Vitamin D binding protein: its role in vitamin D dysregulation and postsurgical outcomes
Creators: name: Meng, Lingqiong
Publisher: name: No Publisher Supplied
Year: 2024

description: Vitamin D binding protein (DBP) is the major carrier for circulating vitamin D and plays an important role in regulating circulating total and free vitamin D metabolites. Since the concentration of DBP and its affinity to vitamin D is varied by different physiological and clinical conditions, only measuring total 25-hydroxyvitamin D (25OHD) may not accurately reflect functional vitamin D status. In addition, DBP is a potential prognostic indicator of clinical outcomes since it has other important functions beyond that as vitamin D carrier, including its role in actin scavenging and inflammation after tissue injury. It is hypothesized that circulating DBP is altered in patients with low vitamin D status and affects the concentration of total and free vitamin D metabolites and can explain postsurgical outcomes. The goal of this research, using two populations, one with primary hyperparathyroidism (PHPT) and the other with hip fracture, was to evaluate if DBP concentration and affinity are altered and determine whether they influence the total and free fraction of vitamin D metabolites and inflammation. In addition, another aim of this research was to examine underlying mechanisms related to DBP and determine whether circulating concentrations affect mortality and mobility in patients with hip fractures. In a prospective study, we measured circulating free 25OHD levels in patients with PHPT and healthy controls (n=40/group). Circulating PTH was about 2.7 times higher and 25OHD was about 20% lower in patients with PHPT than controls. Total DBP was also lower (p &lt; 0.05) in patients with PHPT, but not calculated or measured free 25OHD. In contrast, free fractions of serum 1,25(OH)2D were higher in patients than controls. In a subsequent study with larger population, blood samples were measured in a total of 70 patients before parathyroidectomy (PTX) and were measured again in a subset (n=28) after 3 months. In this second study of patients with PHPT, who also had low serum DBP and total 25OHD, serum interleukin-6 (IL-6) and monocyte chemoattractant protein-1 (MCP-1) were higher compared to controls (p &lt; 0.01). The concentration of DBP was inversely correlated with intact parathyroid hormone (PTH) and IL-6 (p &lt; 0.01), but not with other cytokines. Serum PTH and calcium reduced to the normal range by surgery. After PTX, total and free 25OHD and DBP levels were increased while concentrations of certain cytokines (IL-6 and MCP-1) decreased (p &lt; 0.05) and not others such as C-reactive protein (CRP). In a prospective study to further examine DBP, we conducted a secondary analysis of 260 patients with hip fractures; mobility was assessed at 30 and 60 days and mortality at 60 days after repair surgery. Biochemical markers were measured before, and 2 to 4 days after surgery. Tissue injury markers were measured in 100 randomly selected patients and controls. Among all patients, the highest DBP tertile had greater mobility at 30 and 60 days and reduced mortality (P &lt; 0.05) compared with the lowest tertile. Circulating DBP and gelsolin were lower, and IL-6, CRP, and F-actin were higher (P &lt; 0.01) in patients compared to controls and worsened (P &lt; 0.01) after surgery. Both IL-6 and CRP were inversely associated with DBP (P &lt; 0.01). Overall, our data support that the concentration and affinity of DBP is reduced by high PTH or hip fracture, and results in dysregulation of vitamin D metabolites. Thus, low vitamin D status is more complicated than the simple clinical definition of low total 25OHD. Only certain cytokines, MCP-1 and IL-6, are upregulated by PTH and that in turn may contribute to the reduction in DBP concentrations. PTX surgery not only decreases PTH, but also may affect clinical outcomes by decreasing IL-6 and MCP-1. In addition, the results from patients with hip fracture provide new evidence that higher DBP concentrations are associated with better postsurgical outcomes. This may due to the importance of DBP in actin scavenging system and its association with inflammation after tissue injury. The role of DBP as an acute phase reactant to tissue injury and clinical outcomes should be addressed in future studies.