Robert P. Heaney, MD; Laura A.G. Armas, MD
Disclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M14-2573.
Requests for Single Reprints: Robert P. Heaney, MD, Creighton University, Suite 4841, 601 North 30th Street, Omaha, NE 68131.
Current Author Addresses: Dr. Heaney: Creighton University, Suite 4840, 601 North 30th Street, Omaha, NE 68131.
Dr. Armas: Creighton University, Suite 4820, 601 North 30th Street, Omaha, NE 68131.
Arthur B. Chausmer, MD, PhD
February 18, 2015
Vitamin D Insufficiency
In response to the recent articles about the assessment and need for vitamin D supplementation. The pathologic hallmark of vitamin D insufficiency is an increase in uncalcified osteoid organic matrix in bone. The clinical hallmarks of vitamin D insufficiency are either specific findings, such as Milkman fractures, or unmineralized osteoid on un decalcified bone biopsy specimens. It is not hypocalcemia nor is it osteoporosis, which has uniform loss of both organic and mineralized bone and is a disorder of architecture, not calcification. There has been virtually no direct clinical evidence of vitamin D deficiency in the general US population. The basis on which the diagnosis has been made has, most often, been blood levels of an inactive intermediate, the 25 hydroxy vitamin D metabolite. There is precious little strong evidence of any relationship to the active metabolite, the 1,25 di hydroxy calciferol, in the blood. There is no strong clinical data of any relationship to proven vitamin D deficiency states. It is critical to remember that meta analyses, epidemiologic studies and correlational studies do not, and cannot, provide causal data. There have been no studies which have met the gold standard of being well controlled, randomized with appropriate statistical analyses on which to base the current judgments regarding the need for vitamin D supplementation in the United States general population. Given this lack of solid evidence, as supported by the Task Force report, supplementation with more than a minimal dose of vitamin D or screening in populations other than those at risk, such as with mal absorption syndromes, should not be undertaken, and for those at risk, the 25 hydroxy vitamin D assay may not be the best way to assess the vitamin D status. Arthur B. Chausmer, MD, PhD, FACP, FACE Adjunct Professor of Medicine Johns Hopkins Univ. School of Medicine.
Robert P. Heaney, MD
March 20, 2015
Dr. Chausmer identifies rickets and osteomalacia as the only manifestation of vitamin D deficiency and, presumably, their prevention as the principal effect of vitamin D. That is incorrect. Rickets and osteomalacia are probably the most evident and severe manifestations, but more than 90% of the function of the vitamin occurs outside of the calcium/bone economies, occurring in gene transcription essential for function of most tissues(1). 1,25(OH)2D, needed for that function, is not carried to the cells through the blood, but is synthesized intra-cellularly by the tissues concerned, precisely when they need it to mount a response to myriad physiologic and exobiotic signals. The 1,25(OH)2D used by various tissues cannot be measured in the serum because it never existed there. But 25(OH)D, which is the substrate for tissue-level 1--hydroxylases [and which limits 1,25(OH)2D production] can be measured. It is important to do so, not because 25(OH)D is fortuitously a marker for vitamin D status, but because it tells us precisely what the tissues “see” when they need to make 1,25(OH)2D, and because its availability limits the speed and extent of tissue response. For example, Liu et al.(2) showed definitively that the ability of macrophages to combat the tubercle bacillus was a direct function of serum 25(OH)D concentration. In another, lesser known manifestation, human breast milk contains virtually no vitamin D at prevailing maternal vitamin D status values, but fully meets the infant’s need for vitamin D when maternal 25(OH)D is above 45 ng/mL(3), a value that, not surprisingly, coincides exactly with values in East Africans following ancestral lifestyles(4).It is important to understand that the function of vitamin D and the other micronutrients is facilitative. They are necessary for cell function, but not causative thereof. In the absence of physiological need they do nothing, and increasing their intake has no proper effect. The definition of adequacy for all the micronutrients should not be the absence of some disease (rickets, beri-beri, scurvy), but the optimal functioning of all body systems. The need varies by system; it is relatively high for lactation (>45 ng/mL), and somewhat less for optimal skeletal mineralization (>30 ng/mL). But for the whole organism the requirement is the intake that supports all physiological functioning. Because of wide variation in response to dosing (with a coefficient of variation of nearly 40%), it is only by measuring serum 25(OH)D that we can be assured that we’ve achieved the proper level.References cited:1. Heaney RP, Armas, LAG. Quantifying the vitamin D economy. Nutr Rev 2015 73 (1): 51-672. Liu PT, Stenger S, Li H, et al. Toll-like receptor triggering of a vitamin D-mediated human antimicrobial response. Science. 2006;311(5768):1770–1773.3. Hollis BW, Wagner CL. Clinical review: the role of the parent compound vitamin D with respect to metabolism and function: why clinical dose intervals can affect clinical outcomes. J Clin Endocrinol Metab. 2013;98:4619-28. 4. Luxwolda MF, Kuipers RS, Kema IP, Dijck-Brouwer DA, Muskiet FA. Traditionally living populations in East Africa have a mean serum 25-hydroxyvitamin D concentration of 115 nmol/L. Br J Nutr. 2012;108:1557-61.
Heaney RP, Armas LA. Screening for Vitamin D Deficiency: Is the Goal Disease Prevention or Full Nutrient Repletion?. Ann Intern Med. 2015;162:144–145. doi: https://doi.org/10.7326/M14-2573
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Published: Ann Intern Med. 2015;162(2):144-145.
Endocrine and Metabolism, Prevention/Screening.
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