TISSUE INHIBITOR OF METALLOPROTEINASE IS INCREASED IN THE SERUM OF PRECIRRHOTIC AND CIRRHOTIC ALCOHOLIC PATIENTS AND CAN SERVE AS A MARKER OF FIBROSIS

One of the contributory factors to the development of cirrhosis is a d ecrease in collagenase activity, which may be related to levels of inh ibitors such as serum tissue inhibitor of metalloproteinase. We theref ore measured serum tissue inhibitor of metalloproteinase and serum pro collagen III peptides (another proposed marker of fibrosis) in 16 heal thy controls and 44 alcoholic patients with biopsy-proved liver diseas e, namely steatosis without fibrosis (n = 13), perivenular fibrosis (n = 10), septal fibrosis or cirrhosis or both (n = 15) and alcoholic he patitis (n = 6). In alcoholic patients, serum tissue inhibitor of meta lloproteinase values strongly correlated with fibrosis (r(s) = 0.70, p < 0.001). Compared with values in controls (177 +/- 12 ng/ml), serum tissue inhibitor of metalloproteinase was significantly elevated in pe rivenular fibrosis (330 +/- 22 ng/ml, p < 0.05), in septal fibrosis, c irrhosis or both (406 +/- 29 ng/ml, p < 0.001) and in alcoholic hepati tis (526 +/- 140 ng/ml, p < 0.001) but not in steatosis (204 +/- 17 ng /ml). In contrast, procollagen III peptides were significantly increas ed only in the septal fibrosis-cirrhosis group but not in the perivenu lar fibrosis group. With the threshold defined as the upper value of t he steatosis group (resulting in a specificity of 100%), we found that serum tissue inhibitor of metalloproteinase was elevated in 50% of pa tients with perivenular fibrosis, in 87% of subjects with extensive fi brosis (septal fibrosis, cirrhosis or both) and in 67% of individuals with alcoholic hepatitis. The overall sensitivity of serum tissue inhi bitor of metalloproteinase for detecting either perivenular fibrosis o r more extensive fibrosis was 71%. Receiver operating characteristic c urve analysis revealed that serum tissue inhibitor of metalloproteinas e was significantly better than procollagen III peptides in discrimina ting alcoholics with fibrosis from those with steatosis (area under th e receiver operating characteristic curves, 0.958 +/- 0.028 vs. 0.803 +/- 0.066, p < 0.05). In conclusion, serum tissue inhibitor of metallo proteinase is increased in early fibrotic states in alcoholic liver di sease and is a useful marker of precirrhotic and cirrhotic states.