title: Combined Serum Biomarkers in Non-Invasive Diagnosis of Non-Alcoholic Steatohepatitis.
abstract: BACKGROUND
  Non-alcoholic steatoheaptitis (NASH), the critical stage of non-alcoholic fatty liver disease (NAFLD), is of chronic progression and can develop cirrhosis even hepatocellular carcinoma (HCC). However, non-invasive biomarkers for NASH diagnosis remain poorly applied in clinical practice. Our study aims at testing the accuracy of the combination of cytokeratin-18 M30 fragment (CK-18-M30), fibroblast growth factor 21 (FGF-21), interleukin 1 receptor antagonist (IL-1Ra), pigment epithelium-derived factor (PEDF) and osteoprotegerin (OPG) in diagnosing NAFLD and NASH.
  
  
  METHODS
  179 patients with biopsy-proven NAFLD were enrolled as training group, 91 age- and gender-matched healthy subjects were recruited at the same time as controls. 63 other NAFLD patients were separately collected as validation group. 45 alcoholic fatty liver disease (AFLD) patients, 50 hepatitis B virus (HBV) patients, 52 hepatitis C virus (HCV) patients were also included. Serum biomarker levels were measured by enzyme-linked immunosorbent assay.
  
  
  RESULTS
  Serum levels of CK-18-M30, FGF-21, IL-1Ra and PEDF increased, while OPG decreased in a stepwise fashion in controls, non-NASH NAFLD patients and NASH patients (P < 0.01). The area under receiver-operating characteristics curve to diagnose NASH was 0.86 for CK-18-M30, 0.89 for FGF-21, 0.89 for IL-1Ra, 0.89 for PEDF and 0.89 for OPG. CK-18-M30 had 70% negative predictive value (NPV) and 79% positive predictive value (PPV) to diagnose NASH. A 5-step approach measuring CK-18-M30 followed by FGF21, IL-1Ra, PEDF and OPG gradually improved the NPV to 76% and PPV to 85%, which reached 80% and 76% respectively in the validation cohort.
  
  
  CONCLUSIONS
  Compared to single biomarker, stepwise combination of CK-18-M30, FGF-21, IL-1Ra, PEDF and OPG can further improve the accuracy in diagnosing NASH.
authors.affiliation: Department of Pathology and Hepatology, Beijing 302 Hospital, Beijing, China.
authors.forename: Mei
authors.initials: M
authors.lastname: Yang
authors.affiliation: Institute of Infectious Diseases/Liver Failure Medical Center, Beijing 302 Hospital, Beijing, China.
authors.forename: Dongping
authors.initials: D
authors.lastname: Xu
authors.affiliation: Department of Pathology and Hepatology, Beijing 302 Hospital, Beijing, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Pathology and Hepatology, Beijing 302 Hospital, Beijing, China.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Guo
authors.affiliation: Center for Clinical Trial, Beijing 302 Hospital, Beijing, China.
authors.forename: Wenshu
authors.initials: W
authors.lastname: Li
authors.affiliation: Department of Pathology and Hepatology, Beijing 302 Hospital, Beijing, China.
authors.forename: Chaonan
authors.initials: C
authors.lastname: Guo
authors.affiliation: Department of Pathology and Hepatology, Beijing 302 Hospital, Beijing, China.
authors.forename: Hongping
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Pathology and Hepatology, Beijing 302 Hospital, Beijing, China.
authors.forename: Yinjie
authors.initials: Y
authors.lastname: Gao
authors.affiliation: Center for Clinical Laboratory, Beijing 302 Hospital, Beijing, China.
authors.forename: Yuanli
authors.initials: Y
authors.lastname: Mao
authors.affiliation: Department of Pathology and Hepatology, Beijing 302 Hospital, Beijing, China.
authors.forename: Jingmin
authors.initials: J
authors.lastname: Zhao
mesh_terms: D000328:Adult; D015415:Biomarkers / Q000097:blood*; D016022:Case-Control Studies; D005260:Female; D006801:Humans; D016015:Logistic Models; D008297:Male; D015999:Multivariate Analysis; D065626:Non-alcoholic Fatty Liver Disease / Q000097:blood* / Q000175:diagnosis*; D012372:ROC Curve; D015203:Reproducibility of Results
chemical_list: D015415:Biomarkers