Circulating matrix metalloproteinases 1, 2, 9 and their inhibitors TIMP-1 and TIMP-2 as serum markers of liver fibrosis in patients with chronic hepatitis C: comparison with PIIINP and hyaluronic acid.
OBJECTIVE
Histological examination of liver biopsy is currently required in the management of patients with chronic hepatitis C. Our aim was to evaluate the diagnostic utility of a panel of circulating markers in detecting the stage of fibrosis.


METHODS
One hundred and ninety four-patients who had undergone a percutaneous liver biopsy before antiviral treatment, and 194 age- and sex-matched healthy subjects were studied. Serum levels of hyaluronate, procollagen type III N-terminal peptide (PIIINP), matrix metalloproteinases (MMP)-1, MMP-2, MMP-9 and their tissue inhibitors of metalloproteinases (TIMP)-1 and TIMP-2 were determined by RIA and ELISA. Histological lesions were staged according to the METAVIR score.


RESULTS
Hyaluronate, PIIINP, TIMP-1, and TIMP-2 serum levels were significantly higher in patients than in controls. Six markers were significantly correlated with fibrosis: MMP-2 (r = 0.28; p < 0.01), TIMP-1 (r = 0.42; p < 0.001), HA (r = 0.50; p < 0.001), PIIINP (r = 0.62; p < 0.0001), MMP-1 (r = -0.32; p < 0.01), and MMP-9 (r = -0.22; p < 0.05). By multivariate analysis, only PIIINP and MMP-1 were independently associated with fibrosis, and were combined using the equation of the logistic regression model. Using receiver-operating characteristics analysis, the area under the curve of the score to discriminate mild (FO/F1) from significant fibrosis (F2/F3/F4) was 0.82, with a sensitivity of 60% for a specificity of 92%.


CONCLUSIONS
Our results suggest that combining two serum markers reflecting fibrogenesis (PIIINP) and fibrolysis (MMP-1) may provide a useful tool for evaluating liver fibrosis.
Leroy
Vincent
V
Département d 'Hépato-Gastroentérologie, CHU de Grenoble, France.
Monier
Frederique
F
Bottari
Serge
S
Trocme
Candice
C
Sturm
Nathalie
N
Hilleret
Marie-Noëlle
MN
Morel
Francoise
F
Zarski
Jean-Pierre
JP
D000328:Adult; D015415:Biomarkers / Q000097:blood; D017364:Collagenases / Q000097:blood*; D005260:Female; D019698:Hepatitis C, Chronic / Q000097:blood* / Q000150:complications / Q000473:pathology; D006801:Humans; D006820:Hyaluronic Acid / Q000097:blood; D008103:Liver Cirrhosis / Q000097:blood* / Q000473:pathology; D008297:Male; D020781:Matrix Metalloproteinase 1 / Q000097:blood; D020778:Matrix Metalloproteinase 2 / Q000097:blood; D020780:Matrix Metalloproteinase 9 / Q000097:blood; D008875:Middle Aged; D010446:Peptide Fragments / Q000097:blood; D011347:Procollagen / Q000097:blood; D012720:Severity of Illness Index; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000097:blood; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000097:blood; D019714:Tissue Inhibitor of Metalloproteinases / Q000097:blood*
D015415:Biomarkers; D010446:Peptide Fragments; D011347:Procollagen; D019715:Tissue Inhibitor of Metalloproteinase-1; D019714:Tissue Inhibitor of Metalloproteinases; C041876:procollagen Type III-N-terminal peptide; D019716:Tissue Inhibitor of Metalloproteinase-2; D006820:Hyaluronic Acid; D017364:Collagenases; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D020781:Matrix Metalloproteinase 1