Superior Diagnostic Efficacy of N-Terminal Propeptide of Type III Collagen and Golgi Protein 73 for Detection of Fibrosis in Chronic Hepatitis B Patients

Qianqian Chen; Ming-Hua Zheng; Li Zhu; Fajuan Rui; Wenjing Ni; Yali Xiong; Xinyu Hu; Rahma Issa; Yixuan Zhu; Leyao Jia; Scott Barnett; Shengxia Yin; Chuanwu Zhu; Chao Wu; Mindie H. Nguyen; Jie Li

doi:10.1002/mco2.70236

MedComm ›› 2025, Vol. 6 ›› Issue (6) :e70236 DOI: 10.1002/mco2.70236

ORIGINAL ARTICLE

Superior Diagnostic Efficacy of N-Terminal Propeptide of Type III Collagen and Golgi Protein 73 for Detection of Fibrosis in Chronic Hepatitis B Patients

Qianqian Chen ¹^,²
, Ming-Hua Zheng ³^,⁴
, Li Zhu ⁵
, Fajuan Rui ¹
, Wenjing Ni ¹
, Yali Xiong ⁶^,⁷
, Xinyu Hu ⁶
, Rahma Issa ⁶^,⁸
, Yixuan Zhu ⁶^,⁷
, Leyao Jia ⁹
, Scott Barnett ¹⁰
, Shengxia Yin ⁶^,⁷
, Chuanwu Zhu ⁵
, Chao Wu ⁶^,⁷
, Mindie H. Nguyen ¹⁰^,¹¹
, Jie Li ¹^,⁶^,⁷

Author information +

¹. Department of Infectious Diseases, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China

². Department of Gastroenterology, the Affiliated Huai'an Hospital of Xuzhou Medical University and Huai'an Second People's Hospital, Huai'an, Jiangsu, China

³. MAFLD Research Center, Department of Hepatology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China

⁴. Key Laboratory of Diagnosis and Treatment for the Development of Chronic Liver Disease in Zhejiang Province, Wenzhou, Zhejiang, China

⁵. Department of Hepatology, the Fifth People's Hospital of Suzhou, Suzhou, Jiangsu, China

⁶. Department of Infectious Disease, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China

⁷. Institute of Viruses and Infectious Diseases, Nanjing University, Nanjing, Jiangsu, China

⁸. Department of Pharmacy, Ismailia Teaching Oncology Hospital, Ismailia, Egypt

⁹. Department of Infectious Diseases, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing, Jiangsu, China

¹⁰. Division of Gastroenterology and Hepatology, Stanford University Medical Center, Palo Alto, California, USA

¹¹. Department of Epidemiology and Population Health, Stanford University School of Medicine, Palo Alto, California, USA

dr.wu@nju.edu.cn

mindiehn@stanford.edu

lijier@nju.edu.cn

Show less

History +

PDF

Abstract

Significant liver fibrosis is an indication for antiviral therapy in chronic hepatitis B (CHB). Using liver histology assessed by Scheuer system, we evaluated the diagnostic performance of PRO-C3, GP73, and their combination for the presence of liver fibrosis, and compared them with FIB-4, APRI, Agile 3+, FAST, and LSM in treatment-naïve CHB patients from two centers. The study included 324 patients, of whom 167 had S2–4 (significant fibrosis) and 83 had S3–4 (advanced fibrosis). PRO-C3 levels were higher in those with S2–4 and S3–4 compared with S0–1 and S0–2 (both p < 0.001), with similar findings for GP73. PRO-C3 and GP73 were independently associated with S2–4 and S3–4 in multivariable analyses. The area under the curves (AUCs) of PRO-C3 for S2–4 and S3–4 were 0.81 and 0.80, respectively, and exceeded those of GP73 (0.75 and 0.73). The combination of PRO-C3 and GP73 also had significantly higher AUCs for both S2–4 (0.84 vs. 0.64) and S3–4 (0.80 vs. 0.65) as compared with FIB-4, with similar findings for APRI, GP73, LSM, FAST, and Agile 3+ for S2–4. In conclusion, PRO-C3 alone or in combination with GP73 is highly predictive for detecting significant liver fibrosis among CHB patients.

Keywords

biomarker / chronic hepatitis B / Golgi protein 73 / liver fibrosis / N-terminal propeptide of type III collagen

Cite this article

Download citation ▾

Qianqian Chen, Ming-Hua Zheng, Li Zhu, Fajuan Rui, Wenjing Ni, Yali Xiong, Xinyu Hu, Rahma Issa, Yixuan Zhu, Leyao Jia, Scott Barnett, Shengxia Yin, Chuanwu Zhu, Chao Wu, Mindie H. Nguyen, Jie Li. Superior Diagnostic Efficacy of N-Terminal Propeptide of Type III Collagen and Golgi Protein 73 for Detection of Fibrosis in Chronic Hepatitis B Patients. MedComm, 2025, 6(6): e70236 DOI:10.1002/mco2.70236

登录浏览全文

4963

注册一个新账户忘记密码

References

Publishing order | Descend order by publishing year | Descend order by cited within

[1]	WHO. Hepatitis B. 18 July, 2023, https://www.who.int/news-room/fact-sheets/detail/hepatitis-b.

[2]	H. Devarbhavi, S. K. Asrani, J. P. Arab, Y. A. Nartey, E. Pose, and P. S. Kamath, “Global Burden of Liver Disease: 2023 Update,” Journal of Hepatology 79, no. 2 (2023): 516-537.

[3]	N. A. Terrault, A. S. F. Lok, B. J. McMahon, et al., “Update on Prevention, Diagnosis, and Treatment of Chronic hepatitis B: AASLD 2018 hepatitis B Guidance,” Hepatology 67, no. 4 (2018): 1560-1599.

[4]	A. S. Lok and B. J. McMahon, “Antiviral Therapy for Chronic hepatitis B Viral Infection in Adults: A Systematic Review and Meta-analysis,” Hepatology 63, no. 1 (2016): 284-306.

[5]	EASL 2017 Clinical Practice Guidelines on the Management of Hepatitis B Virus Infection. Journal of Hepatology 2017; 67(2): 370-398.

[6]	P. J. Easterbrook, N. Luhmann, S. Bajis, et al., “WHO 2024 Hepatitis B Guidelines: An Opportunity to Transform Care,” The Lancet Gastroenterology & Hepatology 9, no. 6 (2024): 493-495.

[7]	Q. M. Anstee, L. Castera, and R. Loomba, “Impact of Non-invasive Biomarkers on Hepatology Practice: Past, Present and Future,” Journal of Hepatology 76, no. 6 (2022): 1362-1378.

[8]	H. Xiao, M. Shi, Y. Xie, and X. Chi, “Comparison of Diagnostic Accuracy of Magnetic Resonance Elastography and Fibroscan for Detecting Liver Fibrosis in Chronic hepatitis B Patients: A Systematic Review and Meta-analysis,” PLoS ONE 12, no. 11 (2017): e0186660.

[9]	Y. Li, Y. S. Huang, Z. Z. Wang, et al., “Systematic Review With Meta-analysis: The Diagnostic Accuracy of Transient Elastography for the Staging of Liver Fibrosis in Patients With Chronic hepatitis B,” Alimentary Pharmacology & Therapeutics 43, no. 4 (2016): 458-469.

[10]	W. R. Kim, T. Berg, T. Asselah, et al., “Evaluation of APRI and FIB-4 Scoring Systems for Non-invasive Assessment of Hepatic Fibrosis in Chronic hepatitis B Patients,” Journal of Hepatology 64, no. 4 (2016): 773-780.

[11]	J. Itakura, M. Kurosaki, H. Setoyama, et al., “Applicability of APRI and FIB-4 as a Transition Indicator of Liver Fibrosis in Patients With Chronic Viral hepatitis,” Journal of Gastroenterology 56, no. 5 (2021): 470-478.

[12]	K. Patel and G. Sebastiani, “Limitations of Non-invasive Tests for Assessment of Liver Fibrosis,” JHEP Reports 2, no. 2 (2020): 100067.

[13]	F. Rui, L. Xu, Y. H. Yeo, et al., “Machine Learning-based Models for Advanced Fibrosis and Cirrhosis Diagnosis in Chronic hepatitis B Patients With Hepatic Steatosis,” Clinical Gastroenterology and Hepatology 22, no. 11 (2024): 2250-2260.

[14]	C. Caussy, M. Bhargava, I. F. Villesen, et al., “Collagen Formation Assessed by N-Terminal Propeptide of Type 3 Procollagen Is a Heritable Trait and Is Associated with Liver Fibrosis Assessed by Magnetic Resonance Elastography,” Hepatology 70, no. 1 (2019): 127-141.

[15]	M. Liu, H. Qiu, W. Zhang, et al., “Evaluation of Blood-based PRO-C3 Testing as a Diagnostic Marker for Staging Liver Fibrosis: A Systematic Review and Meta-analysis,” Journal of Gastroenterology and Hepatology 38, no. 7 (2023): 1018-1027.

[16]	M. J. Nielsen, A. F. Nedergaard, S. Sun, et al., “The Neo-epitope Specific PRO-C3 ELISA Measures True Formation of Type III Collagen Associated With Liver and Muscle Parameters,” American Journal of Translational Research 5, no. 3 (2013): 303-315.

[17]	N. Roehlen, E. Crouchet, and T. F. Baumert, “Liver Fibrosis: Mechanistic Concepts and Therapeutic Perspectives,” Cells 9, no. 4 (2020): 875.

[18]	A. J. Sanyal, S. S. Shankar, K. P. Yates, et al., “Diagnostic Performance of Circulating Biomarkers for Non-alcoholic Steatohepatitis,” Nature Medicine 29, no. 10 (2023): 2656-2664.

[19]	M. A. Karsdal, S. T. Hjuler, Y. Luo, et al., “Assessment of Liver Fibrosis Progression and Regression by a Serological Collagen Turnover Profile,” American Journal of Physiology Gastrointestinal and Liver Physiology 316, no. 1 (2019): G25-G31.

[20]	M. Boyle, D. Tiniakos, J. M. Schattenberg, et al., “Performance of the PRO-C3 Collagen Neo-epitope Biomarker in Non-alcoholic Fatty Liver Disease,” JHEP Reports 1, no. 3 (2019): 188-198.

[21]	J. F. Hansen, M. Juul Nielsen, K. Nyström, et al., “PRO-C3: A New and More Precise Collagen Marker for Liver Fibrosis in Patients With Chronic hepatitis C,” Scandinavian Journal of Gastroenterology 53, no. 1 (2018): 83-87.

[22]	M. J. Nielsen, S. S. Veidal, M. A. Karsdal, et al., “Plasma Pro-C3 (N-terminal type III collagen propeptide) Predicts Fibrosis Progression in Patients With Chronic hepatitis C,” Liver International 35, no. 2 (2015): 429-437.

[23]	S. Johansen, M. Israelsen, I. F. Villesen, et al., “Validation of Scores of PRO-C3 to Predict Liver-related Events in Alcohol-related Liver Disease,” Liver International 43, no. 7 (2023): 1486-1496.

[24]	B. S. Madsen, M. Thiele, S. Detlefsen, et al., “PRO-C3 and ADAPT Algorithm Accurately Identify Patients With Advanced Fibrosis due to Alcohol-related Liver Disease,” Alimentary Pharmacology & Therapeutics 54, no. 5 (2021): 699-708.

[25]	M. Y. Liu, L. Huang, J. F. Wu, H. B. Zhang, W. B. Ai, and R. T. Zhang, “Possible Roles of Golgi Protein-73 in Liver Diseases,” Annals of Hepatology 27, no. 5 (2022): 100720.

[26]	Y. Xia, Y. Zhang, M. Shen, H. Xu, Z. Li, and N. He, “Golgi Protein 73 and Its Diagnostic Value in Liver Diseases,” Cell Proliferation 52, no. 2 (2019): e12538.

[27]	Y. Li, Y. Yang, Y. Li, et al., “Use of GP73 in the Diagnosis of Non-alcoholic Steatohepatitis and the Staging of Hepatic Fibrosis,” Journal of International Medical Research 49, no. 11 (2021): 3000605211055378.

[28]	C. Hui-Ling, H. Kang-Ming, Z. Yu, et al., “The Potential Value of Serum GP73 in the Ancillary Diagnosis and Grading of Liver Cirrhosis,” Scandinavian Journal of Clinical and Laboratory Investigation 83, no. 2 (2023): 95-102.

[29]	L. Liu, Z. Al-Dhamin, X. Yuan, et al., “Plasma Golgi Protein 73 Levels Predict Prognosis of HCV-Related Hepatic Fibrosis,” Histology and Histopathology 35, no. 11 (2020): 1309-1318.

[30]	T. Ito, V. H. Nguyen, T. Tanaka, et al., “Poor Diagnostic Efficacy of Noninvasive Tests for Advanced Fibrosis in Obese or Younger than 60 Diabetic NAFLD Patients,” Clinical Gastroenterology and Hepatology 21, no. 4 (2023): 1013-1022. e6.

[31]	S. Petta, V. Wai-Sun Wong, E. Bugianesi, et al., “Impact of Obesity and Alanine Aminotransferase Levels on the Diagnostic Accuracy for Advanced Liver Fibrosis of Noninvasive Tools in Patients with Nonalcoholic Fatty Liver Disease,” American Journal of Gastroenterology 114, no. 6 (2019): 916-928.

[32]	Y. Luo, A. Oseini, R. Gagnon, et al., “An Evaluation of the Collagen Fragments Related to Fibrogenesis and Fibrolysis in Nonalcoholic Steatohepatitis,” Scientific Reports 8, no. 1 (2018): 12414.

[33]	S. J. Daniels, D. J. Leeming, M. Eslam, et al., “ADAPT: An Algorithm Incorporating PRO-C3 Accurately Identifies Patients with NAFLD and Advanced Fibrosis,” Hepatology 69, no. 3 (2019): 1075-1086.

[34]	Y. Tsuji, T. Namisaki, K. Kaji, et al., “Comparison of Serum Fibrosis Biomarkers for Diagnosing Significant Liver Fibrosis in Patients With Chronic hepatitis B,” Experimental and Therapeutic Medicine 20, no. 2 (2020): 985-995.

[35]	X. Liu, X. Wan, Z. Li, C. Lin, Y. Zhan, and X. Lu, “Golgi Protein 73(GP73), a Useful Serum Marker in Liver Diseases,” Clinical Chemistry and Laboratory Medicine 49, no. 8 (2011): 1311-1316.

[36]	R. Iftikhar, R. D. Kladney, N. Havlioglu, et al., “Disease- and Cell-specific Expression of GP73 in human Liver Disease,” American Journal of Gastroenterology 99, no. 6 (2004): 1087-1095.

[37]	R. K. Sterling, K. Patel, A. Duarte-Rojo, et al., “AASLD Practice Guideline on Blood-based Non-invasive Liver Disease Assessments of Hepatic Fibrosis and Steatosis,” Hepatology 81, no. 1 (2024): 321-357.

[38]	A. Dalbeni, R. Lombardi, M. Henrique, et al., “Diagnostic Accuracy of AGILE 3+ Score for Advanced Fibrosis in Patients With NAFLD: A Systematic Review and Meta-analysis,” Hepatology 79, no. 5 (2024): 1107-1116.

[39]

P. N. Newsome, M. Sasso, J. J. Deeks, et al., “FibroScan-AST (FAST) Score for the Non-invasive Identification of Patients With Non-alcoholic Steatohepatitis With Significant Activity and Fibrosis: A Prospective Derivation and Global Validation Study,” The Lancet Gastroenterology & Hepatology 5, no. 4 (2020): 362-373.

[40]

F. Ravaioli, E. Dajti, A. Mantovani, P. N. Newsome, G. Targher, and A. Colecchia, “Diagnostic Accuracy of FibroScan-AST (FAST) Score for the Non-invasive Identification of Patients With Fibrotic Non-alcoholic Steatohepatitis: A Systematic Review and Meta-analysis,” Gut 72, no. 7 (2023): 1399-1409.

[41]	P. J. Scheuer, “Classification of Chronic Viral hepatitis: A Need for Reassessment,” Journal of Hepatology 13, no. 3 (1991): 372-374.

[42]	E. R. DeLong, D. M. DeLong, and D. L. Clarke-Pearson, “Comparing the Areas Under Two or More Correlated Receiver Operating Characteristic Curves: A Nonparametric Approach,” Biometrics 44, no. 3 (1988): 837-845.

[43]	A. J. Vickers and E. B. Elkin, “Decision Curve Analysis: A Novel Method for Evaluating Prediction Models,” Medical Decision Making 26, no. 6 (2006): 565-574.

[44]	K. F. Kerr, M. D. Brown, K. Zhu, and H. Janes, “Assessing the Clinical Impact of Risk Prediction Models with Decision Curves: Guidance for Correct Interpretation and Appropriate Use,” Journal of Clinical Oncology 34, no. 21 (2016): 2534-2540.

[45]	E. W. Steyerberg, A. J. Vickers, N. R. Cook, et al., “Assessing the Performance of Prediction Models: A Framework for Traditional and Novel Measures,” Epidemiology (Cambridge, Mass.) 21, no. 1 (2010): 128-138.

RIGHTS & PERMISSIONS

2025 The Author(s). MedComm published by Sichuan International Medical Exchange & Promotion Association (SCIMEA) and John Wiley & Sons Australia, Ltd.