Hypovitaminosis D

A common deficiency with pervasive consequences

Abstract

Hypovitaminosis D is a common syndrome with well-established risk factors. Only recently, however, are the expansive implications of vitamin D deficiency becoming recognized, including cardiovascular complications, cancer, and dementia. The increased attention to the role of vitamin D has made its assessment more crucial in comprehensive patient management.

Figure

Box 1

Hypovitaminosis D, an insufficiency or deficiency of vitamin D, can affect men and women across the lifespan. This fat-soluble vitamin affects mineral metabolism and numerous other physiologic functions. Without adequate levels of vitamin D, patients are at risk for dental concerns such as periodontal disease, dental caries, and tooth loss; diabetes; cardiovascular and autoimmune diseases; inflammation; neuromusculoskeletal illness; and malignancies. Older adults with hypovitaminosis D are at increased risk of falls and fractures, osteoporosis, hyperparathyroidism, impaired cognitive function, and depression.¹

Hypovitaminosis D may be classified as vitamin D deficiency or vitamin D insufficiency. In adults, vitamin D deficiency is defined as a serum calcidiol (25-hydroxy-vitamin D) level of less than 20 ng/mL (50 nmol/L). Vitamin D insufficiency is defined as a serum calcidiol level of 20 to 30 ng/mL (50 to 75 nmol/L).²

VITAMIN D PHYSIOLOGY

The active form of vitamin D, 1,25-dihydroxyvitamin D, is the major steroid hormone involved in regulating mineral ion homeostasis. Vitamin D and its metabolites are hormones and hormone precursors rather than vitamins because in the proper biologic setting, they can be synthesized endogenously (Figure 1).³ Directly or indirectly, active vitamin D controls genes responsible for the regulation of cellular differentiation, proliferation, apoptosis, and angiogenesis. The vitamin may be responsible for regulating up to 200 genes, including those that regulate immune function and the cell lifecycle.⁴ Vitamin D also helps promote insulin production, inhibit renin production, and stimulate macrophage cathelicidin production.⁵

Figure 1: Vitamin D metabolism

Vitamin D receptors are found in most bodily tissues, and the vitamin has endocrine effects on calcium metabolism and bone health.⁴ Vitamin D is thought to be important for maintaining normal muscle function (including cardiac muscle) and immune function.

Box 2

Studies have shown that vitamin D may be useful as adjunct treatment for tuberculosis, psoriasis, and multiple sclerosis, or for the prevention of certain cancers.⁵ The active form of vitamin D and its active analogues (such as calcipotriene) have been used topically and found beneficial in treating psoriasis.⁵ The immune system activates vitamin D receptors in response to lipopolysaccharide or Mycobacterium tuberculosis, releasing 1,25 dihydroxyvitamin D₃, a potent immunomodulator that activates peptides capable of destroying M. tuberculosis and other pathogens. Patients with hypovitaminosis D cannot mount this type of innate immune response.⁵

PREVALENCE AND CAUSES

About 1 billion people worldwide have hypovitaminosis D; one-third of these people have no identifiable risk factors.⁵ The Third National Health and Nutrition Examination Survey (NHANES III) revealed that vitamin D deficiency is prevalent throughout the United States.^2,3 Vitamin D deficiency in adults was previously thought to be limited to older persons living in long-term-care facilities, but recent evidence suggests otherwise. A group of international experts concluded that about one-half of patients age 65 years and older in North America and 66% of patients of all ages internationally failed to maintain healthy bone density and tooth attachment because of inadequate vitamin D levels.² Deficiency in older adults in the United States and Europe in community settings is estimated to be between 40% and 100%. More than 50% of postmenopausal women taking medication for osteoporosis have suboptimal levels of calcidiol.⁵

Hypovitaminosis D can be a result of several causes. These include deficient production of vitamin D in the skin, a lack of dietary intake, accelerated losses of vitamin D, impaired vitamin D activation, and resistance to the biologic effects of active vitamin D. Humans typically obtain 90% of vitamin D from sunlight (that is, exposure to UV-B), so inadequate exposure to sunlight is a major cause of vitamin D deficiency.⁴ Compared with vitamin D consumed orally, vitamin D produced in the skin may last twice as long in the blood. Sunlight exposure to one minimal erythemal dose of UV radiation (defined as a slight pinkness to the skin 24 hours after exposure) results in vitamin D production equivalent to ingesting 10,000 to 25,000 international units (IU).⁴

Factors that reduce the skin's production of vitamin D₃ include increased skin pigmentation, aging, and the topical application of a sunscreen.⁶ Patients with darker skin tones have natural sun protection and require at least three to five times longer sun exposure to make the same amount of vitamin D as a person with white skin tone.⁴ Geographic location also factors heavily in UV exposure—one study found that about 50% of white preadolescent girls in Maine were deficient in vitamin D.⁵

Sunscreen and clothing have been reported to prevent the conversion of 7-dehydrocholesterol to vitamin D₃. Because of increased concern about skin cancer, increased use of sunblock in North America and Western Europe, and many people spending less time in the sun over the last several decades, reliance on dietary sources of vitamin D has increased. Vitamins D₂ and D₃ have equivalent biologic activity and are activated equally well by the vitamin D hydroxylases in humans.³

Sun-related factors that dramatically influence the skin's production of vitamin D₃ include alterations in the zenith angle of the sun caused by a change in latitude, season of the year, or time of day. Above the 33rd parallel north (about the latitude of Atlanta, Ga.) and below the 33rd parallel south (about the latitude of Santiago, Chile), vitamin D₃ synthesis in the skin is very low or absent during most of the winter.² This causes a deficiency in cutaneously synthesized vitamin D; adults in long-term-care facilities or healthcare institutions are at a particularly high risk.⁷ In older adults, deficiency is related to age and reduced efficiency of vitamin D synthesis by the skin. Even patients living in areas of maximal sun intensity and duration are at risk of impaired vitamin D production if most of their skin is shielded; studies in Saudi Arabia, the United Arab Emirates, Australia, Turkey, India, and Lebanon confirm that 30% to 50% of children and adults have calcidiol levels under 20 ng/mL.¹

Dysfunctional intestinal absorption is another identified risk for vitamin D deficiency. Obese patients; patients with small intestine resections; and patients with intestinal fat malabsorption disorders due to celiac disease, short bowel syndrome, or cystic fibrosis may also develop vitamin D deficiency. Terminal ileal disease, which results in impaired enterohepatic circulation of vitamin D metabolites, also can cause vitamin D deficiency. Finally, calcidiol bound to the vitamin D-binding protein is lost in excess in patients with proteinuria characteristic of nephrotic syndrome.^3,4,7

Certain medications, such as anticonvulsants or glucocorticoids, can increase catabolism and actively destroy vitamin D.² Other medications known to promote deficiency through catabolic pathways are ketoconazole and antiretroviral drugs.⁴ Drugs that induce hepatic cytochrome P450 mixed-function oxidases, such as barbiturates, phenytoin, and rifampin, can accelerate inactivation of vitamin D metabolites. Impaired 25-hydroxylation, associated with severe liver disease or isoniazid, is an uncommon cause of vitamin D deficiency.⁵

A body mass index of greater than 30 kg/m² also is associated with vitamin D deficiency due to an increase of body fat sequestration of the vitamin. Other causes of deficiency include chronic granuloma-forming disorders, some lymphomas, and primary hyperparathyroidism.⁴

Pregnant and lactating women who take prenatal vitamins and calcium supplements with vitamin D₂ as well as pediatric patients fed exclusively by vitamin D-poor breast milk are at increased risk of deficiency. Despite taking prenatal vitamins containing 400 IU of vitamin D and consuming fish and milk, 73% of women and 80% of their infants were found to be deficient (calcidiol of less than 20 ng/mL) at the time of birth. Inadequate intake or supplementation of vitamin D during pregnancy has been shown to increase women's risk of preeclampsia, with potential effect on their infants' well-being.¹

Even healthy-appearing adolescents may be deficient in this nutrient. Up to one-third of otherwise healthy students and healthcare providers in Boston were found to be vitamin D-deficient despite consumption of enriched foods and daily intake of a multivitamin.⁵

EFFECTS OF HYPOVITAMINOSIS D

Vitamin D deficiency causes muscle weakness.^2,4 Skeletal muscles have a vitamin D receptor and may require vitamin D for maximum function. One study found that performance speed and proximal muscle strength were markedly improved when calcidiol levels increased from 4 ng/mL to above 40 ng/mL.⁴

Although the importance of the exact physiologic role of vitamin D in nonskeletal diseases has not been clarified, deficiencies have been linked to pathologies. Women with type 2 diabetes have a higher prevalence of hypovitaminosis D than women without diabetes. This has been attributed to alterations in circulating vitamin D₃ metabolites due to decreased 1-alfa-hydroxylase activity and enhanced renal 25-hydroxylase activity.⁸ Studies suggest that vitamin D supplementation in children reduces the risk of type 1 diabetes; increasing vitamin D intake during pregnancy reduces fetal development of islet autoantibodies. Vitamin D deficiency increases insulin resistance, decreases insulin production, and is associated with metabolic syndrome. A study showed that combined daily intake of 1,200 mg of calcium and 800 IU of vitamin D lowered the risk of type 2 diabetes by 33% compared with lower dosages.⁵

Living at latitudes outside the equatorial band increases the risk of various autoimmune diseases such as type 1 diabetes, rheumatoid arthritis, multiple sclerosis, and Crohn disease.⁵ Living between 35 degrees north and 35 degrees south latitude for the first 10 years of life reduces the risk of multiple sclerosis by about 50%.⁵ Among white men and women, the risk of developing multiple sclerosis decreases as calcidiol levels increase. Similar observations were made regarding osteoarthritis.⁵

Cardiovascular effects are also mediated by vitamin D; the risk of hypertension and other cardiovascular diseases is increased in those living at latitudes outside the equatorial band. Evidence suggests that adults with vitamin D deficiency may have associated increases in overall mortality, including cardiovascular causes.³ 1,25-dihydroxyvitamin D₃ inhibits renin synthesis and increases myocardial contractility; deficiency is associated with heart failure and increased blood levels of inflammatory factors such as C-reactive protein and interleukin-10. In one study, patients with hypertension were exposed to UVB radiation three times per week for 3 months, which increased their vitamin D levels. These patients demonstrated average reductions of 6 mm Hg in systolic and diastolic BP.⁵

Most studies have found a protective relationship between sufficient vitamin D levels and lower cancer risk.^6,9,10 Correspondingly, deficiencies of vitamin D have been associated with an increased risk of cancer and poor prognosis of several types of cancer. Most observational studies have reported that vitamin D reduces the risk of colon, breast, prostate, and ovarian cancer, as well as in the development of premalignant adenomatous polyps of the colon.^6,9 High serum levels of calcidiol are associated with significantly reduced growth of nonmalignant but high-risk epithelial cells in the colon.⁹ Active vitamin D also inhibits mitosis of breast epithelial cells.^6,9 Among black men with abnormal prostate-specific antigen levels or abnormal findings on digital rectal examination of the prostate, biopsies significant for prostate cancer were more likely in men with vitamin D deficiency than in those with normal vitamin D levels.¹⁰ Furthermore, in both American men of European descent and black men with vitamin D deficiency, initial biopsies were more likely to show tumors with a high Gleason grade and more advanced clinical stage.¹⁰

Meta-analyses and cancer-prevention trials indicate that vitamin D₃ supplementation to achieve a serum calcidiol level of 33 ng/mL or greater can lower the incidence of colorectal cancer by 50%.⁶ Evidence further suggests that daily intake of 1,000 to 2,000 IU/day of vitamin D₃ could lessen the incidence of colorectal cancer with minimal risk.⁶ Mixed-effects dose–response meta-analyses showed that each 4 ng/mL increase in serum calcidiol concentration was associated with a 6% reduced risk for colorectal cancer. No statistically significant dose–response relationship was found for prostate and breast cancer.⁹

Combined vitamin D and calcium supplementation can reduce fracture risk, but the effects may be lower among community-dwelling older adults than among those in long-term care facilities.⁹ In older adults in long-term care, daily intake of 800 IU of vitamin D₃ or D₂ plus calcium reduced the risk of falls compared with placebo. Several studies have demonstrated that increased vitamin D₃ intake reduced the risk of hip and nonvertebral fractures.⁵ The Women's Health Initiative study corroborated these findings in postmenopausal women, noting that optimal fracture prevention occurred when supplementing higher dosages of vitamin D₃ (700 to 800 IU) in women who were most deficient in calcidiol (values below 17 ng/mL). Fracture prevention also was maximized in patients whose mean levels rose to 40 ng/mL.⁵

Serum calcidiol levels have an independent, inverse association with recent upper respiratory tract infections. Although the rates of calcidiol levels less than 30 ng/mL and upper respiratory tract infections increased in the winter, the inverse association was accounted for throughout the year. Patients with respiratory tract diseases such as asthma who have low serum calcidiol levels may be even more susceptible to respiratory tract infections. Vitamin D supplementation may reduce the incidence of upper respiratory tract infections and exacerbations of respiratory tract diseases.¹¹

A recent landmark prospective population-based study found that moderate deficiency of vitamin D increased the risk of all types of dementia by 53%, and severe deficiency, defined as levels less than 10 ng/mL increased this risk by 125%.¹² The risk of developing the most common form of dementia, Alzheimer disease, also was significant; 69% and 122% increased risks were found in patients with moderate and severe deficiency, respectively.¹² Generally, a vitamin D level above 20 ng/mL most strongly correlates with optimum cognitive function.¹²

Despite the well-studied associations of low vitamin D levels and the development of chronic diseases such as cancer, diabetes, autoimmune illnesses, infections, and cardiovascular diseases, few random controlled trials have a dosing range adequate to provide strong evidence for the benefit of vitamin D in reducing the risk of these diseases.⁴

PATIENT ASSESSMENT

Ask all patients about their occupation, sun exposure, and use of sunscreen. Also ask about dietary intake, especially use of dietary supplements such as multivitamins and supplemental vitamin D. The patient's past medical history may reveal concurrent illness such as hypertension; cardiovascular disease; obesity; type 1 diabetes; multiple sclerosis; secondary hyperparathyroidism; or prostate, breast, or colorectal cancer.¹

Regardless of the cause, manifestations of vitamin D deficiency are primarily due to impaired intestinal calcium absorption. Mild-to-moderate deficiency is typically asymptomatic. Chronic deficiency causes hypocalcemia that can lead to secondary hyperparathyroidism and impaired skeletal mineralization of the skeleton causing osteopenia and decreased bone mineral densities on radiographs. Muscle pain from proximal myopathy is also possible; in adults, periosteal bone pain is best detected with firm pressure on the sternum or tibia.^3,7 Vitamin D deficiency in children can manifest as rickets, characterized by leg-bowing. In adults, vitamin D deficiency causes osteomalacia, presenting as a poorly mineralized skeletal matrix. These adults can experience chronic muscle aches and pains.⁷ Other symptoms include fatigue, bone pain, and weakness.¹

Although longstanding vitamin D deficiency results in hypocalcemia, the acute symptoms of hypocalcemia such as numbness, tingling, and seizures are rare. If coexistent hypomagnesemia develops (impairing parathyroid function), or the patient is taking potent bisphosphonates that impair bone resorption, acute symptomatic hypocalcemia may become apparent.³ Assessing the patient's clothing and level of skin coverage can provide insight about potential lack of sunlight exposure and its effect on vitamin D levels. Remember that darker skin is an established risk factor for vitamin D insufficiency because increased melanin decreases vitamin D production.¹

DIAGNOSIS

When considering a diagnosis of hypovitaminosis D, consider diseases that may imitate vitamin D insufficiency, including fibromyalgia, chronic fatigue syndrome, myositis, hyperparathyroidism, and depression.¹

A serum calcidiol level is the preferred and most specific screening test to determine vitamin D status; serum levels of active vitamin D should be measured only when monitoring certain conditions, such as acquired and inherited disorders of vitamin D and phosphate metabolism.^3,4,7 The US Preventive Services Task Force does not support routine screening for vitamin D deficiency.¹³ Active vitamin D levels are not accurate reflections of vitamin D stores and should not be used to diagnose vitamin D deficiency in patients with normal renal function.³

With respect to osteoporosis, the range of calcidiol considered deficient is less than 15 ng/mL; serum levels below 30 ng/mL are associated with increased risk of colon cancer. Levels above 150 ng/mL suggest potential toxicity.⁹

A serum parathyroid hormone level may help in the diagnosis of vitamin D insufficiency, but is not always necessary in making the diagnosis. Parathyroid hormone has an inverse relationship with calcidiol, and as a marker of vitamin D insufficiency, begins to rise at calcidiol levels below 31 ng/mL. Increased parathyroid hormone secretion (secondary hyperparathyroidism) in patients with vitamin D insufficiency is aimed at mobilizing calcium and phosphate from bone, and promoting the synthesis of active vitamin D in the kidney.⁷ As serum calcium falls, rising parathyroid hormone levels facilitate phosphate wasting, resulting in severe hypophosphatemia.¹⁴ Usually, parathyroid hormone levels decrease after the correction of vitamin D insufficiency.⁷ Alkaline phosphatase levels are often increased due to parathyroid hormone-induced increase in bone turnover.³

Radiologic features of vitamin D deficiency in children include a widened, expanded growth plate that is characteristic of rickets. If vitamin D deficiency follows epiphyseal fusion, the principal radiographic finding is a reduction of thickness of the cortex and relative skeletal radiolucency. A specific radiologic feature of osteomalacia, either associated with phosphate wasting or vitamin D deficiency, is pseudofractures, or Looser zones. These are a few millimeters wide, several centimeters long, and are especially notable in the scapula, pelvis, and femoral neck.³

TREATMENT

The recommended daily allowance (RDA) of vitamin D is 15 mcg/day (600 IU/day). For bone health optimization, a minimum of 400 IU/day is recommended for infants and children up to age 1 year; children older than age 1 year require at least 600 IU/day. Similarly, 600 IU/day is needed for bone and muscle health in patients ages 19 to 70 years, as well as for pregnant and lactating women. Strengths between 1,500 and 2,000 IU/day may be required to consistently maintain vitamin D levels above the recommended 30 ng/mL in these persons. For people older than age 70 years, the RDA is set at 20 mcg (800 IU). Obese patients; those with malabsorption syndromes; and those taking some anticonvulsants, glucocorticoids, ketoconazole, or AIDS medications should be given at least two to three times more vitamin D to satisfy metabolic requirements.⁴ Most experts agree that children and adults who do not have adequate sun exposure require up to 1,000 IU per day.⁵

Encourage patients to consume foods rich in vitamin D, such as wild or canned salmon, cod liver oil, mackerel, pickled herring, and sun-dried shiitake mushrooms, and fortified foods such as milk, orange juice, yogurt, and margarine.^5,7 Vitamin D produced in the skin as a result of sun exposure may last twice as long in the blood compared with ingested vitamin D. UV-B therapy has demonstrated greater efficacy in raising serum calcidiol levels compared with ingesting a daily vitamin D₃ supplement. Therefore, recommend sensible sun exposure for patients at risk for vitamin D deficiency: 15 minutes per day in the summer and 20 minutes in the winter.⁷ Black patients may require twice as long of a duration of sun exposure to achieve similarly desired effects.⁹

Recommend vitamin D supplementation if patients cannot achieve adequate dietary intake of vitamin D or adequate sun exposure. Supplementation is especially essential during the winter. For vitamin D-deficient patients ages 1 to 18 years, recommended supplementation is 2,000 IU/day of orally administered vitamin D₂ or D₃ for at least 6 weeks. Alternatively, patients can take 50,000 IU/week for 8 weeks, followed by a maintenance dose of 800 to 1,000 IU/day from food and supplement sources after normal plasma levels are realized. In adults over age 18 years, recommend treatment with 50,000 IU/week for 8 weeks, or 2,000 IU/day of vitamin D₂ or D₃ for at least 6 weeks, followed by maintenance treatment of 1,500 to 2,000 IU/day. If calcidiol levels have not risen to a minimum of 30 ng/mL, prescribe a second 8-week course. If levels are still deficient, suspect nonadherence or malabsorption. Patients with malabsorption should be referred to a gastroenterologist.²

The physiologic effects of vitamin D₂ and D₃ are identical when ingested over long periods; vitamin D₂ and vitamin D₃ appear to be equipotent in raising calcidiol concentrations when they are given in daily doses of 1,000 IU.^4,15 Previous studies suggested that vitamin D₃ may be more effective than vitamin D₂ in establishing normal vitamin D stores—patients needed up to three times as much vitamin D₂ as vitamin D₃ to maintain serum calcidiol levels.^5,7

In patients who have vitamin D deficiency and are obese, have a malabsorption syndrome, or are taking medication that affects vitamin D metabolism, recommend 10,000 IU of vitamin D daily, with maintenance dosages of up to 6,000 IU/day once the patient's serum calcidiol level exceeds 30 ng/mL.⁷

Daily intake of a multivitamin (400 IU of vitamin D) is usually not sufficient to prevent vitamin D deficiency. Based on the observation that 800 IU of vitamin D with calcium supplementation decreases the risk of hip fractures in older women, this higher dose is thought to be an appropriate daily intake for prevention of vitamin D deficiency in adults. The safety margin for vitamin D is large, and toxicity usually is observed only in patients taking doses in the range of 40,000 IU daily.³ Toxic levels are suggested by manifestations such as headache, metallic taste, nephrocalcinosis or vascular calcinosis, pancreatitis, nausea, and vomiting. Contraindications to vitamin D therapy include granulomatous diseases, metastatic bone disease, sarcoidosis, or Williams syndrome.²

Treatment of vitamin D deficiency should be directed at the underlying disorder, if possible, and also should be tailored to the severity of the condition. Replacement of vitamin D should always occur with calcium supplementation because most of the ill effects of vitamin D deficiency are due to derangements of normal mineral ion homeostasis.³

Treat patients with 1 alfa-hydroxylation impairment (such as occurs in chronic kidney disease) with metabolites that do not require this activation step. Treatments of choice in these circumstances include calcitriol (0.25 to 0.5 mcg/day) and 1 alfa-hydroxyvitamin D2 (2.5 to 5 mcg/day).³

Treatment of severe vitamin D deficiency entails an initial regimen of 50,000 IU weekly for 3 to 12 weeks followed by maintenance therapy of 800 IU daily. Prescription doses may be required for maintenance therapy in patients who are taking medications such as barbiturates or phenytoin. Providers must also account for other medications that accelerate metabolism of or cause resistance to active vitamin D.³

Calcium supplementation should include 1.5 to 2 g/day of elemental calcium. Expect calcium levels to normalize within 1 week of therapy. However, patients may have an increased parathyroid hormone and alkaline phosphatase level for up to 6 months. Monitor the patient's serum and urinary calcium: 24-hour urinary calcium excretion should be between 100 and 250 mg in patients with normalized vitamin D levels who are supplementing with appropriate amounts of calcium. Lower levels indicate problems with adherence or absorption of calcium or vitamin D. Values above 250 mg in 24 hours increase the likelihood of nephrolithiasis; reduce vitamin D and/or calcium intake.³

Patients should be advised that vitamin D may be consumed on an empty stomach or with a meal. Vitamin D given in frequencies of three times a year, once a week, or once a day can all be effective in maintaining serum calcidiol levels in patients of all ages.⁴ Providers should repeat the serum calcidiol test in 6 to 8 weeks following treatment implementation to ensure adequate vitamin D absorption, with an established target level of at least 30 ng/mL. If serum calcidiol persists below that level, consider injectable vitamin D and reassess the patient for malabsorption or other interference issues.¹

CONCLUSION

Hypovitaminosis D is a common syndrome with well-established risk factors. Only recently, however, are the expansive implications of deficiency becoming recognized. Assessing vitamin D level is crucial in comprehensive management of patients. Although treatment options are readily available, continuous monitoring is necessary to ensure adequate replacement.