Vitamin D Deficiency and Related Disorders
- Author: Vin Tangpricha, MD, PhD; Chief Editor: Romesh Khardori, MD, PhD, FACP more...
Vitamin D deficiency can result from inadequate exposure to sunlight; malabsorption; accelerated catabolism from certain medications; and, in infants, the minimal amount of vitamin D found in breast milk. In children, vitamin D deficiency can result in rickets, which presents as bowing of the legs; in adults, it results in osteomalacia, which presents as a poorly mineralized skeletal matrix. See the image below.
Signs and symptoms
Vitamin D deficiency is often clinically silent. Manifestations are as follows:
Children are often found to have started walking late or prefer to sit down for prolonged periods
Adults can experience chronic muscle aches and pains
Physical findings in severe vitamin D deficiency are as follows:
In children, bowing in the legs
In adults, periosteal bone pain, best detected with firm pressure on the sternum or tibia
See Clinical Presentation for more detail.
Measurement of serum 25-hydroxyvitamin D (25[OH]D) is the best test to determine vitamin D status. levels of 25(OH)D are interpreted as follows :
21-29 ng/mL (52.5-72.5 nmol/L): Vitamin D insufficiency
< 20 ng/mL (< 50 nmol/L): Vitamin D deficiency
Although not always required for the diagnosis of vitamin D insufficiency, measurement of the serum parathyroid hormone (PTH) level may help establish the diagnosis of vitamin D insufficiency. PTH levels are often elevated in patients with vitamin D insufficiency, indicating secondary hyperparathyroidism.
Screening for vitamin D deficiency is recommended only in those individuals who are at high risk for vitamin D deficiency, including the following :
Patients with osteoporosis
Patients with a malabsorption syndrome
Black and Hispanic individuals
Obese persons (body mass index >30 kg/m 2)
Patients with disorders that affect the metabolism of vitamin D and phosphate (eg, chronic kidney disease)
See Workup for more detail.
Recommended treatment for vitamin D–deficient patients up to 1 year of age is as follows :
2000 IU/day of vitamin D 2 or D 3 for 6 weeks or
50,000 IU of vitamin D 2 or D 3 once weekly for 6 weeks
When the serum 25(OH)D level exceeds 30 ng/mL, provide maintenance treatment of 400-1000 IU/day
Recommended treatment for vitamin D–deficient patients 1–18 years of age is as follows :
2000 IU/day of vitamin D 2 or D 3 for at least 6 weeks or
50,000 IU of vitamin D 2 once weekly for at least 6 weeks
When the serum 25(OH)D level exceeds 30 ng/mL, provide maintenance treatment of 600-1000 IU/day
Recommended treatment for vitamin D–deficient adults is as follows :
50,000 IU of vitamin D 2 or D 3 once weekly for 8 weeks or
6000 IU/day of vitamin D 2 or D 3 for 8 weeks
When the serum 25(OH)D level exceeds 30 ng/mL, provide maintenance treatment of 1500-2000 IU/day
Recommended treatment for vitamin D–deficient patients who are obese, have a malabsorption syndrome, or are taking medication that affects vitamin D metabolism, is as follows :
At least 6000-10,000 IU of vitamin D daily
When the serum 25(OH)D level exceeds 30 ng/mL, provide maintenance treatment of 3000-6000 IU/day
If the 25(OH)D concentration remains persistently low despite several attempts at correction with oral vitamin D, a trial of ultraviolet B light therapy (ie, by tanning lamps) may be considered to improve vitamin D status.
Unprotected sun exposure is the major source of vitamin D for both children and adults. Provision of vitamin D from sunlight is as follows:
Sensible sun exposure, especially between the hours of 10 am and 3 pm, produces vitamin D in the skin that may last twice as long in the blood compared with ingested vitamin D 
Full-body sun exposure producing slight pinkness in light-skinned persons results in vitamin D production equivalent to ingesting 10,000-25,000 IU 
Increased skin pigmentation, aging, and sunscreen use reduce the skin’s vitamin D 3 production
Recommended dietary intake of vitamin D for patients at risk of vitamin D deficiency is as follows :
In infants and children up to 1 year old, at least 400 IU/day, to maximize bone health
In children and adolescents 1-18 years of age, at least 600 IU/day to maximize bone health
In adults 19-50 years of age, at least 600 IU/day to maximize bone health and muscle function
Raising the serum 25(OH)D level consistently above 30 ng/mL may require vitamin D intake of at least 1000 IU/day
Whether recommended levels of vitamin D intake will provide all the potential nonskeletal health benefits associated with vitamin D is currently unknown
Most dietary sources of vitamin D do not contain sufficient amounts of the vitamin to satisfy daily requirements. The following foods contain the indicated amounts of vitamin D, as reported by the US Department of Agriculture's (USDA's) Nutrient Data Laboratory:
Fortified milk (8 oz) - 100 IU
Fortified orange juice (8 oz)  - 100 IU
Fortified cereal (1 serving) - 40-80 IU
Pickled herring (100 g) - 680 IU
Canned salmon with bones (100 g) - 624 IU
Mackerel (100 g) - 360 IU
Canned sardines (100 g) - 272 IU
Codfish (100 g) - 44 IU
Swiss cheese (100 g) - 44 IU
Raw shiitake mushrooms (100 g) - 76 IU
Most multivitamins (1 tab) - 400 IU
See Treatment and Medication for more detail.
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 (see the images below). (See Presentation and Prognosis.)
Vitamin D is important for calcium homeostasis and for optimal skeletal health. 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. (See Pathophysiology and Etiology.)
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 involvement in the maturation of osteoclasts, which resorb calcium from the bones. (See Pathophysiology and Etiology.)
The term vitamin D 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. (See Treatment and Medication.)
Past studies suggested that vitamin D3 may be more effective than vitamin D2 in establishing normal vitamin D stores.[8, 9] 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 they are given in daily doses of 1000 IU.
Vitamin D deficiency during pregnancy affects offspring. In a community-based study of 901 mother and offspring pairs, researchers found that maternal vitamin D deficiency (serum 25-hydroxyvitamin D < 50 nmol/L) at 18 weeks' pregnancy was associated with impaired lung development at age 6 in offspring, neurocognitive difficulties at age 10, increased risk of eating disorders in adolescence, and lower peak bone mass at age 20.[11, 12]
Findings suggest that vitamin D plays an active role in fetal development, particularly the development of the brain, lungs, and bones.
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 and is performed 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.
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 leads to 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.
Vitamin D deficiency can result from the following:
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. 
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. 
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.
Occurrence in the United States
Vitamin D insufficiency is highest among people who are elderly, institutionalized, or hospitalized. In the United States, 60% of nursing home residents and 57% of hospitalized patients 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 determined that nearly two thirds of healthy, young adults in Boston were vitamin D insufficient at the end of winter.
An analysis of data on 2877 US children and adolescents (age, 6-18 y) from the National Health and Nutrition Examination Survey (NHANES) 2003-2006 indicated that, based on current Institute of Medicine Committee guidelines, about 10.3% of this population (an estimated 5.5 million) had inadequate vitamin D (25(OH)D) levels (< 16 ng/mL), and 4.6% (an estimated 2.5 million) had levels placing them at risk of frank deficiency (< 12 ng/mL).[20, 21] Adolescents (age, 14-18 y) and obese children had the highest risk of 25(OH)D deficiency and inadequacy, and these risks were also higher among girls than boys (of any age and body mass index) and among nonwhite children.
Vitamin D status may fluctuate throughout the year, with the highest serum 25(OH)D level occurring after the summer and the lowest serum 25(OH)D concentrations after winter. A study by Shoben at el demonstrated that mean serum 25(OH)D concentrations can vary as much as 9.5 ng/mL. Factors such as male sex, higher latitude, and greater physical activity levels were found to be associated with greater differences in serum 25(OH)D concentrations in winter and summer.
Similar rates of vitamin D deficiency have been reported in Europe and Canada. A greater prevalence of vitamin D deficiency exists in Middle Eastern countries. A study of 316 young adults aged 30-50 years 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%, respectively). The difference between sexes probably reflects the cultural and religious practices leading to less skin exposure in women than in men.[24, 25, 26, 27]
Darker skin interferes with the cutaneous synthesis of vitamin D. A study by Holick and coauthors demonstrated that non-Hispanic black subjects require 6 times the amount of UV radiation necessary to produce a serum vitamin D concentration similar to that found in non-Hispanic white subjects. The explanation for the increased radiation necessary to increase vitamin D levels is that melanin absorbs ultraviolet radiation.
The decreased efficacy of vitamin D production by darker-pigmented skin explains the higher prevalence of vitamin D insufficiency among darker-skinned adults. 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.
In a large survey of 1500 healthy black women younger than 50 years, 40% were vitamin D deficient (25[OH]D < 16ng/mL), compared with 4% of 1400 white women in that study.
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.
The treatment of vitamin D insufficiency can decrease the risk of hip and nonvertebral fractures.[32, 33] A meta-analysis by Boonen et al of postmenopausal women and of men aged 50 years or older reporting a risk of hip fracture found that oral vitamin D supplementation reduced the risk of hip fractures by 18% when vitamin D and calcium were taken together. Most of the trials that demonstrated the antifracture efficacy of vitamin D used approximately 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.
Results from another meta-analysis, evaluating the efficacy of oral vitamin D supplementation in the prevention of hip and other nonvertebral bone fractures in individuals aged 65 years or older, indicated that vitamin D offers dose-dependent fracture protection. The analysis, by Bischoff-Ferrari et al, took into account 12 double-blind, randomized, controlled trials (RCTs) for nonvertebral fractures (n = 42,279) and 8 RCTs for hip fractures (n = 40,886), comparing the results obtained from the use of oral vitamin D (with or without calcium) with those derived from the administration of calcium alone and from placebo use.
In this study, doses of more than 400 IU/day were found to reduce fractures by at least 20% in individuals aged 65 years or older. In contrast to the Boonen study, the investigators maintained that these effects were independent of calcium supplementation.
Vitamin D insufficiency contributes to osteoporosis by decreasing intestinal calcium absorption.[7, 36] Treatment of vitamin D deficiency has been shown to improve bone mineral density.[37, 38] 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.
Vitamin D supplementation has been associated with a reduction in falls and improved muscle strength in the elderly. 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.[40, 41] Another meta-analysis examining muscle strength associated with vitamin D supplementation found significant improvement in reduced postural sway, timed up-and-go test results, and lower extremity strength in a pooled analysis of 13 studies.
Epidemiologic data suggest that vitamin D deficiency places adults at risk for developing cancer[43, 44, 45, 46, 47] ; these apparently include breast, colon, and prostate cancer.[48, 49] Several studies using cultured cancer cells in mice models have also supported the notion that vitamin D prevents the growth of cancers. 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.[31, 51] In NHANES III, lower vitamin D status was associated with higher fasting glucose and 2-hour glucose after an oral glucose tolerance test. Furthermore, vitamin D supplementation in adults has been associated with improved insulin sensitivity in several small, case-control studies.
Joergensen et al determined that vitamin D deficiency in type 1 diabetes may predict all causes of mortality but not development of microvascular complications. The contribution of vitamin D deficiency to mortality must be mediated by nonvascular mechanisms.
Low levels of vitamin D have also been linked to increased cardiovascular disease (CVD) biomarkers in older adults. In an observational study of 957 hypertensive older adults, vitamin D deficiency (< 25 nmol/L) was associated with higher levels of biomarkers linked with CVD and conditions such as multiple sclerosis and rheumatoid arthritis.[54, 55] Individuals deficient in vitamin D had significantly higher levels of the inflammatory biomarkers interleukin-6 (IL-6) and C-reactive protein (CRP), and higher IL-6:IL-10 and CRP:IL-10 ratios compared with subjects who had serum vitamin D levels > 75 nmol/L.[54, 55]
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. Severe vitamin D deficiency (25(OH)D < 10 ng/mL) has been associated with increased in-hospital mortality in patients admitted for acute coronary syndrome.
A Cochrane Review of 50 randomized, controlled trials that included more than 94,000 individuals, primarily elderly women, found that vitamin D3 supplementation decreased mortality. Other forms of vitamin D, including vitamin D2, calcitriol, and alpha-calcidiol, did not reduce mortality.
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