Metabolomic Profiling to Identify Predictors of Response to Vitamin E for Non-Alcoholic Steatohepatitis (NASH)

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.