Obesity and steatosis influence serum and hepatic inflammatory markers in chronic hepatitis C.
ABSTRACT Obesity and fatty liver are commonly observed among patients with chronic hepatitis C virus (HCV) and are risk factors for increased hepatic fibrosis. Obesity is accompanied by a low-grade, chronic inflammatory response that may contribute to pathogenesis of obesity-related comorbidities. To assess whether obesity and steatosis potentiate expression of inflammatory markers in chronic HCV, serum protein and hepatic messenger RNA (mRNA) levels of c-reactive protein (CRP), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-alpha) were measured in 171 patients with chronic HCV. The relationships of body mass index, steatosis, histological features of inflammation and fibrosis with serum and hepatic levels of these factors were determined. In comparison with lean patients, overweight and obese subjects had increased circulating (P < 0.001) and hepatic (P = 0.003) CRP, and there was a significant correlation between serum protein and hepatic CRP mRNA levels (r(s)= 0.51, P < 0.001). Obesity (P = 0.001) and steatosis (P < 0.001) were associated with increased circulating but not hepatic IL-6, and a weak correlation was seen between serum protein and hepatic IL-6 mRNA levels (r(s)= 0.29, P = 0.003). An independent relationship was seen between hepatic TNF-alpha mRNA levels and higher total inflammatory score (P < 0.001) and stage of fibrosis (P = 0.037). Subjects with HCV genotype 3 had lower hepatic TNF-alpha mRNA levels compared with subjects with genotype 1 (P = 0.017), but there was no relationship between serum TNF-alpha protein and hepatic TNF-alpha mRNA levels. CONCLUSION: In patients with chronic HCV, obesity and steatosis are associated with increased expression of selected inflammatory markers; however, circulating levels of IL-6 and TNF-alpha do not reflect hepatic expression. Hepatic TNF-alpha was associated with both increased inflammatory activity and hepatic fibrosis, providing support for the key role of this pro-inflammatory cytokine in liver injury in chronic HCV.
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ABSTRACT: A Histology Activity Index has been developed which generates a numerical score for liver biopsy specimens obtained from patients with asymptomatic chronic active hepatitis. Biopsies are graded in four categories: periportal necrosis, intralobular necrosis, portal inflammation, and fibrosis. Under code, three pathologists and three hepatologists evaluated 14 liver biopsy specimens obtained from five patients with asymptomatic chronic active hepatitis. Good correlation was seen between severity of liver biopsy lesions as judged by conventional histological descriptions and Histology Activity Index scores. Significant differences in Histology Activity Index score occurred in only 2 or 28 duplicate scorings of biopsy specimens by two observers. This system provides definitive endpoints for statistical analysis of serial changes in liver histology and offers an alternative to the use of conventional pathological descriptions in following the natural history and treatment responses of asymptomatic chronic active hepatitis.Hepatology 1(5):431-5. · 12.00 Impact Factor
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ABSTRACT: The role of tumor necrosis factor alpha, interleukin 6, leptin, and adiponectin in the pathogenesis of hepatitis C virus (HCV)-associated insulin resistance (IR) remains controversial. We tested the hypothesis that these adipocytokines contribute to chronic HCV-associated IR and liver injury by first comparing their serum levels and homeostasis model assessment of insulin resistance (HOMA-IR) in 154 untreated, non-diabetic, HCV-infected male subjects with fibrosis stage 0-2, to that in 75 healthy volunteers matched for age, body mass index (BMI), and waist-hip ratio (WHR). We next examined whether the adipocytokine levels were associated with the extent of hepatic steatosis, portal/periportal inflammation and fibrosis in our total cohort of 240 HCV-infected male subjects. Significantly higher levels of HOMA-IR (2.12 versus 1.63, P = 0.01), TNFalpha (1.28 versus 0.60 pg/ml, P < 0.001) and IL6 (2.42 versus 1.15 pg/ml, P = 0.001) were noted in the HCV cohort compared with healthy controls respectively, but there were no significant differences in leptin and adiponectin concentrations. By multiple linear regression, independent predictors of HOMA-IR included the body mass index, and the serum levels of leptin (positive correlation) and adiponectin (negative correlation), but not that of TNFalpha and IL6. Only TNFalpha levels were correlated with the extent of histological injury (portal/periportal inflammation, P = 0.02). CONCLUSION: Whereas leptin and adiponectin contribute to IR, none of the adipocytokines accounted for the elevated IR in HCV-infected subjects. The adipocytokines were not associated with histological features of chronic HCV infection except for TNFalpha which correlated with portal/periportal inflammation. HCV-associated IR is most likely an adipocytokine-independent effect of the virus to modulate insulin sensitivity.Hepatology 07/2007; 46(1):66-73. · 12.00 Impact Factor
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ABSTRACT: Tumor necrosis factor alpha (TNF-alpha) is a multifunctional cytokine that has an important role in the pathogenesis of inflammation, cachexia, and septic shock. Although TNF-alpha is mainly produced by macrophages, there is evidence regarding TNF-alpha production by cells that are not derived from bone marrow. TNF-alpha production by normal and inflamed human liver was assessed at both mRNA and protein levels. Using a wide panel of novel anti-TNF-alpha monoclonal antibodies and a specific polyclonal antiserum, TNF-alpha immunoreactivity was found in hepatocytes from patients chronically infected with either hepatitis B virus (HBV) or hepatitis C virus. Minimal TNF-alpha immunoreactivity was detected in the mononuclear cell infiltrate and Kupffer cells. In situ hybridization experiments using a TNF-alpha RNA probe showed a significant expression of TNF-alpha mRNA in hepatocytes, Kupffer cells, and some infiltrating mononuclear cells. By contrast, TNF-alpha was detected at low levels in liver biopsies from normal individuals or patients with alcoholic liver disease and low expression of TNF-alpha mRNA was observed in these specimens. Transfection of HepG2 hepatoblastoma cells with either HBV genome or HBV X gene resulted in induction of TNF-alpha expression. Our results demonstrate that viral infection induces, both in vivo and in vitro, TNF-alpha production in hepatocytes, and indicate that the HBV X protein may regulate the expression of this cytokine. These findings suggest that TNF-alpha may have an important role in human liver diseases induced by viruses.Journal of Experimental Medicine 04/1994; 179(3):841-8. · 13.21 Impact Factor