Tissue inhibitors of metalloproteinases in liver and serum/plasma in chronic active hepatitis C and HCV-induced cirrhosis.
OBJECTIVE
The development of liver cirrhosis can be described as a process of tissue remodeling, which involves increased matrix turnover. In order to determine whether the expression of tissue inhibitors of metalloproteinases (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 serum/plasma of patients with chronic hepatitis C, hepatitis C virus-induced cirrhosis and healthy controls.


METHODS
Northern and Western blot analysis, reverse transcriptase polymerase 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 lymphocytes 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 human liver and increased in fibrosis and cirrhosis. Western blotting demonstrated 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 high TIMP-1 values, while mean circulating TIMP-1 levels were not significantly different between controls, hepatitis C and cirrhotic patients. Serum TIMP-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 studied. The amount of hepatic TIMP-1 protein increases late in the fibrotic process, and there is a weak correlation between the activity of fibroproliferation and hepatic or circulating amounts of TIMP-1. Currently there is no evidence that measurement of TIMP-2 and TIMP-3 in liver or blood improves diagnosis of fibroproliferation in chronic hepatitis C.
Böker
K H
KH
Department of Gastroenterology and Hepatology, Medizinische Hochschule Hannover, Germany.
Pehle
B
B
Steinmetz
C
C
Breitenstein
K
K
Bahr
M
M
Lichtinghagen
R
R
D015415:Biomarkers; D015152:Blotting, Northern; D015153:Blotting, Western; D004797:Enzyme-Linked Immunosorbent Assay; D019698:Hepatitis C, Chronic / Q000097:blood / Q000378:metabolism*; D006801:Humans; D008099:Liver / Q000378:metabolism*; D008103:Liver Cirrhosis / Q000097:blood / Q000175:diagnosis / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019714:Tissue Inhibitor of Metalloproteinases / Q000097:blood / Q000378:metabolism*
D015415:Biomarkers; D019714:Tissue Inhibitor of Metalloproteinases