Cytokines - their pathogenic and therapeutic role in chronic viral hepatitis.

Cytokines make up a network of molecules involved in the regulation of immune response and organ functional homeostasis. Cytokines coordinate both physiological and pathological processes occurring in the liver during viral infection, including infection control, inflammation, regeneration, and fibrosis. Hepatitis B and hepatitis C viruses interfere with the complex cytokine network brought about by the immune system and liver cells in order to prevent an effective immune response, capable of viral control. This situation leads to intrahepatic sequestration of nonspecific inflammatory infiltrates that release proinflammatory cytokines, which in turn favor chronic inflammation and fibrosis. The therapeutical administration of cytokines such as interferon alpha may result in viral clearance during persistent infection, and revert this process.

Cytokines – their pathogenic and therapeutic role in chronic viral hepatitis

Cytokines make up a network of molecules involved in the regulationof immune response and organ functional homeostasis. Cytokinescoordinate both physiological and pathological processesoccurring in the liver during viral infection, including infection control,inflammation, regeneration, and fibrosis. Hepatitis B and hepatitisC viruses interfere with the complex cytokine networkbrought about by the immune system and liver cells in order to preventan effective immune response, capable of viral control. This situationleads to intrahepatic sequestration of nonspecific inflammatoryinfiltrates that release proinflammatory cytokines, which in turnfavor chronic inflammation and fibrosis. The therapeutical administrationof cytokines such as interferon alpha may result in viral clearanceduring persistent infection, and revert this process(AU)

Manifestaciones extrahepáticas de la infección por VHC / Extrahepatic manifestations of HCV infection

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Sobrecarga férrica y hepatitis crónica C: papel de las mutaciones del gen HFE / Iron overload and chronic hepatitis C: the role of HFE gene mutations

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Long-term effect of interferon alpha alone or after prednisone withdrawal in chronic hepatitis B. Interim report and review of the literature.

BACKGROUND/AIMS: This study analyzed the response of two selected groups of asymptomatic chronic hepatitis B patients, treated either with Interferon or with Prednisone plus the same regimen of Interferon, on finalizing treatment and after a long-term follow-up. PATIENTS AND METHODS: Twelve patients received Interferon over 6 months (group I) and 7 patients Prednisone plus Interferon with the same regimen (group II). Both groups were homogeneous in age, sexual preferences, serum ALT levels, liver histology and Knodell's index. Patients with decompensated liver disease, ongoing drug abuse, active alcoholism or viral superinfections were excluded. RESULTS: On finalizing treatment, no statistical differences were observed in either group, except for clearance of HBsAg, found to be better in group II. Both treatments improved hepatic histology. These results were comparable with those reported for both therapeutical regimens in the literature. After a mean follow-up period of 1.8 years for group I and 3.5 years for group II, no patient included in group II relapsed and 2 additionally cleared their replication markers; thus, a complete response was achieved in 6 (86%) out of 7 patients. In group I, however, 3 patients relapsed and 4 presented no change, obtaining a complete response in 3 (27%) out of 11 followed-up patients. When statistically studied, this improved response in the Prednisone plus Interferon group was significant in clearing HBV DNA, HBeAg and HBsAg and, also, in normalizing ALT levels. CONCLUSIONS: In spite of the few number of cases studied, these results could indicate an improved long-term evolution after a short course of steroids prior to Interferon in selected chronic hepatitis B patients.

[Tissue expression of antigenic recognition and intercellular adhesion molecules in chronic viral hepatitis]. / Expresión tisular de moléculas de reconocimiento antigénico y de adhesión intercelular en la hepatitis crónica vírica.

OBJECTIVE: To analyze the expression of different HLA class I antigens and cell adhesion molecules on frozen liver sections from patients with chronic active hepatitis, types B and C. EXPERIMENTAL DESIGN: Liver biopsy samples were divided into two parts, one for routine histological examination and another, after snap-freezing and storing at -80 degrees C, for immunohistochemical analysis. To carry out immunoperoxidase and immunofluorescence stainings, a panel of monoclonal antibodies specific for HLA class I light (beta 2-microglobulin) and heavy chain determinants, and for adhesion molecules such as intercellular adhesion molecule-1 and lymphocyte function associate antigen-3 was used. PATIENTS: Immunohistochemistry was performed in frozen liver biopsy sections from 25 patients with viral chronic active hepatitis, 10 type B and 15 type C. As controls, normal liver samples and liver specimens from patients with cholestasis or steatosis were also studied. RESULTS: HLA class I light and heavy chain determinants were expressed on hepatocytes, biliary duct epithelium, sinusoidal lining cells and lymphocytes from patients and controls; however, the beta 2-microglobulin conformational epitope was undetectable on hepatocytes from normal livers or with cholestasis or steatosis, but clearly positive on hepatocytes from patients with hepatitis. In addition, in liver sections from controls no adhesion molecules positivity was detected on hepatocytes; by contrast, hepatocytes from patients with hepatitis showed markedly enhanced membranous reactivity for both adhesion molecules in areas of piecemeal and lobular necrosis. CONCLUSIONS: Virus B and C infections could induce an increased hepatocellular expression of HLA-class I determinants, including the conformational epitope adequate for antigen presentation, and cell-cell adhesion molecules. These findings underline the role of cell mediated immune reactions in the pathogenesis of hepatic injury in viral chronic hepatitis.

Inhibition of glycolysis by amino acids in ascites tumor cells. Specificity and mechanism.

The effect of glutamine and asparagine on glucose metabolism has been studied in ascites tumor cells. Either of these amino acids decreased the glycolytic flux about 80%. Half-maximal effects were obtained with 0.14 mM glutamine and 0.087 mM asparagine. Among the 20 L-amino acids, only glutamate produced a similar effect. Glutamine and asparagine caused a 70% increase of hexose monophosphates and a large decrease of fructose-1,6-P2 and triose phosphates, evidencing a strong inhibition of the phosphofructokinase (EC 2.7.11) reaction. Analysis of the levels of various phosphofructokinase effectors revealed that fructose-2,6-P2 and AMP decreased 4-fold, phosphoenolpyruvate, citrate, and ATP increased 4-, 3-, and 1.8-fold, respectively, and that there was no change in ADP, Pi, and intracellular pH. Assay of phosphofructokinase at concentrations of substrates and effectors determined to be in the cells showed that the low activity of this enzyme could be accounted for by the change in the concentration of effectors, the major mechanism being the change in adenine nucleotides. The decrease in fructose-2,6-P2 contributed very little to the inhibition of phosphofructokinase activity. The effects of amino acids were prevented by amino-oxyacetate, suggesting that transamination was an obligatory step for these changes.