Vitamin D Binding Protein, Total and Free Vitamin D Levels in Different Physiological and Pathophysiological Conditions.
Front Endocrinol (Lausanne). 2019 May 28;10:317. doi: 10.3389/fendo.2019.00317
Bikle DD1,2, Schwartz J1.
1 Department of Medicine, University of California, San Francisco, San Francisco, CA, United States.
2 Endocrine Research Unit, San Francisco Veterans Affairs Medical Center, San Francisco, CA, United States.
Vitamin D Binding Protein (GC) gene can decrease the bio-available Vitamin D that can get to cells,
- GC is not the only such gene - there are 3 others, all invisible to standard Vitamin D tests
- The bio-available calculation does not notice the effect of GC, CYP27B1, CYP24A1, and VDR
- The actual D getting to the cells is a function of measured D and all 4 genes
- There is >2X increase in 8+ health problems if have poor VDBP (GC)
- It appears that VDBP only blocks oral vitamin D,
- but NOT Vitamin D from sun, UV, topical or inhaled (tissue activated)
- A clue: - Vitamin D from UV is 2X better for MS than oral UV
- Poor Vitamin D response 4X more likely if poor Vitamin D binding proteins - July 2019
- Vitamin D Nutrigenomics - High, Medium, and Low Responders - March 2019
- Vitamin D and critical illness – many questions and unknowns (DBP etc)– Dec 2018
- Genes (CYP2R1 and GC) which restrict the amount of Vitamin D which gets into bloodstream – June 2014
- Response to Vitamin D varies with Vitamin D Binding Protein gene – RCT May 2018
- Poor Vitamin D binding had 30 percent less response to Vitamin D (50,000 IU weekly) – Feb 2019
- Multiple Sclerosis 2.8 X more likely if poor Vitamin D Binding Protein – May 2022
- Gene variants can change Vitamin D response by 1.7X (14,000 IU daily, Multiple Sclerosis) – Dec 2021
- Vitamin D genes increase MS relapses in children by 2X – May 2019
- Mendelian proof that low vitamin D (due to 3 genes) increase risk of MS by 20 percent – Nov 2016
- Genes make Multiple Sclerosis 2X more likely unless get more vitamin D - Aug 2015
- Multiple Sclerosis is associated with about 1.5 X more Vitamin D Binding Protein – Jan 2015
- Late-stage MS associated with protein in spinal cord which blocks vitamin D – Jan 2013
TB and Vitamin D Binding Protein:
- Higher risk of pulmonary tuberculosis if any of 3 vitamin D genes are poor – April 2021
- Tuberculosis not treated by monthly 140,000 IU (Vitamin D binding protein problem) – RCT Sept 2017
- TB lowers vitamin D, then HIV lowers it even more - 2014
- Tuberculosis, Genes, Vitamin D Binding Protein, and RCT – Review Aug 2014
Breathing and Vitamin D Binding Protein:
- Asthma more closely associated with poor VDBP gene than with poor Vitamin D level – June 2014
- COPD in Asians twice as likely if poor Vitamin D Binding Protein – meta-analysis May 2019
- COPD strongly associated with Vitamin D Binding Protein problems – meta-analysis Aug 2015
- Gene makes COPD 2.6X more likely unless get more vitamin D – meta-analysis Dec 2014
- Vitamin D Binding Protein, And Airflow In COPD - April 2012
- Genetic link found between vitamin D and COPD – June 2010
- How vitamin D helps the lung via vitamin D-binding protein - May 2010
Infant-Child and Vitamin D Binding Protein:
- Poor protein binding gene associated with poor Vitamin D response – RCT Nov 2019
- Type 1 Diabetes risk increased if high postpartum Vitamin D binding protein – Jan 2019
- Decreased response to vitamin D in white children having poor Vitamin D binding gene – Feb 2019
- Ear infections in children 3X more likely if poor vitamin D binding protein – July 2018
- Vitamin D is more bio-available when children are critically ill (less Binding Protein) – Sept 2015
- Food allergy 12X more likely if low vitamin D and vitamin D binding gene problem – Aug 2015
This review focuses on the biologic importance of the vitamin D binding protein (DBP) with emphasis on its regulation of total and free vitamin D metabolite levels in various clinical conditions. Nearly all DBP is produced in the liver, where its regulation is influenced by estrogen, glucocorticoids and inflammatory cytokines but not by vitamin D itself. DBP is the most polymorphic protein known, and different DBP alleles can have substantial impact on its biologic functions. The three most common alleles-Gc1f, Gc1s, Gc2-differ in their affinity with the vitamin D metabolites and have been variably associated with a number of clinical conditions. Although DBP has a number of biologic functions independent of vitamin D, its major biologic function is that of regulating circulating free and total levels of vitamin D metabolites. 25 hydroxyvitamin D (25(OH)D) is the best studied form of vitamin D as it provides the best measure of vitamin D status. In a normal non-pregnant individual, approximately 0.03% of 25(OH)D is free; 85% is bound to DBP, 15% is bound to albumin.
The free hormone hypothesis postulates that only free 25(OH)D can enter cells.
This hypothesis is supported by the observation that mice lacking DBP, and therefore with essentially undetectable 25(OH)D levels, do not show signs of vitamin D deficiency unless put on a vitamin D deficient diet.
Similar observations have recently been described in a family with a DBP mutation.
This hypothesis also applies to other protein bound lipophilic hormones including glucocorticoids, sex steroids, and thyroid hormone. However, tissues expressing the megalin/cubilin complex, such as the kidney, have the capability of taking up 25(OH)D still bound to DBP, but most tissues rely on the free level.
Attempts to calculate the free level using affinity constants generated in a normal individual along with measurement of DBP and total 25(OH)D have not accurately reflected directly measured free levels in a number of clinical conditions. In this review, we examine the impact of different clinical conditions as well as different DBP alleles on the relationship between total and free 25(OH)D, using only data in which the free 25(OH)D level was directly measured. The major conclusion is that a number of clinical conditions alter this relationship, raising the question whether measuring just total 25(OH)D might be misleading regarding the assessment of vitamin D status, and such assessment might be improved by measuring free 25(OH)D instead of or in addition to total 25(OH)D.
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