|
1
|
Verhelst X, Dias AM, Colombel JF, Vermeire S, Van Vlierberghe H, Callewaert N, Pinho SS. Protein Glycosylation as a Diagnostic and Prognostic Marker of Chronic Inflammatory Gastrointestinal and Liver Diseases. Gastroenterology 2020; 158:95-110. [PMID: 31626754 DOI: 10.1053/j.gastro.2019.08.060] [Citation(s) in RCA: 95] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2019] [Revised: 08/03/2019] [Accepted: 08/23/2019] [Indexed: 12/16/2022]
Abstract
Glycans are sequences of carbohydrates that are added to proteins or lipids to modulate their structure and function. Glycans modify proteins required for regulation of immune cells, and alterations have been associated with inflammatory conditions. For example, specific glycans regulate T-cell activation, structures, and functions of immunoglobulins; interactions between microbes and immune and epithelial cells; and malignant transformation in the intestine and liver. We review the effects of protein glycosylation in regulation of gastrointestinal and liver functions, and how alterations in glycosylation serve as diagnostic or prognostic factors, or as targets for therapy.
Collapse
Affiliation(s)
- Xavier Verhelst
- Department of Gastroenterology and Hepatology, Ghent University Hospital, Ghent, Belgium
| | - Ana M Dias
- Institute of Molecular Pathology and Immunology, University of Porto, Porto, Portugal; Institute for Research and Innovation in Health, University of Porto, Porto, Portugal
| | | | - Severine Vermeire
- Translational Research in Gastrointestinal Disorders, Department of Clinical and Experimental Medicine, Katholieke Universiteit Leuven, Leuven, Belgium; Department of Gastroenterology and Hepatology, University Hospitals Leuven, Katholieke Universiteit Leuven, Leuven, Belgium
| | - Hans Van Vlierberghe
- Department of Gastroenterology and Hepatology, Ghent University Hospital, Ghent, Belgium
| | - Nico Callewaert
- Vlaams Instituut voor Biotechnologie-UGent Center for Medical Biotechnology, Gent, Belgium
| | - Salomé S Pinho
- Institute of Molecular Pathology and Immunology, University of Porto, Porto, Portugal; Institute for Research and Innovation in Health, University of Porto, Porto, Portugal; Medical Faculty, University of Porto, Porto, Portugal.
| |
Collapse
|
|
2
|
Shimazaki H, Saito K, Matsuda A, Sawakami K, Kariya M, Segawa O, Miyashita Y, Ueda T, Koizuka M, Nakamura K, Kaji H, Tajima H, Kuno A. Lectin Bead Array in a Single Tip Facilitates Fully Automatic Glycoprotein Profiling. Anal Chem 2019; 91:11162-11169. [DOI: 10.1021/acs.analchem.9b01876] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Affiliation(s)
- Hiroko Shimazaki
- Glycoscience and Glycotechnology Research Group, Biotechnology Research Institute for Drug Discovery, National Institute of Advanced Industrial Science and Technology, Tsukuba, Ibaraki 305-8568, Japan
| | - Kozue Saito
- Glycoscience and Glycotechnology Research Group, Biotechnology Research Institute for Drug Discovery, National Institute of Advanced Industrial Science and Technology, Tsukuba, Ibaraki 305-8568, Japan
| | - Atsushi Matsuda
- Glycoscience and Glycotechnology Research Group, Biotechnology Research Institute for Drug Discovery, National Institute of Advanced Industrial Science and Technology, Tsukuba, Ibaraki 305-8568, Japan
| | - Kazumi Sawakami
- Precision System Science, Kamihongou, Matsudo, Chiba 271-0064, Japan
| | - Minoru Kariya
- Precision System Science, Kamihongou, Matsudo, Chiba 271-0064, Japan
| | - Osamu Segawa
- Precision System Science, Kamihongou, Matsudo, Chiba 271-0064, Japan
| | - Yukiko Miyashita
- Precision System Science, Kamihongou, Matsudo, Chiba 271-0064, Japan
| | - Tetsuya Ueda
- Precision System Science, Kamihongou, Matsudo, Chiba 271-0064, Japan
| | - Michinori Koizuka
- Precision System Science, Kamihongou, Matsudo, Chiba 271-0064, Japan
| | - Kazuhiro Nakamura
- Precision System Science, Kamihongou, Matsudo, Chiba 271-0064, Japan
| | - Hiroyuki Kaji
- Glycoscience and Glycotechnology Research Group, Biotechnology Research Institute for Drug Discovery, National Institute of Advanced Industrial Science and Technology, Tsukuba, Ibaraki 305-8568, Japan
| | - Hideji Tajima
- Precision System Science, Kamihongou, Matsudo, Chiba 271-0064, Japan
| | - Atsushi Kuno
- Glycoscience and Glycotechnology Research Group, Biotechnology Research Institute for Drug Discovery, National Institute of Advanced Industrial Science and Technology, Tsukuba, Ibaraki 305-8568, Japan
| |
Collapse
|
|
3
|
Moon HW, Park M, Hur M, Kim H, Choe WH, Yun YM. Usefulness of Enhanced Liver Fibrosis, Glycosylation Isomer of Mac-2 Binding Protein, Galectin-3, and Soluble Suppression of Tumorigenicity 2 for Assessing Liver Fibrosis in Chronic Liver Diseases. Ann Lab Med 2018; 38:331-337. [PMID: 29611383 PMCID: PMC5895862 DOI: 10.3343/alm.2018.38.4.331] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2017] [Revised: 11/14/2017] [Accepted: 01/29/2018] [Indexed: 01/05/2023] Open
Abstract
BACKGROUND Liver biopsies have been partially replaced by noninvasive methods for assessing liver fibrosis. We explored the usefulness of four novel biomarkers, enhanced liver fibrosis (ELF), glycosylation isomer of Mac-2 binding protein (M2BPGi), galectin-3, and soluble suppression of tumorigenicity 2 (sST2), in association with liver fibrosis. METHODS ELF, M2BPGi, galectin-3, and sST2 were assayed in 173 patients with chronic liver diseases. The results were analyzed according to fibrosis grade (F0/1, F2, and F3/4) by transient elastography (TE). RESULTS ELF, M2BPGi, galectin-3, and sST2 values differed significantly according to TE grade; ELF and M2BPGi values were higher in F2 and F3/4 than in F0/1 (P≤0.001, all), sST2 values were higher in F3/4 than in F0/1 and F2 (P<0.05), and galectin-3 values were higher in F3/4 than in F0/1 (P=0.0036). ELF and M2BPGi showed good TE fibrosis detection performance (area under the curves [AUC], 0.841 and 0.833 for ≥F2; and 0.837 and 0.808 for ≥F3). The sensitivity and specificity for predicting TE grade F≥2 were 84.1% and 76.7% for ELF and 63.6% and 91.5% for M2BPGi. CONCLUSIONS This is the first study to compare the liver fibrosis assessment of four novel biomarkers: ELF, M2BPGi, galectin-3, and sST2. The biomarkers varied significantly according to TE grade, and each biomarker showed a different trend. ELF and M2BPGi seem to have comparable good performance for detecting liver fibrosis.
Collapse
Affiliation(s)
- Hee Won Moon
- Department of Laboratory Medicine, Konkuk University School of Medicine, Seoul, Korea
| | - Mikyoung Park
- Department of Laboratory Medicine, Konkuk University School of Medicine, Seoul, Korea
| | - Mina Hur
- Department of Laboratory Medicine, Konkuk University School of Medicine, Seoul, Korea.
| | - Hanah Kim
- Department of Laboratory Medicine, Konkuk University School of Medicine, Seoul, Korea
| | - Won Hyeok Choe
- Department of Internal Medicine, Konkuk University School of Medicine, Seoul, Korea
| | - Yeo Min Yun
- Department of Laboratory Medicine, Konkuk University School of Medicine, Seoul, Korea
| |
Collapse
|
|
4
|
Inoue T, Tsuzuki Y, Iio E, Shinkai N, Matsunami K, Fujiwara K, Matsuura K, Nojiri S, Tanaka Y. Clinical Evaluation of Hepatocarcinogenesis and Outcome Using a Novel Glycobiomarker Wisteria floribunda Agglutinin-Positive Mac-2 Binding Protein (WFA +-M2BP) in Chronic Hepatitis C with Advanced Fibrosis. Jpn J Infect Dis 2018; 71:177-183. [PMID: 29491234 DOI: 10.7883/yoken.jjid.2017.459] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
This study aimed to assess the association between the serum glycobiomarker Wisteria floribunda agglutinin-positive Mac-2 binding protein (WFA+-M2BP) for liver fibrosis and outcomes and carcinogenesis of hepatocellular carcinoma (HCC) in chronic hepatitis C (CHC) patients with advanced fibrosis. Serum WFA+-M2BP levels were measured in 128 consecutive CHC patients including 49 with HCC histopathologically diagnosed with advanced fibrosis (44 with fibrosis stage F3 and 84 with fibrosis stage F4) in our hospital. The median WFA+-M2BP level was significantly higher in F4 than in F3 patients (6.9 vs. 2.3 cutoff index [COI], respectively; p<0.001). The difference in WFA+-M2BP levels between patients with and without HCC was not significant. The respective 5-/8-yr survival rates of patients without HCC at enrollment with high (≥4 COI, n=39), intermediate (1-4 COI, n=33), and low WFA+-M2BP (<1 COI, n=7) levels were 78%/48%, 100%/82%, and 100%/100%, respectively. The differences in survival rates between groups were significant (p=0.0041). Patients with high WFA+-M2BP levels had a significantly higher incidence of HCC than those with low WFA+-M2BP levels (p=0.0019). Cumulative 5-yr carcinogenesis rates in patients with high, intermediate, and low WFA+-M2BP levels were 48.7%, 16.9%, and 0%, respectively; the differences between groups were significant (p=0.002). Serum WFA+-M2BP levels might allow the prediction of carcinogenesis and outcome in CHC patients with advanced fibrosis.
Collapse
MESH Headings
- Adult
- Aged
- Aged, 80 and over
- Antigens, Neoplasm/blood
- Antigens, Neoplasm/chemistry
- Biomarkers/blood
- Biomarkers/chemistry
- Carcinoma, Hepatocellular/complications
- Carcinoma, Hepatocellular/diagnosis
- Carcinoma, Hepatocellular/epidemiology
- Female
- Hepatitis C, Chronic/complications
- Hepatitis C, Chronic/diagnosis
- Hepatitis C, Chronic/epidemiology
- Humans
- Liver Cirrhosis/complications
- Liver Cirrhosis/diagnosis
- Liver Cirrhosis/epidemiology
- Liver Neoplasms/complications
- Liver Neoplasms/diagnosis
- Liver Neoplasms/epidemiology
- Male
- Membrane Glycoproteins/blood
- Membrane Glycoproteins/chemistry
- Middle Aged
- Plant Lectins
- Receptors, N-Acetylglucosamine
- Young Adult
Collapse
Affiliation(s)
- Takako Inoue
- Department of Clinical Laboratory Medicine, Nagoya City University Hospital
| | - Yuji Tsuzuki
- Clinical Laboratory, Nagoya City University Hospital
| | - Etsuko Iio
- Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences
| | - Noboru Shinkai
- Department of Virology and Liver Unit, Nagoya City University Graduate School of Medical Sciences
| | - Kayoko Matsunami
- Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences
| | - Kei Fujiwara
- Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences
| | - Kentaro Matsuura
- Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences
| | - Shunsuke Nojiri
- Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences
| | - Yasuhito Tanaka
- Department of Clinical Laboratory Medicine, Nagoya City University Hospital
- Department of Virology and Liver Unit, Nagoya City University Graduate School of Medical Sciences
| |
Collapse
|
|
5
|
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).
Collapse
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
| |
Collapse
|
|
6
|
Prospects in non-invasive assessment of liver fibrosis: Liquid biopsy as the future gold standard? Biochim Biophys Acta Mol Basis Dis 2018; 1864:1024-1036. [PMID: 29329986 DOI: 10.1016/j.bbadis.2018.01.009] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2017] [Revised: 01/04/2018] [Accepted: 01/07/2018] [Indexed: 12/11/2022]
Abstract
Liver fibrosis is the result of persistent liver injury, and is characterized by sustained scar formation and disruption of the normal liver architecture. The extent of fibrosis is considered as an important prognostic factor for the patient outcome, as an absence of (early) treatment can lead to the development of liver cirrhosis and hepatocellular carcinoma. Till date, the most sensitive and specific way for the diagnosis and staging of liver fibrosis remains liver biopsy, an invasive diagnostic tool, which is associated with high costs and discomfort for the patient. Over time, non-invasive scoring systems have been developed, of which the measurements of serum markers and liver stiffness are validated for use in the clinic. These tools lack however the sensitivity and specificity to detect small changes in the progression or regression of both early and late stages of fibrosis. Novel non-invasive diagnostic markers with the potential to overcome these limitations have been developed, but often lack validation in large patient cohorts. In this review, we will summarize novel trends in non-invasive markers of liver fibrosis development and will discuss their (dis-)advantages for use in the clinic.
Collapse
|
|
7
|
Ito K, Murotani K, Nakade Y, Inoue T, Nakao H, Sumida Y, Kamada Y, Yoneda M. Serum Wisteria floribunda agglutinin-positive Mac-2-binding protein levels and liver fibrosis: A meta-analysis. J Gastroenterol Hepatol 2017; 32:1922-1930. [PMID: 28406534 DOI: 10.1111/jgh.13802] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2017] [Revised: 04/03/2017] [Accepted: 04/05/2017] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND AIM A reliable, non-invasive biomarker for diagnosis of liver fibrosis in chronic liver disease patients is needed. The aim of this study was to assess by meta-analysis the efficacy of measuring serum levels of Wisteria floribunda agglutinin-positive Mac-2-binding protein (WFA+ -M2BP), a novel and promising biomarker, for staging liver fibrosis and predicting the development of hepatocellular carcinoma and overall survival. METHODS We performed a meta-analysis using online journal database searches. We identified 39 studies, 21 of which met the criteria for meta-analysis. Sensitivity and specificity of WFA+ -M2BP for assessing liver fibrosis staging in chronic liver diseases with broad etiologies were determined. Hazard ratios with 95% confidence intervals were also used for predicting hepatocellular carcinoma development and overall survival. RESULTS With WFA+ -M2BP, the sensitivity and specificity for predicting significant fibrosis (≥ F2), advanced fibrosis (≥ F3), and liver cirrhosis (= F4) were 0.690 and 0.778, 0.764 and 0.758, and 0.818 and 0.839, respectively. Sensitivity and specificity for diagnosing liver fibrosis in patients with hepatitis C virus were mostly higher than those in overall patients. However, sensitivity and specificity for diagnosing liver fibrosis in patients with hepatitis B virus were lower than those in overall patients. Overall, hazard ratios for development of hepatocellular carcinoma and overall survival were 5.946 and 1.068, respectively. CONCLUSIONS These results suggest that serum WFA+ -M2BP is a reliable predictor for liver fibrosis staging and a good substitute for liver biopsy. It is also useful for predicting both hepatocellular carcinoma development and overall survival.
Collapse
Affiliation(s)
- Kiyoaki Ito
- Department of Gastroenterology, Aichi Medical University School of Medicine, Nagakute, Japan
| | - Kenta Murotani
- Division of Biostatistics, Clinical Research Center, Aichi Medical University School of Medicine, Nagakute, Japan
| | - Yukiomi Nakade
- Department of Gastroenterology, Aichi Medical University School of Medicine, Nagakute, Japan
| | - Tadahisa Inoue
- Department of Gastroenterology, Aichi Medical University School of Medicine, Nagakute, Japan
| | - Haruhisa Nakao
- Department of Gastroenterology, Aichi Medical University School of Medicine, Nagakute, Japan
| | - Yoshio Sumida
- Department of Gastroenterology, Aichi Medical University School of Medicine, Nagakute, Japan
| | - Yoshihiro Kamada
- Department of Molecular Biochemistry and Clinical Investigation, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Masashi Yoneda
- Department of Gastroenterology, Aichi Medical University School of Medicine, Nagakute, Japan
| |
Collapse
|
|
8
|
Zhang S, Cao X, Gao Q, Liu Y. Protein glycosylation in viral hepatitis-related HCC: Characterization of heterogeneity, biological roles, and clinical implications. Cancer Lett 2017; 406:64-70. [PMID: 28789967 DOI: 10.1016/j.canlet.2017.07.026] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2017] [Revised: 07/26/2017] [Accepted: 07/30/2017] [Indexed: 12/12/2022]
|
|
9
|
Xu H, Kong W, Liu L, Chi X, Wang X, Wu R, Gao X, Wang H, Qu L, Qi Y, Pan Y, Niu J. Accuracy of M2BPGi, compared with Fibro Scan®, in analysis of liver fibrosis in patients with hepatitis C. BMC Gastroenterol 2017; 17:62. [PMID: 28486931 PMCID: PMC5424376 DOI: 10.1186/s12876-017-0618-5] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/19/2016] [Accepted: 05/01/2017] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND Mac-2 Binding Protein Glycosylation isomer (M2BPGi) is a novel serological glyco-biomarker for staging liver fibrosis. Here, we aimed to evaluate the efficiency of serum M2BPGi in identifying liver fibrosis stages in Chinese patients with chronic hepatitis C infection. METHODS Serum M2BPGi levels were evaluated in 680 patients with chronic hepatitis C and 164 healthy controls who underwent the Fibro Scan® test of liver fibrosis. The diagnostic accuracy of serum M2BPGi values was compared to that of other fibrosis markers, including Fibro Scan®, the aspartate transaminase to platelet ratio index (APRI), the fibrosis index based on four factors (FIB4), and the gamma-glutamyltranspeptidase to platelet ratio (GPR). RESULTS Among the chronic hepatitis C patients, the median serum M2BPGi level increased with increasing fibrosis score as follows: 0.88 (≤F2), 1.70 (F2/F3), and 5.68 (cirrhosis). M2BPGi concentrations could also distinguish between healthy controls (0.38 ± 0.24) and hepatitis C patients (1.57 ± 2.28). After adjusting for potential confounders, M2BPGi was the most significant factor associated with the liver stiffness measurement (effect size = 0.275, P < 0.001). The optimum cutoff values of serum M2BPGi for patients with F2 and F4 were 0.945 and 1.355, respectively. The area under the curve of serum M2BPGi for prediction of significant fibrosis (F ≥ 4) using was comparable to that of APRI (0.892 vs. 0.873), while it was superior to that of other alternative markers, including FIB4 (0.818) and GPR (0.851). Compared with other non-invasive markers, M2BPGi had the greatest specificity for diagnosing cirrhosis and cirrhosis in hepatitis C patients. CONCLUSIONS Our results suggest that the level of serum M2BPGi would be a simple and reliable diagnostic tool for identifying liver fibrosis stage in Chinese patients with chronic hepatitis.
Collapse
Affiliation(s)
- Hongqin Xu
- Department of Hepatology, First Hospital of Jilin University, Jilin University, Changchun, 130021, China.,Jilin Province Key Laboratory of Infectious Diseases, Laboratory of Molecular Virology, Changchun, 130061, China
| | - Wenli Kong
- Department of Hepatology, First Hospital of Jilin University, Jilin University, Changchun, 130021, China
| | - Lei Liu
- Department of Hepatology, First Hospital of Jilin University, Jilin University, Changchun, 130021, China
| | - Xiumei Chi
- Department of Hepatology, First Hospital of Jilin University, Jilin University, Changchun, 130021, China.,Jilin Province Key Laboratory of Infectious Diseases, Laboratory of Molecular Virology, Changchun, 130061, China
| | - Xiaomei Wang
- Department of Hepatology, First Hospital of Jilin University, Jilin University, Changchun, 130021, China.,Jilin Province Key Laboratory of Infectious Diseases, Laboratory of Molecular Virology, Changchun, 130061, China
| | - Ruihong Wu
- Department of Hepatology, First Hospital of Jilin University, Jilin University, Changchun, 130021, China.,Jilin Province Key Laboratory of Infectious Diseases, Laboratory of Molecular Virology, Changchun, 130061, China
| | - Xiuzhu Gao
- Department of Hepatology, First Hospital of Jilin University, Jilin University, Changchun, 130021, China.,Jilin Province Key Laboratory of Infectious Diseases, Laboratory of Molecular Virology, Changchun, 130061, China
| | - Huan Wang
- Department of Hepatology, First Hospital of Jilin University, Jilin University, Changchun, 130021, China
| | - Limei Qu
- Department of Pathology, First Hospital of Jilin University, Jilin University, Changchun, 130021, China
| | - Yue Qi
- Department of Hepatology, First Hospital of Jilin University, Jilin University, Changchun, 130021, China
| | - Yu Pan
- Department of Hepatology, First Hospital of Jilin University, Jilin University, Changchun, 130021, China.
| | - Junqi Niu
- Department of Hepatology, First Hospital of Jilin University, Jilin University, Changchun, 130021, China. .,Ministry of Education Key Laboratory of Zoonosis, Changchun, 130061, China. .,Jilin Province Key Laboratory of Infectious Diseases, Laboratory of Molecular Virology, Changchun, 130061, China.
| |
Collapse
|
|
10
|
Kamada Y, Miyoshi E. Mac-2 Binding Protein is a Useful Liver Fibrosis Biomarker for NAFLD/NASH. TRENDS GLYCOSCI GLYC 2017. [DOI: 10.4052/tigg.1714.1j] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Affiliation(s)
- Yoshihiro Kamada
- Department of Molecular Biochemistry & Clinical Investigation, Osaka University, Graduate School of Medicine
| | - Eiji Miyoshi
- Department of Molecular Biochemistry & Clinical Investigation, Osaka University, Graduate School of Medicine
| |
Collapse
|
|
11
|
Kamada Y, Miyoshi E. Mac-2 Binding Protein is a Useful Liver Fibrosis Biomarker for NAFLD/NASH. TRENDS GLYCOSCI GLYC 2017; 29:E85-E92. [DOI: 10.4052/tigg.1714.1e] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/09/2025]
Affiliation(s)
- Yoshihiro Kamada
- Department of Molecular Biochemistry & Clinical Investigation, Osaka University, Graduate School of Medicine
| | - Eiji Miyoshi
- Department of Molecular Biochemistry & Clinical Investigation, Osaka University, Graduate School of Medicine
| |
Collapse
|
|
12
|
Inflammatory glycoproteins in cardiometabolic disorders, autoimmune diseases and cancer. Clin Chim Acta 2016; 459:177-186. [PMID: 27312321 DOI: 10.1016/j.cca.2016.06.012] [Citation(s) in RCA: 54] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2016] [Revised: 06/08/2016] [Accepted: 06/11/2016] [Indexed: 12/25/2022]
Abstract
The physiological function initially attributed to the oligosaccharide moieties or glycans on inflammatory glycoproteins was to improve protein stability. However, it is now clear that glycans play a prominent role in glycoprotein structure and function and in some cases contribute to disease states. In fact, glycan processing contributes to pathogenicity not only in autoimmune disorders but also in atherosclerotic cardiovascular disease, diabetes and malignancy. While most clinical laboratory tests measure circulating levels of inflammatory proteins, newly developed diagnostic and prognostic tests are harvesting the information that can be gleaned by measuring the amount or structure of the attached glycans, which may be unique to individuals as well as various diseases. As such, these newer glycan-based tests may provide future means for more personalized approaches to patient stratification and improved patient care. Here we will discuss recent progress in high-throughput laboratory methods for glycomics (i.e. the study of glycan structures) and glycoprotein quantification by methods such as mass spectrometry and nuclear magnetic resonance spectroscopy. We will also review the clinical utility of glycoprotein and glycan measurements in the prediction of common low-grade inflammatory disorders including cardiovascular disease, diabetes and cancer, as well as for monitoring autoimmune disease activity.
Collapse
|
|
13
|
Jin Y, Kim SC, Kim HJ, Ju W, Kim YH, Kim HJ. Increased sialylation and reduced fucosylation of exfoliated cervical cells are potential markers of carcinogenesis in the cervix. ACTA ACUST UNITED AC 2016; 54:1811-1819. [DOI: 10.1515/cclm-2015-1014] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2015] [Accepted: 03/04/2016] [Indexed: 12/15/2022]
Abstract
AbstractBackground:The Pap test has been used for over 50 years for primary screening of cervical cancer. There has been no study of glycosylation changes in Pap test samples despite considerable potential of the glycosylation changes as biomarkers for detecting cancerous lesions. In this study, we developed a 96-well platform for enzyme-linked lectin assays (ELLAs) to evaluate glycosylation levels in cervical cells.Methods:A total of 117 samples of exfoliated cervical cells (ECCs) from 37 individuals with normal cytology, 20 with cervical intraepithelial neoplasia (CIN) 1, 19 with CIN 2, 26 with CIN 3 and 15 with cervical cancer were analyzed by ELLAs. The wells of 96-well plates were coated with lysates of the cervical cells, and sialylation and fucosylation levels were compared between the groups.Results:Sialylation levels increased and fucosylation levels decreased with increasing grade of cervical dysplasia. ELLAs for sialylation [ELLA-Conclusions:The sialylation and fucosylation levels of ECCs as measured by ELLAs have great potential as biomarkers for primary screening of cervical cancer.
Collapse
|
|
14
|
Sheiko MA, Rosen HR. Hepatic Fibrosis in Hepatitis C. HEPATITIS C VIRUS II 2016:79-108. [DOI: 10.1007/978-4-431-56101-9_3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
|
|
15
|
Lurie Y, Webb M, Cytter-Kuint R, Shteingart S, Lederkremer GZ. Non-invasive diagnosis of liver fibrosis and cirrhosis. World J Gastroenterol 2015; 21:11567-11583. [PMID: 26556987 PMCID: PMC4631961 DOI: 10.3748/wjg.v21.i41.11567] [Citation(s) in RCA: 247] [Impact Index Per Article: 24.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2015] [Revised: 07/23/2015] [Accepted: 09/15/2015] [Indexed: 02/07/2023] Open
Abstract
The evaluation and follow up of liver fibrosis and cirrhosis have been traditionally performed by liver biopsy. However, during the last 20 years, it has become evident that this “gold-standard” is imperfect; even according to its proponents, it is only “the best” among available methods. Attempts at uncovering non-invasive diagnostic tools have yielded multiple scores, formulae, and imaging modalities. All are better tolerated, safer, more acceptable to the patient, and can be repeated essentially as often as required. Most are much less expensive than liver biopsy. Consequently, their use is growing, and in some countries the number of biopsies performed, at least for routine evaluation of hepatitis B and C, has declined sharply. However, the accuracy and diagnostic value of most, if not all, of these methods remains controversial. In this review for the practicing physician, we analyze established and novel biomarkers and physical techniques. We may be witnessing in recent years the beginning of the end of the first phase for the development of non-invasive markers. Early evidence suggests that they might be at least as good as liver biopsy. Novel experimental markers and imaging techniques could produce a dramatic change in diagnosis in the near future.
Collapse
|
|
16
|
Kamada Y, Ono M, Hyogo H, Fujii H, Sumida Y, Mori K, Tanaka S, Yamada M, Akita M, Mizutani K, Fujii H, Yamamoto A, Takamatsu S, Yoshida Y, Itoh Y, Kawada N, Chayama K, Saibara T, Takehara T, Miyoshi E. A novel noninvasive diagnostic method for nonalcoholic steatohepatitis using two glycobiomarkers. Hepatology 2015; 62:1433-1443. [PMID: 26199205 DOI: 10.1002/hep.28002] [Citation(s) in RCA: 56] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2015] [Accepted: 07/20/2015] [Indexed: 12/19/2022]
Abstract
UNLABELLED Nonalcoholic fatty liver disease (NAFLD) is a growing medical problem; thus, discriminating nonalcoholic steatohepatitis (NASH) from NAFLD is of great clinical significance. For the diagnosis of NASH, liver biopsy-proven histological examination is the current gold standard, and noninvasive and reliable biomarkers are greatly needed. Recently, we found that two glycobiomarkers, fucosylated haptoglobin (Fuc-Hpt) and Mac-2 binding protein (Mac2bp), are useful independently for NASH diagnosis. In this study, we confirmed that serum Fuc-Hpt is suitable for the prediction of ballooning hepatocytes and that serum Mac2bp is suitable for the prediction of liver fibrosis severity in 124 biopsy-proven NAFLD patients (training cohort). In addition, we found that the combination of serum Fuc-Hpt and Mac2bp levels was an excellent tool for NASH diagnosis. Using receiver operating characteristic analyses, the area under the receiver operating characteristic curve, sensitivity, and specificity of the combination of these two glycobiomarkers were 0.854, 81.1%, and 79.3%, respectively. We established a prediction model for NASH diagnosis using logistic regression analysis: logit (p)=-2.700+0.00242×Fuc-Hpt+1.225×Mac2bp. To validate the prediction model, another 382 biopsy-proven NAFLD patients were enrolled (validation cohort). In the validation cohort, the area under the receiver operating characteristic curve of this model for NASH diagnosis was 0.844, with 71.4% and 82.3% sensitivity and specificity, respectively. In addition, we investigated the significance of our developed NASH diagnosis model in ultrasound-diagnosed NAFLD subjects who received medical health checkups (n = 803). Our model also could predict NAFLD disease severity in this larger population. CONCLUSION The combination of serum Fuc-Hpt and Mac2bp can distinguish NASH from NAFLD patients. Our noninvasive model using two serum glycobiomarkers contributes to a novel NASH diagnostic methodology that could replace liver biopsy.
Collapse
Affiliation(s)
- Yoshihiro Kamada
- Department of Molecular Biochemistry and Clinical Investigation, Osaka University, Graduate School of Medicine, Osaka, Japan
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Masafumi Ono
- Department of Gastroenterology and Hepatology, Kochi Medical School, Kochi, Japan
| | - Hideyuki Hyogo
- Department of Gastroenterology and Metabolism, Hiroshima University, Hiroshima, Japan
| | - Hideki Fujii
- Department of Hepatology, Osaka City University Graduate School of Medicine, Osaka, Japan
- Department of Gastroenterology, Osaka City Juso Hospital, Osaka, Japan
| | - Yoshio Sumida
- Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Kojiroh Mori
- Center for Digestive and Liver Diseases, Nara City Hospital, Nara, Japan
| | - Saiyu Tanaka
- Center for Digestive and Liver Diseases, Nara City Hospital, Nara, Japan
| | | | - Maaya Akita
- Department of Molecular Biochemistry and Clinical Investigation, Osaka University, Graduate School of Medicine, Osaka, Japan
| | - Kayo Mizutani
- Department of Molecular Biochemistry and Clinical Investigation, Osaka University, Graduate School of Medicine, Osaka, Japan
| | - Hironobu Fujii
- Department of Molecular Biochemistry and Clinical Investigation, Osaka University, Graduate School of Medicine, Osaka, Japan
| | - Akiko Yamamoto
- Department of Molecular Biochemistry and Clinical Investigation, Osaka University, Graduate School of Medicine, Osaka, Japan
| | - Shinji Takamatsu
- Department of Molecular Biochemistry and Clinical Investigation, Osaka University, Graduate School of Medicine, Osaka, Japan
| | - Yuichi Yoshida
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Yoshito Itoh
- Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Norifumi Kawada
- Department of Hepatology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Kazuaki Chayama
- Department of Gastroenterology and Metabolism, Hiroshima University, Hiroshima, Japan
| | - Toshiji Saibara
- Department of Gastroenterology and Hepatology, Kochi Medical School, Kochi, Japan
| | - Tetsuo Takehara
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Eiji Miyoshi
- Department of Molecular Biochemistry and Clinical Investigation, Osaka University, Graduate School of Medicine, Osaka, Japan
| |
Collapse
|
|
17
|
Yan SK, Liu RH, Jin HZ, Liu XR, Ye J, Shan L, Zhang WD. "Omics" in pharmaceutical research: overview, applications, challenges, and future perspectives. Chin J Nat Med 2015; 13:3-21. [PMID: 25660284 DOI: 10.1016/s1875-5364(15)60002-4] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2014] [Indexed: 12/18/2022]
Abstract
In the post-genomic era, biological studies are characterized by the rapid development and wide application of a series of "omics" technologies, including genomics, proteomics, metabolomics, transcriptomics, lipidomics, cytomics, metallomics, ionomics, interactomics, and phenomics. These "omics" are often based on global analyses of biological samples using high through-put analytical approaches and bioinformatics and may provide new insights into biological phenomena. In this paper, the development and advances in these omics made in the past decades are reviewed, especially genomics, transcriptomics, proteomics and metabolomics; the applications of omics technologies in pharmaceutical research are then summarized in the fields of drug target discovery, toxicity evaluation, personalized medicine, and traditional Chinese medicine; and finally, the limitations of omics are discussed, along with the future challenges associated with the multi-omics data processing, dynamics omics analysis, and analytical approaches, as well as amenable solutions and future prospects.
Collapse
Affiliation(s)
- Shi-Kai Yan
- School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China
| | - Run-Hui Liu
- School of Pharmacy, Second Military Medical University, Shanghai 200433, China
| | - Hui-Zi Jin
- School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China
| | - Xin-Ru Liu
- School of Pharmacy, Second Military Medical University, Shanghai 200433, China
| | - Ji Ye
- School of Pharmacy, Second Military Medical University, Shanghai 200433, China
| | - Lei Shan
- School of Pharmacy, Second Military Medical University, Shanghai 200433, China
| | - Wei-Dong Zhang
- School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China; School of Pharmacy, Second Military Medical University, Shanghai 200433, China; Shanghai Institute of Pharmaceutical Industry, Shanghai 200040, China.
| |
Collapse
|
|
18
|
Narimatsu H. Development of M2BPGi: a novel fibrosis serum glyco-biomarker for chronic hepatitis/cirrhosis diagnostics. Expert Rev Proteomics 2015; 12:683-93. [PMID: 26394846 DOI: 10.1586/14789450.2015.1084874] [Citation(s) in RCA: 58] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Many proteins in the living body are glycoproteins, which present glycans linked on their surface. Glycan structures reflect the degree of cell differentiation or canceration and are cell specific. These characteristics are advantageous in the development of various disease biomarkers. Glycoprotein-based biomarkers (glyco-biomarkers) are developed by utilizing the specific changes in the glycan structure on a glycoprotein secreted from the diseased cells of interest. Therefore, quantification of the altered glycan structures is the key to developing a new glyco-biomarker. Glycoscience is a relatively new area of molecular science, and recent advancement of glycotechnologies is remarkable. In the author's institute, new glycoscience technologies have been designed to be efficiently utilized for the development of new diagnostic agents. This paper introduces a strategy for glyco-biomarker development, which was successfully applied in the development of Wisteria floribunda agglutinin-positive Mac-2 binding protein M2BPGi, a liver fibrosis marker now commercially available for clinical use.
Collapse
Affiliation(s)
- Hisashi Narimatsu
- a Research Center for Medical Glycoscience (RCMG), National Institute of Advanced Industrial Science and Technology (AIST), Central 2, 1-1-1 Umezono, Tsukuba, Ibaraki, 305-8568, Japan
| |
Collapse
|
|
19
|
Neuman MG, Cohen LB, Nanau RM. Hyaluronic acid as a non-invasive biomarker of liver fibrosis. Clin Biochem 2015; 49:302-15. [PMID: 26188920 DOI: 10.1016/j.clinbiochem.2015.07.019] [Citation(s) in RCA: 73] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2015] [Revised: 07/07/2015] [Accepted: 07/14/2015] [Indexed: 12/14/2022]
Abstract
UNLABELLED Chronic liver diseases may cause inflammation and progressive scarring, over time leading to irreversible hepatic damage (cirrhosis). As a result, the need to assess and closely monitor individuals for risk factors of components of matrix deposition and degradation, as well as the severity of the fibrosis using biomarkers, has been increasingly recognized. AIM Our aim is to review the use of biomarker for diagnosing and defining the severity of liver fibrosis. METHODS A systematic literature review was done using the terms "hyaluronic acid" and "liver fibrosis" as well as the name of each biomarker or algorithm known to be employed. PubMed and Google Scholar were searched, and English language articles indexed between January 2010 and October 2014 in which HA was used as a marker of liver fibrosis were retrieved, regardless of the underlying liver disease. Each author read the publications separately and the results were analyzed and discussed. RESULTS Biomarkers offer a potential prognostic or diagnostic indicator for disease manifestation, progression, or both. Serum biomarkers, including HA, have been used for many years. Emerging biomarkers such as metalloproteinases have been proposed as tools that provide valuable complementary information to that obtained from traditional biomarkers. Moreover, markers of extracellular matrix degradation provide powerful predictions of risk. In order for biomarkers to be clinically useful in accurately diagnosing and treating disorders, age-specific reference intervals that account for differences in gender and ethnic origin are a necessity. CONCLUSIONS This review attempts to provide a comprehensive analysis of the emerging risk biomarkers of liver fibrosis and to describe the clinical significance and analytical considerations of each biomarker pointing out sentinel features of disease progression.
Collapse
Affiliation(s)
- Manuela G Neuman
- Department of Pharmacology & Toxicology, University of Toronto, CEO In Vitro Drug Safety & BioTechnology, Banting Institute, 100 College Street, Lab 217, Toronto, Ontario M5G 0A3, Canada
| | - Lawrence B Cohen
- Department of Pharmacology & Toxicology, University of Toronto, CEO In Vitro Drug Safety & BioTechnology, Banting Institute, 100 College Street, Lab 217, Toronto, Ontario M5G 0A3, Canada; Sunnybrook HSC, Department of Medicine, University of Toronto, Toronto, Canada
| | - Radu M Nanau
- Department of Pharmacology & Toxicology, University of Toronto, CEO In Vitro Drug Safety & BioTechnology, Banting Institute, 100 College Street, Lab 217, Toronto, Ontario M5G 0A3, Canada
| |
Collapse
|
|
20
|
Abe M, Miyake T, Kuno A, Imai Y, Sawai Y, Hino K, Hara Y, Hige S, Sakamoto M, Yamada G, Kage M, Korenaga M, Hiasa Y, Mizokami M, Narimatsu H. Association between Wisteria floribunda agglutinin-positive Mac-2 binding protein and the fibrosis stage of non-alcoholic fatty liver disease. J Gastroenterol 2015; 50:776-84. [PMID: 25326152 DOI: 10.1007/s00535-014-1007-2] [Citation(s) in RCA: 139] [Impact Index Per Article: 13.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2014] [Accepted: 10/08/2014] [Indexed: 02/04/2023]
Abstract
BACKGROUND Accurately evaluating liver fibrosis in patients with non-alcoholic fatty liver disease (NAFLD) is important for identifying those who may develop complications. The aims of this study were (1) to measure serum Wisteria floribunda agglutinin-positive Mac-2 binding protein (WFA(+)-M2BP) using the glycan sugar chain-based immunoassay and (2) to compare the results with clinical assessments of fibrosis. METHODS Serum WFA(+)-M2BP values were retrospectively evaluated in 289 patients with NAFLD who had undergone liver biopsy. Histological findings were evaluated by three blinded, experienced liver-specific pathologists. RESULTS For stages 0 (n = 35), 1 (n = 113), 2 (n = 49), 3 (n = 41), and 4 (n = 51) of liver fibrosis, the serum WFA(+)-M2BP cutoff indexes were 0.57, 0.70, 1.02, 1.57, and 2.96, respectively. Multivariate regression analysis showed that serum WFA(+)-M2BP values were associated with the stage of fibrosis (≥stage 2). The areas under the receiver operating characteristic curve (AUROC), sensitivity, and specificity of serum WFA(+)-M2BP were 0.876, 85.9, and 74.6%, respectively, for severe fibrosis (≥stage 3) and were 0.879, 74.6, and 87.0%, respectively, for cirrhosis. When compared with six non-invasive conventional markers, serum WFA(+)-M2BP had the greatest AUROC for diagnosing severe fibrosis and cirrhosis. CONCLUSIONS Serum WFA(+)-M2BP values are useful for assessing the stage of liver fibrosis in patients with NAFLD.
Collapse
Affiliation(s)
- Masanori Abe
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Toon, Ehime, 791-0295, Japan,
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
21
|
Enomoto H, Bando Y, Nakamura H, Nishiguchi S, Koga M. Liver fibrosis markers of nonalcoholic steatohepatitis. World J Gastroenterol 2015; 21:7427-7435. [PMID: 26139988 PMCID: PMC4481437 DOI: 10.3748/wjg.v21.i24.7427] [Citation(s) in RCA: 47] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2015] [Revised: 04/27/2015] [Accepted: 05/07/2015] [Indexed: 02/06/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is one of the major causes of chronic liver injury. NAFLD includes a wide range of clinical conditions from simple steatosis to nonalcoholic steatohepatitis (NASH), advanced fibrosis, and liver cirrhosis. The histological findings of NASH indicate hepatic steatosis and inflammation with characteristic hepatocyte injury (e.g., ballooning degeneration), as is observed in the patients with alcoholic liver disease. NASH is considered to be a potentially health-threatening disease that can progress to cirrhosis. A liver biopsy remains the most reliable diagnostic method to appropriately diagnose NASH, evaluate the severity of liver fibrosis, and determine the prognosis and optimal treatment. However, this invasive technique is associated with several limitations in routine use, and a number of biomarkers have been developed in order to predict the degree of liver fibrosis. In the present article, we review the current status of noninvasive biomarkers available to estimate liver fibrosis in the patients with NASH. We also discuss our recent findings on the use of the glycated albumin-to-glycated hemoglobin ratio, which is a new index that correlates to various chronic liver diseases, including NASH.
Collapse
|
|
22
|
Zou X, Chi X, Pan Y, Du D, Sun H, Matsuda A, Li W, Kuno A, Zhang X, Narimatsu H, Niu J, Zhang Y. LecT-Hepa facilitates estimating treatment outcome during interferon therapy in chronic hepatitis C patients. Clin Proteomics 2014; 11:44. [PMID: 25593566 PMCID: PMC4276098 DOI: 10.1186/1559-0275-11-44] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2014] [Accepted: 11/25/2014] [Indexed: 02/07/2023] Open
Abstract
Background A combination treatment of interferon and ribavirin is the standard and the commonly used treatment for chronic hepatitis C (CHC). Developing noninvasive tests like serum indicators that can predict treatment outcome at an early stage of therapy is beneficial for individualized treatment and management of CHC. A glyco-indicator based on the glyco-alteration of serum α1-acid glycoprotein, LecT-Hepa, was discovered by glycomics technologies as a robust indicator of liver fibrosis. Here, we investigated the clinical utility of LecT-Hepa for evaluation of treatment outcome. Results Firstly, ninety-seven patients with CHC were used for comparison of LecT-Hepa in serum and plasma. We found no significant difference in the concentrations of LecT-Hepa in serum and plasma. And then, 213 serum specimens from 45 patients who received 48 weeks of treatment with interferon and ribavirin were followed up for 96 weeks, and were used for evaluation of the role of LecT-Hepa. We found that LecT-Hepa might reflect the change in fibrosis regression during the treatment process. Moreover, the change of LecT-Hepa at the first 12 weeks of treatment could already predict the antiviral treatment response, which was more superior to FIB-4 index and aspartate aminotransferase-to-platelet ratio index (APRI) in this study. Conclusions These results provide a new perspective that serum glycoprotein could be used as a joint diagnosis indicator for estimation treatment outcome of viral hepatitis at earlier stage of therapy. Electronic supplementary material The online version of this article (doi:10.1186/1559-0275-11-44) contains supplementary material, which is available to authorized users.
Collapse
Affiliation(s)
- Xia Zou
- Ministry of Education Key Laboratory of Systems Biomedicine, Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, 800 Dong Chuan Road, Minhang Shanghai, 200240 China.,SCSB (China) - AIST (Japan) Joint Medical Glycomics Laboratory, 800 Dong Chuan Road, Minhang Shanghai, 200240 China.,Department of Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197, Ruijin Er Road, Shanghai, 200025 China
| | - Xiumei Chi
- Department of Hepatology, First Hospital, Jilin University, Changchun, 130021 China
| | - Yu Pan
- Department of Hepatology, First Hospital, Jilin University, Changchun, 130021 China
| | - Dongning Du
- Research Center for Medical Glycoscience (RCMG), National Institute of Advanced Industrial Science and Technology (AIST), 1-1-1 Umezono, Tsukuba, Ibaraki, 305-8568 Japan.,SCSB (China) - AIST (Japan) Joint Medical Glycomics Laboratory, 800 Dong Chuan Road, Minhang Shanghai, 200240 China
| | - Haibo Sun
- Department of Hepatology, First Hospital, Jilin University, Changchun, 130021 China
| | - Atsushi Matsuda
- Research Center for Medical Glycoscience (RCMG), National Institute of Advanced Industrial Science and Technology (AIST), 1-1-1 Umezono, Tsukuba, Ibaraki, 305-8568 Japan.,SCSB (China) - AIST (Japan) Joint Medical Glycomics Laboratory, 800 Dong Chuan Road, Minhang Shanghai, 200240 China
| | - Wei Li
- Ministry of Education Key Laboratory of Systems Biomedicine, Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, 800 Dong Chuan Road, Minhang Shanghai, 200240 China.,SCSB (China) - AIST (Japan) Joint Medical Glycomics Laboratory, 800 Dong Chuan Road, Minhang Shanghai, 200240 China
| | - Atsushi Kuno
- Research Center for Medical Glycoscience (RCMG), National Institute of Advanced Industrial Science and Technology (AIST), 1-1-1 Umezono, Tsukuba, Ibaraki, 305-8568 Japan.,SCSB (China) - AIST (Japan) Joint Medical Glycomics Laboratory, 800 Dong Chuan Road, Minhang Shanghai, 200240 China
| | - Xinxin Zhang
- Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197, Ruijin Er Road, Shanghai, 200025 China
| | - Hisashi Narimatsu
- Research Center for Medical Glycoscience (RCMG), National Institute of Advanced Industrial Science and Technology (AIST), 1-1-1 Umezono, Tsukuba, Ibaraki, 305-8568 Japan.,SCSB (China) - AIST (Japan) Joint Medical Glycomics Laboratory, 800 Dong Chuan Road, Minhang Shanghai, 200240 China
| | - Junqi Niu
- Department of Hepatology, First Hospital, Jilin University, Changchun, 130021 China
| | - Yan Zhang
- Ministry of Education Key Laboratory of Systems Biomedicine, Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, 800 Dong Chuan Road, Minhang Shanghai, 200240 China.,SCSB (China) - AIST (Japan) Joint Medical Glycomics Laboratory, 800 Dong Chuan Road, Minhang Shanghai, 200240 China
| |
Collapse
|
|
23
|
Kamada Y, Fujii H, Fujii H, Sawai Y, Doi Y, Uozumi N, Mizutani K, Akita M, Sato M, Kida S, Kinoshita N, Maruyama N, Yakushijin T, Miyazaki M, Ezaki H, Hiramatsu N, Yoshida Y, Kiso S, Imai Y, Kawada N, Takehara T, Miyoshi E. Serum Mac-2 binding protein levels as a novel diagnostic biomarker for prediction of disease severity and nonalcoholic steatohepatitis. Proteomics Clin Appl 2013; 7:648-656. [PMID: 23775887 DOI: 10.1002/prca.201200137] [Citation(s) in RCA: 51] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2012] [Revised: 02/28/2013] [Accepted: 03/30/2013] [Indexed: 12/12/2022]
Abstract
PURPOSE Mac-2 binding protein (Mac-2 bp) is one of the major fucosylated glycoproteins, which we identified with glycol-proteomic analyses. We previously reported that fucosylated glycoproteins are secreted into bile, but scarcely secreted into sera in normal liver and hypothesized that the fucosylation-based sorting machinery would be disrupted in ballooning hepatocytes due to the loss of cellular polarity. In the present study, we investigated the availability of Mac-2 bp for differential diagnosis of nonalcoholic steatohepatitis (NASH) from nonalcoholic fatty liver disease (NAFLD) as a biomarker. EXPERIMENTAL DESIGN Serum Mac-2 bp levels were determined with our developed ELISA kit. Our cohort of 127 patients with NAFLD had liver biopsy to make a histological diagnosis of NASH and simple fatty liver. RESULTS Mac-2 bp levels were significantly elevated in NASH patients compared with non-NASH (simple steatosis) patients (2.132 ± 1.237 vs. 1.103 ± 0.500 μg/mL, p < 0.01). The area under the receiver-operating characteristic curve for predicting NASH by Mac-2 bp was 0.816. Moreover, multivariate logistic regression analyses showed Mac-2 bp levels could predict the fibrosis stage and the presence of ballooning hepatocytes in NAFLD patients. CONCLUSIONS AND CLINICAL RELEVANCE These results support the potential usefulness of measuring Mac-2 bp levels in clinical practice as a biomarker for NASH.
Collapse
Affiliation(s)
- Yoshihiro Kamada
- Department of Molecular Biochemistry & Clinical Investigation, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
| | - Hideki Fujii
- Department of Hepatology, Graduate School of Medicine, Osaka City University, Abeno-ku, Osaka, Japan
| | - Hironobu Fujii
- Department of Molecular Biochemistry & Clinical Investigation, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
| | - Yoshiyuki Sawai
- Department of Gastroenterology, Ikeda Municipal Hospital, Ikeda, Osaka, Japan
| | - Yoshinori Doi
- Department of Gastroenterology, Otemae Hospital, Osaka, Japan
| | - Naofumi Uozumi
- Department of Molecular Biochemistry & Clinical Investigation, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
- Department of Surgery, Matsumoto Hospital, Kakogawa, Hyogo, Japan
| | - Kayo Mizutani
- Department of Molecular Biochemistry & Clinical Investigation, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
| | - Maaya Akita
- Department of Molecular Biochemistry & Clinical Investigation, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
| | - Motoya Sato
- Department of Molecular Biochemistry & Clinical Investigation, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
| | - Sachiho Kida
- Department of Molecular Biochemistry & Clinical Investigation, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
| | | | | | - Takayuki Yakushijin
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
| | - Masanori Miyazaki
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
| | - Hisao Ezaki
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
| | - Naoki Hiramatsu
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
| | - Yuichi Yoshida
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
| | - Shinichi Kiso
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
| | - Yasuharu Imai
- Department of Gastroenterology, Ikeda Municipal Hospital, Ikeda, Osaka, Japan
| | - Norifumi Kawada
- Department of Hepatology, Graduate School of Medicine, Osaka City University, Abeno-ku, Osaka, Japan
| | - Tetsuo Takehara
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
| | - Eiji Miyoshi
- Department of Molecular Biochemistry & Clinical Investigation, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
| |
Collapse
|
|
24
|
Kamada Y, Akita M, Takeda Y, Yamada S, Fujii H, Sawai Y, Doi Y, Asazawa H, Nakayama K, Mizutani K, Fujii H, Yakushijin T, Miyazaki M, Ezaki H, Hiramatsu N, Yoshida Y, Kiso S, Imai Y, Kawada N, Takehara T, Miyoshi E. Serum Fucosylated Haptoglobin as a Novel Diagnostic Biomarker for Predicting Hepatocyte Ballooning and Nonalcoholic Steatohepatitis. PLoS One 2013; 8:e66328. [PMID: 23805214 PMCID: PMC3689816 DOI: 10.1371/journal.pone.0066328] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2013] [Accepted: 05/03/2013] [Indexed: 12/18/2022] Open
Abstract
UNLABELLED Nonalcoholic fatty liver disease (NAFLD) is a growing medical problem around the world. NAFLD patients with nonalcoholic steatohepatitis (NASH) can develop cirrhosis and hepatocellular carcinoma. The ability to distinguish NASH from simple steatosis would be of great clinical significance. Ballooning hepatocytes are characteristic of typical pathological NASH; here, the polarized secretion of proteins is disrupted due to destruction of the cytoskeleton. We previously reported that fucosylated glycoproteins are secreted into bile, but not into sera in normal liver. Therefore, we hypothesized that the fucosylation-based sorting machinery would be disrupted in ballooning hepatocytes, and serum fucosylated glycoproteins would increase in NASH patients. To confirm our hypothesis, we evaluated serum fucosylated haptoglobin (Fuc-Hpt) levels in biopsy-proven NAFLD patients (n = 126) using a lectin-antibody ELISA kit. Fuc-Hpt levels were significantly increased in NASH patients compared with non-NASH (NAFLD patients without NASH) patients. Interestingly, Fuc-Hpt levels showed a significant stepwise increase with increasing hepatocyte ballooning scores. Multiple logistic regression analysis showed that Fuc-Hpt levels were independent and significant determinants of the presence of ballooning hepatocytes. Moreover, Fuc-Hpt levels were useful in monitoring liver fibrosis staging. Next, to investigate the significance of serum Fuc-Hpt in a larger population, we measured Fuc-Hpt levels in ultrasound-diagnosed NAFLD subjects (n = 870) who received a medical health checkup. To evaluate NAFLD disease severity, we used the FIB-4 index (based on age, serum AST and ALT levels, and platelet counts). Fuc-Hpt levels increased stepwise with increasing FIB-4 index. CONCLUSION Measurement of serum Fuc-Hpt levels can distinguish NASH from non-NASH patients, and predict the presence of ballooning hepatocytes in NAFLD patients with sufficient accuracy. These results support the potential usefulness of measuring Fuc-Hpt levels in clinical practice.
Collapse
Affiliation(s)
- Yoshihiro Kamada
- Department of Molecular Biochemistry and Clinical Investigation, Osaka University, Graduate School of Medicine, Suita, Osaka, Japan
- Department of Gastroenterology and Hepatology, Osaka University, Graduate School of Medicine, Suita, Osaka, Japan
| | - Maaya Akita
- Department of Molecular Biochemistry and Clinical Investigation, Osaka University, Graduate School of Medicine, Suita, Osaka, Japan
| | - Yuri Takeda
- Department of Molecular Biochemistry and Clinical Investigation, Osaka University, Graduate School of Medicine, Suita, Osaka, Japan
| | | | - Hideki Fujii
- Department of Hepatology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Yoshiyuki Sawai
- Department of Gastroenterology, Ikeda Municipal Hospital, Ikeda, Osaka, Japan
| | - Yoshinori Doi
- Department of Gastroenterology, Otemae Hospital, Osaka, Japan
| | - Hitomi Asazawa
- Department of Molecular Biochemistry and Clinical Investigation, Osaka University, Graduate School of Medicine, Suita, Osaka, Japan
| | - Kotarosumitomo Nakayama
- Department of Molecular Biochemistry and Clinical Investigation, Osaka University, Graduate School of Medicine, Suita, Osaka, Japan
| | - Kayo Mizutani
- Department of Molecular Biochemistry and Clinical Investigation, Osaka University, Graduate School of Medicine, Suita, Osaka, Japan
| | - Hironobu Fujii
- Department of Molecular Biochemistry and Clinical Investigation, Osaka University, Graduate School of Medicine, Suita, Osaka, Japan
| | - Takayuki Yakushijin
- Department of Gastroenterology and Hepatology, Osaka University, Graduate School of Medicine, Suita, Osaka, Japan
| | - Masanori Miyazaki
- Department of Gastroenterology and Hepatology, Osaka University, Graduate School of Medicine, Suita, Osaka, Japan
| | - Hisao Ezaki
- Department of Gastroenterology and Hepatology, Osaka University, Graduate School of Medicine, Suita, Osaka, Japan
| | - Naoki Hiramatsu
- Department of Gastroenterology and Hepatology, Osaka University, Graduate School of Medicine, Suita, Osaka, Japan
| | - Yuichi Yoshida
- Department of Gastroenterology and Hepatology, Osaka University, Graduate School of Medicine, Suita, Osaka, Japan
| | - Shinichi Kiso
- Department of Gastroenterology and Hepatology, Osaka University, Graduate School of Medicine, Suita, Osaka, Japan
| | - Yasuharu Imai
- Department of Gastroenterology, Ikeda Municipal Hospital, Ikeda, Osaka, Japan
| | - Norifumi Kawada
- Department of Hepatology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Tetsuo Takehara
- Department of Gastroenterology and Hepatology, Osaka University, Graduate School of Medicine, Suita, Osaka, Japan
| | - Eiji Miyoshi
- Department of Molecular Biochemistry and Clinical Investigation, Osaka University, Graduate School of Medicine, Suita, Osaka, Japan
| |
Collapse
|
|
25
|
Kaji H, Ocho M, Togayachi A, Kuno A, Sogabe M, Ohkura T, Nozaki H, Angata T, Chiba Y, Ozaki H, Hirabayashi J, Tanaka Y, Mizokami M, Ikehara Y, Narimatsu H. Glycoproteomic discovery of serological biomarker candidates for HCV/HBV infection-associated liver fibrosis and hepatocellular carcinoma. J Proteome Res 2013; 12:2630-2640. [PMID: 23586699 DOI: 10.1021/pr301217b] [Citation(s) in RCA: 44] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
We previously proposed a high-throughput strategy to discover serological biomarker candidates of cancer. This strategy focuses on a series of candidate glycoproteins that are specifically expressed in the original tissues (cells) of the target cancer and that carry glycan structures associated with carcinogenesis [Narimatsu, H., et al. FEBS J.2010, 277(1), 95-105]. Here, we examined the effectiveness of our strategy in identifying biomarkers to assess progression of liver fibrosis and for the early detection of hepatocellular carcinoma (HCC). On the basis of the results of lectin array analyses in culture media of hepatoma cell lines, we captured glycopeptides carrying AAL-ligands (fucosylated glycans) or DSA-ligands (branched glycans) from digests of culture media proteins and sera from HCC patients with a background of liver cirrhosis (LC). Glycoproteins were identified by the IGOT-LC-MS method. In all, 21 candidates were selected from 744 AAL-bound glycoproteins for further verification according to (i) their abundance in serum, (ii) their specific expression in liver, and (iii) the availability of antibodies to the glycoproteins. All selected candidates showed enhancement of AAL-reactivity in sera of HCC patients compared with that of healthy volunteers (HV). These results indicate that our glycoproteomic strategy is effective for identifying multiple glyco-biomarker candidates in a high-throughput manner.
Collapse
MESH Headings
- Adult
- Biomarkers/blood
- Carcinoma, Hepatocellular/blood
- Carcinoma, Hepatocellular/etiology
- Carcinoma, Hepatocellular/virology
- Case-Control Studies
- Cell Line, Tumor
- Chromatography, Affinity
- Glycopeptides/blood
- Hepatitis B, Chronic/blood
- Hepatitis B, Chronic/complications
- Hepatitis B, Chronic/virology
- Hepatitis C, Chronic/blood
- Hepatitis C, Chronic/complications
- Hepatitis C, Chronic/virology
- Humans
- Lectins/chemistry
- Liver Cirrhosis/blood
- Liver Cirrhosis/etiology
- Liver Cirrhosis/virology
- Liver Neoplasms/blood
- Liver Neoplasms/etiology
- Liver Neoplasms/virology
- Middle Aged
- Polysaccharides/blood
Collapse
Affiliation(s)
- Hiroyuki Kaji
- Research Center for Medical Glycoscience, National Institute of Advanced Industrial Science and Technology, Tsukuba, Ibaraki, Japan
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
26
|
Hirabayashi J, Yamada M, Kuno A, Tateno H. Lectin microarrays: concept, principle and applications. Chem Soc Rev 2013; 42:4443-58. [PMID: 23443201 DOI: 10.1039/c3cs35419a] [Citation(s) in RCA: 219] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
The lectin microarray is a novel platform for glycan analysis, having emerged only in recent years. Unlike other conventional methods, e.g., liquid chromatography and mass spectrometry, it enables rapid and high-sensitivity profiling of complex glycan features without the need for liberation of glycans. Target samples include an extensive range of glycoconjugates involved in cells, tissues, body fluids, as well as synthetic glycans and their mimics. Various procedures for rapid differential glycan profiling have been developed for glycan-related biomarkers. Such glycoproteomics targeting allows precise diagnosis of chronic diseases potentially related to cancer. Application of this method to evaluation of various types of stem cells resulted in the discovery of a new pluripotent cell-specific glycan marker. To explore this technology a more fundamental and extensive understanding of lectins is necessary in relation to the structural uniqueness of glycans. In this chapter, the essence of the lectin microarray is described with some focus on an evanescent-field-activated fluorescence detection principle as a system to achieve in situ (i.e., washing free) aqueous-phase observation under equilibrium conditions. The developed lectin microarray system allows even researchers with poor experience in glycan profiling to perform extensive high-throughput analysis targeting various forms of glycans and even cells.
Collapse
Affiliation(s)
- Jun Hirabayashi
- National Institute of Advanced Science and Technology, Central-2, 1-1-1, Umezono, Tsukuba, Ibaraki 305-8568, Japan.
| | | | | | | |
Collapse
|
|
27
|
Kuno A, Ikehara Y, Tanaka Y, Ito K, Matsuda A, Sekiya S, Hige S, Sakamoto M, Kage M, Mizokami M, Narimatsu H. A serum "sweet-doughnut" protein facilitates fibrosis evaluation and therapy assessment in patients with viral hepatitis. Sci Rep 2013; 3:1065. [PMID: 23323209 PMCID: PMC3545220 DOI: 10.1038/srep01065] [Citation(s) in RCA: 278] [Impact Index Per Article: 23.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2012] [Accepted: 12/27/2012] [Indexed: 02/08/2023] Open
Abstract
Although liver fibrosis reflects disease severity in chronic hepatitis patients, there has been no simple and accurate system to evaluate the therapeutic effect based on fibrosis. We developed a glycan-based immunoassay, FastLec-Hepa, to fill this unmet need. FastLec-Hepa automatically detects unique fibrosis-related glyco-alteration in serum hyperglycosylated Mac-2 binding protein within 20 min. The serum FastLec-Hepa counts increased with advancing fibrosis and illustrated significant differences in medians between all fibrosis stages. FastLec-Hepa is sufficiently sensitive and quantitative to evaluate the effects of PEG-interferon-α/ribavirin therapy in a short post-therapeutic interval. The obtained fibrosis progression is equivalent to -0.30 stages/year in patients with sustained virological response, and 0.01 stages/year in relapse/nonresponders. Furthermore, long-term follow-up of the severely affected patients found hepatocellular carcinoma developed in patients after therapy whose FastLec-Hepa counts remained above a designated cutoff value. FastLec-Hepa is the only assay currently available for clinically beneficial therapy evaluation through quantitation of disease severity.
Collapse
Affiliation(s)
- Atsushi Kuno
- Research Center for Medical Glycoscience (RCMG), National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba, Japan
- These authors contributed equally to this study
| | - Yuzuru Ikehara
- Research Center for Medical Glycoscience (RCMG), National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba, Japan
- These authors contributed equally to this study
| | - Yasuhito Tanaka
- Department of Virology & Liver Unit, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Kiyoaki Ito
- The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Ichikawa, Japan
| | - Atsushi Matsuda
- Research Center for Medical Glycoscience (RCMG), National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba, Japan
| | - Satoru Sekiya
- Research Center for Medical Glycoscience (RCMG), National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba, Japan
| | - Shuhei Hige
- Department of Internal Medicine, Hokkaido University Graduate School of Medicine, Sapporo, Japan
| | - Michiie Sakamoto
- Department of Pathology, School of Medicine, Keio University, Tokyo, Japan
| | - Masayoshi Kage
- Department of Pathology, Kurume University School of Medicine, Kurume, Japan
| | - Masashi Mizokami
- The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Ichikawa, Japan
| | - Hisashi Narimatsu
- Research Center for Medical Glycoscience (RCMG), National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba, Japan
| |
Collapse
|
|
28
|
Du D, Zhu X, Kuno A, Matsuda A, Tsuruno C, Yu D, Zhang Y, Ikehara Y, Tanaka Y, Zhang X, Narimatsu H. Comparison of LecT-Hepa and FibroScan for assessment of liver fibrosis in hepatitis B virus infected patients with different ALT levels. Clin Chim Acta 2012; 413:1796-1799. [PMID: 22796373 DOI: 10.1016/j.cca.2012.07.005] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2012] [Revised: 07/05/2012] [Accepted: 07/05/2012] [Indexed: 01/06/2023]
Abstract
BACKGROUND FibroScan is one of the noninvasive techniques based on the transient elastography that can assess the progression of liver fibrosis in chronic hepatitis patients in daily clinical practice. Recently, LecT-Hepa was validated as a serological glycomarker correlating well with the fibrosis stage determined by liver biopsy, and was superior to many other noninvasive biochemical markers and tests. We compared the reliability of LecT-Hepa with that of FibroScan for evaluation of liver fibrosis. METHODS The effects of increased alanine aminotransferase (ALT) activities on LecT-Hepa and FibroScan were investigated. RESULTS The areas under the receiver-operating characteristic curves, sensitivity and specificity for detecting cirrhosis, which is one of the outcomes of fibrosis estimation, were 0.82, 72.5% and 78.2% of LecT-Hepa, 0.85, 87.0% and 74.1% of FibroScan; these did not differ significantly. The count distribution of LecT-Hepa in non-cirrhosis group or cirrhosis group did not differ between the patients grouped according to their ALT levels, whereas that of FibroScan was substantially affected. CONCLUSION LecT-Hepa was confirmed as a reliable noninvasive test for the evaluation of liver fibrosis in hepatitis B virus-infected patients with comparable performance to that of FibroScan and proved to be unaffected by inflammation.
Collapse
Affiliation(s)
- Dongning Du
- Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Ruijin Er Road, Shanghai 200025, China
| | | | | | | | | | | | | | | | | | | | | |
Collapse
|