Skip to main content
Top
Published in: BMC Gastroenterology 1/2017

Open Access 01-12-2017 | Research article

Distinct patterns of serum hepatitis B core-related antigen during the natural history of chronic hepatitis B

Authors: Zhan-Qing Zhang, Xiao-Nan Zhang, Wei Lu, Yan-Bing Wang, Qi-Cheng Weng, Yan-Ling Feng

Published in: BMC Gastroenterology | Issue 1/2017

Login to get access

Abstract

Background

The current clinical practice on chronic hepatitis B (CHB) requires better on-treatment monitoring of viral persistence. Quantified assays for hepatitis B surface antigen (HBsAg) and core-related antigen (HBcrAg) hold promise for further optimization of therapy. Here, we aimed to characterize HBcrAg during the natural course of CHB.

Methods

Four-hundred and forty four treatment naïve CHB patients, who all underwent liver histology examination, were enrolled in this cross-sectional study. Their HBV DNA, HBsAg, HBeAg and HBcrAg titres were quantified and analyzed in the context of four distinct clinical phases. Correlation of HBcrAg and HBsAg with other markers were performed. The relationship between liver and serum antigen levels were also assessed.

Results

HBcrAg, like HBsAg, exhibited high degree of correlation with HBV DNA. However, a more significant linear relationship was found between HBcrAg and HBeAg titre in immune tolerant (IT) and immune clearance (IC) phases, while in HBeAg negative hepatitis (ENH) group, HBV DNA is a major determinant of HBcrAg. Significant difference was observed in liver HBcAg score and HBcrAg level in both IT and IC phases whereas barely significant positive correlations between liver HBsAg score and HBsAg titre was documented.

Conclusion

HBcrAg titre exhibited distinct correlative profile in a phase-specific manner. In addition, its level is well-related to the intrahepatic expression of core antigen. It has a considerable utility in monitoring and refining antiviral therapy.
Literature
1.
go back to reference WHO: Guidelines for the prevention, care and treatment of persons with chronic hepatitis B infection.; 2015. WHO: Guidelines for the prevention, care and treatment of persons with chronic hepatitis B infection.; 2015.
2.
go back to reference Nguyen T, Thompson AJ, Bowden S, Croagh C, Bell S, Desmond PV, Levy M, Locarnini SA, Hepatitis B. Surface antigen levels during the natural history of chronic hepatitis B: a perspective on Asia. J Hepatol. 2010;52(4):508–13.CrossRefPubMed Nguyen T, Thompson AJ, Bowden S, Croagh C, Bell S, Desmond PV, Levy M, Locarnini SA, Hepatitis B. Surface antigen levels during the natural history of chronic hepatitis B: a perspective on Asia. J Hepatol. 2010;52(4):508–13.CrossRefPubMed
3.
go back to reference Thompson AJ, Nguyen T, Iser D, Ayres A, Jackson K, Littlejohn M, Slavin J, Bowden S, Gane EJ, Abbott W, 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(6):1933–44.CrossRefPubMed Thompson AJ, Nguyen T, Iser D, Ayres A, Jackson K, Littlejohn M, Slavin J, Bowden S, Gane EJ, Abbott W, 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(6):1933–44.CrossRefPubMed
4.
go back to reference Zhang X, Lu W, Zheng Y, Wang W, Bai L, Chen L, Feng Y, Zhang Z, Yuan Z. In Situ analysis of intrahepatic virological events in chronic hepatitis B virus infection. J Clin Invest. 2016;126(3):1079–92.CrossRefPubMedPubMedCentral Zhang X, Lu W, Zheng Y, Wang W, Bai L, Chen L, Feng Y, Zhang Z, Yuan Z. In Situ analysis of intrahepatic virological events in chronic hepatitis B virus infection. J Clin Invest. 2016;126(3):1079–92.CrossRefPubMedPubMedCentral
5.
go back to reference Kimura T, Rokuhara A, Sakamoto Y, Yagi S, Tanaka E, Kiyosawa K, Maki N. Sensitive enzyme immunoassay for hepatitis B virus core-related antigens and their correlation to virus load. J Clin Microbiol. 2002;40(2):439–45.CrossRefPubMedPubMedCentral Kimura T, Rokuhara A, Sakamoto Y, Yagi S, Tanaka E, Kiyosawa K, Maki N. Sensitive enzyme immunoassay for hepatitis B virus core-related antigens and their correlation to virus load. J Clin Microbiol. 2002;40(2):439–45.CrossRefPubMedPubMedCentral
6.
go back to reference Kimura T, Ohno N, Terada N, Rokuhara A, Matsumoto A, Yagi S, Tanaka E, Kiyosawa K, Ohno S, Maki N, Hepatitis B. Virus DNA-negative dane particles lack core protein but contain a 22-kDa precore protein without C-terminal arginine-rich domain. J Biol Chem. 2005;280(23):21713–9.CrossRefPubMed Kimura T, Ohno N, Terada N, Rokuhara A, Matsumoto A, Yagi S, Tanaka E, Kiyosawa K, Ohno S, Maki N, Hepatitis B. Virus DNA-negative dane particles lack core protein but contain a 22-kDa precore protein without C-terminal arginine-rich domain. J Biol Chem. 2005;280(23):21713–9.CrossRefPubMed
7.
go back to reference Rokuhara A, Tanaka E, Matsumoto A, Kimura T, Yamaura T, Orii K, Sun X, Yagi S, Maki N, Kiyosawa K. Clinical evaluation of a new enzyme immunoassay for hepatitis B virus core-related antigen; a marker distinct from viral DNA for monitoring lamivudine treatment. J Viral Hepat. 2003;10(4):324–30.CrossRefPubMed Rokuhara A, Tanaka E, Matsumoto A, Kimura T, Yamaura T, Orii K, Sun X, Yagi S, Maki N, Kiyosawa K. Clinical evaluation of a new enzyme immunoassay for hepatitis B virus core-related antigen; a marker distinct from viral DNA for monitoring lamivudine treatment. J Viral Hepat. 2003;10(4):324–30.CrossRefPubMed
8.
go back to reference Suzuki F, Miyakoshi H, Kobayashi M, Kumada H. Correlation between serum hepatitis B virus core-related antigen and intrahepatic covalently closed circular DNA in chronic hepatitis B patients. J Med Virol. 2009;81(1):27–33.CrossRefPubMed Suzuki F, Miyakoshi H, Kobayashi M, Kumada H. Correlation between serum hepatitis B virus core-related antigen and intrahepatic covalently closed circular DNA in chronic hepatitis B patients. J Med Virol. 2009;81(1):27–33.CrossRefPubMed
9.
go back to reference Zhang ZQ, Lu W, Wang YB, Weng QC, Zhang ZY, Yang ZQ, Feng YL. Measurement of the hepatitis B core-related antigen is valuable for predicting the pathological status of liver tissues in chronic hepatitis B patients. J Virol Methods. 2016;235:92–8.CrossRefPubMed Zhang ZQ, Lu W, Wang YB, Weng QC, Zhang ZY, Yang ZQ, Feng YL. Measurement of the hepatitis B core-related antigen is valuable for predicting the pathological status of liver tissues in chronic hepatitis B patients. J Virol Methods. 2016;235:92–8.CrossRefPubMed
10.
go back to reference Goodman ZD. Grading and staging systems for inflammation and fibrosis in chronic liver diseases. J Hepatol. 2007;47(4):598–607.CrossRefPubMed Goodman ZD. Grading and staging systems for inflammation and fibrosis in chronic liver diseases. J Hepatol. 2007;47(4):598–607.CrossRefPubMed
11.
go back to reference Garcia PD, JH O, Rutter WJ, Walter P. Targeting of the hepatitis B virus precore protein to the endoplasmic reticulum membrane: after signal peptide cleavage translocation can be aborted and the product released into the cytoplasm. J Cell Biol. 1988;106(4):1093–104.CrossRefPubMed Garcia PD, JH O, Rutter WJ, Walter P. Targeting of the hepatitis B virus precore protein to the endoplasmic reticulum membrane: after signal peptide cleavage translocation can be aborted and the product released into the cytoplasm. J Cell Biol. 1988;106(4):1093–104.CrossRefPubMed
12.
go back to reference Ito K, Kim KH, Lok AS, Tong S. Characterization of genotype-specific carboxyl-terminal cleavage sites of hepatitis B virus e antigen precursor and identification of furin as the candidate enzyme. J Virol. 2009;83(8):3507–17.CrossRefPubMedPubMedCentral Ito K, Kim KH, Lok AS, Tong S. Characterization of genotype-specific carboxyl-terminal cleavage sites of hepatitis B virus e antigen precursor and identification of furin as the candidate enzyme. J Virol. 2009;83(8):3507–17.CrossRefPubMedPubMedCentral
13.
go back to reference Ning X, Nguyen D, Mentzer L, Adams C, Lee H, Ashley R, Hafenstein S, Hu J. Secretion of genome-free hepatitis B virus--single strand blocking model for virion morphogenesis of para-retrovirus. PLoS Pathog. 2011;7(9):e1002255.CrossRefPubMedPubMedCentral Ning X, Nguyen D, Mentzer L, Adams C, Lee H, Ashley R, Hafenstein S, Hu J. Secretion of genome-free hepatitis B virus--single strand blocking model for virion morphogenesis of para-retrovirus. PLoS Pathog. 2011;7(9):e1002255.CrossRefPubMedPubMedCentral
14.
go back to reference van Campenhout MJ, Brouwer WP, van Oord GW, Xie Q, Zhang Q, Zhang N, Guo S, Tabak F, Streinu-Cercel A, Wang J, et al. Hepatitis B core-related antigen levels are associated with response to entecavir and Peginterferon add-on therapy in Hbeag-positive chronic hepatitis B patients. Clin Microbiol Infect. 2016;22(6):571.e5–9. van Campenhout MJ, Brouwer WP, van Oord GW, Xie Q, Zhang Q, Zhang N, Guo S, Tabak F, Streinu-Cercel A, Wang J, et al. Hepatitis B core-related antigen levels are associated with response to entecavir and Peginterferon add-on therapy in Hbeag-positive chronic hepatitis B patients. Clin Microbiol Infect. 2016;22(6):571.e5–9.
15.
go back to reference Honda M, Shirasaki T, Terashima T, Kawaguchi K, Nakamura M, Oishi N, Wang X, Shimakami T, Okada H, Arai K, et al. Hepatitis B virus (HBV) Core-related antigen during Nucleos(t)ide analog therapy is related to intra-hepatic HBV replication and development of hepatocellular carcinoma. J Infect Dis. 2016;213(7):1096–106.CrossRefPubMed Honda M, Shirasaki T, Terashima T, Kawaguchi K, Nakamura M, Oishi N, Wang X, Shimakami T, Okada H, Arai K, et al. Hepatitis B virus (HBV) Core-related antigen during Nucleos(t)ide analog therapy is related to intra-hepatic HBV replication and development of hepatocellular carcinoma. J Infect Dis. 2016;213(7):1096–106.CrossRefPubMed
16.
go back to reference European Association for the Study of the Liver. Electronic address eee, European Association for the Study of the L: EASL 2017 clinical practice guidelines on the management of hepatitis B virus infection. J Hepatol. 2017;67(2):370–98.CrossRef European Association for the Study of the Liver. Electronic address eee, European Association for the Study of the L: EASL 2017 clinical practice guidelines on the management of hepatitis B virus infection. J Hepatol. 2017;67(2):370–98.CrossRef
17.
go back to reference Gerken G, Manns M, Gerlich WH, Hess G, Meyer zum Buschenfelde KH. Immune blot analysis of viral surface proteins in serum and liver of patients with chronic hepatitis B virus infection. J Med Virol. 1989;29(4):261–5.CrossRefPubMed Gerken G, Manns M, Gerlich WH, Hess G, Meyer zum Buschenfelde KH. Immune blot analysis of viral surface proteins in serum and liver of patients with chronic hepatitis B virus infection. J Med Virol. 1989;29(4):261–5.CrossRefPubMed
18.
go back to reference Hadziyannis S, Gerber MA, Vissoulis C, Popper H, Cytoplasmic h B. Antigen in "ground-glass" hepatocytes of carriers. Arch Pathol. 1973;96(5):327–30.PubMed Hadziyannis S, Gerber MA, Vissoulis C, Popper H, Cytoplasmic h B. Antigen in "ground-glass" hepatocytes of carriers. Arch Pathol. 1973;96(5):327–30.PubMed
19.
go back to reference Maasoumy B, Wiegand SB, Jaroszewicz J, Bremer B, Lehmann P, Deterding K, Taranta A, Manns MP, Wedemeyer H, Glebe D, et al. Hepatitis B core-related antigen (HBcrAg) levels in the natural history of hepatitis B virus infection in a large European cohort predominantly infected with genotypes A and D. Clin Microbiol Infect. 2015;21(6) 606 e601–610 Maasoumy B, Wiegand SB, Jaroszewicz J, Bremer B, Lehmann P, Deterding K, Taranta A, Manns MP, Wedemeyer H, Glebe D, et al. Hepatitis B core-related antigen (HBcrAg) levels in the natural history of hepatitis B virus infection in a large European cohort predominantly infected with genotypes A and D. Clin Microbiol Infect. 2015;21(6) 606 e601–610
20.
go back to reference Seto WK, Wong DK, Fung J, Huang FY, Liu KS, Lai CL, Yuen MF, Linearized h B. Surface antigen and hepatitis B core-related antigen in the natural history of chronic hepatitis B. Clin Microbiol Infect. 2014;20(11):1173–80.CrossRefPubMed Seto WK, Wong DK, Fung J, Huang FY, Liu KS, Lai CL, Yuen MF, Linearized h B. Surface antigen and hepatitis B core-related antigen in the natural history of chronic hepatitis B. Clin Microbiol Infect. 2014;20(11):1173–80.CrossRefPubMed
Metadata
Title
Distinct patterns of serum hepatitis B core-related antigen during the natural history of chronic hepatitis B
Authors
Zhan-Qing Zhang
Xiao-Nan Zhang
Wei Lu
Yan-Bing Wang
Qi-Cheng Weng
Yan-Ling Feng
Publication date
01-12-2017
Publisher
BioMed Central
Published in
BMC Gastroenterology / Issue 1/2017
Electronic ISSN: 1471-230X
DOI
https://doi.org/10.1186/s12876-017-0703-9

Other articles of this Issue 1/2017

BMC Gastroenterology 1/2017 Go to the issue
Obesity Clinical Trial Summary

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.