Associations among serum concentrations of interleukin-18, matrix metalloproteinase-2 (MMP-2), tissue inhibitor of metalloproteinase-1 (TIMP-1) and METAVIR fibrosis score in patients with chronic hepatitis

Samuel Olusi, Suad Abdeen, Sunila George
Department of Pathology, Faculty of Medicine, Kuwait University, Kuwait

Abstract: During fibrogenesis, the quantity, proportion, and composition of matrix proteins in the liver change due to the activation of hepatic stellate cells (HSCs) resulting in excessive accumulation of fibrous tissue. The exact mechanisms of these changes are not fully known. In this study, we postulated that IL-18 may upregulate matrix metalloproteinase-2 (MMP-2) and its tissue inhibitor (TIMP-1) in such proportions that will encourage fibrogenesis. To test this hypothesis we estimated the serum concentrations of IL-18, MMP-2, TIMP-1 in 56 patients with chronic hepatitis C virus (HCV), 28 patients with hepatitis B virus (HBV), 16 patients with non-alcoholic steatohepatitis (NASH) and 100 healthy controls using commercially available ELISA kits. The METAVIR activity and fibrosis scores of the liver biopsies from the patients were determined histologically. We found that IL-18 concentrations were significantly higher among HCV, HBV, and NASH patients than in healthy controls. We also found that IL-18 increased progressively from patients with no fibrosis (397.46 ± 73.54 pg/mL) to patients with cirrhosis (1384.11 ± 526.60 pg/mL). Although IL-18 is associated with minimal production of MMP-2 throughout the period of fibrosis from 199.48 ± 18.62 ng/mL at F0 to 225.25 ± 14.75 ng/mL at F4, it is associated with two-fold increase of TIMP-1 from 225.25 ± 14.75 ng/mL to 500.77 ± 30.50 ng/mL. We suggested that the high concentration of TIMP-1 inhibits the relatively low concentration of MMP-2 thus promoting the continuous deposition of collagen fibers in the liver. We concluded that IL-18 and TIMP-1 may be more important than MMP-2 in hepatic fibrogenesis.

Keywords: IL-18, MMP-2, TIMP-1, liver fibrosis