AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Vitamin D is important for calcium homeostasis and for optimal skeletal health. Vitamin D without subscripts refers to either vitamin D-2 or vitamin D-3. Vitamin D-2, also known as ergocalciferol, is obtained from irradiated fungi such as yeast. Vitamin D-2 is often used to supplement food products or is found in multivitamins. Vitamin D-3, also known as cholecalciferol, is either made in the skin or obtained in the diet from fatty fish. Previously, the belief was that vitamin D-2 and vitamin D-3 were equipotent in raising and maintaining adequate vitamin D status; however, recent reports seem to indicate that vitamin D-3 may be more effective in establishing normal vitamin D stores.

Pathophysiology

The production of vitamin D-3 in the skin involves a series of reactions initiating with 7-dehydrocholesterol. Upon exposure to ultraviolet radiation between the wavelengths of 290-315 nm, 7-dehydrocholesterol is converted to previtamin D, which is then converted to vitamin D-3 after a thermally induced isomerization reaction in the skin. From the skin, newly formed vitamin D-3 enters the circulation by adhering to vitamin D binding proteins. In order to become active, vitamin D requires 2 sequential hydroxylations to form 1,25-dihydroxyvitamin D (1,25[OH]2D).

Vitamin D is initially hydroxylated in the 25 position by the hepatic microsomal 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)2D hormone binds to the vitamin D receptor. The bound vitamin D receptor then forms a heterodimer with the retinoic acid X receptor. This heterodimer then goes to the nucleus to bind 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. 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.

Frequency

United States

Vitamin D deficiency is highest among people who are elderly, institutionalized, or hospitalized. Elliot et al reported that 60% of patients in nursing homes were vitamin D deficient in the United States. Thomas et al reported that more than 57% of hospitalized patients were vitamin D deficient. Tangpricha et al reported that nearly one third of healthy adults were vitamin D deficient at the end of winter.

International

Similar rates of vitamin D deficiency have been reported in Europe and Canada. A greater prevalence of vitamin D deficiency exists in people who cover all of their exposed skin with clothing in countries such as Saudi Arabia, Jordan, and Lebanon.

Mortality/Morbidity

• Vitamin D deficiency can lead to osteoporosis. The treatment of vitamin D deficiency can result in increased bone mineral density. An analysis by the Third National Health and Nutrition Examination Survey demonstrated a positive correlation between circulating 25(OH)D levels and bone mineral density.



• Vitamin D supplementation has been associated with a reduction of falls involving the older population. A meta-analysis by Bischoff and colleagues demonstrated that vitamin D supplementation resulted in about a 22% reduction in falls compared to controls.



• Vitamin D deficiency may increase the risk for several cancers including breast, colon, and prostate cancers. Sufficient epidemiologic data suggest that vitamin D deficiency places adults at risk for developing cancer. 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.

Race

Darker skin interferes with the cutaneous synthesis of vitamin D. A higher prevalence of vitamin D deficiency exists among African Americans. Dawson-Hughes and colleagues demonstrated that in Boston, 73% of elderly black people were vitamin D deficient compared to 35% of elderly white people. In a large survey of 1500 healthy black women younger than 50 years, 40% were vitamin D deficient (25[OH]D <16 ng/mL). The reduced capability of darker-pigmented skin to make vitamin D can explain the higher prevalence of vitamin D deficiency among darker-skinned adults. Holick and Clemens et al demonstrated that African Americans required 6 times the amount of ultraviolet radiation necessary to produce the similar serum vitamin D concentration in white adults. The explanation for the increased radiation necessary to increase vitamin D levels is that melanin absorbs ultraviolet radiation.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

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

Vitamin D deficiency is the most common cause of nutritional rickets. Other 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. Therefore, an inability exists in converting 25(OH)D to the more active form of vitamin D, 1,25(OH)2D. Vitamin D–dependent rickets type II occurs when a mutation exists in the vitamin D receptor.

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.



• 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, and cystic fibrosis.



• 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.



• Anticonvulsant medications: Some medications are associated with vitamin D deficiency. Drugs such as Dilantin or phenobarbital can induce hepatic p450 enzymes to accelerate the catabolism of vitamin D.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Lack of dietary intake
Inadequate sunlight exposure
Malabsorptive diseases: celiac sprue, short bowel syndrome, cystic fibrosis
Antiepileptic medications that accelerate vitamin D metabolism: phenytoin or phenobarbital

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• Serum 25(OH)D: 25(OH)D has a circulating half-life of 2 weeks. This is the best test to detect vitamin D deficiency. A 25(OH)D level of less than 20 ng/mL is considered vitamin D deficient. Levels should be greater than 32 ng/mL in patients with osteoporosis to maximize calcium absorption.



• Parathyroid hormone (PTH): Although not always required for the diagnosis of vitamin D deficiency, a serum PTH may be used to help establish the diagnosis of vitamin D deficiency. Often, patients with a vitamin D deficiency have a corresponding elevated PTH, indicating secondary hyperparathyroidism. An inverse relationship exists between PTH and 25(OH)D levels. PTH levels decrease after the correction of a vitamin D deficiency.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

Vitamin D deficiency can be corrected using various methods. No standard treatment regimen exists. The following are therapies that have been used to correct vitamin D deficiency.

• Vitamin D-2 (ergocalciferol) can be given 50,000 IU once a week for 8 weeks or 50,000 IU twice a week for 5 weeks.



• Vitamin D can be given parenterally as an intramuscular injection. No standard protocols for administration exist. Published studies vary concerning the amount and frequency of the injection. Patients have been given 100,000 IU intramuscularly every 4 months to 300,000-500,000 IU intramuscularly once a year. This treatment should be reserved only for those patients who have severe malabsorptive disease.

Diet

Inadequate dietary intake of foods containing vitamin D: Individuals who do not have exposure to sunlight are at risk for vitamin D deficiency if they do not ingest adequate amounts of foods that contain vitamin D. The following foods contain the indicated amounts of vitamin D, as reported by the 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

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

The goals of pharmacotherapy are to correct the vitamin D deficiency, reduce morbidity, and prevent complications.

Drug Category: Fat-soluble vitamins

Vitamin D promotes absorption of calcium and phosphorus in the small intestine. It also promotes renal tubule resorption of phosphate.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Outpatient Care

• After correction of vitamin D status with oral vitamin D, patients should be administered a repeat 25-hydroxyvitamin D level test to confirm that they are in the normal range. If a patient remains persistently low despite several attempts of correction with oral vitamin D, the patient may consider artificial light therapy (ie, tanning) to improve vitamin D status.

Deterrence/Prevention

• See Diet.

Complications

• See Mortality/Morbidity.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Vitamin D status should be assessed in all patients with osteoporosis. If deficient, these patients should have their 25-hydroxyvitamin D levels corrected.



• Infants fed exclusively with breast milk should have vitamin D supplementation as recommended by the American Academy of Pediatrics.



• Physicians should exercise caution when recommending over-the-counter vitamin D supplementation. Some brands may not contain the amount of vitamin D stated on the bottle.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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• Bischoff HA, Stahelin HB, Dick W, et al. Effects of vitamin D and calcium supplementation on falls: a randomized controlled trial. J Bone Miner Res. Feb 2003;18(2):343-51. [Medline].
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• Liu BA, Gordon M, Labranche JM, et al. Seasonal prevalence of vitamin D deficiency in institutionalized older adults. J Am Geriatr Soc. May 1997;45(5):598-603. [Medline].
• Looker AC, Gunter EW. Hypovitaminosis D in medical inpatients. N Engl J Med. Jul 30 1998;339(5):344-5; author reply 345-6. [Medline].
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• Nesby-O'Dell S, Scanlon KS, Cogswell ME, et al. Hypovitaminosis D prevalence and determinants among African American and white women of reproductive age: third National Health and Nutrition Examination Survey, 1988-1994. Am J Clin Nutr. Jul 2002;76(1):187-92. [Medline].
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• Tangpricha V, Flanagan JN, Whitlatch LW, et al. 25-hydroxyvitamin D-1alpha-hydroxylase in normal and malignant colon tissue. Lancet. May 26 2001;357(9269):1673-4. [Medline].
• Tangpricha V, Pearce EN, Chen TC, Holick MF. Vitamin D insufficiency among free-living healthy young adults. Am J Med. Jun 1 2002;112(8):659-62. [Medline].
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• Trang HM, Cole DE, Rubin LA, et al. Evidence that vitamin D3 increases serum 25-hydroxyvitamin D more efficiently than does vitamin D2. Am J Clin Nutr. Oct 1998;68(4):854-8. [Medline].
• Trivedi DP, Doll R, Khaw KT. Effect of four monthly oral vitamin D3 (cholecalciferol) supplementation on fractures and mortality in men and women living in the community: randomised double blind controlled trial. BMJ. Mar 1 2003;326(7387):469. [Medline].

Article Last Updated: Dec 22, 2006