Vitamin D Deficiency and Related Disorders ?>

Vitamin D Deficiency and Related Disorders

Vitamin D Deficiency and Related Disorders


Introduction
Background

Vitamin D deficiency in children can manifest as rickets (it is the most common cause of nutritional rickets), which presents as bowing of the legs. Vitamin D deficiency in adults results in osteomalacia, which presents as a poorly mineralized skeletal matrix. These adults can experience chronic muscle aches and pains.1

Vitamin D is important for calcium homeostasis and for optimal skeletal health. Vitamin D without subscripts refers to either vitamin D2 or vitamin D3. Vitamin D3, also known as cholecalciferol, is either made in the skin or obtained in the diet from fatty fish. Vitamin D2, also known as ergocalciferol, is obtained from irradiated fungi, such as yeast. Vitamin D2 and vitamin D3 are used to supplement food products or are contained in multivitamins. Past studies suggested that vitamin D3 may be more effective than vitamin D2 in establishing normal vitamin D stores.2, 3 However, a study by Holick and colleagues demonstrated that vitamin D2 and vitamin D3 appear to be equipotent in raising 25(OH)D concentrations when given in daily doses of 1000 IU.4

Related eMedicine topics:
Hypocalcemia [Emergency Medicine]
Hypocalcemia [Nephrology]
Hypocalcemia [Pediatrics: General Medicine]

Related Medscape topic:
Resource Center Nutrition
Pathophysiology

Vitamin D deficiency can result from a variety of causes, including inadequate exposure to sunlight, malabsorption problems, lack of vitamin D in breast milk, and the effects of certain medications. (see Causes.)

The production of vitamin D3 in the skin involves a series of reactions initiating with 7-dehydrocholesterol. Upon exposure to ultraviolet B (UVB) radiation between the wavelengths of 290-315 nm, 7-dehydrocholesterol is converted to previtamin D3, which is then converted to vitamin D3 after a thermally induced isomerization reaction in the skin. From the skin, newly formed vitamin D3 enters the circulation by binding to vitamin D binding protein (DBP). In order to become active, vitamin D requires 2 sequential hydroxylations to form 1,25-dihydroxyvitamin D (1,25[OH]2 D).

Vitamin D is initially hydroxylated in the 25 position by the hepatic microsomal and/or mitochondrial enzyme vitamin D 25-hydroxylase. The second hydroxylation occurs in the kidney by the P450 enzyme 25-hydroxyvitamin D-1 alpha-hydroxylase. Upon entering the cell, the 1,25(OH)2 D hormone binds to the vitamin D receptor (VDR). The bound vitamin D receptor then forms a heterodimer with the retinoic acid X receptor (RXR). This heterodimer then goes to the nucleus to bind deoxyribonucleic acid (DNA) and increases transcription of vitamin D–related genes.

The major function of vitamin D is to increase the efficiency of calcium absorption from the small intestine. Heaney and colleagues demonstrated that maximum calcium absorption occurs at levels of 25-hydroxyvitamin D (25[OH]D) greater than 32 ng/mL.5 Vitamin D also enhances the absorption of phosphorus from the distal small bowel. Adequate calcium and phosphorus absorption from the intestine is important for proper mineralization of the bone. The second major function of vitamin D is for the maturation of osteoclasts to resorb calcium from the bones.

Inadequate circulating 25(OH)D is associated with elevated parathyroid hormone (PTH); this condition is called secondary hyperparathyroidism. The rise in PTH may result in increased mobilization of calcium from the bone, which results in decreased mineralization of the bone.

Of note, prolonged exposure to the sun does not cause vitamin D toxicity. This is because after prolonged UVB radiation exposure, the vitamin D made in the skin is further degraded to the inactive vitamin D metabolites tachysterol and lumisterol.

Frequency
United States

Vitamin D insufficiency is highest among people who are elderly, institutionalized, or hospitalized. In the United States, 60% of nursing home residents6 and 57% of hospitalized patients7 were found to be vitamin D deficient.

However, vitamin D insufficiency is not restricted to the elderly and hospitalized population; several studies have found a high prevalence of vitamin D deficiency among healthy, young adults. A study from Boston determined that nearly two thirds of healthy, young adults in Boston were vitamin D insufficient at the end of winter.8
International

Similar rates of vitamin D deficiency have been reported in Europe9 and Canada. A greater prevalence of vitamin D deficiency exists in Middle Eastern countries. A study of 316 young adults aged 30-50 from the Middle East showed that 72.8% had 25(OH)D values of less than 15 ng/dL (that is, severely deficient). This was significantly more common in women than in men (83.9% vs 48.5%). The difference between sexes probably reflects the cultural and religious practices leading to less skin exposure in women than in men.10, 11, 12, 13
Mortality/Morbidity
The treatment of vitamin D insufficiency can decrease the risk of hip and nonvertebral fractures.14, 15 A meta-analysis found that vitamin D supplementation reduces the risk of hip fractures by 18% when vitamin D and calcium are taken together. Most of the trials that demonstrated the antifracture efficacy of vitamin D used 800 IU of vitamin D3. The minimum 25(OH)D level at which antifracture efficacy was observed was 30 ng/ml (74 nmol/L), suggesting a threshold for optimal levels of 25(OH)D for fracture protection.16
Vitamin D insufficiency contributes to osteoporosis by decreasing intestinal calcium absorption.5, 17 Treatment of vitamin D deficiency has been shown to improve bone mineral density.18, 19 An analysis of the Third National Health and Nutrition Examination Survey (NHANES III) demonstrated a positive correlation between circulating 25(OH)D levels and bone mineral density.20
Vitamin D supplementation has been associated with a reduction in falls involving the older population. A meta-analysis demonstrated that vitamin D supplementation resulted in a reduction in falls of about 22% in ambulatory and institutionalized elderly subjects, as compared with controls.21
Epidemiologic data suggest that vitamin D deficiency places adults at risk for developing cancer 22, 23, 24, 25, 26; these apparently include breast, colon, and prostate cancer.27 Several studies using cultured cancer cells in mice models have also supported the notion that vitamin D prevents the growth of cancers.28 Larger, randomized clinical trials are underway in humans to establish the role of vitamin D in the prevention of cancers.
Vitamin D insufficiency may increase the risk for type I and type II diabetes mellitus.29, 30 In NHANES III, lower vitamin D status was associated with higher fasting glucose and 2-hour glucose after an oral glucose tolerance test.31 Furthermore, vitamin D supplementation in adults has been associated with improved insulin sensitivity in several small, case-control studies.29
A meta-analysis evaluated the effect of vitamin D supplementation (using a mean supplementation dosage of about 500 IU daily) on all-cause mortality in 18 randomized controlled trials and found a 7% relative risk reduction for death.32

Related Medscape topics:
CME Further Evidence Supports Vitamin-D-Deficiency Link to CHD
CME Most Breast Cancer Survivors Are at Risk for Vitamin D Deficiency
CME/CE Supplementation With Calcium and Vitamin D: Efficacy Against Fracture and Total Mortality: A Best Evidence Review
CME/CE Vitamin-D Deficiency Now Associated With Increased Mortality
CME Vitamin D Supplementation May Protect Children From Type 1 Diabetes
Resource Center Osteoporosis
Race

Darker skin interferes with the cutaneous synthesis of vitamin D. A study from by Holick and coauthors demonstrated that non-Hispanic black subjects require 6 times the amount of UV radiation necessary to produce the similar serum vitamin D concentration seen in non-Hispanic white subjects.33 The explanation for the increased radiation necessary to increase vitamin D levels is that melanin absorbs ultraviolet radiation.

A higher prevalence of vitamin D insufficiency exists among non-Hispanic black persons. Dawson-Hughes and colleagues demonstrated that in Boston, 73% of elderly black subjects were vitamin D insufficient, compared with 35% of elderly non-Hispanic whites.34 In a large survey of 1500 healthy black women younger than 50 years, 40% were vitamin D deficient (25[OH]D <16 ng/mL), as compared with 4% of 1400 white women in that study.35 The decreased efficacy of vitamin D production by darker-pigmented skin explains the higher prevalence of vitamin D insufficiency among darker-skinned adults.
Age

Vitamin D production in the skin declines with advancing age, making elderly populations more dependent on dietary vitamin D. For the average older person, higher dietary intake of vitamin D may be required to achieve optimal serum levels of 25(OH)D.30

Clinical
History

Vitamin D deficiency is often a silent disease. As previously mentioned, vitamin D deficiency in children can present as bowing of the legs from rickets. In adults, vitamin D deficiency results in osteomalacia, which presents as a poorly mineralized skeletal matrix. Adults in these cases can experience chronic muscle aches and pains.1

Vitamin D deficiency is the most common cause of nutritional rickets. Rare genetic forms of rickets occur because of defects in vitamin D metabolism. Vitamin D – dependent rickets type I occurs because of a defect in the renal 25-hydroxyvitamin D-1 alpha-hydroxylase that results in decreased 1,25(OH) 2 D production. Vitamin D – dependent rickets type II occurs when a mutation exists in the VDR.

Related eMedicine topics:
Osteomalacia and Renal Osteodystrophy
Rickets [Pediatrics: General Medicine]
Rickets [Radiology]
Physical
In children with a severe vitamin D deficiency, the examination may reveal bowing in the legs.
In adults with a severe vitamin D deficiency, the examination can reveal periosteal bone pain. This is best detected using firm pressure on the sternal bone or tibia.
Causes
Inadequate exposure to sunlight – This causes a deficiency in cutaneously synthesized vitamin D. Adults in nursing homes or health care institutions are at a particularly high risk.36
Vitamin D malabsorption problems – People who have undergone resection of the small intestine are at risk for this condition. Diseases associated with vitamin D malabsorption include celiac sprue, short bowel syndrome,37 and cystic fibrosis.38
Minimal amounts of vitamin D in human breast milk – The American Academy of Pediatrics recommends vitamin D supplementation starting at age 2 months for infants fed exclusively with breast milk.39
Medications – Some medications are associated with vitamin D deficiency. Drugs such as Dilantin, phenobarbital, and rifampin can induce hepatic p450 enzymes to accelerate the catabolism of vitamin D.

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