Integrating Fetuin-A and Lipid-Based Phenotyping as Markers of Cardiometabolic Risk in Subclinical Hypothyroidism

Objectives: To evaluate Fetuin-A (FA) as an integrative biomarker for cardiometabolic risk in subclinical hypothyroidism (SCH) and to investigate lipid-based metabolic heterogeneity. Methods: In this cross-sectional study, 192 participants (105 SCH, 87 controls) were evaluated for thyroid function, metabolic parameters, lipid profiles, FA, and high-sensitivity C-reactive protein (hs-CRP). Lipid phenotyping was performed using principal component analysis (PCA) and latent profile analysis (LPA). A composite cardiovascular disease risk index (CVDRI) incorporating FA and the atherogenic index of plasma (AIP), was calculated. Correlation, regression, and receiver operating characteristic (ROC) analysis were conducted. Results: SCH patients exhibited significantly elevated TSH, insulin resistance, dyslipidemia, hs-CRP, and FA compared to controls (p<0.0001). FA showed strong correlation with TSH, lipid parameters, insulin resistance, and CVDRI (ρ=0.60-0.77, p<0.001). PCA and LPA identified three distinct SCH phenotypes with progressively adverse metabolic and inflammatory profiles. ROC analysis demonstrated excellent discriminatory performance of FA and CVDRI (AUC > 95%), while lipid-derived indices differentiated high-risk phenotypes. Conclusion: FA is a promising integrative biomarker linking thyroid dysfunction with cardiometabolic risk in SCH. Lipid-based phenotyping highlights disease heterogeneity and supports the use of composite biomarker strategies for early risk stratification and personalized management.