In a 2013 study published in The New England Journal of Medicine,1 Ravi Thadhani, MD, MPH, Chief of the Division of Nephrology at Massachusetts General Hospital, proposed that defining vitamin D deficiency in terms of bioavailability instead of total levels could resolve this paradox.
To measure the hormones thyroid and testosterone, endocrinologists consider both the smaller component that is bioavailable, and the larger component bound to binding proteins and held in inactive reserve. Deficiencies of these hormones are defined in terms of bioavailable levels. In contrast, vitamin D deficiency is defined in terms of total vitamin D.
The body’s vitamin D comes from precursor molecules made by the skin from UV light and from food. These precursors enter the liver, where they are converted to 25 hydroxyvitamin D (25D). The kidney then converts 25D to the active hormone, 1,25 dihydroxyvitamin D. Like other hormones, 1,25 D is so potent that excess amounts could damage cells, so the kidney converts only what is needed. Most vitamin D in the bloodstream is 25D bound to the vitamin D-binding protein. The remaining 25D, which is freely circulating or more loosely bound to albumin, is the bioavailable portion of total vitamin D.
healthy black and white individuals with no symptoms of vitamin D deficiency. Almost 90 percent of black participants met the definition of vitamin D deficiency while most whites did not (an average of 15.6 ng/ml total vitamin D in black participants versus 25.8 ng/ml in whites), confirming previous studies. However, this difference was explained by the fact that blacks also had significantly less vitamin D-binding protein, which binds most of the vitamin D but is not usually measured (168 µg/ml versus 337 µg/ml). Moreover, genetic differences accounted for the different levels of vitamin D-binding protein in whites and blacks. Analyzing the coding region of the vitamin D–binding protein gene, the researchers identified two single nucleotide polymorphisms (SNPs), rs4588 and rs7041, which were tightly linked to the level of vitamin D-binding protein and the affinity of the binding protein for vitamin D, and thus by extension to total vitamin D levels. The distribution of polymorphisms in these coding regions differed markedly by race—in almost 90 percent of the black population, the “F” allele dominated, whereas it was present in only a small number of white participants.
No reliable test for bioavailable vitamin D exists, so the researchers developed an assay and used published formulas to estimate bioavailable levels. Surprisingly, bioavailable vitamin D levels were similar in blacks and whites (2.9 v. 3.1 ng/ml, respectively), suggesting that each had similar access to vitamin D, despite lower total levels in blacks. As expected, bone density at the femoral neck was slightly higher in blacks, as were levels of calcium (9.11 v. 8.99 mg/ml, respectively), both also indicating that blacks were not truly vitamin D deficient. Prior research to define vitamin D deficiency was conducted largely in white populations, highlighting the importance of a diverse study population.
Are Supplements Recommended?
References
1 Powe, Camille E., S. Ananth Karumanchi and Ravi Thadhani. “Vitamin
D-Binding Protein and Vitamin D in Blacks and Whites.” The New England
Journal of Medicine 370, no. 9 (February 27, 2014): 880–81. http://www.ncbi.nlm.nih.gov/pubmed/24571762
Contributor
Ravi Thadhani, MD, MPH- Chief, Division of Nephrology