Occult Hepatitis B Infectiona potential risk factor

inthe development of HCC

• Bui Dac Chi,MD• Medic Center

The presence of individuals with OBI has been appreciated since the late 1970s, but only extensively studied since 2000, and the current consensus definition was adopted at an international expert meeting in Taormina, Italy, in 2008

• More than 30 years ago(1978), it was shown that patients who received HBsAg-negative, anti–hepatitis B core antibody (HBcAb)–positive blood were still at risk of developing post-transfusional hepatitis B . In addition, patients who were HBsAg negative, hepatitis B surface antibody (HBsAb) positive, undergoing cancer chemotherapy, developed reactivation of HBsAg associated with severe, life-threatening hepatitis . With the development of PCR technology ,it was clearly shown that not only patients with only hepatitis B antibodies in their serum, but also patients with chronic liver disease and with no serological markers of HBVinfection, could still be shown to have HBV DNA present in their serum or liver . Thus the concept of “occult” HBV infection emerged.

• ‘‘the presence of HBV DNA in the liver (with detectable or undetectable HBV DNA in the serum) of individuals testing hepatitis B surface antigen (HBsAg) negative by currently available assays.’’ In addition, OBI can be serologically classified as seropositive OBI (e.g., hepatitis B virus core protein [anti-HBc] and/or hepatitis B virus surface protein [anti-HBs positive]) or seronegative OBI (anti-HBc and anti-HBs negative)

• Reliable OBI diagnosis can at present be performed only in highly specialized laboratories. The development in the near future of valid and commercially available assays (i.e., real time PCR on DNA extracts from liver tissue fine-needle aspiration) allowing the detection of OBI in all cases

• OBI is a phenomenon essentially attributed to the long-lasting presence of HBV cccDNA into the hepatocytes and to a strong inhibition of HBV replication and protein synthesis.

Schematic representation of the various conditions leading to different OBI serological profiles

OBI is related to replication-competent viruses that are strongly suppressed in their activities (replicative and transcriptional) by the host’s defense mechanisms. Very importantly, this suppression (a) does not have an absolute effect and residual, low-levels of replication and transcription may persist over time, and (b) may be reversible in particular circumstances leading to viral reactivation and development of a typical HBsAg-positive (namely, “overt”) infection

• A significantly higher prevalence of OHB was observed in patients with HCC in the presence or absence of HCV infection when compared with control populations without HCC. Correspondingly, among adequately designed prospective studies, the cumulative probability of developing HCC was significantly greater among patients with OHB than among HBV DNA-negative patients in the presence or absence of HCV infection.

• Despite more than a decade of research pertaining to the association of OHB and HCC, knowledge of the role of occult HBV in the development of HCC is still very limited and often confounded by current therapy and testing methodology. Thus, there remain many unanswered questions regarding its pathogenesis and clinical significance. Both epidemiological studies and molecular studies have provided more insight into occult HBV, but the potential role of OHB in HCC requires further investigation.

OBI may maintain most of the pro-oncogenic properties of the overt HBV infection, including the capacity to integrate into the host’s genome, to produce proteins with transforming properties (even if at low levels) and a mild but persisting necroinflammation

OHB should be considered a potential risk factor in the development of HCC whenever it is encountered .

HBV may not be recognized in a certain number of patients if the diagnosis is solely based on detecting HBsAg. Although controlling HBsAg levels can slow down disease progression and prevent HCC,there is still a sgnificant risk of cancer development in OBI patients whose HBsAg markers are negative.