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Review
. 2020 Jan 31;21(3):949.
doi: 10.3390/ijms21030949.

Novel Biomarkers of Hepatitis B and Hepatocellular Carcinoma: Clinical Significance of HBcrAg and M2BPGi

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Free PMC article
Review

Novel Biomarkers of Hepatitis B and Hepatocellular Carcinoma: Clinical Significance of HBcrAg and M2BPGi

Ian Baudi et al. Int J Mol Sci. .
Free PMC article

Abstract

The hepatitis B virus (HBV) cannot be removed completely from infected hepatocytes, owing to the presence of intrahepatic covalently closed circular DNA (cccDNA). As chronic hepatitis B (CHB) can progress to cirrhosis and hepatocellular carcinoma (HCC), predicting HCC development in high-risk patients with high viral replicative activity or advanced fibrosis is important. Novel serological biomarkers reflect intrahepatic viral replicative activity or the progression of liver fibrosis, indicating non-invasive alternatives to liver biopsy: (1) Hepatitis B core-related antigen (HBcrAg) correlates with serum HBV DNA and intrahepatic cccDNA. In CHB patients, a decrease in HBcrAg is associated with favorable outcomes. HBcrAg can predict HCC occurrence or recurrence. (2) Measurement of the Mac-2 binding protein glycosylation isomer (M2BPGi) has been introduced for the evaluation of liver fibrosis. An increase in M2BPGi in CHB patients is related to the progression of liver fibrosis and high potential (risk) of HCC development. Here, we describe the clinical applications of HBcrAg and M2BPGi in CHB patients. Additionally, because new potential therapeutic agents that eliminate intrahepatic cccDNA are being developed, monitoring of HBcrAg or M2BPGi might be suitable for evaluating therapeutic effects and the clinical outcomes. In conclusion, these would be appropriate surrogate markers for predicting disease progression.

Keywords: Wisteria floribunda agglutinin-positive Mac-2 binding protein; chronic hepatitis B (CHB); cirrhosis; hepatitis B core-related antigen (HBcrAg); hepatocellular carcinoma (HCC); intrahepatic covalently closed circular DNA (cccDNA); liver fibrosis.

Conflict of interest statement

Takako Inoue is currently supported by a research grant from Gilead Sciences and MSD. Tanaka is currently conducting research sponsored by Chugai Pharmaceutical Co., Ltd., Bristol-Myers Squibb, Fujirebio, Inc., and Gilead Sciences. Lecture fees are follows: Fujirebio, Inc. and Gilead Sciences.

Figures

Figure 1
Figure 1
Chronic hepatitis B virus (HBV) infection related to liver disease progression. The schematic shows the clinical stages involved in the natural history of chronic hepatitis B (CHB). The novel serum biomarkers hepatitis B core-related antigen (HBcrAg) and Mac-2 binding protein glycosylation isomer (M2BPGi) provide valuable prognostic data for effective management of CHB. It is important to monitor the patients at high risk and to treat them in order to prevent liver complications, cirrhosis, and hepatocellular carcinoma (HCC) development. Abbreviations: HBV, hepatitis B virus; HCC, hepatocellular carcinoma; TACE, transcatheter arterial chemoembolization; TKIs, tyrosine kinase inhibitors; AFP, alpha fetoprotein; PIVKA-II, protein induced by vitamin K absence or antagonist-II; HBcrAg, hepatitis B core-related antigen; M2BPGi, Mac-2 binding protein glycan isomer; HBsAg, hepatitis B surface antigen.
Figure 2
Figure 2
HBV replication cycle. The schematic depicts the steps involved in the HBV replication cycle. It shows the sources of various HBV-related molecules used routinely for diagnosis, clinical monitoring, and prognosis of HBV infection. These include HBcrAg (p22cr, HBeAg, hepatitis B core antigen (HBcAg), HBsAg, and HBV DNA, which can be measured in serum. Covalently closed circular (ccc)DNA is mainly measured from liver biopsy samples. Abbreviations: HBV, hepatitis B virus; HBcrAg, hepatitis B core-related antigen; p22cr, precore protein; HBeAg, hepatitis B envelope antigen; HBcAg, hepatitis B core antigen; HBsAg, hepatitis B surface antigen; cccDNA, covalently closed circular DNA; rcDNA, relaxed circular DNA, pgRNA, pregenomic RNA; HBc and Pol, hepatitis B core antigen and polymerase.
Figure 3
Figure 3
(a) Mac-2 binding protein (M2BP)–Wisteria floribunda agglutinin-positive (WFA) interaction. M2BPGi is a glycobiomarker of liver fibrosis with a unique fibrosis-related glycol-modification. The lectin WFA binds specifically to M2BPGi. This specific lectin–glycan interaction was exploited to develop a lectin-antibody sandwich immunoassay for the quantification of M2BPGi. (b) Automated serum M2BPGi quantification. The schematic depicts the main steps involved in M2BPGi quantification using the fully automated HISCL-2000i immunoanalyzer (Sysmex Co., Hyogo, Japan). Lectin immobilized on magnetic beads is mixed with diluted serum. ALP-labelled anti-M2BP monoclonal antibodies are then added after washing away unbound proteins. Chemiluminescent substrate and stop solution are added following a wash step to remove unbound antibodies. The automated assay takes only 17 minutes. Abbreviations: M2BPGi, Mac-2 binding protein glycan isomer; WFA, Wisteria floribunda agglutinin; ALP, alkaline phosphatase.

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