A. Apolinario

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.

Increased expression of T cell chemokines and their receptors in chronic hepatitis C: relationship with the histological activity of liver disease

OBJECTIVE:Although chemokines seem to be important in certain inflammatory disorders, little is known about the role of these proteins in chronic hepatitis C.METHODS:Expression of selected CXC and CC chemokines and their receptors was assessed by immunohistochemistry and flow cytometry in chronic hepatitis C. Tissue samples from normal liver and that of sustained responders were also evaluated. A comparative analysis between the histological grading and the intrahepatic expression level of chemokines was performed.RESULTS:The majority of liver-derived T lymphocytes expressed CXCR3 and CCR5 chemokine receptors, representing high enrichment over levels of CXCR3+ and CCR5+ T cells in blood from chronic hepatitis C. An intense intrahepatic expression of their respective ligands, the CXC chemokine Mig, and RANTES, was detected in the same patients studied, being restricted to the sinusoidal endothelium and to hepatocytes, respectively. A statistically significant association between the intrahepatic chemokine expression level and the inflammatory activity of chronic hepatitis C was found. Of note was the marked expression of both CXCR3 and its ligand Mig on endothelial cells from portal neovessels in chronic hepatitis C.CONCLUSIONS:Intrahepatic chemokine signaling could play a key role regulating significant pathological events during chronic hepatitis C, opening new avenues for therapeutic interventions based on chemokine activities.

Intrahepatic accumulation of nitrotyrosine in chronic viral hepatitis is associated with histological severity of liver disease

BACKGROUND/AIMS The toxicity of nitric oxide is thought to be engendered, at least in part, by its reaction with superoxide yielding peroxynitrite, a potent oxidant that promotes the formation of nitrotyrosine within cells and tissue lesions. In this study we assessed the intrahepatic localization and distribution of the inducible nitric oxide synthase (iNOS) and nitrotyrosine (NTY) in patients with viral and non-viral liver disease. METHODS We carried out single and double immunostaining experiments on cryostat liver biopsy sections using monoclonal antibodies against iNOS and NTY. We also performed a comparative analysis between the intrahepatic immunostaining score of NTY and the histological activity index of chronic viral hepatitis. RESULTS We found a marked hepatocellular expression of iNOS with a diffuse lobular pattern in all liver samples from patients with viral liver disease, whereas NTY localization was mainly restricted to cellular foci consisting of hepatocytes and Kupffer cells. Interestingly, we demonstrated by means of double immunostaining experiments the existence of hepatocellular co-localization of iNOS and NTY in the majority of NTY-expressing liver cells. The amount of NTY was significantly higher in liver biopsies from viral liver disease than in non-viral liver disease. In addition, a statistically significant association between the intrahepatic amount of NTY and the severity of viral liver disease was found. CONCLUSIONS Nitric oxide-mediated nitration of hepatocellular proteins is markedly induced in the inflamed liver tissue from patients with chronic viral hepatitis, and appears to be associated with the histological severity of viral chronic liver disease.

Increased circulating and intrahepatic T-cell-specific chemokines in chronic hepatitis C: relationship with the type of virological response to peginterferon plus ribavirin combination therapy

Aims : To determine the serum and intrahepatic levels of T‐helper‐1‐associated chemokines in patients with chronic hepatitis C before, during and after peginterferon plus ribavirin combination therapy and to search for correlations with baseline characteristics of hepatitis C virus‐related chronic liver disease and type of therapeutic response.