|
1
|
Kamada Y, Sumida Y, Takahashi H, Fujii H, Miyoshi E, Nakajima A. Utility of Mac-2 binding protein glycosylation isomer as an excellent biomarker for the prediction of liver fibrosis, activity, and hepatocellular carcinoma onset: an expert review. J Gastroenterol 2025; 60:10-23. [PMID: 39652103 DOI: 10.1007/s00535-024-02179-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2024] [Accepted: 11/10/2024] [Indexed: 01/11/2025]
Abstract
Mac-2 binding protein glycosylation isomer (M2BPGi) is a liver fibrosis biomarker that originated in Japan and has been covered by health insurance for 10 years. M2BPGi is useful not only for liver fibrosis stage prediction but also for assessment of the degree of liver inflammation and prediction of hepatocellular carcinoma development. The usefulness of M2BPGi for assessing disease progression in patients with various chronic liver diseases has been demonstrated over the past decade in a large number of patients. Recently, there have been many reports from outside Japan, including reports from South Korea, Taiwan, Hong Kong, and China. These studies demonstrated that M2BPGi is an excellent biomarker that can evaluate the progression of liver fibrosis in chronic liver disease. It is also an excellent indicator of liver activity. Recently, a quantitative M2BPGi (M2BPGi-Qt) assay was developed, and future validation in real-world settings is expected. This will enable diagnosis of the progression of liver fibrosis based on more precise test results and is expected to contribute to the early detection and follow-up of diseases caused by chronic hepatitis, as well as post-treatment monitoring. The significance of the M2BPGi-Qt assay will likely become clearer as real-world data accumulate. If new cutoff values for each chronic liver disease stage and activity level using the M2BPGi-Qt assay are set based on real-world data, it is expected that this will become a useful tool to identify cases of liver fibrosis and monitor the progression of chronic liver disease.
Collapse
Affiliation(s)
- Yoshihiro Kamada
- Department of Advanced Metabolic Hepatology, Osaka University Graduate School of Medicine, 1-7, Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Yoshio Sumida
- Graduate School of Healthcare Management, International University of Healthcare and Welfare, 4-1-26, Akasaka, Minato-ku, Tokyo, 107-8402, Japan.
| | - Hirokazu Takahashi
- Liver Center, Saga University Hospital, 5-1-1 Nabeshima, Saga, 849-8501, Japan
| | - Hideki Fujii
- Department of Hepatology, Graduate School of Medicine, Osaka Metropolitan University, 1-4-3, Asahimachi, Abeno, Osaka, 545-8585, Japan
| | - Eiji Miyoshi
- Department of Molecular Biochemistry and Clinical Investigation, Osaka University Graduate School of Medicine, Suita, Osaka, 565-0871, Japan
| | - Atsushi Nakajima
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, 3-9, Fukuura, Kanazawa-ku, Yokohama, 236-0004, Japan
| |
Collapse
|
|
2
|
Liu X, Zhang W, Ma B, Lv C, Sun M, Shang Q. The value of serum Mac-2 binding protein glycosylation isomer in the diagnosis of liver fibrosis: a systematic review and meta-analysis. Front Physiol 2024; 15:1382293. [PMID: 39558944 PMCID: PMC11570841 DOI: 10.3389/fphys.2024.1382293] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2024] [Accepted: 09/30/2024] [Indexed: 11/20/2024] Open
Abstract
Background The early detection and intervention of liver fibrosis (LF) in patients with chronic liver disease is critical to their management. The accuracy of serum Mac-2 binding protein glycosylation isomer (M2BPGi) in the diagnosis of LF remains controversial. This study aimed to comprehensively assess the value of serum M2BPGi in diagnosing LF. Methods The PubMed, Embase, MEDLINE, Web of Science, and Cochrane Library databases were searched. The effect values were combined using a random-effects model. Meta-regression and subgroup analysis were used to explore the sources of heterogeneity. In addition, publication bias assessment and sensitivity analysis were conducted. Results This study includes 12 studies with 2,416 patients. The pooled sensitivity, specificity, and AUROC of M2BPGi in the diagnosis of significant fibrosis (≥F2) were 0.65 (95% CI: 0.57-0.71), 0.79 (95% CI: 0.72-0.84), and 0.78 (95% CI: 0.74-0.81), respectively, while those for predicting extensive fibrosis (≥F3) were 0.76 (95% CI: 0.71-0.80), 0.75 (95% CI: 0.68-0.81), and 0.81 (95% CI: 0.77-0.84). Sensitivity analysis indicated stable results in this study. The disease type, cut-off values, study country, average age, and male proportion were the sources of heterogeneity in diagnosing significant fibrosis of M2BPGi (p < 0.05). Sample size, disease type, study country, publication year, cut-off values, average age, and male proportion were important sources of heterogeneity in diagnosing extensive fibrosis (p < 0.05). Conclusion Serum M2BPGi has good diagnostic performance for significant fibrosis and extensive fibrosis in patients with chronic hepatitis B (CHB), chronic hepatitis C (CHC), or nonalcoholic fatty liver disease (NAFLD) and is an effective, non-invasive, and convenient marker. Systematic Review Registration https://inplasy.com/inplasy-2023-10-0086/.
Collapse
Affiliation(s)
- Xinyu Liu
- College of First Clinical Medicine, Shandong University of Traditional Chinese Medicine, Jinan, Shandong, China
| | - Wei Zhang
- Department of Liver Disease, The 960th Hospital of the PLA Joint Logistics Support Force, Jinan, China
| | - Baofeng Ma
- The third department of encephalopathy, Jinan Integrated Traditional Chinese and Western Medicine Hospital, Jinan, China
| | - Chunlei Lv
- Diagnosis and Treatment Center for Liver Diseases, Tai’an 88 Hospital, Taian, China
| | - Mimi Sun
- Diagnosis and Treatment Center for Liver Diseases, Tai’an 88 Hospital, Taian, China
| | - Qinghua Shang
- Department of Liver Disease, The 960th Hospital of the PLA Joint Logistics Support Force, Jinan, China
| |
Collapse
|
|
3
|
Najafi N, Razavi A, Jafarpour H, Raei M, Azizi Z, Davoodi L, Abdollahi A, Frouzanian M. Evaluation of hepatic injury in chronic hepatitis B and C using APRI and FIB-4 indices compared to fibroscan results. Ann Med Surg (Lond) 2024; 86:3841-3846. [PMID: 38989210 PMCID: PMC11230742 DOI: 10.1097/ms9.0000000000002095] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2022] [Accepted: 12/24/2023] [Indexed: 07/12/2024] Open
Abstract
Background Hepatitis B (HBV) and hepatitis C viruses (HCV) are significant causes of liver disease worldwide. Liver fibrosis (LF) is a complication of chronic liver damage caused by HBV and HCV due to our limited knowledge comparing the diagnostic performance of platelet to aspartate aminotransferase ratio index (APRI) and fibrosis-4 (FIB-4) index with fibroscan. Methods This study evaluated liver damage in HBV and HCV using APRI, FIB-4, and fibroscan indices. This retrospective cohort descriptive-analytical study was conducted on patients with HBV and HCV. This study uses laboratory results and imaging to investigate liver damage in chronic HBV and HCV patients. APRI and FIB-4 were computed based on laboratory results. Results A total of 185 patients (82 hepatitis B and 103 hepatitis C) were included in the study. Thirteen patients had liver cirrhosis. There was no statistically significant difference between the fibroscan results in the two groups (P=0.99). The HBV group's mean APRI and FIB-4 were lower than HCV, but no significant difference was observed (P>0.05). Our results in HBV and HCV patients showed that APRI and FIB-4 accomplished well anticipating cirrhosis with an area under the receiver operating characteristic curve (AUC) of 0.771-0.845 and 0.871-0.910, respectively. Conclusion Fibroscan is a powerful tool superior to APRI and FIB-4 in predicting LF and cirrhosis. Nevertheless, APRI and FIB-4 are inexpensive and non-invasive indicators with acceptable efficacy in predicting advanced fibrosis or cirrhosis. However, these two measures are not reliable in low-grade fibrosis.
Collapse
Affiliation(s)
- Narges Najafi
- Department of Infectious Diseases, School of Medicine, Antimicrobial Resistance Research Center, Communicable Diseases Research Institutes, Qaem Shahr Razi Hospital, Mazandaran University of Medical Sciences
| | - Alireza Razavi
- Student Research Committee, School of Medicine, Mazandaran University of Medical Sciences
| | - Hamed Jafarpour
- Student Research Committee, School of Medicine, Mazandaran University of Medical Sciences
| | - Maedeh Raei
- Gastrointestinal Cancer Research Center, Non-Communicable Diseases Institute, Mazandaran University of Medical Sciences, Sari, Iran
| | - Zahra Azizi
- Student Research Committee, School of Medicine, Mazandaran University of Medical Sciences
| | - Lotfollah Davoodi
- Department of Infectious Diseases, School of Medicine, Antimicrobial Resistance Research Center, Communicable Diseases Research Institutes, Qaem Shahr Razi Hospital, Mazandaran University of Medical Sciences
| | - Amirsaleh Abdollahi
- Student Research Committee, School of Medicine, Mazandaran University of Medical Sciences
| | - Mehran Frouzanian
- Student Research Committee, School of Medicine, Mazandaran University of Medical Sciences
| |
Collapse
|
|
4
|
Rao W, Fang XH, Zhao Y, Wang Y, Zhang B, Wei Z, Kong X, Cai JZ, Yang G, Xie M. Clinical value of [ 18F]AlF-NOTA-FAPI-04 PET/CT for assessing early-stage liver fibrosis in adult liver transplantation recipients compared with chronic HBV patients. Jpn J Radiol 2024; 42:536-545. [PMID: 38316724 DOI: 10.1007/s11604-024-01528-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2023] [Accepted: 01/03/2024] [Indexed: 02/07/2024]
Abstract
AIMS To investigate the clinical value and performance of [18F]AlF-NOTA-FAPI-04 PET/CT in assessing early-stage liver fibrosis in liver transplantation (LT) recipients. METHODS A prospective study including 17 LT recipients and 12 chronic Hepatitis B (CHB) patients was conducted. All patients received liver biopsy, transient elastography (TE), and [18F]AlF-NOTA-FAPI-04 PET/CT. On [18F]AlF-NOTA-FAPI-04 PET/CT scans, the liver parenchyma's maximum standardized uptake values (SUVmax) were measured. The receiver operating characteristic (ROC) curve analysis was applied to determine the diagnostic efficacy of [18F]AlF-NOTA-FAPI-04 PET/CT in early-stage liver fibrosis (S1-S2) compared with the diagnostic performance of TE. RESULTS Among those 29 patients enrolled in this study, 15(51.7%) had fibrosis S0, 10(34.5%) had S1, and 4(13.8%) had S2, respectively. The SUVmax of patients with early-stage liver fibrosis was significantly higher than those without liver fibrosis in LT recipients and CHB patients (P = 0.004, P = 0.02). In LT recipients, a SUVmax cut-off value of 2.0 detected early-stage liver fibrosis with an AUROC of 0.92 (P = 0.006), and a liver stiffness measurements (LSM) score cut-off value of 8.2 kPa diagnosed early-stage liver fibrosis with an AUROC of 0.80 (P = 0.012). In CHB patients, a SUVmax cut-off value of 2.7 detected early-stage liver fibrosis with an AUROC of 0.94 (P < 0.001) and an LSM scores cut-off value of 8.4 kPa diagnosed early-stage liver fibrosis with an AUROC of 0.91 (P < 0.001). CONCLUSION [18F]AlF-NOTA-FAPI-04 PET/CT could be applied to evaluate early-stage liver fibrosis in LT recipients and CHB patients properly, with the potential additional advantages in monitoring and predicting complications after LT.
Collapse
Affiliation(s)
- Wei Rao
- Division of Hepatology, Liver Disease Center, The Affiliated Hospital of Qingdao University, Qingdao, 266000, Shandong, China
- Department of Organ Transplantation Center, The Affiliated Hospital of Qingdao University, Qingdao, 266000, Shandong, China
- Institute of Organ Donation and Transplantation of Qingdao University Medical College, Qingdao, 266000, Shandong, China
| | - Xiao-Han Fang
- Department of Gastroenterology, The Affiliated Hospital of Qingdao University, Qingdao, 266000, Shandong, China
| | - Youwei Zhao
- Department of Gastroenterology, The Affiliated Hospital of Qingdao University, Qingdao, 266000, Shandong, China
| | - Ye Wang
- Department of Pathology, The Affiliated Hospital of Qingdao University, Qingdao, 266000, Shandong, China
| | - Bei Zhang
- Department of Immunology, Medical College of Qingdao University, Qingdao, 266000, Shandong, China
| | - Zhimin Wei
- Department of Pathology, The Affiliated Hospital of Qingdao University, Qingdao, 266000, Shandong, China
| | - Xinjuan Kong
- Department of Gastroenterology, The Affiliated Hospital of Qingdao University, Qingdao, 266000, Shandong, China
| | - Jin-Zhen Cai
- Division of Hepatology, Liver Disease Center, The Affiliated Hospital of Qingdao University, Qingdao, 266000, Shandong, China
- Department of Organ Transplantation Center, The Affiliated Hospital of Qingdao University, Qingdao, 266000, Shandong, China
- Institute of Organ Donation and Transplantation of Qingdao University Medical College, Qingdao, 266000, Shandong, China
| | - Guangjie Yang
- Department of Nuclear Medicine, The Affiliated Hospital of Qingdao University, Qingdao, 266000, Shandong, China.
| | - Man Xie
- Department of Gastroenterology, The Affiliated Hospital of Qingdao University, Qingdao, 266000, Shandong, China.
| |
Collapse
|
|
5
|
Yamana H, Tokodai K, Fujio A, Kashiwadate T, Miyazawa K, Sasaki K, Matsumura M, Mitsugashira H, Unno M, Kamei T. Clinical Significance of the Mac-2 Binding Protein Glycosylated Isomer as a Surrogate Marker of Graft Fibrosis After Pediatric Liver Transplantation. Transplant Proc 2023:S0041-1345(23)00227-0. [PMID: 37127515 DOI: 10.1016/j.transproceed.2023.03.053] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2023] [Accepted: 03/28/2023] [Indexed: 05/03/2023]
Abstract
BACKGROUND After pediatric liver transplantation, liver fibrosis may occur during long-term follow-up. Noninvasive markers for assessing this liver fibrosis are desired. Mac-2 binding protein glycosylated isomer (M2BPGi) has recently been reported as a useful biomarker for liver fibrosis. However, its usefulness in the pediatric population is yet to be established. This study investigated the clinical significance of M2BPGi levels as a surrogate marker of graft fibrosis after pediatric liver transplantation. METHODS We retrospectively identified 96 patients who underwent pediatric liver transplantation at our institution between 1991 and 2015. The association between M2BPGi levels and other fibrosis markers was analyzed in 60 patients in whom fibrosis markers were measured. The association between fibrosis marker levels and graft fibrosis was assessed in 42 patients who underwent biopsies between 2016 and 2022. RESULTS The M2BPGi levels were statistically correlated with the hyaluronic acid and type-IV collagen levels. None of the fibrosis markers were significantly associated with liver graft fibrosis, although the levels of these markers were slightly higher in patients with severe liver fibrosis than in those with mild fibrosis. CONCLUSIONS The M2BPGi levels had a limited ability to assess liver graft fibrosis after pediatric liver transplantation, similar to other fibrosis markers. Further studies with larger cohorts are required to validate these findings externally.
Collapse
Affiliation(s)
- Hiroki Yamana
- Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan.
| | - Kazuaki Tokodai
- Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Atsushi Fujio
- Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Toshiaki Kashiwadate
- Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Koji Miyazawa
- Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Kengo Sasaki
- Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Muneyuki Matsumura
- Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Hiroaki Mitsugashira
- Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Michiaki Unno
- Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Takashi Kamei
- Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan
| |
Collapse
|
|
6
|
Inoue T, Tanaka Y. Noninvasive assessments of liver disease severity based on biomarkers. COMPREHENSIVE GUIDE TO HEPATITIS ADVANCES 2023:31-60. [DOI: 10.1016/b978-0-323-98368-6.00009-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
|
|
7
|
Vincent JP, Ndow G, Ogawa S, Ceesay A, Njie R, Sanneh B, Baldeh I, D’Alessandro U, Mendy M, Thursz M, Chemin I, Tanaka Y, Lemoine M, Shimakawa Y. Mac-2 binding protein glycosylation isomer (M2BPGi) to evaluate liver fibrosis and cancer in HBV-infected patients in West Africa. J Glob Health 2022; 12:04076. [PMID: 36370422 PMCID: PMC9653177 DOI: 10.7189/jogh.12.04076] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
BACKGROUND To reduce mortality associated with hepatitis B virus (HBV) infection, timely detection of cirrhosis and early-stage hepatocellular carcinoma (HCC) is essential. In low-income countries, however, HBV-infected people have limited access to liver histopathology, a reference test. Recently, Asian studies have suggested the usefulness of an inexpensive serum biomarker called Mac-2 binding protein glycosylation isomer (M2BPGi) in staging liver fibrosis and predicting HCC in HBV-infected patients. METHODS We systematically searched PubMed for studies examining the performance of M2BPGi in staging liver fibrosis in HBV-infected people, published up to September 21, 2021, to elucidate the knowledge gap. We then conducted a cross-sectional study of 339 HBV-infected patients in The Gambia (cirrhosis = 65, HCC = 73, non-cirrhosis non-HCC = 201). We evaluated the association of M2BPGi with cirrhosis and HCC by computing odds ratios (ORs) derived from logistic regression. We also assessed the performance of M2BPGi to stage liver fibrosis in 49 patients who underwent liver biopsy (derivation set) and 217 patients with transient elastography (validation set). Using the derivation set we drew the receiver operating characteristics (ROC) curves to identify optimal M2BPGi thresholds to indicate significant fibrosis and cirrhosis using biopsy as a reference. We then applied these cut-offs to the validation set to obtain its sensitivity and specificity for indicating significant fibrosis and cirrhosis using transient elastography as a reference. RESULTS The systematic review identified 13 studies, all of which were conducted in East Asia and none in Africa. In The Gambia, positive M2BPGi was significantly associated with both cirrhosis (adjusted OR = 7.8, 95% CI = 3.1-19.7) and HCC (adjusted OR = 10.1, 2.6-40.2). The areas under the ROC curve (AUROC) in the derivation and validation set were 0.62 and 0.78, respectively, to diagnose significant fibrosis, and 0.80 and 0.89, respectively, to diagnose cirrhosis. By applying the optimal cut-offs, the sensitivity and specificity in the validation set were 61.5% and 93.4%, respectively, to diagnose significant fibrosis, and 72.5% and 92.2%, respectively, for cirrhosis. CONCLUSIONS To the best of our knowledge, this is the first evaluation of M2BPGi in HBV-infected African population. The findings supported its accuracy in the diagnosis of cirrhosis in HBV-infected patients in West Africa.
Collapse
Affiliation(s)
| | - Gibril Ndow
- Division of Digestive Diseases, Department of Metabolism, Digestion & Reproduction, Imperial College London, London, United Kingdom
- Disease Control & Elimination, MRC Unit The Gambia at London School of Hygiene & Tropical Medicine, Fajara, The Gambia
| | - Shintaro Ogawa
- Department of Virology and Liver Unit, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Amie Ceesay
- Disease Control & Elimination, MRC Unit The Gambia at London School of Hygiene & Tropical Medicine, Fajara, The Gambia
| | - Ramou Njie
- Edward Francis Small Teaching Hospital, Banjul, The Gambia
- School of Medicine & Allied Health Sciences, University of The Gambia, Serekunda, The Gambia
| | - Bakary Sanneh
- National Public Health Laboratories, Ministry of Health, Serekunda, The Gambia
| | - Ignatius Baldeh
- National Public Health Laboratories, Ministry of Health, Serekunda, The Gambia
| | - Umberto D’Alessandro
- Disease Control & Elimination, MRC Unit The Gambia at London School of Hygiene & Tropical Medicine, Fajara, The Gambia
| | - Maimuna Mendy
- International Agency for Research on Cancer (IARC), World Health Organization, Lyon, France
| | - Mark Thursz
- Division of Digestive Diseases, Department of Metabolism, Digestion & Reproduction, Imperial College London, London, United Kingdom
| | - Isabelle Chemin
- INSERM U1052, CNRS UMR5286, Centre de Recherche en Cancérologie, Université Claude Bernard, Lyon, France
| | - Yasuhito Tanaka
- Department of Virology and Liver Unit, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
- Department of Gastroenterology and Hepatology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan
| | - Maud Lemoine
- Division of Digestive Diseases, Department of Metabolism, Digestion & Reproduction, Imperial College London, London, United Kingdom
| | - Yusuke Shimakawa
- Unité d'Épidémiologie des Maladies Émergentes, Institut Pasteur, Paris, France
- International Research Center for Medical Sciences (IRCMS), Kumamoto University, Kumamoto, Japan
| |
Collapse
|
|
8
|
Lian MJ, Chen ZQ, Wang QM, Zheng GS, Hong GL. Diagnostic accuracy of mac-2-binding protein glycosylation isomer for diagnosing hepatitis B-related fibrosis: A meta-analysis. J Dig Dis 2022; 23:550-560. [PMID: 36251470 DOI: 10.1111/1751-2980.13140] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2022] [Revised: 08/24/2022] [Accepted: 10/13/2022] [Indexed: 12/30/2022]
Abstract
OBJECTIVES Mac-2-binding protein glycosylation isomer (M2BPGi) is a novel biomarker for liver fibrosis. The aim of this meta-analysis was to evaluate the accuracy of M2BPGi for predicting hepatitis B virus (HBV)-related liver fibrosis. METHODS EMBASE, PubMed, Web of Science, China National Knowledge Infrastructure, SinoMED, VIP Database for Chinese Technical Periodicals databases were searched comprehensively for articles published up to March 2022. Quality assessment was carried out in accordance with the Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2). The pooled diagnostic estimates including sensitivity, specificity, the area under the summary receiver operating characteristic curve (AUROC) were calculated. Before pooling the estimates, the threshold effect was assessed. Subgroup analysis was performed as well. RESULTS In all, 11 studies including 1836 patients were included. None of the 11 studies met all the criteria of QUADAS-2. The threshold effect was found (r = 0.757, P = 0.011) for predicting HBV-related severe fibrosis. The sensitivity, specificity and AUROC of M2BPGi for the prediction of significant fibrosis were 0.68 (0.65-0.71), 0.67 (0.64-0.70) and 0.741, respectively, while those for predicting cirrhosis were 0.65 (0.57-0.72), 0.79 (0.77-0.81) and 0.792. Additionally, the AUROC of M2BPGi for predicting severe fibrosis reached 0.766. No publication bias was observed. The results of subgroup analyses were similar to the overall results. CONCLUSIONS M2BPGi has moderate diagnostic accuracy for predicting HBV-related significant fibrosis, severe fibrosis, and cirrhosis. Further studies stratified by etiology, liver inflammation, treatment, etc, are urgently needed.
Collapse
Affiliation(s)
- Ming Jian Lian
- Department of Clinical Laboratory, Xiamen Key Laboratory of Genetic Testing, The First Affiliated Hospital Of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian Province, China
| | - Zhi Qi Chen
- Department of Clinical Laboratory, Xiamen Key Laboratory of Genetic Testing, The First Affiliated Hospital Of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian Province, China
| | - Qian Ming Wang
- Department of Clinical Laboratory, Xiamen Key Laboratory of Genetic Testing, The First Affiliated Hospital Of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian Province, China
| | - Gang Sen Zheng
- Department of Clinical Laboratory, Xiamen Key Laboratory of Genetic Testing, The First Affiliated Hospital Of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian Province, China
| | - Guo Lin Hong
- Department of Clinical Laboratory, Xiamen Key Laboratory of Genetic Testing, The First Affiliated Hospital Of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian Province, China
| |
Collapse
|
|
9
|
Seo KI, Hwang H, Yun BC, Moon HH, Choi YI, Shin DH, Yoon M. A prospective study of the correlation between hepatic fibrosis and noninvasively measured fibrosis markers including serum M2BPGi and acoustic radiation force impulse elastography. KOSIN MEDICAL JOURNAL 2022. [DOI: 10.7180/kmj.22.110] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022] Open
Abstract
Background: Mac-2 binding protein glycosylation isomer (M2BPGi) was introduced as a noninvasively measurable serologic marker for liver fibrosis. Acoustic radiation force impulse imaging (ARFI) elastography is another noninvasive method of measuring hepatic fibrosis. There are limited data about the correlations between histologic fibrosis grade and noninvasively measured markers, including M2BPGi and ARFI.Methods: This prospective study was conducted among patients admitted consecutively for liver resection, cholecystectomy, or liver biopsy. ARFI elastography, serum M2BPGi levels, and the AST to Platelet Ratio Index (APRI) score were evaluated before histologic evaluation. Histologic interpretation was performed by a single pathologist using the METAVIR scoring system.Results: In patients with high METAVIR scores, M2BPGi levels and ARFI values showed statistically significant differences between patients with fibrosis and those without fibrosis. In 41 patients with hepatocellular carcinoma, as METAVIR scores increased, M2BPGi levels also tended to increase (p=0.161). ARFI values changed significantly as METAVIR scores increased (p=0.039). In 33 patients without hepatocellular carcinoma, as METAVIR scores increased, M2BPGi levels significantly increased (p=0.040). ARFI values also changed significantly as METAVIR scores increased (p=0.033). M2BPGi levels were significantly correlated with ARFI values (r=0.604, p<0.001), and APRI values (r=0.704, p<0.001), respectively. Conclusions: Serum M2BPGi levels increased with liver fibrosis severity and could be a good marker for diagnosing advanced hepatic fibrosis regardless of the cause of liver disease.
Collapse
|
|
10
|
Kimura Y, Taura K, Hai Nam N, Uemoto Y, Yoshino K, Ikeno Y, Okuda Y, Nishio T, Yamamoto G, Tanabe K, Koyama Y, Anazawa T, Fukumitsu K, Ito T, Yagi S, Kamo N, Seo S, Iwaisako K, Hata K, Imai T, Uemoto S. Utility of Mac-2 Binding Protein Glycosylation Isomer to Evaluate Graft Status After Liver Transplantation. Liver Transpl 2021; 27:403-415. [PMID: 32780942 DOI: 10.1002/lt.25870] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/12/2020] [Revised: 07/12/2020] [Accepted: 07/28/2020] [Indexed: 01/13/2023]
Abstract
Mac-2 binding protein glycosylation isomer (M2BPGi) is a novel liver fibrosis biomarker, but there are few studies on M2BPGi in liver transplantation (LT) recipients. This study aimed to evaluate the utility of M2BPGi measurement in LT recipients. We collected the clinicopathological data of 233 patients who underwent a liver biopsy at Kyoto University Hospital after LT between August 2015 and June 2019. The median values of M2BPGi in patients with METAVIR fibrosis stages F0, F1, F2, and ≥F3 were 0.61, 0.76, 1.16, and 1.47, respectively, whereas those in patients with METAVIR necroinflammatory indexes A0, A1, and ≥A2 were 0.53, 1.145, and 2.24, respectively. Spearman rank correlation test suggested that the necroinflammatory index had a stronger correlation to the M2BPGi value than the fibrosis stage. The area under the receiver operating characteristic curve of M2BPGi to predict ≥A1 was 0.75, which was significantly higher than that of any other liver fibrosis and inflammation marker. Patients with a rejection activity index (RAI) of ≥3 had a higher M2BPGi value than those with RAI ≤ 2 (P = 0.001). Patients with hepatitis C virus viremia had a higher M2BPGi value than sustained virological responders or those with other etiologies. In conclusion, the present study demonstrated that M2BPGi values are more strongly influenced by necroinflammatory activity and revealed M2BPGi, which has been thought to be a so-called fibrosis marker, as a disease activity marker in transplant recipients. M2BPGi measurement may be useful to detect early stage liver inflammation that cannot be detected by routine blood examination of LT recipients.
Collapse
Affiliation(s)
- Yusuke Kimura
- Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Department of Surgery, Kyoto University, Kyoto, Japan
| | - Kojiro Taura
- Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Department of Surgery, Kyoto University, Kyoto, Japan
| | - Nguyen Hai Nam
- Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Department of Surgery, Kyoto University, Kyoto, Japan
| | - Yusuke Uemoto
- Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Department of Surgery, Kyoto University, Kyoto, Japan
| | - Kenji Yoshino
- Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Department of Surgery, Kyoto University, Kyoto, Japan
| | - Yoshinobu Ikeno
- Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Department of Surgery, Kyoto University, Kyoto, Japan
| | - Yukihiro Okuda
- Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Department of Surgery, Kyoto University, Kyoto, Japan
| | - Takahiro Nishio
- Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Department of Surgery, Kyoto University, Kyoto, Japan
| | - Gen Yamamoto
- Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Department of Surgery, Kyoto University, Kyoto, Japan
| | - Kazutaka Tanabe
- Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Department of Surgery, Kyoto University, Kyoto, Japan
| | - Yukinori Koyama
- Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Department of Surgery, Kyoto University, Kyoto, Japan
| | - Takayuki Anazawa
- Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Department of Surgery, Kyoto University, Kyoto, Japan
| | - Ken Fukumitsu
- Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Department of Surgery, Kyoto University, Kyoto, Japan
| | - Takashi Ito
- Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Department of Surgery, Kyoto University, Kyoto, Japan
| | - Shintaro Yagi
- Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Department of Surgery, Kyoto University, Kyoto, Japan
| | - Naoko Kamo
- Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Department of Surgery, Kyoto University, Kyoto, Japan
| | - Satoru Seo
- Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Department of Surgery, Kyoto University, Kyoto, Japan
| | - Keiko Iwaisako
- Department of Medical Life Systems, Doshisha University, Kyoto, Japan
| | - Koichiro Hata
- Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Department of Surgery, Kyoto University, Kyoto, Japan
| | - Takumi Imai
- Department of Medical Statistics, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Shinji Uemoto
- Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Department of Surgery, Kyoto University, Kyoto, Japan
| |
Collapse
|
|
11
|
Sasaki R, Miyaaki H, Narita S, Fukushima M, Haraguchi M, Miuma S, Hidaka M, Eguchi S, Okudaira S, Abe K, Nakao K. Serum Mac-2 binding protein glycosylation isomer as a biomarker of fibrosis in living donor liver transplant graft. Clin Transplant 2020; 35:e14175. [PMID: 33247961 DOI: 10.1111/ctr.14175] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2020] [Revised: 11/16/2020] [Accepted: 11/21/2020] [Indexed: 12/13/2022]
Abstract
INTRODUCTION Non-invasive assessment of graft fibrosis is important in liver transplantation. Mac-2 binding protein glycosylation isomer (M2BPGi) has been reported as a diagnostic marker for this purpose, and thus, this predictive ability of M2BPGi was assessed in this study. PATIENTS AND METHODS In this retrospective study, 236 patients who received living donor liver transplantation (LDLT) from August 1997 to March 2017 were enrolled. Among them, 94 biopsy patients were analyzed. Further, the predictive ability of fibrotic biopsy using M2BPGi, Fibroscan, and Fib-4 index was compared. RESULTS Of 94 LDLT patients (53 men, 41 women), the median ages of recipients and donors were 57.5 and 33.0 years, respectively. The median M2BPGi values in patients with F0 (n = 11), F1 (n = 38), F2 (n = 35), and F3/4 (n = 10) were 0.680, 0.760, 1.240, and 4.110 COI, respectively. There were significant correlations between the fibrotic stage and M2BPGi levels (Kruskal-Wallis test, P < .0001). The area under the ROC curve for the diagnosis of F ≥ 2 in M2BPGi was 0.778, which was superior to Fibroscan (0.701) and Fib-4 index (0.639). CONCLUSION M2BPGi is an accurate, non-invasive detection method for significant fibrosis after LDLT.
Collapse
Affiliation(s)
- Ryu Sasaki
- Department of Gastroenterology and Hepatology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Hisamitsu Miyaaki
- Department of Gastroenterology and Hepatology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Shohei Narita
- Department of Gastroenterology and Hepatology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Masanori Fukushima
- Department of Gastroenterology and Hepatology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Masafumi Haraguchi
- Department of Gastroenterology and Hepatology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Satoshi Miuma
- Department of Gastroenterology and Hepatology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Masaaki Hidaka
- Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Susumu Eguchi
- Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Sadayuki Okudaira
- Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Kuniko Abe
- Department of Pathology, Nagasaki University Hospital, Nagasaki, Japan.,Pathology Department, Japanese Red Cross Nagasaki Genbaku (Atomic Bomb) Hospital, Nagasaki, Japan
| | - Kazuhiko Nakao
- Department of Gastroenterology and Hepatology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| |
Collapse
|
|
12
|
Tamaki N, Kurosaki M, Loomba R, Izumi N. Clinical Utility of Mac-2 Binding Protein Glycosylation Isomer in Chronic Liver Diseases. Ann Lab Med 2020; 41:16-24. [PMID: 32829576 PMCID: PMC7443525 DOI: 10.3343/alm.2021.41.1.16] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2020] [Revised: 06/15/2020] [Accepted: 07/29/2020] [Indexed: 12/15/2022] Open
Abstract
An accurate evaluation of liver fibrosis is clinically important in chronic liver diseases. Mac-2 binding protein glycosylation isomer (M2BPGi) is a novel serum marker for liver fibrosis. In this review, we discuss the role of M2BPGi in diagnosing liver fibrosis in chronic hepatitis B and C, chronic hepatitis C after sustained virologic response (SVR), and nonalcoholic fatty liver disease (NAFLD). M2BPGi predicts not only liver fibrosis but also the hepatocellular carcinoma (HCC) development and prognosis in patients with chronic hepatitis B and C, chronic hepatitis C after SVR, NAFLD, and other chronic liver diseases. M2BPGi can also be used to evaluate liver function and prognosis in patients with cirrhosis. M2BPGi levels vary depending on the etiology and the presence or absence of treatment. Therefore, the threshold of M2BPGi for diagnosing liver fibrosis and predicting HCC development has to be adjusted according to the background and treatment status.
Collapse
Affiliation(s)
- Nobuharu Tamaki
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan.,NAFLD Research Center, Division of Medicine, University of California, San Diego, La Jolla, California, USA
| | - Masayuki Kurosaki
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Rohit Loomba
- NAFLD Research Center, Division of Medicine, University of California, San Diego, La Jolla, California, USA
| | - Namiki Izumi
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| |
Collapse
|
|
13
|
Wu KL, Chen YL, Ko CJ, Lin PY, Chou CT. Comparison of the diagnostic performance of magnetic resonance elastography and Wisteria foribunda agglutinin-positive Mac-2-binding protein in the determination of advanced liver fibrosis stages in patients with chronic liver disease. Exp Ther Med 2020; 20:1953-1960. [PMID: 32782504 PMCID: PMC7401297 DOI: 10.3892/etm.2020.8922] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2019] [Accepted: 04/01/2020] [Indexed: 11/06/2022] Open
Abstract
The present study aimed to compare the accuracy of Wisteria floribunda agglutinin-positive Mac-2-binding protein (WFA+-M2BP) and magnetic resonance elastography (MRE) in determining the liver fibrosis stage in patients with chronic liver disease. A retrospective review of a prospectively maintained database was performed. The eligible patients had hepatic tumors and chronic liver disease, including hepatitis B (HBV) and HCV. All patients underwent blood sampling, MRE and hepatectomy at Changhua Christian Hospital (Changhua, Taiwan). Surgical specimens were used to determine definitive histopathological diagnoses and liver fibrosis stages. Measurement of liver stiffness was performed via MRI. The value of WFA+-M2BP in each patient was also assessed. The area under the receiver operating characteristic (ROC) curve (AUC) was measured to compare the diagnostic accuracy of the two examinations. The results indicated that the serum WFA+-M2BP levels were able to detect severe liver fibrosis (≥F3) in patients with chronic liver disease and performed as well as MRE in patients with HCV. Of the 238 patients enrolled in the present study, 135 had chronic HBV 75 had chronic HCV, 92 had early liver fibrosis (F1-F2) and 139 patients had advanced liver fibrosis (F3-F4). In predicting fibrosis stages ≥F3, MRE had an AUC of 0.89 with a cutoff value of 3.76 and serum WFA+-M2BP had an AUC of 0.65 with a cutoff value of 1.32. MRE had higher AUCs than serum WFA+-M2BP for predicting the severity based on the fibrosis stage in the total cohort and the HBV subgroup. In patients with HCV, no significant differences in diagnostic performance were identified between MRE and serum WFA+-M2BP. In conclusion, determination of WFA+-M2BP as a biomarker for predicting severe liver fibrosis (≥F3) is a reliable and non-invasive method and performs as well as MRE in patients with chronic liver disease, particularly those with HCV.
Collapse
Affiliation(s)
- Kuan-Lin Wu
- Department of Diagnostic Radiology, Changhua Christian Hospital, Changhua 500209, Taiwan, R.O.C
| | - Yao-Li Chen
- Transplant Medicine and Surgery Research Center, Changhua Christian Hospital, Changhua 500209, Taiwan, R.O.C.,Department of Surgery, Changhua Christian Hospital, Changhua 500209, Taiwan, R.O.C.,School of Medicine, Kaohsiung Medical University, Kaohsiung 807378, Taiwan, R.O.C
| | - Chih-Jan Ko
- Transplant Medicine and Surgery Research Center, Changhua Christian Hospital, Changhua 500209, Taiwan, R.O.C.,Department of Surgery, Changhua Christian Hospital, Changhua 500209, Taiwan, R.O.C.,School of Medicine, Kaohsiung Medical University, Kaohsiung 807378, Taiwan, R.O.C
| | - Ping-Yi Lin
- Transplant Medicine and Surgery Research Center, Changhua Christian Hospital, Changhua 500209, Taiwan, R.O.C.,Department of Nursing, Da-Yeh University, Changhua 515006, Taiwan, R.O.C
| | - Chen-Te Chou
- Department of Diagnostic Radiology, Changhua Christian Hospital, Changhua 500209, Taiwan, R.O.C.,School of Medicine, Kaohsiung Medical University, Kaohsiung 807378, Taiwan, R.O.C
| |
Collapse
|
|
14
|
Tsuji Y, Namisaki T, Kaji K, Takaya H, Nakanishi K, Sato S, Saikawa S, Sawada Y, Kitagawa K, Shimozato N, Kawaratani H, Moriya K, Noguchi R, Akahane T, Mitoro A, Yoshiji H. Comparison of serum fibrosis biomarkers for diagnosing significant liver fibrosis in patients with chronic hepatitis B. Exp Ther Med 2020; 20:985-995. [PMID: 32765655 PMCID: PMC7388477 DOI: 10.3892/etm.2020.8798] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2019] [Accepted: 02/04/2020] [Indexed: 12/11/2022] Open
Abstract
Chronic hepatitis B (CHB) virus continues to be a leading cause of morbidity and mortality worldwide. The diagnosis of liver fibrosis has a key role in selecting patients with CHB for antiviral treatment. However, serum biomarkers demonstrate limited diagnostic utility. The present study aimed to compare the performances of fibrosis biomarkers for diagnosing significant liver fibrosis that indicates the need for antiviral therapy in patients with CHB and to identify the most appropriate biomarker for these patients. The current study included 96 antiviral-naïve patients with CHB who underwent liver biopsy. METAVIR scoring system was used to assess liver fibrosis and necroinflammation. The diagnostic performances were evaluated of the platelet (PLT) count; the levels of hyaluronan, serum 7S domain of type 4 collagen, procollagen type III N-terminal peptide, tissue inhibitor of metalloproteinases 1, Mac-2 binding protein glycosylation isomer (M2BPGi) and N-terminal type III collagen propeptide (Pro-C3); the fibrosis index based on four factors; the aspartate aminotransferase-to-platelet ratio index; and enhanced liver fibrosis score for identifying significant liver fibrosis [≥fibrosis stage 2 (F2)]. All fibrosis biomarkers, except the Pro-C3 level, correlated with the fibrosis stage. M2BPGi was better than other biomarkers for diagnosing ≥F2, with the highest area under the curve of 0.902. M2BPGi demonstrated a higher diagnostic accuracy for significant fibrosis than mild/severe fibrosis or cirrhosis. However, no significant correlation was observed between the M2BPGi level and fibrosis stage in patients with CHB having significant liver necroinflammation defined as ≥ necroinflammatory activity 2. The M2BPGi level and PLT count were exclusively correlated with the fibrosis stage in 73 patients without significant liver necroinflammation. M2BPGi demonstrated the highest diagnostic performance for significant fibrosis in patients having significant liver fibrosis with no significant liver necroinflammation. In conclusion, the M2BPGi level can accurately diagnose significant liver fibrosis that indicates the need for antiviral therapy in patients with CHB.
Collapse
Affiliation(s)
- Yuki Tsuji
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara 634-8522, Japan
| | - Tadashi Namisaki
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara 634-8522, Japan
| | - Kosuke Kaji
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara 634-8522, Japan
| | - Hiroaki Takaya
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara 634-8522, Japan
| | - Keisuke Nakanishi
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara 634-8522, Japan
| | - Shinya Sato
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara 634-8522, Japan
| | - Soichiro Saikawa
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara 634-8522, Japan
| | - Yasuhiko Sawada
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara 634-8522, Japan
| | - Kou Kitagawa
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara 634-8522, Japan
| | - Naotaka Shimozato
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara 634-8522, Japan
| | - Hideto Kawaratani
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara 634-8522, Japan
| | - Kei Moriya
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara 634-8522, Japan
| | - Ryuichi Noguchi
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara 634-8522, Japan
| | - Takemi Akahane
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara 634-8522, Japan
| | - Akira Mitoro
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara 634-8522, Japan
| | - Hitoshi Yoshiji
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara 634-8522, Japan
| |
Collapse
|
|
15
|
Masuzaki R, Kanda T, Sasaki R, Matsumoto N, Ogawa M, Matsuoka S, Karp SJ, Moriyama M. Noninvasive Assessment of Liver Fibrosis: Current and Future Clinical and Molecular Perspectives. Int J Mol Sci 2020; 21:4906. [PMID: 32664553 PMCID: PMC7402287 DOI: 10.3390/ijms21144906] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2020] [Revised: 06/29/2020] [Accepted: 07/09/2020] [Indexed: 01/18/2023] Open
Abstract
Liver fibrosis is one of the risk factors for hepatocellular carcinoma (HCC) development. The staging of liver fibrosis can be evaluated only via a liver biopsy, which is an invasive procedure. Noninvasive methods for the diagnosis of liver fibrosis can be divided into morphological tests such as elastography and serum biochemical tests. Transient elastography is reported to have excellent performance in the diagnosis of liver fibrosis and has been accepted as a useful tool for the prediction of HCC development and other clinical outcomes. Two-dimensional shear wave elastography is a new technique and provides a real-time stiffness image. Serum fibrosis markers have been studied based on the mechanism of fibrogenesis and fibrolysis. In the healthy liver, homeostasis of the extracellular matrix is maintained directly by enzymes called matrix metalloproteinases (MMPs) and their specific inhibitors, tissue inhibitors of metalloproteinases (TIMPs). MMPs and TIMPs could be useful serum biomarkers for liver fibrosis and promising candidates for the treatment of liver fibrosis. Further studies are required to establish liver fibrosis-specific markers based on further clinical and molecular research. In this review, we summarize noninvasive fibrosis tests and molecular mechanism of liver fibrosis in current daily clinical practice.
Collapse
Affiliation(s)
- Ryota Masuzaki
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Itabashi-Ku, Tokyo 173-8610, Japan; (T.K.); (R.S.); (N.M.); (M.O.); (S.M.); (M.M.)
| | - Tatsuo Kanda
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Itabashi-Ku, Tokyo 173-8610, Japan; (T.K.); (R.S.); (N.M.); (M.O.); (S.M.); (M.M.)
| | - Reina Sasaki
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Itabashi-Ku, Tokyo 173-8610, Japan; (T.K.); (R.S.); (N.M.); (M.O.); (S.M.); (M.M.)
| | - Naoki Matsumoto
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Itabashi-Ku, Tokyo 173-8610, Japan; (T.K.); (R.S.); (N.M.); (M.O.); (S.M.); (M.M.)
| | - Masahiro Ogawa
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Itabashi-Ku, Tokyo 173-8610, Japan; (T.K.); (R.S.); (N.M.); (M.O.); (S.M.); (M.M.)
| | - Shunichi Matsuoka
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Itabashi-Ku, Tokyo 173-8610, Japan; (T.K.); (R.S.); (N.M.); (M.O.); (S.M.); (M.M.)
| | - Seth J. Karp
- Division of Liver Transplantation, Department of Surgery, Vanderbilt University Medical Center, Nashville, TN 37232, USA;
| | - Mitsuhiko Moriyama
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Itabashi-Ku, Tokyo 173-8610, Japan; (T.K.); (R.S.); (N.M.); (M.O.); (S.M.); (M.M.)
| |
Collapse
|
|
16
|
Inoue T, Tanaka Y. Novel biomarkers for the management of chronic hepatitis B. Clin Mol Hepatol 2020; 26:261-279. [PMID: 32536045 PMCID: PMC7364351 DOI: 10.3350/cmh.2020.0032] [Citation(s) in RCA: 89] [Impact Index Per Article: 17.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/11/2020] [Revised: 04/11/2020] [Accepted: 04/13/2020] [Indexed: 02/06/2023] Open
Abstract
Hepatitis B virus (HBV) cannot be eliminated completely from infected hepatocytes because of the presence of intrahepatic covalently closed circular DNA (cccDNA). As chronic hepatitis B (CHB) can progress to cirrhosis and hepatocellular carcinoma (HCC), it is important to manage CHB to prevent HCC development in high-risk patients with high viral replicative activity or advanced fibrosis. Serum biomarkers are noninvasive and valuable for the management of CHB. Hepatitis B core-related antigen (HBcrAg) correlates with serum HBV DNA and intrahepatic cccDNA. In CHB patients with undetectable serum HBV DNA or loss of HBsAg, HBcrAg still can be detected and the decrease in HBcrAg levels is significantly associated with hopeful outcomes. Therefore, HBcrAg can predict HCC occurrence or recurrence. Measurement of the Mac-2 binding protein glycosylation isomer (M2BPGi) has been introduced for the evaluation of liver fibrosis. Because elevated M2BPGi in CHB is related to liver fibrosis and the prediction of HCC development, monitoring its progression is essential. Because alpha fetoprotein (AFP) has insufficient sensitivity and specificity for early-stage HCC, a combination of AFP plus protein induced by vitamin K absence factor II, or AFP plus Lens culinaris agglutinin-reactive fraction of alpha-fetoprotein might improve the diagnosis of HCC development. Additionally, Dickkopf-1 and circulating immunoglobulin G antibodies are the novel markers to diagnose HCC or assess HCC prognosis. This review provides an overview of novel HBV biomarkers used for the management of intrahepatic viral replicative activity, liver fibrosis, and HCC development.
Collapse
Affiliation(s)
- Takako Inoue
- Department of Clinical Laboratory Medicine, Nagoya City University Hospital, Nagoya, Japan
| | - Yasuhito Tanaka
- Department of Clinical Laboratory Medicine, Nagoya City University Hospital, Nagoya, Japan
- Department of Virology and Liver Unit, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
- Department of Gastroenterology and Hepatology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan
| |
Collapse
|
|
17
|
Wisteria floribunda agglutinin-positive Mac-2-binding protein as a diagnostic biomarker in liver cirrhosis: an updated meta-analysis. Sci Rep 2020; 10:10582. [PMID: 32601332 PMCID: PMC7324360 DOI: 10.1038/s41598-020-67471-y] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2019] [Accepted: 06/04/2020] [Indexed: 02/05/2023] Open
Abstract
Wisteria floribunda agglutinin-positive Mac-2-binding protein (WFA+-M2BP) had been suggested as a possible glycobiomarker for assessing liver fibrosis. Here, we conducted this updated meta-analysis to systematically investigate the predictive accuracy of WFA+-M2BP for diagnosing liver fibrosis and hepatocellular carcinoma (HCC) by comparing with multiple non-invasive indicators. We searched relevant literatures from Pubmed, Web of Science, EMBASE and Cochrane Library and enrolled 36 eligible studies involving 7,362 patients. Summary results were calculated using bivariate random effects model. The pooled sensitivities, specificities and areas under the summary receiver operating characteristic curves (AUSROCs) of WFA+-M2BP for identifying mild fibrosis, significant fibrosis, advanced fibrosis, cirrhosis, and HCC were 0.70/0.68/0.75, 0.71/0.75/0.79, 0.75/0.76/0.82, 0.77/0.86/0.88, and 0.77/0.80/0.85, respectively. The accuracy of WFA+-M2BP was strongly affected by etiology and it was not better than other non-invasive indicators for predicting early fibrosis. It showed similar diagnostic performance to hyaluronic acid and FibroScan for cirrhosis, but was equivalent to α-fetoprotein for HCC. In conclusion, WFA+-M2BP was suitable to diagnose late stage of liver fibrosis, especially cirrhosis. Individual cutoff value of WFA+-M2BP could be used to grade liver fibrosis in different etiology. Combined diagnostic model was suggested to improve its predictive accuracy for HCC.
Collapse
|
|
18
|
Pham TTT, Ho DT, Nguyen T. Usefulness of Mac-2 binding protein glycosylation isomer in non-invasive probing liver disease in the Vietnamese population. World J Hepatol 2020; 12:220-229. [PMID: 32547689 PMCID: PMC7280857 DOI: 10.4254/wjh.v12.i5.220] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/01/2020] [Revised: 03/30/2020] [Accepted: 04/07/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Early diagnosis is critical for successful intervention before liver disease progresses to cirrhosis and hepatocellular carcinoma. AIM To examine a novel biomarker for probing early liver disease quickly using an automated immunology system. METHODS This was a cross-sectional study. 140 patients at various stages of liver disease were randomly selected. The cohort consisted of patients who were treatment naïve and currently undergoing therapy. We included patients with diverse liver disease etiologies. Mac-2 binding protein glycosylation isomer (M2BPGi) levels in addition to different clinical parameters, co-morbidities and transient elastography results were collected and compared. RESULTS M2BPGi levels were significantly correlated with transient elastography for liver fibrosis staging across all disease etiologies. Statistically significant differences were observed in patients with F0-1; F2 and > F3 liver fibrosis. Further examination showed that M2BPGi levels were two-fold higher in F4 than F3 hepatitis C (HCV) patients. M2BPGi was observed to be etiology-specific and HCV patients had higher mean M2BPGi levels. We also observed significant correlations with aspartate aminotransferase to platelet ratio index and fibrosis-4 index as well as HBV DNA levels. Mean M2BPGi levels for HBV patients with a viral load lower than 2000 IU/mL was 1.75-fold lower than those with a viral load greater than 2000 IU/mL. CONCLUSION M2BPGi was observed to be a good indicator of early liver disease in patients with different etiologies. Our results provide reference cut-offs for different causes of liver disease and demonstrated the utility of this marker for early disease monitoring. This is useful for remote regions in developing countries.
Collapse
Affiliation(s)
| | - Dat Tan Ho
- MEDIC Medical Center, Ho Chi Minh 72517, Vietnam
| | - Toan Nguyen
- MEDIC Medical Center, Ho Chi Minh 72517, Vietnam
| |
Collapse
|
|
19
|
Usefulness of Mac-2 binding protein glycosylation isomer in non-invasive probing liver disease in the Vietnamese population. World J Hepatol 2020. [DOI: 10.4254/wjh.v12.i5.210] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
|
|
20
|
Tseng TC, Peng CY, Hsu YC, Su TH, Wang CC, Liu CJ, Yang HC, Yang WT, Lin CH, Yu ML, Lai HC, Tanaka Y, Nguyen MH, Liu CH, Chen PJ, Chen DS, Kao JH. Baseline Mac-2 Binding Protein Glycosylation Isomer Level Stratifies Risks of Hepatocellular Carcinoma in Chronic Hepatitis B Patients with Oral Antiviral Therapy. Liver Cancer 2020; 9:207-220. [PMID: 32399434 PMCID: PMC7206589 DOI: 10.1159/000504650] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2019] [Accepted: 11/08/2019] [Indexed: 02/04/2023] Open
Abstract
BACKGROUND AND AIMS Mac-2 binding protein glycosylation isomer (M2BPGi) is a novel biomarker correlating with liver fibrosis stages. However, little is known about how it predicts risks of hepatocellular carcinoma (HCC) in chronic hepatitis B (CHB) patients receiving long-term antiviral treatment. MATERIALS AND METHODS The study contained 2 parts. The first part was to explore whether M2BPGi could be an HCC predictor in 899 CHB patients receiving long-term entecavir therapy. The second part was to validate the findings in an independent cohort of 384 on-treatment CHB patients with more severe liver disease. RESULTS In the discovery cohort, there were 64 patients developing HCC within an average follow-up of 7.01 years. Our data showed that M2BPGi level was positively associated with HCC development. When stratifying the patients by an M2BPGi level of 1.73 (the third quartile), the high M2BPGi group was shown to have an increased HCC risk compared to the low M2BPGi group with hazard ratio of 5.80 (95% CI 3.50-9.60). Furthermore, we found that the M2BPGi level complements PAGE-B score, a well-validated HCC prediction model, to predict HCC development. Lastly, the cutoff was validated in the independent cohort, especially those with an intermediate PAGE-B score. CONCLUSIONS In CHB patients receiving long-term antiviral treatment, serum M2BPGi level not only serves as an independent HCC predictor but also complements PAGE-B in stratifying HCC risks.
Collapse
Affiliation(s)
- Tai-Chung Tseng
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
- Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
| | - Cheng-Yuan Peng
- School of Medicine, China Medical University, Taichung, Taiwan
- Division of Hepatogastroenterology, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan
| | - Yao-Chun Hsu
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, E-Da Hospital/I-Shou University, Kaohsiung, Taiwan
| | - Tung-Hung Su
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
- Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
| | - Chia-Chi Wang
- Division of Gastroenterology, Department of Internal Medicine, Taipei Tzuchi Hospital, The Buddhist Tzuchi Medical Foundation, Taipei, Taiwan
- School of Medicine, Tzu Chi University, Hualien, Taiwan
| | - Chun-Jen Liu
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
- Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Hung-Chih Yang
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
- Department of Microbiology, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Wan-Ting Yang
- Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
| | - Chia-Hsin Lin
- Division of Hepatogastroenterology, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan
| | - Ming-Lung Yu
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Hsueh-Chou Lai
- Division of Hepatogastroenterology, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan
| | - Yasuhito Tanaka
- Department of Virology and Liver Unit, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Mindie H. Nguyen
- Division of Gastroenterology and Hepatology, Stanford University Medical Center, Palo Alto, California, USA
| | - Chen-Hua Liu
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
- Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
| | - Pei-Jer Chen
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
- Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Ding-Shinn Chen
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
- Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
- Genomics Research Center Academia Sinica, Taipei, Taiwan
| | - Jia-Horng Kao
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
- Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
- Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan
| |
Collapse
|
|
21
|
Hayashi T, Tamaki N, Kurosaki M, Wang W, Okada M, Higuchi M, Takaura K, Takada H, Yasui Y, Tsuchiya K, Nakanishi H, Itakura J, Harada M, Izumi N. Use of the Serum Wisteria floribunda Agglutinin-Positive Mac2 Binding Protein as a Marker of Gastroesophageal Varices and Liver-Related Events in Chronic Hepatitis C Patients. Diagnostics (Basel) 2020; 10:diagnostics10030173. [PMID: 32235806 PMCID: PMC7151084 DOI: 10.3390/diagnostics10030173] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2020] [Revised: 03/18/2020] [Accepted: 03/20/2020] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND A test to narrow down patients who require esophagogastroduodenoscopy (EGD) with a high probability of having gastroesophageal varices (GEV) and a high-risk of liver-related events is an unmet need. METHODS The measurement of serum fibrosis markers and EGD was performed in 166 consecutive chronic hepatitis C patients. The correlation between the grades of GEV and fibrosis markers and the subsequent occurrence of liver-related and fibrosis markers were examined. RESULTS Wisteria floribunda agglutinin-positive human Mac-2 binding protein (WFA+-M2BP) levels increased according to the grade of GEV (3.4 (0.2-18.6) for no GEV, 7.9 (1.8-20.0) for small GEV, and 11.4 (4.0-20.0) for large GEV; p < 0.001). The diagnostic accuracy of the WFA+-M2BP was superior compared to other serum fibrosis markers, and WFA+-M2BP was an independent predictor of GEV in the multivariate analysis. Furthermore, the cumulative incidence of liver-related events at one year was 2.3% in patients with WFA+-M2BP levels ≤ 7.0 and 37.5% in patients with WFA+-M2BP levels > 7.0 (p < 0.001). WFA+-M2BP > 7.0 was a significant predictive factor for liver-related events (Hazard ratio 6.7, p = 0.004) independent of Child-Pughclass. CONCLUSIONS WFA+-M2BP could be used to estimate the presence and grade of GEV and is linked to liver-related events in chronic hepatitis C patients.
Collapse
Affiliation(s)
- Tsuguru Hayashi
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo 180-8610, Japan; (T.H.); (N.T.); (M.K.); (W.W.); (M.O.); (M.H.); (K.T.); (H.T.); (Y.Y.); (K.T.); (H.N.); (J.I.)
- Third Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Kitakyushu 807-8555, Japan;
| | - Nobuharu Tamaki
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo 180-8610, Japan; (T.H.); (N.T.); (M.K.); (W.W.); (M.O.); (M.H.); (K.T.); (H.T.); (Y.Y.); (K.T.); (H.N.); (J.I.)
| | - Masayuki Kurosaki
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo 180-8610, Japan; (T.H.); (N.T.); (M.K.); (W.W.); (M.O.); (M.H.); (K.T.); (H.T.); (Y.Y.); (K.T.); (H.N.); (J.I.)
| | - Wan Wang
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo 180-8610, Japan; (T.H.); (N.T.); (M.K.); (W.W.); (M.O.); (M.H.); (K.T.); (H.T.); (Y.Y.); (K.T.); (H.N.); (J.I.)
| | - Mao Okada
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo 180-8610, Japan; (T.H.); (N.T.); (M.K.); (W.W.); (M.O.); (M.H.); (K.T.); (H.T.); (Y.Y.); (K.T.); (H.N.); (J.I.)
| | - Mayu Higuchi
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo 180-8610, Japan; (T.H.); (N.T.); (M.K.); (W.W.); (M.O.); (M.H.); (K.T.); (H.T.); (Y.Y.); (K.T.); (H.N.); (J.I.)
| | - Kenta Takaura
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo 180-8610, Japan; (T.H.); (N.T.); (M.K.); (W.W.); (M.O.); (M.H.); (K.T.); (H.T.); (Y.Y.); (K.T.); (H.N.); (J.I.)
| | - Hitomi Takada
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo 180-8610, Japan; (T.H.); (N.T.); (M.K.); (W.W.); (M.O.); (M.H.); (K.T.); (H.T.); (Y.Y.); (K.T.); (H.N.); (J.I.)
| | - Yutaka Yasui
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo 180-8610, Japan; (T.H.); (N.T.); (M.K.); (W.W.); (M.O.); (M.H.); (K.T.); (H.T.); (Y.Y.); (K.T.); (H.N.); (J.I.)
| | - Kaoru Tsuchiya
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo 180-8610, Japan; (T.H.); (N.T.); (M.K.); (W.W.); (M.O.); (M.H.); (K.T.); (H.T.); (Y.Y.); (K.T.); (H.N.); (J.I.)
| | - Hiroyuki Nakanishi
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo 180-8610, Japan; (T.H.); (N.T.); (M.K.); (W.W.); (M.O.); (M.H.); (K.T.); (H.T.); (Y.Y.); (K.T.); (H.N.); (J.I.)
| | - Jun Itakura
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo 180-8610, Japan; (T.H.); (N.T.); (M.K.); (W.W.); (M.O.); (M.H.); (K.T.); (H.T.); (Y.Y.); (K.T.); (H.N.); (J.I.)
| | - Masaru Harada
- Third Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Kitakyushu 807-8555, Japan;
| | - Namiki Izumi
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo 180-8610, Japan; (T.H.); (N.T.); (M.K.); (W.W.); (M.O.); (M.H.); (K.T.); (H.T.); (Y.Y.); (K.T.); (H.N.); (J.I.)
- Correspondence: ; Tel.: +81-422-32-3111; Fax: +81-422-32-9551
| |
Collapse
|
|
22
|
Baudi I, Inoue T, Tanaka Y. Novel Biomarkers of Hepatitis B and Hepatocellular Carcinoma: Clinical Significance of HBcrAg and M2BPGi. Int J Mol Sci 2020; 21:949. [PMID: 32023902 PMCID: PMC7037346 DOI: 10.3390/ijms21030949] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2019] [Revised: 01/19/2020] [Accepted: 01/29/2020] [Indexed: 12/12/2022] Open
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.
Collapse
Affiliation(s)
- Ian Baudi
- Department of Virology and Liver Unit, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8601, Japan;
| | - Takako Inoue
- Department of Clinical Laboratory Medicine, Nagoya City University Hospital, Nagoya 467-8602, Japan;
| | - Yasuhito Tanaka
- Department of Virology and Liver Unit, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8601, Japan;
- Department of Clinical Laboratory Medicine, Nagoya City University Hospital, Nagoya 467-8602, Japan;
| |
Collapse
|
|
23
|
Novel Biomarkers of Hepatitis B and Hepatocellular Carcinoma: Clinical Significance of HBcrAg and M2BPGi. Int J Mol Sci 2020. [DOI: 10.3390/ijms21030949
expr 921756688 + 899694353] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/16/2023] Open
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.
Collapse
|
|
24
|
Kim HS, Kim SU, Kim BK, Park JY, Kim DY, Ahn SH, Han KH, Park YN, Han DH, Kim KS, Choi JS, Choi GH, Kim HS. Serum Wisteria floribunda agglutinin-positive human Mac-2 binding protein level predicts recurrence of hepatitis B virus-related hepatocellular carcinoma after curative resection. Clin Mol Hepatol 2020; 26:33-44. [PMID: 31243939 PMCID: PMC6940487 DOI: 10.3350/cmh.2018.0073] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/22/2018] [Revised: 11/17/2018] [Accepted: 04/10/2019] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND/AIMS To investigate whether serum Wisteria floribunda agglutinin-positive human Mac-2-binding protein (WFA+-M2BP) can predict the recurrence of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) after curative resection. METHODS Patients with chronic hepatitis B (CHB) who underwent curative resection for HCC between 2004 and 2015 were eligible for the study. Recurrence was sub-classified as early (<2 years) or late (≥2 years). RESULTS A total of 170 patients with CHB were selected. During the follow-up period (median, 22.6 months), 64 (37.6%) patients developed recurrence. In multivariate analyses, WFA+-M2BP level was an independent predictor of overall (hazard ratio [HR]=1.490), early (HR=1.667), and late recurrence (HR=1.416), together with male sex, des-gamma carboxyprothrombin level, maximal tumor size, portal vein invasion, and satellite nodules (all P<0.05). However, WFA+- M2BP level was not predictive of grade B-C posthepatectomy liver failure. The cutoff value that maximized the sum of sensitivity (30.2%) and specificity (90.6%) was 2.14 (area under receiver operating characteristic curve=0.632, P=0.010). Patients with a WFA+-M2BP level >2.14 experienced recurrence more frequently than those with a WFA+-M2BP level ≤2.14 (P=0.011 by log-rank test), and had poorer postoperative outcomes than those with a WFA+-M2BP level ≤2.14 in terms of overall recurrence (56.0 vs. 34.5%, P=0.047) and early recurrence (52.0 vs. 20.7%, P=0.001). CONCLUSION WFA+-M2BP level is an independent predictive factor of HBV-related HCC recurrence after curative resection. Further studies should investigate incorporation of WFA+-M2BP level into tailored postoperative surveillance strategies for patients with CHB.
Collapse
Affiliation(s)
- Hye Soo Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - Seung Up Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
| | - Beom Kyung Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
| | - Jun Yong Park
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
| | - Do Young Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
| | - Sang Hoon Ahn
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
| | - Kwang-Hyub Han
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
| | - Young Nyun Park
- Department of Pathology, Yonsei University College of Medicine, Seoul, Korea
| | - Dai Hoon Han
- Department of Surgery, Yonsei University College of Medicine, Seoul, Korea
| | - Kyung Sik Kim
- Department of Surgery, Yonsei University College of Medicine, Seoul, Korea
| | - Jin Sub Choi
- Department of Surgery, Yonsei University College of Medicine, Seoul, Korea
| | - Gi Hong Choi
- Department of Surgery, Yonsei University College of Medicine, Seoul, Korea
| | - Hyon-Suk Kim
- Department of Laboratory Medicine, Yonsei University College of Medicine, Seoul, Korea
| |
Collapse
|
|
25
|
Chen CC, Hsu HT, Chen YL, Chen RC, Wu WP, Chou CT. Diagnostic Accuracy of Acoustic Radiation Force Impulse (ARFI) and Wisteria floribunda Agglutinin-Positive Mac-2-Binding Protein (WFA⁺-M2BP) in Patients with Chronic Liver Disease. Med Sci Monit 2019; 25:7169-7174. [PMID: 31548540 PMCID: PMC6775795 DOI: 10.12659/msm.916533] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Background The present study assessed and compared the diagnostic accuracy of elastography (acoustic radiation force impulse, ARFI) with that of Wisteria floribunda agglutinin-positive Mac-2-binding protein (WFA+-M2BP) for estimating the stage of hepatic fibrosis in chronic liver disease patients. Material/Methods This retrospective cross-sectional study enrolled 70 chronic liver disease patients who underwent hepatectomy for hepatic tumors. ARFI and WFA+-M2BP serum level, underlying liver disease, and laboratory data for all patients were recorded. The stage of fibrosis was determined from a surgical specimen. The area under the receiver operating characteristic (ROC) curves (AUC) was measured to compare the diagnostic accuracy. Results The ARFI and serum WFA+-M2BP levels had good performances for detecting severe fibrosis (≥F3). The AUC in characterization of fibrosis stage ≥F3 was 0.79 for ARFI and 0.71 for serum WFA+-M2BP levels. When comparing the diagnostic performances between ARFI and serum WFA+-M2BP levels for the severity of fibrosis stage, no significant differences were found. Then all patients were divided into 2 subgroups, the AUC for serum WFA+-M2BP levels was higher in the hepatitis C virus (HCV) subgroup than in the hepatitis B virus (HBV) subgroup when characterizing fibrosis stages ≥F3. Conclusions WFA+-M2BP is an accurate biomarker and is as good as ARFI in detecting severe fibrosis for chronic liver disease patients.
Collapse
Affiliation(s)
- Chien-Cheng Chen
- Department of Biomedical Imaging and Radiological Sciences, National Yang-Ming University, Taipei, Taiwan.,Division of Gastrointestinal Surgery, Department of Surgery, Ren-Ai Branch, Taipei City Hospital, Taipei, Taiwan
| | - Hui-Ting Hsu
- Department of Pathology, Changhua Christian Hospital, Changhua, Taiwan
| | - Yao-Li Chen
- Transplant Medicine and Surgery Research Center, Changhua Christian Hospital, Changhua, Taiwan.,School of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Ran-Chou Chen
- Department of Biomedical Imaging and Radiological Sciences, National Yang-Ming University, Taipei, Taiwan
| | - Wen-Pei Wu
- Department of Radiology, Changhua Christian Hospital, Changhua, Taiwan
| | - Chen-Te Chou
- School of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.,Department of Radiology, Changhua Christian Hospital, Changhua, Taiwan.,Department of Molecular Biotechnology, College of Biotechnology and Bioresources, Dayeh University, Changhua, Taiwan
| |
Collapse
|
|
26
|
Nishimura T, Iijima H, Nishikawa H, Kondo R, Yano H, Kage M, Aoki T, Nakano C, Yuri Y, Ishii N, Hasegawa K, Takata R, Yoh K, Sakai Y, Takashima T, Aizawa N, Ikeda N, Iwata Y, Enomoto H, Hirota S, Fujimoto J, Nishiguchi S. Liver fibrosis markers as assessed by ultrasound elastography and serum samples: A large comparative study in hepatitis virus B and C liver diseases. Hepatol Res 2019; 49:721-730. [PMID: 30884015 DOI: 10.1111/hepr.13332] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/26/2018] [Revised: 02/23/2019] [Accepted: 03/10/2019] [Indexed: 12/12/2022]
Abstract
AIM We aimed to compare the well-established liver fibrosis (LF) markers in Japanese patients with chronic hepatitis B (CHB, n = 331) and chronic hepatitis C (CHC, n = 886) and to discuss possible causes of differences in results between CHB patients and CHC patients. METHODS Virtual touch quantification (VTQ) in acoustic radiation force impulse, Fibrosis-4 (Fib-4) index, aspartate aminotransferase to platelet ratio index (APRI), and hyaluronic acid (HA) were compared between the two cohorts. As an additional investigation, total collagen proportional area (TCPA, %) was tested using liver pathological samples (n = 83). RESULTS Significant LF (F2 or greater) and advanced LF (F3 or greater) were identified in 153 (46.2%) and 76 (23.0%) patients in the CHB cohort and 579 (65.3%) and 396 (44.7%) patients in the CHC cohort. The median VTQ, Fib-4 index, APRI, and HA values in the CHB cohort were 1.20 m/s, 1.36, 0.44, and 25 ng/mL; those in the CHC cohort were 1.32 m/s, 2.60, 0.74, and 65.5 ng/mL (P-values, all <0.0001). Similar tendencies were noted by F stage-based stratification. The median TCPA in the CHB cohort and the CHC cohort were 8.5% and 12.7% (P < 0.0006). The TCPA values in the CHC cohort were higher than those in the CHB cohort regardless of LF stage. CONCLUSION Values of LF markers in CHB patients can differ from those in CHC patients even in the same LF stage. Difference in total amount of collagen fiber in CHB and CHC appears to be linked to the difference.
Collapse
Affiliation(s)
- Takashi Nishimura
- Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan
- Ultrasound Imaging Center, Hyogo College of Medicine, Nishinomiya, Japan
| | - Hiroko Iijima
- Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan
- Ultrasound Imaging Center, Hyogo College of Medicine, Nishinomiya, Japan
| | - Hiroki Nishikawa
- Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan
| | - Reiichiro Kondo
- Department of Pathology, Kurume University School of Medicine, Kurume, Japan
| | - Hirohisa Yano
- Department of Pathology, Kurume University School of Medicine, Kurume, Japan
| | - Masayoshi Kage
- Kurume University Research Center for Innovative Cancer Therapy, Kurume, Japan
| | - Tomoko Aoki
- Ultrasound Imaging Center, Hyogo College of Medicine, Nishinomiya, Japan
| | - Chikage Nakano
- Ultrasound Imaging Center, Hyogo College of Medicine, Nishinomiya, Japan
| | - Yukihisa Yuri
- Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan
| | - Noriko Ishii
- Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan
| | - Kunihiro Hasegawa
- Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan
| | - Ryo Takata
- Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan
| | - Kazunori Yoh
- Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan
| | - Yoshiyuki Sakai
- Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan
| | - Tomoyuki Takashima
- Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan
| | - Nobuhiro Aizawa
- Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan
| | - Naoto Ikeda
- Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan
| | - Yoshinori Iwata
- Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan
| | - Hirayuki Enomoto
- Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan
| | - Seiichi Hirota
- Department of Surgical Pathology, Hyogo College of Medicine, Nishinomiya, Japan
| | - Jiro Fujimoto
- Division of Hepatobiliary and Pancreatic Disease, Department of Surgery, Hyogo College of Medicine, Nishinomiya, Japan
| | - Shuhei Nishiguchi
- Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan
| |
Collapse
|
|
27
|
Yasui Y, Abe T, Kurosaki M, Matsunaga K, Higuchi M, Tamaki N, Watakabe K, Okada M, Wang W, Shimizu T, Takaura K, Masugi Y, Nakanishi H, Tsuchiya K, Takahashi Y, Itakura J, Sakurai U, Hashiguchi A, Sakamoto M, Izumi N. Non-invasive liver fibrosis assessment correlates with collagen and elastic fiber quantity in patients with hepatitis C virus infection. Hepatol Res 2019; 49:33-41. [PMID: 30419152 DOI: 10.1111/hepr.13286] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2018] [Revised: 10/14/2018] [Accepted: 10/22/2018] [Indexed: 02/08/2023]
Abstract
AIM Elastic fiber deposition is a cause of irreversibility of liver fibrosis. However, to date, its relevance to clinical features has not yet been clarified. This study aimed to clarify the correlation between non-invasive markers of fibrosis and fiber quantity, including elastic fiber, obtained from computational analysis. METHODS This retrospective study included 270 patients evaluated by non-invasive liver fibrosis assessment prior to liver biopsy. Of these patients, 95 underwent magnetic resonance elastography (MRE) and 244 were assessed with Wisteria floribunda agglutinin-positive Mac-2 binding protein (WFA+ -M2BP). Using whole-slide imaging of Elastica van Gieson-stained liver biopsy sections, the quantity of collagen, elastin, and total fiber (elastin + collagen) was determined. RESULTS The total fiber quantity showed significant linear correlation with fibrosis stage F0-F4. Collagen fiber quantity increased from stage F0 to F4, whereas elastic fiber quantity increased significantly only from stage F2 to F3. Spearman's rank correlation test revealed that non-invasive liver fibrosis assessment significantly correlates with each fiber quantity, including correlation between total fiber quantity and the Fibrosis-4 (FIB-4) index (r = 0.361, P < 0.001), WFA+ -M2BP values (r = 0.404, P < 0.001), and liver stiffness value by MRE (r = 0.615, P < 0.001). Receiver operating characteristic (ROC) curve analyses revealed that the area under ROC for predicting higher elastic fiber (>3.6%) is 0.731 by FIB-4 index, 0.716 by WFA+ -M2BP, and 0.822 by liver stiffness by MRE. CONCLUSION Liver fibrosis correlates with fiber quantity through non-invasive assessment regardless of fiber type, including elastic fiber. Moreover, MRE is useful for predicting high amounts of elastic fiber.
Collapse
Affiliation(s)
- Yutaka Yasui
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Tokiya Abe
- Department of Pathology, School of Medicine, Keio University, Tokyo, Japan
| | - Masayuki Kurosaki
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Kotaro Matsunaga
- Department of Pathology, Musashino Red Cross Hospital, Tokyo, Japan.,Department of Internal Medicine, Division of Gastroenterology and Hepatology, School of Medicine, Saint Marianna University, Kawasaki, Japan
| | - Mayu Higuchi
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Nobuharu Tamaki
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Keiya Watakabe
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Mao Okada
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Wan Wang
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Takao Shimizu
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Kenta Takaura
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Yohei Masugi
- Department of Pathology, School of Medicine, Keio University, Tokyo, Japan
| | - Hiroyuki Nakanishi
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Kaoru Tsuchiya
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Yuka Takahashi
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Jun Itakura
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Urara Sakurai
- Department of Pathology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Akinori Hashiguchi
- Department of Pathology, School of Medicine, Keio University, Tokyo, Japan
| | - Michiie Sakamoto
- Department of Pathology, School of Medicine, Keio University, Tokyo, Japan
| | - Namiki Izumi
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| |
Collapse
|
|
28
|
Yasui Y, Kurosaki M, Komiyama Y, Takada H, Tamaki N, Watakabe K, Okada M, Wang W, Shimizu T, Kubota Y, Higuchi M, Takaura K, Tsuchiya K, Nakanishi H, Takahashi Y, Itakura J, Enomoto N, Izumi N. Wisteria floribunda agglutinin-positive Mac-2 binding protein predicts early occurrence of hepatocellular carcinoma after sustained virologic response by direct-acting antivirals for hepatitis C virus. Hepatol Res 2018; 48:1131-1139. [PMID: 30030872 DOI: 10.1111/hepr.13233] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2018] [Revised: 06/23/2018] [Accepted: 07/15/2018] [Indexed: 02/06/2023]
Abstract
AIM The aim of this study is to clarify the value of serum Wisteria floribunda agglutinin-positive Mac-2 binding protein (WFA+ -M2BP) for predicting hepatocellular carcinoma (HCC) in chronic hepatitis C patients who achieved sustained virologic response (SVR) by therapy with interferon-free, direct-acting antivirals (DAAs). METHODS This is a retrospective cohort study that included 567 patients who underwent antiviral therapy with an interferon-free DAA regimen and achieved SVR. Serum WFA+ -M2BP was measured after SVR. Factors predictive of HCC occurrence and recurrence were analyzed in the patients after stratification by previous treatment history of HCC. RESULTS Among 518 patients who had no history of HCC, 13 developed HCC. Post-SVR WFA+ -M2BP ≥1.75 cut-off index (C.O.I., P < 0.001) and α-fetoprotein (AFP) level ≥6 ng/mL (P = 0.01) were significant predictors of HCC development. Multivariate analysis showed that post-SVR WFA+ -M2BP ≥1.75 C.O.I. was an independent factor significantly associated with the development of HCC (hazard ratio [HR] 6.0; 95% confidence interval (CI), 1.8-19.4; P = 0.003). Among 49 patients who had a previous history of HCC, 22 had recurrence after SVR. Post-SVR AFP ≥6 ng/mL was the only factor associated with recurrence-free survival (HR 3.1; 95% CI, 1.3-7.5; P = 0.01). CONCLUSIONS Post-SVR WFA+ -M2BP is a predictive factor for the development of HCC in patients with no previous HCC history and treated with DAAs. Post-SVR AFP was predictive for HCC recurrence after DAA therapy.
Collapse
Affiliation(s)
- Yutaka Yasui
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Masayuki Kurosaki
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Yasuyuki Komiyama
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan.,First Department of Internal Medicine, University of Yamanashi, Yamanashi, Japan
| | - Hitomi Takada
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan.,First Department of Internal Medicine, University of Yamanashi, Yamanashi, Japan
| | - Nobuharu Tamaki
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Keiya Watakabe
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Mao Okada
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Wan Wang
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Takao Shimizu
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Yohei Kubota
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Mayu Higuchi
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Kenta Takaura
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Kaoru Tsuchiya
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Hiroyuki Nakanishi
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Yuka Takahashi
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Jun Itakura
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Nobuyuki Enomoto
- First Department of Internal Medicine, University of Yamanashi, Yamanashi, Japan
| | - Namiki Izumi
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| |
Collapse
|
|
29
|
Uojima H, Hidaka H, Tanaka Y, Inoue T, Onoue M, Wada N, Kubota K, Nakazawa T, Shibuya A, Fujikawa T, Nakayama T, Yamanoue H, Sung JH, Kako M, Koizumi W. Wisteria floribunda agglutinin-positive human Mac-2 binding protein in decompensated cirrhosis. J Gastroenterol Hepatol 2018; 33:1889-1896. [PMID: 29737582 DOI: 10.1111/jgh.14277] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2018] [Revised: 04/14/2018] [Accepted: 04/23/2018] [Indexed: 12/14/2022]
Abstract
BACKGROUND AND AIM An assay for Wisteria floribunda agglutinin-positive human Mac-2 binding protein (WFA+ -M2BP) has been reported as a useful non-invasive marker for the evaluation of the staging of fibrosis in several chronic liver diseases. However, available data on the effect of WFA+ -M2BP level in decompensated cirrhosis patients were limited. It is important that these investigations can validate the diagnostic utility of WFA+ -M2BP in the full range of patients with liver cirrhosis. METHODS A multicenter study was conducted at five locations in Japan. A total of 207 patients with liver cirrhosis were enrolled in the present study. To determine whether or not the WFA+ -M2BP value was associated with a progression of fibrosis among cirrhosis, this study examined WFA+ -M2BP levels between patients with cirrhosis in the decompensated and compensated groups. RESULTS The numbers and proportions of compensated and decompensated patients were 113 (54.6%) and 94 (45.4%), respectively. The average WFA+ -M2BP levels were 2.22 ± 1.61 in the compensated group and 6.91 ± 5.04 in the decompensated group. Significantly higher WFA+ -M2BP levels were observed in the decompensated group than those in the compensated group (P < 0.0001). The respective cut-off index values for decompensated cirrhosis were estimated using receiver-operating characteristic curves for WFA+ -M2BP levels. Using a cut-off index value of 3.37 for WFA+ -M2BP, predicting decompensated cirrhosis had a sensitivity of 77.8% and a specificity of 86.7%. CONCLUSIONS WFA+ -M2BP values were higher in patients with decompensated liver cirrhosis.
Collapse
Affiliation(s)
- Haruki Uojima
- Department of Gastroenterology, Internal Medicine, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan.,Department of Gastroenterology, Shonan Kamakura General Hospital, Kamakura, Kanagawa, Japan
| | - Hisashi Hidaka
- Department of Gastroenterology, Internal Medicine, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
| | - Yoshiaki Tanaka
- Department of Gastroenterology, Internal Medicine, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
| | - Tomoyoshi Inoue
- Department of Gastroenterology, Internal Medicine, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
| | - Mie Onoue
- Department of Gastroenterology, Internal Medicine, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
| | - Naohisa Wada
- Department of Gastroenterology, Internal Medicine, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
| | - Kousuke Kubota
- Department of Gastroenterology, Internal Medicine, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
| | - Takahide Nakazawa
- Department of Gastroenterology, Internal Medicine, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
| | - Akitaka Shibuya
- Department of Gastroenterology, Internal Medicine, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
| | - Tomoaki Fujikawa
- Department of Gastroenterology, Shonan Fujisawa Tokushukai Hospital, Fujisawa, Kanagawa, Japan
| | - Tsuyoshi Nakayama
- Department of Gastroenterology, Shonan Atsugi Hospital, Atsugi, Kanagawa, Japan
| | - Hiroki Yamanoue
- Department of General Internal Medicine, Shizuoka Tokushukai Hospital, Suruga, Shizuoka, Japan
| | - Ji Hyun Sung
- Department of Gastroenterology, Shonan Kamakura General Hospital, Kamakura, Kanagawa, Japan
| | - Makoto Kako
- Department of Gastroenterology, Shonan Kamakura General Hospital, Kamakura, Kanagawa, Japan
| | - Wasaburo Koizumi
- Department of Gastroenterology, Internal Medicine, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
| |
Collapse
|
|
30
|
Chuaypen N, Chittmittraprap S, Pinjaroen N, Sirichindakul B, Poovorawan Y, Tanaka Y, Tangkijvanich P. Serum Wisteria floribunda agglutinin-positive Mac-2 binding protein level as a diagnostic marker of hepatitis B virus-related hepatocellular carcinoma. Hepatol Res 2018; 48:872-881. [PMID: 29732647 DOI: 10.1111/hepr.13187] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2018] [Revised: 04/19/2018] [Accepted: 04/25/2018] [Indexed: 02/08/2023]
Abstract
AIM Serum glycosylated Wisteria floribunda agglutinin-positive Mac-2 binding protein (WFA+ -M2BP) is a novel marker for staging liver fibrosis and predicting hepatocellular carcinoma (HCC) occurrence. This study aimed at evaluating the performance of WFA+ -M2BP in the diagnosis of HCC in patients with chronic hepatitis B virus (HBV) infection. METHODS The WFA+ -M2BP levels were measured in stored samples collected at initial diagnosis of 150 patients with HBV-related HCC and 150 age- and gender-matched patients with non-malignant chronic HBV infection. RESULTS Patients with HCC had higher levels of WFA+ -M2BP than those without HCC (3.9 [1.5-20.6] vs. 1.6 [0.4-9.3] cut-off index [COI], P < 0.001). In the HCC group, WFA+ -M2BP levels correlated with Child-Pugh classification but did not correlate with HBV markers, α-fetoprotein (AFP), or Barcelona Clinic Liver Cancer (BCLC) stage. The areas under the curve (AUROC) for differentiating HCC from non-HCC were 0.92 (95% confidence interval [CI], 0.89-0.95; P < 0.001) for WFA+ -M2BP, 0.90 (95% CI, 0.87-0.94; P < 0.001) for AFP, and 0.97 (95% CI, 0.95-0.98; P < 0.001) for the combination of both markers. At the optimal cut-off (2.4 COI), WFA+ -M2BP had sensitivity, specificity, and accuracy of 79.3%, 91.3%, and 85.3%, respectively. The WFA+ -M2BP marker was superior to AFP in differentiating early-stage HCC (BCLC stages 0 and A) from cirrhosis with AUROC of 0.80 (95% CI, 0.68-0.91; P < 0.001) and 0.73 (95% CI, 0.60-0.86; P = 0.002), respectively. By univariate analysis, elevated WFA+ -M2BP (≥4.0 COI) was correlated with poor overall survival in patients with HCC. CONCLUSIONS Wisteria floribunda agglutinin-positive M2BP showed a better diagnostic performance than AFP in detecting early-stage HCC. Thus, WFA+ -M2BP level could represent a promising marker for early diagnosis of HCC in patients with chronic HBV infection.
Collapse
Affiliation(s)
- Natthaya Chuaypen
- Center of Excellence in Hepatitis and Liver Cancer, Chulalongkorn University, Bangkok, Thailand
| | | | - Nutcha Pinjaroen
- Department of Radiology, Chulalongkorn University, Bangkok, Thailand
| | | | - Yong Poovorawan
- Center of Excellence in Clinical Virology, Chulalongkorn University, Bangkok, Thailand
| | - Yasuhito Tanaka
- Department of Virology and Liver Unit, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Pisit Tangkijvanich
- Center of Excellence in Hepatitis and Liver Cancer, Chulalongkorn University, Bangkok, Thailand
| |
Collapse
|
|
31
|
Alkhouri N, Johnson C, Adams L, Kitajima S, Tsuruno C, Colpitts TL, Hatcho K, Lawitz E, Lopez R, Feldstein A. Serum Wisteria floribunda agglutinin-positive Mac-2-binding protein levels predict the presence of fibrotic nonalcoholic steatohepatitis (NASH) and NASH cirrhosis. PLoS One 2018; 13:e0202226. [PMID: 30161179 PMCID: PMC6116978 DOI: 10.1371/journal.pone.0202226] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2018] [Accepted: 07/30/2018] [Indexed: 12/28/2022] Open
Abstract
OBJECTIVE The race for finding effective treatments for nonalcoholic fatty liver disease (NAFLD) has been slowed down by the high screen-failure rate for including patients in trials due to the lack of a noninvasive biomarker that can identify patients with significant disease. Recently, Wisteria floribunda agglutinin-positive Mac-2-binding protein (WFA+ -M2BP) has shown promise in predicting liver fibrosis. The aims of this study were to evaluate the utility of WFA+ -M2BP as a biomarker to sub-classify patients with NAFLD according to their disease severity and to assess its correlation with histologic features of NAFLD. METHODS Patients undergoing biopsy for clinical suspicion of NAFLD and healthy controls were included. Patients with NAFLD were classified into: NAFL, early NASH (F0-F1), fibrotic NASH (F2-F3), and NASH cirrhosis (F4). Levels of WFA+ -M2BP in sera was measured by a HISCL™ M2BPGi™ assay kit using an automated immunoanalyzer (HISCL™-800; Sysmex, Kobe, Japan). Analysis of covariance was used to assess difference in WFA+ -M2BP between the groups and Spearman's correlation coefficients were used to assess correlation with histological features. RESULTS Our cohort consisted of 20 healthy controls and 198 patients with biopsy-proven NAFLD divided as follows: 52 with NAFL, 62 with early NASH, 52 with fibrotic NASH, and 32 with NASH cirrhosis. WFA+ -M2BP level was found to be significantly increased in the fibrotic NASH and NASH cirrhosis groups compared to healthy controls and those with early NAFLD after adjusting for age, gender and BMI. Furthermore, patients with NASH cirrhosis had significantly higher WFA+ -M2BP levels (2.4[1.5, 4.2] C.O.I (Cut-off Index)) than those with fibrotic NASH (1.2[0.79, 1.9]), p < 0.001. WFA+ -M2BP level had moderate correlation with inflammation, ballooning and NAFLD activity score and strong correlation with fibrosis stage. Additionally, ROC curve analysis demonstrated that WFA+ -M2BP accurately differentiated F2-4 from F0-F1. CONCLUSION In a large cohort of patients with the full spectrum of NAFLD, WFA+ -M2BP levels predicted the presence of advanced disease and correlated strongly with fibrosis stage.
Collapse
Affiliation(s)
- Naim Alkhouri
- The Texas Liver Institute, University of Texas (UT) Health Science Center, San Antonio, Texas, United States of America
- * E-mail:
| | - Casey Johnson
- Department of Pediatrics, University of California – San Diego, La Jolla, California, United States of America
| | - Leon Adams
- The University of Western Australia, Crawley, Australia
| | | | | | - Tracey L. Colpitts
- Sysmex Corporation R&D Center of Americas, Lincolnshire, Illinois, United States of America
| | - Kazuki Hatcho
- Sysmex Corporation R&D Center of Americas, Lincolnshire, Illinois, United States of America
| | - Eric Lawitz
- The Texas Liver Institute, University of Texas (UT) Health Science Center, San Antonio, Texas, United States of America
| | - Rocio Lopez
- Digestive Disease and Surgery Institute, Cleveland Clinic, Cleveland, Ohio, United States of America
| | - Ariel Feldstein
- Department of Pediatrics, University of California – San Diego, La Jolla, California, United States of America
| |
Collapse
|
|
32
|
Shirabe K, Bekki Y, Gantumur D, Araki K, Ishii N, Kuno A, Narimatsu H, Mizokami M. Mac-2 binding protein glycan isomer (M2BPGi) is a new serum biomarker for assessing liver fibrosis: more than a biomarker of liver fibrosis. J Gastroenterol 2018; 53:819-826. [PMID: 29318378 DOI: 10.1007/s00535-017-1425-z] [Citation(s) in RCA: 136] [Impact Index Per Article: 19.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2017] [Accepted: 12/18/2017] [Indexed: 02/04/2023]
Abstract
Assessing liver fibrosis is important for predicting the efficacy of antiviral therapy and patient prognosis. Liver biopsy is the gold standard for diagnosing liver fibrosis, despite its invasiveness and problematic diagnostic accuracy. Although noninvasive techniques to assess liver fibrosis are becoming important, reliable serum surrogate markers are not available. A glycoproteomics study aimed at identifying such markers discovered Mac 2-Binding Protein Gylcan Isomer (M2BPGi), which is a reliable marker for assessing liver fibrosis in patients with viral hepatitis and other fibrotic liver diseases such as primary biliary cholangitis, biliary atresia, autoimmune hepatitis, and nonalcoholic fatty liver disease. M2BPGi predicts the development of hepatocellular carcinoma (HCC) in patients infected with hepatitis B and C as well as the prognosis of liver cirrhosis in those with HCC after therapy. The unique features of M2BPGi are as follows: (1) cut-off values differ for the same stages of fibrosis according to the cause of fibrosis; and (2) M2BPGi levels rapidly decrease after patients achieve a sustained antiviral response to hepatitis C virus. These observations cannot be explained if M2BPGi levels reflect the amount of fibrotic tissue. Hepatic stellate cells (HSCs) secrete M2BPGi, which may serve as a messenger between HSCs and Kupffer cells via Mac-2 (galectin 3) that is expressed in Kupffer cells during fibrosis progression. Here we show that M2BPGi is a surrogate marker for assessing HSC activation. These findings may reveal the roles of HSCs in extrahepatic fibrotic disease progression.
Collapse
Affiliation(s)
- Ken Shirabe
- Division of Hepatobiliary and Pancreatic Surgery, Department of General Surgical Science, Gunma University, Graduate School of Medicine, 3-39-22 Showa Machi, Maebashi, Gunma, 371-8511, Japan.
| | - Yuki Bekki
- Department of Surgery and Science, Kyushu University, Graduate School of Medicine, Fukuoka, Fukuoka, Japan
| | - Dolgormaa Gantumur
- Division of Hepatobiliary and Pancreatic Surgery, Department of General Surgical Science, Gunma University, Graduate School of Medicine, 3-39-22 Showa Machi, Maebashi, Gunma, 371-8511, Japan
| | - Kenichiro Araki
- Division of Hepatobiliary and Pancreatic Surgery, Department of General Surgical Science, Gunma University, Graduate School of Medicine, 3-39-22 Showa Machi, Maebashi, Gunma, 371-8511, Japan
| | - Norihiro Ishii
- Division of Hepatobiliary and Pancreatic Surgery, Department of General Surgical Science, Gunma University, Graduate School of Medicine, 3-39-22 Showa Machi, Maebashi, Gunma, 371-8511, Japan
| | - Atsushi Kuno
- Research Center for Medical Glycoscience, National Institute of Advanced Industrial Science and Technology, Tsukuba, Ibaraki, Japan
| | - Hisashi Narimatsu
- Research Center for Medical Glycoscience, National Institute of Advanced Industrial Science and Technology, Tsukuba, Ibaraki, Japan
| | - Masashi Mizokami
- Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Ichikawa, Chiba, Japan
| |
Collapse
|
|
33
|
Shinkai N, Nojima M, Iio E, Matsunami K, Toyoda H, Murakami S, Inoue T, Ogawa S, Kumada T, Tanaka Y. 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 2018; 53:883-889. [PMID: 29288305 DOI: 10.1007/s00535-017-1424-0] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/11/2017] [Accepted: 12/18/2017] [Indexed: 02/08/2023]
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.
Collapse
Affiliation(s)
- Noboru Shinkai
- Departments of Virology & Liver Unit, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Masanori Nojima
- Center for Translational Research, The Institute of Medical Science Hospital, The University of Tokyo, Tokyo, Japan
| | - Etsuko Iio
- Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Kayoko Matsunami
- Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Hidenori Toyoda
- Department of Gastroenterology and Hepatology, Ogaki Municipal Hospital, Ogaki, Japan
| | - Shuko Murakami
- Departments of Virology & Liver Unit, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Takako Inoue
- Department of Clinical Laboratory, Nagoya City University Hospital, Nagoya, Japan
| | - Shintaro Ogawa
- Departments of Virology & Liver Unit, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Takashi Kumada
- Department of Gastroenterology and Hepatology, Ogaki Municipal Hospital, Ogaki, Japan
| | - Yasuhito Tanaka
- Departments of Virology & Liver Unit, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
| |
Collapse
|
|
34
|
Mak LY, Wong DKH, 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; 9:163. [PMID: 29915243 PMCID: PMC6006340 DOI: 10.1038/s41424-018-0020-9] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/02/2018] [Revised: 02/26/2018] [Accepted: 03/12/2018] [Indexed: 12/16/2022] Open
Abstract
Background Mac-2-binding protein glycosylation isomer (M2BPGi), a novel serum marker for liver fibrosis, was seldom studied in chronic hepatitis B (CHB). We aimed to evaluate its role on diagnosing significant fibrosis and cirrhosis in treated CHB patients. Methods CHB patients treated with nucleos(t)ide analogues (NAs) with baseline liver biopsies and retrievable serum samples were recruited. Paired liver biopsies were performed in patient subgroups at 1 and 3 years. Results In total, 327 NA-treated CHB patients (M:F = 229:98; median age 38.1 years) were recruited. The median M2BPGi values were 0.26, 0.34, 0.57 and 1.21 cutoff index (COI), in liver histology with Ishak F0–1, F2, F3 and F4, respectively (p < 0.01). M2BPGi levels correlated with the Ishak scores (ρ = 0.312, p < 0.001). Using the cutoff values of 0.25, 0.45 and 0.96 COI for ≥F2, ≥F3 and F4, the AUROCs were 0.653, 0.795 and 0.914, respectively. Multivariate analysis with several other serum indices showed that M2BPGi was the most significant independent factor for ≥F3 (OR: 8.197, 95% CI: 2.699–24.897, p < 0.001). In patient subgroups with serial liver biopsies, both the proportion of F3/F4 and M2BPGi decreased at 1 year (8.3% vs. 2.8% and 0.32 vs. 0.21 COI, respectively; both p < 0.001). Histological fibrosis progression after ≥3 years of NA therapy accompanied with an increase in M2BPGi level, compared to patients without progression (+0.14 vs −0.03 COI, p = 0.045). Conclusion Serum M2BPGi is a reliable non-invasive marker for diagnosing ≥F2, ≥F3 and F4. It is the only significant marker for ≥F3 among several other indices. NA produced concordant dynamic changes in M2BPGi levels and histological fibrosis.
Collapse
Affiliation(s)
- Lung-Yi Mak
- Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong, China
| | - Danny Ka-Ho Wong
- Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong, China.,State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong, China
| | - Ka-Shing Cheung
- Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong, China
| | - Wai-Kay Seto
- Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong, China.,State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong, China
| | - Ching-Lung Lai
- Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong, China.,State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong, China
| | - Man-Fung Yuen
- Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong, China. .,State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong, China.
| |
Collapse
|
|
35
|
Kawanaka M, Tomiyama Y, Hyogo H, Koda M, Shima T, Tobita H, Hiramatsu A, Nishino K, Okamoto T, Sato S, Hara Y, Nishina S, Kawamoto H, Chayama K, Okanoue T, Hino K. Wisteria floribunda agglutinin-positive Mac-2 binding protein predicts the development of hepatocellular carcinoma in patients with non-alcoholic fatty liver disease. Hepatol Res 2018; 48:521-528. [PMID: 29316028 DOI: 10.1111/hepr.13054] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2017] [Revised: 12/26/2017] [Accepted: 01/02/2018] [Indexed: 02/06/2023]
Abstract
AIM As it is not practical to perform regular screening for hepatocellular carcinoma (HCC) in all patients with non-alcoholic fatty liver disease (NAFLD), there is a need to identify NAFLD patients who are at high risk for HCC. Wisteria floribunda agglutinin-positive Mac-2 binding protein (WFA+ -M2BP) has been shown to be a surrogate marker for predicting HCC as well as a liver fibrosis marker in patients with chronic hepatitis B and C. The aim of this study was to investigate whether WFA+ -M2BP predicts HCC development in NAFLD patients. METHODS Serum WFA+ -M2BP was retrospectively measured in 331 patients with histologically proven NAFLD, 51 of whom developed HCC. The association of WFA+ -M2BP and HCC development in NAFLD patients was investigated. RESULTS The WFA+ -M2BP values were significantly greater in NAFLD patients with HCC than in those without HCC among patients with liver fibrosis ≥stage 3. Multivariate analysis identified WFA+ -M2BP as one of the predictive factors for HCC development (odds ratio, 1.57; 95% confidence interval, 1.083-2.265; P = 0.017). The optimal cut-off index of WFA+ -M2BP for predicting HCC was 1.255 with specificity of 78.4% and sensitivity of 70.4%. The area under the receiver operating characteristic curve value for the prediction of HCC development was 0.806. The cumulative incidence rate of HCC was significantly greater in patients with WFA+ -M2BP ≥ 1.255 (n = 61) than in those with WFA+ -M2BP < 1.255 (n = 137) among patients who were followed up for more than 2 years after the diagnosis of NAFLD. CONCLUSIONS Wisteria floribunda agglutinin-positive Mac-2 binding protein predicts HCC development and is a useful surrogate marker for identifying NAFLD patients who are at a high risk for HCC.
Collapse
Affiliation(s)
- Miwa Kawanaka
- Department of General Internal Medicine 2, Kawasaki Medical School General Medical Center, Okayama
| | - Yasuyuki Tomiyama
- Department of Hepatology and Pancreatology, Kawasaki Medical School, Kurashiki
| | - Hideyuki Hyogo
- Department of Gastroenterology and Hepatology, JA Hiroshima General Hospital, Hatsukaichi
| | - Masahiko Koda
- Division of Medicine and Clinical Science, Faculty of Medicine, Tottori University, Yonago
| | - Toshihide Shima
- Department of Gastroenterology and Hepatology, Saiseikai Suita Hospital, Suita
| | - Hiroshi Tobita
- Department of Gastroenterology and Hepatology, Shimane University School of Medicine, Izumo
| | - Akira Hiramatsu
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Ken Nishino
- Department of General Internal Medicine 2, Kawasaki Medical School General Medical Center, Okayama
| | - Toshiaki Okamoto
- Division of Medicine and Clinical Science, Faculty of Medicine, Tottori University, Yonago
| | - Shuichi Sato
- Department of Gastroenterology and Hepatology, Shimane University School of Medicine, Izumo
| | - Yuichi Hara
- Department of Hepatology and Pancreatology, Kawasaki Medical School, Kurashiki
| | - Sohji Nishina
- Department of Hepatology and Pancreatology, Kawasaki Medical School, Kurashiki
| | - Hirofumi Kawamoto
- Department of General Internal Medicine 2, Kawasaki Medical School General Medical Center, Okayama
| | - Kazuaki Chayama
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Takeshi Okanoue
- Department of Gastroenterology and Hepatology, Saiseikai Suita Hospital, Suita
| | - Keisuke Hino
- Department of Hepatology and Pancreatology, Kawasaki Medical School, Kurashiki
| |
Collapse
|
|
36
|
Umetsu S, Inui A, Sogo T, Komatsu H, Fujisawa T. Usefulness of serum Wisteria floribunda agglutinin-positive Mac-2 binding protein in children with primary sclerosing cholangitis. Hepatol Res 2018; 48:355-363. [PMID: 29168311 DOI: 10.1111/hepr.13004] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2017] [Revised: 11/13/2017] [Accepted: 11/18/2017] [Indexed: 12/14/2022]
Abstract
BACKGROUND Wisteria floribunda agglutinin-positive Mac-2 binding protein (WFA+ -M2BP) is a novel serum marker of hepatic fibrosis in adults with chronic hepatitis C. However, it remains unclear whether serum WFA+ -M2BP levels are associated with the progression of liver histology in primary sclerosing cholangitis (PSC). METHODS Twenty-eight children and adolescents with pediatric-onset PSC (male : female patient ratio, 20:8; median age at diagnosis, 9 years) were enrolled in this study. The relation between serum WFA+ -M2BP levels and clinical characteristics was retrospectively evaluated. Moreover, receiver operating characteristic (ROC) analysis was used to determine whether serum WFA+ -M2BP levels could be a reliable marker to identify PSC patients with advanced liver histology. RESULTS According to the Ludwig classification of liver histological stage, 28 patients were classified into the four stages. The WFA+ -M2BP level, aspartate aminotransferase (AST) to platelet ratio index (APRI), and hyaluronic acid correlated significantly with liver histological stage. Moreover, WFA+ -M2BP showed a significant positive correlation (P < 0.05) with autoimmune hepatitis overlap, AST, alanine aminotransferase (ALT), γ-glutamyltransferase, total bilirubin, immunoglobulin G, APRI, and hyaluronic acid. A ROC analysis was undertaken to distinguish the patients with advanced stage disease (stage 3-4) from those with early stage disease (stage 0-2). It showed that WFA+ -M2BP yielded the highest area under the ROC curve value (0.898) among four surrogate makers (APRI, 0.850; Fibrosis-4 index, 0.806; and AST/ALT ratio, 0.802). Moreover, WFA+ -M2BP yielded the highest sensitivity, specificity, positive predictive value, and negative predictive value among the four markers. CONCLUSIONS Serum WFA+ -M2BP levels are useful to identify patients with advanced liver histology in pediatric PSC.
Collapse
Affiliation(s)
- Shuichiro Umetsu
- Department of Pediatric Hepatology and Gastroenterology, Saiseikai Yokohamashi Tobu Hospital, Yokohama, Japan
| | - Ayano Inui
- Department of Pediatric Hepatology and Gastroenterology, Saiseikai Yokohamashi Tobu Hospital, Yokohama, Japan
| | - Tsuyoshi Sogo
- Department of Pediatric Hepatology and Gastroenterology, Saiseikai Yokohamashi Tobu Hospital, Yokohama, Japan
| | - Haruki Komatsu
- Department of Pediatrics, Toho University Medical Center Sakura Hospital, Sakura, Japan
| | - Tomoo Fujisawa
- Department of Pediatric Hepatology and Gastroenterology, Saiseikai Yokohamashi Tobu Hospital, Yokohama, Japan
| |
Collapse
|
|
37
|
Eso Y, Takai A, Taura K, Takahashi K, Ueda Y, Marusawa H, Seno H. Association of Mac-2-binding protein glycosylation isomer level with nutritional status in chronic liver disease. J Gastroenterol Hepatol 2018; 33:1649-1658. [PMID: 29473206 DOI: 10.1111/jgh.14130] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/14/2017] [Revised: 01/25/2018] [Accepted: 02/18/2018] [Indexed: 12/11/2022]
Abstract
BACKGROUND AND AIM Mac-2-binding protein glycosylation isomer (M2BPGi) was recently identified as a serum glycobiomarker for liver fibrosis. However, the relationship between M2BPGi and malnutrition in patients with chronic liver disease (CLD) is unknown. We aimed to evaluate whether M2BPGi could be a surrogate marker for malnutrition in patients with CLD. METHODS In total, 338 outpatients with CLD were enrolled (median age: 67 years). We evaluated the associations among liver fibrosis markers (M2BPGi, fibrosis-4 index, and aspartate aminotransferase-to-platelet count ratio index), Child-Pugh stages, and nutritional status markers. RESULTS The median value (range) of serum M2BPGi levels was 0.94 cut-off index (COI) (0.22-11.57) in chronic hepatitis and Child-Pugh A (n = 274), 4.775 COI (1.32-16.68) in Child-Pugh B (n = 46), and 11.37 COI (6.03-18.33) in Child-Pugh C (n = 18) (overall significance, P < 0.001). Serum M2BPGi levels showed a strong correlation with serum albumin concentration and controlling nutritional status score (rs = -0.649, P < 0.001 and rs = 0.671, P < 0.001, respectively). The correlations between M2BPGi and nutritional status markers were especially high in patients with hepatitis C virus infection and non-B non-C hepatitis and patients with hepatocellular carcinoma. Among the three fibrosis markers, M2BPGi yielded the highest area under the receiver operating characteristic curve (0.920) for predicting hypoalbuminemia at an optimal cut-off value of 2.41 (sensitivity, 87.3%; specificity, 87.6%; P < 0.001). CONCLUSIONS Serum M2BPGi levels are correlated with nutritional status markers in patients with CLD and could be a useful clinical marker of malnutrition.
Collapse
Affiliation(s)
- Yuji Eso
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Atsushi Takai
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Kojiro Taura
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Ken Takahashi
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Yoshihide Ueda
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Hiroyuki Marusawa
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Hiroshi Seno
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| |
Collapse
|
|
38
|
Takata R, Nishikawa H, Enomoto H, Iwata Y, Ishii A, Miyamoto Y, Ishii N, Yuri Y, Hasegawa K, Nakano C, Nishimura T, Yoh K, Aizawa N, Sakai Y, Ikeda N, Takashima T, Iijima H, Nishiguchi S. Relationship between skeletal muscle mass and liver fibrosis markers for patients with hepatitis C virus related liver disease. Medicine (Baltimore) 2017; 96:e8761. [PMID: 29310350 PMCID: PMC5728751 DOI: 10.1097/md.0000000000008761] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2017] [Revised: 09/29/2017] [Accepted: 10/23/2017] [Indexed: 02/06/2023] Open
Abstract
We aimed to elucidate the relationship between serum liver fibrosis markers (Mac-2 binding protein glycosylation isomer (M2BPGi), FIB-4 index, aspartate aminotransferase to platelet ratio index and hyaluronic acid), and skeletal muscle mass and to investigate factors linked to skeletal muscle mass loss (SMML) in patients with chronic hepatitis C (CHC, n = 277, median age = 64 years). We defined patients with psoas muscle index [PMI, sum of bilateral psoas muscle mass calculated by manual trace method at the lumber 3 level on the computed tomography images divided by height squared (cm/m)] less than 6.36 cm/m for male and 3.92 cm/m for female as those with SMML based on the recommendations in current guidelines. Receiver operating curve (ROC) analysis was performed for predicting SMML in 4 liver fibrosis markers and parameters linked to SMML were also investigated in the univariate and multivariate analyses. In terms of liver fibrosis stages, F4 was observed in 115 patients, F3 in 67, F2 in 38, F1 in 53, and F0 in 4. The median (range) PMI for male and female were 6.198 (2.999-13.698) and 4.100 (1.691-7.052) cm/m, respectively. There were 72 male patients with SMML (55.4%) and 58 female patients with SMML (39.5%) (P = .0112). In both male and female, a significant inverse correlation between PMI and levels of liver fibrosis markers was observed in all liver fibrosis markers. ROC analyses for predicting SMML revealed that FIB-4 index had the highest area under the ROC (AUC = 0.712), followed by M2BPGi (AUC = 0.692). In the multivariate analysis of factors linked to SMML, gender (P = .0003), body mass index (P < .0001), FIB-4 index (P = .0039), and M2BPGi (P = .0121) were found to be significant predictors. In conclusion, liver fibrosis markers, especially FIB-4 index, can be helpful for predicting SMML in CHC patients.
Collapse
|
|
39
|
Ito K, Murotani K, Nakade Y, Inoue T, Nakao H, Sumida Y, Kamada Y, Yoneda M. Serum Wisteria floribunda agglutinin-positive Mac-2-binding protein levels and liver fibrosis: A meta-analysis. J Gastroenterol Hepatol 2017; 32:1922-1930. [PMID: 28406534 DOI: 10.1111/jgh.13802] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2017] [Revised: 04/03/2017] [Accepted: 04/05/2017] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND AIM A reliable, non-invasive biomarker for diagnosis of liver fibrosis in chronic liver disease patients is needed. The aim of this study was to assess by meta-analysis the efficacy of measuring serum levels of Wisteria floribunda agglutinin-positive Mac-2-binding protein (WFA+ -M2BP), a novel and promising biomarker, for staging liver fibrosis and predicting the development of hepatocellular carcinoma and overall survival. METHODS We performed a meta-analysis using online journal database searches. We identified 39 studies, 21 of which met the criteria for meta-analysis. Sensitivity and specificity of WFA+ -M2BP for assessing liver fibrosis staging in chronic liver diseases with broad etiologies were determined. Hazard ratios with 95% confidence intervals were also used for predicting hepatocellular carcinoma development and overall survival. RESULTS With WFA+ -M2BP, the sensitivity and specificity for predicting significant fibrosis (≥ F2), advanced fibrosis (≥ F3), and liver cirrhosis (= F4) were 0.690 and 0.778, 0.764 and 0.758, and 0.818 and 0.839, respectively. Sensitivity and specificity for diagnosing liver fibrosis in patients with hepatitis C virus were mostly higher than those in overall patients. However, sensitivity and specificity for diagnosing liver fibrosis in patients with hepatitis B virus were lower than those in overall patients. Overall, hazard ratios for development of hepatocellular carcinoma and overall survival were 5.946 and 1.068, respectively. CONCLUSIONS These results suggest that serum WFA+ -M2BP is a reliable predictor for liver fibrosis staging and a good substitute for liver biopsy. It is also useful for predicting both hepatocellular carcinoma development and overall survival.
Collapse
Affiliation(s)
- Kiyoaki Ito
- Department of Gastroenterology, Aichi Medical University School of Medicine, Nagakute, Japan
| | - Kenta Murotani
- Division of Biostatistics, Clinical Research Center, Aichi Medical University School of Medicine, Nagakute, Japan
| | - Yukiomi Nakade
- Department of Gastroenterology, Aichi Medical University School of Medicine, Nagakute, Japan
| | - Tadahisa Inoue
- Department of Gastroenterology, Aichi Medical University School of Medicine, Nagakute, Japan
| | - Haruhisa Nakao
- Department of Gastroenterology, Aichi Medical University School of Medicine, Nagakute, Japan
| | - Yoshio Sumida
- Department of Gastroenterology, Aichi Medical University School of Medicine, Nagakute, Japan
| | - Yoshihiro Kamada
- Department of Molecular Biochemistry and Clinical Investigation, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Masashi Yoneda
- Department of Gastroenterology, Aichi Medical University School of Medicine, Nagakute, Japan
| |
Collapse
|
|
40
|
Yoh K, Nishikawa H, Enomoto H, Iwata Y, Ishii A, Yuri Y, Ishii N, Miyamoto Y, Hasegawa K, Nakano C, Takata R, Nishimura T, Aizawa N, Sakai Y, Ikeda N, Takashima T, Iijima H, Nishiguchi S. Effect of nalfurafine hydrochloride in patients with chronic liver disease with refractory pruritus on sleep disorders: a study protocol for single-arm, prospective, interventional study. BMJ Open Gastroenterol 2017; 4:e000177. [PMID: 29104757 PMCID: PMC5659178 DOI: 10.1136/bmjgast-2017-000177] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/26/2017] [Revised: 09/17/2017] [Accepted: 09/20/2017] [Indexed: 02/06/2023] Open
Abstract
INTRODUCTION Chronic liver disease (CLD)-related pruritus manifests as cholestasis symptoms, which can cause severe itches in the whole body and significantly decrease quality of daily activities and sleep. The actigram, which documents movement by means of an accelerometer, has been demonstrated to be useful for assessing sleep quality. Nalfurafine hydrochloride, which is a selective κ-opioid receptor agonist, exerts its antipruritic efficacies through a novel mechanism. We aimed to prospectively examine the effect of nalfurafine hydrochloride on sleep quality for patients with CLD with pruritus utilising actigram. METHODS AND ANALYSIS This study will be a single-centre, prospective, interventional, single-arm study. Our study participants are subjects whose pruritus was confirmed to be uncontrollable by antihistamines or antiallergics within 6 months before informed consent (IC). Evaluation time points using actigram will be (1) before administration of testing drug; (2) after 1 week; (3) after 4 weeks (primary endpoint); and (4) every 4 weeks thereafter. The follow-up period will be 6 months. We will prospectively assess and compare changes in sleep quality in patients with CLD with pruritus undergoing nalfurafine hydrochloride therapy using actigram. Quantitative variables will be compared by paired t-test. ETHICS AND DISSEMINATION This study has received approval from the Institutional Review Board at Hyogo College of Medicine (approval no 2325). The study protocol, IC form and other documents were reviewed and approved. Final data will be publicly disseminated regardless of the results. A report releasing study results will be submitted in an appropriate journal. TRIAL REGISTRATION NUMBER UMIN000028161; Pre-results.
Collapse
Affiliation(s)
- Kazunori Yoh
- Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan
| | - Hiroki Nishikawa
- Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan
| | - Hirayuki Enomoto
- Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan
| | - Yoshinori Iwata
- Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan
| | - Akio Ishii
- Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan
| | - Yukihisa Yuri
- Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan
| | - Noriko Ishii
- Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan
| | - Yuho Miyamoto
- Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan
| | - Kunihiro Hasegawa
- Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan
| | - Chikage Nakano
- Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan
| | - Ryo Takata
- Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan
| | - Takashi Nishimura
- Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan
| | - Nobuhiro Aizawa
- Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan
| | - Yoshiyuki Sakai
- Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan
| | - Naoto Ikeda
- Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan
| | - Tomoyuki Takashima
- Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan
| | - Hiroko Iijima
- Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan
| | - Shuhei Nishiguchi
- Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan
| |
Collapse
|