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.
OBJECTIVE
The imbalance between matrix metalloproteinases (MMPs) and tissue inhibitors of matrix metalloproteinases (TIMPs) is considered to be an important determinant of extracellular matrix deposition and breakdown. We measured serum MMP-1, MMP-2, TIMP-1 and TIMP-2 levels using the respective one-step sandwich enzyme immunoassays in 98 patients with chronic hepatitis C treated with interferon beta to examine their clinical significance for assessment of liver histology and to determine whether they can be useful as predictors of the interferon response.


RESULTS
Serum TIMP-1 levels showed a positive correlation with the degree of fibrosis (r(s)=0.30, p= 0.004). Serum MMP-2 levels revealed positive relationships with the degree of periportal necrosis (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 response 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 total amounts of serum TIMP-1 were significantly lower in transient responders and non-responders (p<0.01 and p<0.001, respectively). As for serum TIMP-2 levels, a significant decrease was found in transient responders and non-responders (p<0.01). The ratios of serum MMP-2 to TIMP-1 levels were significantly higher in transient responders and non-responders than in sustained responders (p<0.001, respectively) even when HCV RNA levels were low in patients with HCV genome subtype 1b or when the HCV genome subtype was 2a or 2b. Sustained response was never found in type 1b patients with ratios of serum MMP-2 to TIMP-1 levels of over 6.0. In logistic multivariate regression analysis, the ratios of 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 sustained response, while serum MMP-2 level (p=0.0006) was the only predictor for no response.


CONCLUSIONS
Serum MMP-2 and TIMP-1 levels might 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 interferon response in patients with chronic hepatitis C.
Kasahara
A
A
First Department of Medicine, Osaka University School of Medicine, Japan.
Hayashi
N
N
Mochizuki
K
K
Oshita
M
M
Katayama
K
K
Kato
M
M
Masuzawa
M
M
Yoshihara
H
H
Naito
M
M
Miyamoto
T
T
Inoue
A
A
Asai
A
A
Hijioka
T
T
Fusamoto
H
H
Kamada
T
T
D000410:Alanine Transaminase / Q000097:blood; D000914:Antibodies, Viral / Q000276:immunology; D000998:Antiviral Agents / Q000008:administration & dosage / Q000627:therapeutic use; D015415:Biomarkers / Q000097:blood; D002908:Chronic Disease; D017364:Collagenases / Q000097:blood; D005260:Female; D005500:Follow-Up Studies; D018093:Gelatinases / Q000097:blood*; D016679:Genome, Viral; D006023:Glycoproteins / Q000097:blood*; D016174:Hepacivirus / Q000235:genetics / Q000276:immunology; D006526:Hepatitis C / Q000201:enzymology* / Q000473:pathology / Q000628:therapy; D006801:Humans; D007124:Immunoenzyme Techniques; D007275:Injections, Intravenous; D016899:Interferon-beta / Q000008:administration & dosage / Q000627:therapeutic use; D008103:Liver Cirrhosis / Q000201:enzymology* / Q000473:pathology; D008297:Male; D020781:Matrix Metalloproteinase 1; D020778:Matrix Metalloproteinase 2; D008666:Metalloendopeptidases / Q000097:blood*; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D011480:Protease Inhibitors / Q000097:blood*; D011506:Proteins / Q000378:metabolism; D012367:RNA, Viral / Q000032:analysis; D019716:Tissue Inhibitor of Metalloproteinase-2; D019714:Tissue Inhibitor of Metalloproteinases; D016896:Treatment Outcome
D000914:Antibodies, Viral; D000998:Antiviral Agents; D015415:Biomarkers; D006023:Glycoproteins; D011480:Protease Inhibitors; D011506:Proteins; D012367:RNA, Viral; D019714:Tissue Inhibitor of Metalloproteinases; D019716:Tissue Inhibitor of Metalloproteinase-2; D016899:Interferon-beta; D000410:Alanine Transaminase; D017364:Collagenases; D018093:Gelatinases; D008666:Metalloendopeptidases; D020778:Matrix Metalloproteinase 2; D020781:Matrix Metalloproteinase 1