title: A quantitative metabolomics profiling approach for the noninvasive assessment of liver histology in patients with chronic hepatitis C.
abstract: BACKGROUND
  High-throughput technologies have the potential to identify non-invasive biomarkers of liver pathology and improve our understanding of basic mechanisms of liver injury and repair. A metabolite profiling approach was employed to determine associations between alterations in serum metabolites and liver histology in patients with chronic hepatitis C virus (HCV) infection.
  
  
  METHODS
  Sera from 45 non-diabetic patients with chronic HCV were quantitatively analyzed using (1)H-NMR spectroscopy. A metabolite profile of advanced fibrosis (METAVIR F3-4) was established using orthogonal partial least squares discriminant analysis modeling and validated using seven-fold cross-validation and permutation testing. Bioprofiles of moderate to severe steatosis (≥33 %) and necroinflammation (METAVIR A2-3) were also derived. The classification accuracy of these profiles was determined using areas under the receiver operator curves (AUROCSs) measuring against liver biopsy as the gold standard.
  
  
  RESULTS
  In total 63 spectral features were profiled, of which a highly significant subset of 21 metabolites were associated with advanced fibrosis (variable importance score >1 in multivariate modeling; R(2) = 0.673 and Q(2) = 0.285). For the identification of F3-4 fibrosis, the metabolite bioprofile had an AUROC of 0.86 (95 % CI 0.74-0.97). The AUROCs for the bioprofiles for moderate to severe steatosis were 0.87 (95 % CI 0.76-0.97) and for grade A2-3 inflammation were 0.73 (0.57-0.89).
  
  
  CONCLUSIONS
  This proof-of-principle study demonstrates the utility of a metabolomics profiling approach to non-invasively identify biomarkers of liver fibrosis, steatosis and inflammation in patients with chronic HCV. Future cohorts are necessary to validate these findings.
authors.affiliation: Department of Biological Sciences, University of Calgary, 2500 University Drive, North West, Calgary, AB, T2N 1N4, Canada. omair.sarfaraz@medportal.ca.|Department of Medicine-Pathology and Molecular Medicine, McMaster University, Hamilton, ON, L8N 3Z5, Canada. omair.sarfaraz@medportal.ca.|Dept. of Medicine/Dept. of Pathology and Molecular Medicine, McMaster University, 1280 Main Street West, Health Sciences Centre, Hamilton, ON, L8S4K1, Canada. omair.sarfaraz@medportal.ca.
authors.forename: M Omair
authors.initials: MO
authors.lastname: Sarfaraz
authors.affiliation: Liver Unit, Division of Gastroenterology and Hepatology, Cumming School of Medicine, University of Calgary, Hospital Drive North West, Calgary, AB, T2N 4Z6, Canada.
authors.forename: Robert P
authors.initials: RP
authors.lastname: Myers
authors.affiliation: Liver Unit, Division of Gastroenterology and Hepatology, Cumming School of Medicine, University of Calgary, Hospital Drive North West, Calgary, AB, T2N 4Z6, Canada.
authors.forename: Carla S
authors.initials: CS
authors.lastname: Coffin
authors.affiliation: Department of Pathology, McGill University Health Centre, 1001 Decarie Boulevard, Montreal, QC, H4A 3J1, Canada.
authors.forename: Zu-Hua
authors.initials: ZH
authors.lastname: Gao
authors.affiliation: Liver Unit, Division of Gastroenterology and Hepatology, Cumming School of Medicine, University of Calgary, Hospital Drive North West, Calgary, AB, T2N 4Z6, Canada.
authors.forename: Abdel Aziz M
authors.initials: AA
authors.lastname: Shaheen
authors.affiliation: Liver Unit, Teaching and Wellness Building, University of Calgary, Hospital Drive, North West, Calgary, AB, T2N 4Z6, Canada.
authors.forename: Pam M
authors.initials: PM
authors.lastname: Crotty
authors.affiliation: Department of Chemistry, University of Calgary, 2500 University Dr. NW Calgary, Calgary, AB, T2N 1N4, Canada.
authors.forename: Ping
authors.initials: P
authors.lastname: Zhang
authors.affiliation: Department of Biological Sciences, University of Calgary, 2500 University Drive, North West, Calgary, AB, T2N 1N4, Canada.
authors.forename: Hans J
authors.initials: HJ
authors.lastname: Vogel
authors.affiliation: Metabolomics Research Center, Department of Biological Sciences, University of Calgary, Calgary, AB, T2N 1N4, Canada. aalim@mail.med.upenn.edu.|Department of Pharmacology, University of Pennsylvania, Philadelphia, PA, 19104, USA. aalim@mail.med.upenn.edu.|Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19081, USA. aalim@mail.med.upenn.edu.
authors.forename: Aalim M
authors.initials: AM
authors.lastname: Weljie
keywords: 1H-NMR spectroscopy; Hepatitis C; Metabolomics