Vitamin D

Vitamin D is a pleitropic hormone with receptors in the cells of almost all tissues, and it regulates many other cellular functions in addition to the Ca-P and bone metabolism7,8,9

From: Endocrinology of Aging , 2021

Vitamin D

Roger Bouillon , in Endocrinology (Sixth Edition), 2010

Origin of Vitamin D: Nutrition and Photosynthesis

Vitamin D can be obtained from dietary sources of vegetal (vitamin D 2 or ergocalciferol) or animal origin (vitamin D3 or cholecalciferol). About 50% of dietary vitamin D is absorbed by the enterocytes and transported to the blood circulation via chylomicrons. Part of this vitamin D is taken up by a variety of tissues (fat and muscle) before the chylomicron remnants and its vitamin D finally reaches the hepatocytes. The best food sources are fatty fish or its liver oils, but it is also found in small amounts in butter, cream, and egg yolk. Both human and cow's milk are poor sources of vitamin D, providing only 15 to 40 IU/L, and equally minimal concentrations of 25(OH)D or 1,25(OH)2D. 13 Only an intake of pharmacologic amounts of vitamin D (6000 IU/d) can increase the vitamin D concentration of milk to a level equivalent to the daily requirements of an infant. 14 Vitamin D intake is a poor predictor of serum 25(OH)D concentrations in subjects with an intake between 2 and 20 µg/d. 15,16 It is very difficult to obtain adequate vitamin D from a natural diet. However, in North America, 98% of fluid and dried milk (≥400 IU/L), as well as some margarine, butter, and certain cereals, are fortified with vitamin D2 (irradiated ergosterol) or D3, but the real vitamin D content is frequently quite different from the labeling standard. Skim milk and even proprietary infant formula frequently do not have the stated vitamin D content. 17,18 Vitamin D is remarkably stable and does not deteriorate when food is heated or stored for long periods. The Second National Health and Nutrition Survey (NHANES II) reported a median intake of about 3 µg/d in adults (range 0 to 49 µg), 19 whereas a slightly lower median intake (2.3 µg) was recorded in older women. 20 In view of the low vitamin D content of a vegetarian diet (natural vitamin D intake is indeed related to intake of animal fat), vitamin D deficiency and rickets is a risk factor for strictly vegetarian children with insufficient sun exposure or vitamin D supplementation. 21

Nature probably intended that most vitamin D would be generated by photosynthesis in the skin, with minor contribution from food sources. However, exposure to sunlight also increases the risk of dermal photodamage and several skin cancers, including melanoma. This was no real problem during human evolution, but with increasing life expectancy, the benefits of UV light for the photosynthesis of vitamin D should be compared with the lifetime risk of skin damage, especially since vitamin D supplementation can safely replace the skin synthesis. The recommended dietary allowances by the U.S. Food and Nutrition Board of the National Research Council and the 1998 updated recommendations are given in Table 58-1, and similar recommendations are still valid in Europe. 22,23 However, these recommendations were based on rudimentary knowledge of optimal vitamin D status and need to be revised upwards.

Hypervitaminosis can occur when pharmaceutical vitamin D is taken in excess, with a wide variety of symptoms and signs related to hypercalciuria, hypercalcemia, and metastatic calcifications (Table 58-2). The toxic dosage has not been established for all ages, but infants and children are more susceptible. Toxicity should always be monitored when daily doses markedly exceeding the present upper limit of more than 50 µg are given for a longer period. Overproduction of renal 1,25(OH)2D by abnormal hormonal stimuli (as seen in fibroblast growth factor-23 [FGF-23] or Klotho-null mice) or absence of CYP24A1 (see later), the main catabolizing enzyme, causes the same calcemic side effects, with severe multiple-organ calcification (especially kidney, vascular wall, and heart valves) leading to premature death. 24

Most vertebrates also accomplish their needs for vitamin D by photochemical synthesis in the skin; therefore, vitamin D is not a true vitamin. It is formed from 7-dehydrocholesterol (7DHC or provitamin D3), which is present in large amounts in cell membranes of keratinocytes of the basal or spinous epidermal layers. By the action of ultraviolet B (UVB) light (290 to 315 mm), the B ring of 7DHC can be broken to form previtamin D3. Previtamin D3 is unstable, and in the lipid bilayer of membranes, it is rapidly isomerized to vitamin D3 by thermal energy, followed by transport to the serum vitamin D–binding protein and uptake into the liver for further metabolization.

The production of previtamin D3 is a nonenzymatic photochemical reaction which is not subject to regulation other than substrate (7DHC) availability and intensity of UVB irradiation. 7DHC is the last precursor in the de novo biosynthesis of cholesterol. The enzyme 7HDC-Δ7-reductase (or sterol Δ7-reductase) catalyses the production of cholesterol from 7DHC. Inactivating mutations of the 7DHC-Δ7-reductase gene 25 are the hallmark of the autosomal recessive Smith-Lemli-Opitz syndrome, characterized by high tissue and serum 7DHC levels and multiple anomalies, including craniofacial dysmorphism and mental retardation due to the lack of cholesterol synthesis. 26 These patients may exhibit sometimes increased serum vitamin D and 25(OH)D concentrations. 27 Likewise, animals pretreated with a specific sterol-Δ7-reductase inhibitor also exhibit an augmented vitamin D synthesis following UVB irradiation. 28 With increasing human age, cutaneous stores of provitamin D decrease, together with decreased photoproduction of vitamin D. 16 In cats and the feline species in general, the high cutaneous sterol-Δ7-reductase activity hampers photoproduction of vitamin D, making it a true vitamin. 29 Apart from substrate (7DHC) availability, the photochemical synthesis of vitamin D3 in the skin largely depends on the amount of UVB photons that strike the basal epidermal layers. Glass, sunscreen, clothes, and skin pigment absorb UVB and blunt vitamin D3 synthesis. Latitude, time of day, and season are factors that influence the intensity of solar radiation and the cutaneous production of vitamin D3. Therefore, there is a risk for a shortage of vitamin D supply during winter and spring. In both the Northern and Southern hemispheres above 40 degrees latitude, vitamin D3 synthesis of the skin decreases or disappears during winter months, owing to the low inclination of the sun and the atmospheric filtration of the shortest (but effective for vitamin D3 synthesis) UV waves of sunlight. The importance of skin synthesis of vitamin D3 to maintain normal vitamin D status is best reflected by the vitamin D deficiency observed in submarine personnel or inhabitants of Antarctica 30 during prolonged absence of sun exposure, and also by the extremely high prevalence of vitamin D deficiency in countries where exposure to sunlight is extremely low for cultural and religious reasons, as in several Arabian countries with strict adherence to Islamic rules for body covering. 31-34 Solar exposure of 2 hours per week of the face and hands is probably sufficient for maintaining normal 25(OH)D concentrations in children 35 and adults but should be further fine-tuned according to the climate and latitude. 36

Nature has built in several feedback mechanisms to minimize the risk that prolonged sun exposure would cause vitamin D intoxication. Cutaneous vitamin D and especially previtamin D are photosensitive and will be degraded to inactive sterols (lumisterol, tachysterol) before they are translocated to the circulation (Fig. 58-1). Only a maximum of 10% to 15% of the provitamin D will be converted to vitamin D. Sunlight-induced melanin synthesis, acting as a natural sunscreen, provides an additional negative feedback.

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Vitamin D

MURRAY J. FAVUS , in The Aging Skeleton, 1999

Normal Control of Intestinal Ca Absorption and Vitamin D

Dietary Ca absorption is incomplete, and the efficiency of Ca absorption is correlated inversely with Ca intake [1,2]. The relationship between Ca intake and absorption depends on the level of Ca intake, with a greater efficiency of absorption during low intakes and a less efficient but linear relationship at luminal Ca concentrations greater than 1.5 mM [3 ]. Dietary Ca is absorbed by both passive diffusion and a vitamin D-dependent cellular active transport process [ 4,5]. The latter is responsible for the highly efficient transport of Ca during low intakes, while passive diffusional mechanisms, driven by concentration, electrical, and osmotic gradients [5], dominate at higher levels of luminal Ca. In response to a low Ca diet, Ca absorption becomes more efficient through an increase in the number of transporters (V max ) with no change in the affinity of the transport system for Ca [3,5].

The intestinal Ca active transport process is dependent on adequate vitamin D, and therefore vitamin D deficiency will be most evident during low levels of dietary Ca intake. At higher intakes of Ca, when luminal Ca concentrations are greater than 1.5 mM, diffusional, vitamin D-independent Ca transport mechanisms predominate.

The naturally occurring vitamin D3 1 and the synthetic vitamin D2 are biologically inert and require sequential hydroxylation at the C-25 position in the liver and at the C-1 position in the kidney to confer full biologic activity [6]. The cellular actions of vitamin D occur through binding of the steroid to the intracellular vitamin D receptor (VDR), which is a member of the steroid hormone superfamily of trans-activating transcription factors [7]. The dihydroxylated form of vitamin D, 1,25-dihydroxyvitamin D [1,25(OH)2D], is considered to be the hormonal form of the vitamin based on its high specific binding affinity for the VDR compared to vitamin D2 and D3 and the hepatic 25-hydroxyvitamin D (250HD) metabolites and its greater potency in exerting known biologic actions of vitamin D such as stimulation of intestinal Ca transport [7]. Thus, sufficient amounts of 1,25(OH)2D must be synthesized for optimal stimulation of the Ca active transport process, as during low intake of Ca.

Renal proximal tubule synthesis of 1,25(OH)2D is tightly regulated to meet skeletal requirements. Increases in 25-hydroxyvitamin D-1α-hydroxylase (1-OHase) activity, 1,25(OH)2D production, and circulating 1,25(OH)2D levels occur during growth, pregnancy, lactation, or when dietary Ca intake is low or inadequate to meet body Ca requirements. Under these conditions, Ca needs are met through the increased efficiency of intestinal Ca active transport. 1-OHase activity is stimulated by parathyroid hormone (PTH) as during low Ca intake [8] and during low phosphate diet (LPD) [9]. Insulin-like growth factor-I (IGF-I) [10,11] also has direct stimulatory actions on the 1-OHase, whereas calcitonin [12] and estrogen [13] may regulate 1-OHase activity through direct or indirect mechanisms.

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Vitamin D

F. MICHAEL GLOTHIII, in The Aging Skeleton, 1999

INTRODUCTION

Age-Associated Changes in Vitamin D

The role of vitamin D has long been recognized as vital to the growth and development of bone. While the lack of vitamin D may easily be considered as a cause of juvenile rickets, the impact of vitamin D extends beyond childhood and beyond bone. In fact, changes associated with aging may make the elderly population most susceptible to vitamin D deficiency and its consequences.

Vitamin D metabolism is illustrated in Fig. 1. Skin changes associated with aging reduce the amount of 7-dehydrocholesterol the precursor to cholecalciferol (vitamin D3), as well as its rate of conversion [1–4]. Absorption of dietary vitamin D is also reduced by as much as 40% in older individuals compared to younger ones [5]. The aging adult also has a reduction in the quantity and activity of the renal 1-α-hydroxylase, which affects the production of the most active metabolite of vitamin D, 1,25 dihydroxyvitamin D (calcitriol) [6–9].

FIGURE 1. Abbreviated diagram of vitamin D metabolism. Vitamin D precursors in the dermis are influenced by ultraviolet light and temperature and are converted to cholecalciferol (vitamin D3)'. Cholecalciferol (or ergocalciferol, vitamin D2, in the case of some dietary sources absorbed in the gut) is carried by the bloodstream to the liver where hydroxylases act to stimulate conversion to 25-hydroxyvitamin D (calcidiol). These molecules are also carried in the bloodstream and, on reaching the kidney, are converted under the influence of α-hydroxylase and parathyroid hormone to the most active vitamin D metabolite, 1,25-dihydroxyvitamin D (calcitriol). 1,25-Dihydroxyvitamin D regulates calcium homeostasis primarily through the action on vitamin D receptors in the gut (calcium absorption) and the kidney (calcium excretion in the urine).

Physiologic changes in vitamin D metabolism are not the only changes that affect the vitamin D status in older individuals. Reducing sun exposure for a variety of reasons, the increase in use of medications that may interfere with vitamin D metabolism, and the greater likelihood of comorbid conditions that can also interfere with vitamin D metabolism all contribute to a greater prevalence of vitamin D deficiency in older people [10–17].

SUNLIGHT

Lack of sunlight may be the determining factor for the development of vitamin D deficiency in the elderly [ 18–27]. A cross-sectional study from the United States that carefully controlled for diseases and medications that might confound an accurate assessment of vitamin D status demonstrated little problem with vitamin D status across the age span (see Fig. 2) [28]. However, in settings where subjects have not received adequate sunlight, the prevalence of vitamin D deficiency becomes quite high (see Fig. 3) [29,30]. Changes associated with aging alone are rarely substantial enough to result in low levels of vitamin D metabolites [28,31].

FIGURE 2. Stable vitamin D metabolites in the Baltimore Longitudinal Study on Aging across the age span.

 (see Ref. 28)

FIGURE 3. Prevalence of vitamin D deficiency (25-hydroxyvitamin D level less than 10 ng/ml) in two sunlight-deprived elderly groups.

 Adapted from Ref. 30.

In the United States the average vitamin D intake is reportedly among the highest in the world [32,33]. However, even with a relatively high vitamin D intake, the vitamin D status of many of our elderly is likely to be low [13,34].

Despite average intakes of vitamin D in excess of twice the recommended dietary allowance (RDA) of 200 IU per day, a third of elderly homebound (sunlight-deprived) subjects in one study had low vitamin D status with 25-hydroxyvitamin D levels <10 ng/ml (25 nmol/ liter) [18]. At least 30% of sunlight-deprived, nursinghome subjects were reported to have vitamin D deficiency (defined as hypovitaminosis D accompanied by physiological or biochemical abnormalities) [30,35–37].

Risk Factors Understanding the prevalence of vitamin D deficiency in the United States is important, but of perhaps equal importance is understanding the risk factors and the usual clinical presentation for an elderly person in this country with a vitamin D deficit.

One risk factor is clearly sunlight deprivation, which has been associated with depleted vitamin D stores in the elderly [15,20,29]. Other factors that have been linked to vitamin D deficiency include a low intake of foods containing vitamin D, medications that impair vitamin D metabolism (e.g., phenytoin and phenobarbital), medical conditions that increase risk (e.g., partial gastrectomy, renal disease, severe hepatic disease, and malabsorption), obesity, hypocalcemia, and elevated alkaline phosphatase in the serum [1,38,39].

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Calcitriol

Yoshihiko Ohyama , Toshimasa Shinki , in Handbook of Hormones (Second Edition), 2021

Clinical implications

VDDR-I is an autosomal recessive disorder. Patients with VDDR-I have inactivating mutations in the CYP27B1 gene, which encodes 25(OH)D3 1α-hydroxylase. VDDR-I is characterized by the early onset of skeletal disease and severe hypocalcemia. Patients exhibit muscle weakness and rickets. VDDR-II is a rare autosomal recessive disorder. The disorder is characterized by end organ hyporesponsiveness to vitamin D. VDDR-II shows the development of hypocalcemia in infancy, accompanied by rickets, osteomalacia, and secondary hyperparathyroidism. Alopecia is observed in some individuals with VDDR-II.

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Hypercalcemia Due to Vitamin D Toxicity

MISHAELA R. RUBIN , ... JOHN P. BILEZIKIAN , in Vitamin D (Second Edition), 2005

IX. SUMMARY AND CONCLUSIONS

Vitamin D toxicity is not a common cause of hypercalcemia, but it can be life threatening if not identified quickly. The major causes of hypercalcemia are primary hyperparathyroidism and malignancy. If these two etiologies are excluded, vitamin D toxicity becomes an important diagnostic consideration. There are many forms of exogenous and endogenous vitamin D toxicity. Inadvertent excessive use of pharmaceutical preparations is the most common etiology of exogenous toxicity. Excessive amounts of the parent compound, vitamin D, can be most difficult to manage as compared to toxicity due to the metabolites 25OHD or 1,25(OH) 2D. Extensive lipid solubility of vitamin D accounts for its extraordinary half-life and tendency for prolonged hypercalcemia. New clinical applications of 1,25(OH)2D and its synthetic analogs have been accompanied by the increased potential for toxicity. Endogenous etiologies may result from ectopic production of 1,25(OH)2D in granulomatous diseases, such as sarcoidosis and tuberculosis, or in lymphoma. Many different mechanisms have been proposed to account for vitamin D toxicity, including the vitamin D metabolite itself, VDR number, activity of 1α-hydroxylase, inhibition of vitamin D metabolism, and the capacity of DBP. Mounting evidence that higher levels of vitamin D may have beneficial effects on bone and cellular health may predispose to enhanced administration of vitamin D in the future and thereby increased frequency of vitamin D toxicity.

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INTRODUCTION

NICHOLAS J. BISHOP , in Vitamin D (Second Edition), 2005

IX. SUMMARY

Maternal vitamin D intake during the last trimester of pregnancy significantly influences neonatal vitamin D stores and metabolism and may influence growth in infancy. There is no impairment of neonatal vitamin D metabolism consequent on "immaturity," whatever the gestational age or birth weight of the infant. All mothers should receive an adequate vitamin D intake during the last trimester of pregnancy, and all infants should receive vitamin D in their diet, either as a supplement when the infant is completely breast-fed or as part of a modified cow's milk–derived formula. There is no place for the use of active vitamin D metabolites in the routine care of healthy infants.

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Vitamin D and Its Metabolites in the Prevention and Treatment of Osteoporosis

Philip N. Sambrook , in Osteoporosis and the Osteoporosis of Rheumatic Diseases, 2006

DOSAGES REQUIRED TO TREAT VITAMIN D DEFICIENCY

Vitamin D is stored in fat and muscle and is slowly released, particularly during winter. 21 In vitamin D–deficient patients, it is necessary to replenish the vitamin D stores. Although the daily requirement for vitamin D is 400 to 600 IU per day, a much larger dose is used to treat vitamin D–deficient patients. Because vitamin D is fat soluble with a half-life of more than 3 weeks, large doses are needed before changes in serum 25(OH)D are seen. Higher doses (3000-5000 IU daily for 6-12 weeks) may be used to replenish body stores. Even higher doses of 50,000 to 500,000 IU orally or 600,000 IU intramuscularly can effectively treat vitamin D deficiency, but there is the possibility of inducing hypercalcemia/hypercalciuria. The use of active metabolites (calcitriol or alfacalcidol) is not recommended for treating patients with simple vitamin D deficiency, and changes in serum 25(OH)D levels are not a reflection of such therapy.

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INTRODUCTION

DAN FAIBISH , ADELE L. BOSKEY , in Vitamin D (Second Edition), 2005

3. VITAMIN D CARRIER PROTEIN KNOCKOUT

Vitamin D is carried to its receptor (VDR) in the target tissues by the vitamin D binding protein (DBP). The mineral properties in DBP knockout mice have not been reported, but they have an interesting phenotype [ 133]. DBP knockout mice have low levels of serum vitamin D metabolites but otherwise appear normal and show none of the bone abnormalities seen in vitamin D–deficiency rickets or osteomalacia. When stressed with excess exogenous vitamin D (1000 U/g body weight) to induce vitamin D toxicity, they did have elevated serum calcium levels, but did not show the toxic effects found in wild-type animals. Kidney mineral deposits were found in the wild-type but not in the knockout mice. Additionally, when stressed with a diet low in vitamin D, histomorphometry showed increased thickening of the osteoid seams in the DBP knockout mice, consistent with impaired mineralization and "hypovitaminosis D osteopathy."

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Vitamin D derivatives

Yoshihiko Ohyama , Toshimasa Shinki , in Handbook of Hormones (Second Edition), 2021

Structure

Structural features

Vitamin D has a secosteroid structure in which a bond (C9-C10) in ring B of the steroid structure is broken. Vitamin D 3 and vitamin D2 are produced by the photochemical reaction of 7-dehydrocholestrol and ergosterol with ultraviolet light B (naturally with sunlight), and subsequent heat isomerization, respectively. These two nonenzymatic chemical reactions are essential for vitamin D synthesis. In humans, these reactions of 7-dehydrocholestrol occur in the skin. The structural difference between vitamin D3 and vitamin D2 is in their side chains (Fig. 125.2).

Fig. 125.2

Fig. 125.2. Nutritional forms of vitamin D.

Evolutional aspects of vitamin D

Vitamin D is found in phytoplankton and zooplankton, suggesting its existence for millions of years as an inactive product before the emergence of vertebrates. 3,4 With the evolution of metabolic enzymes and receptors in vertebrates, vitamin D acquired its function for calcium maintenance in the body. 5

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The Hypocalcemic Disorders: Differential Diagnosis and Therapeutic Use of Vitamin D

THOMAS O. CARPENTER , KARL L. INSOGNA , in Vitamin D (Second Edition), 2005

c. Hypocalcemia Due to Vitamin D Malabsorption

Because vitamin D is a fat-soluble vitamin, generalized fat malabsorption may result in vitamin D deficiency. Gastrointestinal diseases such as Crohn's disease, celiac sprue, and pancreatic insufficiency can be accompanied by hypocalcemia due to vitamin D malabsorption [ 71] (see also Chapter 75). We have also encountered children presenting with vitamin D deficiency rickets who have ultimately been diagnosed with cystic fibrosis and fat malabsorption. In addition, interruption of the enterohepatic circulation of both 25OHD and 1,25(OH)2D may lower body vitamin D stores. It is also possible that the diseased bowel may not be able to respond to 1,25(OH)2D. Mild hypocalcemia and secondary hyperparathyroidism is also seen in cholestatic liver diseases such as primary biliary cirrhosis [71]. Circulating levels of 25OHD are reduced in this setting owing to impaired hydroxylation of vitamin D in the liver and also because of intestinal malabsorption of vitamin D.

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