To the Editor:

We read with interest the editorial on the correlation between hepatitis B virus (HBV) genotypes and outcome of HBV infection by Fung and Lok.1 This article made a succinct outline of the epidemiology of HBV genotypes and their association with hepatitis B e antigen seroconversion, activity of liver disease, and response to treatment. We believe that this article will be helpful to hepatologists when facing the explosion of knowledge regarding HBV genotypes in the literature. However, the authors inferred from our previous data2 that genotype B may be associated with accelerated progression to hepatocellular carcinoma (HCC). This may be somewhat misleading, and we would like to address some comments to clarify this issue.

In Taiwan, our first cross-sectional study indicated that more than 50% of HBV-related HCC patients were infected with genotype B. In addition, genotype C was more prevalent in patients with HCC who were older than 50 years, whereas genotype B was more common in those with HCC who were age 50 years or younger. This predominance of genotype B was more substantial in younger patients with HCC, amounting to 90% in those age 35 years or younger, and most of them did not have cirrhosis. To confirm this preliminary observation from only 80 HCC patients, a further survey of 200 surgical cases showed that the prevalence of genotype C was indeed higher in older HCC patients, while that of genotype B was higher in young HCC patients.3 This observation also extends to HBV-related childhood HCC. In a recent study, we demonstrated that genotype B was still the major genotype (74%) in 26 children with HCC.4 Taken together, these lines of evidence strongly suggest that certain genotype B subtypes or strains are associated with the earlier development of HCC in Taiwan.

Thus, the genotype B strains in Taiwan may be different from those in Japan and China where HCC development is less frequent and occurs at an older stage in patients with genotype B.5–7 We have proposed that genotype B can be divided into three phenotypes based on the rate of liver disease progression.8 The first is the slowly progressive phenotype that is associated with a tendency for early hepatitis B e antigen seroconversion during a carrier's lifetime or in the course of chronic hepatitis, which subsequently leads to the low death rate from HCC. The second is the intermediately progressive phenotype that runs a typical natural course of chronic HBV infection with the development of HCC, usually in the patient's 50s. The third is the rapidly progressive phenotype that is associated with the development of HCC in young HBV carriers before they reach 40 years of age, even in the absence of cirrhosis.

In summary, HBV genotypes do account for the heterogeneity in clinical manifestations and treatment response among patients with chronic hepatitis B in different parts of the world; however, the paradoxical findings of genotype predominance in HCC patients between Taiwan and other countries deserve further examinations.


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  • 1
    Fung SK, Lok AS. Hepatitis B virus genotypes: do they play a role in the outcome of HBV infection? HEPATOLOGY 2004; 40: 790792.
  • 2
    Kao JH, Chen PJ, Lai MY, Chen DS. Hepatitis B genotypes correlate with clinical outcomes in patients with chronic hepatitis B. Gastroenterology 2000; 118: 554559.
  • 3
    Kao JH. Hepatitis B viral genotypes: clinical relevance and molecular characteristics. J Gastroenterol Hepatol 2002; 17: 643650.
  • 4
    Ni YH, Chang MH, Wang KJ, Hsu HY, Chen HL, Kao JH, et al. Clinical relevance of hepatitis B virus genotype in children with chronic infection and hepatocellular carcinoma. Gastroenterology (in press).
  • 5
    Sumi H, Yokosuka O, Seki N, Arai M, Imazeki F, Kurihara T, et al. Influence of hepatitis B virus genotypes on the progression of chronic type B liver disease. HEPATOLOGY 2003; 37: 1926.
  • 6
    Orito E, Mizokami M, Sakugawa H, Michitaka K, Ishikawa K, Ichida T, et al. A case-control study for clinical and molecular biological differences between hepatitis B viruses of genotypes B and C. Japan HBV Genotype Research Group. HEPATOLOGY 2001; 33: 218223.
  • 7
    Ding X, Mizokami M, Yao G, Xu B, Orito E, Ueda R, et al. Hepatitis B virus genotype distribution among chronic hepatitis B virus carriers in Shanghai, China. Intervirology 2001; 44: 4347.
  • 8
    Kao JH. Hepatitis B virus genotypes and hepatocellular carcinoma in Taiwan. Intervirology 2003; 46: 400407.

Jia-Horng Kao* † ‡, Ding-Shinn Chen†, * Hepatitis Research Center, Division of Gastroenterology National Taiwan University Hospital Taipei, Taiwan, † Department of Internal Medicine National Taiwan University Hospital Taipei, Taiwan, ‡ Department of Medical Research National Taiwan University Hospital Taipei, Taiwan.