Performance of noninvasive markers for liver fibrosis is reduced in chronic hepatitis C with normal transaminases.

In chronic hepatitis C, biopsy is the gold standard for assessment of liver fibrosis. Few studies investigated noninvasive markers of liver fibrosis in hepatitis C virus (HCV) patients with normal alanine aminotrasferase (NALT). Eighty HCV patients with NALT and 164 HCV patients with elevated alanine aminotrasferase (EALT) who underwent a diagnostic liver biopsy were evaluated for AST-to-platelet ratio, Forns' index, AST-to-ALT ratio (AAR), Fibrotest and the recently proposed Fibroindex, using liver histology as reference standard. The primary end-point was the detection of significant fibrosis (> or =F2). Performance of noninvasive markers was expressed as specificity, sensitivity and positive (PPV) and negative (NPV) predictive value, accuracy and area under the receiver operating characteristic curve (AUROC). All noninvasive markers for liver fibrosis tested showed a poorer performance in NALT group than in EALT group. Overall, Fibrotest had the best performance in NALT group, as showed by AUROC of 0.70 and 73.5% accuracy. Performance of AAR, Forns' index and Fibroindex was poor in NALT group and it was significantly lower than in EALT group for Forns and Fibroindex (AUROC 0.6 vs 0.76 and 0.58 vs 0.74, respectively, P = 0.05). In NALT patients, PPV was high for all noninvasive markers (>87%) except for AAR, while NPV was low (<65%), thus none of them was able to reliably exclude significant fibrosis. In conclusion, performance of noninvasive-markers is significantly reduced in HCV patients with NALT. Liver biopsy may still be needed for many of these cases to correctly stage liver fibrosis. Specific noninvasive tools and possibly combination of markers should be developed and validated in this clinical setting.

Hepatic iron, liver steatosis and viral genotypes in patients with chronic hepatitis C.

Hepatic iron has been described in hepatitis C virus (HCV) infection as an important cofactor of disease outcome. The mechanisms leading to hepatic iron deposits (HIDs) in HCV patients are partially understood. We investigated HIDs in the liver biopsies of a consecutive series of 242 HCV-infected patients with well-compensated liver disease. Serum ferritin was elevated in 20.7% and transferrin saturation in 19.0%, while 38.8% had stainable HIDs indicating that serum markers of systemic iron overload have low sensitivity in predicting HIDs in hepatitis C. A cut-off value of serum ferritin (350 microg/L in females and 450 microg/L in males) had good negative predictive value in excluding presence of mild-moderate HIDs (grade II-III). Hepatic iron deposits correlated by multivariate analysis with serum ferritin [odds ratio (OR) 1.008, 95% confidence interval (CI) 1.005-1.011] and albumin (OR 1.15, 95% CI 1.02-1.297). Hepatic iron deposits were more frequent in HCV-3-infected cases than in other genotypes (P = 0.027) while raised serum iron indices were more frequent in non-HCV-3 genotypes (P = 0.02). Furthermore, advanced fibrosis (F3-F4 by METAVIR) was more frequent in non-HCV-3 genotypes (P = 0.04). In HCV-3 cases there was a close association between HIDs and severe (grade II-III) steatosis (P < 0.00001). These results indicate that in well-compensated chronic hepatitis C HIDs are strongly associated with HCV-3 and viral-induced hepatic steatosis, while in the presence of other genotypes they might merely reflect a more advanced stage of liver disease and/or a systemic iron overload. Serum ferritin could identify a subgroup of patients in which the need of venesection could be excluded without liver biopsy.

Review article: chronic hepatitis C--natural history and cofactors.

Chronic hepatitis C is highly heterogeneous in clinical presentation and outcomes. This heterogeneity is largely related to host factors that have been clearly proven to affect the severity and rapidity of disease progression. The most relevant factors that have been shown to accelerate progression to cirrhosis include age at infection, alcohol abuse and the metabolic syndrome with insulin resistance, obesity and hepatic steatosis. Co-infection with HIV and/or HBV also increases the risk of progression to cirrhosis and to hepatocellular carcinoma. Surprisingly enough, viral related factors appear as less important and neither the virus genotype and load have been found to exert a clear influence on disease severity and progression, although more data in this field, and particularly on the role of different viral proteins in causing cytopathic effects, are awaited and may change this view in the near future.

Liver cell apoptosis in chronic hepatitis C correlates with histological but not biochemical activity or serum HCV-RNA levels.

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-UTP-biotin 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 <.0005) and with the amount of infiltrating CD8-positive cells (P =. 01). Apoptosis did not correlate with transaminase levels or with HCV load and genotype. These results support the concept that immune-mediated apoptosis may play a role in the pathogenesis of chronic hepatitis C and indicate that this type of reaction may occur in the absence of significant alanine transaminase (ALT) elevation, thus explaining the lack of correlation between biochemical activity and liver histological damage.