Baseline serum Mac-2 binding protein glycosylation isomer as a predictor of hepatocellular carcinoma in chronic hepatitis B patients: a systematic review and meta-analysis.

Background: A minimally invasive tool to promptly predict hepatocellular carcinoma (HCC) in chronic hepatitis B (CHB) is currently needed. In this study, we aimed via a meta-analysis to identify the serum Mac-2 binding protein glycosylation isomer (M2BPGi) as a novel glycoprotein-based liver fibrosis marker for predicting HCC in CHB patients. Methods: We conducted a systematic search on PubMed, Scopus, ProQuest, Wiley Online Library, and CINAHL Plus (via EBSCOhost). The articles were screened based on several eligibility criteria and were further assessed for study qualities using the Newcastle-Ottawa Scale. The outcomes were presented as standard mean difference (SMD), hazard ratio (HR), and predictive accuracy parameters of a baseline cutoff index (COI) for serum M2BPGi. Results: Fourteen studies involving 5918 CHB patients were included in this systematic review and meta-analysis. Baseline COI serum M2BPGi was significantly higher in CHB patients who developed HCC than in those who did not (SMD 1.32, 95% confidence interval [CI] 0.91-1.72). A significant HCC risk prediction was also observed (multivariate HR 1.18, 95%CI 1.05-1.32). Baseline COI serum M2BPGi could predict HCC with a pooled sensitivity of 74% (95%CI 50-89%), specificity of 80% (95%CI 65-90%), and area under the summary receiver operating characteristic curve of 0.84 (95%CI 0.81-0.87). Conclusion: High baseline COI serum M2BPGi may predict the development of HCC in CHB patients with moderate-to-high accuracy.

Post-treatment serum Wisteria floribunda agglutinin-positive mac-2-binding protein level is a useful predictor of hepatocellular carcinoma development after hepatitis C virus eradication.

AIMS: Recent advances of direct-acting antiviral drugs for hepatitis C virus (HCV) have dramatically improved the sustained virologic response (SVR) rate, but hepatocellular carcinoma (HCC) development rarely occurs even in patients who achieve an SVR. Wisteria floribunda agglutinin-positive mac-2-binding protein (WFA+-M2BP) was recently developed as a noninvasive biomarker of liver fibrosis. However, the association between the WFA+-M2BP level and HCC development after the achievement of an SVR is unclear. METHODS AND RESULTS: We examined the association between WFA+-M2BP and HCC development in 522 HCV patients who achieved an SVR (Interferon [IFN]-based therapy, n = 228; IFN-free therapy, n = 294). Multivariate analysis revealed that a high WFA+-M2BP level at SVR week 24 after treatment (SVR24) (hazard ratio [HR] = 1.215, P = 0.020), low platelet counts (HR = 0.876, P = 0.037), and old age (HR = 1.073, P = 0.012) were independent risk factors for HCC development regardless of the treatment regimen. Receiver operator characteristics curve analysis revealed that a WFA+-M2BP level at SVR24 of ≥1.62 cut-off index (COI) was the cut-off value for the prediction of HCC development (adjusted HR = 12.565, 95% CI 3.501-45.092, P < 0.001). The 3- and 5-year cumulative incidences of HCC were 1% and 1.6% in patients with low WFA+-M2BP at SVR24 (<1.62 COI), and 4.7% and 12.5% in patients with high WFA+-M2BP (≥1.62 COI) were, respectively (P < 0.001). CONCLUSIONS: The assessment of liver fibrosis using the WFA+-M2BP level at SVR24 is a useful predictor of HCC development after HCV eradication even in the IFN-free therapy era.

Daily Monitoring of Serum Wisteria floribunda Agglutinin-Positive Mac-2 Binding Protein Is Useful for Predicting Therapeutic Effect of Tolvaptan in Cirrhotic Ascites.

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.

Post-Treatment M2BPGi Level and the Rate of Autotaxin Reduction are Predictive of Hepatocellular Carcinoma Development after Antiviral Therapy in Patients with Chronic Hepatitis C.

Patients with chronic hepatitis C virus (HCV) develop hepatocellular carcinoma (HCC) regardless of achieving a sustained viral response (SVR). Because advanced liver fibrosis is a powerful risk factor for HCC, we analyzed the association between autotaxin (ATX), a liver fibrosis marker, and post-SVR HCC development within 3 years after antiviral treatment. We included 670 patients with HCV who received direct-acting antivirals, achieved SVR and were followed up for at least 6 months (270 of them were followed up for 3 years or more). We measured serum ATX levels before treatment and 12/24 weeks after treatment. The diagnosis of HCC was based on imaging modalities, such as dynamic computed tomography and dynamic magnetic resonance imaging and/or liver biopsy. The present study revealed that high levels of serum ATX predicted post-SVR HCC development (area under the receiver operating characteristic: 0.70-0.76). However, Wisteria floribunda agglutinin positive Mac-2 binding protein (M2BPGi), another liver fibrosis marker, was a more useful predictive marker especially post-treatment according to a multivariate analysis. Patients with a high rate of ATX reduction before and after antiviral treatment did not develop HCC regardless of high pretreatment ATX levels. In conclusion, post-treatment M2BPGi level and the combination of pretreatment ATX levels and rate of ATX reduction were useful predictive markers for post-SVR HCC development in patients with chronic HCV infection.

Novel Biomarkers of Hepatitis B and Hepatocellular Carcinoma: Clinical Significance of HBcrAg and M2BPGi.

The hepatitis B virus (HBV) cannot be removed completely from infected hepatocytes, owing to the presence of intrahepatic covalently closed circular DNA (cccDNA). As chronic hepatitis B (CHB) can progress to cirrhosis and hepatocellular carcinoma (HCC), predicting HCC development in high-risk patients with high viral replicative activity or advanced fibrosis is important. Novel serological biomarkers reflect intrahepatic viral replicative activity or the progression of liver fibrosis, indicating non-invasive alternatives to liver biopsy: (1) Hepatitis B core-related antigen (HBcrAg) correlates with serum HBV DNA and intrahepatic cccDNA. In CHB patients, a decrease in HBcrAg is associated with favorable outcomes. HBcrAg can predict HCC occurrence or recurrence. (2) Measurement of the Mac-2 binding protein glycosylation isomer (M2BPGi) has been introduced for the evaluation of liver fibrosis. An increase in M2BPGi in CHB patients is related to the progression of liver fibrosis and high potential (risk) of HCC development. Here, we describe the clinical applications of HBcrAg and M2BPGi in CHB patients. Additionally, because new potential therapeutic agents that eliminate intrahepatic cccDNA are being developed, monitoring of HBcrAg or M2BPGi might be suitable for evaluating therapeutic effects and the clinical outcomes. In conclusion, these would be appropriate surrogate markers for predicting disease progression.

Risk assessment of hepatocellular carcinoma development by magnetic resonance elastography in chronic hepatitis C patients who achieved sustained virological responses by direct-acting antivirals.

Prediction of hepatocellular carcinoma (HCC) development after sustained virological response (SVR) is clinically important, and the usefulness of noninvasive markers for prediction HCC have been reported. The aim of this study was to compare the prediction accuracy for HCC development by noninvasive markers. A total of 346 patients with chronic hepatitis C without history of HCC who achieved SVR through direct-acting antivirals were included. Magnetic resonance elastography (MRE) and serum fibrosis markers were measured 12 weeks after the end of treatment, and the subsequent HCC development was examined. The mean observation period was 26.4 ± 7.9 months, and 24 patients developed HCC. Area under the receiver operating characteristic curve of liver stiffness by MRE, Wisteria floribunda agglutinin-positive mac-2 binding protein and FIB-4 for predicting HCC within 3 years was 0.743, 0.697 and 0.647, respectively. The 1/2/3-year rates of HCC development in patients with liver stiffness ≥3.75 KPa were 6.6%, 11.9% and 14.5%, whereas they were 1.4%, 2.5% and 2.5% in patients with liver stiffness <3.75 KPa (P < 0.001). Multivariate analysis revealed that liver stiffness ≥3.75 was an independent predictive factor for HCC development (hazard ratio, 3.51; 95% confidence interval, 1.24-9.99). In subgroup analysis, there were 132 patients who were <73 years old and had liver stiffness <3.75 KPa, and no HCC development was observed in these patients. Diagnostic accuracy for predicting HCC development was higher in MRE than serum fibrosis markers and measurement of liver stiffness by MRE could identify patients with high and low risk of HCC development after SVR.

Serum aldo-keto reductase family 1 member B10 predicts advanced liver fibrosis and fatal complications of nonalcoholic steatohepatitis.

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.

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.

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.

Serum Wisteria floribunda agglutinin-positive Mac-2-binding protein evaluates liver function and predicts prognosis in liver cirrhosis.

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.

Diagnosis of Liver Fibrosis With Wisteria floribunda Agglutinin-Positive Mac-2 Binding Protein (WFA-M2BP) Among Chronic Hepatitis B Patients.

BACKGROUND: Wisteria floribunda agglutinin-positive Mac-2 binding protein (WFA-M2BP) is a protein with altered glycosylation that reacts with lectin, and was recently identified as a useful non-invasive biomarker for the diagnosis of liver fibrosis in patients with hepatitis C virus infection.This study aimed to evaluate the diagnostic efficacy of WFA-M2BP for liver fibrosis in the context of hepatitis B virus (HBV). METHODS: We enrolled 151 patients infected with HBV. Liver biopsy and elastography (Fibroscan) were performed during the initial visit. Fibrosis was graded according to the Knodell histologic activity index (F0-3). WFA-M2BP levels were determined with an automated immunoassay analyzer (M2BPGi, HISCL-5000, Sysmex, Japan). The diagnostic efficacy of WFA-M2BP was compared with those of various conventional or composite biomarkers, including enhanced liver fibrosis (ELF) score, Fibroscan, aspartate transaminase (AST)-to-platelet ratio index (APRI), and FIB-4, based on the area under the ROC curve (AUC) value. RESULTS: The majority of patients were at fibrosis stages F1 and F2. The F2 and F3 AUC values for WFA-M2BP were similar to those for FIB-4, APRI, ELF, and Fibroscan, although the latter showed the best diagnostic efficacy. The diagnostic accuracy of all tested biomarkers for F2 and F3 was 60-70%. In multivariate analysis, WFA-M2BP, ELF, and platelet count significantly predicted stage ≥F2, whereas only platelet count significantly predicted F3. CONCLUSIONS: WFA-M2BP can support a diagnosis of liver fibrosis with similar diagnostic efficacy to other biomarkers, and predicted liver fibrosis stage ≥2 among patients with chronic hepatitis B.

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.

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.

Clinical Evaluation of Hepatocarcinogenesis and Outcome Using a Novel Glycobiomarker Wisteria floribunda Agglutinin-Positive Mac-2 Binding Protein (WFA+-M2BP) in Chronic Hepatitis C with Advanced Fibrosis.

This study aimed to assess the association between the serum glycobiomarker Wisteria floribunda agglutinin-positive Mac-2 binding protein (WFA+-M2BP) for liver fibrosis and outcomes and carcinogenesis of hepatocellular carcinoma (HCC) in chronic hepatitis C (CHC) patients with advanced fibrosis. Serum WFA+-M2BP levels were measured in 128 consecutive CHC patients including 49 with HCC histopathologically diagnosed with advanced fibrosis (44 with fibrosis stage F3 and 84 with fibrosis stage F4) in our hospital. The median WFA+-M2BP level was significantly higher in F4 than in F3 patients (6.9 vs. 2.3 cutoff index [COI], respectively; p<0.001). The difference in WFA+-M2BP levels between patients with and without HCC was not significant. The respective 5-/8-yr survival rates of patients without HCC at enrollment with high (≥4 COI, n=39), intermediate (1-4 COI, n=33), and low WFA+-M2BP (<1 COI, n=7) levels were 78%/48%, 100%/82%, and 100%/100%, respectively. The differences in survival rates between groups were significant (p=0.0041). Patients with high WFA+-M2BP levels had a significantly higher incidence of HCC than those with low WFA+-M2BP levels (p=0.0019). Cumulative 5-yr carcinogenesis rates in patients with high, intermediate, and low WFA+-M2BP levels were 48.7%, 16.9%, and 0%, respectively; the differences between groups were significant (p=0.002). Serum WFA+-M2BP levels might allow the prediction of carcinogenesis and outcome in CHC patients with advanced fibrosis.

Wisteria floribunda agglutinin-positive Mac-2 binding protein predicts the development of hepatocellular carcinoma in patients with non-alcoholic fatty liver disease.

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.

Serum Wisteria floribunda agglutinin-positive Mac-2 binding protein predicts hepatocellular carcinoma incidence and recurrence in nucleos(t)ide analogue therapy for chronic hepatitis B.

BACKGROUND: Hepatocellular carcinoma (HCC) occurs in chronic hepatitis B (CH-B) patients even after treatment with nucleos(t)ide analogues (NAs) by a mechanism involving an association between the oncogenic factors of integrated HBV and liver fibrosis. An association has been demonstrated between advanced chronic liver disease and elevated levels of Wisteria floribunda agglutinin-positive Mac-2 binding protein (WFA(+)-M2BP), a recently discovered serum liver fibrosis marker. Moreover, hepatitis B core-related antigen (HBcrAg) reflects intracellular HBV protein production and its relationship with liver carcinogenesis has been reported. This study aimed to determine whether the incidence and recurrence of HBV-related liver cancer could be predicted using these serum markers. METHODS: We evaluated 141 CH-B cases treated for more than 1 year with NAs. We compared 17 HCC cases with 124 non-HCC cases and evaluated serum WFA(+)-M2BP, HBV markers including HBcrAg, and other clinical factors. We also evaluated 71 CH-B-related HCC cases who started or continued NAs and compared the incidence and recurrence of HCC after successful cancer treatment. RESULTS: Multivariate analysis showed that the incidence of HCC was significantly associated with higher histological stage and grade before NA treatment and with WFA(+)-M2BP and HBcrAg positivity during NA treatment. The cumulative incidence of HCC was strongly associated with higher WFA(+)-M2BP levels and HBcrAg positivity. HCC recurrence after anti-cancer therapy was also significantly associated with higher WFA(+)-M2BP levels compared with those in cases without recurrence during follow-up. CONCLUSION: Serum WFA(+)-M2BP and HBcrAg are useful diagnostic tests for predicting the development and recurrence of HBV-related HCC during NA treatment.

Increased serum Wisteria floribunda agglutinin positive Mac-2 binding protein (Mac-2 binding protein glycosylation isomer) in chronic heart failure: a pilot study.

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.

Diagnosis of Liver Fibrosis With Wisteria floribunda Agglutinin-Positive Mac-2 Binding Protein (WFA-M2BP) Among Chronic Hepatitis B Patients

BACKGROUND: Wisteria floribunda agglutinin-positive Mac-2 binding protein (WFA-M2BP) is a protein with altered glycosylation that reacts with lectin, and was recently identified as a useful non-invasive biomarker for the diagnosis of liver fibrosis in patients with hepatitis C virus infection.This study aimed to evaluate the diagnostic efficacy of WFA-M2BP for liver fibrosis in the context of hepatitis B virus (HBV). METHODS: We enrolled 151 patients infected with HBV. Liver biopsy and elastography (Fibroscan) were performed during the initial visit. Fibrosis was graded according to the Knodell histologic activity index (F0–3). WFA-M2BP levels were determined with an automated immunoassay analyzer (M2BPGi, HISCL-5000, Sysmex, Japan). The diagnostic efficacy of WFA-M2BP was compared with those of various conventional or composite biomarkers, including enhanced liver fibrosis (ELF) score, Fibroscan, aspartate transaminase (AST)-to-platelet ratio index (APRI), and FIB-4, based on the area under the ROC curve (AUC) value. RESULTS: The majority of patients were at fibrosis stages F1 and F2. The F2 and F3 AUC values for WFA-M2BP were similar to those for FIB-4, APRI, ELF, and Fibroscan, although the latter showed the best diagnostic efficacy. The diagnostic accuracy of all tested biomarkers for F2 and F3 was 60–70%. In multivariate analysis, WFA-M2BP, ELF, and platelet count significantly predicted stage ≥F2, whereas only platelet count significantly predicted F3. CONCLUSIONS: WFA-M2BP can support a diagnosis of liver fibrosis with similar diagnostic efficacy to other biomarkers, and predicted liver fibrosis stage ≥2 among patients with chronic hepatitis B.

Effect of interferon-based and -free therapy on early occurrence and recurrence of hepatocellular carcinoma in chronic hepatitis C.

BACKGROUND AND AIMS: Although treatment for hepatitis C virus has been dramatically improved by the development of direct-acting antiviral agents (DAAs), whether interferon (IFN)-free therapy reduces hepatocarcinogenesis in an equivalent manner to IFN-based therapy remains controversial. The aims of this study were to evaluate the occurrence and recurrence of hepatocellular carcinoma (HCC) in chronic hepatitis C (CHC) patients treated with DAAs and to identify biomarkers of HCC development after antiviral treatment. METHODS: A restrospective review of a prospective database of 1,897 CHC patients who were treated with IFN-based (1,145) or IFN-free therapies (752) was carried out. Cumulative HCC occurrence and recurrence rates were compared using propensity score-matched analysis. Predictors of HCC development after viral eradication were identified by multivariate analysis. RESULTS: Propensity score-matched analysis showed no significant difference in HCC occurrence (p=0.49) and recurrence rates (p=0.54) between groups treated with IFN-based or IFN-free therapies. In multivariate analysis, higher levels of post-treatment α-fetoprotein (AFP) or Wisteria floribunda agglutinin positive Mac-2 binding protein (WFA+M2BP) were independently associated with HCC occurrence and recurrence after viral eradication. Only post-treatment WFA+M2BP level was significantly associated with HCC occurrence and recurrence among patients without severe fibrosis. The area under the receiver operating characteristic (ROC) curve for WFA+M2BP levels was greater than that for AFP levels in ROC analysis. CONCLUSION: The risks of early HCC occurrence and recurrence after viral eradication were similar between IFN-based and IFN-free therapies. Post-treatment levels of WFA+M2BP may be helpful screening biomarkers for assessing the risk of HCC after IFN-free therapy. Patients with high WFA+M2BP levels after antiviral treatment, even without severe fibrosis, must be followed up carefully for HCC development. Lay summary: The risks of early HCC occurrence and recurrence after viral eradication were similar between IFN-based and IFN-free therapies. Post-treatment levels of WFA+M2BP may be helpful screening biomarkers for assessing the risk of HCC after IFN-free therapy.

Serum levels of Wisteria floribunda agglutinin-positive Mac-2 binding protein reflect the severity of chronic pancreatitis.

OBJECTIVES: To evaluate the utility of serum Wisteria floribunda agglutinin-positive Mac-2 binding protein (WFA + -M2BP) level as a marker for chronic pancreatitis (CP). METHODS: We measured the serum WFA+ -M2BP level of 74 patients with CP who had undergone endoscopic retrograde cholangiopancreatography and 30 normal controls (NC) using a glycan sugar chain-based immunoassay and investigated the relationship between serum WFA+ -M2BP levels and the Cambridge classification of CP. RESULTS: Serum WFA+ -M2BP level was significantly higher in patients with CP than in NC (0.64 ± 0.28 vs 0.34 ± 0.25, P < 0.001). The levels (expressed as cut-off index) of WFA+ -M2BP for the classification of mild, moderate and marked CP were 0.44, 0.63 and 0.87, respectively. Thus, serum WFA+ -M2BP levels increased with increasing CP severity. With a cut-off value of 0.34, 0.59 and 0.61, the area under the receiver operating characteristic curve, sensitivity and specificity were 0.829, 91.9% and 63.3% for mild CP; 0.891, 81.8% and 85.0% for moderate CP; and 0.888, 92.0% and 74.7% for marked CP, respectively. Multivariate analysis revealed that elevated serum WFA+ -M2BP was independently associated with moderate and marked CP, respectively. CONCLUSION: Serum WFA+ -M2BP level is a useful marker for grading CP severity.

Clinical implications of serum Wisteria floribunda agglutinin-positive Mac-2-binding protein in treatment-naïve chronic hepatitis B.

AIM: To examine the relationship between serum Wisteria floribunda agglutinin-positive Mac-2-binding protein (WFA+ -M2BP) levels and liver histological findings for patients with treatment naïve chronic hepatitis B (CHB). METHODS: A total of 189 treatment naïve-CHB patients were analyzed. We examined the effect of pretreatment serum WFA+ -M2BP levels on histological findings compared with other laboratory markers, including aspartate aminotransferase (AST) to platelet ratio index, Fibrosis-4 index, platelet count, AST to alanine aminotransferase (ALT) ratio, and hyaluronic acid as liver fibrosis markers, and AST value, ALT value, and serum interferon-γ-inducible protein-10 level as liver inflammation markers. RESULTS: The WFA+ -M2BP value ranged from 0.3 cut-off index (COI) to 12.9 COI (median value, 1.2 COI). The degree of liver fibrosis was significantly stratified according to WFA+ -M2BP level in each group except for groups F2 and F3 and the degree of liver inflammation activity was significantly stratified according to WFA+ -M2BP level in each group. For predicting F4, WFA+ -M2BP level yielded the highest area under the receiver operating characteristic curve (AUROC) with a level of 0.87 and for predicting advanced liver fibrosis (≥F3) and significant liver fibrosis (≥F2), WFA+ -M2BP level yielded the second highest AUROCs (both, 0.77) among six fibrotic markers. For predicting severe (A3) or significant liver inflammation activity (≥A2), AUROCs of WFA+ -M2BP level were 0.78 and 0.76. CONCLUSION: The WFA+ -M2BP level can be a useful marker for assessing liver histological findings in patients with treatment-naïve CHB, although it has several limitations.

Impact of Wisteria floribunda Agglutinin-Positive Mac-2-Binding Protein in Patients with Hepatitis C Virus-Related Compensated Liver Cirrhosis.

We aimed to examine the effect of Wisteria floribunda agglutinin-positive Mac-2-binding protein (WFA⁺-M2BP) level on survival comparing with other laboratory liver fibrosis markers in hepatitis C virus (HCV)-related compensated liver cirrhosis (LC) (n = 165). For assessing prognostic performance of continuous fibrosis markers, we adapted time-dependent receiver operating characteristics (ROC) curves for clinical outcome. In time-dependent ROC analysis, annual area under the ROCs (AUROCs) were plotted. We also calculated the total sum of AUROCs in all time-points (TAAT score) in each fibrosis marker. WFA⁺-M2BP value ranged from 0.66 cutoff index (COI) to 19.95 COI (median value, 5.29 COI). Using ROC analysis for survival, the optimal cutoff point for WFA⁺-M2BP was 6.15 COI (AUROC = 0.79348, sensitivity = 80.0%, specificity = 74.78%). The cumulative five-year survival rate in patients with WFA⁺-M2BP ≥ 6.15 COI (n = 69) was 43.99%, while that in patients with WFA⁺-M2BP < 6.15 COI (n = 96) was 88.40% (p < 0.0001). In the multivariate analysis, absence of hepatocellular carcinoma (p = 0.0008), WFA⁺-M2BP < 6.15 COI (p = 0.0132), achievement of sustained virological response (p < 0.0001) and des-γ-carboxy prothrombin < 41 mAU/mL (p = 0.0018) were significant favorable predictors linked to survival. In time-dependent ROC analysis in all cases, WFA⁺-M2BP had the highest TAAT score among liver fibrosis markers. In conclusion, WFA⁺-M2BP can be a useful predictor in HCV-related compensated LC.