Advertisement

Journal of Gastroenterology

, Volume 49, Issue 2, pp 356–362 | Cite as

Clinical significance and evolution of hepatic HBsAg expression in HBeAg-positive patients receiving interferon therapy

  • Tung-Hung Su
  • Chun-Jen Liu
  • Hung-Chih Yang
  • Yung-Ming Jeng
  • Huei-Ru Cheng
  • Chen-Hua Liu
  • Tai-Chung Tseng
  • Thai-Yen Ling
  • Pei-Jer Chen
  • Ding-Shinn Chen
  • Jia-Horng Kao
Original Article—Liver, Pancreas, and Biliary Tract

Abstract

Background

Serum hepatitis B surface antigen (HBsAg) level is important in the management of chronic hepatitis B (CHB). However, it is unclear whether serum HBsAg reflects its expression in liver and the hepatic HBsAg evolution following interferon therapy.

Methods

Forty-five HBeAg-positive CHB patients receiving interferon-based therapy within a randomized, controlled, multicenter study during 1998–1999 were included. The hepatic HBsAg expressions were categorized into cytoplasmic, inclusion, marginal and negative patterns by immunohistochemical staining. The HBsAg-positive hepatocytes were quantified by image-based cytometry and correlated to HBV serological and virological profiles for clinical implications. The evolution of hepatic HBsAg levels was analyzed among 22 patients with paired liver biopsies before and after interferon therapy, sequentially.

Results

There was a positive correlation between pretreatment serum HBsAg and hepatic HBsAg levels (r = 0.67, P < 0.0001). The hepatic HBsAg expression pattern significantly evolved from cytoplasmic/inclusion pattern to marginal/negative pattern after interferon treatment. The serum HBV-DNA, HBsAg and hepatic HBsAg levels all decreased significantly after interferon therapy. Among 36 % patients with HBeAg loss after therapy, pretreatment hepatic HBsAg levels were significantly lower compared with those without HBeAg loss. After multivariate analysis, low pretreatment hepatic HBsAg levels rather than serum HBsAg titers were associated with a higher rate of HBeAg loss (OR: 4.97, 95 % CI: 1.12–22.00, P = 0.035).

Conclusions

The serum HBsAg level positively reflects the HBsAg level in liver which evolves significantly after interferon therapy. A lower hepatic HBsAg level is associated with HBeAg loss after interferon treatment. Hepatic HBsAg may have clinical significance in CHB patients receiving interferon treatment.

Keywords

Cytometry Hepatitis B Hepatitis B surface antigen Histology Immunohistochemical staining 

Abbreviations

HBsAg

Hepatitis B surface antigen

CHB

Chronic hepatitis B

EOF

End-of-follow-up

ALT

Alanine aminotransferase

HAI

Histology activity index

Notes

Acknowledgments

We thank Mr. Ju-Yi Tsai from, Cell-Bio Biotechnology Company, Taiwan for his technical support on TissueFAX Plus cytometry. We also thank the fourth Core Laboratory of the Department of Medical Research, National Taiwan University Hospital for technical assistance. This work was supported by grants from the National Taiwan University Hospital (NTUH 100-S1914), the Department of Health, and the National Science Council, Executive Yuan, Taiwan.

Conflict of interest

Jia-Horng Kao: Consultant for Abbott, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Merck Sharp & Dohme, Novartis, Omrix, Roche; on speaker’s bureau for Abbott, Roche, Bayer, Bristol-Myers Squibb, GlaxoSmithKline, Novartis; Ding-Shinn Chen: Consultant for Novartis and GlaxoSmithKline; Pei-Jer Chen: Consultant for Gilead Sciences, Novartis and Roche; All other authors declare no competing interests.

Supplementary material

535_2013_840_MOESM1_ESM.doc (11.8 mb)
Supplementary material 1 (DOC 12130 kb)

References

  1. 1.
    Su TH, Hsu CS, Chen CL, Liu CH, Huang YW, Tseng TC, et al. Serum hepatitis B surface antigen concentration correlates with HBV DNA level in patients with chronic hepatitis B. Antivir Ther. 2010;15:1133–9.PubMedCrossRefGoogle Scholar
  2. 2.
    Brunetto MR, Oliveri F, Colombatto P, Moriconi F, Ciccorossi P, Coco B, et al. Hepatitis B surface antigen serum levels help to distinguish active from inactive hepatitis B virus genotype D carriers. Gastroenterology. 2010;139:483–90.PubMedCrossRefGoogle Scholar
  3. 3.
    Tseng TC, Liu CJ, Su TH, Wang CC, Chen CL, Chen PJ, et al. Serum hepatitis B surface antigen levels predict surface antigen loss in hepatitis B e antigen seroconverters. Gastroenterology. 2011;141:517–25, 525.e1-2.Google Scholar
  4. 4.
    Tseng TC, Liu CJ, Yang HC, Su TH, Wang CC, Chen CL, et al. High levels of hepatitis B surface antigen increase risk of hepatocellular carcinoma in patients with low HBV load. Gastroenterology. 2012;142:1140–1149.e3; quiz e13-4.Google Scholar
  5. 5.
    Chan HL, Thompson A, Martinot-Peignoux M, Piratvisuth T, Cornberg M, Brunetto MR, et al. Hepatitis B surface antigen quantification: why and how to use it in 2011: a core group report. J Hepatol. 2011;55:1121–31.PubMedCrossRefGoogle Scholar
  6. 6.
    Su TH, Liu CJ, Tseng TC, Liu CH, Yang HC, Chen CL, et al. Longitudinal Change of HBsAg in HBeAg-negative Patients with Genotype B or C Infection. PLoS One. 2013;8:e55916.Google Scholar
  7. 7.
    Brunetto MR, Moriconi F, Bonino F, Lau GK, Farci P, Yurdaydin C, et al. Hepatitis B virus surface antigen levels: a guide to sustained response to peginterferon alfa-2a in HBeAg-negative chronic hepatitis B. Hepatology. 2009;49:1141–50.PubMedCrossRefGoogle Scholar
  8. 8.
    Chan HL, Wong VW, Chim AM, Chan HY, Wong GL, Sung JJ. Serum HBsAg quantification to predict response to peginterferon therapy of e antigen positive chronic hepatitis B. Aliment Pharmacol Ther. 2010;32:1323–31.PubMedCrossRefGoogle Scholar
  9. 9.
    Moucari R, Mackiewicz V, Lada O, Ripault MP, Castelnau C, Martinot-Peignoux M, et al. Early serum HBsAg drop: a strong predictor of sustained virological response to pegylated interferon alfa-2a in HBeAg-negative patients. Hepatology. 2009;49:1151–7.PubMedCrossRefGoogle Scholar
  10. 10.
    Liaw YF. Clinical utility of hepatitis B surface antigen quantitation in patients with chronic hepatitis B: a review. Hepatology. 2011;53:2121–9.PubMedCrossRefGoogle Scholar
  11. 11.
    Chan HL, Wong VW, Tse AM, Tse CH, Chim AM, Chan HY, et al. Serum hepatitis B surface antigen quantitation can reflect hepatitis B virus in the liver and predict treatment response. Clin Gastroenterol Hepatol. 2007;5:1462–8.PubMedCrossRefGoogle Scholar
  12. 12.
    Thompson AJ, Nguyen T, Iser D, Ayres A, Jackson K, Littlejohn M, et al. Serum hepatitis B surface antigen and hepatitis B e antigen titers: disease phase influences correlation with viral load and intrahepatic hepatitis B virus markers. Hepatology. 2010;51:1933–44.PubMedCrossRefGoogle Scholar
  13. 13.
    Hadziyannis S, Gerber MA, Vissoulis C, Popper H. Cytoplasmic hepatitis B antigen in “ground-glass” hepatocytes of carriers. Arch Pathol. 1973;96:327–30.PubMedGoogle Scholar
  14. 14.
    Hsu HC, Lai MY, Su IJ, Chen DS, Chang MH, Yang PM, et al. Correlation of hepatocyte HBsAg expression with virus replication and liver pathology. Hepatology. 1988;8:749–54.PubMedCrossRefGoogle Scholar
  15. 15.
    Wang HC, Wu HC, Chen CF, Fausto N, Lei HY, Su IJ. Different types of ground glass hepatocytes in chronic hepatitis B virus infection contain specific pre-S mutants that may induce endoplasmic reticulum stress. Am J Pathol. 2003;163:2441–9.PubMedCrossRefGoogle Scholar
  16. 16.
    Ramakrishna B, Mukhopadhya A, Kurian G. Correlation of hepatocyte expression of hepatitis B viral antigens with histological activity and viral titer in chronic hepatitis B virus infection: an immunohistochemical study. J Gastroenterol Hepatol. 2008;23:1734–8.PubMedCrossRefGoogle Scholar
  17. 17.
    Liu CJ, Lai MY, Chao YC, Liao LY, Yang SS, Hsiao TJ, et al. Interferon alpha-2b with and without ribavirin in the treatment of hepatitis B e antigen-positive chronic hepatitis B: a randomized study. Hepatology. 2006;43:742–9.PubMedCrossRefGoogle Scholar
  18. 18.
    Yeh SH, Tsai CY, Kao JH, Liu CJ, Kuo TJ, Lin MW, et al. Quantification and genotyping of hepatitis B virus in a single reaction by real-time PCR and melting curve analysis. J Hepatol. 2004;41:659–66.PubMedCrossRefGoogle Scholar
  19. 19.
    Lee RK, Fan CC, Hwu YM, Lu CH, Lin MH, Chen YJ, et al. SERPINE2, an inhibitor of plasminogen activators, is highly expressed in the human endometrium during the secretory phase. Reprod Biol Endocrinol. 2011;9:38.PubMedCentralPubMedCrossRefGoogle Scholar
  20. 20.
    Tsai HW, Lin YJ, Lin PW, Wu HC, Hsu KH, Yen CJ, et al. A clustered ground-glass hepatocyte pattern represents a new prognostic marker for the recurrence of hepatocellular carcinoma after surgery. Cancer. 2011;117:2951–60.PubMedCrossRefGoogle Scholar
  21. 21.
    Buster EH, Hansen BE, Lau GK, Piratvisuth T, Zeuzem S, Steyerberg EW, et al. Factors that predict response of patients with hepatitis B e antigen-positive chronic hepatitis B to peginterferon-alfa. Gastroenterology. 2009;137:2002–9.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Japan 2013

Authors and Affiliations

  • Tung-Hung Su
    • 1
    • 2
    • 3
  • Chun-Jen Liu
    • 1
    • 2
    • 3
  • Hung-Chih Yang
    • 2
    • 4
  • Yung-Ming Jeng
    • 5
  • Huei-Ru Cheng
    • 1
  • Chen-Hua Liu
    • 1
    • 2
    • 3
  • Tai-Chung Tseng
    • 1
    • 6
  • Thai-Yen Ling
    • 7
  • Pei-Jer Chen
    • 1
    • 2
    • 3
  • Ding-Shinn Chen
    • 1
    • 2
    • 3
  • Jia-Horng Kao
    • 1
    • 2
    • 3
  1. 1.Graduate Institute of Clinical MedicineNational Taiwan University College of MedicineTaipeiTaiwan
  2. 2.Department of Internal MedicineNational Taiwan University HospitalTaipeiTaiwan
  3. 3.Hepatitis Research CenterNational Taiwan University HospitalTaipeiTaiwan
  4. 4.Department of MicrobiologyNational Taiwan University College of MedicineTaipeiTaiwan
  5. 5.Department of PathologyNational Taiwan University HospitalTaipeiTaiwan
  6. 6.Division of Gastroenterology, Department of Internal MedicineBuddhist Tzu Chi General Hospital Taipei BranchTaipeiTaiwan
  7. 7.Department of PharmacologyNational Taiwan University College of MedicineTaipeiTaiwan

Personalised recommendations