Plasma sphingolipids predict advanced liver fibrosis development in patients with type 2 diabetes

Patients with type 2 diabetes (T2D) are at an elevated risk of developing metabolic dysfunction-associated steatotic liver disease (MASLD), with a significant likelihood of progression to advanced liver fibrosis (AF)-a stage linked to adverse outcomes. Considering the critical role of lipids in the pathophysiology of MASLD and AF, we aimed to identify lipidomic biomarkers that could predict the development of AF in individuals with T2D.

We included 67 T2D patients, followed for a mean duration of 10.2 ± 3.9 years. We measured baseline plasma concentrations of 148 molecular species of phospholipids, sphingolipids, and free fatty acids. We assessed the development of AF during the follow-up period using liver stiffness measurement (AF if ≥8.0 kPa). Patients who developed ultrasonographic signs of cirrhosis were classified as having AF.

AF developed in 14 patients (20.9%) during the follow-up period. Univariate analysis revealed that baseline plasma levels of two sphingolipids among 148 lipid species assessed, namely d18:1/18:0 sphingomyelin and d18:0/20:0 dihydroceramide, were significantly predictive of AF development. Machine-learning multivariate approaches identified baseline plasma levels of d18:0/20:0 dihydroceramide and d18:1/18:0 sphingomyelin as the most predictive variables for AF development, independently of follow-up duration, baseline body mass index, and baseline levels of transaminases, gamma-glutamyl transferase, and the fibrosis-4 index.

Baseline levels of two plasma sphingolipid species are independent predictors of AF development in patients with T2D. These findings could help identify T2D patients at elevated risk of adverse hepatic and extrahepatic outcomes, potentially allowing for new targeted therapeutic interventions.