Plasma leptin, tumor necrosis factor-alpha and tissue inhibitor of metalloproteinase-1 in chronic hepatitis C patients and their relation to hepatic fibrosis

ABSTRACT

Hepatitis C virus [HCV] infection is a major cause of chronic hepatitis which frequently leads to progressive hepatic fibrosis and ultimately liver cirrhosis. Many humoral factors and cytokines are known to have profibrogenic and proinflammatory role in chronic hepatitis C patients [CHC] including leptin and TNF-alpha that act in an orchestrated manner with other factors to augment hepatic fibragenesis and. High circulating levels of leptin have been observed in CHC patients, and activated hepatic stellate cells [HSCS] are the effector cells producing leptin in addition to the adipose tissue cells. These HSCS secrete also tissue inhibitor of metalloproteinase-l [TIMP-1] which is one of TIMPS that interact with matrix metalloproteinases [MMPS] to regulate the turnover of extracellular matrix. The role of TIMP-1 in hepatic fibrogenesis and its possible value as a serum marker predicting liver fibrosis was reported in many studies. The aim of this study was to evaluate the possible role of leptin and TN F-alpha in hepatic. fibrogenesis and the possible role of TIMP-1 in determining the progression of liver fibrosis in a cohort of CHC patients. We aimed to evaluate the potential use of these serum markers to predict hepatic fibrosis. We measured leptin and TNF-alpha in the plasma of 55 CHC patients and 25 age and sex matched control persons by radioimmunoassay. Serum TIMP-1 was measured in both CHC patients and control persons by ELISA method. Liver disease in CHC patients was evaluated by the stage of hepatic fibrosis, grading of necroinflammation and grading of hepatic steatosis in liver biopsy. The mean age of CHC patients was 42.2 years [27-69 years] and the mean age of normal control persons was 4l.5[25-67 years]. Plasma - leptin, TNF-alpha and TIMP-1 were significantly higher in CHC patients compared to the normal controls [P<0.001 for leptin, P<0.05 for TNF-alpha, P<0.05 for TIMP-1]. Leptin correlated with BMI [body mass index] in CHC patients [males r=0.51 P<0.01, [females r=0.75 P<0.001], while both TNF-alpha and TIMP-1 did not correlate with any of clinical or biochemical parameters in CHC patients. Leptin levels increased as hepatic fibrosis stage progressed both in male and female CHC patients [males P<0.01, females P<0.001]. TNF-alpha levels and TIMP-1 levels were significantly higher in advanced stages of hepatic fibrosis [P<0.01 for TNF-alpha, P<0.001 forTIMP-1]. Plasma leptin and TNF-alpha levels showed no correlation with hepatic steatosis or histological necroinflammatory activity in CHC patients- Serum TIMP-1 levels did not correlate with hepatic steatosis but correlated with histological activity in CHC patients [Knodells score r=0.91 P<0.001; Scheuer's Score r=0.84 P<0.001]. Serum leptin levels did not correlate with TNF-a levels [r=0.18 P>0.05] or TIMP-1 levels [r=0.21 P>0.05]. Our data showed that serum leptin increased in CHC patients according to the severity of hepatic fibrosis. It seems to play a role in regulating hepatic fibrosis in addition to TNF-alpha and other profibrogenic cytokines. TIMP-1 levels increased similarly in advanced stage of hepatic fibrosis and it seems to be involved in determining the progression of hepatic fibrosis. These serum markers are potentially good tools to assess hepatic fibrosis in CHC patients and they may be useful to assess the response to antiviral therapy. They may represent therapeutic targets in the future to modulate or stop hepatic fibrosis