Multiplex Serum Protein Analysis Identifies Novel Biomarkers of Advanced Fibrosis in Patients with Chronic Liver Disease with the Potential to Improve Diagnostic Accuracy of Established Biomarkers

• Published in: PloS one Vol. 11; no. 11; p. e0167001
• Main Authors: Irvine, Katharine M, Wockner, Leesa F, Hoffmann, Isabell, Horsfall, Leigh U, Fagan, Kevin J, Bijin, Veonice, Lee, Bernett, Clouston, Andrew D, Lampe, Guy, Connolly, John E, Powell, Elizabeth E
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 18.11.2016; Public Library of Science (PLoS)
• Subjects: Accuracy; Adult; Analytical chemistry; Bioindicators; Biological markers; Biology; Biology and Life Sciences; Biomarkers; Biomarkers - blood; Biopsy; Blood Proteins; Care and treatment; Cell adhesion & migration; Chemokines; Cirrhosis; Clinical medicine; Cross-Sectional Studies; Cytokines; Development and progression; Diagnosis; Diagnostic systems; Enzyme-Linked Immunosorbent Assay; Etiology; Female; Fibrosis; Gastroenterology; Hepatitis; Hepatology; Hospitals; Humans; Hyaluronic acid; Immunology; Liver; Liver cirrhosis; Liver Cirrhosis - blood; Liver Cirrhosis - diagnosis; Liver diseases; Logistic Models; Male; Mathematical models; Matrilysin; Matrix metalloproteinase; Matrix metalloproteinases; Medical diagnosis; Medical research; Medicine; Medicine and Health Sciences; Metalloproteinase; Middle Aged; Mortality; Patients; Proteases; Regression analysis; Reproducibility of Results; Retrospective Studies; Severity of Illness Index; Studies; Tissue inhibitor of metalloproteinase 1; Singapore; Australia; United States > US; Texas
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0167001

Non-invasive markers of liver fibrosis are urgently required, especially for use in non-specialist settings. The aim of this study was to identify novel serum biomarkers of advanced fibrosis. We performed an unbiased screen of 120 serum analytes including cytokines, chemokines and proteases in 70 patients (35 without fibrosis, 35 with cirrhosis on biopsy), and selected a panel of 44 candidate biomarkers, which were subsequently measured in a mixed-etiology cohort of 432 patients with known serum HA, PIIINP and TIMP1 (which comprise the validated Enhanced Liver Fibrosis (ELF) test). Multivariate logistic regression modelling was used to generate models for the prediction of advanced or significant fibrosis (METAVIR ≥F3 and ≥F2, respectively); in addition to identifying biomarkers of disease activity and steatohepatitis. Seventeen analytes were significantly differentially expressed between patients with no advanced fibrosis and patients with advanced fibrosis, the most significant being hyaluronic acid (HA) and matrix metalloproteinase (MMP) 7 (p = 2.9E-41 and p = 1.0E-26, respectively). The optimal model for the prediction of advanced fibrosis comprised HA, MMP7, MMP1, alphafetoprotein (AFP) and the AST to platelet ratio index (APRI). We demonstrate enhanced diagnostic accuracy (AUROC = 0.938) compared to a model comprising HA, PIIINP and TIMP1 alone (ELF) (AUROC = 0.898, p<0.0001, De Long's test). We have identified novel serum biomarkers of advanced liver fibrosis, which have the potential to enhance the diagnostic accuracy of established biomarkers. Our data suggest MMP7 is a valuable indicator of advanced fibrosis and may play a role in liver fibrogenesis.