CIRCULATING MATRIX METALLOPROTEINASE-2 AND TISSUE INHIBITOR OF METALLOPROTEINASE-1 AS SERUM MARKERS OF FIBROSIS IN PATIENTS WITH CHRONIC HEPATITIS-C - RELATIONSHIP TO INTERFERON RESPONSE

Background/Aims/Methods: The imbalance between matrix metalloproteinas es (MMPs) and tissue inhibitors of matrix metalloproteinases (TIMPs) i s considered to be an important determinant of extracellular matrix de position and breakdown, We measured serum MMP-1, MMP-2, TIMP-1 and TIM P-2 levels using the respective one-step sandwich enzyme immunoassays in 98 patients with chronic hepatitis C treated with interferon beta t o examine their clinical significance for assessment of liver histolog y and to determine whether they can be useful as predictors of the int erferon response. Results: Serum TIMP-1 levels showed a positive corre lation with the degree of fibrosis (r(s)=0.30, p=0.004). Serum MMP-2 l evels revealed positive relationships with the degree of periportal ne crosis (r(s)=0.32, p=0.002), the degree of fibrosis (r(s)=0.26, p=0.01 ) and total score of histological activity index (r(s)=0.24, p=0.02). Serum MMP-2 levels were significantly higher in patients with no respo nse than in those with sustained and transient response (p<0.01 and p< 0.05, respectively), while serum MMP-1 levels did not differ among the three groups, Compared with the levels in sustained responders, the t otal amounts of serum TIMP-1 were significantly lower in transient res ponders and non-responders (p<0.01 and p<0.001, respectively). As for serum TIMP-2 levels, a significant decrease was found in transient res ponders and non-responders (p<0.01). The ratios of serum MMP-2 to TIMP -1 levels were significantly higher in transient responders and non-re sponders than in sustained responders (p<0.001, respectively) even whe n HCV RNA levels were low in patients with HCV genome subtype Ib or wh en the HCV genome subtype was 2a or 2b. Sustained response was never f ound in type Ib patients with ratios of serum MMP-2 to TIMP-1 levels o f over 6.0, In logistic multivariate regression analysis, the ratios o f serum MMP-2 to TIMP-1 level (p=0.0001), HCV genome subtype (p=0.005) and serum TIMP-2 level (p=0.03) were the independent predictors for s ustained response, while serum MMP2 level (p=0.0006) was the only pred ictor for no response. Conclusions: Serum MMP-2 and TIMP-1 levels migh t be useful for estimating the degree of liver fibrosis, The ratio of serum MMP-2 to TIMP-1 levels may serve as a new predictor of interfero n response in patients with chronic hepatitis C.