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Vitamin D has 2 main forms: D2 ( ergocalciferol ) and D3 (cholecalciferol); the latter is the naturally occurring form and the form used for low dose supplementation. Vitamin D3 is synthesized in skin by exposure to direct sunlight (ultraviolet B radiation) and obtained in the diet chiefly in fish liver oils and salt water fish. In some developed countries, milk and other foods are fortified with vitamin D. Human breast milk is low in vitamin D, containing an average of only 10% of the amount in fortified cow's milk. Requirements for vitamin D increase with aging because skin synthesis declines. Sunscreen use and dark skin pigmentation also reduce skin synthesis of vitamin D.
Vitamin D is a prohormone with several active metabolites that act as hormones. Vitamin D is metabolized by the liver to 25(OH)D, which is then converted by the kidneys to 1,25(OH)2D (1,25-dihydroxycholecalciferol, calcitriol , or active vitamin D hormone). 25(OH)D, the major circulating form, has some metabolic activity, but 1,25(OH)2D is the most metabolically active. The conversion to 1,25(OH)2D is regulated by its own concentration, parathyroid hormone (PTH), and serum concentrations of Ca and phosphate.
Vitamin D affects many organ systems (see Table 6: Vitamin Deficiency, Dependency, and Toxicity: Actions of Vitamin D and Its Metabolites ), but mainly it increases Ca and P absorption from the intestine and promotes normal bone formation and mineralization. Vitamin D and related analogs may be used to treat psoriasis, hypoparathyroidism, renal osteodystrophy, and possibly leukemia, breast, prostate, or colon cancer; they may also be used for immunosuppression.
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Table 6
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Actions of
Vitamin D and Its Metabolites
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Organ
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Actions
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Bone
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Promotes bone formation by maintaining appropriate Ca and P concentrations
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Immune system
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Stimulates immunogenic and antitumor activity
Decreases risk of autoimmune disorders
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Intestine
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Enhances Ca and phosphate transport (absorption)
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Kidneys
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Enhances Ca reabsorption by the tubules
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Parathyroid glands
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Inhibits parathyroid hormone secretion
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Pancreas
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Stimulates insulin production
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Vitamin D
Deficiency
and Dependency
Inadequate
exposure to sunlight predisposes to vitamin D deficiency. Deficiency impairs
bone mineralization, causing rickets in children and osteomalacia
in adults and possibly contributing to osteoporosis. Treatment usually
consists of oral vitamin D; Ca and phosphate are supplemented as
needed. Prevention is often possible. Rarely, hereditary disorders
cause impaired metabolism of vitamin D (dependency).
Vitamin D deficiency is a common cause of rickets and osteomalacia, but these disorders may also result from other conditions, such as various renal tubular disorders, familial hypophosphatemic (vitamin D–resistant) rickets (see Renal Transport Abnormalities: Hypophosphatemic Rickets), chronic metabolic acidosis, hypoparathyroidism (which reduces vitamin D absorption), inadequate dietary Ca, and disorders or drugs that impair the mineralization of bone matrix.
Vitamin D deficiency causes hypocalcemia, which stimulates production of PTH, causing hyperparathyroidism. Hyperparathyroidism increases absorption, bone mobilization, and renal conservation of Ca but increases excretion of phosphate. As a result, the serum level of Ca may be normal, but because of hypophosphatemia, bone mineralization is impaired.
Etiology
Vitamin D deficiency may result from the following:
Inadequate
exposure or intake:
Inadequate direct sunlight exposure (or sunscreen use) and inadequate intake usually occur simultaneously to result in clinical deficiency. Susceptible people include the elderly (who are often undernourished and are not exposed to enough sunlight), and certain communities (eg, women and children who are confined to the home or who wear clothing that covers the entire body and face). Inadequate vitamin D stores are common among the elderly, particularly those who are housebound, institutionalized, or hospitalized or who have had a hip fracture. Recommended direct sunlight exposure is 5 to 15 min (suberythemal dose) to arms and legs, or face, arms and hands, at least 3 times a week.
Reduced absorption:
Malabsorption can deprive the body of dietary vitamin D; only a small amount of 25(OH)D is recirculated enterohepatically.
Abnormal
metabolism:
Vitamin D deficiency may result from defects in the production of 25(OH)D or 1,25(OH)2D. People with a chronic renal disorder commonly develop rickets or osteomalacia because renal production of 1,25 (OH)2D is decreased and phosphate levels are elevated. Hepatic dysfunction can also interfere with production of active vitamin D metabolites
Type I hereditary vitamin D-dependent rickets is an autosomal recessive disorder characterized by absent or defective conversion of 25(OH)D to 1,25(OH)2D in the kidneys. X-linked familial hypophosphatemia reduces vitamin D synthesis in the kidneys. Many anticonvulsants, and glucocorticoid use increase the need for vitamin D supplementation.
Resistance
to effects of vitamin D:
Type II hereditary vitamin D-dependent rickets has several forms and is due to mutations in the 1,25(OH)2D receptor. This receptor affects the metabolism of gut, kidney, bone, and other cells. In this disorder, 1,25(OH)2D is abundant but ineffective because the receptor is not functional.
Symptoms and Signs
Vitamin D deficiency can cause muscle aches, muscle weakness, and bone pain at any age.
Vitamin D deficiency in a pregnant woman causes deficiency in the fetus. Occasionally, deficiency severe enough to cause maternal osteomalacia results in rickets with metaphyseal lesions in neonates. In young infants, rickets causes softening of the entire skull (craniotabes). When palpated, the occiput and posterior parietal bones feel like a ping pong ball. In older infants with rickets, sitting and crawling are delayed, as is fontanelle closure; there is bossing of the skull and costochondral thickening. Costochondral thickening can look like beadlike prominences along the lateral chest wall (rachitic rosary). In children 1 to 4 yr, epiphyseal cartilage at the lower ends of the radius, ulna, tibia, and fibula enlarge; kyphoscoliosis develops, and walking is delayed. In older children and adolescents, walking is painful; in extreme cases, deformities such as bowlegs and knock-knees develop.
Tetany is caused by hypocalcemia and may accompany infantile or adult vitamin D deficiency. Tetany may cause paresthesias of the lips, tongue, and fingers; carpopedal and facial spasm; and, if very severe, seizures. Maternal deficiency can cause tetany in neonates.
Osteomalacia predisposes to fractures. In the elderly, hip fractures may result from only minimal trauma.
Diagnosis
Diagnosis may be suspected based on any of the following:
X‑rays of the radius and ulna plus serum levels of Ca, phosphate, alkaline phosphatase, PTH, and 25(OH)D are needed to differentiate vitamin D deficiency from other causes of bone demineralization.
Assessment of vitamin D status and serologic tests for syphilis can be considered for infants with craniotabes based on the history and physical, but most cases of craniotabes resolve spontaneously. Rickets can be distinguished from chondrodystrophy because the latter is characterized by a large head, short extremities, thick bones, and normal serum Ca, phosphate, and alkaline phosphatase levels.
Tetany due to infantile rickets may be clinically indistinguishable from seizures due to other causes. Blood tests and clinical history may help distinguish them.
Bone changes, seen on x‑rays, precede clinical signs. In rickets, changes are most evident at the lower ends of the radius and ulna. The diaphyseal ends lose their sharp, clear outline; they are cup-shaped and show a spotty or fringy rarefaction. Later, because the ends of the radius and ulna have become noncalcified and radiolucent, the distance between them and the metacarpal bones appears increased. The bone matrix elsewhere also becomes more radiolucent. Characteristic deformities result from the bones bending at the cartilage-shaft junction because the shaft is weak. As healing begins, a thin white line of calcification appears at the epiphysis, becoming denser and thicker as calcification proceeds. Later, the bone matrix becomes calcified and opacified at the subperiosteal level.
In adults, bone demineralization, particularly in the spine, pelvis, and lower extremities, can be seen on x‑rays; the fibrous lamellae can also be seen, and incomplete ribbonlike areas of demineralization (pseudofractures, Looser's lines, Milkman's syndrome) appear in the cortex.
Because levels of serum 25(OH)D reflect body stores of vitamin D and correlate with symptoms and signs of vitamin D deficiency better than levels of other vitamin D metabolites, 25(OH)D (D2+D3) measurement is generally considered the best way to diagnose deficiency. Goal 25(OH)D levels are 30 to 40 ng/mL (about 75 to 100 nmol/L); whether levels above this may be beneficial remains uncertain.
If the diagnosis is unclear, serum levels of 1,25(OH)2D and urinary Ca concentration can be measured. In severe deficiency, serum 1,25(OH)2D is abnormally low, usually undetectable. Urinary Ca is low in all forms of the deficiency except those associated with acidosis.
In vitamin D deficiency, serum Ca may be low or, because of secondary hyperparathyroidism, may be normal. Serum phosphate usually decreases, and serum alkaline phosphatase usually increases. Serum PTH is elevated.
Type I hereditary vitamin D–dependent rickets results in normal serum 25(OH)D, low serum 1,25(OH)2D and Ca, and normal or low serum phosphate.
Prevention
Dietary counseling is particularly important in communities whose members are at risk of vitamin D deficiency. Fortifying unleavened chapati flour with vitamin D (125 μg/kg) has been effective among Indian immigrants in Britain. The benefits of sunlight exposure for vitamin D status must be weighed against the increased skin damage and skin cancer risks.
All breastfed infants should be given supplemental vitamin D 5 μg (200 IU) once/day from birth to 6 mo; at 6 mo, a more diversified diet is available. For adolescents at risk, a single IM dose of ergocalciferol 2.5 mg (100,000 IU) given in the fall can maintain adequate 25(OH)D levels throughout the winter. The RDA for vitamin D intake for ages 51 to 70 is 400 IU and for age >70 is 600 IU; this intake is now considered too low, and the 2005 Dietary Guidelines for Americans recommends that healthy older adults consume 1000 IU/day.
Treatment
Ca deficiency (which is common) and P deficiency should be corrected. As long as Ca and P intake is adequate, adults with osteomalacia and children with uncomplicated rickets can be cured by giving vitamin D 40 μg (1600 IU) po once/day. Serum 25(OH)D and 1,25(OH)2D begin to increase within 1 or 2 days. Serum Ca and phosphate increase and serum alkaline phosphatase decreases within about 10 days. During the 3rd wk, enough Ca and P are deposited in bones to be visible on x‑rays. After about 1 mo, the dose can usually be reduced gradually to the usual maintenance level of 10 to 15 μg (400 to 600 IU) once/day. If tetany is present, vitamin D should be supplemented with IV Ca salts for up to 1 wk (see Fluid and Electrolyte Metabolism: Treatment). Older persons may need 25 to > 50 μg (1000 to = 2000 IU) daily to maintain a 25(OH)D level > 30 ng/mL (> 75 nmol/L); this is higher than the RDA for persons > 70 years old (600 IU) and may exceed the current UL of 2000 IU/d.
Because rickets and osteomalacia due to defective production of vitamin D metabolites are vitamin D–resistant, they do not respond to the doses usually effective for rickets due to inadequate intake. Endocrinologic evaluation is required because treatment depends on the specific defect. When 25(OH)D production is defective, vitamin D 50 μg (2000 IU) once/day increases serum levels and results in clinical improvement. Patients with kidney disorders often need 1,25(OH)2D supplementation.
Type I hereditary vitamin D–dependent rickets responds to 1,25(OH)2D 1 to 2 μg po once/day. Some patients with type II hereditary vitamin D–dependent rickets respond to very high doses (eg, 10 to 24 μg/day) of 1,25(OH)2D; others require long-term infusions of Ca.
Vitamin
D Toxicity
Usually, vitamin
D toxicity results from taking excessive amounts. Marked hypercalcemia commonly
causes symptoms. Diagnosis is typically based on elevated blood
levels of 25(OH)D. Treatment consists of stopping vitamin D, restricting
dietary Ca, restoring intravascular volume deficits, and, if toxicity
is severe, giving corticosteroids or bisphosphonates.
Because synthesis of 1,25(OH)2D (the most active metabolite of vitamin D) is tightly regulated, vitamin D toxicity usually occurs only if excessive doses (prescription or megavitamin) are taken. Vitamin D 1000 μg (40,000 IU)/day produces toxicity within 1 to 4 mo in infants. In adults, taking 1250 μg (50,000 IU)/day for several months can produce toxicity. Vitamin D toxicity can occur iatrogenically when hypoparathyroidism is treated too aggressively (see Fluid and Electrolyte Metabolism: Treatment).
Symptoms and Diagnosis
The main symptoms result from hypercalcemia. Anorexia, nausea, and vomiting can develop, often followed by polyuria, polydipsia, weakness, nervousness, pruritus, and eventually renal failure. Proteinuria, urinary casts, azotemia, and metastatic calcifications (particularly in the kidneys) can develop.
A history of excessive vitamin D intake may be the only clue differentiating vitamin D toxicity from other causes of hypercalcemia. Elevated serum Ca levels of 12 to 16 mg/dL (3 to 4 mmol/L) are a constant finding when toxic symptoms occur. Serum 25(OH)D levels are usually elevated >150 ng/mL (>375 nmol/L). Levels of 1,25(OH)2D, which need not be measured to confirm the diagnosis, may be normal.
Serum Ca should be measured often (weekly at first, then monthly) in all patients receiving large doses of vitamin D, particularly the potent 1,25(OH)2D.
Treatment
After stopping vitamin D intake, hydration with IV normal saline and corticosteroids or bisphosphonates (which inhibit bone resorption) are used to reduce blood Ca levels.
Kidney damage or metastatic calcifications, if present, may be irreversible.
Last full review/revision April 2007 by Larry E. Johnson, MD, PhD
Content last modified April 2007
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