RESUMEN
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.
Asunto(s)
Hepatitis C Crónica , Lectinas de Plantas , Receptores N-Acetilglucosamina , Niño , Hepatitis C Crónica/sangre , Humanos , Cirrosis Hepática/sangre , Cirrosis Hepática/diagnóstico , Glicoproteínas de Membrana/sangre , Lectinas de Plantas/sangre , Receptores N-Acetilglucosamina/sangreRESUMEN
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.
Asunto(s)
Antígenos de Neoplasias/sangre , Glicoproteínas de Membrana/sangre , Enfermedad del Hígado Graso no Alcohólico/sangre , Enfermedad del Hígado Graso no Alcohólico/diagnóstico , Lectinas de Plantas/sangre , Receptores N-Acetilglucosamina/sangre , Femenino , Humanos , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Índice de Severidad de la EnfermedadRESUMEN
The extent of liver fibrosis predicts prognosis and is important for determining treatment strategies for chronic hepatitis. During the fibrosis progression, serum levels of Mac2 binding protein (M2BP) increase and the N-glycan structure changes to enable binding to Wisteria floribunda agglutinin (WFA) lectin. As a novel diagnostic marker, glycosylation isomer of M2BP (M2BPGi) has been developed. However, its glycan structures recognized by WFA are unclear. In this study, we analyzed site-specific N-glycan structures of serum M2BP using Glyco-RIDGE (Glycan heterogeneity-based Relational IDentification of Glycopeptide signals on Elution profile) method. We evaluated five sample types: (1) M2BP immunoprecipitated from normal healthy sera (NHS-IP(+)), (2) M2BP immunoprecipitated from sera of patients with liver cirrhosis (stage 4; F4-IP(+)), (3) M2BP captured with WFA from serum of patients with liver cirrhosis (stage 4; F4-WFA(+)), (4) recombinant M2BP produced by HEK293 cells (rM2BP) and (5) WFA-captured rM2BP (rM2BP-WFA(+)). In NHS-IP(+) M2BP, bi-antennary N-glycan was the main structure, and LacNAc extended to its branches. In F4-IP(+) M2BP, many branched structures, including tri-antennary and tetra-antennary N-glycans, were found. F4-WFA(+) showed a remarkable increase in branched structures relative to the quantity before enrichment. In recombinant M2BP, both no sialylated-LacdiNAc and -branched LacNAc structures were emerged. The LacdiNAc structure was not found in serum M2BP. Glycosidase-assisted HISCL assays suggest that reactivity with WFA of both serum and recombinant M2BP depends on unsialylated and branched LacNAc and in part of recombinant depends on LacdiNAc. On M2BPGi, the highly branched LacNAc, probably dense cluster of LacNAc, would be recognized by WFA.
Asunto(s)
Antígenos de Neoplasias/química , Biomarcadores de Tumor/química , Cirrosis Hepática/sangre , Lectinas de Plantas/química , Polisacáridos/química , Receptores N-Acetilglucosamina/química , Antígenos de Neoplasias/sangre , Biomarcadores de Tumor/sangre , Células HEK293 , Voluntarios Sanos , Humanos , Lectinas de Plantas/sangre , Polisacáridos/sangre , Análisis por Matrices de Proteínas , Receptores N-Acetilglucosamina/sangre , Proteínas Recombinantes/sangre , Proteínas Recombinantes/químicaRESUMEN
Wisteria floribunda agglutinin (WFA) is a lectin that binds to the sugar chain of Mac-2 binding protein (M2BP), and WFA-positive M2BP (WFA+-M2BP) has been reported as a useful marker for assessing liver fibrosis in chronic liver disease. Tolvaptan (TLV), a selective vasopressin V2 receptor antagonist, is used for cirrhotic ascites in Japan, but good predictors of treatment efficacy remain to be established. Our aim was to investigate whether WFA+-M2BP monitoring before and after TLV administration can predict treatment efficacy in patients with cirrhotic ascites. Twenty patients (10 men), with a median age of 72 years, were enrolled. Cirrhosis was caused by hepatitis B virus (n = 3), hepatitis C virus (n = 4), alcohol (n = 8), and others (n = 5). Responders were defined as having a body weight loss of ≥ 1.5 kg/week after TLV administration. Serum WFA+-M2BP levels were measured at baseline and days 1, 3, and 7 after TLV treatment. Twelve patients (60%) were responders. Baseline WFA+-M2BP levels were correlated with serum albumin levels (r = -0.544, P = 0.013). The baseline furosemide dose was lower and platelet count was higher in responders than in non-responders (P < 0.05). The ratio of WFA+-M2BP levels on day 1 after TLV administration to baseline was lower in responders than in non-responders (P < 0.05). The decrease in the ratio discriminated responders from non-responders (AUC = 0.844, P < 0.05). In conclusion, monitoring serum WFA+-M2BP is helpful for predicting the efficacy of TLV treatment in patients with cirrhotic ascites.
Asunto(s)
Antígenos de Neoplasias/sangre , Ascitis/tratamiento farmacológico , Biomarcadores de Tumor/sangre , Monitoreo de Drogas , Cirrosis Hepática/sangre , Cirrosis Hepática/tratamiento farmacológico , Lectinas de Plantas/sangre , Receptores N-Acetilglucosamina/sangre , Tolvaptán/uso terapéutico , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Cirrosis Hepática/virología , Masculino , Persona de Mediana Edad , Curva ROC , Tolvaptán/administración & dosificaciónRESUMEN
BACKGROUND: Wisteria floribunda agglutinin-positive Mac-2-binding protein (WFA+-M2BP) was a novel marker of liver fibrosis. We aimed to investigate WFA+-M2BP level in assessing liver fibrosis in patients with chronic hepatitis B (CHB) infection. METHODS: A total of 160 CHB patients, who received a liver biopsy, were consecutively recruited. Serum WFA+-M2BP level was quantified at the time point of biopsy. The results were compared with histopathological manifestations and clinical characteristics of the patients. RESULTS: The median WFA+-M2BP level, aspartate aminotransferase-to-platelet ratio (APRI) and Fibrosis-4 (FIB-4) index were 1.20 COI, 1.19, and 1.63, respectively. Fifty-one (31.9%) patients had advanced fibrosis. There was a significant increase of WFA+-M2BP levels in parallel to necroinflammation/fibrosis stages. The areas under the receiver operating characteristic curve (AUROC) of WFA+-M2BP level for predicting fibrosis stages were 0.780 of F2, 0.785 of F3, and 0.769 of F4, respectively (all p <0.001). The multivariate analysis identified age (Odds ratio [OR] 1.05, 95% confidence interval [CI]: 1.010-1.092, p = 0.014), platelet (OR: 0.99, 95%CI: 0.980-0.998, p = 0.013), and WFA+-M2BP level (OR: 1.97, 95% CI: 1.299-2.984, p = 0.001) as independent factors associated with advanced fibrosis. Combination of age, platelet and WFA+-M2BP level achieved a better diagnostic performance for advanced fibrosis (AUROC: 0.732, accuracy: 81.3%) than APRI (AUROC: 0.577, accuracy: 63.8%) or FIB-4 index (AUROC: 0.691, accuracy: 75.6%). CONCLUSION: WFA+-M2BP had a good performance indistinguishing liver fibrosis in CHB patients. The combination of age, platelet, and WFA+-M2BPaddressed more accuracy in identifying patients with advanced fibrosis.
Asunto(s)
Antígenos de Neoplasias/sangre , Hepatitis B Crónica/diagnóstico , Cirrosis Hepática/diagnóstico , Glicoproteínas de Membrana/sangre , Lectinas de Plantas/sangre , Receptores N-Acetilglucosamina/sangre , Adulto , Factores de Edad , Área Bajo la Curva , Biomarcadores , Femenino , Hepatitis B Crónica/sangre , Humanos , Cirrosis Hepática/sangre , Masculino , Persona de Mediana Edad , Recuento de PlaquetasRESUMEN
As an important glycoprotein of the lectin family, soybean agglutinin (SBA) is an anti-nutritional factor with considerable toxic and side effects and plays a significant role in tumor analysis. In order to achieve the sensitive detection of SBA, a sandwich-structured electrochemiluminescence (ECL) biosensor was constructed using carboxylated carbon nitride (C-g-C3N4) as luminophore and D-galactosamine (galM) as a recognition element. A glassy carbon electrode (GCE) was modified with Au nanoparticles (Au NPs) for capturing the galM via Au-N bond, and further capturing the target SBA by specific recognition between galM and SBA. In the presence of SBA, the composite C-g-C3N4-galM was immobilized onto the electrode. With the increase in the concentration of SBA, the ECL signal from C-g-C3N4 increased, thus achieving a signal-on detection of SBA. The linear range of the biosensor was 1.0 ng/mL~10 µg/mL and detection limit for SBA was as low as 0.33 ng/mL. In this construction strategy, C-g-C3N4 not only acted as an excellent signal probe, but also as an immobilization matrix to easily achieve a high loading of the small molecule recognition element galM. This strategy provides a simple alternative SBA detection platform. Graphical abstract.
Asunto(s)
Galactosamina/química , Grafito/química , Sustancias Luminiscentes/química , Nitrilos/química , Lectinas de Plantas/análisis , Proteínas de Soja/análisis , Técnicas Biosensibles/métodos , Ácidos Carboxílicos/química , Técnicas Electroquímicas/métodos , Oro/química , Humanos , Límite de Detección , Mediciones Luminiscentes/métodos , Nanopartículas del Metal/química , Lectinas de Plantas/sangre , Proteínas de Soja/sangreRESUMEN
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.
Asunto(s)
Antígenos de Neoplasias/sangre , Cirrosis Hepática/sangre , Cirrosis Hepática/diagnóstico , Glicoproteínas de Membrana/sangre , Enfermedad del Hígado Graso no Alcohólico/sangre , Enfermedad del Hígado Graso no Alcohólico/diagnóstico , Lectinas de Plantas/sangre , Receptores N-Acetilglucosamina/sangre , Adulto , Anciano , Biomarcadores/sangre , Estudios de Casos y Controles , Estudios de Cohortes , Femenino , Humanos , Cirrosis Hepática/clasificación , Masculino , Persona de Mediana Edad , Enfermedad del Hígado Graso no Alcohólico/clasificaciónRESUMEN
BACKGROUND AND AIM: An assay for Wisteria floribunda agglutinin-positive human Mac-2 binding protein (WFA+ -M2BP) has been reported as a useful non-invasive marker for the evaluation of the staging of fibrosis in several chronic liver diseases. However, available data on the effect of WFA+ -M2BP level in decompensated cirrhosis patients were limited. It is important that these investigations can validate the diagnostic utility of WFA+ -M2BP in the full range of patients with liver cirrhosis. METHODS: A multicenter study was conducted at five locations in Japan. A total of 207 patients with liver cirrhosis were enrolled in the present study. To determine whether or not the WFA+ -M2BP value was associated with a progression of fibrosis among cirrhosis, this study examined WFA+ -M2BP levels between patients with cirrhosis in the decompensated and compensated groups. RESULTS: The numbers and proportions of compensated and decompensated patients were 113 (54.6%) and 94 (45.4%), respectively. The average WFA+ -M2BP levels were 2.22 ± 1.61 in the compensated group and 6.91 ± 5.04 in the decompensated group. Significantly higher WFA+ -M2BP levels were observed in the decompensated group than those in the compensated group (P < 0.0001). The respective cut-off index values for decompensated cirrhosis were estimated using receiver-operating characteristic curves for WFA+ -M2BP levels. Using a cut-off index value of 3.37 for WFA+ -M2BP, predicting decompensated cirrhosis had a sensitivity of 77.8% and a specificity of 86.7%. CONCLUSIONS: WFA+ -M2BP values were higher in patients with decompensated liver cirrhosis.
Asunto(s)
Antígenos de Neoplasias/sangre , Cirrosis Hepática/diagnóstico , Glicoproteínas de Membrana/sangre , Lectinas de Plantas/sangre , Receptores N-Acetilglucosamina/sangre , Anciano , Biomarcadores/sangre , Enfermedad Crónica , Progresión de la Enfermedad , Femenino , Fibrosis , Humanos , Hígado/patología , Cirrosis Hepática/patología , Masculino , Persona de Mediana Edad , Sensibilidad y EspecificidadRESUMEN
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.
Asunto(s)
Antígenos de Neoplasias/sangre , Colágeno Tipo IV/sangre , Hígado/patología , Glicoproteínas de Membrana/sangre , Enfermedad del Hígado Graso no Alcohólico/diagnóstico , Enfermedad del Hígado Graso no Alcohólico/patología , Lectinas de Plantas/sangre , Receptores N-Acetilglucosamina/sangre , Adulto , Anciano , Biomarcadores/sangre , Diagnóstico por Imagen de Elasticidad , Femenino , Fibrosis , Humanos , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Curva ROC , Sensibilidad y Especificidad , Índice de Severidad de la EnfermedadRESUMEN
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.
Asunto(s)
Antígenos de Neoplasias/sangre , Cirrosis Hepática/fisiopatología , Hígado/fisiopatología , Glicoproteínas de Membrana/sangre , Lectinas de Plantas/sangre , Receptores N-Acetilglucosamina/sangre , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Cirrosis Hepática/sangre , Cirrosis Hepática/mortalidad , Masculino , Persona de Mediana Edad , Pronóstico , Factores de RiesgoRESUMEN
For use in the voltammetric sensing of galactose-dependent proteins, we modified magnetic beads with a peptide that had both electroactive- and molecular recognition properties. The peptide consisted of a YXY sequence and behaved as an electron-transfer carbohydrate-mimetic peptide that would combine with proteins. With this tool, the protein could be detected via a label-free system. We synthesized several penta- and hexa-peptides with a cysteine residue on the C-terminals to examine the properties of peptides. These peptides contained amino acid residues (X) of alanine, serine, or tyrosine. The peptides were immobilized on magnetic beads via N-(8-maleimidocapryloxy) succinimide. Soybean agglutinin(SBA), the in vivo function of which has been well established in animals, was selected as a model protein. The protein was detected via the changes in electrode response due to the oxidation of tyrosine residues from the phenol group to quinone. As a result, SBA was selectively accumulated on the beads modified with YYYYC. The calibration curve of SBA was linear and ranged from 2.5 × 10-12 to 1.0 × 10-10 M. With this system, SBA was recovered in human serum at values that ranged from 98 to 103%. Furthermore, the beads with peptides were regenerated five times using a protein denaturant. Accordingly, this electrochemical system was simple and could be rapidly applied to the detection of galactose-recognition proteins.
Asunto(s)
Técnicas Biosensibles/métodos , Imanes/química , Péptidos/química , Lectinas de Plantas/análisis , Proteínas de Soja/análisis , Secuencia de Aminoácidos , Técnicas Biosensibles/instrumentación , Transporte de Electrón , Diseño de Equipo , Galactosa/metabolismo , Humanos , Masculino , Péptidos/metabolismo , Lectinas de Plantas/sangre , Lectinas de Plantas/metabolismo , Proteínas de Soja/sangre , Proteínas de Soja/metabolismo , Glycine max/química , Glycine max/metabolismoRESUMEN
BACKGROUND: Serum Wisteria floribunda agglutinin positive Mac-2 binding protein (WFA+-M2BP) or Mac-2 Binding Protein Glycosylation Isomer (M2BPGi) is a novel biomarker currently applied for evaluating hepatic fibrosis. The aim of this study was to evaluate the utility of serum WFA+-M2BP level as a biomarker in chronic heart failure (HF) patients with abnormal liver function. METHODS AND RESULTS: Fifty chronic HF patients who underwent measurement of serum WFA+-M2BP were evaluated. The median value of serum WFA+-M2BP was 0.88 (interquartile range 0.48-1.29) cut-off index, and positive WFA+-M2BP (≥ 1.00 cut-off index) was observed in 22 (44%). Elevated WFA + -M2BP was associated with longer HF history, older age, female sex, valvular heart disease, decreased estimated glomerular filtration rate (eGFR), albumin, and cholinesterase. Stepwise multiple regression analysis showed that HF history, eGFR, and albumin were independent determinants of serum WFA+-M2BP values. Repeated measurements of serum WFA+-M2BP suggested association between the decrease of WFA+-M2BP and improvement of New York Heart Association (NYHA) functional class. CONCLUSIONS: Elevation of serum WFA+-M2BP showed a high prevalence in chronic HF patients with abnormal liver function with relation to HF history, decreased hepatic protein synthesis, and renal dysfunction. Our results suggest that serum WFA+-M2BP may be a novel biomarker of chronic HF.
Asunto(s)
Antígenos de Neoplasias/sangre , Insuficiencia Cardíaca/sangre , Glicoproteínas de Membrana/sangre , Lectinas de Plantas/sangre , Receptores N-Acetilglucosamina/sangre , Anciano , Anciano de 80 o más Años , Biomarcadores/sangre , Ecocardiografía , Femenino , Glicosilación , Insuficiencia Cardíaca/diagnóstico , Humanos , Técnicas para Inmunoenzimas , Masculino , Persona de Mediana Edad , Proyectos Piloto , Índice de Severidad de la EnfermedadRESUMEN
BACKGROUND: Noninvasive methods to accurately and conveniently evaluate liver fibrosis are desirable. MicroRNA (miR) is one of the candidates. MiRs are small RNAs consisting of 19-25 nucleotides that negatively regulate many target genes at transcriptional levels. Recently, many researchers have focused on circulating miRs in the blood stream as biomarkers. Hepatic miR-122 has been reported to have an association with viral replication and hepatic fibrosis in chronic hepatitis B virus (HBV) and hepatic C virus (HCV) infection. METHODS: We measured serum miR-122 levels in HBV- and HCV-infected patients confirmed with liver biopsy. We also investigated a novel liver fibrosis marker Wisteria floribunda agglutinin-positive Mac-2 binding protein [WFA(+)-M2BP]. We evaluated the diagnostic usefulness of these markers in hepatic fibrosis and inflammation of patients with chronic viral infection. RESULTS: The serum miR-122 levels of HBV-infected patients were higher than those of the control subjects. In HBV-infected patients, the serum miR-122 levels of patients with advanced liver fibrosis were significantly lower. Serum WFA(+)-M2BP was significantly higher dependent on both the staging of fibrosis and the grading of inflammatory activity in patients with both HBV and HCV infection. We also observed that higher serum WFA(+)-M2BP levels augmented the prediction of advanced liver fibrosis among HBV-infected patients with lower serum miR-122 levels. CONCLUSIONS: A lower serum miR-122 level is a useful predictor of advanced liver fibrosis in HBV-infected patients. Serum WFA(+)-M2BP could predict liver fibrosis in both HBV and HCV infection. The combination of these markers may result in the more accurate evaluation of liver fibrosis in HBV infection.
Asunto(s)
Hepatitis B/diagnóstico , Hepatitis C/diagnóstico , Cirrosis Hepática/diagnóstico , MicroARNs/sangre , Lectinas de Plantas/sangre , Receptores N-Acetilglucosamina/sangre , Adulto , Anciano , Biomarcadores/sangre , Femenino , Hepatitis B/sangre , Virus de la Hepatitis B , Hepatitis C/sangre , Humanos , Cirrosis Hepática/sangre , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
Metabolized by liver sinusoidal endothelial cells, autotaxin (ATX) is a secreted enzyme considered to be associated with liver damage. We sought to clarify the diagnostic ability of ATX for liver fibrosis in 593 biopsy-confirmed hepatitis C virus (HCV)-infected patients. The diagnostic accuracy of ATX was compared with clinical parameters and the established fibrosis biomarkers Wisteria floribunda agglutinin-positive Mac-2-binding protein, FIB-4 index, AST-to-platelet ratio, and Forn's index. Median ATX levels were consistently higher in female controls and patients than in their male counterparts (P < 0.01). Serum ATX concentration increased significantly according to liver fibrosis stage in overall and both genders (P < 0.001). The cutoff values of ATX for prediction of fibrosis stages ≥F1, ≥F2, ≥F3, and F4 were 0.8, 1.1, 1.3, and 1.7 mg/L, respectively, in male patients and 0.9, 1.7, 1.8, and 2.0 mg/L, respectively, in female patients. The area under the receiver operating characteristic curve for ATX to diagnose fibrosis of ≥F2 (0.861) in male patients was superior to those of FIB-4 index and Forn's index (P < 0.001), while that in female patients (0.801) was comparable with those of the other markers. ATX therefore represents a novel non-invasive biomarker for liver fibrosis in HCV-infected patients.
Asunto(s)
Biomarcadores/sangre , Hepatitis C Crónica/complicaciones , Cirrosis Hepática/sangre , Hidrolasas Diéster Fosfóricas/sangre , Anciano , Antígenos de Neoplasias/sangre , Aspartato Aminotransferasas/sangre , Femenino , Humanos , Hígado/patología , Hígado/virología , Cirrosis Hepática/complicaciones , Cirrosis Hepática/diagnóstico , Masculino , Glicoproteínas de Membrana/sangre , Persona de Mediana Edad , Lectinas de Plantas/sangre , Recuento de Plaquetas , Curva ROC , Receptores N-Acetilglucosamina/sangreRESUMEN
Histological molecular classification of hepatocellular carcinoma (HCC) is clinically important for predicting the prognosis. However, a reliable serum marker has not been established. The aim of this study was to evaluate the diagnostic value of serum Wisteria Floribunda agglutinin-positive sialylated mucin 1 (WFA-sialylated MUC1), which is a novel biliary marker, as a marker of HCC with hepatic progenitor cell (HPC)/biliary features and of prognosis. A total of 144 consecutive patients who underwent complete radiofrequency ablation of primary HCC were enrolled. A serum WFA-sialylated MUC1 level of 900 µL/mL was determined as the optimal cutoff value for prediction of immunohistochemical staining for HPC/biliary features [sialylated MUC1 and cytokeratin 19 (CK19)]. Positive staining rate of sialylated MUC1 and CK19 was significantly higher in patients with WFA-sialylated MUC1 ≥900 than those with WFA-sialylated MUC1 <900. Furthermore, cumulative incidence of HCC recurrence was significantly higher in patients with WFA-sialylated MUC1 ≥900 and on multivariate analysis, serum WFA-sialylated MUC1 levels was an independent predictor of HCC recurrence. These results revealed that serum WFA-sialylated MUC1 was associated with histological feature of HCC and recurrence after curative therapy and it could be a novel marker of HPC/biliary features in HCC and of prognosis.
Asunto(s)
Biomarcadores/sangre , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/patología , Mucina-1/sangre , Lectinas de Plantas/sangre , Receptores N-Acetilglucosamina/sangre , Suero/química , Anciano , Carcinoma Hepatocelular/terapia , Femenino , Histocitoquímica , Humanos , Queratina-19/análisis , Hígado/patología , Masculino , Persona de Mediana Edad , Pronóstico , RecurrenciaRESUMEN
BACKGROUND & AIMS: Wisteria floribunda agglutinin-positive human Mac-2 binding protein (WFA+ -M2BP) can be used to assess the degree of liver fibrosis, but few studies have investigated its prognostic utility. We evaluated whether serum WFA+ -M2BP can predict the development of hepatocellular carcinoma (HCC) in chronic hepatitis B (CHB) patients. METHODS: A total of 1323 CHB patients with WFA+ -M2BP test results between 2009 and 2011 were included in this retrospective analysis. RESULTS: The mean age of patients (793 men) was 51.0 years. During the follow-up period (median 60.3 months), 52 (3.9%) patients developed HCC. Age, the proportion of male gender, the presence of diabetes and cirrhosis, and levels of aspartate aminotransferase, alpha-foetoprotein, and WFA+ -M2BP were significantly greater in patients with HCC than in those without HCC, whereas serum albumin levels and platelet counts were significantly lower in patients with HCC than in those without HCC (all P<.05). In multivariate analysis, WFA+ -M2BP level was an independent predictor of HCC development (adjusted hazard ratio 1.143, 95% CI: 1.139-1.829), along with male gender and diabetes (all P<.05). In patients without cirrhosis (n=1087), WFA+ -M2BP levels ≥1.8 were associated with a higher risk of HCC development (P<.001 by log-rank test), whereas WFA+ -M2BP levels ≥1.8 tended to be associated with a higher risk of HCC development in patients with cirrhosis (n=236) (P=.073 by log-rank test). CONCLUSIONS: WFA+ -M2BP level can independently predict HCC development. Further studies should investigate whether WFA+ -M2BP level could be incorporated into surveillance strategies for CHB patients.
Asunto(s)
Antígenos de Neoplasias/sangre , Carcinoma Hepatocelular/sangre , Hepatitis B Crónica/complicaciones , Cirrosis Hepática/complicaciones , Neoplasias Hepáticas/sangre , Glicoproteínas de Membrana/sangre , Lectinas de Plantas/sangre , Receptores N-Acetilglucosamina/sangre , Adulto , Biomarcadores de Tumor/sangre , Carcinoma Hepatocelular/diagnóstico por imagen , Carcinoma Hepatocelular/epidemiología , Diagnóstico por Imagen de Elasticidad , Femenino , Humanos , Estimación de Kaplan-Meier , Hígado/diagnóstico por imagen , Hígado/patología , Neoplasias Hepáticas/diagnóstico por imagen , Neoplasias Hepáticas/epidemiología , Masculino , Persona de Mediana Edad , Análisis Multivariante , Pronóstico , República de Corea/epidemiología , Estudios RetrospectivosRESUMEN
We created a predictive model using serum-based biomarkers for advanced fibrosis (F3 or more) in patients with chronic hepatitis B (CHB) and to confirm the accuracy in an independent cohort.A total of 249 CHB patients were analyzed. To achieve our study aim, a training group (nâ=â125) and a validation group (nâ=â124) were formed. In the training group, parameters related to the presence of advanced fibrosis in univariate and multivariate analyses were examined, and a formula for advanced fibrosis was created. Next, we verified the applicability of the predictive model in the validation group.Multivariate analysis identified that gamma-glutamyl transpeptidase (GGT, Pâ=â0.0343) and platelet count (Pâ=â0.0034) were significant predictors of the presence of advanced fibrosis, while Wisteria floribunda agglutinin-positive Mac-2-binding protein (WFA-M2BP, Pâ=â0.0741) and hyaluronic acid (Pâ=â0.0916) tended to be significant factors. Using these 4 parameters, we created the following formula: GMPH scoreâ=â-0.755â-â(0.015â×âGGT)â-â(0.268â×âWFA-M2BP)â+â(0.167â×âplatelet count)â+â(0.003â×âhyaluronic acid). In 8 analyzed variables (WFA-M2BP, aspartate aminotransferase-to-platelet ratio index, FIB-4 index, prothrombin time, platelet count, hyaluronic acid, Forns index, and GMPH score), GMPH score had the highest area under the receiver operating characteristic (AUROC) curve for advanced fibrosis with a value of 0.8064 in the training group and in the validation group, GMPH score also had the highest AUROC (0.7782). In all subgroup analyses of the hepatitis B virus (HBV) status (HB surface antigen quantification, HBV-DNA quantification, and HBe antigen seropositivity), GMPH score in F3 or F4 was significantly lower than that in F0 to F2. In the above mentioned 8 variables, differences between the liver fibrosis stages (F0 to F1 vs F2, F2 vs F3, F3 vs F4, F0 to F1 vs F3, F0 to F1 vs F4, and F2 vs F4) for the entire cohort (nâ=â249) were all significant only in GMPH score.In conclusion, the GMPH scoring system may be helpful for detecting advanced liver fibrosis in patients with CHB.
Asunto(s)
Biomarcadores/sangre , Hepatitis B Crónica/patología , Cirrosis Hepática/diagnóstico , Modelos Estadísticos , Antígenos de Neoplasias/sangre , Femenino , Antígenos de Superficie de la Hepatitis B/sangre , Antígenos e de la Hepatitis B/sangre , Hepatitis B Crónica/sangre , Humanos , Ácido Hialurónico/sangre , Cirrosis Hepática/sangre , Masculino , Glicoproteínas de Membrana/sangre , Persona de Mediana Edad , Lectinas de Plantas/sangre , Recuento de Plaquetas , Receptores N-Acetilglucosamina/sangre , Reproducibilidad de los Resultados , Estudios Retrospectivos , gamma-Glutamiltransferasa/sangreRESUMEN
AIM: Wisteria floribunda agglutinin positive (WFA+) Mac-2-binding protein (M2BPGi) is a noninvasive glyco-marker for liver fibrosis. This study evaluated the utility of serial measurement of serum M2BPGi and total M2BP as a predictor of fibrosis and the development of hepatocellular carcinoma (HCC). METHODS: This study included 119 patients with chronic hepatitis C (CHC). Of these patients, 97 were treated with IFN-based therapy and 22 were treated with daclatasvir and asunaprevir. Serum M2BPGi values were measured prior to, at the end of, and at 24 weeks after the completion of treatment. As subanalysis, serum total M2BP levels were measured in patients treated with pegylated-interferon and ribavirin. RESULTS: In patients treated with IFN-based therapy, M2BPGi levels were elevated at the end of treatment but decreased afterwards. In contrast, M2BPGi levels in patients treated with IFN-free therapy decreased immediately after starting the treatment without transient elevation. Though pre-treatment M2BPGi levels significantly correlated with fibrosis in both patients with a sustained virological response (SVR) and non-SVR, post-treatment M2BPGi levels decreased regardless of the degree of fibrosis in patients with SVR. In multivariate analysis, non-SVR and HCC development were independent factors associated with M2BPGi level ≥2.2. In patients treated with pegylated-interferon and ribavirin, total M2BP levels were positively correlated with fibrosis and HCC development. CONCLUSION: Real-time monitoring of the serum M2BPGi level after antiviral therapy for CHC patients could be a helpful screening tool for assessing the risk of HCC. M2BP and its glycan structure could be associated together with hepatocarcinogenesis.
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Antígenos de Neoplasias/sangre , Antivirales/uso terapéutico , Carcinoma Hepatocelular/diagnóstico , Hepatitis C Crónica/tratamiento farmacológico , Cirrosis Hepática/diagnóstico , Neoplasias Hepáticas/diagnóstico , Glicoproteínas de Membrana/sangre , Lectinas de Plantas/sangre , Biomarcadores de Tumor/sangre , Carbamatos , Carcinoma Hepatocelular/metabolismo , Proteínas Portadoras , Diagnóstico Precoz , Femenino , Glicoproteínas , Hepatitis C Crónica/complicaciones , Hepatitis C Crónica/metabolismo , Humanos , Imidazoles/uso terapéutico , Interferón-alfa/uso terapéutico , Isoquinolinas/uso terapéutico , Cirrosis Hepática/metabolismo , Neoplasias Hepáticas/metabolismo , Masculino , Pirrolidinas , Sulfonamidas/uso terapéutico , Valina/análogos & derivadosRESUMEN
BACKGROUND: Mac-2 binding protein (M2BP) is a cell-adhesive glycoprotein of the extracellular matrix secreted as a ligand of galectin-3 (Mac-2). Recently, a Wisteria floribunda agglutinin positive-M2BP (WFA(+)-M2BP) assay developed using a lectin-antibody sandwich immunoassay has shown promise as a new fibrotic marker in liver fibrosis to detect unique fibrosis-related glycoalteration. The aim of this study is to evaluate the utility of serum WFA(+)-M2BP levels in patients with idiopathic pulmonary fibrosis (IPF). METHODS: We measured serum WFA(+)-M2BP levels in 116 patients with IPF and 42 healthy volunteers. We examined the relationship between serum WFA(+)-M2BP levels and clinical parameters and further investigated the prognostic significance of serum WFA(+)-M2BP levels in patients with IPF. RESULTS: Serum WFA(+)-M2BP levels were significantly higher in patients with IPF than in healthy controls (1.09 ± 0.89 cutoff index [COI], 0.57 ± 0.24 COI, respectively; P < 0.001). In patients with IPF, a significant positive correlation was found between serum WFA(+)-M2BP levels and age, KL-6, neutrophils in BAL, reticulation and honeycombing scores in HRCT, and fibrotic foci scores in pathological findings, and a significant negative correlation was found between serum WFA(+)-M2BP levels and FVC, %DLco and macrophages in BAL. Furthermore, patients with high serum WFA(+)-M2BP levels had a significantly worse prognosis than those with low levels (log-rank test, P = 0.0209), and a high serum WFA(+)-M2BP level was a significant prognostic factor in Cox proportional hazards regression analysis. CONCLUSIONS: Our results suggest that the serum WFA(+)-M2BP level is a potential biomarker in patients with IPF.
Asunto(s)
Antígenos de Neoplasias/sangre , Fibrosis Pulmonar Idiopática/metabolismo , Fibrosis Pulmonar Idiopática/patología , Glicoproteínas de Membrana/sangre , Lectinas de Plantas/sangre , Receptores N-Acetilglucosamina/sangre , Anciano , Biomarcadores/sangre , Femenino , Humanos , Cirrosis Hepática/metabolismo , Cirrosis Hepática/patología , Masculino , Persona de Mediana Edad , Pronóstico , Índice de Severidad de la EnfermedadRESUMEN
Wisteria floribunda agglutinin-positive human Mac-2 binding protein (WFA-M2BP) is a serologic marker corresponding with degree of hepatic fibrosis. We evaluated its accuracy in assessing hepatic fibrosis and in predicting the risk of developing hepatocellular carcinoma (HCC) in patients with chronic hepatitis B (CHB).In a 5-year period (2009-2013), a total of 95 CHB patients with available serum WFA-M2BP assay and transient elastography assessment [to assess liver stiffness (LS)] who had undergone liver biopsy were recruited for retrospective analysis.Areas under the receiver operating characteristic curve for predicting fibrosis stages via serum WFA-M2BP level were as follows: ≥F2, 0.688; ≥F3, 0.694; and F4, 0.704 (all Pâ<â0.05). During the follow-up period (median, 45 months), HCC developed in 7 patients (7.4%). In patients with HCC, age, use of antiviral therapy, test parameters (HBV DNA, WFA-M2BP, and LS determinations), and histologic stage of fibrosis were all significantly greater than in those free of HCC, whereas platelet count was significantly lower (all Pâ<â0.05). On multivariate analysis, WFA-M2BP was found independently predictive of emergent HCC [hazard ratio (HR)â=â2.375; Pâ=â0.036], although LS and histologic stage of fibrosis were not (Pâ>â0.05). Risk of developing HCC was significantly greater in patients with high WFA-M2BP levels (≥1.8) (adjusted HRâ=â11.5; Pâ=â0.025). Cumulative incidence rates of HCC were also significantly higher in patients with high (vs. low) levels of WFA-M2BP (log-rank test, Pâ=â0.016).WFA-M2BP determination significantly reflected degree/extent of hepatic fibrosis and independently predicted the risk of developing HCC in patients with CHB.