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Large and middle hepatitis B surface antigen: the lower the better?
  1. Hsuan-Ho Lin1,
  2. Tai-Chung Tseng1,2,
  3. Jia-Horng Kao2,3,4
  1. 1Division of Gastroenterology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
  2. 2Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
  3. 3Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan
  4. 4Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
  1. Correspondence to Professor Jia-Horng Kao, Hepatitis Research Center, National Taiwan University Hospital, Taipei 10002, Taiwan; kaojh{at}

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We read with great interest the article entitled ‘Quantification of large and middle proteins of hepatitis B virus surface antigen (HBsAg) as a novel tool for the identification of inactive HBV carriers’ by Pfefferkorn et al.1 Serum hepatitis B surface antigen (HBsAg) level has been shown to complement HBV DNA level in predicting clinical outcomes of patients with chronic HBV infection.2 3 In Asian patients, mostly genotype B and C infection, with a low viral load (HBV DNA  ≤2000 IU/mL), HBsAg level >1000 IU/mL indicates a higher risk of hepatitis flare, cirrhosis and hepatocellular carcinoma (HCC) development.2 3 In this paper, the authors confirmed that inactive carriers (IC) with HBV genotype A and D infection had a lower HBsAg level.1 Furthermore, they compared the composition of HBsAg between IC and patients with chronic hepatitis B and found that IC had lower percentages of large HBsAg (LHBs) and middle HBsAg (MHBs).

Although their findings are clinically important, there exists a concern about the low percentages of LHBs and MHBs in IC. Previous studies including ours showed that pre-S deletions of HBV genome are associated with HCC development.4 5 Such viral variants may affect the secretion of mutant LHBs (figure 1).6 Whether the lower percentages of LHBs in IC are attributed to the emergence of pre-S deletion remains unclear and deserves further studies. If this is the case, these patients are still at a risk of HCC development even they are defined as IC.

Figure 1

Presence of pre-S deletion in HBV genome leads to large hepatitis B surface antigen (HBsAg) accumulation in endoplasmic reticulum (ER), which not only reduces the secretion of large HBsAg but also causes ER oxidative stress thus increases hepatocellular carcinoma (HCC) risk.

In summary, the composition of HBsAg may serve as a new biomarker to categorise the natural history of chronic HBV infection to define IC. However, whether it could be applicable to Asian patients with genotype B and C infection awaits further confirmation. In addition, more studies are needed to explore the biological role of HBsAg components in predicting the long-term adverse outcomes, such as cirrhosis and HCC.


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  • Contributors HHL and TCT drafted the manuscript. JHK did the critical review of the manuscript.

  • Funding This work was supported by the grants from the Ministry of Science and Technology, Executive Yuan, Taiwan (MOST 105-2314-B-303-008).

  • Competing interests JHK is the consultant for Abbvie, Bristol-Myers Squibb and Gilead Sciences; on speaker’s bureau for Abbvie, Bristol-Myers Squibb, Gilead Sciences and Merck.

  • Patient consent Obtained.

  • Provenance and peer review Not commissioned; internally peer reviewed.

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