Skip to main content
SpringerLink
Log in

High levels of serum Mac-2-binding protein glycosylation isomer (M2BPGi) predict the development of hepatocellular carcinoma in hepatitis B patients treated with nucleot(s)ide analogues

  • Original Article—Liver, Pancreas, and Biliary Tract
  • Published:
Journal of Gastroenterology Aims and scope Submit manuscript

Abstract

Background

Nucleot(s)ide analogues (NA) can reduce the risk of hepatocellular carcinoma (HCC), but not completely prevent its development.

Methods

Two hundred and thirty-four chronic hepatitis B patients virologically well controlled with entecavir or tenofovir disoproxil fumarate for more than 1 year were enrolled in this study. Over the median observation period of 51 (12–142) months, 24 of 234 patients developed HCC. We quantified HBV markers, alpha-fetoprotein (AFP) and Mac-2-binding protein glycosylation isomer (M2BPGi) at baseline and 48 weeks after therapy.

Results

Serum AFP and M2BPGi tended to decline from baseline to 48 weeks after treatment both in patients who did and those who did not develop HCC. Univariate Cox regression analysis indicated that serum M2BPGi levels ≥ 1.215 COI at 48 weeks were associated with HCC development [hazard ratio (HR) 5.73; p ≤ 0.001]. Multivariate analysis showed that male sex (HR 5.6; p = 0.01), AFP ≥ 9.65 ng/ml (HR 22.01; p ≤ 0.001), M2BPGi ≥ 1.215 (HR 5.07; p = 0.004) at 48 weeks were significant independent predictive factors for HCC development. Based on a scoring system consisting of three factors above described, Kaplan–Meier analysis for four groups (score 0, 1, 2, ≥ 3), revealed significant differences in cumulative HCC occurrence for each group within 2 years. The rate of incidence of HCC was 0, 5.4, 23.4, and 75% in each group, respectively.

Conclusions

In patients receiving NA therapy, higher M2BPGi at 48 weeks, as well as male sex and higher AFP at 48 weeks were independent risk factors for HCC development.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

Abbreviations

HBV:

Hepatitis B virus

HCC:

Hepatocellular carcinoma

NA:

Nucleos(t)ide analogues

CHB:

Chronic hepatitis B

AFP:

Alpha-fetoprotein

ETV:

Entecavir

WFA+-M2BP:

Wisteria floribunda agglutinin-positive Mac-2-binding protein

M2BPGi:

Mac-2-binding protein glycosylation isomer

CHC:

Chronic hepatitis C

NAFLD:

Non-alcoholic fatty liver disease

TDF:

Tenofovir disoproxil fumarate

ALT:

Alanine Aminotransferase

COI:

Cut-off index

AST:

Aspartate Aminotransferase

Plt:

Platelet count

T-Bil:

Total bilirubin

References

  1. Lai CL, Ratziu V, Yuen MF, et al. Viral hepatitis B. Lancet (London, England). 2003;362(9401):2089–94.

    Article  CAS  Google Scholar 

  2. Chen CJ, Yu MW, Liaw YF. Epidemiological characteristics and risk factors of hepatocellular carcinoma. J Gastroenterol Hepatol. 1997;12(9–10):S294–308.

    Article  PubMed  CAS  Google Scholar 

  3. Liaw YF, Sung JJ, Chow WC, et al. Lamivudine for patients with chronic hepatitis B and advanced liver disease. N Engl J Med. 2004;351(15):1521–31.

    Article  PubMed  CAS  Google Scholar 

  4. Chang TT, Liaw YF, Wu SS, et al. Long-term entecavir therapy results in the reversal of fibrosis/cirrhosis and continued histological improvement in patients with chronic hepatitis B. Hepatology (Baltimore, MD). 2010;52(3):886–93.

    Article  CAS  Google Scholar 

  5. Marcellin P, Gane E, Buti M, et al. Regression of cirrhosis during treatment with tenofovir disoproxil fumarate for chronic hepatitis B: a 5-year open-label follow-up study. Lancet (London, England). 2013;381(9865):468–75.

    Article  CAS  Google Scholar 

  6. Hosaka T, Suzuki F, Kobayashi M, et al. Long-term entecavir treatment reduces hepatocellular carcinoma incidence in patients with hepatitis B virus infection. Hepatology (Baltimore, MD). 2013;58(1):98–107.

    Article  CAS  Google Scholar 

  7. Kumada T, Toyoda H, Tada T, et al. Effect of nucleos(t)ide analogue therapy on hepatocarcinogenesis in chronic hepatitis B patients: a propensity score analysis. J Hepatol. 2013;58(3):427–33.

    Article  PubMed  CAS  Google Scholar 

  8. Wang JP, Kao FY, Wu CY, et al. Nucleos(t)ide analogues associated with a reduced risk of hepatocellular carcinoma in hepatitis B patients: a population-based cohort study. Cancer. 2015;121(9):1446–55.

    Article  PubMed  CAS  Google Scholar 

  9. Wu CY, Lin JT, Ho HJ, et al. Association of nucleos(t)ide analogue therapy with reduced risk of hepatocellular carcinoma in patients with chronic hepatitis B: a nationwide cohort study. Gastroenterology. 2014;147(1):143–51.e5.

    Article  PubMed  CAS  Google Scholar 

  10. Yamada R, Hiramatsu N, Oze T, et al. Impact of alpha-fetoprotein on hepatocellular carcinoma development during entecavir treatment of chronic hepatitis B virus infection. J Gastroenterol. 2015;50(7):785–94.

    Article  PubMed  CAS  Google Scholar 

  11. Nishikawa H, Nishijima N, Enomoto H, et al. Comparison of FIB-4 index and aspartate aminotransferase to platelet ratio index on carcinogenesis in chronic hepatitis B treated with entecavir. J Cancer. 2017;8(2):152–61.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  12. Kuno A, Ikehara Y, Tanaka Y, et al. A serum “sweet-doughnut” protein facilitates fibrosis evaluation and therapy assessment in patients with viral hepatitis. Sci Rep. 2013;3:1065.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  13. Fujiyoshi M, Kuno A, Gotoh M, et al. Clinicopathological characteristics and diagnostic performance of Wisteria floribunda agglutinin positive Mac-2-binding protein as a preoperative serum marker of liver fibrosis in hepatocellular carcinoma. J Gastroenterol. 2015;50(11):1134–44.

    Article  PubMed  CAS  Google Scholar 

  14. Toshima T, Shirabe K, Ikegami T, et al. A novel serum marker, glycosylated Wisteria floribunda agglutinin-positive Mac-2 binding protein (WFA(+)-M2BP), for assessing liver fibrosis. J Gastroenterol. 2015;50(1):76–84.

    Article  PubMed  CAS  Google Scholar 

  15. Narimatsu H. Development of M2BPGi: a novel fibrosis serum glyco-biomarker for chronic hepatitis/cirrhosis diagnostics. Expert Rev Proteom. 2015;12(6):683–93.

    Article  CAS  Google Scholar 

  16. Yamasaki K, Tateyama M, Abiru S, et al. Elevated serum levels of Wisteria floribunda agglutinin-positive human Mac-2 binding protein predict the development of hepatocellular carcinoma in hepatitis C patients. Hepatology (Baltimore, MD). 2014;60(5):1563–70.

    Article  PubMed Central  CAS  Google Scholar 

  17. Abe M, Miyake T, Kuno A, 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):776–84.

    Article  PubMed  CAS  Google Scholar 

  18. Zou X, Zhu MY, Yu DM, 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):35–44.

    Article  PubMed  CAS  Google Scholar 

  19. Kim SU, Heo JY, Kim BK, et al. Wisteria floribunda agglutinin-positive human Mac-2 binding protein predicts the risk of HBV-related liver cancer development. Liver Int. 2017;37(6):879–87.

    Article  PubMed  CAS  Google Scholar 

  20. Kuno A, Sato T, Shimazaki H, et al. Reconstruction of a robust glycodiagnostic agent supported by multiple lectin-assisted glycan profiling. Proteom Clin Appl. 2013;7(9–10):642–7.

    CAS  Google Scholar 

  21. Bellet DH, Wands JR, Isselbacher KJ, et al. Serum alpha-fetoprotein levels in human disease: perspective from a highly specific monoclonal radioimmunoassay. Proc Natl Acad Sci USA. 1984;81(12):3869–73.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. Nishikawa H, Enomoto H, Iwata Y, et al. Serum Wisteria floribunda agglutinin-positive Mac-2-binding protein for patients with chronic hepatitis B and C: a comparative study. J Viral Hepat. 2016;23(12):977–84.

    Article  PubMed  CAS  Google Scholar 

  23. Nakamura M, Kanda T, Jiang X, et al. Serum microRNA-122 and Wisteria floribunda agglutinin-positive Mac-2 binding protein are useful tools for liquid biopsy of the patients with hepatitis B virus and advanced liver fibrosis. PLoS ONE. 2017;12(5):e0177302.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  24. Cheung KS, Seto WK, Wong DK, et al. Wisteria floribunda agglutinin-positive human Mac-2 binding protein predicts liver cancer development in chronic hepatitis B patients under antiviral treatment. Oncotarget. 2017;8(29):47507–17.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was supported in part by a grant-in-aid from the Research Program on Hepatitis from Japan Agency for Medical Research and Development (AMED) and a Grant-in-aid from the Ministry of Education, Culture, Sports, Science, and Technology [Scientific Research (B) No.16H05288 to Y.T.].

Author information

Authors and Affiliations

  1. Departments of Virology & Liver Unit, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan

    Noboru Shinkai, Shuko Murakami, Shintaro Ogawa & Yasuhito Tanaka

  2. Center for Translational Research, The Institute of Medical Science Hospital, The University of Tokyo, Tokyo, Japan

    Masanori Nojima

  3. Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan

    Etsuko Iio & Kayoko Matsunami

  4. Department of Gastroenterology and Hepatology, Ogaki Municipal Hospital, Ogaki, Japan

    Hidenori Toyoda & Takashi Kumada

  5. Department of Clinical Laboratory, Nagoya City University Hospital, Nagoya, Japan

    Takako Inoue

Authors
  1. Noboru Shinkai
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Masanori Nojima
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Etsuko Iio
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kayoko Matsunami
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Hidenori Toyoda
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Shuko Murakami
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Takako Inoue
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Shintaro Ogawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Takashi Kumada
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Yasuhito Tanaka
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yasuhito Tanaka.

Ethics declarations

Conflict of interest

Yasuhito Tanaka received lecture fees from Chugai Pharmaceutical Co., Ltd., GlaxoSmithKline plc, Bristol–Myers Squibb, Fujirebio Inc., and Gilead Sciences, Inc.

Yasuhito Tanaka received research fees from Bristol–Myers Squibb, Chugai Pharmaceutical Co., Ltd., and Fujifilm Corporation.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Shinkai, N., Nojima, M., Iio, E. et al. High levels of serum Mac-2-binding protein glycosylation isomer (M2BPGi) predict the development of hepatocellular carcinoma in hepatitis B patients treated with nucleot(s)ide analogues. J Gastroenterol 53, 883–889 (2018). https://doi.org/10.1007/s00535-017-1424-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00535-017-1424-0

Keywords

Search

Navigation