Our results showed that genotypes B and C of HBV were present in about 40% and 50%, respectively, of patients with an acute form of liver disease. In contrast, genotype C was found in 86% of patients with CLD and 68.4% of patients with acute exacerbation of CLD, suggesting that the distribution of HBV genotype B in acute forms of liver disease was higher than that seen in chronic forms of the disease. Interestingly, the distribution of genotype B was higher in patients with FH than in patients with AH, suggesting a stronger association of genotype B with more severe acute forms of liver disease.
Acute hepatitis B is thought to be transmitted horizontally. As such, our results might reflect the distribution of HBV genotypes in the general population. The distribution of HBV genotypes in patients with an acute form of liver disease suggests that individuals with genotype B are more prevalent in the general population—that is, the prevalence of HBV genotype B might be higher in the general population than in patients with CLD. Fujie et al
reported a higher incidence of genotype B in asymptomatic carrier patients who were positive for antibody to hepatitis B e antigen (43.2%) than in patients with hepatocellular carcinoma who were positive for antibody to hepatitis B e antigen (5.9%), although these authors did not compare the prevalence of genotypes B and C in chronic liver diseases.35
Another reason for the higher distribution of genotype B in acute forms of liver disease might be that the percentage of clinical HBV infection compared with subclinical infection might be higher in patients infected with genotype B than in those with genotype C. Kozik et al
reported that the ratio of clinical and subclinical HBV infection was 1:30 in Thai children, although they did not compare the ratio between HBV genotypes.36
From our results that showed that genotype B was more prevalent in patients with FH than AH, we speculate that genotype B of HBV may induce more liver damage than genotype C.
Currently, we do not know why genotype B viruses might cause more liver damage than genotype C viruses. As HBV is not a cytotoxic virus, hepatocyte death is caused by the immune response of the host to the viral infection. Therefore, the ability of these viruses to replicate themselves, and/or differences in their amino acid sequences that bind to hepatocyte HLA class I molecules, the target of peptide specific CTL responses probably play a role.37–43
Genotype B virus may have the motifs that strongly bind to HLA class I molecules, thereby resulting in activation of a stronger immune response. Full genomic sequence analysis of HBV in FH will be required to more directly address this question.
In our current study, the majority of patients with FH were found to have an A1896 precore stop codon mutation, which confirmed our previous report that most Japanese patients with fatal FH or fatal acute exacerbation of CLD had HBV with A1896.16
Interestingly, the precore stop codon mutation was not found in any of the five patients with genotype A, including the patient with FH. It has been speculated that A1896 could not occur in HBV genotype A (with T at nt 1858) because of its role in stabilising the stem loop structure of the encapsidation sequence.44
In contrast with the higher prevalence of genotypes B and C in the Japanese population, the predominant HBV genotypes in Europe and the US are genotypes A and D. Therefore, the frequency of the A1896 mutation in FH patients in Japan and the USA needs to be examined based on HBV genotypes.
Orito et al
reported that T1762 and A1764 were found more frequently in Japanese patients with CLD who had genotype C virus than in those who had genotype B.12
Our results suggest that this tendency also exists in patients with an acute form of liver disease. Why T1762 and A1764 are found less frequently in viruses with genotype B remains unclear.
Our data also showed that viral mutations tended to be found more frequently in FH patients with nt 1753 and 1754 than in patients with AH. T to C/A/G mutations in nt 1753 were reported to be closely associated with progression of CLD.45
These mutations were found in AT rich regions of the core promoter and as such may change the binding efficiency of transcription factors to the core promoter region, as well as the production of precore and core messages.
In conclusion, we found that genotype B of the HBV occurred more frequently in patients with an acute form of liver disease than in those with CLD, and more frequently in patients with FH than in those with AH, in our cohort of patients in the Chiba region of Japan. Viral genotype as well as the presence of mutations at the core promoter and precore regions may be associated with more severe liver damage in these patients. The molecular mechanisms that account for these associations remain to be investigated.