HBsAg-negative hepatitis B virus infection and hepatocellular carcinoma

Hepatitis B virus (HBV) is the major causative agent of chronic hepatitis, hepatic decompensation, liver cirrhosis, and hepatocellular carcinoma (HCC). HBV-related serum markers are widely used in clinical diagnosis and prognosis for HBV infection. Among them, the HBV surface antigen (HBsAg) was once regarded as the sole marker for infection. The serum levels of HBsAg, along with HBV DNA levels, are the most important predictors of the risk of developing HCC. Higher levels of HBsAg are usually connected with a higher risk and lower levels of HBsAg are usually connected with a lower risk. However, negative results for serum HBsAg tests do not always represent a clearance or inactivating status of HBV viruses. HCC could still develop in the absence of detectable HBsAg in serum. This situation is called occult hepatitis B virus infection (OBI). OBI is characterized by the presence of HBV viral genome in the patient's liver but no virus surface antigen (HBsAg) detected in serum by commonly used immunoassays. Although there may not be much difference in the extent of HBV genome replication in OBI (HBsAg negative) and the overt HBV infections (HBsAg positive), the duration of HBV replication and its pathological consequences last much longer in OBI than in overt infections. This paper provides a comprehensive review on the reasons behind OBI, the clinical impact of OBI on the development of HCC, and the urgency for implementing new methodological techniques for detecting OBI.