Hepatology International

, Volume 13, Issue 2, pp 148–156 | Cite as

Correlation of serum Mac-2-binding protein glycosylation isomer (M2BPGi) and liver stiffness in chronic hepatitis B infection

  • Lung-Yi MakEmail author
  • Danny Ka-Ho Wong
  • Wai-Kay SetoEmail author
  • Qin Ning
  • Ka-Shing Cheung
  • James Fung
  • Ching-Lung Lai
  • Man-Fung YuenEmail author
Original Article


Background and aim

Mac-2-binding protein glycosylation isomer (M2BPGi) is a novel serum diagnostic marker for liver fibrosis in various liver diseases. We aimed to evaluate its role in assessment of liver fibrosis in chronic hepatitis B infection (CHB) with reference to liver stiffness measurement (LSM).


CHB patients with LSM by transient elastography technology and retrievable serum samples were recruited. Ten-year re-assessments of LSM and M2BPGi were repeated in a patient subgroup.


240 CHB patients (M:F = 116:124; median age 47.5 years) were recruited. The median M2BPGi values for F0/F1/F2, F3 and F4 progressively increased with more advanced stages of liver fibrosis: 0.39, 0.46 and 0.82 COI, respectively (p < 0.01). M2BPGi levels correlated well with liver stiffness (r = 0.611), FIB-4 (r = 0.616), and strongly with APRI (r = 0.825) (all p < 0.001). Using cut-off values of 0.605 and 0.615 COI, the AUROCs were 0.754 and 0.799 for ≥ F3 and F4, respectively. M2BPGi identified one-quarter patients at risk of advanced fibrosis/cirrhosis otherwise classified into ‘grey area’ by LSM. In 86 patients with reassessment LSM, 21 (24.4%) showed significant fibrosis regression with corresponding decline in median M2BPGi level (− 0.11 COI) compared with the increase of +0.03 COI in patients without significant fibrosis regression (p = 0.011). Male gender, older age, use of potent antiviral therapy and change in serum M2BPGi were independently associated with significant fibrosis regression.


Serum M2BPGi can risk-stratify CHB patients whose liver stiffness fell into the ‘grey area’. Significant fibrosis regression occurring in one-quarter patients was reflected by a reduction in M2BPGi levels at 10-year interval.


Cirrhosis Elastography Hepatitis B Liver fibrosis M2BPGi 



We would like to thank Sysmex Corp. for supporting the measurement of M2BPGi and Health-Tech for performing the measurement.

Author contributions

LYM was involved in drafting the manuscript. DKHW was involved in performing laboratory tests and collecting the data. WKS, QN and JF were involved in interpretation of the data and critical revision of the manuscript. KSC was involved in analysis of data. CLL was involved in critical revision of the manuscript. MFY was involved in study concept and design, analysis and interpretation of data, critical revision of manuscript, and overall study supervision. All authors have approved the final draft submitted.

Compliance with ethical standards

Conflict of interest

No potential conflicts of interest to disclose for the authors Lung-Yi Mak, Danny Ka-Ho Wong, Wai-Kay Seto, Qin Ning, Ka-Shing Cheung, James Fung, Ching-Lung Lai, and Man-Fung Yuen.

Ethical approval

This study was approved by the Institutional Review Board/Ethics Committee of the University of Hong Kong and the Hong Kong West Cluster of Hospital Authority.

Supplementary material

12072_2019_9928_MOESM1_ESM.docx (6.4 mb)
Supplementary material 1 (DOCX 6557 kb)


  1. 1.
    World Health Organization Fact Sheet on Hepatitis B []
  2. 2.
    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;67:370–398CrossRefGoogle Scholar
  3. 3.
    Regev A, Berho M, Jeffers LJ, Milikowski C, Molina EG, Pyrsopoulos NT, et al. Sampling error and intraobserver variation in liver biopsy in patients with chronic HCV infection. Am J Gastroenterol 2002;97(10):2614–2618CrossRefPubMedGoogle Scholar
  4. 4.
    Castera L, Vergniol J, Foucher J, Le Bail B, Chanteloup E, Haaser M, et al. Prospective comparison of transient elastography, Fibrotest, APRI, and liver biopsy for the assessment of fibrosis in chronic hepatitis C. Gastroenterology. 2005;128(2):343–350CrossRefPubMedGoogle Scholar
  5. 5.
    Chou R, Wasson N. Blood tests to diagnose fibrosis or cirrhosis in patients with chronic hepatitis C virus infection: a systematic review. Ann Intern Med 2013;158(11):807–820CrossRefPubMedGoogle Scholar
  6. 6.
    Friedrich-Rust M, Ong MF, Martens S, Sarrazin C, Bojunga J, Zeuzem S, et al. Performance of transient elastography for the staging of liver fibrosis: a meta-analysis. Gastroenterology 2008;134(4):960–974CrossRefPubMedGoogle Scholar
  7. 7.
    Ichikawa S, Motosugi U, Morisaka H, Sano K, Ichikawa T, Tatsumi A, et al. Comparison of the diagnostic accuracies of magnetic resonance elastography and transient elastography for hepatic fibrosis. Magn Reson Imaging 2015;33(1):26–30CrossRefPubMedGoogle Scholar
  8. 8.
    Poynard T, Morra R, Halfon P, Castera L, Ratziu V, Imbert-Bismut F, et al. Meta-analyses of FibroTest diagnostic value in chronic liver disease. BMC Gastroenterol 2007;7:40CrossRefPubMedGoogle Scholar
  9. 9.
    European Association for Study of Liver. Asociacion Latinoamericana para el Estudio del Higado Clinical Practice Guidelines: Non-invasive tests for evaluation of liver disease severity and prognosis. J Hepatol 2015;63(1):237–264CrossRefGoogle Scholar
  10. 10.
    Kuno A, Ikehara Y, Tanaka Y, Ito K, Matsuda A, Sekiya S, et al. A serum “sweet-doughnut” protein facilitates fibrosis evaluation and therapy assessment in patients with viral hepatitis. Sci Rep 2013;3:1065CrossRefPubMedGoogle Scholar
  11. 11.
    Nishikawa H, Takata R, Enomoto H, Yoh K, Kishino K, Shimono Y, et al. Proposal of a predictive model for advanced fibrosis containing Wisteria floribunda agglutinin-positive Mac-2-binding protein in chronic hepatitis C. Hepatol Res 2017;47(3):E74–E84CrossRefPubMedGoogle Scholar
  12. 12.
    Abe M, Miyake T, Kuno A, Imai Y, Sawai Y, Hino K, et al. Association between Wisteria floribunda agglutinin-positive Mac-2 binding protein and the fibrosis stage of non-alcoholic fatty liver disease. J Gastroenterol 2015;50(7):776–784CrossRefPubMedGoogle Scholar
  13. 13.
    Umemura T, Joshita S, Sekiguchi T, Usami Y, Shibata S, Kimura T, et al. Serum Wisteria floribunda Agglutinin-Positive Mac-2-Binding Protein Level Predicts Liver Fibrosis and Prognosis in Primary Biliary Cirrhosis. Am J Gastroenterol 2015;110(6):857–864CrossRefPubMedGoogle Scholar
  14. 14.
    Nishikawa H, Enomoto H, Iwata Y, Hasegawa K, Nakano C, Takata R, et al. Clinical significance of serum Wisteria floribunda agglutinin positive Mac-2-binding protein level and high-sensitivity C-reactive protein concentration in autoimmune hepatitis. Hepatol Res 2016;46(7):613–621CrossRefPubMedGoogle Scholar
  15. 15.
    Yamada N, Sanada Y, Tashiro M, Hirata Y, Okada N, Ihara Y. Serum Mac-2 binding protein glycosylation isomer predicts grade F4 liver fibrosis in patients with biliary atresia. J Gastroenterol 2017;52(2):245–252CrossRefPubMedGoogle Scholar
  16. 16.
    Zou X, Zhu MY, Yu DM, Li W, Zhang DH, Lu FJ, et al. Serum WFA + -M2BP levels for evaluation of early stages of liver fibrosis in patients with chronic hepatitis B virus infection. Liver Int 2017;37(1):35–44CrossRefPubMedGoogle Scholar
  17. 17.
    Nishikawa H, Enomoto H, Iwata Y, Kishino K, Shimono Y, Hasegawa K, et al. Clinical implication of serum Wisteria floribunda agglutinin positive Mac-2-binding protein level on hepatitis B e-antigen loss or seroconversion in hepatitis B e-antigen positive patients. Hepatol Res 2016;46(11):1065–1073CrossRefPubMedGoogle Scholar
  18. 18.
    Cheung KS, Seto WK, Wong DK, Mak LY, Lai CL, Yuen MF. Wisteria floribunda agglutinin-positive human Mac-2 binding protein predicts liver cancer development in chronic hepatitis B patients under antiviral treatment. Oncotarget 2017;8:47507–17PubMedGoogle Scholar
  19. 19.
    Fung J, Lai CL, Wong DK, Seto WK, Hung I, Yuen MF. Significant changes in liver stiffness measurements in patients with chronic hepatitis B: 3-year follow-up study. J Viral Hepatitis 2011;18(7):e200–e205CrossRefGoogle Scholar
  20. 20.
    Fung J, Lai CL, Cheng C, Wu R, Wong DK, Yuen MF. Mild-to-moderate elevation of alanine aminotransferase increases liver stiffness measurement by transient elastography in patients with chronic hepatitis B. Am J Gastroenterol 2011;106(3):492–496CrossRefPubMedGoogle Scholar
  21. 21.
    Castera L, Foucher J, Bernard PH, Carvalho F, Allaix D, Merrouche W, et al. Pitfalls of liver stiffness measurement: a 5-year prospective study of 13,369 examinations. Hepatology 2010;51(3):828–835PubMedGoogle Scholar
  22. 22.
    Wong GL, Wong VW, Chim AM, Yiu KK, Chu SH, Li MK. Factors associated with unreliable liver stiffness measurement and its failure with transient elastography in the Chinese population. J Gastroenterol Hepatol 2011;26(2):300–305CrossRefPubMedGoogle Scholar
  23. 23.
    Mak LY, Wong DK, Cheung KS, Seto WK, Lai CL, Yuen MF. Role of serum M2BPGi levels on diagnosing significant liver fibrosis and cirrhosis in treated patients with chronic hepatitis B virus infection. Clin Transl Gastroenterol 2018;9(6):163CrossRefPubMedGoogle Scholar
  24. 24.
    Wong GL, Chan HL, Yu Z, Chan HY, Tse CH, Wong VW. Liver fibrosis progression is uncommon in patients with inactive chronic hepatitis B: a prospective cohort study with paired transient elastography examination. J Gastroenterol Hepatol 2013;28(12):1842–1848CrossRefPubMedGoogle Scholar
  25. 25.
    Enomoto M, Mori M, Ogawa T, Fujii H, Kobayashi S, Iwai S, et al. Usefulness of transient elastography for assessment of liver fibrosis in chronic hepatitis B: regression of liver stiffness during entecavir therapy. Hepatol Res 2010;40(9):853–861CrossRefPubMedGoogle Scholar
  26. 26.
    Osakabe K, Ichino N, Nishikawa T, Sugiyama H, Kato M, Kitahara S, et al. Reduction of liver stiffness by antiviral therapy in chronic hepatitis B. J Gastroenterol 2011;46(11):1324–13334CrossRefPubMedGoogle Scholar
  27. 27.
    Schiff ER, Lee SS, Chao YC, Kew Yoon S, Bessone F, Wu SS, et al. Long-term treatment with entecavir induces reversal of advanced fibrosis or cirrhosis in patients with chronic hepatitis B. Clin Gastroenterol Hepatol 2011;9(3):274–276CrossRefPubMedGoogle Scholar
  28. 28.
    Marcellin P, Gane E, Buti M, Afdhal N, Sievert W, Jacobson IM, et al. Regression of cirrhosis during treatment with tenofovir disoproxil fumarate for chronic hepatitis B: a 5-year open-label follow-up study. Lancet 2013;381(9865):468–475CrossRefPubMedGoogle Scholar
  29. 29.
    Schuppan D, Ruehl M, Somasundaram R, Hahn EG. Matrix as a modulator of hepatic fibrogenesis. Semin Liver Dis 2001;21(3):351–372CrossRefPubMedGoogle Scholar
  30. 30.
    Morio K, Imamura M, Daijo K, Teraoka Y, Honda F, Nakamura Y, et al. Wisteria floribunda agglutinin positive Mac-2-binding protein level increases in patients with acute liver injury. J Gastroenterol 2017;52(12):1252–1257CrossRefPubMedGoogle Scholar
  31. 31.
    Kono M, Nakamura Y, Oyama Y, Mori K, Hozumi H, Karayama M, et al. Increased levels of serum Wisteria floribunda agglutinin-positive Mac-2 binding protein in idiopathic pulmonary fibrosis. Respir Med 2016;115:46–52CrossRefPubMedGoogle Scholar
  32. 32.
    Okada A, Kanzaki H, Hamatani Y, Takashio S, Takahama H, Amaki M, et al. Increased serum Wisteria floribunda agglutinin positive Mac-2 binding protein (Mac-2 binding protein glycosylation isomer) in chronic heart failure: a pilot study. Heart Vessels 2017;15:16–17 [Epub ahead of print] Google Scholar
  33. 33.
    Xie H, Zhang Z, Chen L, Zhang P, Cui Y, Liu H, et al. Elevated plasma levels of Mac-2 binding protein predict poor cardiovascular outcomes in patients with acute coronary syndrome. Coron Artery Dis 2017;28(8):683–689CrossRefPubMedGoogle Scholar
  34. 34.
    Waragai Y, Suzuki R, Takagi T, Sugimoto M, Asama H, Watanabe K, et al. Clinical significance of serum Wisteria floribunda agglutinin-positive Mac-2 binding protein in pancreatic ductal adenocarcinoma. Pancreatology 2016;16(6):1044–1050CrossRefPubMedGoogle Scholar

Copyright information

© Asian Pacific Association for the Study of the Liver 2019

Authors and Affiliations

  1. 1.Department of MedicineThe University of Hong Kong, Queen Mary HospitalHong KongChina
  2. 2.State Key Laboratory for Liver ResearchThe University of Hong KongHong KongChina
  3. 3.Institute of Infectious Disease, Tongji Hospital, Huazhong University of Science and TechnologyWuhanChina

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