title: 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)=-2.700+0.00242×Fuc-Hpt+1.225×Mac2bp. To validate the prediction model, another 382 biopsy-proven NAFLD patients were enrolled (validation cohort). In the validation cohort, the area under the receiver operating characteristic curve of this model for NASH diagnosis was 0.844, with 71.4% and 82.3% sensitivity and specificity, respectively. In addition, we investigated the significance of our developed NASH diagnosis model in ultrasound-diagnosed NAFLD subjects who received medical health checkups (n = 803). Our model also could predict NAFLD disease severity in this larger population.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Molecular Biochemistry and Clinical Investigation, Osaka University, Graduate School of Medicine, Osaka, Japan.|Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Kamada
authors.affiliation: Department of Gastroenterology and Hepatology, Kochi Medical School, Kochi, Japan.
authors.forename: Masafumi
authors.initials: M
authors.lastname: Ono
authors.affiliation: Department of Gastroenterology and Metabolism, Hiroshima University, Hiroshima, Japan.
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Hyogo
authors.affiliation: Department of Hepatology, Osaka City University Graduate School of Medicine, Osaka, Japan.|Department of Gastroenterology, Osaka City Juso Hospital, Osaka, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Fujii
authors.affiliation: Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto, Japan.
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Sumida
authors.affiliation: Center for Digestive and Liver Diseases, Nara City Hospital, Nara, Japan.
authors.forename: Kojiroh
authors.initials: K
authors.lastname: Mori
authors.affiliation: Center for Digestive and Liver Diseases, Nara City Hospital, Nara, Japan.
authors.forename: Saiyu
authors.initials: S
authors.lastname: Tanaka
authors.affiliation: aMs New Otani Clinic, Osaka, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Yamada
authors.affiliation: Department of Molecular Biochemistry and Clinical Investigation, Osaka University, Graduate School of Medicine, Osaka, Japan.
authors.forename: Maaya
authors.initials: M
authors.lastname: Akita
authors.affiliation: Department of Molecular Biochemistry and Clinical Investigation, Osaka University, Graduate School of Medicine, Osaka, Japan.
authors.forename: Kayo
authors.initials: K
authors.lastname: Mizutani
authors.affiliation: Department of Molecular Biochemistry and Clinical Investigation, Osaka University, Graduate School of Medicine, Osaka, Japan.
authors.forename: Hironobu
authors.initials: H
authors.lastname: Fujii
authors.affiliation: Department of Molecular Biochemistry and Clinical Investigation, Osaka University, Graduate School of Medicine, Osaka, Japan.
authors.forename: Akiko
authors.initials: A
authors.lastname: Yamamoto
authors.affiliation: Department of Molecular Biochemistry and Clinical Investigation, Osaka University, Graduate School of Medicine, Osaka, Japan.
authors.forename: Shinji
authors.initials: S
authors.lastname: Takamatsu
authors.affiliation: Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Yoshida
authors.affiliation: Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto, Japan.
authors.forename: Yoshito
authors.initials: Y
authors.lastname: Itoh
authors.affiliation: Department of Hepatology, Osaka City University Graduate School of Medicine, Osaka, Japan.
authors.forename: Norifumi
authors.initials: N
authors.lastname: Kawada
authors.affiliation: Department of Gastroenterology and Metabolism, Hiroshima University, Hiroshima, Japan.
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Chayama
authors.affiliation: Department of Gastroenterology and Hepatology, Kochi Medical School, Kochi, Japan.
authors.forename: Toshiji
authors.initials: T
authors.lastname: Saibara
authors.affiliation: Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Takehara
authors.affiliation: Department of Molecular Biochemistry and Clinical Investigation, Osaka University, Graduate School of Medicine, Osaka, Japan.
authors.forename: Eiji
authors.initials: E
authors.lastname: Miyoshi
mesh_terms: D000328:Adult; D000368:Aged; D000951:Antigens, Neoplasm / Q000097:blood*; D015415:Biomarkers / Q000097:blood*; D005260:Female; D005643:Fucose / Q000378:metabolism*; D006242:Haptoglobins / Q000032:analysis*; D006801:Humans; D016015:Logistic Models; D008297:Male; D008562:Membrane Glycoproteins / Q000097:blood*; D008875:Middle Aged; D065626:Non-alcoholic Fatty Liver Disease / Q000097:blood / Q000175:diagnosis*; D012372:ROC Curve
chemical_list: D000951:Antigens, Neoplasm; D015415:Biomarkers; C485359:HP protein, human; D006242:Haptoglobins; D008562:Membrane Glycoproteins; C114782:TAA90K protein, human; D005643:Fucose