The secret history of a virus that never left
In the complex landscape of liver cancer research, a mysterious phenomenon has puzzled scientists for decades—how can people develop hepatocellular carcinoma (HCC) without active infection from hepatitis B or C viruses, the usual culprits? The answer may lie in what doctors call "occult" hepatitis B infection, a silent persistence of the virus that evades standard detection yet may still drive cancer development.
Increase in NBNC-HCC cases from 1991 to 2010 3
This article explores the fascinating science behind occult hepatitis B infection and its weak but significant association with liver cancer in Japan, revealing how a virus thought to be gone can still threaten our health years later.
Occult hepatitis B infection (OBI) represents one of the most intriguing puzzles in virology. It's defined as the presence of replication-competent hepatitis B virus DNA in the liver or blood of individuals who test negative for hepatitis B surface antigen (HBsAg) using currently available assays 6 . In essence, these people carry the virus but don't show the standard marker that would indicate infection.
The remarkable persistence of OBI lies in the unique biology of the hepatitis B virus. Unlike many viruses, HBV creates a covalently closed circular DNA (cccDNA) that embeds itself in the nucleus of infected liver cells 2 5 . This cccDNA serves as a stable viral mini-chromosome that can persist for decades, even after the apparent clearance of the infection 5 .
Individuals have antibodies against HBV (anti-HBc and/or anti-HBs) but no HBsAg—this accounts for approximately 80% of cases 6
Individuals test negative for all HBV markers including antibodies—the most challenging form to detect 6
The host's immune response effectively controls viral replication 2
Chemical modifications to the viral DNA can silence its activity 6
Mutations that affect HBsAg production or detection 2
Simultaneous infection with other viruses like hepatitis C 9
Japan has witnessed a dramatic shift in the landscape of hepatocellular carcinoma over recent decades. While virus-related HCC (from hepatitis B and C) has traditionally dominated, the proportion of non-B non-C cases has steadily increased 7 . This change reflects both the success of antiviral treatments and changing lifestyle factors.
Over half (54%) of NBNC-HCC cases fell into an "unclassified" category, suggesting complex and multifactorial origins 3 . Another important finding was that slightly overweight patients (BMI 22-25) showed the best prognosis among NBNC-HCC patients, pointing to the "obesity paradox" in liver disease 3 .
A pivotal 2007 study published in the Journal of Gastroenterology set out to investigate potential risk factors for carcinogenesis in NBNC-HCC, with a specific focus on occult HBV infection 1 8 .
The research involved 233 HCC patients grouped according to their hepatitis virus status:
To detect occult HBV, they used highly sensitive polymerase chain reaction methods to identify HBV DNA in serum, despite negative HBsAg results 1 .
| Patient Group | Number of Patients | Obesity/Diabetes Prevalence | Occult HBV Detection |
|---|---|---|---|
| HCV-HCC | 152 | Not specified | Not applicable |
| HBV-HCC | 36 | Lower than NBNC group | Not applicable |
| NBNC-HCC | 45 | Significantly higher | 18% (8/45 patients) |
The prevalence of patients with obesity or diabetes was significantly higher in the NBNC-HCC group compared to the HBV-HCC group 1 .
Only 8 patients (18%) in the NBNC-HCC group had detectable serum HBV DNA, and these were at very low levels 1 .
Genotyping of the detected HBV revealed genotype C (specifically Ce/C2) in 7 patients and genotype D in 1 patient 1 .
A critical distinction emerged in the viral sequences: none of the NBNC-HCC patients showed HCC-associated mutations in the studied regions, whereas 25 of 30 HBV-HCC patients carried strains with known mutations (C1653T, T1753V, and/or A1762T/G1764A) 1 .
| Mutation Type | NBNC-HCC Group | Overt HBV-HCC Group |
|---|---|---|
| C1653T | Not detected | Present in multiple cases |
| T1753V | Not detected | Present in multiple cases |
| A1762T/G1764A | Not detected | Present in multiple cases |
| Any HCC-associated mutations | None detected | 83% (25/30 patients) |
The researchers concluded that there was only a weak association between occult HBV infection and HCC development in NBNC patients 1 . The low detection rate of HBV DNA (18%) suggested that occult hepatitis B was not the primary driver of most NBNC-HCC cases in their cohort.
Instead, the study pointed to non-alcoholic steatohepatitis (NASH) as a potentially important contributor that deserved further investigation 1 .
The absence of characteristic HCC-associated mutations in the occult HBV strains further suggested that the pro-oncogenic mechanisms in OBI might differ from those in overt HBV infection 1 .
Studying occult hepatitis B infection requires specialized reagents and approaches due to the low viral levels and technical challenges. Here are key tools researchers use to unravel OBI mysteries:
Function: Highly sensitive detection and quantification of low-level HBV DNA
Application: Detecting serum HBV DNA below standard detection limits 1
Function: Increased sensitivity for amplifying low-copy number viral DNA
Application: Targetting HBV surface-polymerase or surface genes for genotyping 4
Function: Selective detection of covalently closed circular DNA
Application: Confirming persistent viral reservoir in liver tissue 5
Function: Comprehensive analysis of viral genomes and integration sites
Application: Identifying mutations and characterizing viral variants 7
The weak association between occult HBV and NBNC-HCC established by this and subsequent studies has important clinical implications. First, it suggests that successful vaccination against hepatitis B may not completely eliminate HBV-related HCC, since occult infection can persist 5 . Second, it highlights the need for different surveillance strategies in patients with resolved HBV infection compared to those never infected.
For Japan specifically, these findings come at a critical time. As the nation successfully controls conventional viral hepatitis through vaccination and antiviral treatments, the proportion of NBNC-HCC continues to rise 7 .
A 2019 report noted that NBNC HCCs are increasingly found incidentally and tend to be relatively large in size at diagnosis, though patients often have better-preserved liver function than their viral HCC counterparts 7 .
The detective work to unravel the mystery of non-B non-C hepatocellular carcinoma in Japan reveals a complex picture where occult hepatitis B infection plays a minor but notable role. The 2007 landmark study demonstrated that only a minority of NBNC-HCC cases (approximately 18%) showed evidence of occult HBV, suggesting that metabolic factors like obesity and diabetes may be more significant contributors in many cases.
This research underscores a crucial evolution in our understanding of liver cancer—from viewing it primarily as an infectious disease to recognizing the growing impact of metabolic and lifestyle factors. As we move forward, the scientific challenge lies in detecting these hidden viral threats while addressing the expanding health concerns of fatty liver disease and metabolic syndrome.
The story of occult HBV and its weak link to liver cancer in Japan serves as a powerful reminder that in medicine, what we cannot easily see may still affect our health, and that controlling traditional risk factors doesn't eliminate the threat of disease, but rather transforms it.