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Tissue inhibitor of metalloproteinase is increased in the serum of precirrhotic and cirrhotic alcoholic patients and can serve as a marker of fibrosis

Authors

  • Jianjun Li,

    1. Alcohol Research and Treatment Center, Bronx Veterans Affairs Medical Center and Mount Sinai School of Medicine, Bronx, New York 10468
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  • Alan S. Rosman,

    1. Alcohol Research and Treatment Center, Bronx Veterans Affairs Medical Center and Mount Sinai School of Medicine, Bronx, New York 10468
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  • Maria A. Leo,

    1. Alcohol Research and Treatment Center, Bronx Veterans Affairs Medical Center and Mount Sinai School of Medicine, Bronx, New York 10468
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  • Yasuo Nagai,

    1. Fuji Chemical Industries, Ltd., Toyama 933, Japan
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  • Charles S. Lieber M.D.

    Corresponding author
    1. Alcohol Research and Treatment Center, Bronx Veterans Affairs Medical Center and Mount Sinai School of Medicine, Bronx, New York 10468
    • Bronx VA Medical Center (151/G), Alcohol Research and Treatment Center, 130 West Kingsbridge Road, Bronx, NY 10468
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Abstract

One of the contributory factors to the development of cirrhosis is a decrease in collagenase activity, which may be related to levels of inhibitors such as serum tissue inhibitor of metalloproteinase. We therefore measured serum tissue inhibitor of metalloproteinase and serum procollagen III peptides (another proposed marker of fibrosis) in 16 healthy controls and 44 alcoholic patients with biopsy-proved liver disease, namely steatosis without fibrosis (n=13), perivenular fibrosis (n=10), septal fibrosis or cirrhosis or both (n=15) and alcoholic hepatitis (n=6). In alcoholic patients, serum tissue inhibitor of metalloproteinase values strongly correlated with fibrosis (rs=0.70, p<0.001). Compared with values in controls (177 ± 12 ng/ml), serum tissue inhibitor of metalloproteinase was significantly elevated in perivenular fibrosis (330 ± 22 ng/ml, p<0.05), in septal fibrosis, cirrhosis or both (406 ± 29 ng/ml, p<0.001) and in alcoholic hepatitis (526 ± 143 ng/ml, p<0.001) but not in steatosis (204 ± 17 ng/ml). In contrast, procollagen III peptides were significantly increased only in the septal fibrosis-cirrhosis group but not in the perivenular fibrosis group. With the threshold defined as the upper value of the steatosis group (resulting in a specificity of 100%), we found that serum tissue inhibitor of metalloproteinase was elevated in 50% of patients with perivenular fibrosis, in 87% of subjects with extensive fibrosis (septal fibrosis, cirrhosis or both) and in 67% of individuals with alcoholic hepatitis. The overall sensitivity of serum tissue inhibitor of metalloproteinase for detecting either perivenular fibrosis or more extensive fibrosis was 71%. Receiver operating characteristic curve analysis revealed that serum tissue inhibitor of metalloproteinase was significantly better than procollagen III peptides in discriminating alcoholics with fibrosis from those with steatosis (area under the receiver operating characteristic curves, 0.958 ± 0.028 vs. 0.803 ± 0.066, p<0.05). In conclusion, serum tissue inhibitor of metalloproteinase is increased in early fibrotic states in alcoholic liver disease and is a useful marker of precirrhotic and cirrhotic states. (HEPATOLOGY 1994;19:1418–1423.)

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