Apoptosis markers related to pathogenesis of pediatric chronic hepatitis C virus infection: M30 mirrors the severity of steatosis.

Apoptosis involvement in liver damage related to hepatitis C virus (HCV) chronic infection has been suggested. Although liver biopsy represents the gold standard for evaluating disease severity, non-invasive tests are a growing medical need. The aim of this study was to detect apoptosis markers in liver and serum from pediatric HCV-infected patients and to assess its utility to predict liver damage progression. Twenty-three patients were included. Liver biopsies were used for histological analysis as well as for immunodetection of a viral protein (NS3) and apoptosis markers (activated caspase-3 [casp-3a], caspase-generated CK-18 fragment [M30] and TUNEL). M30 was quantified in paired serum and biopsy samples. NS3 correlated both with casp-3a (r = 0.83, P < 0.0001) and TUNEL (r = 0.61, P < 0.0017). Casp-3a and TUNEL also displayed a correlation (r = 0.56, P = 0.005). Both NS3 and casp-3a were associated with fibrosis stage (P = 0.03). Serum M30 [median: 122.15 UL-1 (86.68-794.58)] was higher in patients than in controls [median: 81.44 UL-1 (41.17-129.30)], (P < 0.0001). M30 showed a correlation with steatosis, and indeed it was linked to severe grade (P = 0.004). In children, HCV would be involved in liver damage through apoptosis induction. The apoptosis markers detected reflect liver injury. Serum M30 might be useful as a marker to detect the extent of liver steatosis.

Apoptosis markers in liver biopsy of nonalcoholic steatohepatitis in pediatric patients.

The natural history of pediatric nonalcoholic steatohepatitis is still unknown; however, there are differences between adult and pediatric presentation. Apoptosis may play an important role in pathophysiologic pathways involved in liver damage and progression. Our aim was to detect early apoptosis markers, activated caspase-3 and cleaved cytokeratin-18, in hepatocytes and to correlate their presence with clinical, serologic, and histologic characteristics in pediatric nonalcoholic steatohepatitis. Twenty-five pediatric nonalcoholic steatohepatitis liver biopsies were evaluated by immunohistochemistry for presence of activated caspase-3 and cleaved cytokeratin-18. Biopsy specimens were semiquantitatively graded for activity (steatosis, inflammation, and ballooning) and fibrosis. Records were reviewed for serum aspartate aminotransferase, alanine aminotransferase, cholesterol, triglycerides, and body mass index, which was elevated in 92% of cases. Serum aspartate aminotransferase and alanine aminotransferase were elevated in 32% and 68% of cases, respectively. Sixty percent of biopsies exhibited lobular steatosis grade 3, 84% lobular inflammatory activity grade 1, 72% ballooning grade 1, and 76% fibrosis stage 3. Cleaved cytokeratin-18 was associated with milder fibrosis (P = .02) and inflammation (P = .07), although there was no association with steatosis grade. Activated caspase-3 detection was also associated with low inflammatory grade (P = .03) but not with fibrosis and steatosis. This study reveals interesting differential features concerning nonalcoholic steatohepatitis histologic characteristics and apoptosis markers compared with adult cases. Because, in this pediatric series, apoptosis seemed to be an early event in the cascade of liver injury steps, it would be useful to consider caspase inhibitors as potential therapeutic strategies to prevent liver damage progression.