Continuing Education Activity

Vitamin D is a fat-soluble vitamin used by the body for normal bone development and maintenance by increasing the absorption of calcium, magnesium, and phosphate. A circulating level of 25-hydroxyvitamin D greater than 30 ng/mL is required to maintain a healthy level of vitamin D. Vitamin D deficiency can lead to an array of problems, most notably rickets in children and osteoporosis in adults. The fortification of milk with vitamin D in the 1930s was effective in eradicating rickets in the world. However, vitamin D deficiency is more prevalent than ever, and high-risk populations should be screened. Many conflicting studies are now showing an association between vitamin D deficiency and cancer, cardiovascular disease, diabetes, autoimmune diseases, and depression. This activity reviews the evaluation and management of vitamin D deficiency and explains the role of the interprofessional team in improving care for patients with this condition.

Objectives:

• Review the etiology of vitamin D deficiency.
• Discuss the pathophysiology and epidemiology of vitamin D deficiency.
• Review evaluation and management of vitamin D deficiency.
• Outline the role of the interprofessional team in evaluating and managing patients with vitamin D deficiency.

Introduction

Vitamin D is a fat-soluble vitamin that plays an important role in calcium homeostasis and bone metabolism. Vitamin D deficiency can lead to osteomalacia and rickets in children and osteomalacia in adults. The fortification of milk with vitamin D in the 1930s was effective in eradicating rickets in the world. However, subclinical vitamin D deficiency is still widely prevalent in both developed and developing countries, with a worldwide prevalence of up to 1 billion.[1]  This subclinical vitamin-D deficiency is associated with osteoporosis, increased risk of falls, and fragility fractures. Many conflicting recent studies are now showing an association between vitamin D deficiency and cancer, cardiovascular disease, diabetes, autoimmune diseases, and depression.[2]

Etiology

Dermal synthesis and dietary intake (fatty fish livers, fortified food) are the major sources of ergocalciferol (D2) and cholecalciferol (D3), both of which are converted to 25-hydroxy-vitamin D2 (25-OH-D2) and 25-hydroxy-vitamin D3 (25-OH-D3) respectively in the liver by the enzyme hepatic enzyme 25–hydroxylase. 25-OH-D2 and 25-OH-D3 are then converted to the most active form of vitamin D (1,25 dihydroxyvitamin D) by the enzyme 1-alpha-hydroxylase in the kidneys. This active 1,25 dihydroxyvitamin D increases intestinal absorption of calcium and bone resorption and decreases renal excretion of calcium and phosphate. Vitamin D deficiency can result from several causes.

1. Decreased dietary intake and/or absorption

Certain malabsorption syndromes such as celiac disease, short bowel syndrome, gastric bypass, inflammatory bowel disease, chronic pancreatic insufficiency, and cystic fibrosis may lead to vitamin D deficiency. Lower vitamin D intake orally is more prevalent in the elderly population. [3]

2. Decreased sun exposure

Twenty minutes of sunshine daily with over 40% of skin exposed is required to prevent vitamin D deficiency.[4] Cutaneous synthesis of vitamin D declines with aging. Dark-skinned people have less cutaneous vitamin D synthesis. Decreased exposure to the sun, as seen in individuals who are institutionalized or have prolonged hospitalizations, can also lead to vitamin D deficiency. [5] Effective sun exposure is decreased in individuals who use sunscreens consistently. 

3. Decreased endogenous synthesis

Individuals with chronic liver disease such as cirrhosis can have defective 25-hydroxylation, leading to deficiency of active vitamin D. Defects in 1-alpha 25-hydroxylation can be seen in hyperparathyroidism, renal failure, and 1-alpha hydroxylase deficiency. 

4. Increased hepatic catabolism

Medications such as phenobarbital, carbamazepine, dexamethasone, nifedipine, spironolactone, clotrimazole, and rifampin induce hepatic p450 enzymes, which activate the degradation of vitamin D.[6]

5. End organ resistance

End-organ resistance to vitamin D can be seen in hereditary vitamin D-resistant rickets.

Epidemiology

Vitamin D deficiency is a global public health issue. About 1 billion people worldwide have vitamin D deficiency, while 50% of the population has vitamin D insufficiency.[1] The prevalence of patients with vitamin D deficiency is highest in the elderly, obese patients, nursing home residents, and hospitalized patients. The prevalence of vitamin D deficiency was 35% higher in obese subjects irrespective of latitude and age.[7] In the United States, about 50% to 60% of nursing home residents and hospitalized patients had vitamin D deficiency. [8][9] Vitamin D deficiency may be related to populations who have higher skin melanin content and who use extensive skin coverage, particularly in Middle Eastern countries. In the United States, 47% of African American infants and 56% of Caucasian infants have vitamin D deficiency, while over 90% of infants in Iran, Turkey, and India have vitamin D deficiency. In the adult population, 35% of adults in the United States are vitamin D deficient whereas over 80% of adults in Pakistan, India, and Bangladesh are Vitamin D deficient. In the United States, 61% of the elderly population is vitamin D deficient whereas 90% in Turkey, 96% in India, 72% in Pakistan, and 67% in Iran were vitamin D deficient.[10]

Pathophysiology

Vitamin D plays a crucial role in calcium homeostasis and bone metabolism. With chronic and/or severe vitamin D deficiency, a decline in intestinal calcium and phosphorus absorption leads to hypocalcemia, leading to secondary hyperparathyroidism. This secondary hyperparathyroidism then leads to phosphaturia and accelerated bone demineralization. This can further result in osteomalacia and osteoporosis in adults and osteomalacia and rickets in children.

History and Physical

The majority of patients with vitamin D deficiency are asymptomatic. However, even mild chronic vitamin D deficiency can lead to chronic hypocalcemia and hyperparathyroidism, which can contribute risk of osteoporosis, falls, and fractures, especially in older individuals. Patients with prolonged and severe vitamin D deficiency can experience symptoms associated with secondary hyperparathyroidism, including bone pain, arthralgias, myalgias, fatigue, muscle twitching (fasciculations), and weakness. Fragility fractures may result from chronic vitamin D deficiency, leading to osteoporosis. In children, irritability, lethargy, developmental delay, bone changes, or fractures can be symptoms of vitamin D deficiency.

Evaluation

High-risk individuals shall be evaluated for vitamin D deficiency. Vitamin D sufficiency or deficiency is evaluated by the measurement of serum 25-hydroxyvitamin D. Optimal serum levels of 25-hydroxyvitamin D are still controversial. There are substantial differences in mineral metabolism amongst different races. African Americans, for example, have higher bone density and low fracture risk compared to other races. Further, the effects of calcium and vitamin D supplementation in the non-White population have not yet been completely evaluated or reported. The International Society for Clinical Densitometry and the International Osteoporosis Foundation recommend minimum serum levels of 25-hydroxyvitamin D of 30 ng/mL to minimize the risk of falls and fractures in older individuals. [11] There is insufficient data about the maximum safe upper level of serum 25-hydroxyvitamin D; however, at high levels such as above 100 ng/mL, there is a potential risk of toxicity due to secondary hypercalcemia. In patients where vitamin-D deficiency has been diagnosed, it is important to evaluate for secondary hyperparathyroidism, and levels of parathyroid hormone and serum calcium shall be checked.

Treatment / Management

Several preparations of vitamin D are available. Vitamin D3 (cholecalciferol), compared with vitamin D2 (ergocalciferol), has been shown to be more efficacious in achieving optimal 25-hydroxyvitamin D levels, thus favoring vitamin D3 as a treatment of choice. [12]

Prevention of Vitamin D Deficiency

Adults less than 65 years of age who do not have year-round effective sun exposure shall consume 600 to 800 international units of vitamin D3 daily to prevent deficiency. Older adults 65 years of age or more shall consume 800 to 1000 international units of vitamin D3 daily to prevent deficiency and reduce the risk of fractures and falls.

Management of Vitamin D Deficiency

The amount of vitamin D required to treat the deficiency depends largely on the degree of the deficiency and underlying risk factors.

• Initial supplementation for 8 weeks with Vitamin D3, either 6,000 IU daily or 50,000 IU weekly, can be considered.[13] Once the serum 25-hydroxyvitamin D level exceeds 30 ng/mL, a daily maintenance dose of 1,000 to 2,000 IU is recommended.
• A higher-dose initial supplementation with vitamin D3 at 10,000 IU daily may be needed in high-risk adults who are vitamin D deficient (African Americans, Hispanics, obese, taking certain medications, malabsorption syndrome). Once serum 25-hydroxyvitamin D level exceeds 30ng/mL, 3000 to 6000 IU/day maintenance dose is recommended.
• Children who are vitamin D deficient require 2000 IU/day of vitamin D3 or 50,000 IU of vitamin D3 once weekly for 6 weeks. Once the serum 25(OH)D level exceeds 30 ng/mL, 1000 IU/day maintenance treatment is recommended. According to the American Academy of Pediatrics, breastfed infants and children who consume less than 1 L of vitamin D-fortified milk need 400 IU of vitamin D supplementation.
• Calcitriol can be considered where the deficiency persists despite treatment with vitamin D2 and/or D3. The serum calcium level shall be closely monitored in these individuals due to an increased risk of hypercalcemia secondary to calcitriol.
• Calcidiol can be considered in patients with fat malabsorption or severe liver disease.

Differential Diagnosis

• Celiac sprue

• Cystic fibrosis

• End-stage liver disease

• Inadequate sunlight exposure

• Lack of dietary intake

• Use of antiepileptic medications

Pertinent Studies and Ongoing Trials

A meta-analysis of 18 randomized controlled trials (RCT) including over 57,000 subjects found that intake of daily doses of vitamin D supplements decreased total mortality rates.[14] In the Women’s Health Initiative, calcium and vitamin D supplementation decreased the risk of total cancer, breast cancer, and colorectal cancer while not changing total mortality.[15] One RCT showed that calcium plus vitamin D substantially reduced all cancer risk in postmenopausal women.[16] In a meta-analysis study from three randomized controlled trials, vitamin D supplementation was found to reduce the rate of COPD exacerbations in patients with vitamin D levels below 25 nmol/L.[17]

Toxicity and Adverse Effect Management

Vitamin D is a fat-soluble vitamin; hence, toxicity is possible, although rarely noted. Hypervitaminosis D results from excess oral intake and not due to excessive sunlight exposure. Toxicity has been reported at a serum 25-hydroxyvitamin D level of more than 88 ng/mL. Acute intoxication can lead to acute hypercalcemia that can cause confusion, anorexia, vomiting, polyuria, polydipsia, and muscle weakness. Chronic intoxication can lead to nephrocalcinosis and bone pain.

Staging

The severity of vitamin D deficiency is divided into mild, moderate, and severe.[18]

Mild deficiency: 25-hydroxyvitamin D less than 20 ng/mL

Moderate deficiency: 25-hydroxyvitamin D less than 10 ng/mL

Severe deficiency: 25-hydroxyvitamin D less than 5 ng/mL

Enhancing Healthcare Team Outcomes

Vitamin D deficiency is often overlooked in outpatient and inpatient settings. According to the U.S. Preventive Services Task Force (USPSTF), universal screening for vitamin D levels is not recommended; however, it is important to note that screening for vitamin D deficiency in asymptomatic high-risk individuals is paramount in preventing future complications. High-risk populations include nursing home residents, elderly patients, women with osteoporosis, African American/Hispanic individuals, hospitalized patients, patients with chronic kidney disease, chronic liver disease, and patients with malabsorption syndromes.[9]

Review Questions

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References

1.

Nair R, Maseeh A. Vitamin D: The "sunshine" vitamin. J Pharmacol Pharmacother. 2012 Apr;3(2):118-26. [PMC free article: PMC3356951] [PubMed: 22629085]

2.

Holick MF. Vitamin D: important for prevention of osteoporosis, cardiovascular heart disease, type 1 diabetes, autoimmune diseases, and some cancers. South Med J. 2005 Oct;98(10):1024-7. [PubMed: 16295817]

3.

Czernichow S, Fan T, Nocea G, Sen SS. Calcium and vitamin D intake by postmenopausal women with osteoporosis in France. Curr Med Res Opin. 2010 Jul;26(7):1667-74. [PubMed: 20446889]

4.

Naeem Z. Vitamin d deficiency- an ignored epidemic. Int J Health Sci (Qassim). 2010 Jan;4(1):V-VI. [PMC free article: PMC3068797] [PubMed: 21475519]

5.

Thomas MK, Lloyd-Jones DM, Thadhani RI, Shaw AC, Deraska DJ, Kitch BT, Vamvakas EC, Dick IM, Prince RL, Finkelstein JS. Hypovitaminosis D in medical inpatients. N Engl J Med. 1998 Mar 19;338(12):777-83. [PubMed: 9504937]

6.

Gröber U, Kisters K. Influence of drugs on vitamin D and calcium metabolism. Dermatoendocrinol. 2012 Apr 01;4(2):158-66. [PMC free article: PMC3427195] [PubMed: 22928072]

7.

Pereira-Santos M, Costa PR, Assis AM, Santos CA, Santos DB. Obesity and vitamin D deficiency: a systematic review and meta-analysis. Obes Rev. 2015 Apr;16(4):341-9. [PubMed: 25688659]

8.

Elliott ME, Binkley NC, Carnes M, Zimmerman DR, Petersen K, Knapp K, Behlke JM, Ahmann N, Kieser MA. Fracture risks for women in long-term care: high prevalence of calcaneal osteoporosis and hypovitaminosis D. Pharmacotherapy. 2003 Jun;23(6):702-10. [PubMed: 12820811]

9.

Kennel KA, Drake MT, Hurley DL. Vitamin D deficiency in adults: when to test and how to treat. Mayo Clin Proc. 2010 Aug;85(8):752-7; quiz 757-8. [PMC free article: PMC2912737] [PubMed: 20675513]

10.

Palacios C, Gonzalez L. Is vitamin D deficiency a major global public health problem? J Steroid Biochem Mol Biol. 2014 Oct;144 Pt A:138-45. [PMC free article: PMC4018438] [PubMed: 24239505]

11.

Dawson-Hughes B, Mithal A, Bonjour JP, Boonen S, Burckhardt P, Fuleihan GE, Josse RG, Lips P, Morales-Torres J, Yoshimura N. IOF position statement: vitamin D recommendations for older adults. Osteoporos Int. 2010 Jul;21(7):1151-4. [PubMed: 20422154]

12.

Tripkovic L, Lambert H, Hart K, Smith CP, Bucca G, Penson S, Chope G, Hyppönen E, Berry J, Vieth R, Lanham-New S. Comparison of vitamin D2 and vitamin D3 supplementation in raising serum 25-hydroxyvitamin D status: a systematic review and meta-analysis. Am J Clin Nutr. 2012 Jun;95(6):1357-64. [PMC free article: PMC3349454] [PubMed: 22552031]

13.

Holick MF, Binkley NC, Bischoff-Ferrari HA, Gordon CM, Hanley DA, Heaney RP, Murad MH, Weaver CM., Endocrine Society. Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2011 Jul;96(7):1911-30. [PubMed: 21646368]

14.

Autier P, Gandini S. Vitamin D supplementation and total mortality: a meta-analysis of randomized controlled trials. Arch Intern Med. 2007 Sep 10;167(16):1730-7. [PubMed: 17846391]

15.

Bolland MJ, Grey A, Gamble GD, Reid IR. Calcium and vitamin D supplements and health outcomes: a reanalysis of the Women's Health Initiative (WHI) limited-access data set. Am J Clin Nutr. 2011 Oct;94(4):1144-9. [PMC free article: PMC3173029] [PubMed: 21880848]

16.

Lappe JM, Travers-Gustafson D, Davies KM, Recker RR, Heaney RP. Vitamin D and calcium supplementation reduces cancer risk: results of a randomized trial. Am J Clin Nutr. 2007 Jun;85(6):1586-91. [PubMed: 17556697]

17.

Jolliffe DA, Greenberg L, Hooper RL, Mathyssen C, Rafiq R, de Jongh RT, Camargo CA, Griffiths CJ, Janssens W, Martineau AR. Vitamin D to prevent exacerbations of COPD: systematic review and meta-analysis of individual participant data from randomised controlled trials. Thorax. 2019 Apr;74(4):337-345. [PubMed: 30630893]

18.

Gani LU, How CH. PILL Series. Vitamin D deficiency. Singapore Med J. 2015 Aug;56(8):433-6; quiz 437. [PMC free article: PMC4545131] [PubMed: 26311908]

Disclosure: Omeed Sizar declares no relevant financial relationships with ineligible companies.

Disclosure: Swapnil Khare declares no relevant financial relationships with ineligible companies.

Disclosure: Amandeep Goyal declares no relevant financial relationships with ineligible companies.

Disclosure: Amy Givler declares no relevant financial relationships with ineligible companies.