Distinctive intrahepatic characteristics of paediatric and adult pathogenesis of chronic hepatitis C infection

Abstract

Mechanisms leading to liver damage in chronic hepatitis C (CHC) are being discussed, but both the immune system and the virus are involved. The aim of this study was to evaluate intrahepatic viral infection, apoptosis and portal and periportal/interface infiltrate in paediatric and adult patients to elucidate the pathogenesis of chronic hepatitis C. HCV-infected, activated caspase-3(+) and TUNEL(+) hepatocytes, as well as total, CD4(+), CD8(+), Foxp3(+) and CD20(+) lymphocytes infiltrating portal and periportal/interface tracts were evaluated in 27 paediatric and 32 adult liver samples by immunohistochemistry or immunofluorescence. The number of infected hepatocytes was higher in paediatric than in adult samples (p 0.0078). In children, they correlated with apoptotic hepatocytes (activated caspase-3(+) r = 0.74, p < 0.0001; TUNEL(+) r = 0.606, p 0.0017). Also, infected (p = 0.026) and apoptotic hepatocytes (p = 0.03) were associated with the severity of fibrosis. In adults, activated caspase-3(+) cell count was increased in severe hepatitis (p = 0.009). Total, CD4(+), CD8(+) and Foxp3(+) lymphocyte count was higher in adult samples (p < 0.05). Paediatric CD8(+) cells correlated with infected (r = 0.495, p 0.04) and TUNEL(+) hepatocytes (r = 0.474, p = 0.047), while adult ones correlated with activated caspase-3(+) hepatocytes (r = 0.387, p 0.04). In adults, CD8(+) was associated with hepatitis severity (p < 0.0001) and correlated with inflammatory activity (CD8(+) r = 0.639, p 0.0003). HCV, apoptosis and immune response proved to be involved in CHC pathogenesis of both paediatric and adult patients. However, liver injury in paediatric CHC would be largely associated with a viral cytopathic effect mediated by apoptosis, while in adults it would be mainly associated with an exacerbated immune response.

Human embryonic stem cell–derived hepatoblasts are an optimal lineage stage for hepatitis C virus infection

“…The epidemiological data showed that similar percentages of chronic HCV infections were found in both adults and children (41) ; however, the numbers of infected hepatocytes were significantly higher in liver tissues of pediatric patients than in those of adults. (42) It was found that clusters of HCV-infected cells often present close in proximity to fibrous septae that appeared to bridge portal tracts (3) where EpCAM 1 progenitor cells are mainly located (38) ; IHC staining with HCV NS5 protein indicated that HCV prefers regeneration conditions, comprised of higher numbers of EpCAM 1 cells located in the pseudo-lobules in HCV-infected adult liver tissue. These regenerating progenitor cells are in small numbers but contain high levels of HCV and may serve as an HCV reservoir.…”

Generalized Liver- and Blood-Derived CD8+ T-Cell Impairment in Response to Cytokines in Chronic Hepatitis C Virus Infection

“…No other associations were detected between CD8 + T-cell activities and fibrosis stage, although the selection of study subjects was not stratified to examine immune function associations with liver damage. Few associations between fibrosis and CD8 + T-cell function in HCV infection have been described; fibrosis has been associated with increased infiltration of CD8 + T-cells as well as increased CD8 + T-cell apoptosis in pediatric and adult livers in HCV infection [ 63 , 64 ]. Whether the impairment observed is due to chronic liver disease, or HCV specifically, was not determined.…”

Chronic hepatitis C liver microenvironment: role of the Th17/Treg interplay related to fibrogenesis

“…Another critical point is that the “virological cure” does not necessarily mean that the patients are cured of liver disease or protected against the development of potential HCC, consequently the mechanisms leading to liver injury in CHC are under constant revision 4 . The fact that both immune system-mediated reactions and viral cytopathic effect are involved in pathogenesis is widely accepted 5 , 6 , thus, the interplay between virus and host immune response may influence infection outcome.…”

“…We have previously demonstrated, in a comparative study between a pediatric and adult CHC cohorts that HCV, apoptosis and immune response are all involved in CHC pathogenesis; however, there are certain differences between children and adults regarding the role played by each component on the final scenario 6 . Liver injury in pediatric CHC would be largely associated with viral cytopathic effect mediated by apoptosis, while in adults it would be mainly associated with an exacerbated immune response.…”

“…Liver injury in pediatric CHC would be largely associated with viral cytopathic effect mediated by apoptosis, while in adults it would be mainly associated with an exacerbated immune response. Taking this into account; we decided to explore the immune pathogenesis in a new cohort of CHC adult patients 6 . Therefore, in this study, the inflammatory intrahepatic microenvironment, comprising both cells and cytokines, was assessed in order to get a more comprehensive picture of the relation between immune response and CHC damage.…”