigan, USA. rfontana@med.umich.edu
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Fontana
authors.forename: Jules L
authors.initials: JL
authors.lastname: Dienstag
authors.forename: Herbert L
authors.initials: HL
authors.lastname: Bonkovsky
authors.forename: Richard K
authors.initials: RK
authors.lastname: Sterling
authors.forename: Deepa
authors.initials: D
authors.lastname: Naishadham
authors.forename: Zachary D
authors.initials: ZD
authors.lastname: Goodman
authors.forename: Anna S F
authors.initials: AS
authors.lastname: Lok
authors.forename: Elizabeth C
authors.initials: EC
authors.lastname: Wright
authors.forename: Grace L
authors.initials: GL
authors.lastname: Su
mesh_terms: D000328:Adult; D015415:Biomarkers / Q000097:blood; D018450:Disease Progression; D004359:Drug Therapy, Combination; D005260:Female; D005500:Follow-Up Studies; D019698:Hepatitis C, Chronic / Q000150:complications* / Q000188:drug therapy; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000627:therapeutic use; D008103:Liver Cirrhosis / Q000175:diagnosis / Q000473:pathology / Q000821:virology*; D008297:Male; D008875:Middle Aged; D015233:Models, Statistical; D011092:Polyethylene Glycols / Q000627:therapeutic use; D011379:Prognosis; D011994:Recombinant Proteins; D012254:Ribavirin / Q000627:therapeutic use
chemical_list: D015415:Biomarkers; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D011994:Recombinant Proteins; D011092:Polyethylene Glycols; D012254:Ribavirin; C100416:peginterferon alfa-2a