Vitamin D for Health: A Global Perspective

Vitamin D (D represents D 2 , D 3 , or both) is a secosterol produced endogenously in the skin from sun exposure or obtained from foods that naturally contain vitamin D, including cod liver oil and fatty fish (eg, salmon, mackerel, and tuna); UV-irradiated mushrooms; foods fortified with vitamin D; and supplements. 2 , 7 During exposure to sunlight, 7-dehydrocholesterol (7-DHC) in the skin is converted to previtamin D 3 . The 7-DHC is present in all the layers of human skin. 7 – 9 Approximately 65% of 7-DHC is found in the epidermis, and greater than 95% of the previtamin D 3 that is produced is in the viable epidermis and, therefore, cannot be removed from the skin when it is washed. 9 Once previtamin D 3 is synthesized in the skin, it can undergo either a photoconversion to lumisterol, tachysterol, and 7-DHC or a heat-induced membrane-enhanced isomerization to vitamin D 3 ( Figure 1 ). 7 , 8 The cutaneous production of previtamin D 3 is regulated. Solar photoproducts (tachysterol and lumisterol) inactive on calcium metabolism are produced at times of prolonged exposure to solar UVB radiation, thus preventing sun-induced vitamin D intoxication. 7 , 8 Vitamin D 3 is also sensitive to solar irradiation and is, thereby, inactivated to suprasterol 1 and 2 and to 5,6-trans-vitamin D 3 . 7 Cutaneous vitamin D 3 production is influenced by skin pigmentation, sunscreen use, time of day, season, latitude, altitude, and air pollution. 1 , 2 , 7 , 8 An increase in the zenith angle of the sun during winter and early morning and late afternoon results in a longer path for the solar UVB photons to travel through the ozone layer, which efficiently absorbs them. This is the explanation for why above and below approximately 33° latitude little if any vitamin D 3 is made in the skin during winter. 10 , 11 This is also the explanation for why—whether being at the equator and in the far northern and southern regions of the world in summer, where the sun shines almost 24 hours a day—vitamin D 3 synthesis occurs only between approximately 10 AM and 3 PM. 1 , 11 Similarly, in urban areas, such as Los Angeles, California, and Mexico City, Mexico, where nitrogen dioxide and ozone levels are high, few vitamin D 3 -producing UVB photons reach the people living in these cities. 7 , 11 Similarly, because glass absorbs all UVB radiation, no vitamin D 3 is produced in the skin when the skin is exposed to sunlight that passes through glass. Once formed, vitamin D 3 is ejected out of the keratinocyte plasma membrane and is drawn into the dermal capillary bed by the vitamin D binding protein (DBP). 7 , 8 Vitamin D that is ingested is incorporated into chylomicrons, which are released into the lymphatic system, and enters the venous blood, 2 , 7 where it binds to DBP and lipoproteins transported to the liver. 1 , 2 , 7 Vitamin D 2 and vitamin D 3 are 25-hydroxylated by the liver vitamin D-25-hydroxylase (CYP2R1) to produce the major circulating vitamin D metabolite, 25(OH)D, which is used to determine a patient’s vitamin D status. 1 , 2 , 7 This metabolite undergoes further hydroxylation by the 25(OH)D-1α-hydroxylase (CYP27B1) in the kidneys to form the secosteroid hormone 1α,25-dihydroxyvitamin D (1,25[OH] 2 D) ( Figure 1 ). 2 , 7 , 12 The 25(OH)D bound to DBP is filtered in the kidneys and is reabsorbed in the proximal renal tubules by megalin cubilin receptors. 6 , 12 The renal 1α-hydroxylation is closely regulated, being enhanced by parathyroid hormone (PTH), hypocalcemia, and hypophosphatemia and inhibited by hyperphosphatemia, fibroblast growth factor-23, and 1,25(OH) 2 D itself. 7 , 13 , 14 The 1,25(OH) 2 D performs many of its biologic functions by regulating gene transcription through a nuclear high-affinity vitamin D receptor (VDR). 15 , 16 This active metabolite of vitamin D binds to the nuclear VDR, which binds retinoic acid X receptor to form a heterodimeric complex that binds to specific nucleotide sequences in the DNA known as vitamin D response elements. Once bound, a variety of transcription factors attach to this complex, resulting in either up- or down-regulation of the gene’s activity. 2 , 7 , 17 There are estimated to be 200 to 2000 genes that have vitamin D response elements or that are influenced indirectly, possibly by epigenetics, to control a multitude of genes across the genome. 2 , 16 A recent microarray study on the influence of vitamin D status and vitamin D 3 supplementation on genome-wide expression in white blood cells before and after vitamin D 3 supplementation found that an improved serum 25(OH)D concentration was associated with at least a 1.5-fold alteration in the expression of 291 genes. 17 This study suggested that any improvement in vitamin D status will significantly affect the expression of genes that have a variety of biologic functions of more than 80 pathways linked to cancer, autoimmune disorders, and cardiovascular disease, which have been associated with vitamin D deficiency. 17 One of the m

Epidemiologic evidence has suggested a link between fetal life events and susceptibility to disease in adult life. 45 – 47 This paradigm, referred to as “fetal programming” or “developmental origins of health and disease,” may have a profound effect on public health strategies for the prevention of major illnesses. 2 , 48 The role of vitamin D in implantation tolerance and placental development has been studied. The 1,25(OH) 2 D 3 regulates key target genes associated with implantation, such as Homeobox A10 ( HOXA10 ), whereas the potent immunosuppressive effects of 1,25(OH) 2 D 3 suggest a role in placental development. 49 Increasing expression of CYP27B1 and VDR in first-trimester human trophoblasts and deciduas 50 may be related to the immunosuppressive effects of 1,25(OH) 2 D 3 and may help improve implantation tolerance. Placental development plays a critical role in pregnancy health, and its link to maternal vitamin D deficiency may explain related adverse outcomes. 5 , 45 In neonatal rats exposed prenatally to low maternal serum 25(OH)D levels, there was a general slowing of cardiac development, with significantly lower heart weights, decreased citrate synthase and 3-hydroxyacyl CoA dehydrogenase activity, and a 15% lower myofibrillar protein content. 46 A 2-month-old human infant with dilated cardiomyopathy and severe vitamin D deficiency had dramatic improvement of her ejection fraction (17%–66%) after vitamin D supplementation. 47 In addition, maternal vitamin D deficiency in rats stimulated nephrogenesis in offspring, with a 20% increase in nephron number but a decrease in renal corpuscle size observed between replete and deficient rats, despite there being no difference in body weight or kidney weight and volume. 5 , 51 These findings support the role of vitamin D influencing fetal programming and placental development. Epigenetic modification refers to heritable changes in gene expression that are not mediated by alterations in DNA sequence. 52 This hypothesis, first articulated by Barker et al, 53 postulated that in utero epigenetic fetal programming (as a result of environmental events during pregnancy) induced specific genes and genomic pathways that controlled fetal development and subsequent disease risk. The role of vitamin D in epigenetic modification and fetal programming could potentially explain why vitamin D has been reported to have such wide-ranging health benefits. Recent studies have suggested that epigenetic decoupling of vitamin D feedback catabolism plays an important role in maximizing 1,25(OH)D bioavailability at the fetomaternal interface. 25 , 44 Modified expression of the genes encoding placental calcium transporters, by epigenetic regulation by 1,25(OH) 2 D, might represent the means whereby maternal vitamin D status could influence bone mineral accrual in the neonate. 54 , 55 Vitamin D deficiency during pregnancy may, therefore, not only impair maternal skeletal preservation and fetal skeletal formation but also influence fetal “imprinting” that may affect chronic disease susceptibility soon after birth as well as later in life ( Figure 3 ). 15 , 56 Transgenerational hormonal imprinting caused by vitamin D treatment of newborn rats has been previously reported. 57 A recent study reported that VDR binds to the ε germline gene promoter and exhibits transrepressive activity. 58 Inhibition of IgE production by 1,25(OH) 2 D was mediated by its transrepressive activity through the VDR-corepressor complex, affecting chromatin compacting around the Iε region. 58 Also, the associations of early-life sun exposure and germline variation in VDR and CYP24A1 with non-Hodgkin lymphoma risk was reported in a clinic-based case-control study. 59

According to current evidence from biochemical testing, observational studies, and randomized controlled trials (RCTs), serum 25(OH)D levels of at least 20 ng/mL are required for normalization of PTH levels, to minimize the risk of osteomalacia, and for optimal bone and muscle function, with many experts regarding 30 ng/mL as the threshold for optimal bone health. 7 , 16 , 64 – 66 The skeletal consequences of 25(OH)D insufficiency include secondary hyperparathyroidism, increased bone turnover and bone loss, and increased risk of low-trauma fractures. 7 , 15 , 61 , 64 The most common etiology of rickets, historically and presently, is vitamin D deficiency. Low maternal 25(OH)D levels were found to correlate with increased fetal distal femoral splaying, determined by ultrasonography measurements of femoral length and metaphyseal width. 63 , 65 Children begin to manifest classical clinical signs of rickets between 6 months and 1.5 years that include rachitic rosary, widened epiphyseal plates at the end of long bones, and bowing deformities of the legs. 66 A common early symptom in newborns is excessive sweating due to neuromuscular irritability, 66 and a 25(OH)D level less than 20 ng/mL is common in children presenting with vague limb or back pain. From a skeletal perspective for adults, evidence from RCTs suggests that vitamin D may be considered a threshold nutrient, with little bone benefit observed at levels of 25(OH)D above which PTH is normalized. 62 , 67 A literature review of 70 studies generally found a threshold for a decline in serum PTH levels with increasing serum 25(OH)D levels, but there was no consistency in the threshold level of serum 25(OH)D, which varied from 20 to 50 ng/mL. 68 A study of 4100 older adults (>60 years old) from the Third National Health and Nutrition Examination Survey (NHANES III) found that higher 25(OH)D levels were associated with better lower-extremity function. 61 Much of the improvement occurred at 25(OH)D levels ranging from 9 to 16 ng/mL, but was continued to be seen up to 40 ng/mL. 69 A systematic review revealed that supplemental vitamin D at daily doses of 800 to 1000 IU consistently had beneficial effects on muscle strength and balance. 70 Several RCTs have reported positive effects of vitamin D supplementation on muscle function and fall prevention. 71 – 73 Adequate calcium intake is imperative to gain optimal benefit from improving the vitamin D status in those with insufficient 25(OH)D levels. 67 In contrast, in a study of 173 young Asian-Indian females revealed that after supplementation with vitamin D 3 (60,000 IU/wk for 8 weeks followed by 60,000 IU for 2 weeks) and calcium (500 mg twice per day for 6 months), and despite significant improvement in serum 25(OH)D levels, there was no significant change in their skeletal muscle strength. 74 Thus, age, baseline and final 25(OH)D concentrations, and whether and how much calcium supplementation was included in the clinical trial could affect outcome measures related to muscle performance and vitamin D status. Proximal muscle weakness is a prominent clinical feature of vitamin D deficiency. 7 , 60 The relative contributions of vitamin D and calcium to reducing fracture risk remain unclear 75 because improving calcium intake is also associated with suppression of PTH levels independent of vitamin D status. 67 , 76 , 77 A meta-analysis of data from RCTs found a dose-response relationship between a higher vitamin D dose and higher achieved serum 25(OH)D levels, with prevention of falls and fractures. 73 The greatest benefit was observed at 700 to 1000 IU/d or a mean serum 25(OH)D concentration of 30 to 44 ng/mL. 71 , 73 Similar results were reported in a more recent meta-analysis of pooled participant-level data from 11 double-blind RCTs of oral vitamin D supplementation, with or without calcium, compared with placebo or calcium alone in persons 65 years or older. 78 Reduction in the risk of fracture occurred only at the highest vitamin D intake level (median, 800 IU/d; range, 792–2000 IU), with a 30% reduction in the risk of hip fracture and a 14% reduction in the risk of any nonvertebral fracture. 77 This reduction was independent of the assigned treatment dose of vitamin D, age group, sex, type of dwelling, and study. 78 Several previous meta-analyses have suggested that the dose of vitamin D is irrelevant when vitamin D is combined with calcium. 79 – 82 In contrast, a pooled subgroup analysis of the 8 double-blind RCTs that used vitamin D combined with calcium indicated that with combined supplementation, the risk of fracture was reduced only at the highest actual intake level of vitamin D. These findings support that a 25(OH)D level of more than 24 ng/mL may be most beneficial for reducing the risk of fractures. 78 With a similar tone and theme, a report from the US Preventive Services Task Force concluded that current evidence is insufficient to assess the balance of benefits and harms of combined vitamin

Cancers Association studies have related higher serum levels of 25(OH)D to reduced incidence of many types of cancers. It has been hypothesized that the local conversion of 25(OH)D to 1,25(OH) 2 D in healthy cells in the colon, breast, and prostate can help prevent malignancy by inducing cellular maturation, inducing apoptosis, and inhibiting angiogenesis while enhancing the expression of genes including P21 and P27 to control cellular proliferation ( Figure 1 ). 1 , 2 , 7 , 19 , 30 , 80 – 82 Another vitamin D–regulated gene is CYP3A4 , whose protein product detoxifies the bile acid lithocholic acid. 114 Lithocholic acid is believed to damage the DNA of intestinal cells, and it may promote colon carcinogenesis. Stimulating the production of a detoxifying enzyme by 1,25(OH) 2 D could explain a protective role for improving vitamin D status against colon cancer. 115 Because vitamin D regulates a gamut of physiologic processes, including immune modulation, resistance to oxidative stress, and modulation of other hormones, it is not surprising that low vitamin D status has been associated with increased risk of several cancers and cancer mortality. 84 – 86 , 94 – 97 As the importance of noncoding RNAs has emerged, the ability of 1,25(OH) 2 D to regulate microRNAs (miRNAs) had been found in several cancer cell lines, patient tissues, and sera. In vitamin D 3 intervention trials, significant differences in miRNAs were observed between treatment groups or between baseline and follow-up. 116 In patient sera from population studies, specific miRNA differences were associated with serum levels of 25(OH)D. The findings thus far indicate that increasing vitamin D 3 intake in patients and 1,25(OH) 2 D 3 in vitro not only regulates specific miRNA(s) but also up-regulates global miRNA levels. 116 Epidemiologic studies have suggested that adequate levels of 25(OH)D are critical for the prevention of various solid tumors, including prostate, breast, ovarian, and colon cancers. 97 , 114 , 115 , 117 – 120 A meta-analysis for the US Preventive Services Task Force regarding vitamin D supplementation concluded that each 4-ng/mL increase in blood 25(OH)D levels was associated with a 6% reduced risk of colorectal cancer but not with statistically significant dose-response relationships for prostate and breast cancer. 97 In a large prospective study of lethal prostate cancer (1260 cases vs 1331 controls), men with the highest quartile of plasma 25(OH)D levels had less than half the risk of lethal prostate cancer compared with men who were in the lowest quartile of plasma 25(OH)D levels. 115 A meta-analysis including 1822 colon and 868 rectal cancers reported an inverse association between circulating 25(OH)D levels and colorectal cancer, with a stronger association for rectal cancer. 97 , 121 Participants in the WHI who had a baseline 25(OH)D level less than 12 ng/mL and who took 400 IU of vitamin D 3 and 1000 mg of calcium daily had a 253% increased risk of colorectal cancer compared with women who took the same amount of vitamin D 3 and calcium for 7 years and had baseline serum 25(OH)D levels greater than 24 ng/mL. 122 Although cross-sectional data have many limitations, the findings are hypothesis generating and can be used to develop protocols for RCTs. 123 , 124 The findings from prospective case-control cohort studies in which blood collection occurred many years before diagnosis add another dimension to the evidence. 118 The results of these studies generally support vitamin D supplementation in those with “low” vitamin D status. However, some have argued for caution before increasing 25(OH)D levels and associated dosing regimens beyond quantities clearly supported by RCTs and meta-analyses. 7 , 95 , 103 There are now several observational studies reporting a U- or J-shaped association between some cancers and serum 25(OH)D and latitude or UVB radiation levels, in which those in the highest percentiles have an inverse risk compared with those in the lowest. 118 , 125 – 127 Many RCTs that were evaluated for nonskeletal benefits of vitamin D had problems with a high incidence of nonadherence, misinterpretation of the original data, and use of doses of vitamin D below the 2010 IOM recommendations. 62 , 123 , 124 , 128 A good example is the WHI. 129 More than 50% of participants in the WHI admitted not taking their calcium and vitamin D daily, and blood concentrations of 25(OH)D were often not measured at baseline or at study end. 124 , 129 Furthermore, the authors acknowledged that the 400 IU of vitamin D was inadequate to raise the blood level of 25(OH)D above 30 ng/mL, which most studies have suggested is required to reduce cancer risk and other nonskeletal acute and chronic diseases. 7 , 26 , 61 , 127 , 128 A reanalysis of the WHI concluded that in 15,646 women (43%) who were not taking personal calcium or vitamin D supplements at randomization, the calcium and vitamin D intervention significantly decreased the risk of total

Observational studies in humans found that 25(OH)D and 1,25(OH) 2 D levels are inversely related to coronary artery calcifications 147 , 148 and are lower in patients with myocardial infarction. 149 An in vitro study suggested that low 25(OH)D levels influence the activity/expression of macrophages and lymphocytes in atherosclerotic plaques, thus promoting chronic inflammation in the artery wall. 150 Additionally, 1,25(OH) 2 D 3 inhibited foam cell formation and promoted angiogenesis in endothelial colony-forming cells in vitro, possibly due to an increase in vascular endothelial growth factor expression and pro–matrix metalloproteinase-2 activity. 4 , 151 A short course of treatment with vitamin D (4000 IU for 5 days) effectively attenuated the increase in circulating levels of inflammatory cytokines after an acute coronary event. 150 These findings provide support for the anti-inflammatory effects of vitamin D on the vascular system and suggest mechanisms that mediate some of its cardioprotective properties. 4 , 150 In addition, low 25(OH)D concentrations result in elevations in PTH levels, which have been linked to insulin resistance and significant increases in the serum levels of many acute phase proteins. 149 Wang et al 152 studied 1739 Framingham Offspring Study participants (mean age, 59 years; 55% women; all of white race) without previous cardiovascular disease. During mean follow-up of 5.4 years, 120 individuals developed a first cardiovascular event. Individuals with 25(OH)D levels less than 15 ng/mL had a multivariable-adjusted HR of 1.62 for incident cardiovascular events compared with those with 25(OH)D levels of 15 ng/mL or greater. This effect was evident in participants with hypertension (HR, 2.13; 95% CI, 1.30–3.48) but not in those without hypertension. 152 The observational studies indicated that a serum 25(OH)D level less than 30 ng/mL was strongly associated with hypertension and metabolic syndrome. 153 This effect is thought to be partly mediated through regulation of the renin-angiotensin-aldosterone axis. 154 The Intermountain Heart Collaborative Study Group prospectively analyzed a large electronic medical records database that contained 41,504 patient records. Serum 25(OH)D levels less than 30 ng/mL were associated with highly significant increases in the prevalence of diabetes, hypertension, hyperlipidemia, and peripheral vascular disease. Serum 25(OH)D levels were also highly associated with coronary artery disease, myocardial infarction, heart failure, and stroke and with incident death, heart failure, coronary artery disease/myocardial infarction, stroke, and their composite. 153 Black normotensive children who received 2000 IU/d of vitamin D 3 were compared with those who received 400 IU/d for 16 weeks in an RCT. Teenagers who received 400 IU/d of vitamin D 3 increased their mean ± SD plasma levels of 25(OH)D from 13.6±4.2 to 23.9±7.2 ng/mL and showed no reduction in arterial stiffness. In contrast, teenagers who received 2000 IU/d of vitamin D 3 increased their mean ± SD plasma levels of 25(OH)D from 13.2±3.4 to 34.2±12.1 ng/mL and significantly lowered their arterial wall stiffness. 155 This is supported by the observation that serum 25(OH)D levels less than 30 ng/mL were strongly associated with hypertension, elevated blood glucose, and metabolic syndrome in adolescents. 156 Children who were vitamin D deficient or insufficient had a 2.5-fold higher risk of an elevated blood glucose level, a 2.4-fold increased risk of elevated blood pressure, and a 4-fold increased risk of metabolic syndrome, a prelude to type 2 diabetes. 156 A meta-analysis of 11 prospective studies involving 3612 cases and 55,713 noncase participants provided the largest and most comprehensive assessment thus far of the association between circulating 25(OH)D levels and type 2 diabetes. It suggested a strong inverse association between serum 25(OH)D concentration and incidence of type 2 diabetes. The combined RR of 0.59 suggested that the risk of future diabetes may be reduced by 41% (95% CI, 33%–48%) by having a serum 25(OH)D level greater than 32 ng/mL compared with a serum 25(OH)D level less than 19.5 ng/mL at baseline. 157 The MIDSPAN family study was a prospective study of 1040 men and 1298 women from the West of Scotland recruited in 1996 and followed up for a median of 14.4 years. 158 Plasma levels of 25OHD less than 15 ng/mL were not associated with a risk of cardiovascular disorders in this cohort with very low 25(OH)D levels. The median plasma 25(OH)D level was 18.6 ng/mL, and the median vitamin D intake was 3.2 µg/d (128 IU/d). However, there was some evidence that a 25(OH)D level less than 15 ng/mL was associated with all-cause mortality. 158 There was an association between 25(OH)D levels and incidence of type 2 diabetes, but there was no evidence in this study of a beneficial effect of vitamin D supplementation on type 2 diabetes outcomes. 106 A meta-analysis of 15 trials by George et al 1

At the turn of the past century, children with rickets were at higher risk for upper respiratory tract infections and for dying of them. 26 , 183 Macrophages have a VDR, and when they ingest an infectious agent, such as tuberculosis bacillus, the toll-like receptors are activated, resulting in signal transduction to increase the expression of VDR and CYP27B1 . 7 , 26 , 145 In turn, 25(OH)D is converted to 1,25(OH) 2 D, which signals the nucleus to increase the expression of cathelicidin, a defensin protein that kills infective agents, such as tuberculosis bacillus. 7 , 26 Cord blood 25(OH)D levels were associated with tolerogenic immune regulation and fewer respiratory tract infections in newborns. 184 Also, high 25(OH)D levels during maternity were associated with a decrease in childhood wheezing by nearly 50% compared with low maternal 25(OH)D levels. Newborns with 25(OH)D levels less than 10 ng/mL were twice as likely to develop respiratory tract infections compared with those with levels of 30 ng/mL or greater, and every 4-ng/mL increase in the cord blood 25(OH)D level lowered the cumulative risk of wheezing by age 5 years. 184 Serum concentrations of 25(OH)D in 198 healthy adults revealed that a concentration of 38 ng/mL or higher reduced the risk of acute viral respiratory tract infections and number of days ill by 2-fold. 185 Japanese children who received 1200 IU/d of vitamin D from December through March compared with those who received placebo reduced their risk of influenza A by 42%. 181 It was also observed that children who took vitamin D daily had a relative risk reduction of 93% for having an asthma attack compared with children who did not take a vitamin D supplement. 186 Vitamin D has also been implicated in the reversal of corticosteroid resistance and in airway remodeling, which are the hallmarks of chronic obstructive pulmonary disease and severe asthma. Dietary vitamin D may regulate epigenetic events, in particular on genes that are responsible for chronic obstructive pulmonary disease susceptibility. 187 The potential role of vitamin D in reducing the risk of allergies also may be related to epigenetic regulation. 188 , 189 Misdirected epigenetic programming offered an explanation for why vitamin D deficiency in pregnancy may be associated with increased allergy rates in the offspring. The cord blood level of 25(OH)D found a U-shaped association, with a 2.4-fold odds ratio (OR) of low and a 4-fold OR of high levels of 25(OH)D to develop allergen-specific IgE. 188 , 190 Eczema was significantly more likely in those with 25(OH)D levels less than 20 ng/mL compared with those with 25(OH)D levels of 30 ng/mL or greater (OR, 2.66; 95% CI, 1.24–5.72; P =.01). 189 On a molecular level, maternal vitamin D intake during pregnancy increased the mRNA levels of immunoglobulin-like transcript (ILT) 3 and ILT4 in umbilical cord blood. 191 Because ILT3 and ILT4 are critical for the generation of T suppressor cells and the induction of immunologic tolerance, this finding may point toward an early induction of tolerogenic immune responses by maternal vitamin D intake in the developing child. In addition, vitamin D stimulates natural killer cells that are known to play an immunoregulatory role in the prevention of autoimmune diseases. 2 Thus, although vitamin D can favorably influence several pathways associated with respiratory tract diseases, there are few clinical trials to support the beneficial effect of vitamin D supplementation for these patients. Meta-analyses on respiratory outcomes 111 and recovery from tuberculosis 112 did not report a beneficial effect of supplementation for patients with cystic fibrosis or tuberculosis, respectively.

A recent meta-analysis of data from 24 studies found that women with circulating 25(OH)D levels less than 20 ng/mL in pregnancy experienced an increased risk of preeclampsia (OR, 2.09; 95% CI, 1.50–2.90), gestational diabetes mellitus (OR, 1.38; 95% CI, 1.12–1.70), preterm birth (OR, 1.58; 95% CI, 1.08–2.31), and small for gestational age (OR, 1.52; 95% CI, 1.08–2.15). 209 However, many of these outcomes are rare and require a large sample size to study, representing a challenge for cohorts with a limited number of preserved samples. Experimental studies have provided evidence of disrupted vitamin D metabolic homeostasis in the preeclamptic placenta and have suggested that increased oxidative stress could be a causative factor of altered vitamin D metabolism in preeclamptic placentas. 50 In normal placenta, DBP, CYP24A1 , and VDR expressions were localized mainly in trophoblasts, whereas CYP2R1 and CYP27B1 expressions were localized mainly in villous core fetal vessel endothelium. 50 Protein expression of CYP2R1 and VDR were reduced, but CYP27B1 and CYP24A1 expressions were elevated in preeclamptic compared with normotensive placentas. 50 A similar pattern was observed in an in vitro model that found that hypoxia induced down-regulation of DBP, CYP2R1 , and VDR and up-regulation of CYP27B1 and CYP24A1 . 50 These data indicate that fetal (trophoblastic) autocrine synthesis of 1,25(OH) 2 D 3 may play a pivotal role in controlling placental inflammation and preeclampsia. One of the main pathogenic features of preeclampsia is maternal endothelial dysfunction that results from impaired angiogenesis and reduced endothelial repair capacity. The 1,25(OH) 2 D 3 improves the angiogenic properties of endothelial progenitor cells. These findings could explain the positive influence of vitamin D 3 in reducing preeclampsia risk. 151 There was an inverse association with having a cesarean delivery and serum 25(OH)D levels. In a case-control study, after adjustment for race, age, educational level, insurance status, and alcohol use, women with 25(OH)D levels less than 15 ng/mL were almost 4 times as likely to have a cesarean delivery than were women with 25(OH)D levels of at least 15 ng/mL. 210 A meta-analysis of 3 trials involving 463 women suggested that women who received vitamin D supplements during pregnancy less frequently had a baby with a birth weight less than 2500 g than did those who received no treatment or placebo; the statistical significance was borderline. 89 In terms of other conditions, there were no significant differences in adverse effects, including nephrotic syndrome, stillbirths, and neonatal deaths, between women who received vitamin D supplements and women who received no treatment or placebo. 89 A meta-analysis indicated a significant inverse relation between serum 25(OH)D level and the incidence of gestational diabetes mellitus. Overall, vitamin D deficiency (25[OH]D <20 ng/mL) in pregnancy was significantly related to the incidence of gestational diabetes mellitus, with an OR of 1.61. 211 However, it remains unclear whether this association is causal owing to the observational design of the studies. Recently, meta-analyses by Thorne-Lyman and Fawzi 88 and De-Regil et al 89 reported a similar beneficial effect of vitamin D supplementation on birth weight but no significant effect on other maternal and neonatal outcomes.

Maternal vitamin D deficiency predisposes to low vitamin D stores in the newborn and increases infantile rickets 224 because the mother is the only source of vitamin D during pregnancy. The prevalence of vitamin D deficiency and insufficiency during pregnancy is of special concern and ranges from 8% to 100%, depending on the country of residence and the definitions of vitamin D deficiency and insufficiency ( Figure 5 ). 2 In the United States, vitamin D deficiency and insufficiency is estimated to be 27% to 91% in pregnant women. 2 As shown in Figure 5 , this rate is estimated to be 39% to 65% in Canada, 45% to 100% in Asia, 19% to 96% in Europe, and 25% to 87% in Australia and New Zealand. The prevalence of vitamin D deficiency and insufficiency in children in China was high, especially in children aged 6 to 16 years. 211 In the United States, it is estimated that 50% of children aged 1 to 5 years and 70% of children aged 6 to 11 years are vitamin D deficient or insufficient. 156 Recent studies reported that adolescents and young adults are also at risk for vitamin D deficiency. 200 – 205 Also, a high prevalence of vitamin D deficiency was reported in a cross-sectional study conducted at a tertiary care center in western India. 225 Evidence suggests that children and adults in the United States are becoming more vitamin D deficient and insufficient because of an increase in the incidence of obesity, a decrease in milk consumption, and an increase in sun protection. 211 , 215 This recent evidence emphasizes the high prevalence of vitamin D deficiency throughout the world, not only in at-risk groups ( Figure 5 ). 226 , 227

Traditional risk groups for vitamin D deficiency include pregnant women, children, older persons, the institutionalized, and nonwestern immigrants. 7 , 228 The major source of vitamin D for children and adults is exposure to natural sunlight. 7 , 61 The Maasai and Hadzabe tribes in Tanzania (East Africa) with traditional lifestyles, living in the presumed cradle of humankind, who are exposed daily to tropical sunlight had a mean circulating 25(OH)D levels of 46 ng/mL. 140 A variety of factors influence the cutaneous production of vitamin D. A sunscreen with a sun protection factor of 30 applied properly reduces the ability of the skin to produce vitamin D by as much as 95% to 99%. People of color who have natural sunscreen protection from their increased melanin pigment are less efficient by more than 90% in producing vitamin D in their skin compared with white individuals. 233 In addition, air pollution with increased ozone and nitrogen dioxide levels (both known to compromise several health outcomes)absorbs UVB radiation and is an often-neglected risk factor for hypovitaminosis D. 61 , 231 , 234 Important risk factors for vitamin D deficiency are shown in Figure 6 . The prevalence of vitamin D deficiency and insufficiency was affected by seasonal variation and latitude. The prevalence increased in late winter/spring and decreased in summer. 235 A study of the effect of education on vitamin D status found that low-educated women had lower 25(OH)D levels compared with high-educated women, and women in the lowest 25(OH)D quartile had a higher risk of small-for-gestational-age offspring. 236 The elderly population is particularly at risk for clinical complications related to low 25(OH)D levels. With increasing age, solar exposure is usually limited because of changes in lifestyle factors, such as clothing and less outdoor activity. Diet may also become less varied, with a lower natural vitamin D content. Most important, however, the cutaneous production of vitamin D after exposure to solar UVB radiation decreases with age because of atrophic skin changes, with a reduced amount of its precursor 7-DHC. 237 , 238 A comparison of the amount of previtamin D 3 produced in skin from 8- and 18-year-old individuals with the amount produced in skin from 77- and 82-year-old individuals revealed that aging can decrease by greater than 2-fold the capacity of the skin to produce previtamin D 3. 238 Although the heritability of vitamin D status seems considerable, the specific genetic determinants of 25(OH)D levels are only beginning to be identified. A recent examination of 141 single nucleotide polymorphisms (SNPs) in a discovery cohort of 1514 white participants from the community-based Cardiovascular Health Study found that lower serum 25(OH)D levels were associated with HRs for the risk of the composite outcome of 1.40 for those who had 1 minor allele at rs7968585 (in VDR) and 1.82 for those with 2 minor alleles. 215 , 216 This candidate gene study indicates that known associations of low serum 25(OH)D levels with clinical outcomes may vary according to genetic differences in the VDR. In black patients, there were significant associations in 3 SNPs in vitamin D pathway genes (rs2282679, rs2298849, and rs10877012), all of which replicate earlier findings in populations of European ancestry. 239 Included among these was rs2282679, a highly significant result from 2 recent genome-wide association studies (GWASs), 240 , 241 one of which reported a 49% increased risk of vitamin D deficiency (25[OH]D <20 ng/mL) associated with the rs2282679 minor allele in white individuals. 218 In another study of genetic predictors of 25(OH)D in black individuals involved 513 participants from 42 families in Los Angeles, California, and evaluated 30 SNPs in GC, VDR, and CYP27B1. 242 Recent epigenomic findings confirmed 3 genes ( DHCR7, CYP2R1 , and CYP24A1 ) of the 4 genes in the GWAS findings, which reinforces the crucial roles played by those 3 genes in vitamin D metabolism. 243 DHCR7 encodes the enzyme 7-DHC reductase, which converts 7-DHC to cholesterol, thereby removing the substrate from the synthetic pathway of vitamin D 3. 239 DHCR7 is a novel gene for association with 25(OH)D levels, as identified in 2 recent GWASs. 228 , 229 CYP24A1 , which encodes 25(OH)D–24-hydroxylase, has been identified as a candidate gene for vitamin D insufficiency in one GWAS but not in the other. 217 , 218 This mitochondrial protein initiates the degradation of 1,25(OH) 2 D 3 and plays a role in calcium homeostasis and vitamin D metabolism. These epigenomic findings suggest that individuals with vitamin D deficiency are more likely to have reduced synthesis and increased catabolism of 25(OH)D and 1,25(OH) 2 D. 243 The genetic contributions to circulating 25(OH)D represents a complex trait for which family studies have estimated heritability ranging from 43% to 80%. 231 Genomic and epigenomic data integration provided greater understanding of the physi

The RDA for vitamin D and tolerable upper limit levels vary in different age groups and in certain circumstances. 7 , 60 , 61 Although it is recommended that RDAs of 600 to 800 IU daily should meet the requirements to optimize bone health 62 in most of the population, higher vitamin D intakes (1000–2000 IU) are needed to reach and maintain 25(OH)D levels greater than 30 ng/mL. 7 , 60 It is recognized that for every 100 IU of vitamin D ingested, the blood level of 25(OH)D increases by approximately 0.6 to 1 ng/mL. 253 When the serum 25(OH)D level is less than 15 ng/mL, 100 IU of vitamin D will increase the 25(OH)D level by as much as 2 to 3 ng/mL. 7 , 71 An effective strategy to treat vitamin D deficiency and insufficiency in children and adults is to give them 50,000 IU of vitamin D 2 once a week for 6 and 8 weeks, respectively. 60 , 254 To prevent recurrence of vitamin D deficiency in children, administration of 600 to 1000 IU/d is effective. 60 For adults, to prevent recurrence of vitamin D deficiency, administration of 50,000 IU of vitamin D 2 every 2 weeks is effective. 7 , 60 , 128 This strategy was shown to be effective in maintaining blood levels of 25(OH)D at approximately 40 to 60 ng/mL for up to 6 years without any evidence of toxic effects. 255 Vitamin D can be administered daily, weekly, monthly, or every 4 months to sustain an adequate serum 25(OH)D concentration. 7 , 232 – 234 A bolus of high doses of vitamin D (up to 300,000 IU) can be initially used in persons with extreme vitamin D deficiency. Repeated boluses of high-dose vitamin D at 6- to 12-month intervals have been used in a nursing home setting, but a steady state serum 25(OH)D concentration is likely to be maintained by more frequent, lower doses of vitamin D. One study has suggested that a 500,000-IU bolus dose of vitamin D 3 increases the risk of fracture within 3 months, 256 but other studies have reported reduced risk of fracture. 257 , 258

Because body fat can sequester vitamin D, it is now recognized that children and adults who are obese require 2 to 5 times more vitamin D to treat and prevent vitamin D deficiency. 7 , 60 Patients taking antiseizure medications, AIDS medications, and glucocorticoids often require more vitamin D to satisfy their requirements. 7 , 60 However, patients with granulomatous disorders, such as sarcoidosis and tuberculosis, are at risk for hypercalciuria and hypercalcemia when blood levels of 25(OH)D are greater than 30 ng/mL owing to the increased serum levels of 1,25(OH) 2 D produced in the macrophages in the granulomas. 7 Therefore, their vitamin D intake needs to be carefully monitored and controlled. 7 , 60 Hence, daily requirements of vitamin D to reach and maintain the desired serum 25(OH)D level can be estimated from the baseline 25(OH)D concentration. Supplemental vitamin D is preferentially administered orally or intramuscularly (not available in the United States), and the vitamin D–producing Sperti lamp can be used, where available, in patients with malabsorption syndromes. 248 , 262

Vitamin D intoxication is characterized by hypercalcemia, hypercalciuria, and hyperphosphatemia, which, in turn, are responsible for soft-tissue and vascular calcifications and nephrolithiasis in the long-term. Serum 25(OH)D levels are usually markedly elevated (>150 ng/mL) in individuals with vitamin D intoxication. 7 , 60 , 90 Daily doses of vitamin D 3 up to 10,000 IU were safe in healthy males, and there was no evidence of hypercalcemia or hypercalciuria for 5 months. 253 , 268 This amount is far above the tolerable upper level indicated in the IOM guidelines (4000 IU). Higher doses of vitamin D (up to 40,000 IU/d) are still safe provided that a serum 25(OH)D concentration of 200 ng/mL is not exceeded. A recent report of an infant inadvertently receiving 12,000 IU of vitamin D 3 daily for 20 days and achieving a serum 25(OH)D level of 425 ng/mL had no signs of vitamin D intoxication. Once the vitamin D use was stopped, the serum 25(OH)D level was less than 100 ng/mL within 2 months. 269