title: Metabolomic profiling to identify predictors of response to vitamin E for non-alcoholic steatohepatitis (NASH).
abstract: Vitamin E was recently shown to improve hepatic histology in a randomized controlled trial of pioglitazone or vitamin E for nonalcoholic steatohepatitis (PIVENS). The current study utilized samples collected in the PIVENS trial to identify: (1) baseline metabolomic profiles that could identify who would respond to vitamin E treatment and (2) end of treatment metabolomic profiles reflective of histologic improvement. A comprehensive analysis of metabolomics profiles (n = 547) quantified by mass spectrometry was performed in vitamin E responders (n = 16), vitamin E non-responders (n = 15), and placebo responders (n = 15). At baseline, phenyl-propionic acid (Odds ratio: 29.4, p<0.01), indole-propionic acid levels (Odds ratio: 16.2, p<0.01) were directly associated with a subsequent histologic response to vitamin E treatment whereas γ-carboxyethylhydroxychroman (CEHC) levels were inversely related to histologic response. Adjusting for baseline values by analysis of covariance, the end of treatment levels of gamma-glutamyl leucine (Fold change: 0.82, p<0.02) and gamma-glutamyl valine (Fold change: 0.8, p<0.03) were significantly lower in vitamin E responders compared to non-responders. The levels of gamma-glutamyl transpeptidase were not significantly different across the two groups. Subjects receiving placebo who demonstrated a histologic improvement also demonstrated lower levels of gamma-glutamylated amino acids (leucine, valine and isoleucine) compared to vitamin E non-responders. These data provide exploratory proof that there are measurable differences in the metabolic profile of subjects who are likely (vs unlikely) to respond to vitamin E treatment for NASH and in those experiencing histologic improvement (vs no improvement) on treatment and support further studies to validate these biomarkers.
authors.affiliation: Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, Virginia Commonwealth University School of Medicine, Richmond, Virginia, United States of America.
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Cheng
authors.forename: Andrew
authors.initials: A
authors.lastname: Joyce
authors.forename: Katherine
authors.initials: K
authors.lastname: Yates
authors.forename: Bradley
authors.initials: B
authors.lastname: Aouizerat
authors.forename: Arun J
authors.initials: AJ
authors.lastname: Sanyal
mesh_terms: D000328:Adult; D015415:Biomarkers / Q000097:blood; D005234:Fatty Liver / Q000175:diagnosis / Q000188:drug therapy* / Q000378:metabolism*; D005260:Female; D006801:Humans; D008297:Male; D055442:Metabolome; D055432:Metabolomics; D008875:Middle Aged; D065626:Non-alcoholic Fatty Liver Disease; D011379:Prognosis; D016896:Treatment Outcome; D014810:Vitamin E / Q000627:therapeutic use*
chemical_list: D015415:Biomarkers; D014810:Vitamin E