A novel noninvasive diagnostic method for nonalcoholic steatohepatitis using two glycobiomarkers

Abstract

Nonalcoholic fatty liver disease (NAFLD) is a growing medical problem; thus, discriminating nonalcoholic steatohepatitis (NASH) from NAFLD is of great clinical significance. For the diagnosis of NASH, liver biopsy-proven histological examination is the current gold standard, and noninvasive and reliable biomarkers are greatly needed. Recently, we found that two glycobiomarkers, fucosylated haptoglobin (Fuc-Hpt) and Mac-2 binding protein (Mac2bp), are useful independently for NASH diagnosis. In this study, we confirmed that serum Fuc-Hpt is suitable for the prediction of ballooning hepatocytes and that serum Mac2bp is suitable for the prediction of liver fibrosis severity in 124 biopsy-proven NAFLD patients (training cohort). In addition, we found that the combination of serum Fuc-Hpt and Mac2bp levels was an excellent tool for NASH diagnosis. Using receiver operating characteristic analyses, the area under the receiver operating characteristic curve, sensitivity, and specificity of the combination of these two glycobiomarkers were 0.854, 81.1%, and 79.3%, respectively. We established a prediction model for NASH diagnosis using logistic regression analysis: logit (p) 5 22.700 1 0.00242 3 Fuc-Hpt 1 1.225 3 Mac2bp. To validate the prediction model, another 382 biopsy-proven NAFLD patients were enrolled (validation cohort). In the validation cohort, the area under the receiver operating characteristic curve of this model for NASH diagnosis was 0.844, with 71.4% and 82.3% sensitivity and specificity, respectively. In addition, we investigated the significance of our developed NASH diagnosis model in ultrasound-diagnosed NAFLD subjects who received medical health checkups (n 5 803). Our model also could predict NAFLD disease severity in this larger population. Conclusion: The combination of serum Fuc-Hpt and Mac2bp can distinguish NASH from NAFLD patients. Our noninvasive model using two serum glycobiomarkers contributes to a novel NASH diagnostic methodology that could replace liver biopsy. (HEPATOLOGY 2015;62:1433-1443

Inflammatory glycoproteins in cardiometabolic disorders, autoimmune diseases and cancer

“…The authors hypothesized that the fucosylation-based sorting machinery is disrupted in ballooning hepatocytes and that hyperfucosylated glycoproteins are secreted from the liver into serum in the diseased liver. Based on this hypothesis they developed a lectin-based ELISA to quantify fucosylated haptoglobin and showed that this assay was useful for the prediction of ballooning hepatocytes in NASH [80]. They also showed that Mac-2 binding protein, quantified by traditional ELISA, was a good biomarker for liver fibrosis.…”

“…Recently it was shown that quantification of two inflammatory glycoproteins quantified by ELISA, fucosylated haptoglobin and Mac-2 binding protein (also known as galectin-3 binding protein), may be useful for the diagnosis of NASH and liver fibrosis ( Table 2) [80]. The authors hypothesized that the fucosylation-based sorting machinery is disrupted in ballooning hepatocytes and that hyperfucosylated glycoproteins are secreted from the liver into serum in the diseased liver.…”

“…They also showed that Mac-2 binding protein, quantified by traditional ELISA, was a good biomarker for liver fibrosis. Moreover, the combination of the two glycoproteins was able to distinguish NASH from simple hepatic steatosis [80]. However, additional clinical validation studies are needed to fully understand the clinical usefulness of this combined biomarker test.…”

Association of Body Mass Index with DNA Methylation and Gene Expression in Blood Cells and Relations to Cardiometabolic Disease: A Mendelian Randomization Approach

“…LGALS3BP was recently identified as a promising biomarker for non-alcoholic steatohepatitis and pancreatitis [82,83], known obesity-related diseases. Methylation at the LGALS3BP locus demonstrated a significant sex interaction, with a stronger effect in men.…”

Serum Wisteria Floribunda Agglutinin-Positive Mac-2 Binding Protein Could Not Always Predict Early Cirrhosis in Non-Viral Liver Diseases

“…Kamada et al [27,28] reported that serum M2BP level is a useful diagnostic biomarker for the prediction of disease severity in NASH. As the present study does not include the patients with obvious cirrhosis, in whom liver biopsy cannot be performed, we cannot examine the effects of damage of liver functions well.…”