Increased intrahepatic and circulating levels of endoglin, a TGF-beta1 co-receptor, in patients with chronic hepatitis C virus infection: relationship to histological and serum markers of hepatic fibrosis.

Endoglin, a transforming growth factor (TGF)-beta1 co-receptor, has been associated with renal and cutaneous fibrosis, as overexpression of this protein has been observed in biopsies from patients with glomerulosclerosis and scleroderma, respectively. Our aim was to evaluate whether endoglin may be associated with hepatic fibrosis featuring chronic hepatitis C virus (HCV) infection. Fifty-two anti-HCV+ patients, five anti-HCV- patients and 27 healthy subjects were studied. Western blot and immunohistochemistry were used to quantify the expression levels of endoglin and TGF-beta1 in liver biopsy samples, and serum concentrations of endoglin and hyaluronic acid were determined by enzyme-linked immunosorbent assays (ELISAs). In patients with advanced fibrosis, intrahepatic expression levels of endoglin and TGF-beta1 were significantly higher than those in patients with early fibrosis (mean: 3- and 5.8-fold, respectively) and normal liver (mean: 3.9- and 12-fold, respectively). Interestingly, activated hepatic stellate cells as well as portal and septal myofibroblasts expressed endoglin. Serum levels of endoglin were also significantly higher in patients with advanced fibrosis than in those with early fibrosis (55.5 +/- 1.6 vs 47.5 +/- 0.9 ng/mL, P < 0.001), showing a positive correlation with serum hyaluronic acid concentrations (r = 0.57, P = 0.01). In conclusion, increased intrahepatic endoglin and TGF-beta1 expression is significantly associated with progressive hepatic fibrosis in chronic HCV infection. Circulating endoglin levels are elevated in HCV patients showing a significant correlation with histological and serum markers of hepatic fibrosis. These data suggest an active role for endoglin in the fibrotic process featuring chronic HCV infection.

Association of pretreatment serum interferon gamma inducible protein 10 levels with sustained virological response to peginterferon plus ribavirin therapy in genotype 1 infected patients with chronic hepatitis C.

BACKGROUND: Increased serum and intrahepatic interferon gamma inducible protein 10 (IP-10) levels in patients with chronic hepatitis C (CHC) have been described. AIM: To analyse the possible association of serum IP-10 levels with different outcomes to antiviral therapy. PATIENTS: A total of 137 CHC patients treated with peginterferon plus ribavirin. METHODS: Serum IP-10 levels were determined by enzyme linked immunosorbent assay before therapy, after 12 weeks of treatment, and 24 weeks after cessation of therapy. Variables significantly associated with a sustained virological response (SVR) on univariate analysis were included in a multivariate logistic regression model. RESULTS: Pretreatment serum IP-10 levels in patients with SVR were significantly lower than in non-responders (NR) (332.4 (222.1) v 476.8 (305.3) pg/ml, respectively; p=0.004). Serum IP-10 concentrations significantly decreased in patients with SVR (pretreatment: 332.4 (222.1) pg/ml; post-treatment: 170.2 (140.1) pg/ml; p<0.001) but not in NR (pretreatment: 476.8 (305.3) pg/ml; post treatment: 387.3 (268.1) pg/ml; p=0.06). By multivariate analysis, non-1 genotype (odds ratio (OR) 3.5 (95% confidence interval (CI) 1.1-10.4); p=0.003) and low viral load at baseline (OR 0.34 (95% CI 0.14-0.79); p=0.01) were independent predictors of SVR in all patients. When multivariate analysis was restricted to patients with genotype 1, only baseline viral load (OR 0.38 (95% CI 0.155-0.96); p=0.04) and pretreatment serum IP-10 levels (OR 0.99 (95% CI 0.996-0.999); p=0.03) were identified as predictive factors of SVR. CONCLUSION: Pretreatment serum IP-10 behaves as a predictive factor of SVR to peginterferon plus ribavirin therapy in genotype 1 infected patients.

Characterization of pathogenic and prognostic factors of nonalcoholic steatohepatitis associated with obesity.

BACKGROUND/AIMS: Nonalcoholic steatohepatitis is an emerging clinical problem among the obese population. However, risk factors of progression to advanced forms of liver disease in this particular group of patients remain to be defined. METHODS: The demographics and clinical and histologic features of 46 obese patients were evaluated. The intrahepatic immunological phenotype was assessed in all liver biopsy samples by immunohistochemistry. RESULTS: Histologic findings of nonalcoholic steatohepatitis were observed in 69.5% of the obese population studied and significant fibrosis was evident in 41% of patients with nonalcoholic steatohepatitis. Age (p=0.003), degree of steatosis (p=0.000002), and grade of inflammation (p=0000) at liver biopsy were independent variables positively associated with fibrosis. Intrahepatic expression levels of several immunologic markers of inflammation as well as nitric oxide derivatives were significantly higher in the severe forms of nonalcoholic steatohepatitis than in the mildest forms. CONCLUSIONS: Obese persons with higher age, with greater degrees of hepatic steatosis, and specially those with increased grades of intrahepatic inflammation have the greatest risk for progression to fibrotic liver disease. An oxidative stress-triggered intrahepatic inflammatory response appears to be important in the pathogenesis of nonalcoholic steatohepatitis in obesity.