title: Increased urinary lipocalin-2 reflects matrix metalloproteinase-9 activity in chronic hepatitis C with hepatic fibrosis.
abstract: Hepatic fibrosis is characterized by excessive accumulation of extracellular matrix. Matrix metalloproteinases (MMPs) play an important role in the remodeling of the extracellular matrix during hepatic fibrosis. Lipocalin-2 (LCN2) forms complexes with MMP-9 and can be detected in the urine of patients with several types of cancers. The objective of this study was to examine the relationship between urinary LCN2 levels and MMP-9 activity with respect to the stage of liver fibrosis in patients with chronic hepatitis C (CHC), and to assess the utility of urine LCN2 as a non-invasive marker of hepatic fibrosis. Fresh spot urine samples were prospectively collected from forty-two interferon-naive CHC patients who underwent liver biopsy. The stage of hepatic fibrosis was assessed according to the METAVIR fibrosis score; 18 patients had no or mild fibrosis (stages F0 and F1) and 24 patients showed significant fibrosis (stages F2-F4). Immunoblot analyses demonstrated co-migration of urine LCN2 and MMP-9. Gelatin zymography showed that urinary MMP-9/MMP-2 activity ratios were higher in patients with significant fibrosis (F2-F4) than in patients no or mild fibrosis (F0-F1). Urine LCN2 levels which were normalized to urine creatinine concentration (urine LCN2-to-creatinine ratio; ULCR) were higher in F2-F4 patients compared to F0-F1 patients. There was a positive correlation between ULCR and urine MMP-9/MMP-2 activity ratios (r = 0.735). ULCR and AST-to-platelet ratio index were independent predictors of significant fibrosis by multivariate analysis. The present study suggests that urinary LCN2 is a novel marker of hepatic fibrosis by reflecting urine MMP-9 activity in CHC.
authors.affiliation: Department of Internal Medicine, Seoul National University College of Medicine, Seoul, South Korea. kimjw@snubh.org
authors.forename: Jin-Wook
authors.initials: JW
authors.lastname: Kim
authors.forename: Sang Hyub
authors.initials: SH
authors.lastname: Lee
authors.forename: Sook-Hyang
authors.initials: SH
authors.lastname: Jeong
authors.forename: Haeryoung
authors.initials: H
authors.lastname: Kim
authors.forename: Keun Soo
authors.initials: KS
authors.lastname: Ahn
authors.forename: Jai Young
authors.initials: JY
authors.lastname: Cho
authors.forename: Yoo-Seok
authors.initials: YS
authors.lastname: Yoon
authors.forename: Ho-Seong
authors.initials: HS
authors.lastname: Han
mesh_terms: D000209:Acute-Phase Proteins / Q000652:urine*; D003404:Creatinine / Q000652:urine; D005260:Female; D019698:Hepatitis C, Chronic / Q000150:complications / Q000201:enzymology* / Q000652:urine*; D006801:Humans; D000071068:Lipocalin-2; D054834:Lipocalins / Q000652:urine*; D008103:Liver Cirrhosis / Q000150:complications / Q000201:enzymology* / Q000652:urine*; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000652:urine*; D008875:Middle Aged; D015999:Multivariate Analysis; D011518:Proto-Oncogene Proteins / Q000652:urine*
chemical_list: D000209:Acute-Phase Proteins; C489506:LCN2 protein, human; D000071068:Lipocalin-2; D054834:Lipocalins; D011518:Proto-Oncogene Proteins; D003404:Creatinine; D020780:Matrix Metalloproteinase 9