Plasma Levels of Matrix Metalloproteinase-2 (MMP-2) and Tissue Inhibitors of Metalloproteinases -1 and -2 (TIMP-1 and TIMP-2) as Noninvasive Markers of Liver Disease in Chronic Hepatitis C Comparison Using ROC Analysis KEVIN MICHAEL WALSH, MRCPI, PETER TIMMS, BSc, STEWART CAMPBELL, MRCP, RONALD NORMAN MACIVER MACSWEEN, FRCPath, and ALLAN JOHN MORRIS, MRCP As chronic liver disease progre sses, an imbalance occurs between synthe sis and breakdown of extracellular matrix (ECM). Matrix metalloprote inases (MMPs) are involve d in degrading ECM while tissue inhibitors of metalloprote inases (TIMPs) prevent their ®brolytic action. We determined if plasma levels of MMP-2, TIMP-1 and TIMP-2 are related to live r histology in patients with chronic hepatitis C. Plasma MMP-2, TIMP-1 and TIMP-2 levels were measured in 43 patients with chronic hepatitis C. Plasma levels of MMP-2, TIMP-1 and TIMP-2 and serum ALT were correlated with liver biopsy score and speci®city and sensitivity of the assays in detecting advanced liver disease were calculated from ROC analysis. Plasma TIMP-1 was signi®cantly correlated with histological activity index (r 5 0.45), portal in¯am- mation (r 5 0.48), periportal necrosis (r 5 0.34) and focal necrosis (r 5 0.38) . Plasma TIMP-2 was signi®cantly correlated with ®brosis (r 5 0.43) and con¯uent necrosis (r 5 0.41). Using ROC analysis both TIMP-1 and TIMP-2 had signi®cant diagnostic ability in detecting advanced liver disease (Area under the curve 0.73 for both, p 0.015 and 0.036 respectively). A normal plasma TIMP-1 excluded advance d liver disease. Neither plasma MMP-2 or serum ALT were related to ®brosis or to histological activity index. With increased severity of liver disease in chronic hepatitis C there is increased plasma levels of TIMPs -1 and -2. Plasma TIMP-1 and TIMP-2 are sensitive and to a lesser extent speci®c in detecting advanced liver disease in chronic hepatitis C and could be used in preference to serum ALT. KEY WORDS: Hepatitis C; metalloproteinase inhibitors; liver biopsy; ROC analysis; noninvasive marker; matrix metalloproteinase 2. Since its discovery in 1989 (1), hepatitis C has been found to be the etiological agent for a signi®cant number of patients with chronic liver disease (2, 3). Many patients with clotting disorders have contracted Manuscript received July 9, 1998; revised manuscript received October 5, 1998; accepted October 19, 1998. From the Department of Biochemistry, Stobhill Hospital; and De- partment of Pathology, Western In®rmary, Departments of Human Nutrition and Gastroenterology, Royal In®rmary, Glasgow, UK. Address for reprint requests: Dr. John Morris, Glasgow Royal In®rmary, Castle Street, Glasgow G4 0SF, UK. Digestive Diseases and Sciences, Vol. 44, No. 3 (March 1999), pp. 624±630 624 Digestive Diseases and Sciences, Vol. 44, No. 3 (March 1999) 0163-2116/99/0300-0624$16.00/0 Ñ 1999 Plenum Publishing Corporation