Well-known risk factors for the development of NAFLD include the presence of metabolic syndrome, visceral adiposity, and type 2 diabetes, all of which display distinct sex-related differences. Despite this, research into sex differences underpinning NAFLD pathophysiology remains scarce.
This study aimed to identify serum metabolic signatures associated with sex in 210 metabolically diverse NAFLD patients via nuclear magnetic resonance. It further aimed to characterise the relationship between metabolite fluctuations and NAFLD progression in this patient population.
Increased levels of alanine, histidine, and tyrosine were found to be significantly associated with NAFLD severity in both men and women. However, higher serum concentrations of valine, aspartic acid, and mannose positively correlated with NAFLD progression in male subjects, while negative associations were observed with creatine, phosphorylcholine, and acetic acid. All displayed an AUROC>0.7 and were thus identified as male-specific metabolite markers of NAFLD. Conversely, among female subjects, increases in serum glucose were found to be positively associated with NAFLD progression (AUROC=0.802), and negative associations were observed with threonine. Circulating acetoacetate was also significantly reduced, and glycine serum concentrations significantly disturbed, in female NAFLD patients. These findings hint at the possibility of developing surrogate markers of NAFLD progression using metabolic profiling and remain to be confirmed in larger and more diverse patient cohorts.