Progressnotes - October/November 2012
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Swathed in modern-day comfort as part of a primarily indoor culture, we tend to think with disdain or at least a sense of superiority about our primitive ancestors, who were forced to hunt or labor many hours outside each day. But the joke may be on us. Our primitive ancestors could manufacture enough vitamin D from sun exposure alone, whereas we are short on sunshine and, studies are beginning to show, often deficient in vitamin D. Score one for primitive man.
It is well established that vitamin D is necessary for the maintenance of calcium homeostasis and that deficiency can lead to rickets in children and osteomalacia (softening of the bones) and osteoporosis in adults.¹ In recent years, vitamin D deficiency has been linked to a host of chronic conditions, including obesity,² heart disease,³,⁴ diabetes,⁵ and autoimmune diseases⁶; increased mortality from cancer and other causes⁴; and development of dementia and other neurologic or psychiatric diseases or conditions.⁷ According to Bruce Hollis, PhD, a noted vitamin D researcher and Professor in the Department of Pediatrics at MUSC Children’s Hospital, “One of the most important things in human health is to be vitamin D sufficient because it is implicated in more diseases than any other individual component that I know of. The implications for disease are so broad because receptors for vitamin D are everywhere in the body.” Because receptors are particularly abundant in the brain, vitamin D is thought to be crucial to proper brain development.⁷
Although a few foods are rich in vitamin D, including shitake mushrooms, sockeye salmon, mackerel, sardines, and cod liver oil, it is difficult to obtain adequate vitamin D through diet alone. Fortification of milk and other foods was necessary to bolster vitamin D levels and to ward off the threat of rickets in children. Despite these efforts at fortification, a recent study of national populations found that 75% of Americans, British, and Germans were not meeting the daily reference intake (DRI) specified by national guidelines.⁸ Vitamin D supplements, inexpensive and readily available over the counter, may be the easiest way to address such deficiencies.
Vitamin D is produced when ultraviolet B light reacts with 7-dehydrocholesterol in the skin to produce pre-vitamin D₃. Whether produced in this way or derived from food or a supplement, this previtamin must be metabolized into 25(OH)D₃ (25-hydroxyvitamin) in the liver and finally to 1α25(OH)₂D₃ (1,25-dihydroxyvitamin D) in the kidneys before it becomes biologically available (Figure). The half-life of 25(OH)D₃ is two to three weeks, much longer than for 1α25(OH)₂D₃, making it the preferred measure of vitamin D sufficiency. Levels of 1α25(OH)₂D are not reliable indicators of vitamin D sufficiency because they may be elevated even in those with a deficiency.
Estimates of the prevalence of vitamin D deficiency vary greatly depending on how “deficiency” and “sufficiency” are defined. Indeed, in its 2011 report setting DRI for vitamin D, the Institute of Medicine (IOM) expressed concern that the prevalence of vitamin D deficiency is overestimated because the cutoff points for deficiency are set too high.⁹ Basing its reference values solely on the role of vitamin D in skeletal health, which is supported by data from randomized controlled trials (RCT), and expressly excluding consideration of nonskeletal effects for which only observational evidence exists, the IOM defined deficiency as less than 30 nmol/L and sufficiency as 50 nmol/L. In clinical guidelines published after the release of the IOM report, the Endocrine Society set the bar considerably higher for 25(OH)D levels, defining deficiency as less than 50 nmol/L and sufficiency as 52.5 to 72.5 nmol/L¹⁰ (for more information, see Table 1). Many vitamin D researchers think a value of 75 nmol/L may be required for the potential nonskeletal benefits of vitamin D. Unlike the IOM, which set the upper limit (UL) for vitamin D intake as 4,000 IU/d (up from 2,000 IU/d in its 1997 report), the Endocrine Society established a UL of 10,000 IU/d. Vitamin D researchers consider such a dosage safe because the body itself can easily manufacture that much vitamin D if exposed to the sun for several hours.
The differences in the recommendations for DRI result from the IOM’s refusal to consider data not obtained in RCT vs the Endocrine Society’s willingness to consider evidence from observational studies for the nonskeletal consequences of vitamin D deficiency. Barriers to RCT of vitamin D’s nonskeletal benefits include extremely tight funding from the National Institutes of Heath, especially for expensive clinical projects; lack of interest by pharmaceutical companies in supporting such research because there is little room for profit; and what vitamin D researchers consider to be unfounded fears over vitamin D toxicity that makes it difficult to obtain permission to run clinical trials using the dosages necessary to produce a nonskeletal effect. The Vitamin D and Omega-3 Trial (VITAL; NCT01169259), a large RCT (N=20,000) led by one of the authors of the IOM report, seeks to determine whether taking a 2,000 IU/d dose of vitamin D (or fish oil) will reduce the risk of heart disease, cancer, and stroke in those with no history of these conditions and could perhaps provide data that would lead to greater consensus. However, vitamin D advocates have questioned whether nonskeletal benefits will be seen with a dose as low as 2,000 IU/d.
TABLE 1. Recent Guidelines on Daily Reference Intake (DRI) of Vitamin D and Treatment of Vitamin D Deficiency
Deficiency, nmol/L of 25(OH)D
Sufficiency, nmol/L of 25(OH)D
DRI (age, <1 y)
DRI (age, 1-69 y)
DRI (age, ≥70 y)
Institute of Medicine
50 for virtually everyone
To achieve skeletal effects
1,200–1,800 IU/d for high-risk patients (eg, obese)
To achieve potential (not yet proven) nonskeletal benefits
1–18 y, 1,000 IU/d
To treat a
2,000 IU/d or 50,000 IU/wk for 6 wk; maintain on 400–1,000 IU/d
Obese adults, 6,000–10,000 IU/d; maintain on 3,000–6,000 IU/d
6,000 IU/d or 50,000 IU/wk for 8 wk; maintain on 1,500-2,000 IU/d
Among the populations most at risk for vitamin deficiency are African Americans and Hispanics,¹¹ who do not produce vitamin D as effectively because of the melanin in their skin; the obese (BMI >30),¹¹ because vitamin D is a fat-soluble vitamin and can be stored in fat, reducing the amount of circulating vitamin D available for the body’s needs; and patients taking certain anticonvulsive and antifungal medications (Table 2). Also at risk are exclusively breastfed infants, because they do not ingest any products fortified in vitamin D.
TABLE 2. When to Screen for Vitamin D Deficiency
African-American and Hispanic children and adults
Obese children and adults (BMI ≥30 kg/m2)
Pregnant and lactating women
Older adults with history of falls or nontraumatic fractures
Chronic kidney disease
Antifungals (eg, ketoconazole)
Observational studies have suggested an association between low 25(OH)D levels and lower birth weights, higher rates of preterm delivery, as well as preeclampsia, which can have implications for the health of both the mother (increased lifetime risk of chronic hypertension, ischemic heart disease, and stroke) and the child (increased risk of stroke, coronary heart disease, and metabolic syndrome as adults).¹²,¹³ Despite this research, the IOM, citing inconsistent results, chose not to vary its DRI for either pregnant or lactating women and stated that the recommended 600 IU/d could be obtained by diet alone. However, a recent meta-analysis confirms that vitamin D deficiency is widespread among pregnant women and breastfed infants despite the mothers consistently taking the standard prenatal vitamins and eating a diet that included vitamin D–rich foods.¹⁴ Concern is highest for at-risk populations like women of color and the obese.
Many physicians may hesitate to advise adequate supplementation with vitamin D because they associate it with toxicity, especially in the context of pregnancy, because of a series of cases of hypercalcemia leading to facial and other deformities that occurred after milk and other food sources were fortified with vitamin D to prevent rickets.¹⁵ Those children have since been identified as having a genetic disorder (Williams syndrome),¹⁵ one of the symptoms of which is trouble metabolizing vitamin D. Although it had in no way caused this syndrome, which is in fact a genetic disorder, vitamin D became branded as toxic to the developing fetus, a prejudice that remains common among clinicians today. In the eyes of many vitamin D researchers, this prejudice has led to reluctance by clinicians to recommend levels of vitamin D necessary for sufficiency as well as to artificially low ULs for vitamin D (ie, the 2,000 IU/d UL set by the 1997 IOM report) that have hampered vitamin D research.
In a study (Clinical Trials Identifier: NCT00292591) conducted at the Medical University of South Carolina from January 4, 2004, through July 31, 2009, the results of which were published after the release of the IOM report, 502 pregnant South Carolinian women were randomized to receive 400 IU, the DRI recommended by the IOM at study initiation in 2004 (n=111), 2,000 IU (n=122), or 4,000 IU (n=117) of vitamin D₃.¹⁶ According to that study, 50% of the total cohort of women receiving 400 IU/d (very near the current IOM DRI recommendation of 600 IU/d) and more than 80% of black women receiving that dosage did not achieve sufficiency, even using the conservative IOM definition (50 nmol/L).
Of interest, though one of the study doses (4,000 IU/d) was twice that of the UL set by the IOM in its 1997 report and the same as the UL set in its most recent report, no adverse effects of any type were reported. One woman, although asymptomatic, was removed from the study when her 25(OH)D levels neared 225 nmol/L, the level set by the institutional review board as indicating a risk of hypervitaminosis D. Because participants did not enter the study until at least their twelfth week of pregnancy, the study can make no claims about the safety of vitamin D in the first weeks of pregnancy.
Other findings of note were that 25(OH)D levels of at least 80 nmol/L are necessary to achieve 50 nmol/L, the IOM definition of sufficiency, in the cord blood that supplies the fetus. Levels of 25(OH)D in the cord blood met IOM criteria for sufficiency in 31 (39.7%) of 76 neonates in the 400-IU group, 53 (58.2%) of 91 in the 2,000-IU group, and 66 (78.6%) of 84 in the 4,000-IU group (P<.001). The study also confirmed that pregnant women have far higher levels of 1α25(OH)₂D (as high as 700 pmol/L) than men or nonpregnant women, and that they show no adverse consequences due to these levels. It is thought that these higher levels help promote innate immunity, though the mechanism is not well understood. Whereas production of 1α25(OH)₂D in men and nonpregnant women is regulated by a parathyroid hormone feedback loop, in pregnancy it seems to depend instead on the amount of 25(OH)D available, meaning that it is essential to ensure a robust substrate of 25(OH)D from which the biologically active 1α25(OH)₂D can be derived. On the basis of these findings, the principal investigators of this RCT concluded that the requirements of both mothers and neonates of all races are best met with a DRI of 4,000 IU. This dose is not yet endorsed by any guideline.
The medical community has done much in recent years to tout the benefits of breastfeeding. Not only does breast milk strengthen the immunity of the nursing child, it serves as a near-perfect form of nutrition, lacking only in vitamin D. Many physicians continue to believe (erroneously) that vitamin D cannot be transmitted from the mother to the nursing child through breast milk.
Because they consume no fortified milk products, exclusively breastfed babies are at high risk of vitamin D deficiency. To prevent such deficiency, the American Academy of Pediatricians recommends that they be supplemented with 400 IU/d of vitamin D, delivered via liquid drops. Unfortunately, not all breastfeeding mothers adhere to this directive, some because they are not informed about it by their pediatricians. As a result, some infants develop rickets or fractures that can be misinterpreted as child abuse or even result in the death of the child. “I receive several calls a year from mothers who have lost their child due to this,” notes Dr. Hollis, “and it is devastating.”
The drops can also be difficult to administer, discouraging adherence. In 2010, The US Food and Drug Administration (FDA) expressed concern that excessive vitamin D could inadvertently be administered because some of the droppers used to administer these drops held much more than 400 IU/d or did not clearly enough designate the 400 IU/d dose. The FDA asked the industry to manufacture droppers that did not exceed 400 IU/d for use in infants and advised parents to take great care when administering the drops. Given the problems with adherence and administration associated with supplementing the infant, vitamin D advocates suggest that a far better solution would be to supplement the mother with a dose of vitamin D sufficient to ensure that breast milk is replete.¹⁴,¹⁷
In May 2013, Carol Wagner, M.D., Professor of Pediatrics at MUSC Children’s Hospital, on behalf of research teams at the Medical University of South Carolina and the University of Rochester, will present data from a lactation trial that was conducted to determine whether adequate supplementation of the mother could ensure sufficient levels of vitamin D in the nursing infant. The study randomized 476 mother/infant dyads into three vitamin D treatment groups: 400 IU (mother)/400 IU (infant) (n=206), 2,400 IU/placebo (n=71), or 6,400 IU/placebo (n=199).¹⁷ The study found that 25(OH)D levels differed significantly among women in the three treatment groups but that those of the infants did not, meaning that infants in all three groups attained adequate levels of 25(OH)D and that maternal supplementation was at least as effective as infant supplementation in preventing deficiency.
Although both 2,400 IU/d and 6,400 IU/d achieved sufficiency in infants in some women, the higher dose ensures that women of color, who may have more severe deficiencies, also attain 25(OH)D levels sufficient to render their breast milk replete. No adverse events were reported for any of the treatment groups, even those with women receiving the higher doses of vitamin D. Although levels as high as 6,000 to 7,000 IU/d are not yet recommended by any guideline for lactating women, these results could serve to inform future guidelines on how to address or prevent vitamin D deficiency or insufficiency in the exclusively breastfed child.
Dr. Wagner, a principal investigator on both the pregnancy and lactation trials, puts these studies’ findings into perspective: “We are not suggesting that people take pharmacological doses of vitamin D but rather that, unless they are able to obtain the levels they would get by being out in the sun for five to nine hours a day, they need to take a supplement. It is really important to understand the purpose of vitamin D beyond calcium and bone health—the role of vitamin D in immune function and therefore its role in general health not only during childhood but throughout the lifespan.”
¹ Chung M, Balk EM, Brendel M, et al. Vitamin D and calcium: a systematic review of health outcomes. Evidence Report No. 183. (Prepared by the Tufts Evidence-based Practice Center under Contract No. HHSA 290-2007-10055-I.) AHRQ Publication No. 09-E015. 1999. Rockville, MD: Agency for Healthcare Research and Quality.
² González-Molero I, Rojo-Martínez G, Morcillo S, et al. Hypovitaminosis D and incidence of obesity: a prospective study. Eur J Clin Nutr 2013 Feb 20. Available at http://dx.doi.org/10.1038/ejcn.2013.48. [Epub ahead of print]
³ Pourdjabbar A, Dwivedi G, Haddad H. The role of vitamin D in chronic heart failure.Curr Opin Cardiol 2013 Jan;28(2):216-22. Available at http://dx.doi.org/10.1097/HCO.0b013e32835bd480.
⁴ Schöttker B, Haug U, Schomburg L, et al. Strong associations of 25-hydroxyvitamin D concentrations with all-cause, cardiovascular, cancer, and respiratory disease mortality in a large cohort study. Am J Clin Nutr 2013 Feb 27. [Epub ahead of print]
⁵ Takiishi T, Gysemans C, Bouillon R, Mathieu C. Vitamin D and diabetes. Endocrinol Metab Clin North Am 2010 Jun;39(2):419-46.
⁶ Gatenby P, Lucas R, Swaminathan A. Vitamin D deficiency and risk for rheumatic diseases: an update. Curr Opin Rheumatol 2013 Mar;25(2):184-91.
⁷ Deluca GC, Kimball SM, Kolasinski J, et al. The role of vitamin D in nervous system health and disease. Neuropathol Appl Neurobiol 2013 Jan 21. doi: 10.1111/nan.12020. [Epub ahead of print].
⁸ Troesch B, Hoeft B, McBurney M, et al. Dietary surveys indicate vitamin intakes below recommendations are common in representative Western countries. British Journal of Nutrition 2012; 108:692-698. Available at http://dx.doi.org/10.1017/S0007114512001808
⁹ IOM (Institute of Medicine) 2011 dietary reference intakes for calcium and vitamin D. Washington, DC: The National Academies Press. Pdf available at http://www.nap.edu/catalog.php?record id=13050
¹⁰ Holick MF, Binkley NC, Bischoff-Ferrari HA, et al. Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2011;96(7):1911-1930.
¹¹ Freedman DM, Cahoon EK, Rajaraman P, et al. Sunlight and other determinants of circulating 25-hydroxyvitamin D levels in black and white participants in a nationwide U.S. study. Am J Epidemiol. 2013;177(2):180-92. Available at http://dx.doi.org/10.1093/aje/kws223. Epub 2013 Jan 4.
¹³ Hollis BW, Wagner, CL. Vitamin D and pregnancy: skeletal effects, nonskeletal effects, and birth outcomes. Calcif Tissue Int 2013; 92(2):128-139. Available at http://dx.doi.org/10.1007/s00223-012-9607-4.
¹⁴ Thiele DK, Senti JL, Anderson CM. Maternal vitamin D supplementation to meet the needs of the breastfed infant: a systematic review. J Hum Lact 2013 Mar 4. [Epub ahead of print]. Available at http://dx.doi.org/10.1177/0890334413477916
¹⁵ Burn J. Syndrome of the month: Williams syndrome. Journal of Medical Genetics 1986; 23:389-395.
¹⁶ Hollis BW, Johnson D, Hulsey TC, et al. Vitamin D supplementation during pregnancy: double-blind, randomized clinical trial of safety and effectiveness. Journal of Bone and Mineral Research 2011;26(10):2341–2357. Available at http://dx.doi.org/10.1002/jbmr.463
¹⁷ Wagner CL. Results of NICHD two-site maternal vitamin D supplementation randomized controlled trial during lactation. Abstract presented at Pediatric Academic Societies Annual Meeting (May 2013); Washington, DC.