Metabolomic and lipidomic plasma profiles according to metabolic dysfunction-associated steatotic liver diseases (MASLD) stages in the absence of type 2 diabetes (T2D).

Introduction: Amino acids (AAs), tricarboxylic acid (TCA) cycle intermediates, and acylcarnitines (ACs) can reflect energetic metabolism. Metabolic dysfunction-associated steatotic liver (MASLD) has been associated with the modification of plasma AAs, ACs and TCA cycle intermediates' profiles, but the changes in advanced fibrosis without type 2 diabetes (T2D) are not well studied.

Objectives: The objective of this pilot study was to describe the targeted plasma metabolomic profile in individuals with advanced fibrosis to test research hypotheses concerning hepatic energy metabolism.

Methods: We compared plasma fasting concentrations of 21 AAs, 11 organic acids (including ketone bodies and TCA cycle intermediates) and 14 ACs between individuals with advanced fibrosis stages (F3-F4/4) (n = 10) and individuals with no advanced fibrosis (n = 10), all without T2D and with similar clinical characteristics.

Results: Median age (IQR) (51 [43-67] vs. 57 [43-66] years), sex (30 vs. 50% men) and BMI (35 [28-37] vs. 37 [32-39] kg/m²) were comparable between groups. The advanced fibrosis (AF) group presented higher plasma tyrosine (p = 0.04), α-ketoglutarate (p = 0.04), and a lower level of medium-chain ACs C8 and C10 (p = 0.04). The glutamate-glycine-serine (GSG) index, which combines AAs involved in glutathione metabolism, was higher in the AF group (p = 0.04).

Conclusion: Overall, our results suggest impaired AAs catabolism and mitochondrial dysfunction. While the limited sample size and study design preclude causal inferences, these findings highlight potential metabolic signatures of advanced fibrosis in MASLD. They also underscore the need for larger, longitudinal studies to clarify their origin, significance, and clinical implications.