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In hepatitis C virus (HCV) infection, mechanisms responsible for liver cell damage are still poorly understood and both necrosis and apoptosis may be operative. By using terminal deoxynucleotydil transferase-mediated d-UTPbiotin nick-end labeling (TUNEL) we have evaluated and quantified apoptosis in liver biopsy specimens from 61 patients with chronic hepatitis C. All patients had detectable apoptotic cells in the liver. Presence of increased apoptotic activity was confirmed in selected cases by electron microscopy and by DNA gel electrophoresis. The amount of liver cell apoptosis expressed as apoptotic index, ranged between 0.01% to 0.54% and showed a positive correlation with histological activity grading (P F .0005) and with the amount of infiltrating CD8-positive cells (P ‫؍‬ Hepatitis C virus (HCV) is a major cause of chronic liver disease, cirrhosis, and hepatocellular carcinoma 1 worldwide. The infection has a high propensity to chronicity and the majority of HCV carriers have histological evidence of liver inflammation and chronic damage, although with a very wide spectrum of severity and progression rate. 2 The mechanisms leading to liver cell injury, inflammation, and fibrosis in chronic hepatitis C, are not fully understood. Both immunemediated reactions and more direct cytopathic effects of HCV and of its proteins may be involved. Evidence has been provided that apoptosis of liver cells may play a significant role in the pathogenesis of hepatitis C. [3][4][5] Apoptosis is an active, genetically programmed phenomenon of cell death characterized by a unique sequence of events, with morphological features distinct from necrosis. 6 Three pathomorphologic features are suggestive of increased apoptosis in the liver of patients with chronic hepatitis C including (1) presence of shrinkage and fragmentation of nucleus/cytoplasm in areas of piecemeal necrosis, (2) presence of acidophilic bodies, and (3) focal cell drop out in the liver lobule. 7,8 Increased expression of Fas, one of the most important members of the tumor necrosis factor family receptors able to transduce the apoptotic signal to programmed cell death, has been described in chronic hepatitis C. Hepatic up-regulation of Fas was found to correlate with more severe inflammation 9 and with ongoing HCV infection. 10 Parallel activation of T lymphocytes expressing Fas ligand was detected in liver infiltrating mononuclear cells, allowing transduction of the apoptotic death signal to Fas-bearing hepatocytes 3 and to proinflammatory activated cells that continuously migrate from extrahepatic sites. 11 In addition, both structural and nonstructural HCV proteins have been shown to interact with apoptosis mediators and possibly modulate the active cascade of events leading to programmed cell death. The core protein has shown both proapoptotic or antiapoptotic activities, depending of the experimental conditions and type of cell used, 12-14 whereas both the NS3 15 and the NS5A 16 proteins were shown to have antiapoptotic effects. In this study we have quant...

AIM: To assess the performance of several noninvasive markers and of our recently proposed stepwise combination algorithms to diagnose significant fibrosis (F ≥ 2 by METAVIR) and cirrhosis (F4 by METAVIR) in chronic hepatitis B (CHB).METHODS: One hundred and ten consecutive patients (80 males, 30 females, mean age: 42.6 ± 11.3) with CHB undergoing diagnostic liver biopsy were included. ASTto-Platelet ratio (APRI), Forns' index, AST-to-ALT Ratio, Goteborg University Cirrhosis Index (GUCI), Hui's model and Fibrotest were measured on the day of liver biopsy. The performance of these methods and of sequential algorithms combining Fibrotest, APRI and biopsy was defined by positive (PPV) and negative (NPV) predictive values, accuracy and area under the curve (AUC).RESULTS: PPV for significant fibrosis was excellent (100%) with Forns and high (> 92%) with APRI, GUCI, Fibrotest and Hui. However, significant fibrosis could not be excluded by any marker (NPV < 65%). Fibrotest had the best PPV and NPV for cirrhosis (87% and 90%, respectively). Fibrotest showed the best AUC for both significant fibrosis and cirrhosis (0.85 and 0.76, respectively). Stepwise combination algorithms of APRI, Fibrotest and biopsy showed excellent performance (0.96 AUC, 100% NPV) for significant fibrosis and 0.95 AUC, 98% NPV for cirrhosis, with 50%-80% reduced need for liver biopsy. CONCLUSION:In CHB sequential combination of APRI, Fibrotest and liver biopsy greatly improves the diagnostic performance of the single non-invasive markers. Need for liver biopsy is reduced by 50%-80% but cannot be completely avoided. Non-invasive markers and biopsy should be considered as agonists and not antagonists towards the common goal of estimating liver fibrosis.

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