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

TLDR

The study aimed to assess whether circulating markers could diagnose fibrosis stages in chronic hepatitis C patients, potentially replacing liver biopsy. The authors measured hyaluronate, PIIINP, MMP‑1, 2, 9, TIMP‑1, 2 in 194 hepatitis C patients and 194 matched controls and correlated the results with METAVIR fibrosis stages. Six markers correlated with fibrosis, but only PIIINP and MMP‑1 independently predicted fibrosis; a combined score achieved an AUC of 0.82 (60 % sensitivity, 92 % specificity) for distinguishing mild from significant fibrosis.

Abstract

OBJECTIVES 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 (F0/F1) from significant fibrosis (F2/F3/F4) was 0.82, with a sensitivity of 60% for a specificity of 92%. CONCLUSION Our results suggest that combining two serum markers reflecting fibrogenesis (PIIINP) and fibrolysis (MMP-1) may provide a useful tool for evaluating liver fibrosis.