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 Table of Contents  
Year : 2023  |  Volume : 3  |  Issue : 2  |  Page : 35-38

The burden of occult hepatitis B virus infection in hepatocellular carcinoma in Nigeria

1 Department of Internal Medicine, Federal Medical Centre, Yenagoa, Bayelsa, Nigeria
2 Department of Internal Medicine, Jos University Teaching Hospital, Jos, Plateau, Nigeria

Date of Submission30-Nov-2022
Date of Decision15-Jan-2023
Date of Acceptance16-Jan-2023
Date of Web Publication09-Mar-2023

Correspondence Address:
Stella-Maris Chinma Egboh
Department of Internal Medicine, Federal Medical Centre, Yenagoa, Bayelsa
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ghep.ghep_34_22

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The WHO guideline advocates for hepatitis B surface antigen (HBsAg) as the initial diagnostic test for hepatitis B virus (HBV) infection. There are, however, patients who may have the persistence of viral DNA in the liver or blood despite having undetectable HBsAg; these patients also need to be accounted for, especially in endemic areas. These groups of patients are also at risk of developing hepatocellular carcinoma, and they need to be identified. We advocate for funding to support projects and research centers that are able to detect occult HBV infection. This will be valuable in the reduction of the occult transmission of HBV and reactivation of quiescent HBV.

Keywords: Hepatitis B virus prevention, hepatocellular carcinoma, occult hepatitis B virus

How to cite this article:
Egboh SMC, Davwar PM. The burden of occult hepatitis B virus infection in hepatocellular carcinoma in Nigeria. Gastroenterol Hepatol Endosc Pract 2023;3:35-8

How to cite this URL:
Egboh SMC, Davwar PM. The burden of occult hepatitis B virus infection in hepatocellular carcinoma in Nigeria. Gastroenterol Hepatol Endosc Pract [serial online] 2023 [cited 2023 Mar 27];3:35-8. Available from: http://www.ghepjournal.com/text.asp?2023/3/2/35/371277

  Introduction Top

Hepatitis B virus (HBV) is a DNA virus of the Hepadnaviridea family recognized globally as a major disease of public health importance. It has been estimated that up to 2 billion individuals have evidence of exposure and 248 million persons are chronically infected.[1] Epidemiologically, approximately 15%–40% of chronically infected patients develop serious complications such as cirrhosis, liver failure, and hepatocellular carcinoma (HCC). Nearly 1 million people die annually as a result of these complications.[2],[3] Majority of the infected individuals are of eastern Asian or sub-Saharan African origin. Sub-Saharan Africa is considered to be a region of high endemicity with an average carrier rate of 10%–20% in the general population and with 70%–95% having at least a marker of previous infection.[4],[5] Studies have shown that the risk of HCC is higher for subjects who despite the persistence of viral genomes in the liver are negative for circulating hepatitis B surface antigen (HBsAg) and show absence or very low levels of serum viral DNA.[6],[7] These are subjects who have occult HBV infection (OBI). While effort is being put in place to ensure that the transmission of HBV infection is halted, OBI remains a risk that has been ignored. OBI is immunologically, classified as seropositive-occult B infection which accounts for the majority of OBI and defined as positive hepatitis B core (anti-HBC) with or without hepatitis B surface (anti-HBS) or seronegative OBI, when there is no demonstrable immunological evidence of infection as shown by negative anti-HBC and anti-HBS.[8] False occult hepatitis B are cases with negative serological marker of HBV but serum HBV-DNA levels comparable to overt HBV infection. This could be as a result of a mutation in the S gene (escape mutant), producing an immunogenically modified HBsAg not recognized by some or all commercially available kits.[6],[9],[10] In this review, we aim to discuss the challenges associated with the diagnosis of OBI and its impact on the burden of HCC in Nigeria.

Epidemiology of occult hepatitis B virus infection

Occult HBV was reported for the 1st time more than 30 years ago in the context of blood transfusion of anti-HBC-positive donor and has been implicated in the etiology of HCC. Ondigui et al. in a systematic review reported an occult HBV prevalence of 14.8% in Africa with 7.4% having seronegative OBI, while 20% were seropositive.[11] They also found that patients with malignancies and other liver disorders had the highest prevalence of OBI at 41.9% and 33.1%, respectively, and yet this seems to be poorly represented in the true prevalence of HBV infection in Africa.[11] In Nigeria, the prevalence of OBI in the general population has not been well studied. Most studies were done among blood donors, HIV and hemodialysis patients. Among blood donors, it has remained an ongoing threat to the eradication of HBV, and some studies in Nigeria have suggested an OBI prevalence of 3%–17%.[12],[13],[14] Another group that has been studied are hemodialysis patients, where the prevalence of occult hepatitis B was found to be 14.6%.[15] While among HIV patients, the prevalence of up to 11.2% has been reported.[16] Studies have demonstrated that HIV and HCV-infected patients tend to have higher rates of occult hepatitis B. This is not surprising since they share a common route of transmission.[16],[17]

Transmission of hepatitis B virus infection

HBV is transmitted through percutaneous, mucosal, or nonintact skin exposure to infectious blood or body fluids. Blood, semen, and vaginal secretions are considered highly infectious, while peritoneal fluid, cerebrospinal fluid, pleural fluid, synovial fluid, pericardial fluid, and amniotic fluid are also potentially infectious.[18] HBV can also be detected in saliva, tears, and bile, but the risk of transmission via these body fluids remains controversial.[19] In a Brazilian study, HBV DNA was detected in 80% of oral fluid of 5 patients with OBI.[20] In sub-Saharan Africa, horizontal transmission such as close contact within households, use of nonsterile medical equipment, and traditional medical practice are the predominant modes of childhood infections.[21] in contrast to Asia where perinatal transmission is more prevalent.[22],[23] Up to 90% of infants who acquire HBV infection from their mothers at birth become chronically infected, whereas, in adults, only 5%–10% of acute HBV cases remain chronically infected.[24],[25] A major reason for the relatively low rate of perinatal transmission in Africa is the lower prevalence of HBeAg positivity, which is considered a marker of active viral replication.[26] Other methods of transmission include sexual, cultural practices such as scarification and tattooing, blood transfusion, and healthcare-related transmission.[27],[28] Healthcare-related transmission is usually from HBV-infected patients to health-care workers or vice versa, especially via needle stick injury. The risk of infecting a healthcare worker is higher with percutaneous exposure when compared to mucocutaneous.[29] In countries with low endemicity, most of the new infections occur among young adults and are acquired sexually or through intravenous drug use.[29] Sexual transmission of hepatitis B may occur, particularly in unvaccinated men who have sex with men and heterosexual persons with multiple sex partners.[19]

Insights on pathogenesis of occult hepatitis B virus infection

OBI exerts both indirect and direct oncogenic mechanisms that might favor HCC development. HBV is a DNA virus associated with replication and transcription in the hepatocytes. A fundamental step in HBV replication is the conversion of the ~3 kb relaxed circular genome into a covalently closed-circular DNA (cccDNA), an intermediate that persists in the cell nuclei as a stable chromatinized episome serving as a template for gene transcription.[30] The stability of viral cccDNA ensures progressive active multiplication of the virus in the hepatocytes and consequent activation of pro-oncogenes leading to HCC.[31],[32] Histologically, during the viral replication period, there could be mild liver necroinflammation, that progresses to cirrhosis, which is considered a recognized predisposing factor for HCC.[31] Also, the nucleotide mutation rate of HBV is approximately 10-fold higher than that of other DNA viruses thereby increasing the risk of liver cancer.[33] Mutations in this genomic region of HBV can affect antigenicity, immunogenicity, cell elimination, or expression of HBsAg. In addition, the host's immune-response has an indirect role in the pathogenesis of OBI.[34] The delayed exaggerated memory T-cell response against HBV antigens, following recovery from acute B hepatitis suggests a prolonged persistence of the occult infection triggered by antigenic stimulation of T-cells. Another evidence is the reactivation of serological markers of infection in patients who are immunosuppressed.[35],[36] Reactivation of OBI is possible in liver transplant recipients with serological profile of past exposure to hepatitis B (anti-HBC positive), as a consequence of immunosuppression or from occult HBV infected graft and this could lead to fulminant hepatitis.[37]

Challenges in the diagnosis of occult hepatitis B virus in Nigeria

Despite the future implications of occult HBV in clinical medicine, there is still some knowledge gap among clinicians and the general population, magnified by the paucity of local studies addressing the role of OBI in the etiology of HCC in Nigeria. This could result to unwillingness to screen for other serological markers of HBV infection particularly in patients with cryptogenic liver disease. There is also an enormous challenge with the system of referral in resource-poor countries, thereby depriving patients of the opportunity of being reviewed by a specialist gastroenterologist whose expert opinion will be valuable in the identification of cases of OBI.

One of the major diagnostic requirements for OBI is the real time quantitative PCR, which is usually not available or located in distant laboratories that require logistic system for sampling and transportation, thereby affecting the quality of the samples with consequent preanalytical errors. The cost of this molecular testing is also exorbitant for the Nigerian populace and compounded by poor universal health coverage and out of pocket payments. Therefore, HBsAg remains the only marker of HBV infection, assessed in the majority of HCC patients, thereby excluding patients with potential OBI and undermining the actual burden of HBV infection.

Considering the low viremia in patients with occult hepatitis B, the detection of the viral DNA reservoir in hepatocytes would provide the best evaluation for occult HBV.[10],[34] However, the clinical utility of intrahepatic cccDNA assay is very limited because of some existing drawback associated with liver biopsy, such as sampling error, cost, and risk of complications.[38],[39]

Tackling existing issues, the present and the future

The issue of funding and the unavailability of diagnostic facilities should be addressed by governmental and nongovernmental organizations. Considering the asymptomatic nature of the majority of the OBI, it is pertinent that all serological markers are determined to enable policy makers understand the true burden of HBV infection, thereby reducing the occult transmission of infection. Furthermore, several clinical and biological aspects of OBI need to be further explored. This can be achieved by funding and support of research aimed at understanding the immunological mechanisms that drive the development of OBI thereby providing directions into therapeutic insights.

Birth dose vaccination will be an effective strategy to achieve the WHO targets for the elimination of hepatitis as a public health problem by 2030. This is evidenced by 100% reduction of perinatal HBV transmission, following birth dose vaccination of HBV exposed infants in Ile-Ife, Nigeria.[40] However, a systematic review of the impact of HBV prevention in 39 African countries, reported that the test and treat strategy had the most sustained effect on HBV prevention with a predicted reduction of 33% prevalence by 20 years, 62% at 50 years, followed by routine neonatal vaccination and prevention of mother to child transmission at 100% coverage, conversely, catch-up vaccination in adults had a negligible effect on the population studied.[41] Additional measures include use of antiviral agents during pregnancy to decrease maternal DNA levels to undetectable concentrations, community health education, inter-familial screening of house hold contacts of HBV carriers and screening of blood donors using the serological markers of HBV.[24],[42]

Considering the invasiveness of the conventional liver biopsy, the use of liquid biopsy can be explored for the diagnosis of occult hepatitis B in HCC. Liquid biopsy is a noninvasive method used for the identification of circulating tumor cells, circulating micropathies, or circulating miRNA/DNA released into the bloodstream by the solid tumor.[43],[44] The specimen will be further subjected to real-time polymerase chain reaction assay to determine the levels of HBV DNA.[43]

  Conclusion Top

The burden of HCC is yet to be fully unraveled, owing to the challenges associated with the diagnosis of OBI especially in patients with cryptogenic liver disease. Strategic efforts aimed at exploring the impact of OBI in liver diseases should be initiated in the health-care system.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

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