The Role of Homocysteine in Pediatric MASLD: A Bipotential Biomarker of Cardiovascular Risk and Liver Fibrosis

The increasing prevalence of metabolic dysfunction-associated fatty liver disease (MASLD) in children requires robust, non-invasive biomarkers to enable accurate disease staging and risk stratification. Elevated serum levels of homocysteine (Hcy) have emerged as potential risk factors of cardiometabolic disease including MASLD in adults. In this observational retrospective study, we investigated the role of serum Hcy levels as a potential biomarker for disease severity and liver fibrosis in a pediatric cohort of 182 children with MASLD. Liver biopsies in 89 patients, allowed the classification into metabolic dysfunction-associated steatohepatitis (MASH). Associations between Hcy, metabolic parameters, fibrosis scores, and histological features were examined, and the Hcy diagnostic performance for liver fibrosis evaluated through ROC analysis. Multivariate analyses identified elevated Hcy levels as independently associated with HOMA-IR (β=0.55; p=0.049), TG/HDL ratio (β=3.23; p=0.002) and liver fibrosis (β=2.59; p=0.04). HCy showed excellent predictive accuracy for fibrosis (AUC= 0.0809) superior to that of other fibrosis scores. Finally, combined diagnostic models of Hcy with APRI, FIB-4, or TG/HDL ratio showed only modest accuracy, (AUC=0.62-0.69). Our data demonstrated that serum Hcy is a strong independent predictor of fibrosis in pediatric MASLD patients, supporting its role as a non-invasive biomarker to identify patients at risk of severe liver complications.