title: Serum proteome profiling identifies novel and powerful markers of cystic fibrosis liver disease.
abstract: OBJECTIVE
  Cystic Fibrosis associated liver disease (CFLD) develops in approximately 30% of CF patients. However, routine sensitive diagnostic tools for CFLD are lacking. Within this study, we aimed to identify new experimental biomarkers for the detection of CFLD.
  
  
  METHODS
  45 CF patients were included in the study and received transient elastography. Differential regulation of 220 different serum proteins was assessed in a subgroup of patients with and without CFLD. Most interesting candidate proteins were further quantified and validated by ELISA in the whole patient cohort. To assess a potential relation of biomarker expression to the degree of hepatic fibrosis, serum biomarkers were further determined in 18 HCV patients where liver histology was available.
  
  
  RESULTS
  43 serum proteins differed at least 2-fold in patients with CFLD compared to those without liver disease as identified in proteome profiling. In ELISA quantifications, TIMP-4 and Endoglin were significantly up-regulated in patients with CFLD as diagnosed by clinical guidelines or increased liver stiffness. Pentraxin-3 was significantly decreased in patients with CFLD. Serum TIMP-4 and Endoglin showed highest values in HCV patients with liver cirrhosis compared to those with fibrosis but without cirrhosis. At a cut-off value of 6.3 kPa, transient elastography compassed a very high diagnostic accuracy and specificity for the detection of CFLD. Among the biomarkers, TIMP-4 and Endoglin exhibited a high diagnostic accuracy for CFLD. Diagnostic sensitivities and negative predictive values were increased when elastography and TIMP-4 and Endoglin were combined for the detection of CFLD.
  
  
  CONCLUSIONS
  Serum TIMP-4 and Endoglin are increased in CFLD and their expression correlates with hepatic staging. Determination of TIMP-4 and Endoglin together with transient elastography can increase the sensitivity for the non-invasive diagnosis of CFLD.
authors.affiliation: Justus-Liebig-University Giessen, Department of Internal Medicine, Division of Gastroenterology, Giessen, Germany.
authors.forename: Timo
authors.initials: T
authors.lastname: Rath
authors.forename: Lisa
authors.initials: L
authors.lastname: Hage
authors.forename: Marion
authors.initials: M
authors.lastname: Kügler
authors.forename: Katrin
authors.initials: K
authors.lastname: Menendez Menendez
authors.forename: Reinhart
authors.initials: R
authors.lastname: Zachoval
authors.forename: Lutz
authors.initials: L
authors.lastname: Naehrlich
authors.forename: Richard
authors.initials: R
authors.lastname: Schulz
authors.forename: Martin
authors.initials: M
authors.lastname: Roderfeld
authors.forename: Elke
authors.initials: E
authors.lastname: Roeb
mesh_terms: D000293:Adolescent; D000328:Adult; D015415:Biomarkers / Q000097:blood; D002648:Child; D002675:Child, Preschool; D003550:Cystic Fibrosis / Q000150:complications*; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D008103:Liver Cirrhosis / Q000097:blood / Q000150:complications / Q000175:diagnosis / Q000378:metabolism; D008107:Liver Diseases / Q000097:blood* / Q000150:complications* / Q000175:diagnosis / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D040901:Proteomics; D019714:Tissue Inhibitor of Metalloproteinases / Q000097:blood; D055815:Young Adult; D000097792:Tissue Inhibitor of Metalloproteinase-4
chemical_list: D015415:Biomarkers; D019714:Tissue Inhibitor of Metalloproteinases; D000097792:Tissue Inhibitor of Metalloproteinase-4