Vitamin D status: measurement, interpretation, and clinical application

Abstract

Vitamin D, the sunshine vitamin, is now recognized not only for its importance in promoting bone health in children and adults but also for other health benefits, including reducing the risk of chronic diseases such as autoimmune diseases, common cancer, and cardiovascular disease. Vitamin D made in the skin or ingested in the diet is biologically inert and requires 2 successive hydroxylations first in the liver on carbon 25 to form 25-hydroxyvitamin D [25(OH)D], and then in the kidney for a hydroxylation on carbon 1 to form the biologically active form of vitamin D, 1,25-dihydroxyvitamin D [1,25(OH)(2)D]. With the identification of 25(OH)D and 1,25(OH)(2)D, methods were developed to measure these metabolites in the circulation. Serum 25(OH)D is the barometer for vitamin D status. Serum 1,25(OH)(2)D provides no information about vitamin D status and is often normal or even increased as the result of secondary hyperparathyroidism associated with vitamin D deficiency. Most experts agree that 25(OH)D of <20 ng/mL is considered to be vitamin D deficiency, whereas a 25(OH)D of 21-29 ng/mL is considered to be insufficient. The goal should be to maintain both children and adults at a level >30 ng/mL to take full advantage of all the health benefits that vitamin D provides.

Figure 1

The metabolism and biologic function of vitamin D. During exposure to sunlight, 7-dihydrocholesterol (7-DHC) is photolyzed to previtamin D₃ (preD₃). Body heat converts preD₃ to vitamin D₃. Vitamin D₂ and vitamin D₃ in the diet and vitamin D made in the skin enters the circulation and either is stored in the body’s fat adipocytes or enters the liver and is converted to 25-hydroxyvitamin D [25(OH)D]. For regulation of calcium metabolism, 25(OH)D is converted in the kidneys to 1,25-dihydroxyvitamin D [1,25(OH)₂D]. 1,25(OH)₂D interacts with its vitamin D receptor (VDR) in the small intestine and on osteoblasts to regulate calcium and phosphorus metabolism. 25(OH)D is metabolized in various tissues and cells for regulating cellular proliferation and differentiation as well as inducing cathelicidin D(CD) in macrophages. The induction of 1,25(OH)₂D in the macrophage is controlled by the 2/1 toll-like receptors (TLR) and its interaction with lipopolysaccharide (LPS). In addition, circulating concentrations of 1,25(OH)₂D may help increase insulin production and decrease renin production and alter adipocyte lipogenesis. With permission; copyright Michael F. Holick.

FIG. 2

A, Mean (±SE) serum PTH (picograms per milliliter) by serum 25(OH)D subgroups. Subject PTH concentrations (picograms per milliliter) relative to serum 25(OH)D concentrations sorted by subgroups delineated by predefined cutoffs for analyses of 25(OH)D inadequacy. Serum PTH values began to increase with 25(OH)D concentrations less than 29.8 ng/ml. B, Percent of subjects with secondary hyperparathyroidism by 25(OH)D level. The percent of subjects with secondary hyperparathyroidism (PTH > 40 pg/ml) sorted by subgroups with serum 25(OH)D concentrations delineated by predefined cutoffs for analyses of 25(OH)D inadequacy. Reproduced with permission.

Figure 3

(A) Serum levels of 25(OH)D (-Δ-) and PTH (-o-) before and after therapy with 50,000 IU of vitamin D₂ and calcium supplementation once a week for 8 weeks. (B) Serum levels of PTH levels in patients who had serum 25(OH)D levels of between 10 and 25 ng/ml and who were stratified in increments of 5 ng/ml before and after receiving 50,000 IU of vitamin D₂ and calcium supplementation for 8 weeks. Reproduced with permission.

FIG. 4

Laboratory personnel basal serum 25(OH)D concentration. A, In these 10 individuals, the mean serum 25(OH)D varied widely [from 17.1 (4.6) to 35.6 (5.2) ng/ml; P < 0.005] between laboratories (error bars represent SEM). B, Similarly, marked within-individual variation was observed in 25(OH)D measurement in different laboratories. Whether an individual has hypovitaminosis D (arbitrary threshold, 32 ng/ml shown as dashed line) depends on which laboratory was used. Note that laboratory H used HPLC and was considered to be the “gold standard” against which others were compared. Reproduced with permission.