S P E C I A L
F E A T U R E E d i t o r i a l
Here Comes the Sun—Is Vitamin D a Cure For All That Ails Us? Sheela N. Magge Division of Endocrinology and Diabetes, Children’s National Health Systems, George Washington University School of Medicine and Health Sciences, Washington, DC 20010
D
eficiency of 25-hydroxyvitamin D (25[OH]D) has received a great deal of attention in the past several years for its potential nontraditional effects, outside of the skeleton. Vitamin D deficiency has been touted to be associated with increased risk of everything from cancer (1), to diabetes (2) and cardiovascular disease (CVD) (3), and even overall mortality (4). In this issue of the JCEM, Juonala et al (5) address the relationship between vitamin D deficiency and CVD. 25[OH]D deficiency has been associated with incident CVD in multiple adult studies (3, 6), but a large meta-analysis of randomized clinical trials of vitamin D supplementation did not show beneficial effects on stroke or myocardial infarction (7). Juonala et al (5) attempt to determine whether vitamin D deficiency during youth predisposes to increased CVD risk as an adult. The effects of vitamin D in the body are widespread. 25[OH]D represents overall vitamin D stores, but calcitriol or 1,25-dihydroxyvitamin D (1,25[OH]2D) is the biologically active form of vitamin D. PTH stimulates the hydroxylation of 25[OH]D to 1,25[OH]2D in the kidneys. Calcitriol has multiple biological effects, and vitamin D response elements have been found in the promoters of numerous genes. In fact, a recent genome-wide array study showed that vitamin D supplementation affected gene expression in more than 160 biological pathways (8). Furthermore, calcitriol can have both paracrine and autocrine actions, and the latter may relate to its nontraditional effects. Not only do most cells in the human body express vitamin D receptor, most also express the enzyme necessary to convert 25[OH]D to 1,25[OH]2D (9, 10). Thus, in response to an external signal, 25[OH]D might be triggered for intracellular conversion to 1,25[OH]2D, exerting a local action unrelated to PTH levels. If substantiated,
this would allow for 25[OH]D to bring about tissue-specific effects. Pathophysiological mechanisms corroborate the plausibility of a relationship between mineral metabolism and CVD. Vitamin D receptors are present on many different tissue types, including myocardium, endothelium, and vascular smooth muscle (11). In humans, 1,25[OH]2D inhibits renin synthesis; thus, its deficiency could contribute to hypertension (12). In addition, vitamin D deficiency leads to hypertrophy of vascular and left ventricular smooth muscle cells (13). Increased PTH, resulting from chronic vitamin D deficiency, is associated with increased blood pressure and myocardial contractility, which can lead to hypertrophy, apoptosis, and fibrosis in the vascular smooth muscle and left ventricle (11, 13). Decreased 25[OH]D and increased PTH both increase inflammation, as evidenced by increased C-reactive protein and IL-10, (13) and increase the risk of CVD events (14). 25[OH]D deficiency has been associated with increased insulin resistance and pancreatic -cell dysfunction as well (15). However, one source of confusion for many clinicians is that scientists cannot agree on what a “normal” 25[OH]D is. Although the Institute of Medicine (16) and the Pediatric Endocrine Society (17) define 25[OH]D sufficiency as a level ⬎ 20 ng/mL (50 nmol/L), others such as The Endocrine Society consider 25[OH]D sufficiency to be levels ⱖ 30 ng/mL (75 nmol/L), insufficiency to be values of 20 –29 ng/mL (50 –72.4 nmol/L), and deficiency to be ⬍ 20 ng/mL (18). These different definitions could be due to the fact that optimal cutoffs for 25[OH]D may vary depending on the associated outcome. For example, the optimal level for bone health may differ from the level associated with decreased CVD risk. Studies have at-
ISSN Print 0021-972X ISSN Online 1945-7197 Printed in U.S.A. Copyright © 2015 by the Endocrine Society Received February 10, 2015. Accepted February 23, 2015.
Abbreviations: CIMT, carotid intima-media thickness; CVD, cardiovascular disease; 1,25[OH]2D, 1,25-dihydroxyvitamin D; 25[OH]D, 25-hydroxyvitamin D; VDBP, vitamin D binding protein.
For related articles see pages 1469
doi: 10.1210/jc.2015-1396
J Clin Endocrinol Metab, April 2015, 100(4):1237–1240
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tempted to define the optimal 25[OH]D level for skeletal effects as the level below which PTH rises. Previous adult studies found this to occur at 25[OH]D ⬍ 75 nmol/L (19, 20). However, a more recent study in children found a significantly lower 25[OH]D corresponding to PTH elevation (21), whereas another study did not find an inflection point for 25[OH]D for maximal PTH suppression in children (22). Valcour et al (23) found that the level varied with age and that levels of 25[OH]D required to suppress PTH increase with age. However, there is also evidence that 25[OH]D ⬎ 56 ng/mL (140 nmol/L) is associated with increased mortality, suggesting a possible reverse Jshaped relationship between mortality and 25[OH]D (24). Thus, the optimal 25[OH]D level is highly controversial, and likely differs depending on the outcome examined. Interest in potential vitamin D effects on cardiometabolic outcomes has also peaked in the pediatric community. Because of the need for endpoint surrogate markers in children for conditions such as diabetes and CVD events, outcomes such as insulin resistance and inflammatory markers have been used. Results have been mixed, with some studies showing increased 25[OH]D associated with decreased insulin resistance and improved CVD risk factors in children (25, 26), whereas other studies have not (27). One of the strengths of the current study by Juonala et al (5) is its design. It is longitudinal, using the cohort from the Cardiovascular Risk in Young Finns Study (28) to look at the association between 25[OH]D levels in children, ages 3–18 years in 1980, and carotid intima-media thickness (CIMT) as an adult, 27 years later in 2007. Of note, this Finnish cohort would be at increased risk for low 25[OH]D levels, given Finland’s high latitude and decreased sun exposure. CIMT is an established surrogate marker of atherosclerosis and CVD, and studies of the association between 25[OH]D as an adult and CIMT have had conflicting results (29, 30), with some evidence of sexspecific relationships (31). This new Finnish study provides insight into the potential long-term CVD implications of vitamin D deficiency during childhood. The study by Juonala et al (5) is significant in the size of the cohort and in the attempt to establish a connection between a childhood state and an adult health risk. The authors found that when analyzed as a continuous variable in analyses adjusted for relevant confounding variables, childhood 25[OH]D was inversely related to adult CIMT in females but not males. However, in both sexes, those with the lowest quartile of 25[OH]D (⬍40 nmol/L or 16 ng/mL) as children had significantly increased odds (odds ratio ⫽ 1.7) of having high-risk CIMT (highest decile of common carotid or carotid bulb intima-media
J Clin Endocrinol Metab, April 2015, 100(4):1237–1240
thickness, or carotid plaque) as an adult. This is an impressive finding that seems to lend credence to the many providers screening and treating patients with supplemental vitamin D. Interestingly, after adjusting for age and sex, there was not a significant relationship between adult 25[OH]D and adult CIMT, suggesting that the timing of vitamin D supplementation may be important. Vitamin D (25[OH]D) screening by clinical providers has increased as awareness of the high prevalence of vitamin D deficiency, particularly among Blacks and obese patients, has increased. The adult prevalence of vitamin D deficiency (as defined by 25[OH]D ⬍ 20 ng/mL or 50 nmol/L) has been estimated at 42%, with a prevalence of 31% in Whites and 82% in Blacks (32). Among overweight and obese adults, 38% and 54% are deficient, respectively (32). Among adolescents (12–19 y old), 14% are deficient overall, with 50% of Black adolescents being deficient, and with increased deficiency in overweight and obese adolescents (33). Because of increased skin melanin content, individuals of African descent are at increased risk for 25[OH]D levels ⬍ 20 ng/mL (50 nmol/L). Explanations for the etiology of low 25[OH]D levels in obese individuals have included possible sequestration of 25[OH]D in adipose tissue (34), as well as potential volumetric dilution of 25[OH]D due to large body size (35). Typical vitamin D treatment guidelines may not apply to those at high risk for deficiency, such as the obese, who may require up to three times the traditional treatment doses (36). As Juonala et al (5) themselves point out, one of the major limitations of this study is that the cohort was purely White, making their results not generalizable beyond the White population. In studies of more racially diverse cohorts, further questions arise. Powe et al (37) reported results from the Healthy Aging in Neighborhoods of Diversity across the Life Span study, which included a large cohort of both Black and White Americans. They measured 25[OH]D as well as vitamin D binding protein (VDBP), the main carrier protein for vitamin D. Common genetic polymorphisms in the VDBP gene produce variants with different binding affinities for vitamin D. The investigators found that Blacks have a higher prevalence of a VDBP polymorphism associated with low levels of VDBP. Blacks had decreased levels of both 25[OH]D and VDBP compared to Whites, resulting in equivalent bioavailable vitamin D levels. Low 25[OH]D may be irrelevant if bioavailable vitamin D is normal. Interestingly, some clinical patients with severe vitamin D deficiency have normal PTH. Whether this could be because of a normal bioavailable vitamin D is not known. The study by Powe et al (37) emphasizes the importance of measuring free or bioavailable vitamin D, as opposed to only
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doi: 10.1210/jc.2015-1396
25[OH]D. The form of vitamin D measured may also be one reason for inconsistencies in the outcomes of previous studies. Although 25[OH]D is the preferred form for uptake in the renal proximal tubules and may be representative of skeletal effects, free or bioavailable vitamin D levels act in other cells to produce nontraditional actions. Thus, measuring the biologically active free form is quite important. Moreover, some studies have shown differential relationships between 25[OH]D and CVD by race. RobinsonCohen et al (38) found that lower 25[OH]D levels were associated with increased incident coronary heart disease in White and Chinese subjects, but not in Black or Hispanic subjects. Another study in adolescent females found that, contrary to the investigators’ a priori hypothesis, total, free, and bioavailable vitamin D was positively associated with the females’ augmentation index (a surrogate measure of arterial stiffness), but specifically in Black females (39). Most of these studies use VDBP and standardized equations to calculate bioavailable vitamin D (37), which also require genetic polymorphism data; therefore, these equations are not feasible in clinical care. Cost-effective direct bioavailable vitamin D measurement techniques are needed. The scientific literature to date leaves us with many unanswered questions. Is vitamin D deficiency truly related to increased CVD, and if so, is this relationship sexand/or race-specific? Can we reverse this effect by vitamin D treatment? Does the timing of treatment, ie, during childhood vs adulthood, impact CVD outcomes? What measure of vitamin D should be treated? Perhaps the safest clinical course from a CVD point of view, in light of the current study, is to keep 25[OH]D between 20 ng/mL (50 nmol/L) and 50 ng/dL (140 nmol/L), a reasonable range given that 25[OH]D levels ⬍ 40 nmol/L were associated with high-risk CIMT in adults, and taking into consideration the association between increased mortality with higher 25[OH]D levels mentioned earlier (24). However, it should be noted that a recent report by the US Preventative Task Force did not find sufficient evidence either for or against routine 25[OH]D screening in adults (40). Further studies are clearly needed. Specifically, we need longitudinal randomized clinical treatment trials of vitamin D deficiency, including measures of 25[OH]D, PTH, and free and bioavailable vitamin D, in both sexes and in racially diverse populations. Such studies will be long, large, and costly, but they are necessary if we are to know whether treatment of “vitamin D deficiency” actually confers a long-term benefit to health, and in whom.
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Acknowledgments Address all correspondence and requests for reprints to: Dr Sheela Natesh Magge, MD, MSCE, Associate Professor of Pediatrics, Division of Endocrinology and Diabetes, Children’s National Health Systems, George Washington University School of Medicine and Health Sciences, 111 Michigan Avenue NW, CTS Suite, M7659 CRI-6, 6th Floor Main, Washington, DC 20010 – 2916. E-mail: [email protected]. Disclosure Summary: The author has nothing to declare.
References 1. Garland CF, Gorham ED, Mohr SB, et al. Vitamin D and prevention of breast cancer: pooled analysis. J Steroid Biochem Mol Biol. 2007; 103:708 –711. 2. Pittas AG, Dawson-Hughes B, Li T, et al. Vitamin D and calcium intake in relation to type 2 diabetes in women. Diabetes Care. 2006; 29:650 – 656. 3. Wang TJ, Pencina MJ, Booth SL, et al. Vitamin D deficiency and risk of cardiovascular disease. Circulation. 2008;117:503–511. 4. Autier P, Gandini S. Vitamin D supplementation and total mortality: a meta-analysis of randomized controlled trials. Arch Intern Med. 2007;167:1730 –1737. 5. Juonala M, Voipio A, Pahkala K, et al. Childhood 25-OH vitamin D levels and carotid intima-media thickness in adulthood. The Cardiovascular Risk in Young Finns Study. J Clin Endocrinol Metab. 2015;100:1469-1476 6. Giovannucci E, Liu Y, Hollis BW, Rimm EB. 25-Hydroxyvitamin D and risk of myocardial infarction in men: a prospective study. Arch Intern Med. 2008;168:1174 –1180. 7. Elamin MB, Abu Elnour NO, Elamin KB, et al. Vitamin D and cardiovascular outcomes: a systematic review and meta-analysis. J Clin Endocrinol Metab. 2011;96:1931–1942. 8. Hossein-nezhad A, Spira A, Holick MF. Influence of vitamin D status and vitamin D3 supplementation on genome wide expression of white blood cells: a randomized double-blind clinical trial. PloS One. 2013;8:e58725. 9. Schwartz GG, Whitlatch LW, Chen TC, Lokeshwar BL, Holick MF. Human prostate cells synthesize 1,25-dihydroxyvitamin D3 from 25-hydroxyvitamin D3. Cancer Epidemiol Biomarkers Prev. 1998; 7:391–395. 10. Holick MF. Resurrection of vitamin D deficiency and rickets. J Clin Invest. 2006;116:2062–2072. 11. Lee JH, O’Keefe JH, Bell D, Hensrud DD, Holick MF. Vitamin D deficiency an important, common, and easily treatable cardiovascular risk factor? J Am Coll Cardiol. 2008;52:1949 –1956. 12. Li YC. Vitamin D regulation of the renin-angiotensin system. J Cell Biochem. 2003;88:327–331. 13. Zittermann A. Vitamin D and disease prevention with special reference to cardiovascular disease. Prog Biophys Mol Biol. 2006;92: 39 – 48. 14. Ogard CG, Engelmann MD, Kistorp C, Nielsen SL, Vestergaard H. Increased plasma N-terminal pro-B-type natriuretic peptide and markers of inflammation related to atherosclerosis in patients with primary hyperparathyroidism. Clin Endocrinol (Oxf). 2005;63: 493– 498. 15. Chiu KC, Chu A, Go VL, Saad MF. Hypovitaminosis D is associated with insulin resistance and  cell dysfunction. Am J Clin Nutr. 2004; 79:820 – 825. 16. Ross AC, Taylor CL, Yaktine AL, Del Valle HB. Dietary Reference Intakes for Calcium and Vitamin D. Food and Nutrition Board. Institute of Medicine. Washington, DC: The National Academies Press; 2011.
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17. Misra M, Pacaud D, Petryk A, Collett-Solberg PF, Kappy M. Vitamin D deficiency in children and its management: review of current knowledge and recommendations. Pediatrics. 2008;122:398 – 417. 18. 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; 96:1911–1930. 19. Thomas MK, Lloyd-Jones DM, Thadhani RI, et al. Hypovitaminosis D in medical inpatients. N Engl J Med. 1998;338:777–783. 20. Chapuy MC, Preziosi P, Maamer M, et al. Prevalence of vitamin D insufficiency in an adult normal population. Osteoporos Int. 1997; 7:439 – 443. 21. Atapattu N, Shaw N, Högler W. Relationship between serum 25hydroxyvitamin D and parathyroid hormone in the search for a biochemical definition of vitamin D deficiency in children. Pediatr Res. 2013;74:552–556. 22. Hill KM, McCabe GP, McCabe LD, Gordon CM, Abrams SA, Weaver CM. An inflection point of serum 25-hydroxyvitamin D for maximal suppression of parathyroid hormone is not evident from multi-site pooled data in children and adolescents. J Nutr. 2010; 140:1983–1988. 23. Valcour A, Blocki F, Hawkins DM, Rao SD. Effects of age and serum 25-OH-vitamin D on serum parathyroid hormone levels. J Clin Endocrinol Metab. 2012;97:3989 –3995. 24. Durup D, Jørgensen HL, Christensen J, Schwarz P, Heegaard AM, Lind B. A reverse J-shaped association of all-cause mortality with serum 25-hydroxyvitamin D in general practice: the CopD study. J Clin Endocrinol Metab. 2012;97:2644 –2652. 25. Walker GE, Ricotti R, Roccio M, et al. Pediatric obesity and vitamin D deficiency: a proteomic approach identifies multimeric adiponectin as a key link between these conditions. PloS One. 2014;9: e83685. 26. Belenchia AM, Tosh AK, Hillman LS, Peterson CA. Correcting vitamin D insufficiency improves insulin sensitivity in obese adolescents: a randomized controlled trial. Am J Clin Nutr. 2013;97:774 – 781. 27. Rajakumar K, de las Heras J, Lee S, Holick MF, Arslanian SA. 25-Hydroxyvitamin D concentrations and in vivo insulin sensitivity and -cell function relative to insulin sensitivity in black and white youth. Diabetes Care. 2012;35:627– 633.
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28. Raitakari OT, Juonala M, Rönnemaa T, et al. Cohort profile: the Cardiovascular Risk in Young Finns study. Int J Epidemiol. 2008; 37:1220 –1226. 29. Blondon M, Sachs M, Hoofnagle AN, et al. 25-Hydroxyvitamin D and parathyroid hormone are not associated with carotid intimamedia thickness or plaque in the multi-ethnic study of atherosclerosis. Arterioscler Thromb Vasc Biol. 2013;33:2639 –2645. 30. Carrelli AL, Walker MD, Lowe H, et al. Vitamin D deficiency is associated with subclinical carotid atherosclerosis: the Northern Manhattan study. Stroke. 2011;42:2240 –2245. 31. Moore A, Hochner H, Sitlani CM, et al. Plasma vitamin D is associated with fasting insulin and homeostatic model assessment of insulin resistance in young adult males, but not females, of the Jerusalem Perinatal Study. Public Health Nutr. 2014;22:1– 8. 32. Forrest KY, Stuhldreher WL. Prevalence and correlates of vitamin D deficiency in US adults. Nutr Res. 2011;31:48 –54. 33. Saintonge S, Bang H, Gerber LM. Implications of a new definition of vitamin D deficiency in a multiracial US adolescent population: the National Health and Nutrition Examination Survey III. Pediatrics. 2009;123:797– 803. 34. Wortsman J, Matsuoka LY, Chen TC, Lu Z, Holick MF. Decreased bioavailability of vitamin D in obesity. Am J Clin Nutr. 2000;72: 690 – 693. 35. Drincic AT, Armas LA, Van Diest EE, Heaney RP. Volumetric dilution, rather than sequestration best explains the low vitamin D status of obesity. Obesity (Silver Spring). 2012;20:1444 –1448. 36. Golden NH, Abrams SA. Optimizing bone health in children and adolescents. Pediatrics. 2014;134:e1229 – e1243. 37. Powe CE, Evans MK, Wenger J, et al. Vitamin D-binding protein and vitamin D status of black Americans and white Americans. N Engl J Med. 2013;369:1991–2000. 38. Robinson-Cohen C, Hoofnagle AN, Ix JH, et al. Racial differences in the association of serum 25-hydroxyvitamin D concentration with coronary heart disease events. JAMA. 2013;310:179 –188. 39. Ashraf AP, Alvarez JA, Dudenbostel T, et al. Associations between vascular health indices and serum total, free and bioavailable 25hydroxyvitamin D in adolescents. PloS One. 2014;9:e114689. 40. LeFevre ML. Screening for vitamin D deficiency in adults: U.S. Preventive Services task force recommendation statement. Ann Intern Med. 2015;162:133–140.
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F E A T U R E E d i t o r i a l
Here Comes the Sun—Is Vitamin D a Cure For All That Ails Us? Sheela N. Magge Division of Endocrinology and Diabetes, Children’s National Health Systems, George Washington University School of Medicine and Health Sciences, Washington, DC 20010
D
eficiency of 25-hydroxyvitamin D (25[OH]D) has received a great deal of attention in the past several years for its potential nontraditional effects, outside of the skeleton. Vitamin D deficiency has been touted to be associated with increased risk of everything from cancer (1), to diabetes (2) and cardiovascular disease (CVD) (3), and even overall mortality (4). In this issue of the JCEM, Juonala et al (5) address the relationship between vitamin D deficiency and CVD. 25[OH]D deficiency has been associated with incident CVD in multiple adult studies (3, 6), but a large meta-analysis of randomized clinical trials of vitamin D supplementation did not show beneficial effects on stroke or myocardial infarction (7). Juonala et al (5) attempt to determine whether vitamin D deficiency during youth predisposes to increased CVD risk as an adult. The effects of vitamin D in the body are widespread. 25[OH]D represents overall vitamin D stores, but calcitriol or 1,25-dihydroxyvitamin D (1,25[OH]2D) is the biologically active form of vitamin D. PTH stimulates the hydroxylation of 25[OH]D to 1,25[OH]2D in the kidneys. Calcitriol has multiple biological effects, and vitamin D response elements have been found in the promoters of numerous genes. In fact, a recent genome-wide array study showed that vitamin D supplementation affected gene expression in more than 160 biological pathways (8). Furthermore, calcitriol can have both paracrine and autocrine actions, and the latter may relate to its nontraditional effects. Not only do most cells in the human body express vitamin D receptor, most also express the enzyme necessary to convert 25[OH]D to 1,25[OH]2D (9, 10). Thus, in response to an external signal, 25[OH]D might be triggered for intracellular conversion to 1,25[OH]2D, exerting a local action unrelated to PTH levels. If substantiated,
this would allow for 25[OH]D to bring about tissue-specific effects. Pathophysiological mechanisms corroborate the plausibility of a relationship between mineral metabolism and CVD. Vitamin D receptors are present on many different tissue types, including myocardium, endothelium, and vascular smooth muscle (11). In humans, 1,25[OH]2D inhibits renin synthesis; thus, its deficiency could contribute to hypertension (12). In addition, vitamin D deficiency leads to hypertrophy of vascular and left ventricular smooth muscle cells (13). Increased PTH, resulting from chronic vitamin D deficiency, is associated with increased blood pressure and myocardial contractility, which can lead to hypertrophy, apoptosis, and fibrosis in the vascular smooth muscle and left ventricle (11, 13). Decreased 25[OH]D and increased PTH both increase inflammation, as evidenced by increased C-reactive protein and IL-10, (13) and increase the risk of CVD events (14). 25[OH]D deficiency has been associated with increased insulin resistance and pancreatic -cell dysfunction as well (15). However, one source of confusion for many clinicians is that scientists cannot agree on what a “normal” 25[OH]D is. Although the Institute of Medicine (16) and the Pediatric Endocrine Society (17) define 25[OH]D sufficiency as a level ⬎ 20 ng/mL (50 nmol/L), others such as The Endocrine Society consider 25[OH]D sufficiency to be levels ⱖ 30 ng/mL (75 nmol/L), insufficiency to be values of 20 –29 ng/mL (50 –72.4 nmol/L), and deficiency to be ⬍ 20 ng/mL (18). These different definitions could be due to the fact that optimal cutoffs for 25[OH]D may vary depending on the associated outcome. For example, the optimal level for bone health may differ from the level associated with decreased CVD risk. Studies have at-
ISSN Print 0021-972X ISSN Online 1945-7197 Printed in U.S.A. Copyright © 2015 by the Endocrine Society Received February 10, 2015. Accepted February 23, 2015.
Abbreviations: CIMT, carotid intima-media thickness; CVD, cardiovascular disease; 1,25[OH]2D, 1,25-dihydroxyvitamin D; 25[OH]D, 25-hydroxyvitamin D; VDBP, vitamin D binding protein.
For related articles see pages 1469
doi: 10.1210/jc.2015-1396
J Clin Endocrinol Metab, April 2015, 100(4):1237–1240
jcem.endojournals.org
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tempted to define the optimal 25[OH]D level for skeletal effects as the level below which PTH rises. Previous adult studies found this to occur at 25[OH]D ⬍ 75 nmol/L (19, 20). However, a more recent study in children found a significantly lower 25[OH]D corresponding to PTH elevation (21), whereas another study did not find an inflection point for 25[OH]D for maximal PTH suppression in children (22). Valcour et al (23) found that the level varied with age and that levels of 25[OH]D required to suppress PTH increase with age. However, there is also evidence that 25[OH]D ⬎ 56 ng/mL (140 nmol/L) is associated with increased mortality, suggesting a possible reverse Jshaped relationship between mortality and 25[OH]D (24). Thus, the optimal 25[OH]D level is highly controversial, and likely differs depending on the outcome examined. Interest in potential vitamin D effects on cardiometabolic outcomes has also peaked in the pediatric community. Because of the need for endpoint surrogate markers in children for conditions such as diabetes and CVD events, outcomes such as insulin resistance and inflammatory markers have been used. Results have been mixed, with some studies showing increased 25[OH]D associated with decreased insulin resistance and improved CVD risk factors in children (25, 26), whereas other studies have not (27). One of the strengths of the current study by Juonala et al (5) is its design. It is longitudinal, using the cohort from the Cardiovascular Risk in Young Finns Study (28) to look at the association between 25[OH]D levels in children, ages 3–18 years in 1980, and carotid intima-media thickness (CIMT) as an adult, 27 years later in 2007. Of note, this Finnish cohort would be at increased risk for low 25[OH]D levels, given Finland’s high latitude and decreased sun exposure. CIMT is an established surrogate marker of atherosclerosis and CVD, and studies of the association between 25[OH]D as an adult and CIMT have had conflicting results (29, 30), with some evidence of sexspecific relationships (31). This new Finnish study provides insight into the potential long-term CVD implications of vitamin D deficiency during childhood. The study by Juonala et al (5) is significant in the size of the cohort and in the attempt to establish a connection between a childhood state and an adult health risk. The authors found that when analyzed as a continuous variable in analyses adjusted for relevant confounding variables, childhood 25[OH]D was inversely related to adult CIMT in females but not males. However, in both sexes, those with the lowest quartile of 25[OH]D (⬍40 nmol/L or 16 ng/mL) as children had significantly increased odds (odds ratio ⫽ 1.7) of having high-risk CIMT (highest decile of common carotid or carotid bulb intima-media
J Clin Endocrinol Metab, April 2015, 100(4):1237–1240
thickness, or carotid plaque) as an adult. This is an impressive finding that seems to lend credence to the many providers screening and treating patients with supplemental vitamin D. Interestingly, after adjusting for age and sex, there was not a significant relationship between adult 25[OH]D and adult CIMT, suggesting that the timing of vitamin D supplementation may be important. Vitamin D (25[OH]D) screening by clinical providers has increased as awareness of the high prevalence of vitamin D deficiency, particularly among Blacks and obese patients, has increased. The adult prevalence of vitamin D deficiency (as defined by 25[OH]D ⬍ 20 ng/mL or 50 nmol/L) has been estimated at 42%, with a prevalence of 31% in Whites and 82% in Blacks (32). Among overweight and obese adults, 38% and 54% are deficient, respectively (32). Among adolescents (12–19 y old), 14% are deficient overall, with 50% of Black adolescents being deficient, and with increased deficiency in overweight and obese adolescents (33). Because of increased skin melanin content, individuals of African descent are at increased risk for 25[OH]D levels ⬍ 20 ng/mL (50 nmol/L). Explanations for the etiology of low 25[OH]D levels in obese individuals have included possible sequestration of 25[OH]D in adipose tissue (34), as well as potential volumetric dilution of 25[OH]D due to large body size (35). Typical vitamin D treatment guidelines may not apply to those at high risk for deficiency, such as the obese, who may require up to three times the traditional treatment doses (36). As Juonala et al (5) themselves point out, one of the major limitations of this study is that the cohort was purely White, making their results not generalizable beyond the White population. In studies of more racially diverse cohorts, further questions arise. Powe et al (37) reported results from the Healthy Aging in Neighborhoods of Diversity across the Life Span study, which included a large cohort of both Black and White Americans. They measured 25[OH]D as well as vitamin D binding protein (VDBP), the main carrier protein for vitamin D. Common genetic polymorphisms in the VDBP gene produce variants with different binding affinities for vitamin D. The investigators found that Blacks have a higher prevalence of a VDBP polymorphism associated with low levels of VDBP. Blacks had decreased levels of both 25[OH]D and VDBP compared to Whites, resulting in equivalent bioavailable vitamin D levels. Low 25[OH]D may be irrelevant if bioavailable vitamin D is normal. Interestingly, some clinical patients with severe vitamin D deficiency have normal PTH. Whether this could be because of a normal bioavailable vitamin D is not known. The study by Powe et al (37) emphasizes the importance of measuring free or bioavailable vitamin D, as opposed to only
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doi: 10.1210/jc.2015-1396
25[OH]D. The form of vitamin D measured may also be one reason for inconsistencies in the outcomes of previous studies. Although 25[OH]D is the preferred form for uptake in the renal proximal tubules and may be representative of skeletal effects, free or bioavailable vitamin D levels act in other cells to produce nontraditional actions. Thus, measuring the biologically active free form is quite important. Moreover, some studies have shown differential relationships between 25[OH]D and CVD by race. RobinsonCohen et al (38) found that lower 25[OH]D levels were associated with increased incident coronary heart disease in White and Chinese subjects, but not in Black or Hispanic subjects. Another study in adolescent females found that, contrary to the investigators’ a priori hypothesis, total, free, and bioavailable vitamin D was positively associated with the females’ augmentation index (a surrogate measure of arterial stiffness), but specifically in Black females (39). Most of these studies use VDBP and standardized equations to calculate bioavailable vitamin D (37), which also require genetic polymorphism data; therefore, these equations are not feasible in clinical care. Cost-effective direct bioavailable vitamin D measurement techniques are needed. The scientific literature to date leaves us with many unanswered questions. Is vitamin D deficiency truly related to increased CVD, and if so, is this relationship sexand/or race-specific? Can we reverse this effect by vitamin D treatment? Does the timing of treatment, ie, during childhood vs adulthood, impact CVD outcomes? What measure of vitamin D should be treated? Perhaps the safest clinical course from a CVD point of view, in light of the current study, is to keep 25[OH]D between 20 ng/mL (50 nmol/L) and 50 ng/dL (140 nmol/L), a reasonable range given that 25[OH]D levels ⬍ 40 nmol/L were associated with high-risk CIMT in adults, and taking into consideration the association between increased mortality with higher 25[OH]D levels mentioned earlier (24). However, it should be noted that a recent report by the US Preventative Task Force did not find sufficient evidence either for or against routine 25[OH]D screening in adults (40). Further studies are clearly needed. Specifically, we need longitudinal randomized clinical treatment trials of vitamin D deficiency, including measures of 25[OH]D, PTH, and free and bioavailable vitamin D, in both sexes and in racially diverse populations. Such studies will be long, large, and costly, but they are necessary if we are to know whether treatment of “vitamin D deficiency” actually confers a long-term benefit to health, and in whom.
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Acknowledgments Address all correspondence and requests for reprints to: Dr Sheela Natesh Magge, MD, MSCE, Associate Professor of Pediatrics, Division of Endocrinology and Diabetes, Children’s National Health Systems, George Washington University School of Medicine and Health Sciences, 111 Michigan Avenue NW, CTS Suite, M7659 CRI-6, 6th Floor Main, Washington, DC 20010 – 2916. E-mail: [email protected]. Disclosure Summary: The author has nothing to declare.
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