Vitamin D in health and disease

Abstract

Vitamin D functions in the body through both an endocrine mechanism (regulation of calcium absorption) and an autocrine mechanism (facilitation of gene expression). The former acts through circulating calcitriol, whereas the latter, which accounts for more than 80% of the metabolic utilization of the vitamin each day, produces, uses, and degrades calcitriol exclusively intracellularly. In patients with end-stage kidney disease, the endocrine mechanism is effectively disabled; however, the autocrine mechanism is able to function normally so long as the patient has adequate serum levels of 25(OH)D, on which its function is absolutely dependent. For this reason, calcitriol and its analogs do not constitute adequate replacement in managing vitamin D needs of such patients. Optimal serum 25(OH)D levels are greater than 32 ng/mL (80 nmol/L). The consequences of low 25(OH)D status include increased risk of various chronic diseases, ranging from hypertension to diabetes to cancer. The safest and most economical way to ensure adequate vitamin D status is to use oral dosing of native vitamin D. (Both daily and intermittent regimens work well.) Serum 25(OH)D can be expected to rise by about 1 ng/mL (2.5 nmol/L) for every 100 IU of additional vitamin D each day. Recent data indicate that cholecalciferol (vitamin D(3)) is substantially more potent than ergocalciferol (vitamin D(2)) and that the safe upper intake level for vitamin D(3) is 10,000 IU/d.

Figure 1.

Metabolic pathways by which vitamin D exerts its many effects in the body. (A) The prevailing scheme before recognition of the role of peripheral 1-α-hydroxylation. In this scheme, essentially all conversion of 25-hydroxyvitamin D [25(OH)D] to calcitriol occurs in the kidney, and the synthesized calcitriol appears in the serum, where it can be measured. Calcium-binding protein (CaBP) is a stand-in for the complex calcium absorptive apparatus induced in the enterocyte by calcitriol. (B) The current scheme, explicitly incorporating extrarenal 1-α-hydroxylation, with the resulting calcitriol appearing mainly intracellularly, where it is clinically unmeasureable. (Copyright Robert P. Heaney, 2008. Used with permission.)

Figure 2.

Diagram of the key role that calcitriol, synthesized within the cell concerned, plays in cellular responses requiring gene expression. (Copyright Robert P. Heaney, 2008. Used with permission.)

Figure 3.

Relationship of calcium absorption fraction to vitamin D nutritional status [as measured by serum 25(OH)D] (9). Note that efficiency rises up to 25(OH)D levels of approximately 80 nmol/L (32 ng/ml), above which regulation of absorption is no longer limited by vitamin D status. (Copyright Robert P. Heaney, 2005. Used with permission.)

Figure 4.

Kaplan-Meier survival (free of cancer) for postmenopausal women in the randomized trial of Lappe et al. (32). In the three treatment arms of the study (placebo, 1500 mg calcium [Ca], and 1500 mg of Ca + 1100 IU of vitamin D₃ [Ca + D]), 6.9% of participants had developed cancer by the end of the trial on placebo, 3.8% on Ca only, and 2.9% on Ca + D (P < 0.02). The risk for the group that received vitamin D relative to placebo was 0.402 (95% confidence interval 0.20 to 0.82). (Copyright Robert P. Heaney, 2006. Used with permission.)