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The Essential Vitamin D

A primer for primary care providers.

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Vitamin D was discovered in 1921 by biochemist Elmer McCollum as he sought to identify a treatment for rickets. Since that time, studies have revealed the significant role this vitamin plays in human health.

Vitamin D was the fourth vitamin discovered, after vitamins A, B and C. The practice of naming vitamins alphabetically in the order of discovery was employed before exact molecular structures could be determined to choose an appropriate chemical name.1

Adequate vitamin D levels are essential for bone health, calcium and phosphorus regulation, and muscle strength.2 Serum vitamin D levels also influence cellular proliferation and differentiation, immunomodulation, renin synthesis, insulin production and myocardial contractility. Vitamin D receptors are found in most tissues and cells in the body, and more than 200 genes in the body are controlled by vitamin D levels.3 Vitamin D is of such biological importance to the human body that, unlike other vitamins obtained exclusively through dietary means, vitamin D can be produced endogenously as a result of minimal sunlight exposure to the skin.

Given that vitamin D is essential to normal functioning of such a vast array of body functions, it is of great concern that approximately 36% of healthy young adults in the United States have inadequate levels of vitamin D.4 The cumulative detrimental health effects of chronic vitamin D insufficiency are not entirely reversible, but they are preventable with competent management by a healthcare provider.

Forms and Origin

Vitamin D is a blanket term that encompasses a collection of lipid-soluble secosteroid prohormones and metabolites.5,6 Potential confusion can arise from the fact that the term "vitamin D" can refer to either the entire class of similar compounds or to any of the multitude of vitamin D metabolites that each possess unique structural and functional characteristics. Multiple forms of vitamin D have been identified. They have each been labeled with numeric subscripts, including, but not limited to: D1 (a compound of ergocalciferol and lumisterol), D2 (ergocalciferol), D3 (cholecalciferol), D4 (22-dihydroergocalciferol) and D5 (sitocalciferol).1,7

Of the many designated forms of vitamin D, only D2 and D3 are clinically relevant in humans and both can be obtained through dietary intake. However, natural dietary sources are limited. Vitamin D2 is found naturally in mushrooms, yeasts and phytoplankton, where it is produced from the precursor ergosterol when exposed to ultraviolet radiation.3 Vitamin D3 is found naturally in tuna, salmon, catfish, mackerel, herring, sardines, cod liver oil, eggs and beef liver.3 Vitamin D3 is synthesized photochemically from the precursor 7-dehydroergoesterol in humans and many other vertebrates when exposed to ultraviolet radiation.2

Many food sources are now fortified with vitamin D, particularly milk and cereal. Endogenous synthesis of vitamin D in humans begins when solar ultraviolet B radiation of wavelengths between 290 nm and 315 nm provokes the conversion of 7-dehydroergoesterol in the epidermis and dermis into pre-vitamin D3, which is immediately converted into vitamin D3 in a temperature-dependent, thermal isomerization reaction.3 Excessive ultraviolet light exposure can break down previtamin D3 and vitamin D3, which prevents vitamin D toxicity from prolonged sunlight exposure. Dark skin pigmentation absorbs ultraviolet light and reduces cutaneous vitamin D3 production.4,5 Endogenous and dietary D3 and dietary D2 are transported by chylomicrons via the lymphatic system into venous circulation to be stored in fat cells or transported to the liver to undergo hydroxylation, yielding vitamin D-25-hydroxyvitamin D [25(OH)D] (calcifediol or calcidiol), the predominant form of vitamin D in circulation.2,3 Vitamin 25(OH)D is biologically inactive and requires a second hydroxylation transformation in the kidneys to produce the biologically active 1,25-dihydroxyvitamin D [1,25(OH) 2D] (calcitriol).2,3 

The rate of renal calcitriol production is controlled by parathyroid hormone released in response to decreased levels of serum calcium or increased levels of serum phosphorus, a substance that binds to serum calcium, thus preventing parathyroid calcium receptor activation. Normal endocrine calcitriol production takes place only in the kidneys, but pathologic calcitriol production can result from granulomatous conditions such as sarcoidosis, lymphoma and tuberculosis. Normal extrarenal autocrine or paracrine calcitriol is also synthesized in limited amounts in other tissues. These include bone, prostate, macrophages, T-lymphocytes, B-lymphocytes, dendritic cells, liver, keratinocytes, epithelial cells and in placental and decidual cells during pregnancy.2,3 Normal extrarenal calcitriol is utilized at the site of production and does not enter systemic circulation or respond to parathyroid hormone regulation.3

Physiologic Functions

Perhaps the most widely recognized role of vitamin D is that of maintaining serum electrolyte levels necessary for skeletal health. Calcitriol binds to vitamin D receptors on intestinal tract cells, which stimulate active absorption of calcium and phosphorus. Sufficient levels of vitamin D can increase intestinal calcium absorption 30% to 40% and increase phosphorus absorption 80%.3 Calcitriol promotes resorption of calcium in the renal tubules of the kidneys. Calcitriol further increases serum calcium and phosphorus levels by stimulating osteoblasts, the bone-forming cells, to release the surface protein RANKL, which triggers preosteoclast maturation into osteoclasts.3 Osteoclasts resorb bone to mobilize calcium and phosphorus, necessary for new bone construction.

Calcifediol has a bone protective role through its suppression of parathyroid hormone release. Low serum levels of calcifediol are correlated with elevated parathyroid hormone levels. Parathyroid hormone stimulates renal conversion of calcifediol to calcitriol, upregulates renal calcium reabsorption, and triggers the osteoblasts to activate osteoclastogenesis. Elevated parathyroid hormone also increases phosphaturia, which has the effect of elevating free serum calcium levels in circulation. Unless calcifediol levels are replenished, they will become progressively more depleted when converted to calcitriol in response to rising parathyroid hormone levels. In the presence of sufficient serum calcifediol levels, parathyroid hormone secretion is suppressed, preventing parathyroid hormone-initiated bone resorption.

Vitamin D also plays a role in proper skeletal muscle function. Vitamin D receptors are present on skeletal muscles and vitamin D deficiency can cause muscle weakness that is alleviated when adequate vitamin D levels are restored.3

Vitamin D plays a role in immune response. Vitamin D receptors present on monocytes and macrophages are upregulated in the presence of pathogens such as Mycobacterium tuberculosis and lead to the production of peptides capable of destroying such pathogens. Deficient serum vitamin D levels inhibit this immune response.

Other functions of calcitriol include a cardiovascular role through the inhibition of renin synthesis in the kidneys and an endocrine role through the promotion of insulin production in the pancreas.3

Measurement and What It Means

The standard method to assess a patient's vitamin D level is the measurement of serum 25(OH)D (calcifediol). It is the most abundant vitamin D metabolite, it has a long circulating half-life of 2 to 3 weeks, and it is physiologically not subject to rapid or drastic serum level changes.3,4 The serum level of 1,25(OH) 2D (calcitriol) is not a reliable indicator of vitamin D reserves due to its short 4- to 6-hour circulating half-life and dynamic fluctuations in serum level in response to changing serum levels of calcium, phosphorus and parathyroid hormone. In the presence of hyperparathyroidism, serum calcitriol levels may be maintained at normal levels after all calcifediol stores are depleted to the point of deficiency.

Optimal vitamin D levels are the subject of ongoing research and debate.8,9 Proposed optimal serum levels of vitamin D are the consensus of opinion based on existing evidence. Vitamin D deficiency denotes serum levels of 25(OH)D of less than 20 ng/mL.8 Vitamin D insufficiency denotes serum levels of 25(OH)D of 21 ng/mL to 29 ng/mL.8 Sufficient serum levels of vitamin D are greater than 30 ng/mL.8

The Endocrine Society published guidelines for vitamin D screening and treatment in 2011. The organization recommends target 25(OH)D levels of between 40 ng/mL and 60 ng/mL for children and adults.8 The Institute of Medicine (IOM) has also published guidelines. It suggests a conservative normal upper limit of 50 ng/mL, reflecting caution in the absence of supportive research studies.9 Nevertheless, in many labs, a "normal" 25(OH)D reference range is 20 ng/mL to 100 ng/mL. Toxic 25(OH)D levels are greater than 150 ng/mL.3 Vitamin D intoxication is uncommon and results in hypercalcemia and initial symptoms of nausea, vomiting and fatigue.

Screening and Risk Considerations

The Endocrine Society recommends screening for vitamin D deficiency only in patients at risk for deficiency. It recommends using the serum 25(OH)D level for diagnosis.8 Due to the multiple risks for vitamin D deficiency and the existence of insufficiency at all ages, the primary care provider can find ample justification for vitamin D screening in the majority of patients. Indications for screening include: dark-pigmented skin, pregnancy, obesity, advanced age with a history of falls or nontraumatic fractures, lactation, rickets, osteomalacia, osteoporosis, chronic kidney disease, hepatic failure, malabsorption syndromes, cystic fibrosis, inflammatory bowel disease, Crohn disease, bariatric surgery, radiation enteritis, hyperparathyroidism, granuloma-forming disorders, sarcoidosis, tuberculosis, histoplasmosis, coccidiomycosis, beryliosis, and lymphomas.8 Use of the following medications also supports vitamin D screening: antiseizure medications, glucocorticoids, AIDS treatments, antifungals and cholestyramine.8

Other deficiency risk considerations relate to diet and sunlight exposure. Restrictive diets such as vegetarianism significantly limit the opportunity to achieve adequate vitamin D intake through diet alone. Limited sunlight exposure in extreme latitudes, night shift work and reduced daylight hours in winter months are all risks for low natural vitamin D synthesis.8

Recommended Intakes for Adequacy

The IOM Dietary Reference Intakes (DRIs) propose reference values stratified by age and gender for healthy North Americans. DRIs incorporate the Recommended Dietary Allowance (RDA) sufficient for more than 97% of healthy patients, Adequate Intake (AI) when RDA cannot be established, and the Tolerable Upper Intake Level (UL), which is unlikely to pose toxicity risks.9 The IOM DRI for vitamin D is 600 IU for people 1 to 70 years old and 800 IU for people older than 70. For people less than 1 year old, an adequate intake level of 400 IU is proposed.

The IOM daily vitamin D upper limit dosage levels are as follows: age 0 to 6 months: 1,000 IU; age 6 to 12 months: 1,500 IU; age 1 to 3 years: 2,500 IU; age 4 to 8 years: 3,000 IU; age 9 years and older: 4,000 IU.9 The evidence for increased benefit at dosages above the DRI is inconsistent, thus the upper limit levels are not intended as target dosages. The IOM recommendations are intended to apply to normal healthy people who live in North America.

The Endocrine Society guidelines provide daily intake level ranges for vitamin D supplementation among patients of all ages with inadequate vitamin D levels. The recommended daily vitamin D dosage ranges are as follows: less than 1 year old: 400 to 1,000 IU; 1 to 18 years old: 600 to 1,000 IU; 19 years and older: 1,500 to 2,000 IU.8

The Endocrine Society provides upper limit recommendations for patients with inadequate vitamin D levels as follows: 0 to 12 months: 2,000 IU; 1 to 18 years: 4,000 IU; ages 19 years and older: 10,000 IU.8

The upper tolerable daily limits proposed by the Endocrine Society for inadequate vitamin D levels are much greater than those of the IOM for normal, healthy members of the North American population. The guidelines provide support for clinical management decisions. Clinical decisions made by the provider to manage a patient's vitamin D status will always require a thorough work-up, a serum 25(OH)D level to monitor status and response to treatment, and perhaps other indicated tests such as a parathyroid level or bone density scan. 

Supplementation Options and Treatment Strategies

Adequate amounts of vitamin D may be achieved by twice weekly sun exposure of the arms and legs for 5 to 30 minutes between the hours of 10 a.m. and 3 p.m.3 Surplus vitamin D stored in adipose tissue is then available to compensate for reduced endogenous production during the winter months. Many variables affect cutaneous vitamin D production, including season, geographic latitude, weather conditions and skin pigmentation. Endogenous vitamin D production is not always an ideal option, and sun exposure does not come without the health risks of sunlight damage to the skin.

Vitamin D supplementation can be employed as prevention, based on IOM dosage guidelines via over-the-counter vitamin D2 and D3 supplements.9 For at-risk groups, a serum 25(OH)D level should be drawn to assess need for intervention. For patients with vitamin D insufficiency or deficiency, the Endocrine Society guidelines provide treatment strategies: weekly D2 50,000 IU capsule doses for 6 weeks in children and 8 weeks in adults. This should be followed by daily D3 capsule maintenance doses of age-based strengths detailed in the guidelines.8

Response to therapy should be monitored via a repeat 25(OH)D level performed after 3 or 4 months of therapy and then annually. Titration of dosage is based on serum 25(OH)D level with a goal of achieving levels of at least 30 ng/mL. Providers must use clinical judgment in combination with published guidelines to manage each clinical case.                                                                                                     

References

1. Wolf G. The discovery of vitamin D: the contribution of Adolf Windaus. J Nutr. 2004;134(6):1299-1302.

2. Reichel H, et al. The role of the vitamin D endocrine system in health and disease. N Engl J Med. 1989;320(15):980-991.

3. Holick MF. Vitamin D deficiency. N Engl J Med. 2007;357(3):266-281.

4. Holick MF. High prevalence of vitamin D inadequacy and implications for health. Mayo Clin Proc. 2006;81(3):353-73. 

5. Geller JL, Adams JS. Vitamin D therapy. Curr Osteoporos Rep. 2008;6(1):5-11.

6. Dixon KM, et al. Vitamin D-fence. Photochem Photobiol Sci. 2010;9(4):564-70.

7. Dewick PM. Vitamin D. In: Dewick PM. Medicinal Natural Products: A Biosynthetic Approach. Chichester, England: Wiley; 2002: 257-260.

8. Holick MF, et al. Evaluation, treatment, and prevention of vitamin D deficiency: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2011;96(7):1911-1930.

9. Institute of Medicine. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: National Academies Press; 2011.

David Arps is an adult and gerontologic nurse practitioner who practices at the Veterans Affairs Medical Center in Cincinnati. Shelley Crane is an adult and gerontologic nurse practitioner who practices at Humana in Cincinnati. The authors have completed disclosure statements and report no relationships related to this article.

 

 


 

The Vitamin D Bandwagon takes another hit

Cochrane Database Syst Rev. 2014 Jan 10;1:CD007470. [Epub ahead of print]
Vitamin D supplementation for prevention of mortality in adults.
Author information
Abstract
BACKGROUND:
Available evidence on the effects of vitamin D on mortality has been inconclusive. In a recent systematic review, we found evidence that vitamin D3 may decrease mortality in mostly elderly women. The present systematic review updates and reassesses the benefits and harms of vitamin D supplementation used in primary and secondary prophylaxis of mortality.
OBJECTIVES:
To assess the beneficial and harmful effects of vitamin D supplementation for prevention of mortality in healthy adults and adults in a stable phase of disease.
SEARCH METHODS:
We searched The Cochrane Library, MEDLINE, EMBASE, LILACS, the Science Citation Index-Expanded and Conference Proceedings Citation Index-Science (all up to February 2012). We checked references of included trials and pharmaceutical companies for unidentified relevant trials.
SELECTION CRITERIA:
Randomised trials that compared any type of vitamin D in any dose with any duration and route of administration versus placebo or no intervention in adult participants. Participants could have been recruited from the general population or from patients diagnosed with a disease in a stable phase. Vitamin D could have been administered as supplemental vitamin D (vitamin D3 (cholecalciferol) or vitamin D2 (ergocalciferol)) or as an active form of vitamin D (1α-hydroxyvitamin D (alfacalcidol) or 1,25-dihydroxyvitamin D (calcitriol)).
MAIN RESULTS:
We identified 159 randomised clinical trials. Ninety-four trials reported no mortality, and nine trials reported mortality but did not report in which intervention group the mortality occurred. Accordingly, 56 randomised trials with 95,286 participants provided usable data on mortality. The age of participants ranged from 18 to 107 years. Most trials included women older than 70 years. The mean proportion of women was 77%. Forty-eight of the trials randomly assigned 94,491 healthy participants. Of these, four trials included healthy volunteers, nine trials included postmenopausal women and 35 trials included older people living on their own or in institutional care. The remaining eight trials randomly assigned 795 participants with neurological, cardiovascular, respiratory or rheumatoid diseases. Vitamin D was administered for a weighted mean of 4.4 years. More than half of the trials had a low risk of bias. All trials were conducted in high-income countries. Forty-five trials (80%) reported the baseline vitamin D status of participants based on serum 25-hydroxyvitamin D levels. Participants in 19 trials had vitamin D adequacy (at or above 20 ng/mL). Participants in the remaining 26 trials had vitamin D insufficiency (less than 20 ng/mL).Vitamin D decreased mortality in all 56 trials analysed together (5,920/47,472 (12.5%) vs 6,077/47,814 (12.7%); RR 0.97 (95% confidence interval (CI) 0.94 to 0.99); P = 0.02; I2 = 0%). More than 8% of participants dropped out. 'Worst-best case' and 'best-worst case' scenario analyses demonstrated that vitamin D could be associated with a dramatic increase or decrease in mortality. When different forms of vitamin D were assessed in separate analyses, only vitamin D3 decreased mortality (4,153/37,817 (11.0%) vs 4,340/38,110 (11.4%); RR 0.94 (95% CI 0.91 to 0.98); P = 0.002; I2 = 0%; 75,927 participants; 38 trials). Vitamin D2, alfacalcidol and calcitriol did not significantly affect mortality. A subgroup analysis of trials at high risk of bias suggested that vitamin D2 may even increase mortality, but this finding could be due to random errors. Trial sequential analysis supported our finding regarding vitamin D3, with the cumulative Z-score breaking the trial sequential monitoring boundary for benefit, corresponding to 150 people treated over five years to prevent one additional death. We did not observe any statistically significant differences in the effect of vitamin D on mortality in subgroup analyses of trials at low risk of bias compared with trials at high risk of bias; of trials using placebo compared with trials using no intervention in the control group; of trials with no risk of industry bias compared with trials with risk of industry bias; of trials assessing primary prevention compared with trials assessing secondary prevention; of trials including participants with vitamin D level below 20 ng/mL at entry compared with trials including participants with vitamin D levels equal to or greater than 20 ng/mL at entry; of trials including ambulatory participants compared with trials including institutionalised participants; of trials using concomitant calcium supplementation compared with trials without calcium; of trials using a dose below 800 IU per day compared with trials using doses above 800 IU per day; and of trials including only women compared with trials including both sexes or only men. Vitamin D3 statistically significantly decreased cancer mortality (RR 0.88 (95% CI 0.78 to 0.98); P = 0.02; I2 = 0%; 44,492 participants; 4 trials). Vitamin D3 combined with calcium increased the risk of nephrolithiasis (RR 1.17 (95% CI 1.02 to 1.34); P = 0.02; I2 = 0%; 42,876 participants; 4 trials). Alfacalcidol and calcitriol increased the risk of hypercalcaemia (RR 3.18 (95% CI 1.17 to 8.68); P = 0.02; I2 = 17%; 710 participants; 3 trials).
AUTHORS' CONCLUSIONS:
Vitamin D3 seemed to decrease mortality in elderly people living independently or in institutional care. Vitamin D2, alfacalcidol and calcitriol had no statistically significant beneficial effects on mortality. Vitamin D3 combined with calcium increased nephrolithiasis. Both alfacalcidol and calcitriol increased hypercalcaemia. Because of risks of attrition bias originating from substantial dropout of participants and of outcome reporting bias due to a number of trials not reporting on mortality, as well as a number of other weaknesses in our evidence, further placebo-controlled randomised trials seem warranted.


Jerry Goddard,  M.D.,  SIU School of MedicineJanuary 31, 2014
Carbondale, IL




     

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