Tissue inhibitors of metalloproteinases in liver and serum/plasma in chronic active hepatitis C and HCV-induced cirrhosis

Background/Aims: The development of liver cirrhosis can be described as a p rocess of tissue remodeling, which involves increased matrix turnover. In o rder to determine whether the expression of tissue inhibitors of metallopro teinases (TIMPs) reflects these changes and can be used as a marker for the activity of ongoing fibrosis, we studied TIMP-1, 2 and -3 in liver and ser um/plasma of patients with chronic hepatitis C, hepatitis C virus-induced c irrhosis and healthy controls. Methodology: Northern and Western blot analysis, reverse transcriptase poly merase chain reaction and ELISA measurements were performed. Results: Reverse transcriptase polymerase chain reaction showed transcripts of all 3 TIMPs in liver tissue. TIMP-1 and -2 were also detectable in lymp hocytes and granulocytes, which did not contain any TIMP-3. mRNA for TIMP-1 and -3, but not for TIMP-2, was detectable by Northern blot in normal huma n liver and increased in fibrosis and cirrhosis. Western blotting demonstra ted the presence of all 3 TIMP proteins in healthy liver. TIMP-1 and TIMP-2 levels increased, but TIMP-3 was unchanged in cirrhosis compared to normal tissue. ELISA studies showed that the increase of TIMP-1 occurred only in advanced cirrhosis, while levels did not Elevate in chronic hepatitis with or without fibrosis. In plasma, some of the cirrhotic patients had very hig h TIMP-1 values, while mean circulating TIMP-1 levels were not significantl y different between controls, hepatitis C and cirrhotic patients. Serum TIM P-2 levels were higher in chronic hepatitis and cirrhosis than in controls, but did not differ between patients with or without histologic fibrosis. Conclusions: In normal human liver there is expression of all 3 TIMPs studi ed. The amount of hepatic TIMP-1 protein increases late in the fibrotic pro cess, and there is a weak correlation between the activity of fibroprolifer ation and hepatic or circulating amounts of TIMP-1. Currently there is no e vidence that measurement of TIMP-2 and TIMP-3 in liver or blood improves di agnosis of fibroproliferation in chronic hepatitis C.