Retrospective Study
Copyright ©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Mar 14, 2020; 26(10): 1067-1079
Published online Mar 14, 2020. doi: 10.3748/wjg.v26.i10.1067
Serum N-glycan markers for diagnosing liver fibrosis induced by hepatitis B virus
Xi Cao, Qing-Hua Shang, Xiao-Ling Chi, Wei Zhang, Huan-Ming Xiao, Mi-Mi Sun, Gang Chen, Yong An, Chun-Lei Lv, Lin Wang, Yue-Min Nan, Cui-Ying Chen, Zong-Nan Tan, Xue-En Liu, Hui Zhuang
Xi Cao, Lin Wang, Xue-En Liu, Hui Zhuang, Department of Microbiology and Center of Infectious Diseases, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China
Qing-Hua Shang, Wei Zhang, Mi-Mi Sun, Gang Chen, Yong An, Chun-Lei Lv, Department of Liver Disease, No. 88 Hospital of Chinese People’s Liberation Army, Tai'an 271000, Shandong Province, China
Xiao-Ling Chi, Huan-Ming Xiao, Department of Hepatology, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou 510120, Guangdong Province, China
Yue-Min Nan, Department of Traditional and Western Medical Hepatology, Third Hospital of Hebei Medical University, Shijiazhuang 050051, Hebei Province, China
Cui-Ying Chen, Zong-Nan Tan, Department of Molecular Biomedical Research, Xian si-da Biotechnology Company Limited, Nanjing 210000, Jiangsu Province, China
Author contributions: All authors performed the research, Liu XE and Zhuang H designed the study. Cao X, Wang L and Tan ZN did the experiments. Cao X analyzed data and drafted the manuscript. Shang QH, Chi XL, Zhang W, Xiao HM, Sun MM, Chen G, An Y, Lv CL and Nan YM were responsible for serum sample collection and clinical data acquisition. Liu XE, Zhuang H and Chen CY critically reviewed the manuscript for important intellectual content. All authors agreed to be accountable for all aspects of the work and approved the final version of the manuscript.
Supported by Major Science and Technology Special Project of China Thirteenth Five-Year Plan, No. 2018ZX10732401-003-015; Guangxi Key Laboratory for the Prevention and Control of Viral Hepatitis, No. GXCDCKL201901.
Institutional review board statement: This study was reviewed and approved by the Ethics Committee of Peking University Health Science Center.
Informed consent statement: Patients were not required to give informed consent to the study because the analysis used anonymous clinical data that were obtained after each patient agreed to treatment by written consent.
Conflict-of-interest statement: All authors declare no conflicts-of-interest related to this article.
Data sharing statement: No additional data are available.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
Corresponding author: Xue-En Liu, MD, Academic Research, Associate Professor, Department of Microbiology and Center of Infectious Diseases, School of Basic Medical Sciences, Peking University Health Science Center, No. 38 Xueyuan Road, Haidian District, Beijing 100191, China.
Received: November 5, 2019
Peer-review started: November 5, 2019
First decision: December 5, 2019
Revised: January 10, 2020
Accepted: January 19, 2020
Article in press: January 19, 2020
Published online: March 14, 2020

Hepatitis B virus (HBV) infection is the primary cause of hepatitis with chronic HBV infection, which may develop into liver fibrosis, cirrhosis and hepatocellular carcinoma. Detection of early-stage fibrosis related to HBV infection is of great clinical significance to block the progression of liver lesion. Direct liver biopsy is regarded as the gold standard to detect and assess fibrosis; however, this method is invasive and prone to clinical sampling error. In order to address these issues, we attempted to find more convenient and effective serum markers for detecting HBV-induced early-stage liver fibrosis.


To investigate serum N-glycan profiling related to HBV-induced liver fibrosis and verify multiparameter diagnostic models related to serum N-glycan changes.


N-glycan profiles from the sera of 432 HBV-infected patients with liver fibrosis were analyzed. Significant changed N-glycan levels (peaks) (P < 0.05) in different fibrosis stages were selected in the modeling group, and multiparameter diagnostic models were established based on changed N-glycan levels by logistic regression analysis. The receiver operating characteristic (ROC) curve analysis was performed to evaluate diagnostic efficacy of N-glycans models. These models were then compared with the aspartate aminotransferase to platelet ratio index (APRI) , fibrosis index based on the four factors (FIB-4), glutamyltranspeptidase platelet albumin index (S index), GlycoCirrho-test, and GlycoFibro-test. Furthermore, we combined multiparameter diagnostic models with alanine aminotransferase (ALT) and platelet (PLT) tests and compared their diagnostic power. In addition, the diagnostic accuracy of N-glycan models was also verified in the validation group of patients.


Multiparameter diagnostic models constructed based on N-glycan peak 1, 3, 4 and 8 could distinguish between different stages of liver fibrosis. The area under ROC curves (AUROCs) of Model A and Model B were 0.890 and 0.752, respectively differentiating fibrosis F0-F1 from F2-F4, and F0-F2 from F3-F4, and surpassing other serum panels. However, AUROC (0.747) in Model C used for the diagnosis of F4 from F0-F3 was lower than AUROC (0.795) in FIB-4. In combination with ALT and PLT, the multiparameter models showed better diagnostic power (AUROC = 0.912, 0.829, 0.885, respectively) when compared with other models. In the validation group, the AUROCs of the three combined models (0.929, 0.858, and 0.867, respectively) were still satisfactory. We also applied the combined models to distinguish adjacent fibrosis stages of 432 patients (F0-F1/F2/F3/F4), and the AUROCs were 0.917, 0.720 and 0.785.


Multiparameter models based on serum N-glycans are effective supplementary markers to distinguish between adjacent fibrosis stages of patients caused by HBV, especially in combination with ALT and PLT.

Keywords: Chronic hepatitis B, Liver fibrosis, N-glycan, Multiparameter diagnostic models, Receiver operating characteristic curve analysis, Diagnostic power

Core tip: GlycoFibroTest and GlycoCirrhoTest are unsuitable for assessing stage of fibrosis induced by hepatitis B virus (HBV). We constructed three multiparameter diagnostic models based on serum N-glycans in HBV-related fibrosis patients and combined them with alanine aminotransferase and platelet tests for distinguishing liver fibrosis F0-F1 from F2-F4, F0-F2 from F3-F4 and F0-F3 from F4, and excellent diagnostic power was obtained [area under receiver operating characteristic curves (AUROC) = 0.912, 0.829 and 0.885, respectively]. In addition, the three combined models were verified in the validation group and diagnostic accuracy remained high (AUROC = 0.929, 0.858 and 0.867, respectively). Moreover, our combined models could also be used to discriminate adjacent fibrosis stages (F0-1/F2/F3/F4) (AUROC = 0.917, 0.720 and 0.785, respectively).