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Tomino T, Itoh S, Toshima T, Yoshiya S, Bekki Y, Iseda N, Izumi T, Tsutsui Y, Toshida K, Yoshizumi T. Clinical validation of preoperative serum markers for liver fibrosis in living donor liver transplantation recipients. Surg Today 2025; 55:627-637. [PMID: 39317845 DOI: 10.1007/s00595-024-02941-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2024] [Accepted: 09/05/2024] [Indexed: 09/26/2024]
Abstract
PURPOSE To validate the reliability of fibrosis markers as predictors of graft survival in living donor liver transplantation (LDLT) recipients. METHODS We reviewed data retrospectively, from 163 patients who underwent adult LDLT with preoperative measurements of type IV collagen (CIV), Mac-2 binding protein glycosylation isomer (M2BPGi), and hyaluronic acid (HA). Patients were divided into high and low groups for each biomarker, based on optimal cutoff values, and graft loss within 6 months was evaluated in each group. RESULTS The high CIV level group showed significantly lower 6-month graft survival rates and significantly higher rates of postoperative sepsis and sepsis from pneumonia. However, the groups with high and low M2BPGi levels and those with high and low HA levels did not show significant differences in 6-month graft survival rates or rates of postoperative sepsis. Multivariate analysis revealed that a CIV level ≥ 590 was a significant predictor of graft loss within 6 months, postoperative sepsis, and sepsis from pneumonia. CONCLUSION Unlike other fibrosis markers, preoperative CIV levels can predict graft survival, postoperative sepsis, and sepsis from pneumonia after LDLT.
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Affiliation(s)
- Takahiro Tomino
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-Ku, Fukuoka, 812-8582, Japan
| | - Shinji Itoh
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-Ku, Fukuoka, 812-8582, Japan.
| | - Takeo Toshima
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-Ku, Fukuoka, 812-8582, Japan
| | - Shohei Yoshiya
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-Ku, Fukuoka, 812-8582, Japan
| | - Yuki Bekki
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-Ku, Fukuoka, 812-8582, Japan
| | - Norifumi Iseda
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-Ku, Fukuoka, 812-8582, Japan
| | - Takuma Izumi
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-Ku, Fukuoka, 812-8582, Japan
| | - Yuriko Tsutsui
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-Ku, Fukuoka, 812-8582, Japan
| | - Katsuya Toshida
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-Ku, Fukuoka, 812-8582, Japan
| | - Tomoharu Yoshizumi
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-Ku, Fukuoka, 812-8582, Japan
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Ananchuensook P, Moonlisarn K, Boonkaew B, Bunchorntavakul C, Tangkijvanich P. Diagnostic Performance of Serum Mac-2-Binding Protein Glycosylation Isomer as a Fibrosis Biomarker in Non-Obese and Obese Patients with MASLD. Biomedicines 2025; 13:415. [PMID: 40002828 PMCID: PMC11853689 DOI: 10.3390/biomedicines13020415] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2024] [Revised: 01/30/2025] [Accepted: 02/06/2025] [Indexed: 02/27/2025] Open
Abstract
Background: Serum mac-2-binding protein glycosylation isomer (M2BPGi) is a new biomarker for liver fibrosis. However, its performance in metabolic dysfunction-associated steatotic liver disease (MASLD), particularly in obese patients, remains to be explored. Methods: This study evaluated the role of M2BPGi in predicting liver fibrosis in 205 patients with MASLD using magnetic resonance elastography (MRE) as a reference. The performance of M2BPGi was compared to vibration-controlled transient elastography (VCTE), FIB-4, APRI, and NFS. The PNPLA3, TM6SF2, and HSD17B13 polymorphisms were assessed by allelic discrimination assays. Results: The area under the ROC curves for VCTE, M2BPGi FIB-4, APRI, and NFS in differentiating significant fibrosis were 0.95 (95% CI; 0.91-0.98), 0.85 (0.79-0.92), 0.81 (0.74-0.89), 0.79 (0.71-0.87), and 0.80 (0.72-0.87) (all p < 0.001), respectively. The optimal cut-off values of M2BPGi in predicting significant fibrosis, advanced fibrosis, and cirrhosis were 0.82, 0.95, and 1.23 cut-off index (COI); yielding satisfactory sensitivity, specificity, and diagnostic accuracy. The performance of M2BPGi was consistent among subgroups according to BMI, while the AUROCs of FIB-4, APRI, and NFS were remarkably decreased in patients with BMI ≥ 30 kg/m2. Patients with the PNPLA3 GG genotype had significantly higher M2BPGi than those with the CC/CG genotypes. In multivariate analysis, the independent factors associated with significant liver fibrosis were VCTE, M2BPGi, and PNPLA3 rs738409. Conclusions: Our data demonstrated that serum M2BPGi accurately assessed liver fibrosis across different BMI, indicating that this biomarker could apply to non-obese and obese patients with MASLD in clinical settings.
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Affiliation(s)
- Prooksa Ananchuensook
- Division of Gastroenterology, Department of Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand;
- Academic Affair, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand
| | - Kamonchanok Moonlisarn
- Center of Excellence in Hepatitis and Liver Cancer, Department of Biochemistry, Chulalongkorn University, Bangkok 10330, Thailand; (K.M.); (B.B.)
| | - Bootsakorn Boonkaew
- Center of Excellence in Hepatitis and Liver Cancer, Department of Biochemistry, Chulalongkorn University, Bangkok 10330, Thailand; (K.M.); (B.B.)
| | | | - Pisit Tangkijvanich
- Center of Excellence in Hepatitis and Liver Cancer, Department of Biochemistry, Chulalongkorn University, Bangkok 10330, Thailand; (K.M.); (B.B.)
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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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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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Xu Q, Feng M, Ren Y, Liu X, Gao H, Li Z, Su X, Wang Q, Wang Y. From NAFLD to HCC: Advances in noninvasive diagnosis. Biomed Pharmacother 2023; 165:115028. [PMID: 37331252 DOI: 10.1016/j.biopha.2023.115028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2023] [Revised: 06/10/2023] [Accepted: 06/14/2023] [Indexed: 06/20/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) has gradually become one of the major liver health problems in the world. The dynamic course of the disease goes through steatosis, inflammation, fibrosis, and carcinoma. Before progressing to carcinoma, timely and effective intervention will make the condition better, which highlights the importance of early diagnosis. With the further study of the biological mechanism in the pathogenesis and progression of NAFLD, some potential biomarkers have been discovered, and the possibility of their clinical application is gradually being discussed. At the same time, the progress of imaging technology and the emergence of new materials and methods also provide more possibilities for the diagnosis of NAFLD. This article reviews the diagnostic markers and advanced diagnostic methods of NAFLD in recent years.
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Affiliation(s)
- Qinchen Xu
- Department of Clinical Laboratory, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250033, China
| | - Maoxiao Feng
- Department of Clinical Laboratory, Shandong Provincial Hospital Affiliated to Shandong First Medical University, 250021, Jinan, Shandong Province, China
| | - Yidan Ren
- Department of Clinical Laboratory, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250033, China
| | - Xiaoyan Liu
- Department of Clinical Laboratory, Shandong Provincial Hospital Affiliated to Shandong First Medical University, 250021, Jinan, Shandong Province, China
| | - Huiru Gao
- Department of Clinical Laboratory, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250033, China
| | - Zigan Li
- Department of Clinical Laboratory, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250033, China
| | - Xin Su
- Department of Clinical Laboratory, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250033, China
| | - Qin Wang
- Department of Anesthesiology, Qilu Hospital, Shandong University, 107 Wenhua Xi Road, Jinan 250012, China.
| | - Yunshan Wang
- Department of Clinical Laboratory, Shandong Provincial Hospital Affiliated to Shandong First Medical University, 250021, Jinan, Shandong Province, China.
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Yamana H, Tokodai K, Fujio A, Kashiwadate T, Miyazawa K, Sasaki K, Matsumura M, Mitsugashira H, Unno M, Kamei T. Clinical Significance of the Mac-2 Binding Protein Glycosylated Isomer as a Surrogate Marker of Graft Fibrosis After Pediatric Liver Transplantation. Transplant Proc 2023:S0041-1345(23)00227-0. [PMID: 37127515 DOI: 10.1016/j.transproceed.2023.03.053] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2023] [Accepted: 03/28/2023] [Indexed: 05/03/2023]
Abstract
BACKGROUND After pediatric liver transplantation, liver fibrosis may occur during long-term follow-up. Noninvasive markers for assessing this liver fibrosis are desired. Mac-2 binding protein glycosylated isomer (M2BPGi) has recently been reported as a useful biomarker for liver fibrosis. However, its usefulness in the pediatric population is yet to be established. This study investigated the clinical significance of M2BPGi levels as a surrogate marker of graft fibrosis after pediatric liver transplantation. METHODS We retrospectively identified 96 patients who underwent pediatric liver transplantation at our institution between 1991 and 2015. The association between M2BPGi levels and other fibrosis markers was analyzed in 60 patients in whom fibrosis markers were measured. The association between fibrosis marker levels and graft fibrosis was assessed in 42 patients who underwent biopsies between 2016 and 2022. RESULTS The M2BPGi levels were statistically correlated with the hyaluronic acid and type-IV collagen levels. None of the fibrosis markers were significantly associated with liver graft fibrosis, although the levels of these markers were slightly higher in patients with severe liver fibrosis than in those with mild fibrosis. CONCLUSIONS The M2BPGi levels had a limited ability to assess liver graft fibrosis after pediatric liver transplantation, similar to other fibrosis markers. Further studies with larger cohorts are required to validate these findings externally.
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Affiliation(s)
- Hiroki Yamana
- Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan.
| | - Kazuaki Tokodai
- Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Atsushi Fujio
- Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Toshiaki Kashiwadate
- Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Koji Miyazawa
- Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Kengo Sasaki
- Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Muneyuki Matsumura
- Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Hiroaki Mitsugashira
- Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Michiaki Unno
- Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Takashi Kamei
- Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan
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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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Mac-2 binding protein glycosylation isomer, the FIB-4 index, and a combination of the two as predictors of non-alcoholic steatohepatitis. PLoS One 2022; 17:e0277380. [DOI: 10.1371/journal.pone.0277380] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2022] [Accepted: 10/25/2022] [Indexed: 11/12/2022] Open
Abstract
Approximately 10% non-alcoholic fatty liver disease (NAFLD) cases progress to non-alcoholic steatohepatitis (NASH). Liver biopsy, the gold standard for diagnosing NASH and associated liver fibrosis, is invasive with a risk of life-threatening complications. Therefore, reliable non-invasive biomarkers for predicting NASH are required to prevent unnecessary liver biopsies. We evaluated the performance of two non-invasive fibrosis markers, Mac-2 binding protein glycosylation isomer (M2BPGi) and the FIB-4 index for predicting the fibrosis staging, NAFLD activity scoring (NAS) index, and NASH. We also analyzed the correlation between the two markers. The sensitivities, specificities, positive predictive values (PPV), and negative predictive values of the FIB-4 index, M2BPGi, and a combination of both markers for NASH diagnosis were evaluated. The M2BPGi and FIB-4 index showed a good performance in diagnosing NASH, the fibrosis stage, and the NAS index in NAFLD patients. While both markers were well-correlated with each other in most cases, no correlation was found in some patients. Compared with the FIB-4 index or the M2BPGi alone, a combination of the two showed a higher specificity, PPV, and accuracy for NASH diagnosis. The M2BPGi and the FIB-4 index are easily accessible and reliable liver fibrosis markers. Diseases other than liver disease may cause dissociation between the two markers, causing failure to predict NASH. However, the combination of both markers can compensate for their disadvantages. Because the PPV of the combination was relatively high, patients who test positive for both markers should undergo liver biopsy for NASH diagnosis.
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Miwa T, Hanai T, Sakai Y, Kochi T, Katsumura N, Shimizu M. Mac-2-binding protein glycosylation isomer is useful to predict muscle cramps in patients with chronic liver disease. Medicine (Baltimore) 2022; 101:e31145. [PMID: 36254085 PMCID: PMC9575787 DOI: 10.1097/md.0000000000031145] [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: 11/26/2022] Open
Abstract
Muscle cramps are frequently overlooked and worsen the quality of life in patients with chronic liver disease (CLD). Therefore, a valuable biomarker for predicting muscle cramps is required in the clinical setting. This study aimed to investigate whether the serum Mac-2-binding protein glycosylation isomer (M2BPGi) levels, a reliable liver fibrosis marker, could predict muscle cramps in patients with CLD. This retrospective study included 80 patients with CLD. Muscle cramps were assessed using a questionnaire regarding their presence, frequency, pain severity, and duration. The associated predictors were analyzed using logistic regression analysis. The diagnostic accuracy and optimal cutoff values were evaluated using receiver operating characteristic curves. Of the 80 patients, 55% had muscle cramps and showed significantly higher serum M2BPGi levels than those without them (4.54 cutoff index [COI] vs 2.20; P = .001). Multivariate analysis revealed that M2BPGi (odds ratio [ORs], 1.19; 95% confidence interval, 1.003-1.42; P = .046) was independently associated with the presence of muscle cramps. The optimal COI value for predicting muscle cramps was 3.95, and the sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were 61.4%, 80.6%, 79.4%, 63.0%, and 70.0%, respectively. Patients with a COI value ≥3.95 had a 2-fold higher incidence of muscle cramps than patients with a COI value <3.95 (79% vs 37%; P < .001). M2BPGi levels were also associated with the duration of muscle cramps. Serum M2BPGi appears useful as a biomarker for predicting muscle cramps in patients with CLD.
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Affiliation(s)
- Takao Miwa
- Department of Gastroenterology/Internal Medicine, Gifu University Graduate School of Medicine, Gifu, Japan
- Department of Gastroenterology, Chuno Kosei Hospital, Seki, Japan
- *Correspondence: Takao Miwa, Department of Gastroenterology/Internal Medicine, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu 501-1194, Japan (e-mail: )
| | - Tatsunori Hanai
- Department of Gastroenterology/Internal Medicine, Gifu University Graduate School of Medicine, Gifu, Japan
- Center for Nutrition Support & Infection Control, Gifu University Hospital, Gifu University Hospital, Gifu, Japan
| | - Yuko Sakai
- Department of Nutrition, Chuno Kosei Hospital, Seki, Japan
| | - Takahiro Kochi
- Department of Gastroenterology, Chuno Kosei Hospital, Seki, Japan
| | - Naoki Katsumura
- Department of Gastroenterology, Chuno Kosei Hospital, Seki, Japan
| | - Masahito Shimizu
- Department of Gastroenterology/Internal Medicine, Gifu University Graduate School of Medicine, Gifu, Japan
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10
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Lian MJ, Chen ZQ, Wang QM, Zheng GS, Hong GL. Diagnostic accuracy of mac-2-binding protein glycosylation isomer for diagnosing hepatitis B-related fibrosis: A meta-analysis. J Dig Dis 2022; 23:550-560. [PMID: 36251470 DOI: 10.1111/1751-2980.13140] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2022] [Revised: 08/24/2022] [Accepted: 10/13/2022] [Indexed: 12/30/2022]
Abstract
OBJECTIVES Mac-2-binding protein glycosylation isomer (M2BPGi) is a novel biomarker for liver fibrosis. The aim of this meta-analysis was to evaluate the accuracy of M2BPGi for predicting hepatitis B virus (HBV)-related liver fibrosis. METHODS EMBASE, PubMed, Web of Science, China National Knowledge Infrastructure, SinoMED, VIP Database for Chinese Technical Periodicals databases were searched comprehensively for articles published up to March 2022. Quality assessment was carried out in accordance with the Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2). The pooled diagnostic estimates including sensitivity, specificity, the area under the summary receiver operating characteristic curve (AUROC) were calculated. Before pooling the estimates, the threshold effect was assessed. Subgroup analysis was performed as well. RESULTS In all, 11 studies including 1836 patients were included. None of the 11 studies met all the criteria of QUADAS-2. The threshold effect was found (r = 0.757, P = 0.011) for predicting HBV-related severe fibrosis. The sensitivity, specificity and AUROC of M2BPGi for the prediction of significant fibrosis were 0.68 (0.65-0.71), 0.67 (0.64-0.70) and 0.741, respectively, while those for predicting cirrhosis were 0.65 (0.57-0.72), 0.79 (0.77-0.81) and 0.792. Additionally, the AUROC of M2BPGi for predicting severe fibrosis reached 0.766. No publication bias was observed. The results of subgroup analyses were similar to the overall results. CONCLUSIONS M2BPGi has moderate diagnostic accuracy for predicting HBV-related significant fibrosis, severe fibrosis, and cirrhosis. Further studies stratified by etiology, liver inflammation, treatment, etc, are urgently needed.
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Affiliation(s)
- Ming Jian Lian
- Department of Clinical Laboratory, Xiamen Key Laboratory of Genetic Testing, The First Affiliated Hospital Of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian Province, China
| | - Zhi Qi Chen
- Department of Clinical Laboratory, Xiamen Key Laboratory of Genetic Testing, The First Affiliated Hospital Of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian Province, China
| | - Qian Ming Wang
- Department of Clinical Laboratory, Xiamen Key Laboratory of Genetic Testing, The First Affiliated Hospital Of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian Province, China
| | - Gang Sen Zheng
- Department of Clinical Laboratory, Xiamen Key Laboratory of Genetic Testing, The First Affiliated Hospital Of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian Province, China
| | - Guo Lin Hong
- Department of Clinical Laboratory, Xiamen Key Laboratory of Genetic Testing, The First Affiliated Hospital Of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian Province, China
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11
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Tajiri H, Suzuki M, Bessho K, Ito Y, Murakami J, Hatori R, Takano T, Miyoshi Y, Brooks S. The role of serum Wisteria floribunda agglutinin-positive Mac-2 binding protein in the assessment of fibrosis in children with chronic hepatitis C. Sci Rep 2022; 12:11205. [PMID: 35778417 PMCID: PMC9249794 DOI: 10.1038/s41598-022-14553-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2021] [Accepted: 06/08/2022] [Indexed: 11/28/2022] Open
Abstract
At present, noninvasive fibrosis markers are not available for the assessment of liver fibrosis in children with chronic hepatitis C. Sixty-three children with chronic hepatitis C were included. Changes in Wisteria floribunda agglutinin-positive Mac-2 binding protein (M2BPGi) levels were evaluated in l3 of 27 treatment-naive patients during the natural course of disease (median 4, range 3–6 years). Changes during treatment were evaluated in 27 of 36 patients for 4 (2–9) years of posttreatment follow-up. There were significant differences in the levels of M2BPGi between control group and HCV F0 group (P = 0.002) and between control group and HCV F1 group (P < 0.001). Receiver operating characteristic curve analysis showed that to discriminate stage F1 fibrosis from F0, the cut-off value was 0.95 for M2BPGi with a sensitivity of 52%, specificity of 90%, and area under the curve of 0.687. A substantial decrease in M2BPGi levels by treatment was shown from 0.98 ± 0.57 at pretreatment to 0.42 ± 0.15 at posttreatment (P < 0.001) in the 27 treated patients. Our study shows new findings that M2BPGi may be useful to predict the presence of a mild degree of fibrosis in children with chronic hepatitis C, and such mild fibrosis may be quickly resolved by treatment.
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Affiliation(s)
- Hitoshi Tajiri
- Department of Pediatrics, Kinki University Faculty of Medicine, 377-2 Ohno-higashi, Osaka-Sayama, Japan.
| | - Mitsuyoshi Suzuki
- Department of Pediatrics, Juntendo University Faculty of Medicine, Tokyo, Japan
| | - Kazuhiko Bessho
- Department of Pediatrics, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Yoshinori Ito
- Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Jun Murakami
- Division of Pediatrics and Perinatology, Tottori University Faculty of Medicine, Tottori, Japan
| | - Reiko Hatori
- Department of Pediatrics, Gunma University Graduate School of Medicine, Maebashi, Japan
| | - Tomoko Takano
- Department of Pediatrics, Osaka General Medical Center, Osaka, Japan
| | - Yoko Miyoshi
- Department of Pediatrics, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Stephen Brooks
- Department of Microbiology/Immunology, State University of New York at Buffalo, Buffalo, USA
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12
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Ando W, Kaneko F, Shimamoto S, Igarashi K, Otori K, Yokomori H. Long-term prediction of hepatocellular carcinoma using serum autotaxin levels after antiviral therapy for hepatitis C. Ann Hepatol 2022; 27:100660. [PMID: 35007770 DOI: 10.1016/j.aohep.2022.100660] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/22/2021] [Accepted: 12/31/2021] [Indexed: 02/04/2023]
Abstract
INTRODUCTION AND OBJECTIVES Continuous monitoring for hepatocellular carcinoma is necessary following treatment with direct-acting antivirals in patients with hepatitis C virus infection. We investigated whether the long-term follow-up of serum autotaxin levels could predict the development of hepatocellular carcinoma. PATIENTS AND METHODS This prospective observational study enrolled adult patients with chronic hepatitis C virus infection who presented to the study center from January 2016 to March 2021. Among the patients who achieved a sustained viral response, the relationship between the development of hepatocellular carcinoma and serum autotaxin levels was assessed before treatment with direct-acting antivirals; at the end of therapy; at 12 and 24 weeks; and at 12, 24, 36, and 48 months after treatment. RESULTS Data were analyzed for 139 patients. Thirteen patients developed hepatocellular carcinoma 48 months after treatment. The cut-off serum autotaxin values that predicted hepatocellular carcinoma after 24 weeks were 1.22 (men) and 1.92 (women) mg/L. The area under the curve for serum autotaxin was 0.83 (95% confidence interval [CI]:0.71-0.95) in men and 0.90 (95% CI: 0.82-0.99) in women. The positive predictive value of serum autotaxin was 0.208 (95% CI: 0.139-0.248), and the negative predictive value was 0.971 (95% CI: 0.939-0.990). The cumulative incidence of hepatocellular carcinoma was significantly higher when serum autotaxin levels were above the cut-off value after 24 weeks (p < 0.0001). CONCLUSIONS Serum autotaxin is a candidate biomarker for predicting hepatocellular carcinoma during the long-term follow-up of patients with a sustained viral response following treatment with direct-acting antivirals.
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Affiliation(s)
- Wataru Ando
- Department of Clinical Pharmacy, Center for Clinical Pharmacy and Sciences, School of Pharmacy, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan.
| | - Fumihiko Kaneko
- Department of Gastroenterology and Hepatology, Saitama City Hospital, 2460 Mimuro, Midori-ku, Saitama 336-8522, Japan
| | - Satoshi Shimamoto
- Bioscience Division, Tosoh Corporation, 2743-1 Hayakawa, Ayase-shi, Kanagawa 252-1123, Japan
| | - Koji Igarashi
- Bioscience Division, Tosoh Corporation, 2743-1 Hayakawa, Ayase-shi, Kanagawa 252-1123, Japan
| | - Katsuya Otori
- Department of Clinical Pharmacy, Center for Clinical Pharmacy and Sciences, School of Pharmacy, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan
| | - Hiroaki Yokomori
- Department of Internal Medicine, Kitasato University Medical Center, 6-100 Arai, Kitamoto-shi, Saitama 364-8641, Japan
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13
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Jang TY, Huang CF, Yeh ML, Huang CI, Dai CY, Tsai PC, Hsu PY, Wei YJ, Hou NJ, Liang PC, Lin YH, Wang CW, Hsieh MY, Lin ZY, Huang JF, Yu ML, Chuang WL. Serum Wisteria floribunda agglutinin-positive Mac-2-binding protein expression predicts disease severity in nonalcoholic steatohepatitis patients. Kaohsiung J Med Sci 2022; 38:261-267. [PMID: 34786828 DOI: 10.1002/kjm2.12474] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2021] [Revised: 10/05/2021] [Accepted: 10/15/2021] [Indexed: 01/18/2023] Open
Abstract
The role of Wisteria floribunda agglutinin-positive Mac-2 binding protein (WFA+ -M2BP) in the prediction of disease severity in nonalcoholic fatty liver disease (NAFLD) remains elusive. This study evaluated the performance of WFA+ -M2BP in predicting fibrosis in patients with NAFLD. A total of 80 patients with biopsy-proven nonalcoholic steatohepatitis (NASH) were enrolled. Serum WFA+ -M2BP levels were measured using standard methods. The fibrosis-4 (FIB-4) index was also measured. The mean values of WFA+ -M2BP were 1.0, 1.0, 0.8, and 2.2 in Metavir fibrosis stage F0, F1, F2, and F3-4, respectively (linear trend p = 0.005). The optimal cut-off value of WFA+ -M2BP in predicting advanced fibrosis (F3-4) was 1.37 cut-off index (COI), yielding the sensitivity, specificity, positive predictive value (PPV), negative predictive value, and accuracy of 75.0, 79.4, 39.1, 94.7, and 78.7%, respectively (p < 0.001). Combining WFA+ -M2BP with FIB-4 significantly increased the diagnostic performance for advanced fibrosis, yielding specificity, PPV, and accuracy of 100, 100, and 93%, respectively. The significant factors predicting advanced liver fibrosis in the multivariate regression analysis were WFA+ -M2BP ≥ 1.37 COI (OR/confidence interval [CI]: 9.49/1.63-55.21, p = 0.01) and FIB-4 ≥ 2.80 (OR/CI: 38.18/4.89-297.93, p = 0.001). Monitoring WFA+ -M2BP is suitable for noninvasive assessment of liver fibrosis in NASH patients, particularly in combination with FIB-4.
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Affiliation(s)
- Tyng-Yuan Jang
- Hepatobiliary Division and Hepatitis Center, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- Department of Internal Medicine, Pingtung Hospital, Ministry of Health and Welfare, Pingtung, Taiwan
| | - Chung-Feng Huang
- Hepatobiliary Division and Hepatitis Center, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- Faculty of Internal Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Ming-Lun Yeh
- Hepatobiliary Division and Hepatitis Center, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- Faculty of Internal Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Ching-I Huang
- Hepatobiliary Division and Hepatitis Center, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- Faculty of Internal Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Chia-Yen Dai
- Hepatobiliary Division and Hepatitis Center, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- Faculty of Internal Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Pei-Chien Tsai
- Hepatobiliary Division and Hepatitis Center, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Po-Yau Hsu
- Hepatobiliary Division and Hepatitis Center, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Yi-Ju Wei
- Department of Internal Medicine, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung, Taiwan
| | - Nai-Jen Hou
- Department of Internal Medicine, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung, Taiwan
| | - Po-Cheng Liang
- Hepatobiliary Division and Hepatitis Center, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Yi-Hung Lin
- Hepatobiliary Division and Hepatitis Center, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Chih-Wen Wang
- Hepatobiliary Division and Hepatitis Center, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Ming-Yen Hsieh
- Department of Internal Medicine, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung, Taiwan
| | - Zu-Yau Lin
- Hepatobiliary Division and Hepatitis Center, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- Faculty of Internal Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Jee-Fu Huang
- Hepatobiliary Division and Hepatitis Center, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- Faculty of Internal Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Center for Liquid Biopsy and Cohort Research, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Ming-Lung Yu
- Hepatobiliary Division and Hepatitis Center, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- Faculty of Internal Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Center for Liquid Biopsy and Cohort Research, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Wan-Long Chuang
- Hepatobiliary Division and Hepatitis Center, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- Faculty of Internal Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
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14
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Toyoda H, Yasuda S, Shiota S, Sone Y, Maeda A, Kaneoka Y, Kumada T, Tanaka J. Identification of the suitable candidates for EOB-MRI with the high risk of the presence of non-hypervascular hypointense nodules in patients with HCV infection. Eur Radiol 2022; 32:5016-5023. [PMID: 35142900 DOI: 10.1007/s00330-022-08570-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2021] [Revised: 12/08/2021] [Accepted: 01/07/2022] [Indexed: 12/24/2022]
Abstract
OBJECTIVES Non-hypervascular hypointense nodules (NHHNs) depicted by gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid-enhanced magnetic resonance imaging (EOB-MRI) have a high likelihood of progressing to hepatocellular carcinoma (HCC). The presence of NHHNs is a strong risk factor for HCC development in patients with chronic hepatitis C virus (HCV) infection after the achievement of sustained virologic response (SVR). However, it is difficult for all patients with HCV infection to undergo EOB-MRI for NHHN detection. We therefore explored serum markers that potentially indicate the presence of NHHNs. METHODS Three serum markers, alpha-fetoprotein (AFP), FIB-4 index, and Wisteria floribunda agglutinin-positive Mac-2 binding protein glycan isomer (M2BPGi), were measured in 481 patients with HCV infection and no history of HCC who underwent EOB-MRI. The associations between these serum marker levels and the presence of NHHNs were investigated. RESULTS All three markers were associated with the presence of NHHNs. M2BPGi predicted the presence of NHHNs more accurately than AFP and FBB-4 index; M2BPGi had the highest area under the receiver operating characteristic curve. Multivariate analysis identified male gender and high M2BPGi as factors associated with the presence of NHHNs. When patients were stratified by the degree of liver fibrosis, M2BPGi increased with the progression of fibrosis. In addition, NHHNs were more prevalently detected in patients with higher M2BPGi (COI > 3.46) in patients with similar fibrosis degree. CONCLUSIONS M2BPGi is a serum marker that potentially identifies HCV patients with high risk of the presence of NHHNs, for whom EOB-MRI should be considered. KEY POINTS • Non-hypervascular hypointense nodule on EOB-DTPA-enhanced MRI is pre-HCC nodule with high likelihood of progressing to HCC, which is a strong predictor for HCC that develops after the eradication of HCV in patients with HCV infection. • It is difficult for all patients with HCV infection to undergo EOB-MRI for NHHN detection due to limited access, limited availability of MRI equipment, and high costs. • Serum Wisteria floribunda agglutinin-positive Mac-2 binding protein glycan isomer (M2BPGi) levels effectively indicate the presence of NHHNs and can be used to identify patients with high risk of their presence, for whom EOB-DTPA-enhanced MRI should be considered.
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Affiliation(s)
- Hidenori Toyoda
- Department of Gastroenterology, Ogaki Municipal Hospital, 4-86 Minaminokawa, Ogaki, Gifu, 503-8502, Japan.
| | - Satoshi Yasuda
- Department of Gastroenterology, Ogaki Municipal Hospital, 4-86 Minaminokawa, Ogaki, Gifu, 503-8502, Japan
| | - Shohei Shiota
- Department of Gastroenterology, Ogaki Municipal Hospital, 4-86 Minaminokawa, Ogaki, Gifu, 503-8502, Japan
| | - Yasuhiro Sone
- Department of Radiology, Ogaki Municipal Hospital, Ogaki, Japan
| | - Atsuyuki Maeda
- Department of Surgery, Ogaki Municipal Hospital, Ogaki, Japan
| | - Yuji Kaneoka
- Department of Surgery, Ogaki Municipal Hospital, Ogaki, Japan
| | - Takashi Kumada
- Department of Nursing, Gifu Kyoritsu University, Ogaki, Japan
| | - Junko Tanaka
- Department of Epidemiology, Infectious Disease Control, and Prevention, Hiroshima University Institute of Biomedical and Health Sciences, Hiroshima, Japan
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15
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Sato N, Kenjo A, Nishimagi A, Kimura T, Okada R, Ishigame T, Kofunato Y, Yamada S, Hashimoto Y, Marubashi S. Accuracy comparison of MR elastography and biological markers in detecting liver fibrosis and predicting postoperative ascites. HPB (Oxford) 2021; 23:1383-1391. [PMID: 33583734 DOI: 10.1016/j.hpb.2021.01.011] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/25/2020] [Revised: 01/14/2021] [Accepted: 01/25/2021] [Indexed: 02/06/2023]
Abstract
BACKGROUND This retrospective study aimed to compare the discriminative performance between magnetic resonance elastography (MRE) and biological markers in detecting liver fibrosis and in predicting postoperative ascites (PA). METHODS We enrolled 77 patients consecutively who underwent hepatectomy between March 2017 and June 2019. Liver fibrosis was histopathologically graded using the METAVIR scoring system as reference. Discriminative performance of non-invasive assessments in detecting different stages of liver fibrosis and predicting PA was evaluated by receiver-operator curve analysis. RESULTS The concordance indices (C-indices) for MRE and biological markers for detecting significant fibrosis (≥F2) and cirrhosis (F4) were: MRE, 0.84 and 0.86; Wisteria floribunda agglutinin + Mac-2 binding protein (WM2BP), 0.63 and 0.71; Hyaluronic acid (HA), 0.72 and 0.75; 7 S-type 4 collagen (T4C), 0.61 and 0.66; APRI, 0.76 and 0.83; and Fib-4, 0.75 and 0.76. Univariable logistic analysis for predicting PA showed that C-indices were 0.751 (p = 0.007), 0.798 (p = 0.106), 0.771 (p = 0.050), 0.674 (p = 0.855), 0.655 (p = 0.263), and 0.560 (p = 0.640) for MRE, WM2BP, Fib-4, HA, APRI, and T4C, respectively. CONCLUSION MRE has a higher diagnostic performance than biological markers in detecting the stages of liver fibrosis and is a predictor for PA after hepatectomy.
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Affiliation(s)
- Naoya Sato
- Department of Hepato-Biliary-Pancreatic and Transplant Surgery, Fukushima Medical University, Hikagigaoka-1, Fukushima, Japan.
| | - Akira Kenjo
- Department of Hepato-Biliary-Pancreatic and Transplant Surgery, Fukushima Medical University, Hikagigaoka-1, Fukushima, Japan
| | - Atsushi Nishimagi
- Department of Hepato-Biliary-Pancreatic and Transplant Surgery, Fukushima Medical University, Hikagigaoka-1, Fukushima, Japan
| | - Takashi Kimura
- Department of Hepato-Biliary-Pancreatic and Transplant Surgery, Fukushima Medical University, Hikagigaoka-1, Fukushima, Japan
| | - Ryo Okada
- Department of Hepato-Biliary-Pancreatic and Transplant Surgery, Fukushima Medical University, Hikagigaoka-1, Fukushima, Japan
| | - Teruhide Ishigame
- Department of Hepato-Biliary-Pancreatic and Transplant Surgery, Fukushima Medical University, Hikagigaoka-1, Fukushima, Japan
| | - Yasuhide Kofunato
- Department of Hepato-Biliary-Pancreatic and Transplant Surgery, Fukushima Medical University, Hikagigaoka-1, Fukushima, Japan
| | - Shoki Yamada
- Department of Diagnostic Pathology, Fukushima Medical University, Hikarigaoka-1, Fukushima, Japan
| | - Yuko Hashimoto
- Department of Diagnostic Pathology, Fukushima Medical University, Hikarigaoka-1, Fukushima, Japan
| | - Shigeru Marubashi
- Department of Hepato-Biliary-Pancreatic and Transplant Surgery, Fukushima Medical University, Hikagigaoka-1, Fukushima, Japan
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16
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Chuaypen N, Chittmittrapap S, Avihingsanon A, Siripongsakun S, Wongpiyabovorn J, Tanpowpong N, Tanaka Y, Tangkijvanich P. Liver fibrosis improvement assessed by magnetic resonance elastography and Mac-2-binding protein glycosylation isomer in patients with hepatitis C virus infection receiving direct-acting antivirals. Hepatol Res 2021; 51:528-537. [PMID: 33615687 DOI: 10.1111/hepr.13630] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2020] [Revised: 02/12/2021] [Accepted: 02/16/2021] [Indexed: 12/07/2022]
Abstract
AIM Fibrosis regression has been observed in patients with chronic hepatitis C virus (HCV) infection treated with direct-acting antivirals. This study was aimed at evaluating dynamic changes of serum Mac-2-binding protein glycosylation isomer (M2BPGi) in patients with HCV genotype 1 receiving elbasvir/grazoprevir. METHODS M2BPGi were serially measured at baseline, during and after therapy. Its diagnostic performance at baseline and sustained virological response at 24 weeks after treatment (SVR24) were compared with transient elastography (TE) and the aspartate aminotransferase/platelet ratio index (APRI) using magnetic resonance elastography (MRE) as a reference. RESULTS Overall, 60 HCV mono-infected and 36 HCV/HIV co-infected patients were included with SVR24 rates of 93.3% and 97.2%, respectively. At baseline, TE, M2BPGi and APRI were correlated with MRE (r = 0.788, r = 0.703 and r = 0.564, respectively, p < 0.001). The area under the receiver operator characteristics curves for TE, M2BPGi and APRI in differentiating significant fibrosis were 0.88 (95% confidence interval; 0.81-0.95, p < 0.001), 0.86 (0.79-0.94, p < 0.001) and 0.74 (0.64-0.83, p < 0.001), respectively. The corresponding figures for cirrhosis were 0.95 (0.90-1.00, p < 0.001), 0.96 (0.92-1.00, p < 0.001) and 0.88 (0.79-0.97, p < 0.001), respectively. Compared with baseline, all fibrosis markers significantly declined after achieving SVR24. The correlations of TE, M2BPGi and APRI with MRE at time of SVR24 were r = 0.587 (p < 0.001), r = 0.457 (p < 0.001) and r = 0.293 (p = 0.004), respectively. In multivariate analysis, high baseline alanine aminotransferase level, HCV mono-infection and advanced fibrosis were factors associated with M2BPGi reduction. CONCLUSIONS HCV eradication is associated with liver fibrosis improvement. M2BPGi has a better performance than APRI in monitoring liver fibrosis in patients treated with direct-acting antivirals. This marker is applicable in resource-limited settings where imaging-based modalities are not widely accessible.
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Affiliation(s)
- Natthaya Chuaypen
- Center of Excellence in Hepatitis and Liver Cancer, Department of Biochemistry, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Salyavit Chittmittrapap
- Center of Excellence in Hepatitis and Liver Cancer, Department of Biochemistry, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Anchalee Avihingsanon
- The HIV Netherlands Australia Thailand Research Collaboration (HIV NAT), Department of Medicine, Bangkok, Thailand
| | - Surachate Siripongsakun
- Sonographer School, Department of Medical Imaging, Faculty of Health Science Technology, Chulabhorn Royal Academy, Bangkok, Thailand
| | | | - Natthaporn Tanpowpong
- Department of Radiology, Faculty of Medicine, 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, Department of Biochemistry, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
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Yoneda M, Honda Y, Ogawa Y, Kessoku T, Kobayashi T, Imajo K, Ozaki A, Nogami A, Taguri M, Yamanaka T, Kirikoshi H, Iwasaki T, Kurihashi T, Saito S, Nakajima A. Comparing the effects of tofogliflozin and pioglitazone in non-alcoholic fatty liver disease patients with type 2 diabetes mellitus (ToPiND study): a randomized prospective open-label controlled trial. BMJ Open Diabetes Res Care 2021; 9:e001990. [PMID: 33593749 PMCID: PMC7888333 DOI: 10.1136/bmjdrc-2020-001990] [Citation(s) in RCA: 47] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2020] [Revised: 01/13/2021] [Accepted: 01/24/2021] [Indexed: 12/15/2022] Open
Abstract
INTRODUCTION The treatment of diabetes has a significant impact on the pathogenesis of non-alcoholic fatty liver disease (NAFLD). We compared the effectiveness of tofogliflozin, a selective sodium-glucose cotransporter 2 inhibitor, and pioglitazone for the treatment of NAFLD patients with type 2 diabetes mellitus. RESEARCH DESIGN AND METHODS This open-label, prospective, single-center, randomized clinical trial recruited NAFLD patients with type 2 diabetes mellitus and a hepatic fat fraction of at least 10% as assessed based on the MRI-proton density fat fraction (MRI-PDFF). Eligible patients were stratified according to hemoglobin A1c (HbA1c), alanine transaminase, and MRI-PDFF levels and randomly assigned (1:1) to receive either 20 mg tofogliflozin or 15-30 mg pioglitazone, orally, once daily for 24 weeks. The primary endpoint was an absolute change in MRI-PDFF at 24 weeks. Efficacy and safety was assessed in all treated patients. This trial was registered in the Japan Registry of Clinical Trials. RESULTS Overall, 40 eligible patients were randomly assigned to receive tofogliflozin (n=21) or pioglitazone (n=19). Changes in hepatic steatosis after 24 weeks of treatment were evaluated by MRI-PDFF, which showed a significant decrease in both groups (-7.54% (p<0.0001) and -4.12% (p=0.0042) in the pioglitazone and tofogliflozin groups, respectively). Compared with baseline, the body weight decreased by 2.83±2.86 kg (-3.6%, p=0.0443) in the tofogliflozin group and increased by 1.39±2.62 kg (1.7%, p=0.0002) in the pioglitazone group after 24 weeks. No life-threatening events or treatment-related deaths occurred. CONCLUSIONS Tofogliflozin was well tolerated, and it reduced the MRI-PDFF levels in NAFLD patients with type 2 diabetes mellitus. TRIAL REGISTRATION NUMBER jRCTs031180159.
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Affiliation(s)
- Masato Yoneda
- Department of Gastroenterology and Hepatology, Yokohama City University, Yokohama, Japan
| | - Yasushi Honda
- Department of Gastroenterology and Hepatology, Yokohama City University, Yokohama, Japan
| | - Yuji Ogawa
- Department of Gastroenterology and Hepatology, Yokohama City University, Yokohama, Japan
| | - Takaomi Kessoku
- Department of Gastroenterology and Hepatology, Yokohama City University, Yokohama, Japan
| | - Takashi Kobayashi
- Department of Gastroenterology and Hepatology, Yokohama City University, Yokohama, Japan
| | - Kento Imajo
- Department of Gastroenterology and Hepatology, Yokohama City University, Yokohama, Japan
| | - Anna Ozaki
- Department of Gastroenterology and Hepatology, Yokohama City University, Yokohama, Japan
| | - Asako Nogami
- Department of Gastroenterology and Hepatology, Yokohama City University, Yokohama, Japan
| | - Masataka Taguri
- Department of Data Science, Yokohama City University, Yokohama, Japan
| | - Takeharu Yamanaka
- Department of Biostatistics, Yokohama City University, Yokohama, Japan
| | - Hiroyuki Kirikoshi
- Clinical Laboratory Department, Yokohama City University, Yokohama, Japan
| | | | - Takeo Kurihashi
- Department of Internal Medicine, Kanagawa Dental University Yokohama Clinic, Yokohama, Japan
| | - Satoru Saito
- Department of Gastroenterology and Hepatology, Yokohama City University, Yokohama, Japan
| | - Atsushi Nakajima
- Department of Gastroenterology and Hepatology, Yokohama City University, Yokohama, Japan
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18
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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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19
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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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20
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Sumida Y, Yoneda M, Seko Y, Ishiba H, Hara T, Toyoda H, Yasuda S, Kumada T, Hayashi H, Kobayashi T, Imajo K, Yoneda M, Tada T, Kawaguchi T, Eguchi Y, Oeda S, Takahashi H, Tomita E, Okanoue T, Nakajima A. Surveillance of Hepatocellular Carcinoma in Nonalcoholic Fatty Liver Disease. Diagnostics (Basel) 2020; 10:E579. [PMID: 32785100 PMCID: PMC7459689 DOI: 10.3390/diagnostics10080579] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2020] [Revised: 07/30/2020] [Accepted: 08/03/2020] [Indexed: 02/08/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is becoming the leading cause of hepatocellular carcinoma (HCC), liver-related mortality, and liver transplantation. There is sufficient epidemiological cohort data to recommend the surveillance of patients with NAFLD based upon the incidence of HCC. The American Gastroenterology Association (AGA) expert review published in 2020 recommends that NAFLD patients with cirrhosis or advanced fibrosis estimated by non-invasive tests (NITs) consider HCC surveillance. NITs include the fibrosis-4 (FIB-4) index, the enhanced liver fibrosis (ELF) test, FibroScan, and MR elastography. The recommended surveillance modality is abdominal ultrasound (US), which is cost effective and noninvasive with good sensitivity. However, US is limited in obese patients and those with NAFLD. In NAFLD patients with a high likelihood of having an inadequate US, or if an US is attempted but inadequate, CT or MRI may be utilized. The GALAD score, consisting of age, gender, AFP, the lens culinaris-agglutinin-reactive fraction of AFP (AFP-L3), and the protein induced by the absence of vitamin K or antagonist-II (PIVKA-II), can help identify a high risk of HCC in NAFLD patients. Innovative parameters, including a Mac-2 binding protein glycated isomer, type IV collagen 7S, free apoptosis inhibitor of the macrophage, and a combination of single nucleoside polymorphisms, are expected to be established. Considering the large size of the NAFLD population, optimal screening tests must meet several criteria, including high sensitivity, cost effectiveness, and availability.
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Affiliation(s)
- Yoshio Sumida
- Division of Hepatology and Pancreatology, Department of Internal Medicine, Aichi Medical University, Nagakute, Aichi 480-1195, Japan;
| | - Masashi Yoneda
- Division of Hepatology and Pancreatology, Department of Internal Medicine, Aichi Medical University, Nagakute, Aichi 480-1195, Japan;
| | - Yuya Seko
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan;
| | - Hiroshi Ishiba
- Department of Gastroenterology, Japanese Redcross Kyoto daiichi Hospital, Kyoto 605-0981, Japan;
| | - Tasuku Hara
- Department of Gastroenterology, Fukuchiyama City Hospital, Fukuchiyama, Kyoto 620-8505, Japan;
| | - Hidenori Toyoda
- Department of Gastroenterology, Ogaki Municipal Hospital, Ogaki, Gifu 503-8502, Japan; (H.T.); (S.Y.); (T.K.)
| | - Satoshi Yasuda
- Department of Gastroenterology, Ogaki Municipal Hospital, Ogaki, Gifu 503-8502, Japan; (H.T.); (S.Y.); (T.K.)
| | - Takashi Kumada
- Department of Gastroenterology, Ogaki Municipal Hospital, Ogaki, Gifu 503-8502, Japan; (H.T.); (S.Y.); (T.K.)
| | - Hideki Hayashi
- Department of Gastroenterology, Gifu Municipal Hospital, Gifu 500-8513, Japan; (H.H.); (E.T.)
| | - Takashi Kobayashi
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Yohokama, Kanagawa 236-0004, Japan; (T.K.); (K.I.); (M.Y.); (A.N.)
| | - Kento Imajo
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Yohokama, Kanagawa 236-0004, Japan; (T.K.); (K.I.); (M.Y.); (A.N.)
| | - Masato Yoneda
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Yohokama, Kanagawa 236-0004, Japan; (T.K.); (K.I.); (M.Y.); (A.N.)
| | - Toshifumi Tada
- Department of Hepatology, Himeji Redcross Hospital, Himeji, Hyogo 670-8540, Japan;
| | - Takumi Kawaguchi
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume 830-0011, Japan;
| | - Yuichiro Eguchi
- Loco Medical General Institute, 1178-1 Kanada Mikatsuki Ogi, Saga 849-8501, Japan;
| | - Satoshi Oeda
- Liver Center, Saga Medical Hospital, Saga, Saga 849-8501, Japan; (H.T.); (S.O.)
| | - Hirokazu Takahashi
- Liver Center, Saga Medical Hospital, Saga, Saga 849-8501, Japan; (H.T.); (S.O.)
| | - Eiichi Tomita
- Department of Gastroenterology, Gifu Municipal Hospital, Gifu 500-8513, Japan; (H.H.); (E.T.)
| | - Takeshi Okanoue
- Hepatology Center, Saiseikai Suita Hospital, Suita, Osaka 564-0013, Japan;
| | - Atsushi Nakajima
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Yohokama, Kanagawa 236-0004, Japan; (T.K.); (K.I.); (M.Y.); (A.N.)
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Masuzaki R, Kanda T, Sasaki R, Matsumoto N, Ogawa M, Matsuoka S, Karp SJ, Moriyama M. Noninvasive Assessment of Liver Fibrosis: Current and Future Clinical and Molecular Perspectives. Int J Mol Sci 2020; 21:4906. [PMID: 32664553 PMCID: PMC7402287 DOI: 10.3390/ijms21144906] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2020] [Revised: 06/29/2020] [Accepted: 07/09/2020] [Indexed: 01/18/2023] Open
Abstract
Liver fibrosis is one of the risk factors for hepatocellular carcinoma (HCC) development. The staging of liver fibrosis can be evaluated only via a liver biopsy, which is an invasive procedure. Noninvasive methods for the diagnosis of liver fibrosis can be divided into morphological tests such as elastography and serum biochemical tests. Transient elastography is reported to have excellent performance in the diagnosis of liver fibrosis and has been accepted as a useful tool for the prediction of HCC development and other clinical outcomes. Two-dimensional shear wave elastography is a new technique and provides a real-time stiffness image. Serum fibrosis markers have been studied based on the mechanism of fibrogenesis and fibrolysis. In the healthy liver, homeostasis of the extracellular matrix is maintained directly by enzymes called matrix metalloproteinases (MMPs) and their specific inhibitors, tissue inhibitors of metalloproteinases (TIMPs). MMPs and TIMPs could be useful serum biomarkers for liver fibrosis and promising candidates for the treatment of liver fibrosis. Further studies are required to establish liver fibrosis-specific markers based on further clinical and molecular research. In this review, we summarize noninvasive fibrosis tests and molecular mechanism of liver fibrosis in current daily clinical practice.
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Affiliation(s)
- Ryota Masuzaki
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Itabashi-Ku, Tokyo 173-8610, Japan; (T.K.); (R.S.); (N.M.); (M.O.); (S.M.); (M.M.)
| | - Tatsuo Kanda
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Itabashi-Ku, Tokyo 173-8610, Japan; (T.K.); (R.S.); (N.M.); (M.O.); (S.M.); (M.M.)
| | - Reina Sasaki
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Itabashi-Ku, Tokyo 173-8610, Japan; (T.K.); (R.S.); (N.M.); (M.O.); (S.M.); (M.M.)
| | - Naoki Matsumoto
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Itabashi-Ku, Tokyo 173-8610, Japan; (T.K.); (R.S.); (N.M.); (M.O.); (S.M.); (M.M.)
| | - Masahiro Ogawa
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Itabashi-Ku, Tokyo 173-8610, Japan; (T.K.); (R.S.); (N.M.); (M.O.); (S.M.); (M.M.)
| | - Shunichi Matsuoka
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Itabashi-Ku, Tokyo 173-8610, Japan; (T.K.); (R.S.); (N.M.); (M.O.); (S.M.); (M.M.)
| | - Seth J. Karp
- Division of Liver Transplantation, Department of Surgery, Vanderbilt University Medical Center, Nashville, TN 37232, USA;
| | - Mitsuhiko Moriyama
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Itabashi-Ku, Tokyo 173-8610, Japan; (T.K.); (R.S.); (N.M.); (M.O.); (S.M.); (M.M.)
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22
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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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23
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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: 10] [Impact Index Per Article: 2.0] [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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Nah EH, Cho S, Kim S, Kim HS, Cho HI. Diagnostic performance of Mac-2 binding protein glycosylation isomer (M2BPGi) in screening liver fibrosis in health checkups. J Clin Lab Anal 2020; 34:e23316. [PMID: 32227396 PMCID: PMC7439422 DOI: 10.1002/jcla.23316] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2020] [Revised: 02/27/2020] [Accepted: 03/07/2020] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Mild-to-moderate fibrosis is rarely diagnosed because the disease is asymptomatic in the early stage. The serum level of Mac-2 binding protein glycosylation isomer (M2BPGi) has been found to increase with the severity of liver fibrosis. The aim of this study was to determine the diagnostic performance of M2BPGi in screening liver fibrosis using magnetic resonance elastography (MRE) as a reference standard and to compare it with using the aspartate aminotransferase-to-platelet ratio (APRI) and the Fibrosis-4 index (FIB-4) in health checkups. METHODS This cross-sectional study consecutively selected subjects at health examinations who underwent MRE and M2BPGi testing at eight health promotion centers in Korea between January and September 2019. The serum M2BPGi level was measured using the chemiluminescence enzyme immunoassay method. The measured levels were indexed using the cutoff index (COI). COI values of M2BPGi were compared with the MRE results. RESULTS The median (interquartile) values of COI for fibrosis stages F0 (normal liver stiffness), F1 (mild fibrosis), F2 (significant fibrosis), and ≥F3 (advanced fibrosis) were 0.49 (0.34-0.61), 0.48 (0.38-0.68), 0.64 (0.43-1.03), and 1.01 (0.75-1.77), respectively (P < .0001). The AUCs of the COI for the screening of fibrosis stage ≥F1, ≥F2, and ≥F3 were 0.591, 0.698, and 0.853, respectively. Using a threshold of 0.75 for COI to exclude advanced fibrosis had a sensitivity, specificity, and negative predictive value of 80.0%, 77.9%, and 98.9%, respectively. The AUC for excluding advanced fibrosis was better for M2BPGi than for FIB-4 and APRI. CONCLUSION Serum M2BPGi was useful for screening significant and advanced fibrosis in health checkups.
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Affiliation(s)
- Eun-Hee Nah
- Department of Laboratory Medicine, Health Promotion Research Institute, Korea Association of Health Promotion, Seoul, Korea
| | - Seon Cho
- Department of Laboratory Medicine, Health Promotion Research Institute, Korea Association of Health Promotion, Seoul, Korea
| | - Suyoung Kim
- Department of Laboratory Medicine, Health Promotion Research Institute, Korea Association of Health Promotion, Seoul, Korea
| | - Hye-Sun Kim
- MEDIcheck LAB, Korea Association of Health Promotion, Cheongju, Korea
| | - Han-Ik Cho
- MEDIcheck LAB, Korea Association of Health Promotion, Cheongju, Korea
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25
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Kanno M, Kawaguchi K, Honda M, Horii R, Takatori H, Shimakami T, Kitamura K, Arai K, Yamashita T, Sakai Y, Yamashita T, Mizukoshi E, Kaneko S. Serum aldo-keto reductase family 1 member B10 predicts advanced liver fibrosis and fatal complications of nonalcoholic steatohepatitis. J Gastroenterol 2019; 54:549-557. [PMID: 30707282 DOI: 10.1007/s00535-019-01551-3] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2018] [Accepted: 01/19/2019] [Indexed: 02/07/2023]
Abstract
BACKGROUND Nonalcoholic steatohepatitis (NASH) is associated with liver inflammation in patients with nonalcoholic fatty liver disease, and it can progress to liver fibrosis at an advanced stage, as well as hepatocellular carcinoma (HCC) and portal hypertension. Although liver fibrosis is accurately diagnosed via biopsy, noninvasive methods are preferable. Aldo-keto reductase family 1 member B10 (AKR1B10) is associated with HCC and is secreted into the blood by liver cells via a lysosome-mediated nonclassical pathway. Accordingly, we analyzed whether secretion of AKR1B10 protein is associated with advanced NASH. METHODS We performed histological staging in 85 Matteoni classification type III and IV NASH patients and evaluated the incidence of HCC, formation of gastroesophageal varices, and prognosis according to serum AKR1B10 and Wisteria floribunda agglutinin-positive Mac-2 binding protein (WFA(+)-M2BP)(M2BPGi) and by comparison with conventional markers of fibrosis. RESULTS A positive correlation was found between the Brunt classification and serum AKR1B10 level. In Brunt stage 4 patients, AKR1B10 levels were higher than those of other liver fibrosis markers, with higher specificity. The cutoff values for AKR1B10 and WFA(+)-M2BP for stage 4 fibrosis were 1.03 and 3.11, respectively. The rates of stage 4 fibrosis, HCC incidence, and gastroesophageal varix formation were significantly different between the two groups subdivided according to these cutoff levels. Moreover, the patients in the higher value group had significantly worse prognosis after NASH diagnosis CONCLUSION: AKR1B10 is a useful serum biomarker for advanced liver fibrosis in NASH and, combined with serum WFA(+)-M2BP, can predict HCC development, gastroesophageal varix formation, and poor prognosis.
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Affiliation(s)
- Masataka Kanno
- Department of Gastroenterology, Kanazawa University Graduate School of Medical Science, 13-1 Takara-Machi, Kanazawa, Ishikawa, 920-8641, Japan
| | - Kazunori Kawaguchi
- Department of Gastroenterology, Kanazawa University Graduate School of Medical Science, 13-1 Takara-Machi, Kanazawa, Ishikawa, 920-8641, Japan
| | - Masao Honda
- Department of Gastroenterology, Kanazawa University Graduate School of Medical Science, 13-1 Takara-Machi, Kanazawa, Ishikawa, 920-8641, Japan.
| | - Rika Horii
- Department of Gastroenterology, Kanazawa University Graduate School of Medical Science, 13-1 Takara-Machi, Kanazawa, Ishikawa, 920-8641, Japan
| | - Hajime Takatori
- Department of Gastroenterology, Kanazawa University Graduate School of Medical Science, 13-1 Takara-Machi, Kanazawa, Ishikawa, 920-8641, Japan
| | - Tetsuro Shimakami
- Department of Gastroenterology, Kanazawa University Graduate School of Medical Science, 13-1 Takara-Machi, Kanazawa, Ishikawa, 920-8641, Japan
| | - Kazuya Kitamura
- Department of Gastroenterology, Kanazawa University Graduate School of Medical Science, 13-1 Takara-Machi, Kanazawa, Ishikawa, 920-8641, Japan
| | - Kuniaki Arai
- Department of Gastroenterology, Kanazawa University Graduate School of Medical Science, 13-1 Takara-Machi, Kanazawa, Ishikawa, 920-8641, Japan
| | - Taro Yamashita
- Department of Gastroenterology, Kanazawa University Graduate School of Medical Science, 13-1 Takara-Machi, Kanazawa, Ishikawa, 920-8641, Japan
| | - Yoshio Sakai
- Department of Gastroenterology, Kanazawa University Graduate School of Medical Science, 13-1 Takara-Machi, Kanazawa, Ishikawa, 920-8641, Japan
| | - Tatsuya Yamashita
- Department of Gastroenterology, Kanazawa University Graduate School of Medical Science, 13-1 Takara-Machi, Kanazawa, Ishikawa, 920-8641, Japan
| | - Eishiro Mizukoshi
- Department of Gastroenterology, Kanazawa University Graduate School of Medical Science, 13-1 Takara-Machi, Kanazawa, Ishikawa, 920-8641, Japan
| | - Shuichi Kaneko
- Department of Gastroenterology, Kanazawa University Graduate School of Medical Science, 13-1 Takara-Machi, Kanazawa, Ishikawa, 920-8641, Japan
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Agbim U, Asrani SK. Non-invasive assessment of liver fibrosis and prognosis: an update on serum and elastography markers. Expert Rev Gastroenterol Hepatol 2019; 13:361-374. [PMID: 30791772 DOI: 10.1080/17474124.2019.1579641] [Citation(s) in RCA: 90] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Non-invasive assessment of fibrosis is increasingly utilized in clinical practice to diagnose hepatic fibrosis. Non-invasive assessment of liver fibrosis relies on biologic and/or physical properties to assess tissue fibrosis. Serum markers estimate fibrosis by incorporating markers reflecting hepatic function (indirect markers) and/or markers measuring extracellular matrix degradation/fibrogenesis (direct markers). Radiology based techniques relay the mechanical properties and stiffness of a tissue, with increased stiffness associated with more advanced fibrosis. Areas covered: In this comprehensive review, the recent literature discussing serum markers and elastography-based techniques will be covered. These modalities are also explored in the setting of various liver diseases. Expert opinion: The etiology of liver disease and clinical context should be taken into consideration when non-invasive markers are incorporated in clinical practice. Non-invasive assessment of fibrosis has been most extensively utilized in hepatitis C, followed by hepatitis B and nonalcoholic fatty liver disease, but its role remains less developed in other etiologies of liver disease such as alcohol-associated liver disease and autoimmune liver disease. The role of non-invasive markers in predicting progression or regression of fibrosis, development of liver-related events and survival needs to be further explored.
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Affiliation(s)
- Uchenna Agbim
- a Division of Transplant Surgery, Department of Surgery , University of Tennessee Health Science Center , Memphis , TN , USA
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27
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Abstract
Alteration of glycosylation, a hallmark of cancer, results in the production of tumor-associated glycans or glycoproteins. These molecules are subsequently secreted or membrane-shed into the blood stream and thus serve as tumor-associated markers. Increased glycosylation in cancer is triggered by overexpression of glycoproteins that carry certain specific glycans, increase or decrease of nucleotide sugar donors and altered expression of glycosyltransferase and glycosidase enzymes. In this chapter, the biochemistry and function of glycoprotein, glycan and enzyme markers are reviewed. These glycosylation markers, applicable for detection and monitoring of cancer, include CA19-9, CA125, CEA, PSA and AFP. Because of their specific affinity to distinct sugar moieties, lectins are useful for developing assays to detect these tumor associated glycans and glycoproteins in clinical samples. As such, various enzyme-linked lectin assays (ELLA) have been developed for diagnosis, monitoring and prognosis. Because glycosylation changes occur early in cancer, the detection of tumor associated glycosylation markers using lectin based assays is an effective strategy to improve diagnosis and treatment resulting better outcomes clinically.
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Affiliation(s)
- Atit Silsirivanit
- Department of Biochemistry, Research Group for Glycosciences and Glycotechnology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand.
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28
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Sumida Y, Murotani K, Saito M, Tamasawa A, Osonoi Y, Yoneda M, Osonoi T. Effect of luseogliflozin on hepatic fat content in type 2 diabetes patients with non-alcoholic fatty liver disease: A prospective, single-arm trial (LEAD trial). Hepatol Res 2019; 49:64-71. [PMID: 30051943 DOI: 10.1111/hepr.13236] [Citation(s) in RCA: 85] [Impact Index Per Article: 14.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2018] [Revised: 07/16/2018] [Accepted: 07/19/2018] [Indexed: 12/12/2022]
Abstract
AIMS No pharmacological therapies are approved for non-alcoholic fatty liver disease (NAFLD). Luseogliflozin, a sodium glucose cotransporter 2 inhibitor, has been developed for the treatment of adults with type 2 diabetes (T2DM). The aim of this prospective, single-arm study is to evaluate the efficacy of luseogliflozin on hepatic fat content and glycated hemoglobin (HbA1c) in T2DM patients with NAFLD. METHODS Forty T2DM patients with NAFLD were treated with luseogliflozin 2.5 mg/day for 24 weeks. Primary end-points were changes in HbA1c and hepatic steatosis evaluated by magnetic resonance imaging-hepatic fat fraction from baseline. Secondary end-points were changes in metabolic and hepatic function-related parameters, including hepatic fibrosis markers (Fibrosis-4 index, NAFLD fibrosis score, type IV collagen 7S. and Wisteria floribunda agglutinin-positive Mac-2 binding protein). RESULTS Not only HbA1c and transaminase activities but also hepatic fat content were significantly decreased after 24 weeks of therapy with luseogliflozin. The reduction of hepatic fat content was significantly correlated with the reduction of alanine aminotransferase. Although hepatic fibrosis markers were unchanged, serum ferritin levels reduced and serum albumin significantly increased after the treatment. CONCLUSION Luseogliflozin can be a novel promising agent for the treatment of T2DM patients with NAFLD. Prospective randomized controlled trials are warranted to confirm this impact of luseogliflozin onT2DM with NAFLD.
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Affiliation(s)
- Yoshio Sumida
- Division of Hepatology and Pancreatology, Department of Internal Medicine, Aichi Medical University, Aichi, Japan
| | - Kenta Murotani
- Biostatistics Center, Graduate School of Medicine, Kurume University, Fukuoka, Japan
| | - Miyoko Saito
- Nakakinen Clinic Medical Corporation Kenseikai, Ibaraki, Japan
| | - Atsuko Tamasawa
- Nakakinen Clinic Medical Corporation Kenseikai, Ibaraki, Japan
| | - Yusuke Osonoi
- Nakakinen Clinic Medical Corporation Kenseikai, Ibaraki, Japan
| | - Masashi Yoneda
- Division of Hepatology and Pancreatology, Department of Internal Medicine, Aichi Medical University, Aichi, Japan
| | - Takeshi Osonoi
- Nakakinen Clinic Medical Corporation Kenseikai, Ibaraki, Japan
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29
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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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30
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Yasui Y, Kurosaki M, Komiyama Y, Takada H, Tamaki N, Watakabe K, Okada M, Wang W, Shimizu T, Kubota Y, Higuchi M, Takaura K, Tsuchiya K, Nakanishi H, Takahashi Y, Itakura J, Enomoto N, Izumi N. Wisteria floribunda agglutinin-positive Mac-2 binding protein predicts early occurrence of hepatocellular carcinoma after sustained virologic response by direct-acting antivirals for hepatitis C virus. Hepatol Res 2018; 48:1131-1139. [PMID: 30030872 DOI: 10.1111/hepr.13233] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2018] [Revised: 06/23/2018] [Accepted: 07/15/2018] [Indexed: 02/06/2023]
Abstract
AIM The aim of this study is to clarify the value of serum Wisteria floribunda agglutinin-positive Mac-2 binding protein (WFA+ -M2BP) for predicting hepatocellular carcinoma (HCC) in chronic hepatitis C patients who achieved sustained virologic response (SVR) by therapy with interferon-free, direct-acting antivirals (DAAs). METHODS This is a retrospective cohort study that included 567 patients who underwent antiviral therapy with an interferon-free DAA regimen and achieved SVR. Serum WFA+ -M2BP was measured after SVR. Factors predictive of HCC occurrence and recurrence were analyzed in the patients after stratification by previous treatment history of HCC. RESULTS Among 518 patients who had no history of HCC, 13 developed HCC. Post-SVR WFA+ -M2BP ≥1.75 cut-off index (C.O.I., P < 0.001) and α-fetoprotein (AFP) level ≥6 ng/mL (P = 0.01) were significant predictors of HCC development. Multivariate analysis showed that post-SVR WFA+ -M2BP ≥1.75 C.O.I. was an independent factor significantly associated with the development of HCC (hazard ratio [HR] 6.0; 95% confidence interval (CI), 1.8-19.4; P = 0.003). Among 49 patients who had a previous history of HCC, 22 had recurrence after SVR. Post-SVR AFP ≥6 ng/mL was the only factor associated with recurrence-free survival (HR 3.1; 95% CI, 1.3-7.5; P = 0.01). CONCLUSIONS Post-SVR WFA+ -M2BP is a predictive factor for the development of HCC in patients with no previous HCC history and treated with DAAs. Post-SVR AFP was predictive for HCC recurrence after DAA therapy.
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Affiliation(s)
- Yutaka Yasui
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Masayuki Kurosaki
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Yasuyuki Komiyama
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan.,First Department of Internal Medicine, University of Yamanashi, Yamanashi, Japan
| | - Hitomi Takada
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan.,First Department of Internal Medicine, University of Yamanashi, Yamanashi, Japan
| | - Nobuharu Tamaki
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Keiya Watakabe
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Mao Okada
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Wan Wang
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Takao Shimizu
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Yohei Kubota
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Mayu Higuchi
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Kenta Takaura
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Kaoru Tsuchiya
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Hiroyuki Nakanishi
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Yuka Takahashi
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Jun Itakura
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Nobuyuki Enomoto
- First Department of Internal Medicine, University of Yamanashi, Yamanashi, Japan
| | - Namiki Izumi
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
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31
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Ogawa Y, Honda Y, Kessoku T, Tomeno W, Imajo K, Yoneda M, Kawanaka M, Kirikoshi H, Ono M, Taguri M, Saito S, Yamanaka T, Wada K, Nakajima A. Wisteria floribunda agglutinin-positive Mac-2-binding protein and type 4 collagen 7S: useful markers for the diagnosis of significant fibrosis in patients with non-alcoholic fatty liver disease. J Gastroenterol Hepatol 2018; 33:1795-1803. [PMID: 29633352 DOI: 10.1111/jgh.14156] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2018] [Revised: 03/16/2018] [Accepted: 03/25/2018] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND AIM The fibrosis stage of liver is associated with the long-term outcomes in patients with non-alcoholic fatty liver disease (NAFLD). However, significant fibrosis, defined as fibrosis stages 2-4, is associated with an elevated risk of progression to severe liver disease; there have been scant reports about diagnosing significant fibrosis. We compare the noninvasive method and aim to identify appropriate liver fibrosis markers for detecting significant fibrosis in NAFLD patients. METHODS We compared the usefulness of liver fibrosis markers (Wisteria floribunda agglutinin-positive Mac-2-binding protein [WFA+ -M2BP], type 4 collagen 7S, etc.), clinical scoring systems, and liver stiffness measurement obtained using vibration-controlled transient elastography and magnetic resonance imaging-based magnetic resonance elastography in the same individuals and identified the most appropriate noninvasive method for detecting significant fibrosis in 165 patients with liver biopsy-diagnosed NAFLD. RESULTS The area under the receiver operating characteristic curve based on the serum cutoff index values of WFA+ -M2BP/the serum levels of type IV collagen 7S for the diagnosis of significant fibrosis was 0.832 (95% confidence interval: 0.771-0.894)/0.837 (95% confidence interval: 0.778-0.898). "WFA+ -M2BP (cutoff index) ≥ 0.83 or type IV collagen 7S ≥ 5.2 ng/mL" showed a high sensitivity (91.4%) and negative predictive value (87.9%) for the diagnosis of significant fibrosis. CONCLUSIONS We showed that serum WFA+ -M2BP or type IV collagen 7S levels serve as useful independent markers for detecting significant fibrosis and that use of both WFA+ -M2BP and type IV collagen 7S together increased the sensitivity and negative predictive value for the diagnosis of liver fibrosis. These results need to be validated in larger populations from multiple clinical centers.
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Affiliation(s)
- Yuji Ogawa
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Yasushi Honda
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Takaomi Kessoku
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Wataru Tomeno
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Kento Imajo
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Masato Yoneda
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Miwa Kawanaka
- Department of General Internal Medicine 2, General Medical Center, Kawasaki Medical School, Okayama, Japan
| | - Hiroyuki Kirikoshi
- Clinical Laboratory Department, Yokohama City University Hospital, Yokohama, Japan
| | - Masafumi Ono
- Department of Gastroenterology and Hepatology, Kochi Medical School, Kochi, Japan
| | - Masataka Taguri
- Department of Biostatistics and Epidemiology, Yokohama City University School of Medicine, Yokohama, Japan
| | - Satoru Saito
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Takeharu Yamanaka
- Department of Biostatistics and Epidemiology, Yokohama City University School of Medicine, Yokohama, Japan
| | - Koichiro Wada
- Department of Pharmacology, Shimane University Faculty of Medicine, Izumo, Japan
| | - Atsushi Nakajima
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
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32
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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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33
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Ugamura A, Chu PS, Nakamoto N, Taniki N, Ojiro K, Hibi T, Shinoda M, Obara H, Masugi Y, Yamaguchi A, Shiba S, Morikawa R, Usui S, Ebinuma H, Kitagawa Y, Saito H, Kanai T. Liver Fibrosis Markers Improve Prediction of Outcome in Non-Acetaminophen-Associated Acute Liver Failure. Hepatol Commun 2018; 2:1331-1343. [PMID: 30411080 PMCID: PMC6211334 DOI: 10.1002/hep4.1233] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/18/2018] [Accepted: 06/20/2018] [Indexed: 12/17/2022] Open
Abstract
A prognostic system for acute liver failure (ALF) with a higher predictive value is urgently needed. The role of extracellular matrix (ECM) remodeling in ALF has not been fully elucidated. We hypothesized that serologic fibrosis markers, which reflect ECM remodeling, are predictive of ALF outcome at first presentation. This observational study included 110 patients with acute liver dysfunction, of which 73 had non-acetaminophen-associated ALF (NAA-ALF). We evaluated serum levels of hyaluronic acid, 7S domain of type IV collagen (4COL7S), and Wisteria floribunda agglutinin-positive Mac-2-binding protein at first presentation to a tertiary center. Serologic fibrosis markers were significantly higher in NAA-ALF compared with acute hepatitis. Elevated hyaluronic acid and 4COL7S levels at first presentation correlated significantly with worse clinical outcomes. 4COL7S, along with age, ammonia, and the Model for End-Stage Liver Disease (MELD) score, was a significant prognostic factor in multivariate analysis; 4COL7S correlated significantly with coagulopathy, decreased hepatic synthetic functions, advanced hepatic encephalopathy, and liver atrophy and also predicted 180-day transplant-free survival. Cox regression models incorporating 4COL7S with the MELD system had profoundly improved predictive values that significantly surpassed the MELD system alone. Conclusion: Elevation of serologic fibrosis markers reflecting ECM remodeling in NAA-ALF predicted a worse clinical outcome. Incorporation of 4COL7S at first presentation to a transplant center improves the specificity while retaining the sensitivity of the MELD system. External validation of a fibrosis marker as part of a clinical prediction tool in ALF warrants further investigation.
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Affiliation(s)
- Aya Ugamura
- Division of Gastroenterology and Hepatology, Department of Internal Medicine Keio University School of Medicine Tokyo Japan
| | - Po-Sung Chu
- Division of Gastroenterology and Hepatology, Department of Internal Medicine Keio University School of Medicine Tokyo Japan
| | - Nobuhiro Nakamoto
- Division of Gastroenterology and Hepatology, Department of Internal Medicine Keio University School of Medicine Tokyo Japan
| | - Nobuhito Taniki
- Division of Gastroenterology and Hepatology, Department of Internal Medicine Keio University School of Medicine Tokyo Japan
| | - Keisuke Ojiro
- Division of Gastroenterology and Hepatology, Department of Internal Medicine Keio University School of Medicine Tokyo Japan.,Department of Gastroenterology and Hepatology Tokyo Dental College Ichikawa General Hospital Ichikawa City Japan
| | - Taizo Hibi
- Department of Surgery Keio University School of Medicine Tokyo Japan
| | - Masahiro Shinoda
- Department of Surgery Keio University School of Medicine Tokyo Japan
| | - Hideaki Obara
- Department of Surgery Keio University School of Medicine Tokyo Japan
| | - Yohei Masugi
- Department of Pathology Keio University School of Medicine Tokyo Japan
| | - Akihiro Yamaguchi
- Division of Gastroenterology and Hepatology, Department of Internal Medicine Keio University School of Medicine Tokyo Japan
| | - Shunsuke Shiba
- Division of Gastroenterology and Hepatology, Department of Internal Medicine Keio University School of Medicine Tokyo Japan
| | - Rei Morikawa
- Division of Gastroenterology and Hepatology, Department of Internal Medicine Keio University School of Medicine Tokyo Japan
| | - Shingo Usui
- Division of Gastroenterology and Hepatology, Department of Internal Medicine Keio University School of Medicine Tokyo Japan.,Department of Gastroenterology and Hepatology National Hospital Organization Saitama Hospital Wako City Japan
| | - Hirotoshi Ebinuma
- Division of Gastroenterology and Hepatology, Department of Internal Medicine Keio University School of Medicine Tokyo Japan.,International University of Health and Welfare Mita Hospital Tokyo Japan
| | - Yuko Kitagawa
- Department of Surgery Keio University School of Medicine Tokyo Japan
| | - Hidetsugu Saito
- Division of Gastroenterology and Hepatology, Department of Internal Medicine Keio University School of Medicine Tokyo Japan.,Division of Pharmacotherapeutics Keio University School of Pharmacy Tokyo Japan
| | - Takanori Kanai
- Division of Gastroenterology and Hepatology, Department of Internal Medicine Keio University School of Medicine Tokyo Japan
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34
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Alkhouri N, Johnson C, Adams L, Kitajima S, Tsuruno C, Colpitts TL, Hatcho K, Lawitz E, Lopez R, Feldstein A. Serum Wisteria floribunda agglutinin-positive Mac-2-binding protein levels predict the presence of fibrotic nonalcoholic steatohepatitis (NASH) and NASH cirrhosis. PLoS One 2018; 13:e0202226. [PMID: 30161179 PMCID: PMC6116978 DOI: 10.1371/journal.pone.0202226] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2018] [Accepted: 07/30/2018] [Indexed: 12/28/2022] Open
Abstract
OBJECTIVE The race for finding effective treatments for nonalcoholic fatty liver disease (NAFLD) has been slowed down by the high screen-failure rate for including patients in trials due to the lack of a noninvasive biomarker that can identify patients with significant disease. Recently, Wisteria floribunda agglutinin-positive Mac-2-binding protein (WFA+ -M2BP) has shown promise in predicting liver fibrosis. The aims of this study were to evaluate the utility of WFA+ -M2BP as a biomarker to sub-classify patients with NAFLD according to their disease severity and to assess its correlation with histologic features of NAFLD. METHODS Patients undergoing biopsy for clinical suspicion of NAFLD and healthy controls were included. Patients with NAFLD were classified into: NAFL, early NASH (F0-F1), fibrotic NASH (F2-F3), and NASH cirrhosis (F4). Levels of WFA+ -M2BP in sera was measured by a HISCL™ M2BPGi™ assay kit using an automated immunoanalyzer (HISCL™-800; Sysmex, Kobe, Japan). Analysis of covariance was used to assess difference in WFA+ -M2BP between the groups and Spearman's correlation coefficients were used to assess correlation with histological features. RESULTS Our cohort consisted of 20 healthy controls and 198 patients with biopsy-proven NAFLD divided as follows: 52 with NAFL, 62 with early NASH, 52 with fibrotic NASH, and 32 with NASH cirrhosis. WFA+ -M2BP level was found to be significantly increased in the fibrotic NASH and NASH cirrhosis groups compared to healthy controls and those with early NAFLD after adjusting for age, gender and BMI. Furthermore, patients with NASH cirrhosis had significantly higher WFA+ -M2BP levels (2.4[1.5, 4.2] C.O.I (Cut-off Index)) than those with fibrotic NASH (1.2[0.79, 1.9]), p < 0.001. WFA+ -M2BP level had moderate correlation with inflammation, ballooning and NAFLD activity score and strong correlation with fibrosis stage. Additionally, ROC curve analysis demonstrated that WFA+ -M2BP accurately differentiated F2-4 from F0-F1. CONCLUSION In a large cohort of patients with the full spectrum of NAFLD, WFA+ -M2BP levels predicted the presence of advanced disease and correlated strongly with fibrosis stage.
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Affiliation(s)
- Naim Alkhouri
- The Texas Liver Institute, University of Texas (UT) Health Science Center, San Antonio, Texas, United States of America
- * E-mail:
| | - Casey Johnson
- Department of Pediatrics, University of California – San Diego, La Jolla, California, United States of America
| | - Leon Adams
- The University of Western Australia, Crawley, Australia
| | | | | | - Tracey L. Colpitts
- Sysmex Corporation R&D Center of Americas, Lincolnshire, Illinois, United States of America
| | - Kazuki Hatcho
- Sysmex Corporation R&D Center of Americas, Lincolnshire, Illinois, United States of America
| | - Eric Lawitz
- The Texas Liver Institute, University of Texas (UT) Health Science Center, San Antonio, Texas, United States of America
| | - Rocio Lopez
- Digestive Disease and Surgery Institute, Cleveland Clinic, Cleveland, Ohio, United States of America
| | - Ariel Feldstein
- Department of Pediatrics, University of California – San Diego, La Jolla, California, United States of America
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35
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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: 136] [Impact Index Per Article: 19.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2017] [Accepted: 12/18/2017] [Indexed: 02/04/2023]
Abstract
Assessing liver fibrosis is important for predicting the efficacy of antiviral therapy and patient prognosis. Liver biopsy is the gold standard for diagnosing liver fibrosis, despite its invasiveness and problematic diagnostic accuracy. Although noninvasive techniques to assess liver fibrosis are becoming important, reliable serum surrogate markers are not available. A glycoproteomics study aimed at identifying such markers discovered Mac 2-Binding Protein Gylcan Isomer (M2BPGi), which is a reliable marker for assessing liver fibrosis in patients with viral hepatitis and other fibrotic liver diseases such as primary biliary cholangitis, biliary atresia, autoimmune hepatitis, and nonalcoholic fatty liver disease. M2BPGi predicts the development of hepatocellular carcinoma (HCC) in patients infected with hepatitis B and C as well as the prognosis of liver cirrhosis in those with HCC after therapy. The unique features of M2BPGi are as follows: (1) cut-off values differ for the same stages of fibrosis according to the cause of fibrosis; and (2) M2BPGi levels rapidly decrease after patients achieve a sustained antiviral response to hepatitis C virus. These observations cannot be explained if M2BPGi levels reflect the amount of fibrotic tissue. Hepatic stellate cells (HSCs) secrete M2BPGi, which may serve as a messenger between HSCs and Kupffer cells via Mac-2 (galectin 3) that is expressed in Kupffer cells during fibrosis progression. Here we show that M2BPGi is a surrogate marker for assessing HSC activation. These findings may reveal the roles of HSCs in extrahepatic fibrotic disease progression.
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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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36
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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: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2017] [Revised: 12/26/2017] [Accepted: 01/02/2018] [Indexed: 02/06/2023]
Abstract
AIM As it is not practical to perform regular screening for hepatocellular carcinoma (HCC) in all patients with non-alcoholic fatty liver disease (NAFLD), there is a need to identify NAFLD patients who are at high risk for HCC. Wisteria floribunda agglutinin-positive Mac-2 binding protein (WFA+ -M2BP) has been shown to be a surrogate marker for predicting HCC as well as a liver fibrosis marker in patients with chronic hepatitis B and C. The aim of this study was to investigate whether WFA+ -M2BP predicts HCC development in NAFLD patients. METHODS Serum WFA+ -M2BP was retrospectively measured in 331 patients with histologically proven NAFLD, 51 of whom developed HCC. The association of WFA+ -M2BP and HCC development in NAFLD patients was investigated. RESULTS The WFA+ -M2BP values were significantly greater in NAFLD patients with HCC than in those without HCC among patients with liver fibrosis ≥stage 3. Multivariate analysis identified WFA+ -M2BP as one of the predictive factors for HCC development (odds ratio, 1.57; 95% confidence interval, 1.083-2.265; P = 0.017). The optimal cut-off index of WFA+ -M2BP for predicting HCC was 1.255 with specificity of 78.4% and sensitivity of 70.4%. The area under the receiver operating characteristic curve value for the prediction of HCC development was 0.806. The cumulative incidence rate of HCC was significantly greater in patients with WFA+ -M2BP ≥ 1.255 (n = 61) than in those with WFA+ -M2BP < 1.255 (n = 137) among patients who were followed up for more than 2 years after the diagnosis of NAFLD. CONCLUSIONS Wisteria floribunda agglutinin-positive Mac-2 binding protein predicts HCC development and is a useful surrogate marker for identifying NAFLD patients who are at a high risk for HCC.
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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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37
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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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38
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Yoneda M, Imajo K, Takahashi H, Ogawa Y, Eguchi Y, Sumida Y, Yoneda M, Kawanaka M, Saito S, Tokushige K, Nakajima A. Clinical strategy of diagnosing and following patients with nonalcoholic fatty liver disease based on invasive and noninvasive methods. J Gastroenterol 2018; 53:181-196. [PMID: 29177681 PMCID: PMC5846871 DOI: 10.1007/s00535-017-1414-2] [Citation(s) in RCA: 53] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2017] [Accepted: 11/13/2017] [Indexed: 02/04/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is an important cause of chronic liver injury in many countries. The incidence of NAFLD is rising rapidly in both adults and children, because of the currently ongoing epidemics of obesity and type 2 diabetes. Notably, histological liver fibrosis is recognized as the main predictive factor for the overall long-term outcome of NAFLD, including cardiovascular disease and liver-related mortality. Thus, staging of liver fibrosis is essential in determining the prognosis and optimal treatment for patients with NAFLD and in guiding surveillance for the development of hepatocellular carcinoma (HCC). Whereas liver biopsy remains the gold standard for staging liver fibrosis, it is impossible to enforce liver biopsy in all patients with NAFLD. Noninvasive biological markers, scoring systems and noninvasive modalities are increasingly being developed and investigated to evaluate fibrosis stage of NAFLD patients. This review will highlight recent studies on the diagnosis and staging of NAFLD based on invasive (liver biopsy) or noninvasive (biomarker, scoring systems, US-based elastography and MR elastography) methods.
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Affiliation(s)
- Masato Yoneda
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, 236-0004, Japan
| | - Kento Imajo
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, 236-0004, Japan
| | - Hirokazu Takahashi
- Division of Metabolism and Endocrinology, Faculty of Medicine, Saga University, 5-1-1 Nabeshima, Saga, 849-8501, Japan
| | - Yuji Ogawa
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, 236-0004, Japan
| | - Yuichiro Eguchi
- Liver Center, Saga University, 5-1-1 Nabeshima, Saga, 849-8501, Japan
| | - Yoshio Sumida
- Division of Hepatology and Pancreatology, Department of Internal Medicine, Aichi Medical University School of Medicine, 1-1 Yazakokarimata, Nagakute, Aichi, 480-1195, Japan
| | - Masashi Yoneda
- Division of Hepatology and Pancreatology, Department of Internal Medicine, Aichi Medical University School of Medicine, 1-1 Yazakokarimata, Nagakute, Aichi, 480-1195, Japan
| | - Miwa Kawanaka
- General Internal Medicine 2, General Medical Center, Kawasaki Medical School, 2-6-1 Nakasange, Kutaku, Okayama, 700-8505, Japan
| | - Satoru Saito
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, 236-0004, Japan
| | - Katsutoshi Tokushige
- Department of Internal Medicine and Gastroenterology, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo, 162-8666, 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 J, Hu HH, Lee MH, Korenaga M, Jen CL, Batrla-Utermann R, Lu SN, Wang LY, Mizokami M, Chen CJ, Yang HI. Serum Levels of M2BPGi as Short-Term Predictors of Hepatocellular Carcinoma in Untreated Chronic Hepatitis B Patients. Sci Rep 2017; 7:14352. [PMID: 29085039 PMCID: PMC5662597 DOI: 10.1038/s41598-017-14747-5] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2017] [Accepted: 10/13/2017] [Indexed: 12/13/2022] Open
Abstract
This study examines the role of M2BPGi, a novel seromarker for chronic hepatitis, in predicting hepatocellular carcinoma (HCC) among untreated chronic hepatitis B (CHB) patients. In this nested case-control study, 1070 samples were assayed for M2BPGi, including 357 samples from HCC cases, and 713 samples from non-HCC controls, collected at various times throughout follow-up. HCC case samples were stratified according to years prior to diagnosis. Associations between M2BPGi and HCC were examined with multivariate logistic regression. M2BPGi, α-fetoprotein (AFP), and hepatitis B surface antigen (HBsAg) levels were significant independent short-term predictors of HCC, while M2BPGi was insignificant in long-term analyses. Compared to M2BPGi levels <1.0 cut-off index (COI), those with levels ≥2.0 COI had multivariate odds ratios (95% CI) for HCC of 7.40 (2.40-22.78), 6.46 (2.58-16.18), and 2.24 (0.97-5.15), respectively, for prediction of HCC within 1-2, 2-5, and ≥5 years. Higher proportions of individuals had M2BPGi levels ≥2.0 COI in samples closer to HCC diagnosis. Areas under receiver operating characteristic curves for models with M2BPGi, AFP, and HBsAg levels predicting HCC within 1-2, 2-5, and >5 years were 0.84, 0.81, and 0.75. M2BPGi is a strong and independent short-term predictor of HCC in CHB patients.
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Affiliation(s)
- Jessica Liu
- Genomics Research Center, Academia Sinica, Taipei, Taiwan
| | - Hui-Han Hu
- Genomics Research Center, Academia Sinica, Taipei, Taiwan
| | - Mei-Hsuan Lee
- Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan
| | - Masaaki Korenaga
- The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Ichikawa, Japan
| | - Chin-Lan Jen
- Genomics Research Center, Academia Sinica, Taipei, Taiwan
| | | | - Sheng-Nan Lu
- Department of Gastroenterology, Chang-Gung Memorial Hospital, Kaohsiung, Taiwan
| | - Li-Yu Wang
- MacKay Medical College, New Taipei City, Taiwan
| | - Masashi Mizokami
- The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Ichikawa, Japan
| | - Chien-Jen Chen
- Genomics Research Center, Academia Sinica, Taipei, Taiwan
- Graduate Institute of Epidemiology and Preventative Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan
| | - Hwai-I Yang
- Genomics Research Center, Academia Sinica, Taipei, Taiwan.
- Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan.
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