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Hanamatsu H, Suda G, Ohara M, Ogawa K, Tamaki N, Hikita H, Haga H, Maekawa S, Sugiyama M, Kakisaka T, Nakai M, Sho T, Miura N, Kurosaki M, Asahina Y, Taketomi A, Ueno Y, Takehara T, Nishikaze T, Furukawa JI, Sakamoto N. Elevated A2F bisect N-glycans of serum IgA reflect progression of liver fibrosis in patients with MASLD. J Gastroenterol 2025; 60:456-468. [PMID: 39849179 PMCID: PMC11922979 DOI: 10.1007/s00535-024-02206-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2024] [Accepted: 12/25/2024] [Indexed: 01/25/2025]
Abstract
BACKGROUND Advanced liver fibrosis in cases of metabolic dysfunction-associated steatotic liver disease (MASLD) leads to cirrhosis and hepatocellular carcinoma. The current gold standard for liver fibrosis is invasive liver biopsy. Therefore, a less invasive biomarker that accurately reflects the stage of liver fibrosis is highly desirable. METHODS This study enrolled 269 patients with liver biopsy-proven MASLD. Patients were divided into three groups (F0/1 (n = 41/85), F2 (n = 47), and F3/4 (n = 72/24)) according to fibrosis stage. We performed serum N-glycomics and identified glycan biomarker for fibrosis stage. Moreover, we explored the carrier proteins and developed a sandwich ELISA to measure N-glycosylation changes of carrier protein. RESULTS Comprehensive N-glycomic analysis revealed significant changes in the expression of A2F bisect and its precursors as fibrosis progressed. The sum of neutral N-glycans carrying bisecting GlcNAc and core Fuc (neutral sum) had a better diagnostic performance to evaluate advanced liver fibrosis (AUC = 0.804) than conventional parameters (FIB4 index, aspartate aminotransferase-to-alanine aminotransferase ratio (AAR), and serum level of Mac-2-binding protein glycol isomer (M2BPGi). The combination of the neutral sum and FIB4 index enhanced diagnostic performance (AUC = 0.840). IgM, IgA, and complement C3 were identified as carrier proteins with A2F bisect N-glycan. A sandwich ELISA based on N-glycans carrying bisecting GlcNAc and IgA showed similar diagnostic performance than the neutral sum. CONCLUSIONS A2F bisect N-glycan and its precursors are promising candidate biomarkers for advanced fibrosis in MASLD patients. Analysis of these glycan alterations on IgA may have the potential to serve as a novel ELISA diagnostic tool for MASLD in routine clinical practice. CLINICAL TRIAL NUMBER UMIN000030720.
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Affiliation(s)
| | - Goki Suda
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Hokkaido, Japan
| | - Masatsugu Ohara
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Hokkaido, Japan
| | - Koji Ogawa
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Hokkaido, Japan
| | - Nobuharu Tamaki
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Hayato Hikita
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Hiroaki Haga
- Department of Gastroenterology, Faculty of Medicine, Yamagata University, Yamagata, Japan
| | - Shinya Maekawa
- First Department of Internal Medicine, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan
| | - Masaya Sugiyama
- Department of Viral Pathogenesis and Controls, National Center for Global Health and Medicine, Tokyo, Japan
| | - Tatsuhiko Kakisaka
- Department of Gastroenterological Surgery I, Graduate School of Medicine, Hokkaido University, Hokkaido, Japan
| | - Masato Nakai
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Hokkaido, Japan
| | - Takuya Sho
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Hokkaido, Japan
| | - Nobuaki Miura
- Institute for Glyco-Core Research (iGCORE), Nagoya University, Aichi, Japan
| | - Masayuki Kurosaki
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Yasuhiro Asahina
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Akinobu Taketomi
- Department of Gastroenterological Surgery I, Graduate School of Medicine, Hokkaido University, Hokkaido, Japan
| | - Yoshiyuki Ueno
- Department of Gastroenterology, Faculty of Medicine, Yamagata University, Yamagata, Japan
| | - Tetsuo Takehara
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Takashi Nishikaze
- Solutions COE, Analytical and Measuring Instruments Division, Shimadzu Corporation, Kyoto, Japan
| | - Jun-Ichi Furukawa
- Institute for Glyco-Core Research (iGCORE), Nagoya University, Aichi, Japan.
- Department of Orthopaedic Surgery, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Hokkaido, Japan.
| | - Naoya Sakamoto
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Hokkaido, Japan.
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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.
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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
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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/.
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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
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Uojima H, Yamasaki K, Sugiyama M, Kage M, Ishii N, Shirabe K, Hidaka H, Kusano C, Murakawa M, Asahina Y, Nishimura T, Iijima H, Sakamoto K, Ito K, Amano K, Kawaguchi T, Tamaki N, Kurosaki M, Suzuki T, Matsuura K, Taketomi A, Joshita S, Umemura T, Nishina S, Hino K, Toyoda H, Yatsuhashi H, Mizokami M. Quantitative measurements of M2BPGi depend on liver fibrosis and inflammation. J Gastroenterol 2024; 59:598-608. [PMID: 38625546 DOI: 10.1007/s00535-024-02100-3] [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: 02/16/2024] [Accepted: 03/19/2024] [Indexed: 04/17/2024]
Abstract
BACKGROUND The relationship between liver fibrosis and inflammation and Mac-2-binding protein glycosylation isomer (M2BPGi) in patients with chronic liver disease (CLD) other than hepatitis C remains uncertain, owing to the limitations of qualitative methods. Here, we evaluated the influence of liver fibrosis and inflammation on quantitative M2BPGi (M2BPGi-Qt) in CLD, considering each etiology. METHODS We recruited 1373 patients with CLD. To evaluate the influence of liver fibrosis and inflammation on M2BPGi-Qt levels, we assessed M2BPGi-Qt levels at each fibrosis and activity stage within different etiologies of CLD based on pathological findings. Subsequently, we evaluated if the accuracy of fibrosis staging based on M2BPGi-Qt could be improved by considering the influence of liver inflammation. RESULTS In patients with viral hepatitis, non-alcoholic fatty liver disease, and primary biliary cholangitis, the median M2BPGi-Qt levels increased liver fibrosis progression. Median M2BPGi-Qt levels were not associated with the degree of fibrosis in patients with autoimmune hepatitis (AIH). Median M2BPGi-Qt levels increased with the progression of liver activity in all etiologies. A significant difference was found at each stage in AIH. Considering the liver inflammation, we established an algorithm, M2BPGi-Qt, to determine the alanine aminotransferase-to-platelet ratio (MAP-R) in liver cirrhosis (LC). The area under the receiver operating characteristic curve (AUC) of MAP-R was higher than that of the M2BPGi-Qt for detecting LC (AUC MAP-R = 0.759 and M2BPGi-Qt = 0.700, p < 0.001). CONCLUSIONS The quantitative measurement system for M2BPGi depends on liver fibrosis and inflammation, regardless of etiology. Liver inflammation complicates the interpretation of M2BPGi-Qt results when assessing the fibrosis stage.
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Affiliation(s)
- Haruki Uojima
- Genome Medical Sciences Project, Research Institute, National Center for Global Health and Medicine, 1-7-1, Kohnodai, Ichikawa, Chiba, 272-8516, Japan.
- Department of Gastroenterology, Internal Medicine, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan.
| | - Kazumi Yamasaki
- Clinical Research Center, National Hospital Organization, Nagasaki Medical Center, Ōmura, Japan
| | - Masaya Sugiyama
- Department of Viral Pathogenesis and Controls, Research Institute, National Center for Global Health and Medicine, Ichikawa, Chiba, Japan
| | - Masayoshi Kage
- Department of Pathology, Junshin Gakuen University, Fukuoka, Japan
| | - Norihiro Ishii
- Division of Hepatobiliary and Pancreatic Surgery, Department of General Surgical Science, Gunma University, Graduate School of Medicine, Maebashi, Gunma, Japan
| | - Ken Shirabe
- Division of Hepatobiliary and Pancreatic Surgery, Department of General Surgical Science, Gunma University, Graduate School of Medicine, Maebashi, Gunma, Japan
| | - Hisashi Hidaka
- Department of Gastroenterology, Internal Medicine, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
| | - Chika Kusano
- Department of Gastroenterology, Internal Medicine, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
| | - Miyako Murakawa
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Yushima, Bunkyo-Ku, Tokyo, Japan
| | - Yasuhiro Asahina
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Yushima, Bunkyo-Ku, Tokyo, Japan
- Department of Liver Disease Control, Tokyo Medical and Dental University, Yushima, Bunkyo-Ku, Tokyo, Japan
| | - Takashi Nishimura
- Division of Hepatobiliary and Pancreatic Disease, Department of Gastroenterology, Hyogo Medical University, Nishinomiya, Hyogo, Japan
| | - Hiroko Iijima
- Division of Hepatobiliary and Pancreatic Disease, Department of Gastroenterology, Hyogo Medical University, Nishinomiya, Hyogo, Japan
| | - Kazumasa Sakamoto
- Department of Gastroenterology, Aichi Medical University, Nagakute, Aichi, Japan
| | - Kiyoaki Ito
- Department of Gastroenterology, Aichi Medical University, Nagakute, Aichi, Japan
| | - Keisuke Amano
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Asahi-Machi, Kurume, Fukuoka, Japan
| | - Takumi Kawaguchi
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Asahi-Machi, Kurume, Fukuoka, Japan
| | - Nobuharu Tamaki
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Musashino, Tokyo, Japan
| | - Masayuki Kurosaki
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Musashino, Tokyo, Japan
| | - Takanori Suzuki
- Department of Gastroenterology and Metabolism, Graduate School of Medical Sciences, Nagoya City University, Nagoya, Japan
| | - Kentaro Matsuura
- Department of Gastroenterology and Metabolism, Graduate School of Medical Sciences, Nagoya City University, Nagoya, Japan
| | - Akinobu Taketomi
- Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Sapporo, Japan
| | - Satoru Joshita
- Department of Medicine, Division of Gastroenterology and Hepatology, Shinshu University School of Medicine, Asahi, Matsumoto, Japan
| | - Takeji Umemura
- Department of Medicine, Division of Gastroenterology and Hepatology, Shinshu University School of Medicine, Asahi, Matsumoto, Japan
| | - Sohji Nishina
- Department of Hepatology and Pancreatology, Kawasaki Medical School, Aichi, Japan
| | - Keisuke Hino
- Department of Hepatology and Pancreatology, Kawasaki Medical School, Aichi, Japan
- Digestive Disease Center, Shunan Memorial Hospital, Yamaguchi, Japan
| | - Hidenori Toyoda
- Department of Gastroenterology, Ogaki Municipal Hospital, Ogaki, Japan
| | - Hiroshi Yatsuhashi
- Clinical Research Center, National Hospital Organization, Nagasaki Medical Center, Ōmura, Japan
| | - Masashi Mizokami
- Genome Medical Sciences Project, Research Institute, National Center for Global Health and Medicine, 1-7-1, Kohnodai, Ichikawa, Chiba, 272-8516, Japan
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Maroto-García J, Moreno Álvarez A, Sanz de Pedro MP, Buño-Soto A, González Á. Serum biomarkers for liver fibrosis assessment. ADVANCES IN LABORATORY MEDICINE 2024; 5:115-130. [PMID: 38939201 PMCID: PMC11206202 DOI: 10.1515/almed-2023-0081] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 07/13/2023] [Accepted: 10/12/2023] [Indexed: 06/29/2024]
Abstract
Liver fibrosis is the result of chronic liver injury of different etiologies produced by an imbalance between the synthesis and degeneration of the extracellular matrix and dysregulation of physiological mechanisms. Liver has a high regenerative capacity in the early stage of chronic diseases so a prompt liver fibrosis detection is important. Consequently, an easy and economic tool that could identify patients with liver fibrosis at the initial stages is needed. To achieve this, many non-invasive serum direct, such as hyaluronic acid or metalloproteases, and indirect biomarkers have been proposed to evaluate liver fibrosis. Also, there have been developed formulas that combine these biomarkers, some of them also introduce clinical and/or demographic parameters, like FIB-4, non-alcoholic fatty liver disease fibrosis score (NFS), enhance liver fibrosis (ELF) or Hepamet fibrosis score (HFS). In this manuscript we critically reviewed different serum biomarkers and formulas for their utility in the diagnosis and progression of liver fibrosis.
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Affiliation(s)
| | - Ana Moreno Álvarez
- Biochemistry Department, Clínica Universidad de Navarra, Pamplona, Spain
| | | | - Antonio Buño-Soto
- Laboratory Medicine Department, Hospital Universitario La Paz, Madrid, Spain
- Hospital La Paz Institute for Health Research (IdiPaz), Madrid, Spain
| | - Álvaro González
- Biochemistry Department, Clínica Universidad de Navarra, Pamplona, Spain
- Navarra Institute for Health Research (IdiSNA), Pamplona, Spain
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Maroto-García J, Moreno-Álvarez A, Sanz de Pedro MP, Buño-Soto A, González Á. Biomarcadores séricos para la evaluación de la fibrosis hepática. ADVANCES IN LABORATORY MEDICINE 2024; 5:131-147. [PMID: 38939202 PMCID: PMC11206201 DOI: 10.1515/almed-2023-0172] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 07/13/2023] [Accepted: 10/12/2023] [Indexed: 06/29/2024]
Abstract
La fibrosis hepática se desarrolla como respuesta a la presencia de daño hepático crónico de diferentes etiologías, provocando un desequilibrio entre la síntesis y degeneración de la matriz extracelular y la desregulación de diversos mecanismos fisiológicos. En los estadios iniciales de las patologías crónicas, el hígado posee una elevada capacidad de regeneración, por lo que la detección temprana de la fibrosis hepática resulta esencial. En este contexto, es preciso contar con herramientas sencillas y económicas que permitan detectar la fibrosis hepática en sus fases iniciales. Para evaluar la fibrosis hepática, se han propuesto multitud de biomarcadores séricos no invasivos, tanto directos, como el ácido hialurónico o las metaloproteasas, como indirectos. Así mismo, se han desarrollado diversas fórmulas que combinan dichos biomarcadores junto con parámetros demográficos, como el índice FIB-4, el índice de fibrosis en la enfermedad de hígado graso no alcohólico (NFS, por sus siglas en inglés), la prueba ELF o el score de fibrosis Hepamet (HFS, por sus siglas en inglés). En el presente manuscrito, realizamos una revisión crítica del valor diagnóstico y pronóstico de los diferentes biomarcadores séricos y fórmulas actualmente existentes.
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Affiliation(s)
- Julia Maroto-García
- Departamento de Bioquímica, Clínica Universidad de Navarra, Pamplona, España
| | - Ana Moreno-Álvarez
- Departamento de Bioquímica, Clínica Universidad de Navarra, Pamplona, España
| | | | - Antonio Buño-Soto
- Departamento de Análisis Clínicos, Hospital Universitario La Paz, Madrid, España
- Instituto de investigación en salud del Hospital La (IdiPaz), Madrid, España
| | - Álvaro González
- Departamento de Bioquímica, Clínica Universidad de Navarra, Pamplona, España
- Instituto Navarro de investigación en salud (IdiSNA), Pamplona, España
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Kong F, Dong R, Chen G, Sun S, Yang Y, Jiang J, Meng L, Chen H, Zhu J, Zheng S. Progress in Biomarkers Related to Biliary Atresia. J Clin Transl Hepatol 2024; 12:305-315. [PMID: 38426193 PMCID: PMC10899875 DOI: 10.14218/jcth.2023.00260] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2023] [Revised: 12/12/2023] [Accepted: 01/02/2024] [Indexed: 03/02/2024] Open
Abstract
Biliary atresia (BA) is a congenital cholestatic disease that can seriously damage children's liver function. It is one of the main reasons for liver transplantation in children. Early diagnosis of BA is crucial to the prognosis of patients, but there is still a lack of reliable non-invasive diagnostic methods. Additionally, as some children are in urgent need of liver transplantation, evaluating the stage of liver fibrosis and postoperative native liver survival in children with BA using a straightforward, efficient, and less traumatic method is a major focus of doctors. In recent years, an increasing number of BA-related biomarkers have been identified and have shown great potential in the following three aspects of clinical practice: diagnosis, evaluation of the stage of liver fibrosis, and prediction of native liver survival. This review focuses on the pathophysiological function and clinical application of three novel BA-related biomarkers, namely MMP-7, FGF-19, and M2BPGi. Furthermore, progress in well-known biomarkers of BA such as gamma-glutamyltransferase, circulating cytokines, and other potential biomarkers is discussed, aiming to provide a reference for clinical practice.
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Affiliation(s)
- Fanyang Kong
- Department of Pediatric Surgery, Children’s Hospital of Fudan University, Shanghai Key Laboratory of Birth Defect, and Key Laboratory of Neonatal Disease, Ministry of Health, Shanghai, China
| | - Rui Dong
- Department of Pediatric Surgery, Children’s Hospital of Fudan University, Shanghai Key Laboratory of Birth Defect, and Key Laboratory of Neonatal Disease, Ministry of Health, Shanghai, China
| | - Gong Chen
- Department of Pediatric Surgery, Children’s Hospital of Fudan University, Shanghai Key Laboratory of Birth Defect, and Key Laboratory of Neonatal Disease, Ministry of Health, Shanghai, China
| | - Song Sun
- Department of Pediatric Surgery, Children’s Hospital of Fudan University, Shanghai Key Laboratory of Birth Defect, and Key Laboratory of Neonatal Disease, Ministry of Health, Shanghai, China
| | - Yifan Yang
- Department of Pediatric Surgery, Children’s Hospital of Fudan University, Shanghai Key Laboratory of Birth Defect, and Key Laboratory of Neonatal Disease, Ministry of Health, Shanghai, China
| | - Jingying Jiang
- Department of Pediatric Surgery, Children’s Hospital of Fudan University, Shanghai Key Laboratory of Birth Defect, and Key Laboratory of Neonatal Disease, Ministry of Health, Shanghai, China
| | - Lingdu Meng
- Department of Pediatric Surgery, Children’s Hospital of Fudan University, Shanghai Key Laboratory of Birth Defect, and Key Laboratory of Neonatal Disease, Ministry of Health, Shanghai, China
| | - Huifen Chen
- Department of Pediatric Surgery, Children’s Hospital of Fudan University, Shanghai Key Laboratory of Birth Defect, and Key Laboratory of Neonatal Disease, Ministry of Health, Shanghai, China
| | - Jiajie Zhu
- Department of Pediatric Surgery, Children’s Hospital of Fudan University, Shanghai Key Laboratory of Birth Defect, and Key Laboratory of Neonatal Disease, Ministry of Health, Shanghai, China
| | - Shan Zheng
- Department of Pediatric Surgery, Children’s Hospital of Fudan University, Shanghai Key Laboratory of Birth Defect, and Key Laboratory of Neonatal Disease, Ministry of Health, Shanghai, China
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Bui HH, Nguyen STB, Phan ST, Nguyen KM, Nguyen CD. Evaluating M2BPGi as a Marker for Liver Fibrosis in Patients with Chronic Hepatitis B. Dig Dis Sci 2023; 68:4407-4417. [PMID: 37861877 PMCID: PMC10635958 DOI: 10.1007/s10620-023-08143-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2023] [Accepted: 10/02/2023] [Indexed: 10/21/2023]
Abstract
BACKGROUND The accurate evaluation of liver fibrosis is crucial for the treatment and follow up of chronic hepatitis B (CHB) patients. AIM We examined the efficiency of serum Mac-2 Binding Protein Glycosylation isomer (M2BPGi) in diagnosing liver fibrosis stages in CHB patients. METHODS A cross-sectional study was conducted on 177 adult CHB patients visiting the University Medical Center Ho Chi Minh City, Vietnam between October 2019 and December 2021. M2BPGi, ARFI, APRI, and FIB-4 were tested against FibroScan® for sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). The optimal M2BPGi cut-off values were identified based on the area under the receiver operating characteristic (AUROC) curve. RESULTS There was a strong agreement between M2BPGi and FibroScan® (r = 0.77, P < 0.001). The optimal M2BPGi cut-off index (C.O.I) for detecting significant fibrosis (F ≥ 2) was 0.79 with an AUROC of 0.77, 67.3% sensitivity, 70% specificity, 60.6% NPV, and 75.3% PPV. Compared with APRI (61%) and FIB-4 (47%), M2BPGi had the greatest sensitivity for diagnosing F ≥ 2. M2BPGi combined with APRI yielded highest diagnosis performance for F ≥ 2 with an AUROC of 0.87. The optimal cut-off index of M2BPGi for diagnosing cirrhosis (F4) was 1.3 with an AUROC of 0.91, 88% sensitivity, 87.4% specificity, 97% NPV, and 61% PPV. The AUROC of M2BPGi for diagnosing F4 was comparable to that of ARFI (0.93). CONCLUSIONS With cut-off values of 0.79 C.O.I and 1.3 C.O.I, M2BPGi could be an effective method for diagnosing significant fibrosis and cirrhosis in CHB patients, respectively.
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Affiliation(s)
- Hoang Huu Bui
- Department of Gastroenterology, University Medical Center Ho Chi Minh City, 215 Hong Bang Street, Ward 11, District 5, Ho Chi Minh City, 70000, Vietnam
- Department of Internal Medicine, University of Medicine and Pharmacy, Ho Chi Minh City, Vietnam
| | - Suong Thi-Bang Nguyen
- Department of Clinical Laboratory, University Medical Center Ho Chi Minh City, 215 Hong Bang Street, Ward 11, District 5, Ho Chi Minh City, 70000, Vietnam
- Department of Biochemistry, University of Medicine and Pharmacy, Ho Chi Minh City, Vietnam
| | - Sang The Phan
- Department of Gastroenterology, University Medical Center Ho Chi Minh City, 215 Hong Bang Street, Ward 11, District 5, Ho Chi Minh City, 70000, Vietnam
| | - Khue Minh Nguyen
- Vietnam National University, 227 Nguyen Van Cu Street, District 5, Ho Chi Minh City, 700000, Vietnam
| | - Chuong Dinh Nguyen
- Department of Gastroenterology, University Medical Center Ho Chi Minh City, 215 Hong Bang Street, Ward 11, District 5, Ho Chi Minh City, 70000, Vietnam.
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9
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Chen H, Shen Y, Wu SD, Zhu Q, Weng CZ, Zhang J, Wang MX, Jiang W. Diagnostic role of transient elastography in patients with autoimmune liver diseases: A systematic review and meta-analysis. World J Gastroenterol 2023; 29:5503-5525. [PMID: 37900994 PMCID: PMC10600811 DOI: 10.3748/wjg.v29.i39.5503] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/02/2023] [Revised: 09/09/2023] [Accepted: 10/11/2023] [Indexed: 10/19/2023] Open
Abstract
BACKGROUND Noninvasive methods have been developed to detect fibrosis in many liver diseases due to the limits of liver biopsy. However, previous studies have focused primarily on chronic viral hepatitis and nonalcoholic fatty liver disease. The diagnostic value of transient elastography for autoimmune liver diseases (AILDs) is worth studying. AIM To compare the diagnostic accuracy of imaging techniques with serum biomarkers of fibrosis in AILD. METHODS The PubMed, Cochrane Library and EMBASE databases were searched. Studies evaluating the efficacy of noninvasive methods in the diagnosis of AILDs [autoimmune hepatitis (AIH), primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC)] were included. The summary area under the receiver operating characteristic curve (AUROC), diagnostic odds ratio, sensitivity and specificity were used to assess the accuracy of these noninvasive methods for staging fibrosis. RESULTS A total of 60 articles were included in this study, and the number of patients with AIH, PBC and PSC was 1594, 3126 and 501, respectively. The summary AUROC of transient elastography in the diagnosis of significant fibrosis, advanced fibrosis and cirrhosis in patients with AIH were 0.84, 0.88 and 0.90, respectively, while those in patients with PBC were 0.93, 0.93 and 0.91, respectively. The AUROC of cirrhosis for patients with PSC was 0.95. However, other noninvasive indices (aspartate aminotransferase to platelet ratio index, aspartate aminotransferase/alanine aminotransferase ratio, fibrosis-4 index) had corresponding AUROCs less than 0.80. CONCLUSION Transient elastography exerts better diagnostic accuracy in AILD patients, especially in PBC patients. The appropriate cutoff values for staging advanced fibrosis and cirrhosis ranged from 9.6 to 10.7 and 14.4 to 16.9 KPa for PBC patients.
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Affiliation(s)
- Hong Chen
- Department of Gastroenterology and Hepatology, Zhongshan Hospital (Xiamen), Fudan University, Xiamen 361015, Fujian Province, China
- Department of Gastroenterology and Hepatology, Zhongshan Hospital of Fudan University, Shanghai 200032, China
- Shanghai Institute of Liver Diseases, Fudan University Shanghai Medical College, Shanghai 200032, China
| | - Yue Shen
- Department of Gastroenterology and Hepatology, Zhongshan Hospital of Fudan University, Shanghai 200032, China
- Shanghai Institute of Liver Diseases, Fudan University Shanghai Medical College, Shanghai 200032, China
| | - Sheng-Di Wu
- Department of Gastroenterology and Hepatology, Zhongshan Hospital (Xiamen), Fudan University, Xiamen 361015, Fujian Province, China
- Department of Gastroenterology and Hepatology, Zhongshan Hospital of Fudan University, Shanghai 200032, China
- Shanghai Institute of Liver Diseases, Fudan University Shanghai Medical College, Shanghai 200032, China
| | - Qin Zhu
- Department of Gastroenterology and Hepatology, Zhongshan Hospital of Fudan University, Shanghai 200032, China
- Shanghai Institute of Liver Diseases, Fudan University Shanghai Medical College, Shanghai 200032, China
| | - Cheng-Zhao Weng
- Department of Gastroenterology and Hepatology, Zhongshan Hospital (Xiamen), Fudan University, Xiamen 361015, Fujian Province, China
| | - Jun Zhang
- Department of Gastroenterology and Hepatology, Zhongshan Hospital (Xiamen), Fudan University, Xiamen 361015, Fujian Province, China
| | - Mei-Xia Wang
- Department of Gastroenterology and Hepatology, Zhongshan Hospital (Xiamen), Fudan University, Xiamen 361015, Fujian Province, China
| | - Wei Jiang
- Department of Gastroenterology and Hepatology, Zhongshan Hospital (Xiamen), Fudan University, Xiamen 361015, Fujian Province, China
- Department of Gastroenterology and Hepatology, Zhongshan Hospital of Fudan University, Shanghai 200032, China
- Shanghai Institute of Liver Diseases, Fudan University Shanghai Medical College, Shanghai 200032, China
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10
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Sulaiman AS, Hasan I, Hustrini NM, Lydia A, Hanifa RS, Gani RA. Diagnostic performance of Mac-2-binding protein glycosylation isomer (M2BPGi) as a liver fibrosis marker in chronic hepatitis C patients with chronic kidney disease on hemodialysis. Clin Exp Nephrol 2023; 27:557-564. [PMID: 36995542 DOI: 10.1007/s10157-023-02319-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2022] [Accepted: 01/16/2023] [Indexed: 03/31/2023]
Abstract
BACKGROUND/AIM Liver fibrosis assessment is essential to determine the initiation, duration, and evaluation of chronic hepatitis C treatment. Therefore, the study aimed to assess the role of Mac-2-binding protein glycosylation isomer (M2BPGi) as a biomarker to measure liver fibrosis in chronic hepatitis C patients with chronic kidney disease on hemodialysis. METHODS This study used a cross-sectional design. Serum M2BPGi level and transient elastography results were evaluated in 102 chronic hepatitis C patients with CKD on HD, 36 CKD on HD patients, and 48 healthy controls. ROC analysis was conducted to identify the optimal cutoff values to assess significant fibrosis and cirrhosis among chronic hepatitis C patients with CKD on HD. RESULTS In chronic hepatitis C patients with CKD on HD, the level of serum M2BPGi had a moderately significant correlation with transient elastography (r = 0.447, p < 0.001). The median serum M2BPGi was higher among CKD on HD patients compared to healthy controls (1.260 COI vs. 0.590 COI, p < 0.001) and was even higher in chronic hepatitis C patients with CKD on HD compared to CKD on HD group (2.190 COI vs. 1.260 COI, p < 0.001). It is also increased according to the severity of liver fibrosis: 1.670 COI, 2.020 COI, and 5.065 COI for F0-F1, significant fibrosis, and cirrhosis, respectively. The optimal cutoff values for diagnosing significant fibrosis and cirrhosis were 2.080 and 2.475 COI, respectively. CONCLUSION Serum M2BPGi could be a simple and reliable diagnostic tool for evaluating cirrhosis in chronic hepatitis C patients with CKD on HD.
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Affiliation(s)
- Andri Sanityoso Sulaiman
- Hepatobiliary Division, Department of Internal Medicine, Faculty of Medicine, Universitas Indonesia, Dr. Cipto Mangunkusumo National General Hospital, Jakarta, Indonesia.
| | - Irsan Hasan
- Hepatobiliary Division, Department of Internal Medicine, Faculty of Medicine, Universitas Indonesia, Dr. Cipto Mangunkusumo National General Hospital, Jakarta, Indonesia
| | - Ni Made Hustrini
- Nephrology and Hypertension Division, Department of Internal Medicine, Faculty of Medicine, Universitas Indonesia, Dr. Cipto Mangunkusumo National General Hospital, Jakarta, Indonesia
| | - Aida Lydia
- Nephrology and Hypertension Division, Department of Internal Medicine, Faculty of Medicine, Universitas Indonesia, Dr. Cipto Mangunkusumo National General Hospital, Jakarta, Indonesia
| | - Rachmadianti Sukma Hanifa
- Hepatobiliary Division, Department of Internal Medicine, Faculty of Medicine, Universitas Indonesia, Dr. Cipto Mangunkusumo National General Hospital, Jakarta, Indonesia
| | - Rino Alvani Gani
- Hepatobiliary Division, Department of Internal Medicine, Faculty of Medicine, Universitas Indonesia, Dr. Cipto Mangunkusumo National General Hospital, Jakarta, Indonesia
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11
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Early detection of liver fibrosis with serum Mac-2 binding protein glycosylation-modified isomer (M2BPGi) during follow-up intestinal failure patients without intestinal failure-associated liver disease (IFALD). Pediatr Surg Int 2022; 38:1807-1813. [PMID: 36125546 DOI: 10.1007/s00383-022-05240-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 09/09/2022] [Indexed: 10/14/2022]
Abstract
PURPOSE Mac-2 binding protein glycosylation-modified isomer (M2BPGi) is a new marker for hepatic fibrosis progression. We examined the relationship between serum M2BPGi levels and liver histological findings in intestinal failure (IF) patients without IF-associated liver disease (IFALD). METHODS This study included IF patients without IFALD followed at our hospital. All patients underwent routine liver biopsies per protocol every 1-2 years. We examined M2BPGi levels and histological findings in relation to aspartate aminotransferase (AST) to platelet ratio index, fibrosis-4 index, and AST/ALT ratio. Liver fibrosis was evaluated based on the METAVIR score. RESULTS Total 18 liver biopsies out of eight patients were included. The median age was 11.5 years. Mean M2BPGi was 0.44 cutoff index (COI) in patients with F0 fibrosis, 0.78 COI in patients with F1 fibrosis and 1.63 COI in patients with F2 fibrosis. Mean M2BPGi was significantly higher in patients with F2 versus F1 or F0 fibrosis (P < 0.016 and P < 0.028, respectively). M2BPGi levels were more strongly correlated with fibrosis stage than with other conventional fibrosis markers. CONCLUSION Serum M2BPGi is a novel marker of liver fibrosis in patients with IF. It is useful for follow-up prior to IFALD. Serum M2BPGi levels can support the interpretation of liver status.
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12
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Park HJ, Seo KI, Lee SU, Han BH, Yun BC, Park ET, Lee J, Hwang H, Yoon M. Clinical usefulness of Mac-2 binding protein glycosylation isomer for diagnosing liver cirrhosis and significant fibrosis in patients with chronic liver disease: A retrospective single-center study. Medicine (Baltimore) 2022; 101:e30489. [PMID: 36221351 PMCID: PMC9542736 DOI: 10.1097/md.0000000000030489] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Accurate diagnosis of liver cirrhosis (LC) and significant fibrosis in patients with chronic liver disease (CLD) is important. The Mac-2 binding protein glycosylation isomer (M2BPGi) has emerged as a novel serum biomarker for liver fibrosis; however, insufficient clinical data of M2BPGi are available in patients with CLD. Therefore, we performed a retrospective cohort study to investigate the clinical usefulness of serum M2BPGi for assessing LC and significant fibrosis in CLD patients. We retrospectively reviewed the CLD patients with measured serum M2BPGi at Kosin University Gospel Hospital between January 2016 and December 2019. Multivariate logistic regression analyses were conducted to identify the independent factors associated with LC. The diagnostic power of serum M2BPGi for LC and significant fibrosis (≥F2) was evaluated and compared to that of other serum biomarkers using receiver operating characteristic curve and area under the curve (AUC). A total of 454 patients enrolled in this study. M2BPGi (adjusted odds ratio [aOR], 1.77; 95% confidence interval [CI], 1.52-2.07) and fibrosis index based on four factors (aOR, 1.23; 95% CI, 1.11-1.37) were identified as significant independent factors for LC. The AUC of M2BPGi for LC (0.866) and significant fibrosis (0.816) were comparable to those of fibrosis index based on four factors (0.860, 0.773), aspartate aminotransferase-to-platelet ratio index (0.806, 0.752), and gamma-glutamyl transpeptidase-to-platelet ratio (0.759, 0.710). The optimal cut-off values for M2BPGi for LC and significant fibrosis were 1.37 and 0.89, respectively. Serum M2BPGi levels were significantly correlated with liver stiffness measurements (ρ = 0.778). Serum M2BPGi is a reliable noninvasive method for the assessment of LC and significant fibrosis in patients with CLD.
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Affiliation(s)
- Hyun Joon Park
- Department of Internal Medicine, Kosin University College of Medicine, Busan, South Korea
- Chang Kee-Ryo Memorial Liver Institute, Kosin University College of Medicine, Busan, South Korea
| | - Kwang Il Seo
- Department of Internal Medicine, Kosin University College of Medicine, Busan, South Korea
- Chang Kee-Ryo Memorial Liver Institute, Kosin University College of Medicine, Busan, South Korea
- *Correspondence: Kwang Il Seo, MD, PhD, Department of Internal Medicine, Kosin University College of Medicine, 262 Gamcheon-ro, Seo-gu, Busan, 49267, South Korea. (e-mail: )
| | - Sang Uk Lee
- Department of Internal Medicine, Kosin University College of Medicine, Busan, South Korea
- Chang Kee-Ryo Memorial Liver Institute, Kosin University College of Medicine, Busan, South Korea
| | - Byung Hoon Han
- Department of Internal Medicine, Kosin University College of Medicine, Busan, South Korea
- Chang Kee-Ryo Memorial Liver Institute, Kosin University College of Medicine, Busan, South Korea
| | - Byung Cheol Yun
- Department of Internal Medicine, Kosin University College of Medicine, Busan, South Korea
- Chang Kee-Ryo Memorial Liver Institute, Kosin University College of Medicine, Busan, South Korea
| | - Eun Taek Park
- Department of Internal Medicine, Kosin University College of Medicine, Busan, South Korea
- Chang Kee-Ryo Memorial Liver Institute, Kosin University College of Medicine, Busan, South Korea
| | - Jinwook Lee
- Department of Internal Medicine, Kosin University College of Medicine, Busan, South Korea
- Chang Kee-Ryo Memorial Liver Institute, Kosin University College of Medicine, Busan, South Korea
| | - Hyunyong Hwang
- Department of Laboratory Medicine, Kosin University College of Medicine, Busan, South Korea
| | - Myunghee Yoon
- Division of Hepatobiliary and Pancreas Surgery, Department of Surgery Biomedical Research Institute, Pusan National University, College of Medicine, Busan, South Korea
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13
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Mechref Y, Peng W, Gautam S, Ahmadi P, Lin Y, Zhu J, Zhang J, Liu S, Singal AG, Parikh ND, Lubman DM. Mass spectrometry based biomarkers for early detection of HCC using a glycoproteomic approach. Adv Cancer Res 2022; 157:23-56. [PMID: 36725111 PMCID: PMC10014290 DOI: 10.1016/bs.acr.2022.07.005] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Hepatocellular carcinoma (HCC) is the fourth most common cause of cancer-related mortality worldwide and 80%-90% of HCC develops in patients that have underlying cirrhosis. Better methods of surveillance are needed to increase early detection of HCC and the proportion of patients that can be offered curative therapies. Recent work in novel mass spec-based methods for glycomic and glycopeptide analysis for discovery and confirmation of markers for early detection of HCC versus cirrhosis is reviewed in this chapter. Results from recent work in these fields by several groups and the progress made in developing markers of early HCC which can outperform the current serum-based markers are described and discussed. Also, recent developments in isoform analysis of glycans and glycopeptides and in various mass spec fragmentation methods will be described and discussed.
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Affiliation(s)
- Yehia Mechref
- Department of Chemistry and Biochemistry, Texas Tech University, Lubbock, TX, United States.
| | - Wenjing Peng
- Department of Chemistry and Biochemistry, Texas Tech University, Lubbock, TX, United States
| | - Sakshi Gautam
- Department of Chemistry and Biochemistry, Texas Tech University, Lubbock, TX, United States
| | - Parisa Ahmadi
- Department of Chemistry and Biochemistry, Texas Tech University, Lubbock, TX, United States
| | - Yu Lin
- Department of Surgery, University of Michigan Medical Center, Ann Arbor, MI, United States
| | - Jianhui Zhu
- Department of Surgery, University of Michigan Medical Center, Ann Arbor, MI, United States
| | - Jie Zhang
- Department of Surgery, University of Michigan Medical Center, Ann Arbor, MI, United States
| | - Suyu Liu
- Department of Biostatistics, University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Amit G Singal
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, United States
| | - Neehar D Parikh
- Division of Gastroenterology and Hepatology, University of Michigan Medical Center, Ann Arbor, MI, United States
| | - David M Lubman
- Department of Surgery, University of Michigan Medical Center, Ann Arbor, MI, United States.
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14
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Nakai M, Morikawa K, Hosoda S, Yoshida S, Kubo A, Tokuchi Y, Kitagataya T, Yamada R, Ohara M, Sho T, Suda G, Ogawa K, Sakamoto N. Pre-sarcopenia and Mac-2 binding protein glycosylation isomer as predictors of recurrence and prognosis of early-stage hepatocellular carcinoma. World J Hepatol 2022; 14:1480-1494. [PMID: 36158914 PMCID: PMC9376769 DOI: 10.4254/wjh.v14.i7.1480] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2022] [Revised: 04/20/2022] [Accepted: 06/26/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND The Mac-2 binding protein glycosylation isomer (M2BPGi), a fibrosis marker in various liver diseases, is reportedly a prognostic marker in patients with hepatocellular carcinoma (HCC) who underwent hepatectomy.
AIM To evaluate whether the M2BPGi value, M2BP, and pre-sarcopenia before radiofrequency ablation (RFA) could be useful recurrence and prognostic markers in patients with early-stage HCC.
METHODS In total, 160 patients with early-stage primary HCC treated with RFA were separately analyzed as hepatitis C virus (HCV)-positive and HCV-negative. Factors contributing to recurrence and liver-related death, including M2BP, M2BPGi, and skeletal muscle mass index, were statistically analyzed. Eighty-three patients were HCV-positive and 77 were HCV-negative.
RESULTS In HCV-positive patients, only des-γ-carboxy-prothrombin ≥ 23 mAU/mL was a significant poor prognostic factor affecting survival after RFA. In HCV-negative patients, M2BPGi ≥ 1.86 cutoff index was significantly associated with tumor recurrence, while M2BP was not. M2BPGi ≥ 1.86 cutoff index (hazard ratio, 4.89; 95% confidence interval: 1.97-12.18; P < 0.001) and pre-sarcopenia (hazard ratio, 3.34, 95% confidence interval: 1.19-9.37; P = 0.022) were independent significant poor prognostic factors in HCV-negative patients.
CONCLUSION In HCV-negative patients with primary HCC treated with RFA, lower M2BPGi contributed to a lower tumor recurrence rate and longer survival period. Pre-sarcopenia contributed to the poor prognosis independently in HCV-negative patients. These factors might be useful recurrence and prognostic markers for early-stage primary HCC.
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Affiliation(s)
- Masato Nakai
- Department of Gastroenterology and Hepatology, Hokkaido University Faculty of Medicine and Graduate School of Medicine, Sapporo 060-8638, Japan
| | - Kenichi Morikawa
- Department of Gastroenterology and Hepatology, Hokkaido University Faculty of Medicine and Graduate School of Medicine, Sapporo 060-8638, Japan
| | - Shunichi Hosoda
- Department of Gastroenterology and Hepatology, Hokkaido University Faculty of Medicine and Graduate School of Medicine, Sapporo 060-8638, Japan
| | - Sonoe Yoshida
- Department of Gastroenterology and Hepatology, Hokkaido University Faculty of Medicine and Graduate School of Medicine, Sapporo 060-8638, Japan
| | - Akinori Kubo
- Department of Gastroenterology and Hepatology, Hokkaido University Faculty of Medicine and Graduate School of Medicine, Sapporo 060-8638, Japan
| | - Yoshimasa Tokuchi
- Department of Gastroenterology and Hepatology, Hokkaido University Faculty of Medicine and Graduate School of Medicine, Sapporo 060-8638, Japan
| | - Takashi Kitagataya
- Department of Gastroenterology and Hepatology, Hokkaido University Faculty of Medicine and Graduate School of Medicine, Sapporo 060-8638, Japan
| | - Ren Yamada
- Department of Gastroenterology and Hepatology, Hokkaido University Faculty of Medicine and Graduate School of Medicine, Sapporo 060-8638, Japan
| | - Masatsugu Ohara
- Department of Gastroenterology and Hepatology, Hokkaido University Faculty of Medicine and Graduate School of Medicine, Sapporo 060-8638, Japan
| | - Takuya Sho
- Department of Gastroenterology and Hepatology, Hokkaido University Faculty of Medicine and Graduate School of Medicine, Sapporo 060-8638, Japan
| | - Goki Suda
- Department of Gastroenterology and Hepatology, Hokkaido University Faculty of Medicine and Graduate School of Medicine, Sapporo 060-8638, Japan
| | - Koji Ogawa
- Department of Gastroenterology and Hepatology, Hokkaido University Faculty of Medicine and Graduate School of Medicine, Sapporo 060-8638, Japan
| | - Naoya Sakamoto
- Department of Gastroenterology and Hepatology, Hokkaido University Faculty of Medicine and Graduate School of Medicine, Sapporo 060-8638, Japan
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15
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Ohira H, Takahashi A, Zeniya M, Abe M, Arinaga-Hino T, Joshita S, Takaki A, Nakamoto N, Kang JH, Suzuki Y, Sogo T, Inui A, Koike K, Harada K, Nakamoto Y, Kondo Y, Genda T, Tsuneyama K, Matsui T, Tanaka A. Clinical practice guidelines for autoimmune hepatitis. Hepatol Res 2022; 52:571-585. [PMID: 35533021 DOI: 10.1111/hepr.13776] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2022] [Revised: 04/22/2022] [Accepted: 04/28/2022] [Indexed: 02/08/2023]
Affiliation(s)
- Hiromasa Ohira
- Department of Gastroenterology, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Atsushi Takahashi
- Department of Gastroenterology, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Mikio Zeniya
- Akasaka Sanno Medical Center, International University of Health and Welfare, Tokyo, Japan
| | - Masanori Abe
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Ehime, Japan
| | | | - Satoru Joshita
- Department of Medicine, Division of Gastroenterology and Hepatology, Shinshu University School of Medicine, Matsumoto, Japan
| | - Akinobu Takaki
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan
| | - Nobuhiro Nakamoto
- Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
| | - Jong-Hon Kang
- Center for Gastroenterology, Teine Keijinkai Hospital, Sapporo, Japan
| | | | - Tsuyosi Sogo
- 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
| | - Kazuhiko Koike
- Department of Gastroenterology and Hepatology, The Third Hospital of Jikei University School of Medicine, Tokyo, Japan
| | - Kenichi Harada
- Department of Human Pathology, Kanazawa University Graduate School of Medicine, Kanazawa, Japan
| | - Yasunari Nakamoto
- Second Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, Fukui, Japan
| | - Yasuteru Kondo
- Department of Hepatology, Sendai Kousei Hospital, Sendai, Japan
| | - Takuya Genda
- Department of Gastroenterology and Hepatology, Juntendo University Shizuoka Hospital, Izunokuni, Japan
| | - Koichi Tsuneyama
- Department of Pathology and Laboratory Medicine, Institute of Biomedical Sciences, Tokushima University Graduate School, Takushima, Japan
| | - Tsuyoshi Matsui
- Center for Gastroenterology, Teine Keijinkai Hospital, Sapporo, Japan
| | - Atsushi Tanaka
- Department of Medicine, Teikyo University School of Medicine, Tokyo, Japan
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16
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Dong B, Chen Y, Lyu G, Yang X. Aspartate Aminotransferase to Platelet Ratio Index and Fibrosis-4 Index for Detecting Liver Fibrosis in Patients With Autoimmune Hepatitis: A Meta-Analysis. Front Immunol 2022; 13:892454. [PMID: 35663945 PMCID: PMC9157437 DOI: 10.3389/fimmu.2022.892454] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2022] [Accepted: 04/21/2022] [Indexed: 11/13/2022] Open
Abstract
Background Aspartate aminotransferase-to-platelet ratio index (APRI) and fibrosis-4 index (FIB-4) are the two most widely studied noninvasive markers of liver fibrosis. We aimed to assess the diagnostic accuracy of APRI and FIB-4 for liver fibrosis in patients with autoimmune hepatitis (AIH) using liver biopsy as the reference standard. Methods PubMed, EMBASE, Cochrane Library and Web of Science databases were searched for studies (published as of May 1st, 2021) that assessed the diagnostic performance of APRI and FIB-4 for liver fibrosis in AIH. The summary area under receiver operating characteristics curve (AUROC), sensitivity, specificity, diagnostic odds ratios were used to assess the diagnostic accuracy of APRI and FIB-4 for detecting liver fibrosis. Results Fourteen studies (including 1015 patients) were selected with 13 studies each evaluating the use of APRI and FIB-4 for detecting different stages of fibrosis in AIH. For prediction of significant fibrosis, advanced fibrosis, and cirrhosis, the summary AUROC value was 0.66 [95% confidence interval (CI): 0.61-0.70], 0.71 (95% CI: 0.67-0.75), and 0.75 (95% CI: 0.71-0.79) for APRI, and the summary AUROC value was 0.75 (95% CI: 0.71-0.79), 0.73 (95% CI: 0.69-0.77) and 0.79 (95% CI: 0.75-0.82) for FIB-4, respectively. The summary sensitivity and specificity for diagnosis of significant fibrosis, advanced fibrosis, and cirrhosis were 90% and 36%, 78% and 55%, and 77% and 61% for APRI, and 70% and 70%, 65% and 70%, and 78% and 65% for FIB-4, respectively. Conclusions APRI and FIB-4 showed suboptimal diagnostic performance for identifying liver fibrosis in AIH with mediocre sensitivity and specificity.
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Affiliation(s)
- Bingtian Dong
- Department of Ultrasound, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, China
| | - Yuping Chen
- Department of Endocrinology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, China
| | - Guorong Lyu
- Department of Ultrasound, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, China.,Department of Clinical Medicine, Quanzhou Medical College, Quanzhou, China
| | - Xiaocen Yang
- Department of Ultrasound, Chenggong Hospital, Xiamen University, Xiamen, China
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17
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Hu M, You Z, Li Y, Huang B, Cui N, Wang R, Wei Y, Li B, Liang J, Liu Q, Li Y, Wang H, Qian Q, Zhang J, Chen R, Lyu Z, Chen Y, Xiao X, Lian M, Tang R, Miao Q, Wang Q, Ma X. Serum Biomarkers for Autoimmune Hepatitis Type 1: the Case for CD48 and a Review of the Literature. Clin Rev Allergy Immunol 2022; 63:342-356. [PMID: 35657576 DOI: 10.1007/s12016-022-08935-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/10/2022] [Indexed: 11/25/2022]
Abstract
In autoimmune hepatitis (AIH), the persisting inflammation contributes to fibrosis progression, for which conventional biochemical markers manifest relatively unsatisfactory prediction. Herein, we assessed the value of serum CD48 (sCD48) as an indicator for inflammation and fibrosis in AIH type 1. The levels of sCD48 were detected first in an exploratory cohort using ELISA. In this cohort, compared with healthy controls (4.90 ng/mL, P < 0.0001), primary biliary cholangitis (7.32 ng/mL, P < 0.0001), and non-alcoholic fatty liver disease (7.76 ng/mL, P < 0.0001), sCD48 levels were elevated in AIH (12.81 ng/mL) and correlated with histological inflammation and fibrosis. Further using multivariate logistic regression analysis, sCD48 was identified as an independent predictor for both significant inflammation (G3-4) and advanced fibrosis (S3-4). Two predictive scores, based on sCD48, were constructed for diagnosing significant inflammation and advanced fibrosis (sCD48-AIH-SI and sCD48-AIH-AF, respectively). Using these data as a premise, predictive abilities were subsequently evaluated and verified in a validation cohort. In the exploratory cohort, the area under the receiver operating characteristic curve of sCD48 and sCD48-AIH-SI, for significant inflammation, were 0.748 and 0.813, respectively. Besides, during treatment follow-up, sCD48 levels gradually decreased from immunosuppression initiation to re-evaluation biopsy, in parallel with aspartate transaminase, total sera IgG, and fibrosis-4 score. For AIH patients in a re-evaluation biopsy cohort, sCD48 could predict significant fibrosis (S2-4). Further using immunohistochemistry, hepatic CD48 expression was elevated in AIH patients and decreased after treatment. In conclusion, sCD48 and sCD48-based predictive scores predict histological inflammation and fibrosis in AIH-1. Detecting sCD48 might help in the clinical management of AIH.
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Affiliation(s)
- Mingli Hu
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, 145 Middle Shandong Road, Shanghai, 200001, China
| | - Zhengrui You
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, 145 Middle Shandong Road, Shanghai, 200001, China
| | - You Li
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, 145 Middle Shandong Road, Shanghai, 200001, China
| | - Bingyuan Huang
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, 145 Middle Shandong Road, Shanghai, 200001, China
| | - Nana Cui
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, 145 Middle Shandong Road, Shanghai, 200001, China
| | - Rui Wang
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, 145 Middle Shandong Road, Shanghai, 200001, China
| | - Yiran Wei
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, 145 Middle Shandong Road, Shanghai, 200001, China
| | - Bo Li
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, 145 Middle Shandong Road, Shanghai, 200001, China
| | - Jubo Liang
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, 145 Middle Shandong Road, Shanghai, 200001, China
| | - Qiaoyan Liu
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, 145 Middle Shandong Road, Shanghai, 200001, China
| | - Yikang Li
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, 145 Middle Shandong Road, Shanghai, 200001, China
| | - Hanxiao Wang
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, 145 Middle Shandong Road, Shanghai, 200001, China
| | - Qiwei Qian
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, 145 Middle Shandong Road, Shanghai, 200001, China
| | - Jun Zhang
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, 145 Middle Shandong Road, Shanghai, 200001, China
| | - Ruiling Chen
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, 145 Middle Shandong Road, Shanghai, 200001, China
| | - Zhuwan Lyu
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, 145 Middle Shandong Road, Shanghai, 200001, China
| | - Yong Chen
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, 145 Middle Shandong Road, Shanghai, 200001, China
| | - Xiao Xiao
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, 145 Middle Shandong Road, Shanghai, 200001, China
| | - Min Lian
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, 145 Middle Shandong Road, Shanghai, 200001, China
| | - Ruqi Tang
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, 145 Middle Shandong Road, Shanghai, 200001, China
| | - Qi Miao
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, 145 Middle Shandong Road, Shanghai, 200001, China.
| | - Qixia Wang
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, 145 Middle Shandong Road, Shanghai, 200001, China.
| | - Xiong Ma
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, 145 Middle Shandong Road, Shanghai, 200001, China.
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18
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Ustaoglu M, Aktas G, Avcioglu U, Bas B, Bahceci BK. Elevated platelet distribution width and red cell distribution width are associated with autoimmune liver diseases. Eur J Gastroenterol Hepatol 2021; 33:e905-e908. [PMID: 34643621 DOI: 10.1097/meg.0000000000002296] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/10/2022]
Abstract
OBJECTIVE Red blood cell distribution width (RDW) and platelet distribution width (PDW) are reported to be associated with inflammation. We aimed to determine the association between RDW and PDW with autoimmune liver disease (ALD). MATERIAL AND METHODS We retrospectively analyzed 126 patients who were diagnosed with ALD. Sixty-nine healthy individuals represented the control group. Characteristics and laboratory parameters of the ALD patients and control subjects were compared. RESULTS The aspartate transaminase (AST) (P < 0.001), alanine transaminase (ALT) (P < 0.001), C-reactive protein (CRP) (P < 0.001), RDW (P < 0.001) and PDW (P < 0.001) levels of the ALD group were significantly higher than those of the control subjects. RDW was significantly correlated with AST (r = 0.17, P = 0.02) and CRP (r = 0.19, P = 0.01) levels. Moreover, PDW was significantly correlated with AST (r = 0.23, P = 0.002), ALT (r = 0.23, P = 0.001) and CRP (r = 0.23, P = 0.001) levels. The sensitivity and specificity of RDW higher than 13.7% level were 76% and 62%, respectively [AUC: 0.74, P < 0.001, 95% confidence interval (CI): 0.67-0.81]. The sensitivity and specificity of PDW higher than 17.9% level were 80% and 71%, respectively (AUC: 0.85, P < 0.001, 95% CI: 0.79-0.90). The sensitivity and specificity of CRP higher than 2.9 U/l level were 92% and 85%, respectively (AUC: 0.91, P < 0.001, 95% CI: 0.86-0.95). CONCLUSION Our study demonstrates that RDW and PDW have considerable sensitivity and specificity in determining ALD.
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Affiliation(s)
- Muge Ustaoglu
- Department of Gastroenterology, Faculty of Medicine, Ondokuz Mayis University, Samsun
| | - Gulali Aktas
- Department of Internal Medicine, Faculty of Medicine, Abant Izzet Baysal University, Bolu
| | - Ufuk Avcioglu
- Department of Gastroenterology, Faculty of Medicine, Ondokuz Mayis University, Samsun
| | - Berk Bas
- Department of Gastroenterology, Faculty of Medicine, Ondokuz Mayis University, Samsun
| | - Bugra Kaan Bahceci
- Department of Internal Medicine, Ondokuz Mayis University, Faculty of Medicine, Samsun, Turkey
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19
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Jang SY, Tak WY, Park SY, Kweon YO, Lee YR, Kim G, Hur K, Han MH, Lee WK. Diagnostic Efficacy of Serum Mac-2 Binding Protein Glycosylation Isomer and Other Markers for Liver Fibrosis in Non-Alcoholic Fatty Liver Diseases. Ann Lab Med 2021; 41:302-309. [PMID: 33303715 PMCID: PMC7748098 DOI: 10.3343/alm.2021.41.3.302] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2020] [Revised: 07/23/2020] [Accepted: 11/30/2020] [Indexed: 02/07/2023] Open
Abstract
Background Mac-2 binding protein glycosylation isomer (M2BPGi) has been established as a non-invasive biomarker for liver fibrosis. We evaluated the diagnostic efficacy of M2BPGi compared with those of other liver fibrosis markers in liver fibrosis in non-alcoholic fatty liver disease (NAFLD). Methods We analyzed serum M2BPGi levels in 113 NAFLD patients. A pathologist graded liver fibrosis histopathologically. The diagnostic efficacies of serum M2BPGi and other liver fibrosis markers (aspartate aminotransferase to platelet ratio index, fibrosis index based on four factors, and NAFLD fibrosis score [NFS]) were evaluated using correlation, area under the ROC curve (AUC), logistic regression, and C-statistics. Results Serum M2BPGi level and other liver fibrosis markers showed a moderate correlation with fibrosis grade. The AUC values of M2BPGi were 0.761, 0.819, 0.866, and 0.900 for diagnosing fibrosis (F)>0, F>1, F>2, and F>3, respectively. Logistic regression analysis showed M2BPGi as the only independent factor associated with F>2 and F>3. Although C-statistics showed that NFS was the best diagnostic factor for F>2 and F>3, M2BPGi with NFS had an increased C-statistics value, indicating that it is a better diagnostic model. Conclusions The serum M2BPGi level increased with liver fibrosis severity and could be a good biomarker for diagnosing advanced fibrosis and cirrhosis in NAFLD patients. A well-controlled, prospective study with a larger sample size is needed to validate the diagnostic power of M2BPGi and other fibrosis markers in NAFLD.
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Affiliation(s)
- Se Young Jang
- Department of Internal Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu, Korea
| | - Won Young Tak
- Department of Internal Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu, Korea
| | - Soo Young Park
- Department of Internal Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu, Korea
| | - Young-Oh Kweon
- Department of Internal Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu, Korea
| | - Yu Rim Lee
- Department of Internal Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu, Korea
| | - Gyeonghwa Kim
- Department of Biochemistry and Cell Biology, Cell and Matrix Research Institute, School of Medicine, Kyungpook National University, Daegu, Korea
| | - Keun Hur
- Department of Biochemistry and Cell Biology, Cell and Matrix Research Institute, School of Medicine, Kyungpook National University, Daegu, Korea
| | - Man-Hoon Han
- Department of Pathology, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu, Korea
| | - Won Kee Lee
- Department of Medical Informatics, School of Medicine, Kyungpook National University, Daegu, Korea
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20
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Berzigotti A, Tsochatzis E, Boursier J, Castera L, Cazzagon N, Friedrich-Rust M, Petta S, Thiele M. EASL Clinical Practice Guidelines on non-invasive tests for evaluation of liver disease severity and prognosis - 2021 update. J Hepatol 2021; 75:659-689. [PMID: 34166721 DOI: 10.1016/j.jhep.2021.05.025] [Citation(s) in RCA: 1007] [Impact Index Per Article: 251.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2021] [Accepted: 05/28/2021] [Indexed: 02/07/2023]
Abstract
Non-invasive tests are increasingly being used to improve the diagnosis and prognostication of chronic liver diseases across aetiologies. Herein, we provide the latest update to the EASL Clinical Practice Guidelines on the use of non-invasive tests for the evaluation of liver disease severity and prognosis, focusing on the topics for which relevant evidence has been published in the last 5 years.
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21
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The role of fibrosis index FIB-4 in predicting liver fibrosis stage and clinical prognosis: A diagnostic or screening tool? J Formos Med Assoc 2021; 121:454-466. [PMID: 34325952 DOI: 10.1016/j.jfma.2021.07.013] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2021] [Revised: 04/09/2021] [Accepted: 07/12/2021] [Indexed: 12/14/2022] Open
Abstract
This review evaluates the ability of the fibrosis index based on four factors (FIB-4) identifying fibrosis stages, long-time prognosis in chronic liver disease, and short-time outcomes in acute liver injury. FIB-4 was accurate in predicting the absence or presence of advanced fibrosis with cut-offs of 1.0 and 2.65 for viral hepatitis B, 1.45 and 3.25 for viral hepatitis C, 1.30 (<65 years), 2.0 (≥65 years), and 2.67 for non-alcoholic fatty liver disease (NAFLD), respectively, but had a low-to-moderate accuracy in alcoholic liver disease (ALD) and autoimmune hepatitis. It performed better in excluding fibrosis, so we built an algorithm for identifying advanced fibrosis by combined methods and giving work-up and follow-up suggestions. High FIB-4 in viral hepatitis, NAFLD, and ALD was associated with significantly high hepatocellular carcinoma incidence and mortality. Additionally, FIB-4 showed the ability to predict high-risk varices with cut-offs of 2.87 and 3.91 in cirrhosis patients and predict long-term survival in hepatocellular carcinoma patients after hepatectomy. In acute liver injury caused by COVID-19, FIB-4 had a predictive value for mechanical ventilation and 30-day mortality. Finally, FIB-4 may act as a screening tool in the secondary prevention of NAFLD in the high-risk population.
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22
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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.
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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
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23
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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.
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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
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24
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Seike T, Komura T, Shimizu Y, Omura H, Kumai T, Kagaya T, Ohta H, Kawashima A, Harada K, Kaneko S, Unoura M. The Serum Mac-2-binding Protein Glycosylation Isomer Dynamics in Acute Liver Injury. Intern Med 2020; 59:1581-1588. [PMID: 32269188 PMCID: PMC7402970 DOI: 10.2169/internalmedicine.3867-19] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/27/2023] Open
Abstract
Objective We aimed to examine the dynamics of serum Wisteria floribunda agglutinin-positive human Mac-2-binding protein glycosylation isomer (M2BPGi) in patients with acute liver injury. Methods Serum M2BPGi levels at the time of the diagnosis (n=77) and normalization of the serum alanine aminotransferase (ALT) level (n=26) were examined retrospectively. The difference in the serum M2BPGi level according to the etiology, and the correlations with other laboratory parameters were evaluated. Results The serum M2BPGi level at the time of the diagnosis was increased in 59 of 77 patients [2.3 cutoff index (COI); range, 0.31-11.1 COI] and was significantly decreased at the time of serum ALT normalization (0.68 COI; range, 0.15-1.87 COI; p<0.0001). The serum M2BPGi level was positively correlated with the duration for which serum ALT normalization was achieved (n=46, Spearman rho=0.53, p<0.0001). A multivariate analysis identified total bilirubin (T-bil), albumin, ALT, alkaline phosphatase, and etiology (e.g., drug-induced liver injury or etiology unknown) as independent factors for increased serum M2BPGi. In patients with infectious mononucleosis, the serum M2BPGi level was higher relative to the degree of increase of serum ALT or T-bil levels in comparison to other etiologies. Conclusion The serum M2BPGi level in patients with acute liver injury reflects the magnitude and duration of liver injury. However, it should be noted that the degree of increase of serum M2BPGi in patients with acute liver injury may differ according to the etiology.
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Affiliation(s)
- Takuya Seike
- Department of Gastroenterology, National Hospital Organization Kanazawa Medical Center, Japan
- System Biology, Graduate School of Advanced Preventive Medical Science, Kanazawa University, Japan
| | - Takuya Komura
- Department of Gastroenterology, National Hospital Organization Kanazawa Medical Center, Japan
| | - Yoshiaki Shimizu
- Department of Gastroenterology, National Hospital Organization Kanazawa Medical Center, Japan
| | - Hitoshi Omura
- Department of Gastroenterology, National Hospital Organization Kanazawa Medical Center, Japan
| | - Tatsuo Kumai
- Department of Gastroenterology, National Hospital Organization Kanazawa Medical Center, Japan
| | - Takashi Kagaya
- Department of Gastroenterology, National Hospital Organization Kanazawa Medical Center, Japan
| | - Hajime Ohta
- Department of Gastroenterology, National Hospital Organization Kanazawa Medical Center, Japan
| | - Atsuhiro Kawashima
- Department of Clinical Laboratory, National Hospital Organization Kanazawa Medical Center, Japan
| | - Kenichi Harada
- Department of Pathology, Kanazawa University Graduate School of Medical Science, Japan
| | - Shuichi Kaneko
- System Biology, Graduate School of Advanced Preventive Medical Science, Kanazawa University, Japan
| | - Masashi Unoura
- Department of Gastroenterology, National Hospital Organization Kanazawa Medical Center, Japan
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25
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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.
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Kamada Y, Morishita K, Koseki M, Nishida M, Asuka T, Naito Y, Yamada M, Takamatsu S, Sakata Y, Takehara T, Miyoshi E. Serum Mac-2 Binding Protein Levels Associate with Metabolic Parameters and Predict Liver Fibrosis Progression in Subjects with Fatty Liver Disease: A 7-Year Longitudinal Study. Nutrients 2020; 12:1770. [PMID: 32545650 PMCID: PMC7353396 DOI: 10.3390/nu12061770] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2020] [Revised: 06/02/2020] [Accepted: 06/10/2020] [Indexed: 12/12/2022] Open
Abstract
Background: Mac-2 binding protein (M2BP) is a highly glycosylated secreted glycoprotein that is involved in immune defense and regulation. Our cross-sectional studies indicated that serum M2BP was a useful liver fibrosis biomarker for nonalcoholic fatty liver disease (NAFLD). In this study, we conducted a 7-year longitudinal study to investigate the significance of serum M2BP levels (baseline and at 7-year follow-up) and their relationships with other metabolic parameters of fatty liver disease. Methods: We enrolled 715 study subjects (521 male and 194 female) during health examinations. Study subjects received blood sampling tests and abdominal ultrasound tests at baseline and follow-up. Results: Univariate analyses demonstrated that serum M2BP levels were significantly correlated with various parameters related to metabolic risk (body mass index (BMI), systolic blood pressure, triglyceride, high density lipoprotein (HDL)-cholesterol) and metabolic syndrome diseases (obesity, hypertension, dyslipidemia, diabetes mellitus, fatty liver (FL)). Multiple logistic regression analyses demonstrated that BMI and FL were independent determinants for serum M2BP levels. Baseline serum M2BP levels were significant independent determinants for changes in platelet count, Fibrosis-4 (FIB4) index, and NAFLD fibrosis score. Higher serum M2BP levels (>1.80 μg/mL) strongly correlated with changes in the FIB4-index. Conclusions: The results of this study suggest that changes in serum M2BP levels reflect changes in specific metabolic disease-related parameters, and baseline serum M2BP levels could predict changes in liver fibrosis.
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Affiliation(s)
- Yoshihiro Kamada
- Department of Molecular Biochemistry and Clinical Investigation, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan; (Y.K.); (K.M.); (M.N.); (T.A.); (Y.N.); (S.T.)
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan;
| | - Koichi Morishita
- Department of Molecular Biochemistry and Clinical Investigation, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan; (Y.K.); (K.M.); (M.N.); (T.A.); (Y.N.); (S.T.)
| | - Masahiro Koseki
- Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan; (M.K.); (Y.S.)
| | - Mayu Nishida
- Department of Molecular Biochemistry and Clinical Investigation, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan; (Y.K.); (K.M.); (M.N.); (T.A.); (Y.N.); (S.T.)
| | - Tatsuya Asuka
- Department of Molecular Biochemistry and Clinical Investigation, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan; (Y.K.); (K.M.); (M.N.); (T.A.); (Y.N.); (S.T.)
| | - Yukiko Naito
- Department of Molecular Biochemistry and Clinical Investigation, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan; (Y.K.); (K.M.); (M.N.); (T.A.); (Y.N.); (S.T.)
| | | | - Shinji Takamatsu
- Department of Molecular Biochemistry and Clinical Investigation, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan; (Y.K.); (K.M.); (M.N.); (T.A.); (Y.N.); (S.T.)
| | - Yasushi Sakata
- Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan; (M.K.); (Y.S.)
| | - Tetsuo Takehara
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan;
| | - Eiji Miyoshi
- Department of Molecular Biochemistry and Clinical Investigation, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan; (Y.K.); (K.M.); (M.N.); (T.A.); (Y.N.); (S.T.)
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Saleh SA, Salama MM, Alhusseini MM, Mohamed GA. M2BPGi for assessing liver fibrosis in patients with hepatitis C treated with direct-acting antivirals. World J Gastroenterol 2020; 26:2864-2876. [PMID: 32550761 PMCID: PMC7284180 DOI: 10.3748/wjg.v26.i21.2864] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2020] [Revised: 03/27/2020] [Accepted: 05/28/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Assessing liver fibrosis is important for predicting the efficacy of direct-acting antivirals (DAAs) and patient prognosis. Non-invasive techniques to assess liver fibrosis are becoming important. Recently, serum Mac-2 binding protein glycosylation isomer (M2BPGi) was identified as a non-invasive marker of liver fibrosis.
AIM To investigate the diagnostic accuracy of M2BPGi in assessing liver fibrosis in patients with chronic hepatitis C (CHC) treated with DAAs.
METHODS From December 2017 to August 2018, 80 treatment-naïve adult patients with CHC who were eligible for DAAs therapy were consecutively enrolled in this observational cohort study. For 12 weeks, 65 patients were treated with sofosbuvir/daclatasvir, and 15 patients were treated with sofosbuvir/daclatasvir and a weight-based dose of ribavirin at knowledge and technology association for hepatitis C management clinic, Cairo, Egypt. We measured serum M2BPGi levels, PAPAS index, fibrosis-4 (FIB-4) score and liver stiffness measurements (LSM) at baseline and 12 weeks after the end of treatment. Serum M2BPGi levels were measured using enzyme-linked immunosorbent assay.
RESULTS All patients achieved sustained virologic response (SVR12) (100%). Serum M2BPGi levels, LSM, FIB-4 score and PAPAS index decreased significantly at SVR12 (P < 0.05). Serum M2BPGi levels correlated positively with LSM at baseline and SVR12 (P < 0.001). At baseline, compared with the FIB-4 score and PAPAS index, M2BPGi was the best marker to distinguish patients with grade F4 fibrosis (AUC = 0.801, P < 0.001), patients with grade F2 from grade F0-1 fibrosis (AUC = 0.713, P = 0.012), patients with grade F3-4 from grade F0-2 fibrosis (AUC = 0.730, P < 0.001), and patients with grade F2-4 from grade F0-1 fibrosis (AUC = 0.763, P < 0.001). At SVR12, M2BPGi had the greatest AUCs for differentiating patients with grade F4 fibrosis (AUC = 0.844, P < 0.001), patients with grade F3 from grade F0-2 fibrosis (AUC = 0.893, P = 0.002), patients with grade F3-4 from grade F0-2 fibrosis (AUC = 0.891, P < 0.001), and patients with grade F2-4 from grade F0-1 fibrosis (AUC = 0.750, P < 0.001).
CONCLUSION M2BPGi is a reliable marker for the non-invasive assessment and prediction of liver fibrosis regression in patients with CHC who achieved an SVR with DAAs therapy.
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Affiliation(s)
- Shereen A Saleh
- Gastroenterology and Hepatology Unit, Department of Internal Medicine, Faculty of Medicine, Ain Shams University, Cairo 11341, Egypt
| | - Mohamed M Salama
- Gastroenterology and Hepatology Unit, Department of Internal Medicine, Faculty of Medicine, Ain Shams University, Cairo 11341, Egypt
| | - Marwan M Alhusseini
- Gastroenterology and Hepatology Unit, Department of Internal Medicine, Faculty of Medicine, Ain Shams University, Cairo 11341, Egypt
| | - Ghada A Mohamed
- Gastroenterology and Hepatology Unit, Department of Internal Medicine, Faculty of Medicine, Ain Shams University, Cairo 11341, Egypt
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Lin J, Ko CJ, Hung YJ, Lin PY, Lin KH, Hsieh CE, Chou CT, Chen YL. Prognostic Role of Serum Wisteria Floribunda Agglutinin-Positive Mac-2 Binding Protein Level in Early Stage Hepatocellular Carcinoma. Sci Rep 2020; 10:5651. [PMID: 32221384 PMCID: PMC7101373 DOI: 10.1038/s41598-020-62631-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2019] [Accepted: 02/27/2020] [Indexed: 12/28/2022] Open
Abstract
The purpose of this study is to evaluate the prognostic value of preoperative Wisteria floribunda agglutinin-positive Mac-2 binding protein (WFA+-M2BP) in predicting overall survival for patients with hepatitis B- and hepatitis C-related early-stage hepatocellular carcinoma (ESHCC) after liver resection. Post-operative survival rates were compared according to WFA+-M2BP level and tumor stage. Six hundred and ten patients were identified and 198 were removed after application of the exclusion criteria; the median follow-up time was 4.33 years, and cancer-related death occurred in 117 (28.4%) patients. Age (p = 0.03), fibrosis grade (p = 0.042), cancer stage (p = 0.01), and WFA+-M2BP level (p = 0.001) were identified as independent risk factors for poor overall survival. The overall survival rates at 3 and 5 years for patients with WFA+-M2BP ≤ 1.12 were 0.92 and 0.90, respectively, and 0.76 and 0.61 for patients with WFA+-M2BP > 1.12 (p < 0.001). During the analysis of survival prediction, serum WFA+-M2BP level exhibited a higher log-likelihood and a lower AIC value compared to TNM stage (log likelihood: -638; AIC: 1279). Pre-operative serum WFA+-M2BP level provided important prognostic information after curative hepatic resection in our study.
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Affiliation(s)
- Joseph Lin
- Department of General Surgery, Changhua Christian Hospital, Changhua, Taiwan
| | - Chih-Jan Ko
- Department of General Surgery, Changhua Christian Hospital, Changhua, Taiwan.,School of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Yu-Ju Hung
- Department of General Surgery, Changhua Christian Hospital, Changhua, Taiwan
| | - Ping-Yi Lin
- Transplant Medicine & Surgery Research Centre, Changhua Christian Hospital, Changhua, Taiwan
| | - Kuo-Hua Lin
- Department of General Surgery, Changhua Christian Hospital, Changhua, Taiwan
| | - Chia-En Hsieh
- Department of General Surgery, Changhua Christian Hospital, Changhua, Taiwan
| | - Chen-Te Chou
- School of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan. .,Department of Molecular Biotechnology, College of Biotechnology and Bioresources, Dayeh University, Changhua City, Taiwan. .,Department of Radiology, Changhua Christian Hospital, Changhua City, Taiwan.
| | - Yao-Li Chen
- Department of General Surgery, Changhua Christian Hospital, Changhua, Taiwan. .,School of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan. .,Transplant Medicine & Surgery Research Centre, Changhua Christian Hospital, Changhua, Taiwan. .,College of Nursing and Health Sciences, Dayeh University, Changhua City, Taiwan.
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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.
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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
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Su TH, Peng CY, Tseng TC, Yang HC, Liu CJ, Liu CH, Chen PJ, Chen DS, Kao JH. Serum Mac-2-Binding Protein Glycosylation Isomer at Virological Remission Predicts Hepatocellular Carcinoma and Death in Chronic Hepatitis B-Related Cirrhosis. J Infect Dis 2020; 221:589-597. [PMID: 31574141 DOI: 10.1093/infdis/jiz496] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2019] [Accepted: 09/27/2019] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND To investigate serum Mac-2-binding protein glycosylation isomer (M2BPGi) levels in predicting hepatocellular carcinoma (HCC) and mortality at virological remission (VR, HBV DNA <20 IU/mL) following antiviral therapy in chronic hepatitis B (CHB) patients with cirrhosis. METHODS This retrospective cohort study included patients with CHB-related Child-Pugh A cirrhosis undergoing long-term antiviral therapy. Serum M2BPGi levels were quantified and multivariable Cox proportional hazards regression models were used to identify risk predictors for HCC and death. RESULTS A total of 126 and 145 patients were included in the derivation and validation cohorts, respectively. The mean age was 56, and the mean M2BPGi level was 1.86 cut-off index (COI) in the derivation cohort. After adjustment for confounders, a higher M2BPGi level at VR significantly predicted HCC (hazard ratio [HR]: 1.58, 95% confidence interval [CI]: 1.19-2.10, P=0.002) and death (HR: 2.17, 95% CI: 1.02-4.62, P=0.044). The M2BPGi ≥3 COI significantly increased the risk of HCC and death in the derivation and validation cohorts. Serial M2BPGi levels declined significantly (P=0.0001) in non-HCC patients only, and remained significantly lower than those who developed HCC afterwards (P=0.039). CONCLUSIONS Serum M2BPGi levels at antiviral therapy-induced VR predict HCC development and death in patients with CHB-related Child-Pugh A cirrhosis.
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Affiliation(s)
- 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
| | - Cheng-Yuan Peng
- School of Medicine, China Medical University, Taichung, Taiwan
- Division of Hepatogastroenterology, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan
| | - 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
| | - Hung-Chih Yang
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, 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
| | - 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
- Department of Medical Research, National Taiwan University Hospital, 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
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Miyoshi E, Kamada Y, Suzuki T. Functional glycomics: Application to medical science and hepatology. Hepatol Res 2020; 50:153-164. [PMID: 31750967 DOI: 10.1111/hepr.13459] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/18/2019] [Revised: 10/20/2019] [Accepted: 10/29/2019] [Indexed: 02/08/2023]
Abstract
Glycomics refers to the comprehensive analysis of glycans. Recent progress in glycotechnology enables the determination of a variety of biological functions of glycans. Among different glycosylation patterns, certain types of aberrant glycosylation are linked to cancer and/or inflammation, and thus have biological importance. Glycotechnology has been applied to many fields of medical science, including hepatology. In particular, dramatic changes in glycosylation are observed in the progression of liver diseases. As the liver produces so many serum glycoproteins, changes in glycosylation of these proteins might provide useful disease biomarkers. Furthermore, many patients with genetic diseases of glycosylation who have liver dysfunction have been found as a result from whole genome sequencing, and various kinds of glycotherapy have been developed, especially in immunotherapy. In this review, we describe our basic knowledge of glycobiology and discuss the application of these data to medical science, especially hepatology.
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Affiliation(s)
- Eiji Miyoshi
- Department of Molecular Biochemistry & Clinical Investigation, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Yoshihiro Kamada
- Department of Molecular Biochemistry & Clinical Investigation, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Tadashi Suzuki
- Glycometabolic Biochemistry Laboratory, RIKEN Cluster for Pioneering Research (CPR), Wako, Saitama, Japan
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Galectin-9 as a biomarker for disease activity in systemic lupus erythematosus. PLoS One 2020; 15:e0227069. [PMID: 31986153 PMCID: PMC6984724 DOI: 10.1371/journal.pone.0227069] [Citation(s) in RCA: 40] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2019] [Accepted: 12/10/2019] [Indexed: 12/21/2022] Open
Abstract
Background Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by elevated interferon (IFN) signature genes. Galectin-9 (Gal-9) is a β-galactoside-binding lectin that is reportedly useful as a biomarker for IFN gene signatures. In a cross-sectional study of Japanese patients with recent-onset SLE, we aimed to determine whether raised serum Gal-9 levels were associated with the disease activity or organ damage seen in SLE patients. Methods The current study included 58 Japanese patients with SLE and 31 age-matched healthy individuals. Disease activity and organ damage were assessed using SLE Disease Activity 2000 (SLEDAI-2K) and Systemic Lupus International Collaborating Clinics (SLICC) damage index. Serum and cerebrospinal fluid (CSF) Gal-9 concentrations were quantified using ELISA. Correlation analyses between Gal-9 and clinical parameters including disease activity were performed. Results Serum levels of Gal-9 were significantly increased in patients with SLE compared with the control group (16.6 ng/ml, [interquartile range (IQR); 3.6–59.7] versus 4.74 ng/ml, [IQR; 3.0–9.5], p<0.0001). Gal-9 was significantly correlated with disease activity measures in the SLEDAI-2K. Serum Gal-9 levels were significantly greater in patients with SLE-related organ involvement (23.1 ng/ml, [IQR; 5.1–59.7] versus 12.5ng/ml, [IQR; 3.6–39.0], p = 0.013). Whereas there was no difference in serum levels of CXCL10 or M2BPGi between patients with and without SLE-related organ involvement. Serum levels of Gal-9 were significantly higher in SLE patients with active renal involvement determined by BILAG renal score (A-B) compared to those without active renal involvement (C-E). Whereas there was no significant difference in serum levels of Gal-9 between SLE patients with or without active other organ involvements (neurological or hematological) determined by BILAG score. SLE patients with detectable circulating IFN-α had raised serum Gal-9 levels. Levels of Gal-9 were significantly higher in the CSF from patients with recent-onset neuropsychiatric SLE (NPSLE) than in those from non-SLE controls (3.5 ng/ml, [IQR; 1.0–27.2] versus 1.2 ng/ml, [IQR; 0.9–2.1], p = 0.009). Conclusions Gal-9 could be a serologic marker of disease activity and organ involvement in SLE patients. Future studies evaluating the role of Gal-9 in the SLE phenotype may provide insights into SLE pathogenesis.
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Mak LY, Ko M, To E, Wong DKH, Ma JHC, Hui TLY, Seto WK, Fung J, Lai CL, Yuen MF. Serum Mac-2-binding protein glycosylation isomer and risk of hepatocellular carcinoma in entecavir-treated chronic hepatitis B patients. J Gastroenterol Hepatol 2019; 34:1817-1823. [PMID: 30786068 DOI: 10.1111/jgh.14637] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2018] [Revised: 02/02/2019] [Accepted: 02/18/2019] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND AIM Hepatocellular carcinoma (HCC) can still develop in chronic hepatitis B (CHB) patients receiving antiviral treatment. Serum Mac-2-binding protein glycosylation isomer (M2BPGi) is a novel marker for liver fibrosis. We investigated its role on incidence of HCC in entecavir (ETV)-treated CHB patients. METHODS We identified HCC cases diagnosed at ≥ 1 year of ETV treatment. CHB patients without HCC (matched for age, gender, baseline hepatitis B virus-DNA, and duration of ETV treatment) were identified in approximately 1:2 ratio (HCC: non-HCC) for comparison. Serum samples were retrieved at baseline (initiation of ETV), 3, and 5 years of ETV for serum M2BPGi measurement (expressed in cut-off index [COI]). RESULTS One hundred HCC cases were matched with 185 CHB patients without HCC (median age 56.7 years, 78.9% male, baseline hepatitis B virus-DNA 5.6 logIU/mL, and median follow-up 7.1 years). Median time from ETV initiation to incident HCC was 3.9 years. Serum M2BPGi levels were significantly higher in HCC cases compared with controls at baseline and year 3 (1.25 vs 0.98 [P = 0.004], 0.89 vs 0.74 [P = 0.018] COI, respectively). Multivariate analysis showed that baseline M2BPGi was the only independent factor associated with incident HCC (odds ratio 1.241, 95% confidence interval 1.039-1.482, P = 0.017). Using a cut-off value of 1.15 COI, the sensitivity, specificity, positive predictive value, and negative predictive value of baseline serum M2BPGi in cirrhotic patients to predict incident HCC were 90%, 53.8%, 69.6%, and 82.1%, respectively. CONCLUSIONS Baseline and 3-year serum M2BPGi may be useful to identify high risk patients on antiviral treatment for subsequent HCC development.
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Affiliation(s)
- Lung-Yi Mak
- Department of Medicine, Queen Mary Hospital, Hong Kong
| | - Michael Ko
- Department of Medicine, Queen Mary Hospital, Hong Kong
| | - Elvis To
- Department of Medicine, Queen Mary Hospital, Hong Kong
| | - Danny Ka-Ho Wong
- Department of Medicine, Queen Mary Hospital, Hong Kong.,State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong
| | | | | | - Wai-Kay Seto
- Department of Medicine, Queen Mary Hospital, Hong Kong.,State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong
| | - James Fung
- Department of Medicine, Queen Mary Hospital, Hong Kong.,State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong
| | - Ching-Lung Lai
- Department of Medicine, Queen Mary Hospital, Hong Kong.,State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong
| | - Man-Fung Yuen
- Department of Medicine, Queen Mary Hospital, Hong Kong.,State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong
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Imai D, Maeda T, Wang H, Sanefuji K, Kayashima H, Yoshiya S, Takeishi K, Itoh S, Harada N, Ikegami T, Yoshizumi T, Mori M. Elevation of Mac-2 binding protein glycosylation isomer after hepatectomy is associated with post-hepatectomy liver failure, total Pringle time, and renal dysfunction. Ann Gastroenterol Surg 2019; 3:515-522. [PMID: 31549011 PMCID: PMC6749955 DOI: 10.1002/ags3.12271] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2019] [Revised: 05/30/2019] [Accepted: 06/04/2019] [Indexed: 12/26/2022] Open
Abstract
BACKGROUND Mac-2 binding protein glycosylation isomer (M2BPGi) is a novel serum glycomarker used to assess liver fibrosis. However, it has been reported that M2BPGi is likely to reflect other factors not limited to liver fibrosis. METHODS We retrospectively analyzed 79 patients with liver tumors who underwent liver resection. M2BPGi was measured within 1 week before operation and almost 1 month after operation. We introduced a value termed the "ΔM2BPGi ratio" (=M2BPGiafter operation/M2BPGibefore operation), and analyzed factors that influenced the ΔM2BPGi ratio. RESULTS The median value of the ΔM2BPGi ratio was 1.28 (range, 0.36-5.68). In 64 patients (81.0%), the cutoff index values of M2BPGi were elevated approximately 1 month after operation, especially in patients who experienced post-hepatectomy liver failure (PHLF). Multiple linear regression showed total Pringle time, PHLF grade ≥B, and preoperative value of creatinine were significant predictors of the ΔM2BPGi ratio. The mean values of the ΔM2BPGi ratio were 1.37 ± 0.07, 1.52 ± 0.22, and 2.94 ± 0.30 for PHLF grade 0, grade A, and grade B, respectively, resulting in statistically significant differences by the Kruskal-Wallis test (P = 0.022). CONCLUSIONS Total Pringle time, PHLF grade ≥B, and preoperative creatinine significantly influenced the elevation of M2BPGi almost 1 month after liver resection. This study strongly affirms the previous suggestion that M2BPGi is likely to reflect other factors not limited to liver fibrosis.
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Affiliation(s)
- Daisuke Imai
- Department of SurgeryHiroshima Red Cross Hospital & Atomic Bomb Survivors HospitalHiroshimaJapan
- Department of Surgery and ScienceGraduate School of Medical SciencesKyushu UniversityFukuokaJapan
| | - Takashi Maeda
- Department of SurgeryHiroshima Red Cross Hospital & Atomic Bomb Survivors HospitalHiroshimaJapan
| | - Huanlin Wang
- Department of SurgeryHiroshima Red Cross Hospital & Atomic Bomb Survivors HospitalHiroshimaJapan
| | - Kensaku Sanefuji
- Department of SurgeryHiroshima Red Cross Hospital & Atomic Bomb Survivors HospitalHiroshimaJapan
| | - Hiroto Kayashima
- Department of SurgeryHiroshima Red Cross Hospital & Atomic Bomb Survivors HospitalHiroshimaJapan
| | - Shohei Yoshiya
- Department of Surgery and ScienceGraduate School of Medical SciencesKyushu UniversityFukuokaJapan
| | - Kazuki Takeishi
- Department of Surgery and ScienceGraduate School of Medical SciencesKyushu UniversityFukuokaJapan
| | - Shinji Itoh
- Department of Surgery and ScienceGraduate School of Medical SciencesKyushu UniversityFukuokaJapan
| | - Noboru Harada
- Department of Surgery and ScienceGraduate School of Medical SciencesKyushu UniversityFukuokaJapan
| | - Toru Ikegami
- Department of Surgery and ScienceGraduate School of Medical SciencesKyushu UniversityFukuokaJapan
| | - Tomoharu Yoshizumi
- Department of Surgery and ScienceGraduate School of Medical SciencesKyushu UniversityFukuokaJapan
| | - Masaki Mori
- Department of Surgery and ScienceGraduate School of Medical SciencesKyushu UniversityFukuokaJapan
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Nagy N, Sunkari VG, Kaber G, Hasbun S, Lam DN, Speake C, Sanda S, McLaughlin TL, Wight TN, Long SR, Bollyky PL. Hyaluronan levels are increased systemically in human type 2 but not type 1 diabetes independently of glycemic control. Matrix Biol 2019; 80:46-58. [PMID: 30196101 PMCID: PMC6401354 DOI: 10.1016/j.matbio.2018.09.003] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2018] [Revised: 09/04/2018] [Accepted: 09/05/2018] [Indexed: 01/19/2023]
Abstract
Hyaluronan (HA), an extracellular matrix glycosaminoglycan, is implicated in the pathogenesis of both type 1 diabetes (T1D) as well as type 2 diabetes (T2D) and has been postulated to be increased in these diseases due to hyperglycemia. We have examined the serum and tissue distribution of HA in human subjects with T1D and T2D and in mouse models of these diseases and evaluated the relationship between HA levels and glycemic control. We found that serum HA levels are increased in T2D but not T1D independently of hemoglobin-A1c, C-peptide, body mass index, or time since diabetes diagnosis. HA is likewise increased in skeletal muscle in T2D subjects relative to non-diabetic controls. Analogous increases in serum and muscle HA are seen in diabetic db/db mice (T2D), but not in diabetic DORmO mice (T1D). Diabetes induced by the β-cell toxin streptozotozin (STZ) lead to an increase in blood glucose but not to an increase in serum HA. These data indicate that HA levels are increased in multiple tissue compartments in T2D but not T1D independently of glycemic control. Given that T2D but not T1D is associated with systemic inflammation, these patterns are consistent with inflammatory factors and not hyperglycemia driving increased HA. Serum HA may have value as a biomarker of systemic inflammation in T2D.
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Affiliation(s)
- Nadine Nagy
- Division of Infectious Diseases and Geographic Medicine, Dept. of Medicine, Stanford University School of Medicine, Beckman Center, 279 Campus Drive, Stanford, CA, 94305
| | - Vivekananda G. Sunkari
- Division of Infectious Diseases and Geographic Medicine, Dept. of Medicine, Stanford University School of Medicine, Beckman Center, 279 Campus Drive, Stanford, CA, 94305
| | - Gernot Kaber
- Division of Infectious Diseases and Geographic Medicine, Dept. of Medicine, Stanford University School of Medicine, Beckman Center, 279 Campus Drive, Stanford, CA, 94305
| | - Sonia Hasbun
- Department of Cardiology, Good Samaritan Regional Medical Center, 3600 NW Samaritan Dr, Corvallis, OR, 97330
| | - Dung N. Lam
- Division of Infectious Diseases and Geographic Medicine, Dept. of Medicine, Stanford University School of Medicine, Beckman Center, 279 Campus Drive, Stanford, CA, 94305
| | - Cate Speake
- Diabetes Clinical Research Program, Benaroya Research Institute, 1201 Ninth Ave, Seattle, WA, 98101
| | - Srinath Sanda
- Department of Pediatrics, UCSF School of Medicine, 513 Parnassus Avenue, San Francisco, CA, 94143
| | - Tracey L. McLaughlin
- Department of Medicine, Medicine – Endocrinology, Endocrine Clinic, Stanford School of Medicine, 300 Pasteur Drive, Stanford, CA, 94305
| | - Thomas N. Wight
- Matrix Biology Program, Benaroya Research Institute, 1201 Ninth Ave, Seattle, WA, 98101
| | - Steven R. Long
- Department of Pathology, Stanford University School of Medicine, Lane 235, 300 Pasteur Drive, Stanford, CA, 94305
| | - Paul L. Bollyky
- Division of Infectious Diseases and Geographic Medicine, Dept. of Medicine, Stanford University School of Medicine, Beckman Center, 279 Campus Drive, Stanford, CA, 94305
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Asada S, Douhara A, Murata K, Yanase K, Tsutsumi M, Yoshiji H. A Histologically Proven Case of Autoimmune Hepatitis with Eosinophilic Fasciitis. Intern Med 2019; 58:667-673. [PMID: 30333401 PMCID: PMC6443560 DOI: 10.2169/internalmedicine.1299-18] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Both autoimmune hepatitis (AIH) and eosinophilic fasciitis (EF) are known to be complicated by other autoimmune diseases. However, AIH complicated by EF has never been reported. We experienced a 58-year-old man with AIH complicated by EF. He was admitted to our hospital with acute hepatic injury and edema of the legs in April 201X. The etiologies of these symptoms were histologically proven as AIH and EF. The administration of prednisolone (PSL) drastically improved his liver injury and edema of the legs. When we make a diagnosis of AIH, we should carefully evaluate the physical findings, including the appearance of the legs, in order to detect other coexisting autoimmune diseases.
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Affiliation(s)
- Shohei Asada
- Department of Internal Medicine, Saiseikai Chuwa Hospital, Japan
| | - Akitoshi Douhara
- Department of Internal Medicine, Saiseikai Chuwa Hospital, Japan
| | - Koji Murata
- Department of Internal Medicine, Saiseikai Chuwa Hospital, Japan
| | - Koji Yanase
- Department of Internal Medicine, Saiseikai Chuwa Hospital, Japan
| | | | - Hitoshi Yoshiji
- Third department of Internal Medicine, Nara Medical University, Japan
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Correlation of serum Mac-2-binding protein glycosylation isomer (M2BPGi) and liver stiffness in chronic hepatitis B infection. Hepatol Int 2019; 13:148-156. [PMID: 30671807 DOI: 10.1007/s12072-019-09928-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/16/2018] [Accepted: 01/07/2019] [Indexed: 02/07/2023]
Abstract
BACKGROUND AND AIM Mac-2-binding protein glycosylation isomer (M2BPGi) is a novel serum diagnostic marker for liver fibrosis in various liver diseases. We aimed to evaluate its role in assessment of liver fibrosis in chronic hepatitis B infection (CHB) with reference to liver stiffness measurement (LSM). METHODS CHB patients with LSM by transient elastography technology and retrievable serum samples were recruited. Ten-year re-assessments of LSM and M2BPGi were repeated in a patient subgroup. RESULTS 240 CHB patients (M:F = 116:124; median age 47.5 years) were recruited. The median M2BPGi values for F0/F1/F2, F3 and F4 progressively increased with more advanced stages of liver fibrosis: 0.39, 0.46 and 0.82 COI, respectively (p < 0.01). M2BPGi levels correlated well with liver stiffness (r = 0.611), FIB-4 (r = 0.616), and strongly with APRI (r = 0.825) (all p < 0.001). Using cut-off values of 0.605 and 0.615 COI, the AUROCs were 0.754 and 0.799 for ≥ F3 and F4, respectively. M2BPGi identified one-quarter patients at risk of advanced fibrosis/cirrhosis otherwise classified into 'grey area' by LSM. In 86 patients with reassessment LSM, 21 (24.4%) showed significant fibrosis regression with corresponding decline in median M2BPGi level (- 0.11 COI) compared with the increase of +0.03 COI in patients without significant fibrosis regression (p = 0.011). Male gender, older age, use of potent antiviral therapy and change in serum M2BPGi were independently associated with significant fibrosis regression. CONCLUSIONS Serum M2BPGi can risk-stratify CHB patients whose liver stiffness fell into the 'grey area'. Significant fibrosis regression occurring in one-quarter patients was reflected by a reduction in M2BPGi levels at 10-year interval.
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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.
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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
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Migita K, Horai Y, Kozuru H, Koga T, Abiru S, Yamasaki K, Komori A, Fujita Y, Asano T, Sato S, Suzuki E, Matsuoka N, Kobayashi H, Watanabe H, Naganuma A, Naeshiro N, Yoshizawa K, Ohta H, Sakai H, Shimada M, Nishimura H, Tomizawa M, Ario K, Yamashita H, Kamitsukasa H, Kohno H, Nakamura M, Furukawa H, Takahashi A, Kawakami A, Ohira H, Yastuhashi H. Serum cytokine profiles and Mac-2 binding protein glycosylation isomer (M2BPGi) level in patients with autoimmune hepatitis. Medicine (Baltimore) 2018; 97:e13450. [PMID: 30557999 PMCID: PMC6320116 DOI: 10.1097/md.0000000000013450] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2018] [Accepted: 11/06/2018] [Indexed: 12/12/2022] Open
Abstract
Autoimmune hepatitis (AIH) is an autoimmune liver disease that is characterized by a progressive destruction of the liver parenchyma and the development of liver fibrosis. We aimed to examine the relationship between circulating cytokines/chemokines and the Mac-2 binding protein glycosylation isomer (M2BPGi) levels in Japanese patients with autoimmune hepatitis (AIH).We investigated the relationship between circulating cytokines/chemokines and M2BPGi levels in Japanese patients with AIH. Seventy-seven patients with well-documented AIH were enrolled in the National Hospital Organization (NHO)-AIH-liver-network database. We measured the serum levels of 20 cytokines in 31 selected AIH patients before and after steroid treatment using multisuspension cytokine array.Eleven cytokines and soluble adhesion molecules were increased in untreated AIH patients compared with treated AIH patients. Among these cytokines and soluble adhesion molecules, soluble intercellular adhesion molecule-1 (sICAM-1) and interferon-γ-inducible protein 10 (IP-10) were most downregulated by steroid therapy in AIH patients. We measured serum sICAM-1 and IP-10 by ELISA and found the levels were significantly higher in AIH patients (n = 77) compared with chronic viral hepatitis C patients (n = 32). Furthermore, there was a positive correlation between sICAM-1 or IP-10 and alanine aminotransferase, total bilirubin, and circulating M2BPGi levels. M2BPGi levels were increased in AIH patients with high stages of liver fibrosis. Additionally, M2BPGi levels were correlated with the histological grade of inflammation in AIH. Circulating M2BPGi levels were significantly reduced by steroid treatment in AIH patients.sICAM-1 and IP-10 are useful markers to assess immune-mediated hepatitis activity in AIH and they correlate with circulating M2BPGi. Serum M2BPGi levels increased in untreated AIH patients with active hepatitis and were decreased by steroid therapy. M2BPGi reflects autoimmune-mediated hepatic inflammation as well as liver fibrosis.
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Affiliation(s)
- Kiyoshi Migita
- Department of Rheumatology, Fukushima Medical University, Fukushima
- Clinical Research Center, Nagasaki Medical Center, Nagasaki
| | - Yoshiro Horai
- Clinical Research Center, Nagasaki Medical Center, Nagasaki
| | - Hideko Kozuru
- Clinical Research Center, Nagasaki Medical Center, Nagasaki
| | - Tomohiro Koga
- Department of Immunology and Rheumatology, Unit of Translational Medicine, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki
| | - Seigo Abiru
- Clinical Research Center, Nagasaki Medical Center, Nagasaki
| | | | | | - Yuya Fujita
- Department of Rheumatology, Fukushima Medical University, Fukushima
| | - Tomoyuki Asano
- Department of Rheumatology, Fukushima Medical University, Fukushima
| | - Shuzo Sato
- Department of Rheumatology, Fukushima Medical University, Fukushima
| | - Eiji Suzuki
- Department of Rheumatology, Fukushima Medical University, Fukushima
| | - Naoki Matsuoka
- Department of Rheumatology, Fukushima Medical University, Fukushima
| | - Hiroko Kobayashi
- Department of Rheumatology, Fukushima Medical University, Fukushima
| | - Hiroshi Watanabe
- Department of Rheumatology, Fukushima Medical University, Fukushima
| | - Atsushi Naganuma
- National Hospital Organization, Takasaki Medical Center, Takasaki
| | - Noriaki Naeshiro
- National Hospital Organization, Higashihiroshima Medical center, Higashihiroshima, Hiroshima
| | - Kaname Yoshizawa
- National Hospital Organization, Shinsyu-Ueda Medical Center, Ueda, Nagano
| | - Hajime Ohta
- National Hospital Organization, Kanazawa Medical Center, Kanazawa, Ishikawa
| | - Hironori Sakai
- National Hospital Organization, Beppu Medical Center, Beppu, Oita
| | - Masaaki Shimada
- National Hospital Organization, Nagoya Medical Center, Naka-ku, Nagoya, Aichi
| | - Hideo Nishimura
- National Hospital Organization, Asahikawa Medical Center, Asahikawa, Hokkaido
| | - Minoru Tomizawa
- National Hospital Organization, Shimoshizu Hospital, Yotsukaido, Chiba
| | - Keisuke Ario
- National Hospital Organization, Ureshino Medical Center, Ureshino, Saga
| | - Haruhiro Yamashita
- National Hospital Organization, Okayama Medical Center, Okayama, Okayama
| | | | - Hiroshi Kohno
- National Hospital Organization, Kure Medical Center, Kure, Hiroshima
| | - Minoru Nakamura
- Department of Hepatology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki
| | - Hiroshi Furukawa
- Molecular and Genetic Epidemiology Laboratory, Faculty of Medicine, University of Tsukuba, Tsukuba
| | - Atsushi Takahashi
- Department of Gastroenterology, Fukushima Medical University, Fukushima
| | - Atsushi Kawakami
- Department of Immunology and Rheumatology, Unit of Translational Medicine, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki
| | - Hiromasa Ohira
- Department of Gastroenterology, Fukushima Medical University, Fukushima
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Hsu YC, Jun T, Huang YT, Yeh ML, Lee CL, Ogawa S, Cho SH, Lin JT, Yu ML, Nguyen MH, Tanaka Y. Serum M2BPGi level and risk of hepatocellular carcinoma after oral anti-viral therapy in patients with chronic hepatitis B. Aliment Pharmacol Ther 2018; 48:1128-1137. [PMID: 30306612 DOI: 10.1111/apt.15006] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/07/2018] [Revised: 06/26/2018] [Accepted: 09/10/2018] [Indexed: 12/20/2022]
Abstract
BACKGROUND Mac-2 binding protein glycosylation isomer (M2BPGi) is an emerging biomarker for risk prediction of liver disease, but data remain sparse for patients with chronic hepatitis B (CHB) who are treated with nucleos(t)ide analogues (NA). AIM To clarify serial changes in M2BPGi and its association with subsequent hepatocellular carcinoma (HCC) development in NA-treated CHB patients. METHODS We enrolled 384 previously untreated CHB patients who received NAs. Among them, 195 had baseline cirrhosis (n = 142:48:5 for Child A:B:C). Sera were collected at NA initiation, and after 1 and 2 years. Serum M2BPGi levels were measured and expressed as cut-off index (COI) at different time points. The association between M2BPGi and HCC was evaluated by the Cox proportional hazard model. RESULTS The median M2BPGi levels significantly decreased from 1.68 COI at baseline, to 1.0 at year 1, and 0.88 at year 2. During median follow-up of 72.7 months, HCC occurred in 37 patients, 36 of whom had cirrhosis. In patients with cirrhosis, baseline M2BPGi level was associated with HCC risk (adjusted hazard ratio, 1.07 per COI; 95% CI, 1.01-1.14) on the multivariable Cox analysis, whereas levels at year 1 or 2 were not independently predictive. A risk score for HCC was developed using baseline M2BPGi, age and body mass index with c statistics of 0.77, 0.79 and 0.87 at 3, 5 and 10 years, respectively. CONCLUSIONS Serum M2BPGi level significantly decreases after NA treatment in CHB patients. Baseline level can be factored into the risk prediction of HCC in NA-treated patients with cirrhosis.
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Affiliation(s)
- Yao-Chun Hsu
- Division of Gastroenterology and Hepatology, Fu-Jen Catholic University Hospital, New Taipei, Taiwan
- School of Medicine, College of Medicine, Fu-Jen Catholic University, New Taipei, Taiwan
- Division of Gastroenterology and Hepatology, E-Da Hospital, Kaohsiung, Taiwan
- Graduate Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan
| | - Tomi Jun
- Department of Medicine, Stanford University Medical Center, Palo Alto, California
| | - Yen-Tsung Huang
- Institute of Statistical Science, Academia Sinica, Taipei, Taiwan
| | - Ming-Lun Yeh
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Chia-Long Lee
- Department of Internal Medicine, Cathay General Hospital, Taipei, Taiwan
| | - Shintaro Ogawa
- Department of Virology and Liver Unit, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Shu-Hsien Cho
- Institute of Statistical Science, Academia Sinica, Taipei, Taiwan
| | - Jaw-Town Lin
- Division of Gastroenterology and Hepatology, Fu-Jen Catholic University Hospital, New Taipei, Taiwan
- School of Medicine, College of Medicine, Fu-Jen Catholic University, New Taipei, Taiwan
| | - Ming-Lung Yu
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Mindie H Nguyen
- Division of Gastroenterology and Hepatology, Stanford University Medical Center, Palo Alto, California
| | - Yasuhito Tanaka
- Department of Virology and Liver Unit, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
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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.
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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
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42
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Ueno T, Kodama T, Noguchi Y, Saka R, Takama Y, Tazuke Y, Bessho K, Okuyama H. Clinical implications of serum Mac-2-binding protein (M2BPGi) during regular follow-up of patients with biliary atresia. Pediatr Surg Int 2018; 34:1065-1071. [PMID: 30128700 DOI: 10.1007/s00383-018-4317-2] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/26/2018] [Indexed: 12/20/2022]
Abstract
PURPOSE The Mac-2-binding protein glycosylation-modified isomer (M2BPGi) is a new marker for progression of hepatic fibrosis. We examined the relationship between serum M2BPGi levels and liver histological findings in patients with biliary atresia (BA) who were not transplant candidates. METHODS Patients with BA who were not transplant candidates with good liver function were included. We examined M2BPGi levels and histological findings in relation to other laboratory markers of liver fibrosis, including aspartate aminotransferase (AST) to platelet ratio index, fibrosis-4 index, and type IV collagen 7s domain. Liver fibrosis was evaluated based on the METVIR score. RESULTS 37 patients were included. The median age was 18 years (range 3-38 years). M2BPGi values ranged from 0.3 to 6.9 cutoff index (COI) (median 1.6). The degree of liver fibrosis varied with M2BPGi level. For predicting cirrhosis (F4) and advanced liver fibrosis (≥ F3), M2BPGi had higher areas under the curve (AUCs; 0.93, respectively) with cutoff COIs of 1.84 and 1.67, respectively, than for the four conventional markers for fibrosis. CONCLUSION M2BPGi is a novel marker for liver fibrosis in patients with BA. It is especially useful for following patients with BA with a native liver and supporting liver biopsy interpretation findings.
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Affiliation(s)
- Takehisa Ueno
- Department of Pediatric Surgery, Osaka University of Graduation School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan.
| | - Tasuku Kodama
- Department of Pediatric Surgery, Osaka University of Graduation School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Yuki Noguchi
- Department of Pediatric Surgery, Osaka University of Graduation School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Ryuta Saka
- Department of Pediatric Surgery, Osaka University of Graduation School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Yuichi Takama
- Department of Pediatric Surgery, Osaka University of Graduation School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Yuko Tazuke
- Department of Pediatric Surgery, Osaka University of Graduation School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Kazuhiko Bessho
- Department of Pediatrics, Osaka University of Graduation School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Hiroomi Okuyama
- Department of Pediatric Surgery, Osaka University of Graduation School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan
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Bellan M, Castello LM, Pirisi M. Candidate Biomarkers of Liver Fibrosis: A Concise, Pathophysiology-oriented Review. J Clin Transl Hepatol 2018; 6:317-325. [PMID: 30271745 PMCID: PMC6160308 DOI: 10.14218/jcth.2018.00006] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/24/2018] [Revised: 04/25/2018] [Accepted: 05/03/2018] [Indexed: 12/11/2022] Open
Abstract
Repair of sustained liver injury results in fibrosis (i.e. the accumulation of extracellular matrix proteins), and ultimately the complete distortion of parenchymal architecture of the liver, which we call cirrhosis. Detecting and staging of fibrosis is thus a mainstay in the management of chronic liver diseases, since many clinically relevant decisions, such as starting treatment and/or monitoring for complications including hepatocellular carcinoma, may depend on it. The gold standard for fibrosis staging is liver biopsy, the role of which, however, is questioned nowadays because of cost, hazards and poor acceptance by patients. On the other hand, imaging techniques and/or measurement of direct and indirect serum markers have not proved to be completely satisfactory under all circumstances as alternatives to liver biopsy. Making progress in this field is now more crucial than ever, since treatments for established fibrosis appear on the horizon. Fine dissection of the pathways involved in the pathophysiology of liver diseases has put forward several novel candidate biomarkers of liver fibrosis, such as growth arrest-specific6, Mac-2-binding protein, osteopontin, placental growth factor, growth/differentiation factor 15 and hepatocyte growth factor. All molecules have been suggested to have potential to complement or substitute methods currently used to stage liver diseases. Here, we review the pros and cons for their use in this setting.
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Affiliation(s)
- Mattia Bellan
- Department of Translational Medicine, Università del Piemonte Orientale UPO, Novara, Italy
- Division of Internal Medicine, “Sant’Andrea Hospital”, Vercelli, Italy
- IRCAD, Interdisciplinary Research Center of Autoimmune Diseases, Novara, Italy
- *Correspondence to: Mattia Bellan, Department of Translational Medicine, Università del Piemonte Orientale UPO, via Solaroli 17, Novara (NO) 28100, Italy. Tel: +39-321-3733966, Fax: +39-321-3733361, E-mail:
| | - Luigi Mario Castello
- Department of Translational Medicine, Università del Piemonte Orientale UPO, Novara, Italy
- Emergency Medicine Department, “AOU Maggiore della Carità”, Novara, Italy
| | - Mario Pirisi
- Department of Translational Medicine, Università del Piemonte Orientale UPO, Novara, Italy
- Division of Internal Medicine, “AOU Maggiore della Carità, Novara, Italy
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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: 137] [Impact Index Per Article: 19.6] [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.
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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
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45
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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.
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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.
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46
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Kawaguchi K, Honda M, Ohta H, Terashima T, Shimakami T, Arai K, Yamashita T, Sakai Y, Yamashita T, Mizukoshi E, Komura T, Unoura M, Kaneko S. Serum Wisteria floribunda agglutinin-positive Mac-2 binding protein predicts hepatocellular carcinoma incidence and recurrence in nucleos(t)ide analogue therapy for chronic hepatitis B. J Gastroenterol 2018; 53:740-751. [PMID: 28849280 DOI: 10.1007/s00535-017-1386-2] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2017] [Accepted: 08/17/2017] [Indexed: 02/07/2023]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) occurs in chronic hepatitis B (CH-B) patients even after treatment with nucleos(t)ide analogues (NAs) by a mechanism involving an association between the oncogenic factors of integrated HBV and liver fibrosis. An association has been demonstrated between advanced chronic liver disease and elevated levels of Wisteria floribunda agglutinin-positive Mac-2 binding protein (WFA(+)-M2BP), a recently discovered serum liver fibrosis marker. Moreover, hepatitis B core-related antigen (HBcrAg) reflects intracellular HBV protein production and its relationship with liver carcinogenesis has been reported. This study aimed to determine whether the incidence and recurrence of HBV-related liver cancer could be predicted using these serum markers. METHODS We evaluated 141 CH-B cases treated for more than 1 year with NAs. We compared 17 HCC cases with 124 non-HCC cases and evaluated serum WFA(+)-M2BP, HBV markers including HBcrAg, and other clinical factors. We also evaluated 71 CH-B-related HCC cases who started or continued NAs and compared the incidence and recurrence of HCC after successful cancer treatment. RESULTS Multivariate analysis showed that the incidence of HCC was significantly associated with higher histological stage and grade before NA treatment and with WFA(+)-M2BP and HBcrAg positivity during NA treatment. The cumulative incidence of HCC was strongly associated with higher WFA(+)-M2BP levels and HBcrAg positivity. HCC recurrence after anti-cancer therapy was also significantly associated with higher WFA(+)-M2BP levels compared with those in cases without recurrence during follow-up. CONCLUSION Serum WFA(+)-M2BP and HBcrAg are useful diagnostic tests for predicting the development and recurrence of HBV-related HCC during NA treatment.
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Affiliation(s)
- Kazunori Kawaguchi
- Department of Gastroenterology, School of Medical Sciences, Kanazawa University, 13-1 Takara-machi, Kanazawa, Ishikawa, 920-8641, Japan
| | - Masao Honda
- Department of Gastroenterology, School of Medical Sciences, Kanazawa University, 13-1 Takara-machi, Kanazawa, Ishikawa, 920-8641, Japan.
| | - Hajime Ohta
- Department of Gastroenterology, National Hospital Organization Kanazawa Medical Center, Kanazawa, Japan
| | - Takeshi Terashima
- Department of Gastroenterology, School of Medical Sciences, Kanazawa University, 13-1 Takara-machi, Kanazawa, Ishikawa, 920-8641, Japan
| | - Tetsuro Shimakami
- Department of Gastroenterology, School of Medical Sciences, Kanazawa University, 13-1 Takara-machi, Kanazawa, Ishikawa, 920-8641, Japan
| | - Kuniaki Arai
- Department of Gastroenterology, School of Medical Sciences, Kanazawa University, 13-1 Takara-machi, Kanazawa, Ishikawa, 920-8641, Japan
| | - Taro Yamashita
- Department of Gastroenterology, School of Medical Sciences, Kanazawa University, 13-1 Takara-machi, Kanazawa, Ishikawa, 920-8641, Japan
| | - Yoshio Sakai
- Department of Gastroenterology, School of Medical Sciences, Kanazawa University, 13-1 Takara-machi, Kanazawa, Ishikawa, 920-8641, Japan
| | - Tatsuya Yamashita
- Department of Gastroenterology, School of Medical Sciences, Kanazawa University, 13-1 Takara-machi, Kanazawa, Ishikawa, 920-8641, Japan
| | - Eishiro Mizukoshi
- Department of Gastroenterology, School of Medical Sciences, Kanazawa University, 13-1 Takara-machi, Kanazawa, Ishikawa, 920-8641, Japan
| | - Takuya Komura
- Department of Gastroenterology, School of Medical Sciences, Kanazawa University, 13-1 Takara-machi, Kanazawa, Ishikawa, 920-8641, Japan.,Department of Gastroenterology, National Hospital Organization Kanazawa Medical Center, Kanazawa, Japan
| | - Masashi Unoura
- Department of Gastroenterology, National Hospital Organization Kanazawa Medical Center, Kanazawa, Japan
| | - Shuichi Kaneko
- Department of Gastroenterology, School of Medical Sciences, Kanazawa University, 13-1 Takara-machi, Kanazawa, Ishikawa, 920-8641, Japan
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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: 21] [Impact Index Per Article: 3.0] [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.
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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
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48
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Atsukawa M, Tsubota A, Okubo T, Arai T, Nakagawa A, Itokawa N, Kondo C, Kato K, Hatori T, Hano H, Oikawa T, Emoto N, Abe M, Kage M, Iwakiri K. Serum Wisteria floribunda agglutinin-positive Mac-2 binding protein more reliably distinguishes liver fibrosis stages in non-alcoholic fatty liver disease than serum Mac-2 binding protein. Hepatol Res 2018; 48:424-432. [PMID: 29274190 DOI: 10.1111/hepr.13046] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2017] [Revised: 12/01/2017] [Accepted: 12/16/2017] [Indexed: 12/12/2022]
Abstract
AIM Serum Mac-2 binding protein (M2BP) and Wisteria floribunda agglutinin-positive Mac-2 binding protein (WFA+ -M2BP) are used to estimate the liver fibrosis stage in chronic liver diseases. However, few head-to-head studies have been carried out to compare the two biomarkers in non-alcoholic fatty liver disease (NAFLD). METHODS Serum M2BP and WFA+ -M2BP levels were compared against clinical characteristics and liver histological manifestations in the same samples collected from 213 biopsy-proven NAFLD patients. RESULTS Median levels (range) of M2BP and WFA+ -M2BP were 1.58 (0.70-7.75) pg/mL and 0.85 (0.22-11.32) cut-off index (COI), respectively. Fibrosis stages 1, 2, 3, and 4 were determined in 136, 37, 17, and 23 patients, respectively. Median levels of both biomarkers increased stepwise with fibrosis progression. The M2BP and WFA+ -M2BP levels showed a significant positive correlation (r = 0.643, P = 2.91 × 10-26 ), but a marked discrepancy between both biomarkers was noted in five stage 4 and three stage 1 patients, who had high WFA+ -M2BP but relatively low M2BP levels. Most of these outliers had findings suggestive of more advanced fibrosis. For diagnosing any fibrosis severity, WFA+ -M2BP had greater area under the receiver operating characteristic curve (AUC) and predictive accuracy than M2BP. Among eight fibrosis markers/indices, WFA+ -M2BP yielded the second highest AUC (0.832) and the highest predictive accuracy (82.2%) to diagnose cirrhosis. In addition, WFA+ -M2BP showed the second highest predictive accuracy to diagnose severe fibrosis (78.4%) and significant fibrosis (76.1%). CONCLUSION This head-to-head comparison suggests that WFA+ -M2BP is superior to M2BP for distinguishing liver fibrosis stages in NAFLD patients. A marked discrepancy between the two biomarkers may be indicative of advanced NAFLD (UMIN000023286).
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Affiliation(s)
- Masanori Atsukawa
- Department of Internal Medicine, Division of Gastroenterology, Nippon Medical School Chiba Hokusoh Hospital, Chiba, Japan.,Department of Internal Medicine, Division of Gastroenterology and Hepatology, Nippon Medical School, Tokyo, Japan
| | - Akihito Tsubota
- Core Research Facilities for Basic Science, Research Center for Medical Sciences, The Jikei University School of Medicine, Tokyo, Japan
| | - Tomomi Okubo
- Department of Internal Medicine, Division of Gastroenterology, Nippon Medical School Chiba Hokusoh Hospital, Chiba, Japan
| | - Taeang Arai
- Department of Internal Medicine, Division of Gastroenterology, Nippon Medical School Chiba Hokusoh Hospital, Chiba, Japan
| | - Ai Nakagawa
- Department of Internal Medicine, Division of Gastroenterology, Nippon Medical School Chiba Hokusoh Hospital, Chiba, Japan
| | - Norio Itokawa
- Department of Internal Medicine, Division of Gastroenterology, Nippon Medical School Chiba Hokusoh Hospital, Chiba, Japan
| | - Chisa Kondo
- Department of Internal Medicine, Division of Gastroenterology, Nippon Medical School Chiba Hokusoh Hospital, Chiba, Japan
| | - Keizo Kato
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, Shinmatsudo Central General Hospital, Chiba, Japan
| | - Tsutomu Hatori
- Department of Pathology, Nippon Medical School Chiba Hokusoh Hospital, Chiba, Japan
| | - Hiroshi Hano
- Department of Pathology, The Jikei University School of Medicine, Tokyo, Japan
| | - Tsunekazu Oikawa
- Department of Gastroenterology and Hepatology, The Jikei University School of Medicine, Tokyo, Japan
| | - Naoya Emoto
- Department of Internal Medicine, Division of Endocrinology, Nippon Medical School Chiba Hokusoh Hospital, Chiba, Japan
| | - Masanori Abe
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Ehime, Japan
| | - Masayoshi Kage
- Molecular Targeting Therapeutics Division, Research Center for Innovative Cancer Therapy, Kurume University, Fukuoka, Japan
| | - Katsuhiko Iwakiri
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, Nippon Medical School, Tokyo, Japan
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Nagy N, Kuipers HF, Marshall PL, Wang E, Kaber G, Bollyky PL. Hyaluronan in immune dysregulation and autoimmune diseases. Matrix Biol 2018; 78-79:292-313. [PMID: 29625181 DOI: 10.1016/j.matbio.2018.03.022] [Citation(s) in RCA: 51] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2017] [Revised: 03/10/2018] [Accepted: 03/30/2018] [Indexed: 02/06/2023]
Abstract
The tissue microenvironment contributes to local immunity and to the pathogenesis of autoimmune diseases - a diverse set of conditions characterized by sterile inflammation, immunity against self-antigens, and destruction of tissues. However, the specific factors within the tissue microenvironment that contribute to local immune dysregulation in autoimmunity are poorly understood. One particular tissue component implicated in multiple autoimmune diseases is hyaluronan (HA), an extracellular matrix (ECM) polymer. HA is abundant in settings of chronic inflammation and contributes to lymphocyte activation, polarization, and migration. Here, we first describe what is known about the size, amount, and distribution of HA at sites of autoimmunity and in associated lymphoid structures in type 1 diabetes, multiple sclerosis, and rheumatoid arthritis. Next, we examine the recent literature on HA and its impact on adaptive immunity, particularly in regards to the biology of lymphocytes and Foxp3+ regulatory T-cells (Treg), a T-cell subset that maintains immune tolerance in healthy individuals. We propose that HA accumulation at sites of chronic inflammation creates a permissive environment for autoimmunity, characterized by CD44-mediated inhibition of Treg expansion. Finally, we address potential tools and strategies for targeting HA and its receptor CD44 in chronic inflammation and autoimmunity.
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Affiliation(s)
- Nadine Nagy
- Division of Infectious Diseases and Geographic Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA.
| | - Hedwich F Kuipers
- Division of Infectious Diseases and Geographic Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA
| | - Payton L Marshall
- Division of Infectious Diseases and Geographic Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA
| | - Esther Wang
- Division of Infectious Diseases and Geographic Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA
| | - Gernot Kaber
- Division of Infectious Diseases and Geographic Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA
| | - Paul L Bollyky
- Division of Infectious Diseases and Geographic Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA
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50
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Xu WP, Wang ZR, Zou X, Zhao C, Wang R, Shi PM, Yuan ZL, Yang F, Zeng X, Wang PQ, Sultan S, Zhang Y, Xie WF. Serum Wisteria floribunda agglutinin-positive Mac-2-binding protein evaluates liver function and predicts prognosis in liver cirrhosis. J Dig Dis 2018; 19:242-253. [PMID: 29607614 DOI: 10.1111/1751-2980.12596] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/30/2018] [Revised: 03/21/2018] [Accepted: 03/29/2018] [Indexed: 12/11/2022]
Abstract
OBJECTIVE Wisteria floribunda agglutinin-positive Mac-2-binding protein (WFA+ -M2BP) is a novel glycobiomarker for evaluating liver fibrosis, but less is known about its role in liver cirrhosis (LC). This study aimed to investigate the utility of WFA+ -M2BP in evaluating liver function and predicting prognosis of cirrhotic patients. METHODS We retrospectively included 197 patients with LC between 2013 and 2016. Serum WFA+ -M2BP and various biochemical parameters were measured in all patients. With a median follow-up of 23 months, liver-related complications and deaths of 160 patients were recorded. The accuracy of WFA+ -M2BP in evaluating liver function, predicting decompensation and mortality were measured by the receiver operating characteristic (ROC) curve, logistic and Cox's regression analyses, respectively. RESULTS WFA+ -M2BP levels increased with elevated Child-Pugh classification, especially in patients with hepatitis B virus (HBV) infection. ROC analysis confirmed the high reliability of WFA+ -M2BP for the assessment of liver function using Child-Pugh classification. WFA+ -M2BP was also significantly positively correlated with the model for end-stage liver disease (MELD) score. Multivariate logistic regression analysis indicated WFA+ -M2BP as an independent predictor of clinical decompensation for compensated patients (odds ratio 11.958, 95% confidence interval [CI] 1.876-76.226, P = 0.009), and multivariate Cox's regression analysis verified WFA+ -M2BP as an independent risk factor for liver-related death in patients with HBV infection (hazards ratio 10.596, 95% CI 1.356-82.820, P = 0.024). CONCLUSION Serum WFA+ -M2BP is a reliable predictor of liver function and prognosis in LC and could be incorporated into clinical surveillance strategies for LC patients, especially those with HBV infection.
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Affiliation(s)
- Wen Ping Xu
- Department of Gastroenterology, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Ze Rui Wang
- Department of Gastroenterology, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Xia Zou
- Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai, China
| | - Chen Zhao
- Department of Gastroenterology, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Rui Wang
- Department of Health Statistics, Faculty of Health Service, Second Military Medical University, Shanghai, China
| | - Pei Mei Shi
- Department of Gastroenterology, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Zong Li Yuan
- Department of Gastroenterology, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Fang Yang
- Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai, China
| | - Xin Zeng
- Department of Gastroenterology, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Pei Qin Wang
- Department of Gastroenterology, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Sakhawat Sultan
- Department of Gastroenterology, Combined Military Hospital, Dhaka, Bangladesh
| | - Yan Zhang
- Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai, China
| | - Wei Fen Xie
- Department of Gastroenterology, Changzheng Hospital, Second Military Medical University, Shanghai, China
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