title: Diagnostic potential of circulating TIMP-1 and MMP-2 as markers of liver fibrosis in patients with chronic hepatitis C.
abstract: BACKGROUND
  Circulating levels of tissue inhibitor of metalloproteinase (TIMP)-1 and matrix metalloproteinase (MMP)-2 are investigated as parameters for the diagnosis of fibrosis in chronic liver disease. We evaluated their diagnostic potential in comparison to hepatic histology, serum hyaluronate and standard liver function tests.
  
  
  METHODS
  Commercially available ELISA assays were used to study circulating values of TIMP-1 and MMP-2 (Bindazyme, Biotrak, Quantikine) in patients with chronic hepatitis C (CAH; n=59), hepatitis C virus-induced cirrhosis (n=19) and 30 healthy controls. Hepatic histology was evaluated using the Hepatitis-Activity-Index according to Ishak et al. [J. Hepatol., 22 (1995) 696-699], quantifying separately inflammatory activity and fibrosis.
  
  
  RESULTS
  Normal ranges for TIMP-1 and MMP-2 values differed for the different assays. Nevertheless, the various assays showed similar diagnostic ability and linear correlation. MMP-2 values were similar in controls and in CAH patients with and without fibrosis, but increased significantly in cirrhosis. TIMP-1 values showed a steady increase from normal to CAH without fibrosis, hepatitis with fibrosis, and cirrhosis. The diagnostic potential of serum MMP-2 to detect fibrosis was low with a sensitivity of 7% in the two assays used and an overall diagnostic efficiency of 56% and 58%. The potential of circulating MMP-2 to detect cirrhosis was higher with sensitivities of 74% and 83% and specificities of 96% and 100%, resulting in a diagnostic efficiency of 92% in the different assays. Plasma TIMP-1 values detect fibrosis with a sensitivity of 52% and 67% and a specificity of 68% and 88% resulting in overall efficiency rates of 68% and 71%, respectively. TIMP-1 values detect cirrhosis with 100% sensitivity but only 56% and 75% specificity. The diagnostic potential of circulating TIMP-1 was similar to that of hyaluronate and better than that of enzymes or albumin values.
  
  
  CONCLUSIONS
  Plasma values of TIMP-1 and MMP-2 are able to detect cirrhosis with high sensitivity. TIMP-1 values also detect fibrosis with comparable efficiency. Regular determinations of both TIMP-1 and MMP-2 in CAH patients may be used as indicators of increasing fibrosis and the development of cirrhosis.
authors.affiliation: Department of Gastroenterology and Hepatology, Medizinische Hochschule, D-30623 Hanover, Germany.
authors.forename: Klaus H W
authors.initials: KH
authors.lastname: Boeker
authors.forename: Christian I
authors.initials: CI
authors.lastname: Haberkorn
authors.forename: Dirk
authors.initials: D
authors.lastname: Michels
authors.forename: Peer
authors.initials: P
authors.lastname: Flemming
authors.forename: Michael P
authors.initials: MP
authors.lastname: Manns
authors.forename: Ralf
authors.initials: R
authors.lastname: Lichtinghagen
mesh_terms: D015415:Biomarkers / Q000097:blood; D001706:Biopsy; D016022:Case-Control Studies; D019698:Hepatitis C, Chronic / Q000097:blood / Q000150:complications*; D006801:Humans; D006820:Hyaluronic Acid / Q000097:blood; D008099:Liver / Q000737:chemistry / Q000378:metabolism / Q000473:pathology; D008103:Liver Cirrhosis / Q000097:blood / Q000175:diagnosis* / Q000821:virology; D020778:Matrix Metalloproteinase 2 / Q000097:blood*; D012333:RNA, Messenger / Q000032:analysis; D012372:ROC Curve; D011933:Reagent Kits, Diagnostic / Q000592:standards; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000097:blood*
chemical_list: D015415:Biomarkers; D012333:RNA, Messenger; D011933:Reagent Kits, Diagnostic; D019715:Tissue Inhibitor of Metalloproteinase-1; D006820:Hyaluronic Acid; D020778:Matrix Metalloproteinase 2