Screening for Vitamin D Deficiency: Is the Goal Disease Prevention or Full Nutrient Repletion?
Authors: Robert P. Heaney, Laura A.G. Armas
Journal: Annals of Internal Medicine (2014)

Editorials20 January 2015Screening for Vitamin D Deficiency: Is the Goal Disease Prevention or Full Nutrient Repletion?FREERobert P. Heaney, MD and Laura A.G. Armas, MDRobert P. Heaney, MDFrom Creighton University, Omaha, NebraskaSearch for more papers by this author and Laura A.G. Armas, MDFrom Creighton University, Omaha, NebraskaSearch for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/M14-2573 SectionsAboutVisual AbstractPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail Since its founding, the U.S. Preventive Services Task Force (USPSTF) has sought to provide a firm evidential base for early detection strategies, evaluating such screening methods as mammography and prostate-specific antigen testing. Although it has also evaluated a few interventions, its predominant focus has been testing for markers that identify persons at risk who are likely to benefit from preventive action. Only recently has the USPSTF ventured into the field—or perhaps the minefield—of nutrition, a territory distant from screening tests and risk assessment, with different and unfamiliar landmarks.In this issue, the USPSTF presents its conclusions on testing for vitamin D deficiency (1), reporting that it was unable to find evidence for or against such testing. It noted that one of the likely reasons was the absence of a scientific consensus on both the level of vitamin D status that should be judged “deficient” and what the measurable manifestations of deficiency might be. These are also issues for many other nutrients, such as folate, ascorbate, calcium, and protein. Vitamin D may have seemed to offer a way out of this confusion because serum 25-hydroxyvitamin D [25-(OH)D] concentration is generally recognized as one of the best indices of status for any of a broad array of nutrients. Also, it is now readily measurable and widely utilized.One of the reasons its promise has not been realized is that most studies of vitamin D efficacy have used a disease-avoidance model, which is the standard approach used by the Institute of Medicine (IOM) for most nutrients (2). Furthermore, disease prevention is the explicit focus of the USPSTF. Nevertheless, the IOM and USPSTF approaches effectively equate health with the absence of disease, an equivalence that nutritionists have long rejected. Instead, nutritionists focus on full nutrient repletion when possible. The inevitable gap between disease prevention and nutrient repletion is still largely unexplored territory. For many nutrients, it can be surprisingly wide, as suggested in this case by studies of the intake required to provide vitamin D in human breast milk in quantities sufficient to meet the needs of infants (3). The IOM's adult requirement for vitamin D is 600 IU/d (4), which is judged to be sufficient to protect against osteoporotic fracture. In contrast, quantitative and empirical evidence indicates that vitamin D intake from breastfeeding needs to be approximately 6000 IU/d (3, 5). Although high compared with the adult recommendation, such an intake almost exactly reproduces the measured vitamin D status of contemporary Africans leading ancestral lifestyles (6). Such populations provide perhaps our best window on vitamin D levels prevailing during the millennia over which human physiology was adapted to its environment by natural selection.Whatever the actual requirement or 25-(OH)D cutoff may be, there is another likely reason that the evidence is unclear. The USPSTF drew from systematic reviews and meta-analyses of studies of vitamin D effects, such as the one accompanying the current report (7). In general, the criteria for including studies in such reviews are methodological rather than biological. Of the 6 published biological criteria (8) for including published reports in meta-analyses, the review published in this issue met only 2 (comparable basal status and same chemical form), and several of its component studies met none. Including studies that could never have been informative in the first place (especially when they are large) inevitably biases any review toward the null.What seems not to have been widely appreciated is that vitamin D exhibits flat response regions at both low and high values of vitamin D status, with a sharp rise in the approximate center of the physiologic range of 25-(OH)D values (8). Studies like the WHI (Women's Health Initiative), which enrolled women with low vitamin D status values and used a vitamin D dose insufficient to move them into the response range, provide little useful information about vitamin D efficacy. Yet, precisely such studies were included in the review by LeBlanc and colleagues (7). This is not to criticize the WHI, which was designed more than 20 years ago (before vitamin D pharmacology was well-understood), but it is to criticize contemporary reviews and meta-analyses that fail to take advantage of newer information or to use critical biological criteria (8) for selection of studies for analysis of biological effects.In addition, a disease-avoidance approach becomes problematic for micronutrients in general (and vitamin D in particular) when one understands that micronutrients do not actually cause any of the effects simplistically attributed to them. Although necessary for cell response, such micronutrients by themselves do not initiate or cause the response concerned. For example, vitamin D is a component of the biochemical apparatus that opens the genome to allow access to DNA information needed for a particular cell or tissue response. In terms of cell function, this dependence means that when supplies of the micronutrient are inadequate, cellular response is blunted. This is dysfunction, but not clinically manifest disease. Such dysfunction may indeed lead ultimately to various diseases, but disease prevention remains a dull tool for discerning the defect, and a disease-prevention approach clearly does not measure whether the organism has enough of the nutrient to enable appropriate physiologic responses, such as lactation.Finally, and aside from the USPSTF's findings, one must ask whether treating without first testing is sound practice. Certainly, it would be rational to do so if the condition being treated is prevalent and the treatment is safe and inexpensive. That is the case with another micronutrient, iodine, and the iodination of salt. However, the current situation is different because consuming sufficient iodine generally does not require conscious adherence to a particular regimen, whereas taking vitamin D does. Usually, testing improves patient adherence because it provides patient-specific, personally applicable information. General assurances that one probably needs extra vitamin D are not as compelling a motivator as knowing one's number. Thus, whether the practitioner adheres to the widely divergent guidelines of the IOM (4), the Endocrine Society (9), or the American Geriatrics Society (10), measuring vitamin D status seems to be warranted, not so much to diagnose deficiency but to determine patient status relative to the selected guideline.Robert P. Heaney, MDLaura A.G. Armas, MDCreighton UniversityOmaha, NebraskaReferences1. LeFevre ML; U. S. Preventive Services Task Force. Screening for vitamin D deficiency in adults: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. 2015;162:133-40. doi:10.7326/M14-2450 LinkGoogle Scholar2. Institute of Medicine. Dietary Reference Intakes. The Essential Guide to Nutrient Requirements. Washington, DC: National Academies Pr; 2004. Google Scholar3. 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. [PMID: 24106283] doi:10.1210/jc.2013-2653 CrossrefMedlineGoogle Scholar4. Institute of Medicine. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: National Academies Pr; 2011. Google Scholar5. Heaney RP, Armas LAG. Quantifying the vitamin D economy. Nutr Rev. 2014;:. Google Scholar6. 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. [PMID: 22264449] doi:10.1017/S0007114511007161 CrossrefMedlineGoogle Scholar7. LeBlanc ES, Zakher B, Daeges M, Pappas M, Chou R. Screening for vitamin D deficiency: a systematic review for the U.S. Preventive Services Task Force. Ann Intern Med. 2015;162:109-22. doi:10.7326/M14-1659 LinkGoogle Scholar8. Heaney RP. Guidelines for optimizing design and analysis of clinical studies of nutrient effects. Nutr Rev. 2014;72:48-54. [PMID: 24330136] doi:10.1111/nure.12090 CrossrefMedlineGoogle Scholar9. Holick MF, Binkley NC, Bischoff-Ferrari HA, Gordon CM, Hanley DA, Heaney RP, et al. Guidelines for preventing and treating vitamin D deficiency and insufficiency revisited. J Clin Endocrinol Metab. 2012;97:1153-8. [PMID: 22442274] doi:10.1210/jc.2011-2601 CrossrefMedlineGoogle Scholar10. American Geriatrics Society Workgroup on Vitamin D Supplementation for Older Adults. Recommendations abstracted from the American Geriatrics Society Consensus Statement on Vitamin D for Prevention of Falls and Their Consequences. J Am Geriatr Soc. 2014;62:147-52. [PMID: 24350602] doi:10.1111/jgs.12631 CrossrefMedlineGoogle Scholar Comments0 CommentsSign In to Submit A Comment Robert P. Heaney, MDCreighton University20 March 2015 Author's Response 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. Arthur B. Chausmer, MD, PhDJohns Hopkins18 February 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. Author, Article, and Disclosure InformationAffiliations: From Creighton University, Omaha, NebraskaDisclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M14-2573.Corresponding Author: 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.This article was published online first at www.annals.org on 25 November 2014. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetailsSee AlsoScreening for Vitamin D Deficiency: A Systematic Review for the U.S. Preventive Services Task Force Erin S. LeBlanc , Bernadette Zakher , Monica Daeges , Miranda Pappas , and Roger Chou Screening for Vitamin D Deficiency in Adults: U.S. Preventive Services Task Force Recommendation Statement Michael L. LeFevre and Screening for Vitamin D Deficiency in Adults: U.S. Preventive Services Task Force Recommendation Statement Michael L. LeFevre and Screening for Vitamin D Deficiency: A Systematic Review for the U.S. Preventive Services Task Force Erin S. LeBlanc , Bernadette Zakher , Monica Daeges , Miranda Pappas , and Roger Chou Screening for Vitamin D Deficiency: Is the Goal Disease Prevention or Full Nutrient Repletion? Robert P. Heaney Screening for Vitamin D Deficiency: Is the Goal Disease Prevention or Full Nutrient Repletion? Arthur B. Chausmer Metrics Cited BySunlight in Vitamin D Deficiency: Clinical ImplicationsCan vitamin D deficiency influence muscle performance in postmenopausal women? 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LeBlanc, MD, MPH, Roger Chou, MD, and Miranda Pappas, MAScreening for Vitamin D Deficiency: Is the Goal Disease Prevention or Full Nutrient Repletion?Arthur B. Chausmer, MD, PhD 20 January 2015Volume 162, Issue 2Page: 144-145KeywordsDisclosureNutrientsNutritionProteinsSaltsSystematic reviewsVitamin DVitamin D deficiency ePublished: 20 January 2015 Issue Published: 20 January 2015 CopyrightCopyright © 2015 by American College of Physicians. All Rights Reserved.PDF DownloadLoading ...