by Ronald Hoffman, MD
Generations of medical professionals have been taught to approach vitamin D supplementation with great caution and trepidation. As a fat-soluble vitamin known to enhance calcium absorption, vitamin D taken in excessive amounts was thought to raise the specter of hypercalcemia with its attendant risks of nephrolithiasis and even metastatic calcification. Our understanding of vitamin D's health benefits was limited to its familiar role in maintaining bone strength by means of regulating calcium uptake. But thanks to an explosion in vitamin D research, a broader perspective is rapidly evolving.
Powered by its pervasive influence on myriad physiological processes, vitamin D is staking its claim as "Nutrient of the Decade." We now recognize that vitamin D transcends the definition of a mere vitamin: It is actually a prohormone, and vitamin D receptors are expressed by cells in most organs, including the brain, heart, skin, gonads, prostate gland, and mammary glands. In the digestive tract and parathyroid glands, active vitamin D metabolites are responsible for calcium uptake. Vitamin D receptors are also involved in immune regulation and mediate response to infection and inflammatory processes. Additionally, the nutrient is associated with cell proliferation and differentiation.
Vitamin D's traditionally acknowledged role is in bone metabolism. The pathognomonic vitamin D deficiency disease is rickets, but less overt prolonged insufficiency results in osteomalacia. This condition is characterized by softening of the bones and musculoskeletal pain, the result of periosteal traction. Not surprisingly, an association between vitamin D repletion and relief of unexplained body aches has been observed in some studies.
Chronic vitamin D deficiency can result in secondary hyperparathyroidism with consequent osteoporosis. Vitamin D deficiency in childhood and adolescence impairs attainment of optimal bone mass. Frequently, clinicians neglect to assess vitamin D status and don't consider the treatment option of aggressive repletion when using drugs to manage osteopenia or osteoporosis. A new minimum threshold for vitamin D of 50-75 nmol/L (20-30 ng/mL) was recently proposed to prevent osteoporosis. However, vitamin D receptor polymorphisms modulate skeletal response to vitamin D supplementation even in healthy girls, and individual requirements for bone optimization may vary. A minimal threshold of 40 ng/mL for healthy bone metabolism has also been proposed.
The ultimate goal of osteoporosis treatment is fracture prevention. Considerable evidence suggests vitamin D can support muscle strength and thereby reduce the incidence of falls, particularly in elderly, at-risk patients. In addition, vitamin D arguably has an indirect role in staving off fractures: As a nondrug treatment for osteoporosis, the use of vitamin D reduces polypharmacy with various cardiovascular, anti-inflammatory, and psychiatric medications that can induce nutrient depletions and impair balance in frail seniors.
Vitamin D deficiency is associated with increased risk for cardiovascular events and mortality. In the Multi-Ethnic Study of Atherosclerosis, 25-hydroxyvitamin D (25[OH]D)levels were inversely associated with the risk of coronary artery calcification, a measure of coronary atherosclerosis.
Cardiovascular disease (CVD) represents the culmination of an array of predisposing influences, and vitamin D may intervene beneficially in several ways. Studies confirm an association between obesity and vitamin D deficiency, and low vitamin D status is predictive of insulin resistance. Overweight women replete with vitamin D shed pounds more successfully. Moreover, studies have found correlation between suboptimal vitamin D status and both hypertension and diabetes.
In renal disease, characterized by problematic vitamin D metabolism, CVD is rampant—but cardiovascular risk is known to be attenuated by vitamin D administration.
Evidence also indicates that vitamin D deficiency—common in elderly, debilitated patients—plays a role in congestive heart failure, which is mediated by the nutrient's effect on myocyte contractility.
Sun exposure is clearly required for vitamin D sufficiency. However, latitude, season, time of day, weather conditions, shade, skin pigmentation, air pollution, clothing, use of sunscreen, and age impact cutaneous vitamin D activation. Below 32º latitude (corresponding to a line stretching from Los Angeles to Columbia, S.C.), sunlight exposure can activate vitamin D year-round. But above 44º north latitude (which extends from the northern tip of California to Boston), no cutaneous activation is possible from November through February.
It has long been noted that colon cancer rates increase with higher geographic latitude. This epidemiologic correlation was initially attributed to Western diet and lifestyle, but subsequent studies controlled for extraneous factors and confirmed the protective role of sunlight. Scientists were then able to establish the biological plausibility for the impact of vitamin D in cancer prevention, recognizing the vitamin's effects on cell proliferation, oncogenesis, and apoptosis. Since then, investigators have explored a putative involvement of vitamin D in both primary and secondary prevention of prostate cancer and breast cancer as well as non-Hodgkin's lymphoma, melanoma, and other malignancies.
Cells involved in innate and adaptive immune responses —including macrophages, dendritic cells, T cells, and B cells—express the vitamin D receptor. In the 19th century, before the advent of antibiotics, caregivers recognized that individuals with TB could benefit from sunlight and fresh air during their stays in mountain sanitoria. Research has confirmed that host response to TB is partially mediated by vitamin D, and that vitamin D deficiency is associated with dysregulation of macrophage response.
The observed seasonal correlation between sunlight exposure and the incidence of viral upper respiratory infections has prompted speculation about the role played by vitamin D. Research confirms that vitamin D dramatically stimulates the expression of potent antimicrobial peptides. These compounds exist in neutrophils, monocytes, natural killer cells, and epithelial cells lining the respiratory tract, where they play a major role in protecting the lung from infection. The action of vitamin D serves as a key link between Toll-like receptor activation and antibacterial responses in innate immunity. An association between vitamin D insufficiency (25[OH]D <40 nmol/L) and acute respiratory tract infection was recently confirmed. As yet, prospective intervention studies are few and small in scale.
The incidence of certain autoimmune diseases correlates positively with latitude from the equator, as reflected by the epidemiology of rheumatoid arthritis, inflammatory bowel disease, type 1 diabetes, and multiple sclerosis (MS). Studies confirm that patients suffering from autoimmune disease have vitamin D levels below the international norm. There is substantial biological rationale for vitamin D as a cytokine modulator.
Animal models of autoimmune disease suggest a response effect with vitamin D administration; large human therapeutic trials using vitamin D are still lacking, but the first results of phase I/II studies are promising. Meanwhile, it is now acknowledged that administering vitamin D in patients with autoimmune diseases is justifiable.
Perhaps the most persuasive rationale for considering vitamin D optimization comes from a study of 3,400 French men, age 50 years and older, correlating vitamin D status with all-cause mortality. Men in the lowest quartile of 25(OH)D levels had a 44% higher death rate. The authors qualified their findings by stating that although the study controlled for lifestyle variables and comorbidities, a possibility exists that low levels of vitamin D are merely reflective, and not causative, of poor health status.
Because of the ubiquity of the nutrient's impact on physiologic processes, some researchers have proposed associations between vitamin D status and incidence of autism, allergic diseases, depression, schizophrenia, cognitive impairment, pre-eclampsia, fibromyalgia, Parkinson disease, polycystic ovary syndrome, and benign prostatic hyperplasia. Athletic trainers, cognizant of research suggesting that vitamin D may augment muscle strength, are increasingly embracing oral supplementation and UV-light exposure for purposes of performance enhancement.
Of course, a long-observed relationship between sunlight exposure and severity of psoriasis suggests mediation by vitamin D; topical calcipotriene (Dovonex), a synthetic vitamin D analogue, is a standard dermatologic treatment for the condition.
Vitamin D has received renewed interest for its role in pregnancy. Studies suggest that higher levels of vitamin D supplementation than are currently recommended for pregnant women may safeguard offspring from the risks of low birth weight, autism, juvenile diabetes, asthma and allergic rhinitis, and infectious diseases. The Canadian Pediatric Society recently recommended that pregnant women increase their intake of vitamin D to 2,000 IU/day.
Pervasiveness of deficiency and risk factors
A number of health authorities now acknowledge that vitamin D deficiency is a pervasive problem in the United States and the developed world. Sun deprivation, already a problem for inhabitants of temperate latitudes, is exacerbated by indoor occupations and recreation and is further encouraged by warnings against sun exposure to prevent skin cancer.
Although overt vitamin D deficiency is no longer common in U.S. children, lesser degrees of vitamin D insufficiency are widespread. Groups at heightened risk for vitamin D deficiency include: the homebound elderly; older individuals overall (due to the declining potential for vitamin D production as the skin ages); darker-skinned individuals (melanin in skin protects the skin from UV radiation but increases the exposure time required for photoactivation of pre-vitamin D in the skin); and members of communities that require their constituents to cover up. Obesity also is associated with vitamin D deficiency, and some evidence indicates that adipose tissue is involved in sequestration of the nutrient.
Conditions that predispose a person to vitamin D deficiency include liver disease, which interferes with the 25 hydroxylation of vitamin D; chronic renal failure, which interferes with 1 hydroxylation; and malabsorption syndromes, which are either iatrogenic (e.g., status after bariatric surgery or in users of fat-sequestering medications such as cholestyramine) or the result of biliary tract disease, cystic fibrosis, celiac disease, inflammatory bowel disease, or similar conditions. Certain drugs, including anti-epileptic medications, deplete vitamin D. To complicate matters, research points to vitamin D receptor polymorphisms, which attenuate end-organ response to circulating levels of vitamin D.
Routine, modest supplementation is not a reliable bulwark against vitamin D deficiency. Researchers were recently surprised to note the high prevalence of vitamin D deficiency in pregnant women—the very group most likely to be shielded from this problem because of high compliance with prenatal-vitamin regimens. Additionally, living in the sunny, warm regions of the country may raise a person's chances of achieving vitamin D sufficiency, but a recent study of Hispanics in Arizona uncovered a high rate of vitamin D inadequacy.
Dietary sources of vitamin D are limited (Table 1). Milk, which is the only dairy product routinely fortified with the nutrient, supplies a mere 100 IU/cup, which represents only a quarter of the minimal requirement for adults. Human breast milk delivers only 25 IU/L on average. Herring, tuna, eel, and mackerel are all good sources of vitamin D, but many people avoid these foods because they do not like the taste.
The two forms of vitamin D most commonly measured by clinical laboratories are 25(OH)D (calcidiol) and 1,25 hydroxyvitamin D (1,25[OH]2D) (calcitriol). Until recently, health-care providers predominantly relied on the latter for vitamin D assessment, but new findings suggest that its utility is limited (except in renal disease, in which 1 hydroxylation is an issue). Not infrequently, 1,25(OH)2D levels are found to be sufficient or even supra-normal while 25(OH)D levels remain suboptimal.
Because of its greater reliability, a 25(OH)D level is now favored as the accepted method for determining vitamin D nutritional status. The optimal level of serum 25(OH)D is 35-55 ng/mL (90-140 nmol/L), with some medical scientists advocating for the slightly higher value.
Many reference labs have adopted a classification system that stratifies vitamin D levels as follows (to convert conventional [ng/mL] units to SI [nmol/L] units, multiply by 2.5):
0-14.9 ng/mL = Severely deficient
15.0-31.9 ng/mL = Mildly deficient
32.0-100.0 ng/mL = Optimal
>100.0 ng/mL = Toxicity possible
Findings of elevated bone isoforms of alkaline phosphorous, elevated parathyroid hormone, or urinary N-telopeptide should prompt suspicion of vitamin D deficiency (to be confirmed by serum measurement of 25[OH]D).
The threshold for vitamin D toxicity is currently being re-evaluated, with most experts now agreeing that previous benchmarks have been unduly conservative (Table 2). This change in thinking stems partially from the realization that a single, minimal erythemal dose of sun exposure promotes synthesis of 10,000 IU of vitamin D. Early reports of vitamin D toxicity with doses as low as 3,600 IU/day have been challenged due to methodologic flaws. It has been reported that human toxicity likely begins to occur after chronic daily vitamin D consumption of approximately 40,000 IU/day.
A theoretical risk of vitamin D toxicity exists when prolonged sunlight exposure is combined with aggressive supplementation, but feedback inhibition occurs with UV-light activation of vitamin D in the dermis, rendering this possibility less likely.
Clinicians must administer vitamin D cautiously in patients with certain medical conditions. For example, individuals with primary hyperparathyroidism are at risk for hypercalcemia, which might be exacerbated by additional vitamin D. (Conversely, in secondary hyperparathyroidism, correction of the underlying vitamin D deficiency helps normalize elevated calcium).
In sarcoidosis and such malignancies as oat-cell cancer and non-Hodgkin's lymphoma, aberrant conversion of 25(OH)D to calcitriol results in hypercalcemia, offering a relative contraindication to vitamin D administration.
The main symptoms associated with vitamin D toxicity result from hypercalcemia. Anorexia, nausea, and vomiting can develop, followed in some cases by renal failure. The diagnosis can be confirmed through measurement of serum 25(OH)D (typically >140 ng/mL) in the presence of elevated serum calcium.
Treatment involves stopping vitamin D intake. If necessary, the clinician can hydrate the patient with IV normal saline and administer corticosteroids or bisphosphonates (which inhibit bone resorption) to reduce blood calcium levels.
Recommendations for supplementation
The longtime government recommendation for vitamin D intake in adults and older children was set rather arbitrarily at 400 IU/day. This is thought to derive from the historical precedent that a teaspoon of cod liver oil, a traditional source of supplementation, delivers approximately 400 IU of vitamin D.
For infants younger than age 4 years, the Daily Value (developed by the FDA to help consumers compare the nutrient contents of products within the context of a total diet) is just 200 IU, but in 2008 the American Academy of Pediatrics took the lead in advancing the threshold to 400 IU in light of evidence of the safety and benefits of vitamin D.
The Food and Nutrition Board of the Institute of Medicine is currently re-examining Daily Values for vitamin D and calcium and plans to issue revised guidelines this year. Most nutrition scientists are expecting upward revisions.
Controversy now rages over what constitutes "deficiency" versus "sufficiency." Alternatively, optimal therapeutic levels may be appropriate for various health conditions. Guidelines for prevention of rickets, for example, may be inadequate for prevention or reversal of osteoporosis. Some argue that nutritional support for such autoimmune diseases as MS might call for pharmacologic doses of vitamin D. In a recent study, 16% of 25 MS patients who were given an average of 14,000 IU/day of vitamin D for one year suffered relapses. In contrast, close to 40% of 24 MS patients who took an average of 1,000 IU/day—the stepped-up supplementation belatedly acknowledged to be necessary by many MS specialists—relapsed.
A clue to the amount of vitamin D needed to optimize serum levels of 25(OH)D in seniors comes from a study of men and women older than age 64 years. The intakes required to maintain serum 25(OH)D concentrations of >15 ng/mL, >20 ng/mL, and >32 ng/mL in 97.5% of the sample were 688 IU/day, 988 IU/day, and 1,548 IU/day, respectively. Note that these levels of supplementation are well above the current Daily Values yet do not even attain what some consider being optimal thresholds for vitamin D.
Vitamin D supplements are available in two forms, D2 (ergocalciferol) and D3 (cholecalciferol). High-dose prescription vitamin D 50,000 IU (Drisdol, Calderol, Calciferol), commonly prescribed for rapid remediation of vitamin D deficiency, is vitamin D2. Vitamin D2 is manufactured by the UV irradiation of ergosterol in yeast, and vitamin D3 is manufactured by the irradiation of 7-dehydrocholesterol from lanolin and the chemical conversion of cholesterol.
Some argue that vitamin D3 could be more than three times as effective as vitamin D2 in raising serum 25(OH)D concentrations and maintaining those levels for a longer time, and that its metabolites have superior affinity for vitamin D-binding proteins in plasma. Further research is required to compare the clinical efficacy of the two forms.
Most supplements available from health-food stores are vitamin D3. Commonly available doses range from 400 to 5,000 IU, variously delivered in tablet, capsule, and liquid forms. Parenteral forms of vitamin D are also available but are seldom needed to reach target levels outside the settings of chronic renal failure and dialysis.
Suggested treatment of vitamin D deficiency
Vitamin D deficiency (25[OH]D level <20 ng/mL): Vitamin D 50,000 IU once a week for three months; repeat 25(OH)D level.
If >20 ng/mL but <30ng/mL, change the vitamin D supplement to 5,000 IU/day until levels of 40-50 ng/mL are attained.
If still <20 ng/mL, advance vitamin D to 50,000 IU twice a week, or consider giving it more frequently. (In certain clinical situations, especially those involving malabsorption syndromes, up to 50,000 IU three times a week may be needed.)
Vitamin D insufficiency (25[OH]D level 20-30 ng/mL): Administer vitamin D 5,000 IU daily for three months, repeat 25(OH)D level.
If <30 ng/mL, advance vitamin D to 50,000 IU once a week or more frequently if needed.
Once 25(OH)D levels are restored to >40 ng/mL, administer maintenance supplementation of 2,000-5,000 IU/day.
For reasons that are not yet completely clear, considerable variability in response to vitamin D supplementation exists among patients. Clinicians should monitor a patient's 25(OH)D levels frequently to assess reaction to therapy until stable levels are achieved, subject to seasonal variations and changes in health status.
- Ronald Hoffman, MD
Dr. Hoffman is founder and Medical Director of the Hoffman Center in New York City. The author has no relationships to disclose relating to the content of this article.
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All electronic documents accessed February 10, 2010.
Published March 1, 2010. The Clinical Advisor. What Lies Behind the Vitamin D Revolution. By Ronald Hoffman, MD.