Vitamin D Hypersensitivity as a Potential Trigger for Worsening Atherosclerosis and Hypercholesterolemia

The role of vitamin D (VD) in cardiovascular health remains controversial. Observational studies have associated low serum 25(OH)D₃ levels with increased cardiovascular risk, whereas interventional and Mendelian randomization trials have failed to demonstrate causality. This discrepancy may reflect unrecognized interindividual variability in VD responsiveness and the weak correlation between circulating VD metabolites and tissue-specific biological effects. This review introduces the emerging concept of variable VD sensitivity, encompassing a continuum from vitamin D resistance (VDRES) to vitamin D hypersensitivity (VDHY). VDRES results from genetic or acquired alterations that impair VD metabolism, transport, or receptor signaling, leading to an insufficient biological response. Conversely, VDHY involves excessive local VD activation, frequently due to CYP24A1 variants or granulomatous activity. The resulting surplus of active VD suppresses parathyroid hormone–related peptide (PTHrP), promoting vascular smooth muscle cell calcification and accelerating atherosclerosis. VD metabolism also appears to intersect with lipid regulation. Patients carrying CYP24A1 mutations, which impair the catabolism of 1,25(OH)₂D₃, exhibit abnormalities in lipid metabolism, including hypercholesterolemia. Dysregulated VD signaling may therefore disrupt cholesterol homeostasis through feedback mechanisms. These opposing phenotypes may help explain the inconsistent cardiovascular outcomes observed in clinical studies. Integrating evidence from endocrinology, vascular biology, and genetics, this review argues for individualized rather than uniform VD supplementation strategies. A deeper understanding of the molecular determinants of VD responsiveness could enhance cardiovascular risk assessment and therapeutic precision. Until assays become available to predict individual responsiveness, clinicians should exercise caution when prescribing VD, particularly in populations at risk for suboptimal response or toxicity.