Hepatitis B virus core-related antigen is a serum prediction marker for hepatocellular carcinoma

Serum hepatitis B virus (HBV)-DNA is a useful measurement for chronic hepatitis B (CH-B) patients and can help determine when to start antiviral therapies, such as nucleos(t)ide analogues (NAs) and interferon (IFN), as well as monitoring of the antiviral effects of therapy. It is reported that the development of advanced chronic liver disease, cirrhosis, and the incidence of hepatocellular carcinoma (HCC) can be prevented by decreasing serum HBV-DNA levels. Serum HBV-related markers can be conveniently measured along with other serum liver function markers such as AST, ALT, rGTP, and ALP at regular intervals from small serum samples. However, serum HBV-DNA levels in many cases during NAs treatment are below detection limits despite the presence of HBV-related proteins in patients’ hepatocytes. HBV-DNA decrease is not the aim of therapy in recent years; rather, the absence of HBs antigen has become essential. This indicates that HBs antigen loss is associated with intrahepatic HBV loss, so a HBV marker that reflects the production of intrahepatic HBV is needed. Kimura et al. reported that HBV core-related antigen (HBcrAg) reflects HBcAg in Dane particles, p22cr in empty particles, and HBeAg, and is detected by CLEIA method after pretreatment to inactivate the antibodies (1). The results of the study suggested that most Dane particles lack viral HBV-DNA and core capsids, but contain p22cr (2). This study additionally provided a model for the formation of the HBV-DNA-negative Dane particles. The precore proteins, which lack the arginine-rich nucleotide-binding domain, form viral RNA/DNA-negative capsid-like particles and are enveloped and released as empty particles. To measure HBcrAg, antibodies such as HBeAb and HBcAb are inactivated and HBV core antigen (HBcAg) is contained within the Dane particles. However, HBcAg cannot be directly detected in serum, unlike HBcAb, which indicates only past and current infection status. The lower limit of detection of HBcrAg is 3.0 logU/mL and the upper limit is 7.0 logU/mL, and detection reflects the production of intrahepatic HBV including HBV cccDNA, which if eradicated, corresponds with decreased HBcrAg in serum. HBcrAg includes HBeAg but is of little use in HBeAg-positive patients. On the other hand, measurement is useful when serum HBV-DNA cannot be detected and the patient has a negative HBeAg and positive HBeAb status. Previous reports showed that there is a significant correlation between intrahepatic HBV cccDNA and the detection of serum HBcrAg (3,4). Moreover, HBcAg staining in liver tissue has been found to