Evaluating and Treating Vitamin D Deficiency

Margaret A. Fitzgerald, DNP, FNP-BC, NP-C, FAANP, CSP, FAAN, DCC, FNAP

Vitamin D has long been recognized as essential for the efficient absorption and utilization of dietary calcium as well as for bone and muscle health.1 Intestinal calcium absorption is significantly enhanced by the presence of adequate vitamin D and, conversely, is reduced in deficiency of this important micronutrient.1 Over the past 20 years, research has highlighted an association between multiple nonskeletal chronic diseases and vitamin D deficiency,2,3 including certain cancers,4-6 cardiovascular diseases,7,8 autoimmune diseases,9-11 metabolic disorders,12 and infectious diseases.13 Indeed, many observational studies have shown that patients with low vitamin D levels are at high risk for poor COVID outcomes, including a 3.7-fold increase in the odds of dying from COVID-19 for those with a vitamin D level below 20 ng/mL.14 Low levels of vitamin D also have been associated with increased risk for hospitalization for COVID-19 and for developing severe and lethal disease.14 In addition, there is also evidence of an association between vitamin D deficiency and testing positive for COVID-19; however, randomized trials are needed to determine whether vitamin D affects COVID-19 acquisition risk.15 Numerous clinical trials are currently exploring the role of vitamin D status in COVID-19, including studies focused on using vitamin D for prevention and treatment.14

As an inhibitor of abnormal cellular growth, vitamin D is needed to help with cell differentiation and thereby minimize abnormal cell proliferation; this abnormality is a key step in cancer development.1,4 Vitamin D plays a role in the maintenance of normoglycemia by stimulating insulin secretion in response to increased blood glucose. Ongoing large-scale randomized clinical trials are exploring the effect of vitamin D supplementation on glycemic control and incidence of diabetes mellitus.12 Because vitamin D receptors are expressed by most cells of the immune system, vitamin D plays an important role as an immunomodulator.16 When vitamin D is available in physiologic amounts, this micronutrient acts to decrease renin production, therefore contributing to blood pressure control.17

Sources of Vitamin D

A combination of regular dietary intake of foods rich in vitamin D along with regular periods of skin exposure to the sun should provide the body with an adequate supply of this important micronutrient. However, the average person’s lifestyle allows little time to be spent outdoors, and diets are usually replete with highly processed foods; thus, vitamin D intake and synthesis are seldom adequate to avoid deficiency. Fatty fish and vitamin D–enriched dairy products can supply some of the estimated amount of vitamin D that is needed daily. The recommended dietary allowance (RDA, or the average daily intake sufficient to meet the nutrient requirements of nearly all [97%–98%] healthy individuals) of vitamin D, established by a Food and Nutrition Board committee, is 400 IU for infants (0-12 months), 600 IU for persons aged 1-69 years, and 800 IU for those 70 and older. However, recommendations for daily vitamin D intake vary across countries and professional societies. For example, the Endocrine Society notes that, to maintain serum 25(OH)D levels above 75 nmol/L (30 ng/mL), adults might need at least 1,500–2,000 IU/day of supplemental vitamin D, and children and adolescents might need at least 1,000 IU/day. At the same time, the United Kingdom government recommends intakes of 400 IU/day for its citizens aged 4 years and older. Nonetheless, the average dietary intake nationwide is typically less than the body’s vitamin D requirement, as reflected in these governmental and society recommendations. Many clinicians and patients believe that adequate vitamin D intake can be obtained by diet alone, but with the exception of fatty fish, the vitamin D content of most foods (including fortified dairy products) is relatively low or nonexistent (Table).18,19

Table. Why Most Dietary Sources of Vitamin D Do Not Contain Sufficient Amounts of Vitamin D to Satisfy Daily Requirements

Source IUs per Serving Percent DV
Cod liver oil, 1 tablespoon 1,360 170
Trout (rainbow), farmed, cooked, 3 oz 645 81
Salmon (sockeye), cooked, 3 oz 570 71
Mushrooms, white, raw, sliced, exposed to UV light, ½ cup 366 46
Soy, almond, and oat milks, vitamin D fortified, various brands, 1 cup 100-144 13-18
Milk, 2% milkfat, vitamin D fortified, 1 cup 120 15
Ready-to-eat cereal, fortified with 10% of the DV for vitamin D, 0.75-1 cup* 80 10
Sardines (Atlantic), canned in oil, drained, 2 sardines 46 6
Egg, 1 large (vitamin D is in yolk) 44 6
Liver, beef, braised, 3 oz 42 5
Tuna fish, canned in water, drained, 3 oz 40 5
Cheese, cheddar, 1 ounce 12 2
Mushrooms, portabella, raw, diced, ½ cup 4 1

IUs, international units; DV, daily value.

*More heavily fortified cereals might provide more of the DV.

NOTE: The DV for vitamin D on the new Nutrition Facts and Supplement Facts labels and used for the values in this table is 20 mcg (800 IU) for adults and children aged 4 years and older. The FDA required all manufacturers to use these new labels by January 2021. Note that DVs are used on food and dietary supplement labels and suggest how much of a nutrient a serving of the food or supplement provides in the context of a total daily diet. Recommended Dietary Allowance (RDA) are recommended average daily intakes of a nutrient for healthy people.

Source: Adapted from the National Institutes of Health Office of Dietary Supplements. Vitamin D. Fact Sheet for Health Professionals.

Risk Factors

A number of factors influence the body’s ability to synthesize vitamin D from sun exposure to the skin, including the skin’s melanin content.1 A person with a darker skin tone will synthesize less vitamin D with sun exposure compared with a person who has a lighter skin tone. The use of sunscreen, while helpful in minimizing the risk of certain skin cancers and other solar damage, likely increases the risk of vitamin D deficiency, as application of sunscreen with a sun protection factor of 30 reduces the capacity of the skin to produce vitamin D by as much as 95%.20 Obviously, individuals who spend little time outdoors have a significant risk for vitamin D deficiency.

The time of year and place of residence also influence sun-induced vitamin D synthesis, with winter sun and northern latitudes providing the weakest effect. Even people who are regularly involved in outdoor activities that facilitate exposure to sunshine can have vitamin D deficiency if little skin is left sun exposed. General guidelines about the amount of sun exposure needed to maintain adequate vitamin D levels are difficult to provide. However, it has been suggested by some researchers that approximately 5 to 30 minutes of sun exposure between 10 AM and 3 PM at least twice a week to the face, arms, legs, or back without sunscreen usually lead to sufficient vitamin D synthesis.18 This level of sun exposure is unlikely to induce sunburn or increase skin cancer risk. At the same time, in parts of the country with a cold winter, even this degree of sun exposure is not likely to be achievable. A study conducted in Minnesota demonstrated that fewer than half of days provided enough solar UVB radiation at noon to effect cutaneous vitamin D production.19

Certain prescription medications and supplements, including phenytoin (Dilantin), phenobarbital, and St. John’s wort, are potentially vitamin D–depleting. As a result, patients taking these medications and supplements require two to five times the recommended daily amount of vitamin D. Vitamin D deficiency is also common in the presence of hepatic or renal disease as well as after gastric bypass. Body mass index ≥30 kg/m2 is associated with lower serum 25-hydroxyvitamin D (25(OH)D) levels compared with nonobese body mass index values.16 Additional risk factors for vitamin D deficiency include age ≥65 years or ≤25 years and fat malabsorption due to conditions such as inflammatory bowel disease and celiac disease.1,19

A Common Problem

Vitamin D deficiency is a common problem.19 The US Centers for Disease Control and Prevention reported that the percentage of adults achieving vitamin D sufficiency has declined from about 60% in 1988-1994 to approximately 30% in 2001-2004 in whites and from about 10% to approximately 5% in African Americans during this same period, and more people have been found to be severely deficient in vitamin D.19 Many patients routinely encountered in clinical practice are deficient in vitamin D.19

• 25%-50% of nursing home or housebound residents (mean age, 81 years)

• 44% of elderly ambulatory women (age >80 years)

• 42% of African American women (age 15-49 years)

• 57% of hospitalized adult patients (mean age, 62 years)

The US Preventive Services Task Force has stated in a previous recommendation that there is insufficient evidence to recommend screening for vitamin D deficiency in asymptomatic adults,21 and a more recent draft recommendation statement notes that the balance of benefits and harms of screening for vitamin D deficiency in asymptomatic adults cannot be determined due to a lack of evidence on the benefits of screening for vitamin D deficiency.22 However, I encounter patients with vitamin D deficiency daily in my practice. While testing those at high risk, once—only once—in 15 years of testing did I have a patient who was actually at an acceptable level of vitamin D. Vitamin D deficiency or depletion is asymptomatic because vitamin D3 is stored in fat and has a long half-life; thus, the deficiency takes a while to show up after conditions contributing to vitamin D deficiency or depletion have begun.

Musculoskeletal Effects

In infants and children, severe vitamin D deficiency results in the failure of growing bone to mineralize, resulting in rickets.1 Although fortified milk has made rickets rare in the United States, it is still reported periodically, most often among African American children and infants and immigrants from Asia, Africa, and the Middle East.18 One reason for vitamin D deficiency in infants and children is prolonged breastfeeding without recommended vitamin D supplements, especially in dark-skinned infants breast-fed by mothers themselves not vitamin D replete.

In contrast, adult bones are no longer growing but are in a state of constant cell renewal and therefore susceptible to problems related to vitamin D deficiency, including persistent, nonspecific musculoskeletal pain.1 To appreciate this, consider some of the clinical effects of vitamin D deficiency. Without sufficient amounts of vitamin D, intestinal calcium absorption is inadequate. The resulting calcium deficiency prompts an increase in production and secretion of parathyroid hormone (PTH). PTH acts at the level of the kidney, where it facilitates an increase in tubular calcium reabsorption and stimulates renal production of 1,25-dihydroxyvitamin D, the hormonally active form of vitamin D. With a continued deficiency, unusually high levels of PTH allow osteoclast activation so that bone can serve as a calcium source. In addition, the continued presence of high levels of circulating PTH cause phosphate to be wasted via the kidney. The calcium phosphate product in the circulation decreases and becomes inadequate to mineralize the bone properly, potentially leading to osteopenia and osteoporosis. At the same time, osteoblasts deposit a rubbery collagen matrix layer on the skeleton. This surface cannot provide sufficient structural support; the clinical effect is osteomalacia. This abnormal collagen matrix can absorb fluids and expand. With expansion, pressure builds under the richly innervated periosteal covering. This process likely, at least in part, explains the origin of the constant, dull bone ache often reported in patients with osteomalacia. In these patients, minimal pressure applied with a fingertip on the sternum, anterior tibia, radius, or ulna elicits a painful response. Since vitamin D deficiency symptoms overlap considerably with those of fibromyalgia, one condition is often mistaken for the other.1

Vitamin D deficiency has also been long recognized as a cause of muscle weakness and muscle aches and pain in all ages. Aside from osteomalacia and localized bone pain, antigravity muscle weakness, difficulty rising from a chair or walking, and pseudofractures are also noted in persons with vitamin D deficiency. These findings resolve with appropriate treatment. Vitamin D deficiency also contributes to the development of hypocalcemia and hypophosphatemia. In this situation, unless the vitamin D deficiency is addressed, replacing calcium or phosphate alone does not restore the body to homeostasis.

Diagnosis

The preferred test for assessment of vitamin D status is measurement of serum 25(OH)D.18,19 The results of this test are minimally influenced by recent dietary intake or recent sun exposure, and it is considered the most accurate functional indicator of vitamin D stores. The serum level of the biologically active form of vitamin D—1,25-dihydroxy vitamin D (1,25(OH)2D)—is not an accurate indicator of nutritional vitamin D status because levels of 1,25(OH)2D typically are not altered until vitamin D deficiency is well advanced. The cost of testing ranges from $50 to $220 per test in commercial laboratories.23

Opinions differ on what constitutes deficiency.19 Physiologic deficiency is defined as a level of serum 25(OH)D that is sufficiently low to cause an increase in PTH levels. Production and secretion of PTH increases to correct low calcium levels via increased bone turnover and accelerated bone loss, effects that clearly occur later in the disease process. The National Academy of Medicine has concluded that persons are at risk for vitamin D deficiency at serum 25(OH)D concentrations <30 nmol/L (<12 ng/mL); some are at risk for inadequacy at levels ranging from 30 to 50 nmol/L (12-20 ng/mL); and practically all people are sufficient at levels ≥50 nmol/L (≥20 ng/mL).18

Treatment and Prevention of Recurrence

Vitamin D3 is the preferred form of the micronutrient for the treatment of vitamin D deficiency and for maintenance of vitamin D levels. Low-dose (400-800 IU/d) vitamin D3 supplementation is not sufficient to correct a deficiency. Approximately 100 IU given daily for three months will increase the 25(OH)D level by just 1 ng/mL (2.5 nmol/L); considered in multiples of 100 IU, 400 IU taken for three months will increase the level by 4 ng/mL (10 nmol/L).

For treatment of vitamin D deficiency in adults, a dose of 50,000 IU of vitamin D3 by mouth once per week for at least eight weeks is advised, with extension of this course to 16 weeks if the initial 25(OH)D level was below 30 ng/mL.1 For long-term prevention, patients should be given 50,000 IU of vitamin D3 once or twice per month plus 1,000 to 2,000 IU of vitamin D3 per day. Consuming a diet rich in vitamin D–containing foods and exposing the skin to a sensible and safe level of sunlight can aid in preventing the condition. A confirmation of vitamin D correction should be obtained after the recommended length of high-dose repletion therapy.

For a person following a vegan or vegetarian diet who has vitamin D deficiency, vitamin D2 might be preferred.19 Whether vitamin D2 or vitamin D3 is used for treatment, it is recommended that it be consumed with a meal containing fat to promote maximum absorption.19 People who are obese likely need larger-than usual intakes of vitamin D to achieve 25(OH)D levels comparable to those of normal-weight people.

Vitamin D Toxicity: An Uncommon Problem

Excessive supplementation, though not excessive sun exposure, can cause vitamin D toxicity, leading to a variety of problems, including calcium deposition into solid organs. This is rarely seen and is usually a consequence of chronic use of 10,000 IU/d of vitamin D3.

Conclusion

On a personal note, I have treated numerous patients for vitamin D deficiency, with many achieving great health benefits. Maintaining a high index of suspicion for this common clinical problem is the first step in successful diagnosis and treatment. •

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References
1. Holick MF. Vitamin D deficiency. N Engl J Med. 2007;357(3):266-281.
2. Chowdhury R, Kunutsor S, Vitezova A, et al. Vitamin D and risk of cause-specific death: systematic review and meta-analysis of observational cohort and randomised intervention studies. BMJ. 2014;348:g1903.
3. Theodoratou E, Tzoulaki I, Zgaga L, Ioannidis JPA. Vitamin D and multiple health outcomes: umbrella review of systematic reviews and meta-analyses of observational studies and randomised trials. BMJ. 2014;348:g2035.
4. Keum N, Lee DH, Greenwood DC, Manson JE, Giovannucci E. Vitamin D supplementation and total cancer incidence and mortality: a meta-analysis of randomized controlled trials. Ann Oncol. 2019;30:733-743.
5. Budhathoki S, Hidaka A, Yamaji T, et al. Plasma 25-hydroxyvitamin D concentration and subsequent risk of total and site specific cancers in Japanese population: large case-cohort study within Japan Public Health Center-based Prospective Study cohort. BMJ. 2018 Mar 7;360:k671.
6. Jenab M, Bueno-de-Mesquita HB, Ferrari P, et al. Association between pre-diagnostic circulating vitamin D concentration and risk of colorectal cancer in European populations: a nested case-control study. BMJ. 2010 Jan 21;340:b5500.
7. Wang TJ, Pencina MJ, Booth SL, et al. Vitamin D deficiency and risk of cardiovascular disease. Circulation. 2008;117:503-511.
8. Al Mheid I, Quyyumi AA. Vitamin D and cardiovascular disease: controversy unresolved. J Am Coll Cardiol. 2017;70(1):89-100.
9. Lips P, Eekhoff M, van Schoor N, et al. Vitamin D and type 2 diabetes. J Steroid Biochem Mol Biol. 2017;173:280-285.
10. Sabetta JR, DePetrillo P, Cipriani RJ, Smardin J, Burns LA, Landry ML. Serum 25-hydroxyvitamin D and the incidence of acute viral respiratory tract infections in healthy adults. PLoS One. 2010;5:e11088.
11. Rosen Y, Daich J, Soliman I, Brathwaite E, Shoenfeld Y. Vitamin D and autoimmunity. Scand J Rheumatol. 2016;45:439-447.
12. Jeffery LE, Raza K, Hewison M. Vitamin D in rheumatoid arthritis-towards clinical application. Nat Rev Rheumatol. 2016;12(4):201-210.
13. Burton JM, Costello FE. Vitamin D in multiple sclerosis and central nervous system demyelinating disease–a review. J Neuroophthalmol. 2015;35(2):194-200.
14. McCall B. Medscape. Vitamin D deficiency in COVID-19 quadrupled death rate. https://www.medscape.com/viewarticle/942497#vp_1. Accessed January 18, 2021.
15. Meltzer DO, Best TJ, Zhang H, et al. Association of vitamin D status and other clinical characteristics with COVID-19 test results. JAMA Netw Open. 2020;3(9):e2019722.
16. Bouillon R, Carmeliet G, Verlinden L, et al. Vitamin D and human health: lessons from vitamin D receptor null mice. Endocr Rev. 2008;29(6):726-776.
17. Forman JP, Williams JS, Fisher NDL. Vitamin D. Plasma 25-hydroxyvitamin D and regulation of the renin-angiotensin system in humans. Hypertension. 2010;55:1283-1288.
18. National Institutes of Health Office of Dietary Supplements. Vitamin D. Fact Sheet for Health Professionals. https://ods.od.nih.gov/factsheets/VitaminD-HealthProfessional. Accessed January 18, 2021.
19. Kennel KA, Drake MT, Hurley DL. Vitamin D deficiency in adults: when to test and how to treat. Mayo Clin Proc. 2010;85:752-758.
20. Wacker M, Holick MF. Sunlight and vitamin D. Dermatoendocrinol. 2013;5:51-108.
21. US Preventive Services Task Force. Final recommendation statement. Vitamin D deficiency: screening. www.uspreventiveservicestaskforce.org/Page/Document/RecommendationStatementFinal/vitamin-d-deficiency-screening. Accessed January 18, 2021.
22. Kopes-Kerr C. Should family physicians screen for vitamin D deficiency? Am Fam Physician. 2013;15:87(8). https://www.aafp.org/afp/2013/0415/od2.html. Accessed January 21, 2021.
23. US Preventive Services Task Force. Draft Recommendation Statement. Vitamin D deficiency in adults: screening. www.uspreventiveservicestaskforce.org/uspstf/draft-recommendation/vitamin-d-deficiency-screening-adults#tab. Accessed January 21, 2021.