In view of the findings that high hepatitis B virus (HBV) deoxyribonucleic acid (DNA) is associated with increased risk of chronic hepatitis B (CHB)-related complications, disease progression in CHB patients in the immune-tolerant phase is uncertain. We evaluated disease progression in 57 immune-tolerant CHB patients with high HBV DNA. Each subject underwent an initial liver biopsy. In those who remained in the immune-tolerant phase, a follow-up liver biopsy was performed after 5 years of follow-up. Patients who developed elevated serum alanine aminotransferase (ALT) levels were discontinued from the study after a follow-up liver biopsy. Traditionally, serum alanine aminotransferase (ALT) level and HBV serology analysis have been widely used for the assessment of patients with CHB infection. The annual incidence of cirrhosis has been estimated to be 2%-6% for hepatitis B e antigen (HBeAg)-positive CHB patients and 8%-10% for HBeAg-negative CHB patients. 4,5 The higher incidence of cirrhosis among HBeAg-negative patients is related to older age and more advanced liver disease at presentation. 2,4,5 More advanced fibrosis stage at presentation correlates with risk of cirrhosis, and those with milder forms of hepatitis have a longer time to cirrhosis. 6 HBeAg positivity has also been found to be associated with higher hepatic inflammation and an increased risk of HCC. Although seroconversion of HBeAg to hepatitis B e antibody (anti-HBe) often leads to hepatic inflammation subsiding and an improved prognosis, the identification of precore/core promoter mutations and recognition of HBeAg-negative CHB disease explain the disease progression noted after HBeAg seroconversion. [7][8][9][10] Recent studies have demonstrated a strong link between viral replication, liver injury, and progression to cirrhosis with increased risk of HCC in CHB-infected From the

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Hepatitis B virus (HBV), a serious infectious and widespread human pathogen, represents a major health problem worldwide. Chronic HBV infection has a very high risk of evolving into hepatocellular carcinoma. Although considerable progress was made during the recent past, the pathogenesis of HBV infection is still elusive and a definite diagnosis of HBV infected liver information still relies on biopsy histological test. In this report, we used proteomics technology to globally examine HBV infected serum samples aiming at searching for disease-associated proteins that can be used as serological biomarkers for diagnosis and/or target proteins for pathogenetic study. By comparing with normal and HBV negative serum samples, we found that at least seven proteins were significantly changed in HBV infected sera. These greatly altered proteins were identified to be haptoglobin beta and alpha2 chain, apolipoprotein A-I and A-IV, alpha1-antitrypsin, transthyretin and DNA topoisomerase IIbeta. The alteration of these proteins is displayed not only in quantity but also in patterns (or specificity), which can be correlated with necroinflammatory scores. In particular, apolipoprotein A-I presents heterogeneous change in expression level with different isoforms and alpha1-antitrypsin produces evidently different fragments implying diverse cleavage pathways. These unique phenomena appear specific to HBV infection. A combination simultaneously considering the quantities and isoforms of these proteins could be a useful serum biomarker (or index) for HBV diagnosis and therapy.