Metabolic phenotyping for enhanced mechanistic stratification of chronic hepatitis C-induced liver fibrosis.

TitleMetabolic phenotyping for enhanced mechanistic stratification of chronic hepatitis C-induced liver fibrosis.
Publication TypeJournal Article
Year of Publication2015
AuthorsSands CJ, Guha IN, Kyriakides M, Wright M, Beckonert O, Holmes E, Rosenberg WM, Coen M
JournalAm J Gastroenterol
Volume110
Issue1
Pagination159-69
Date Published01/2015
ISSN1572-0241
KeywordsAdult, Biological Markers, Female, Hepatitis C, Chronic, Humans, Lipid Metabolism, Liver Cirrhosis, Magnetic Resonance Spectroscopy, Male, Middle Aged, Phenotype, Severity of Illness Index
Abstract

OBJECTIVES: The invasive nature of biopsy alongside issues with categorical staging and sampling error has driven research into noninvasive biomarkers for the assessment of liver fibrosis in order to stratify and personalize treatment of patients with liver disease. Here, we sought to determine whether a metabonomic approach could be used to identify signatures reflective of the dynamic, pathological metabolic perturbations associated with fibrosis in chronic hepatitis C (CHC) patients.

METHODS: Plasma nuclear magnetic resonance (NMR) spectral profiles were generated for two independent cohorts of CHC patients and healthy controls (n=50 original and n=63 validation). Spectral data were analyzed and significant discriminant biomarkers associated with fibrosis (as graded by enhanced liver fibrosis (ELF) and METAVIR scores) identified using orthogonal projection to latent structures (O-PLS).

RESULTS: Increased severity of fibrosis was associated with higher tyrosine, phenylalanine, methionine, citrate and, very-low-density lipoprotein (vLDL) and lower creatine, low-density lipoprotein (LDL), phosphatidylcholine, and N-Acetyl-α1-acid-glycoprotein. Although area under the receiver operator characteristic curve analysis revealed a high predictive performance for classification based on METAVIR-derived models, <40% of identified biomarkers were validated in the second cohort. In the ELF-derived models, however, over 80% of the biomarkers were validated.

CONCLUSIONS: Our findings suggest that modeling against a continuous ELF-derived score of fibrosis provides a more robust assessment of the metabolic changes associated with fibrosis than modeling against the categorical METAVIR score. Plasma metabolic phenotypes reflective of CHC-induced fibrosis primarily define alterations in amino-acid and lipid metabolism, and hence identify mechanistically relevant pathways for further investigation as therapeutic targets.

DOI10.1038/ajg.2014.370
Alternate JournalAm. J. Gastroenterol.
PubMed ID25533003
Grant List / / Department of Health / United Kingdom
/ / Medical Research Council / United Kingdom