The vitamin D deficiency pandemic: Approaches for diagnosis, treatment and prevention
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Vitamin D deficiency and insufficiency is a global health issue that afflicts more than one billion children and adults worldwide. The consequences of vitamin D deficiency cannot be under estimated. There has been an association of vitamin D deficiency with a myriad of acute and chronic illnesses including preeclampsia, childhood dental caries, periodontitis, autoimmune disorders, infectious diseases, cardiovascular disease, deadly cancers, type 2 diabetes and neurological disorders. This review is to put into perspective the controversy surrounding the definition for vitamin D deficiency and insufficiency as well as providing guidance for how to treat and prevent vitamin D deficiency.
KeywordsVitamin D deficiency Vitamin D insufficiency Sunlight Rickets Vitamin D2 Vitamin D3 25-hydroxyvitamin D Vitamin D toxicity
1 Definition of vitamin D deficiency and insufficiency
Up until 1998 vitamin D deficiency was defined as a blood level of 25-hydroxyvitamin D [25(OH)D]; which represents a total concentration of both 25-hydroxyvitamin D2 and 25-hydroxyvitamin D3] of less than 10 ng/mL (25 nmol/L). This definition was mainly based on reports relating blood levels of 25(OH)D and the development of rickets.  It was also recognized that vitamin D deficiency was associated with an increase in the circulating levels of parathyroid hormone (PTH). It had been reported that there is an inverse relationship with serum PTH levels and 25(OH)D levels and that the PTH levels began to plateau at approximately 30 ng/mL.  Malabanan et al.  in 1998 reported that when healthy adults who had blood levels of 25(OH)D of 11–25 ng/mL were given 50,000 IUs of vitamin D2 once a week for 8 weeks they observed a statistically significant decline in the blood levels of PTH for the adults who have blood levels of 25(OH)D between 11 and 19 ng/mL. There was no significant change in the PTH levels for the adults who had levels of 25(OH)D between 20 and 25 ng/mL. Thus the definition for vitamin D deficiency was redefined in 1998 as a blood level of 25(OH)D < 20 ng/mL .
In 2011 the Institute of Medicine (IOM), after an extensive review of the literature, came to the conclusion that for maximum bone health, a blood level of 25(OH)D of 20 ng/mL and above was adequate . This was based on several observations including those by Malabanan et al.(3) and Priemel et al.  Priemel et al.  had collected bone biopsies and blood from 675 German adults between the ages of 20–90 years who died in an accident. They related evidence for osteomalacia, based on wide unmineralized osteoid seams in the bone biopsies with their blood levels of 25(OH)D. The authors concluded that remarkably upwards of 25% and 35% of these otherwise presumed healthy German adults had evidence of vitamin D deficiency osteomalacia and osteoidosis respectively. They further concluded that when the adults had a blood level of 25(OH)D of at least 30 ng/mL there was no evidence of vitamin D deficiency bone disease based on the bone biopsies demonstrating no evidence for osteomalacia or osteoidosis. The IOM reviewed the Priemel data in detail and incorrectly concluded that less than 1% of adults in the study who had blood levels of 25(OH)D between 21 and 29 ng/mL had evidence of vitamin D deficiency osteomalacia and therefore concluded that a blood level of 20 ng/mL was adequate for bone health .
The Endocrine Society in 2011 reported on the findings from their assembled panel of vitamin D experts. In the published Endocrine Society’s Practice Guidelines on Vitamin D, vitamin D deficiency was defined as a 25(OH)D < 20 ng/mL, insufficiency as 21–29 ng/mL and sufficiency as at least 30 ng/mL for maximum musculoskeletal health.  They also recognized the several studies reporting on the inverse relationship with serum PTH levels and serum 25(OH)D levels whereby most but not all studies [5, 6] reported that PTH levels begin to plateau when 25(OH)D levels were at approximately 30–40 ng/mL. In addition the expert panel evaluated the Priemel et al.  data. They realized that when you take the number of presumed healthy adults with evidence of osteomalacia and who had a blood level of 25(OH)D between 21 and 29 ng/mL and divide it by the number of adults who also had blood levels of 25(OH)D between 21 and 29 ng/mL it was determined that not less than 1% as suggested by the IOM but 24% of these German adults had evidence of vitamin D deficiency osteomalacia [9, 10]. In addition the Endocrine Society’s Practice Guidelines Committee conducted a meta-analysis on vitamin D status and falls and concluded that a blood level of 25(OH)D of at least 30 ng/mL was required to reduce risk for falls [9, 11]. Therefore the Committee recommended that for maximum musculoskeletal health that the blood level of at least 30 ng/mL for serum 25(OH)D should be considered to be vitamin D sufficient. This definition has also been accepted by the National Osteoporosis Foundation, International Osteoporosis Foundation, American Association for Clinical Endocrinologists, and the American Geriatric Society [12, 13].
2 The vitamin D deficiency pandemic
It has been estimated that approximately 30% and 60% of children and adults worldwide are vitamin D deficient and insufficient respectively . Even in Australia it was reported at 31% (22% in men and 39% in women) of adults had a blood level of 25(OH)D < 20 ng/mL and 73% less than 30 ng/mL .
3 Causes for the vitamin D deficiency pandemic
It has been estimated at no more than 1% of the total solar UVB radiation ever reaches the earth’s surface at the equator in the summer [34, 35, 38, 39]. There are several factors that influence how much solar UVB reaches the earth surface including first-order Rayleigh scattering by the atmosphere, attenuation by air, absorption by molecular oxygen and ozone, and the line structure in the solar spectrum [38, 39, 40, 41, 42]. The ozone in the atmosphere is very efficient in absorbing UVB radiation. When the zenith the angle of the sun becomes more oblique the path length increases resulting in ozone absorbing more of the UVB radiation thereby decreasing the amount reaching the earth surface [34, 38, 39, 40, 41, 42]. This is the explanation for why exposure to the sun above and below approximately 33° in the winter does not result in any significant production of vitamin D [34, 35, 43]. This also explains why very little if any vitamin D is produced in the skin during sun exposure before 9 AM and after 3 PM [34, 35, 39, 43]. Melanin and sunscreens both efficiently absorb UVB radiation thereby diminishing the effectiveness of the sun in producing vitamin D and the skin [34, 44]. A person with a skin type VI requires at least 5–10 times longer exposure compared to a person with skin type II . The proper application of a sunscreen (2 mg/square centimeter) with a sun protection factor (SPF) of 30 absorbs 97.5% of the UVB radiation on the surface of the skin thereby decreasing production of vitamin D by 97.5% [34, 45]. Clothing and glass absorbs all UVB radiation and therefore prevents vitamin D production during sun exposure [34, 46, 47].
4 Treatment and prevention of vitamin D deficiency and insufficiency
There are 2 forms of vitamin D. Vitamin D3 (cholecalciferol) is produced in the skin during sun exposure and is also present in oily fish and cod liver oil [1, 25, 34]. (Fig. 5) Vitamin D3 in supplements is either derived from fish oil or produced from cholesterol that is obtained from lanolin in sheep’s wool. Vitamin D2 (ergocalciferol) was produced commercially from UV irradiated yeast. It is also present in mushrooms exposed to sunlight or ultraviolet B radiation and in sun-dried mushrooms . Vitamin D2 has been used for more than 50 years for the treatment and prevention of vitamin D deficiency [1, 25, 34]. It is also used to fortify some foods such as milk with vitamin D. However some reports raised the question as to whether vitamin D2 was as effective as vitamin D3 in maintaining blood levels of 25(OH)D [49, 50, 51, 52, 53]. One study reported that vitamin D2 increased the destruction of vitamin D3 suggesting that ingestion of vitamin D2 increased risk for that patient becoming vitamin D deficient more quickly if vitamin D2 was used . This may be true when given as a single bolus dose but it is not true when given chronically. Several additional studies have appeared evaluating physiologic doses (1000 IUs or 2000 IUs) of vitamin D2 and vitamin D3 on total blood levels of 25(OH)D [48, 54, 55]. These studies reported not only did ingesting 1000 IUs of vitamin D2 raise blood levels of 25(OH)D to the same levels as those ingesting 1000 IUs of vitamin D3 but that the 25(OH)D3 did not significantly decline. Studies evaluating 50,000 IUs of vitamin D2 every 2 weeks for the treatment and prevention of recurrent vitamin D deficiency for up to 6 years demonstrated it was effective in maintaining total 25(OH)D levels above 30 ng/mL . To be certain that 25(OH)D2 was converted in the kidneys to 1,25(OH)2D2 as efficiently as 25(OH)D3 serum samples from the study where adults receive 1000 IUs of vitamin D2 or vitamin D3 were analyzed for 1,25(OH)2D2 and 1,25(OH)2D3. Remarkably, as expected, when the kidney was provided 25(OH)D2 it converted it to 1,25(OH)2D2. As a result of the increase in 1,25(OH)2D2 the 1,25(OH)2D3 decreased by the same amount so that the total 1,25(OH)2D did not change from baseline . This was expected since the blood level of 1,25(OH)2D is tightly regulated by parathyroid hormone and other factors [1, 25].
In the United States only vitamin D2 is available as a pharmaceutical because it predated the FDA and was grandfathered as a pharmaceutical. Vitamin D3 was never evaluated as a pharmaceutical but is widely available as a supplement. The problem in the United States is that a pharmacy can obtain this supplement from several different manufacturers and we don’t know the quality of the supplement whereas we do for the pharmaceutical vitamin D2. With this said, vitamin D3 supplements produced by respected national brands are perfectly fine. I have tested and demonstrated that there was an appropriate amount of vitamin D3 as stated on the label in many well-respected national brands. For my patients who wish to take a vitamin D supplements, I recommend that they take a national brand of vitamin D3. However if they are vegans I will recommend they take vitamin D2.
It’s been argued that most studies have used vitamin D3 to demonstrate fracture efficacy and therefore why should we be using vitamin D2 to treat our patients for vitamin D deficiency. Based on all the evidence there is no reason to suspect that vitamin D2 would not have the same fracture benefit as vitamin D3 because vitamin D2 has the same biological functions on calcium metabolism as vitamin D3. It is also been suggested that vitamin D2 does not have any other health benefits such as decreasing risk for mortality and malignancies . However these conclusions are mainly based on meta-analyses of studies that reported on vitamin D2 intake but not on studies specifically comparing vitamin D2 to vitamin D3. Furthermore most of these studies did not report on blood levels of 25(OH)D2. Evidence does suggest that the half-life of 25(OH)D2 is shorter than 25(OH)D3. (58) This might suggest that vitamin D2 is less effective than vitamin D3 in its biologic actions. However one of the reasons why 25(OH)D2 has a shorter half-life is because it is not bound as tightly to DBP as 25(OH)D3 . This suggests that there would be a higher free level of 25(OH)D2 compared to the free level of 25(OH)D3 and therefore theoretically since it is the free level that is thought to have the most physiologic benefit that it might be expected that vitamin D2 would be more biologically effective than vitamin D3. The observation by Chun et al.  supports this hypothesis. They evaluated the effect of dietary vitamin D2 in comparison to dietary vitamin D3 on free total levels of 25(OH)D in C56BL/6 mice and at 16 weeks evaluated by histomorphometry the effect of these levels on bone morphology. The total 25(OH)D were essentially the same for the mice ingesting vitamin D2 (33.3+ −4.4 ng/mL) compared to the mice receiving dietary vitamin D3 (31.7+ −2.1 ng/mL) which is consistent with the clinical observations [54, 55, 58].The free 25(OH)D levels however were almost twice as high in the mice that received vitamin D2 (17.4 pg/mL) compared to the mice that received vitamin D3 (8.4 pg/mL) in their diets for 16 weeks. This translated into a positive benefit by the demonstration that the mice that received dietary vitamin D2 had significantly higher bone volume/total volume and trabecular number compared to the mice receiving the same amount of dietary vitamin D3. This study helps support the concept that vitamin D2 supplementation is as effective, and may be even more effective, than vitamin D3 supplementation at least regarding bone health. All of these observations in total would suggest that vitamin D2 is at least if not more beneficial than supplemental vitamin D3 and should put to rest the scientifically unfounded reluctance to use vitamin D2 to treat and prevent vitamin D deficiency.
Because vitamin D2 is a pharmaceutical and is only available in the form of 50,000 IUs in a capsule it was evaluated for the treatment and prevention of vitamin D deficiency in adults. 50,000 IUs of vitamin D2 given once a week for 8 weeks is an effective strategy to treat vitamin D deficiency [3, 56]. It has been suggested that patients who have undetectable blood levels of 25(OH)D be treated with more vitamin D for a longer period of time. Although this may seem like good common sense, it turns out not to be true. The reason is that there are at least 4 different 25-hydroxylases in the liver some of which efficiently convert even a small amount of vitamin D rapidly to 25(OH)D. This is the explanation for why giving 600–800 IUs of vitamin D daily will rapidly raise blood levels of 25(OH)D into the range of 15–20 ng/mL [9, 59]. However once a person with normal body weight reaches approximately 20 ng/mL it now requires 100 IUs of vitamin D to raise blood levels of 25(OH)D by approximately 0.6–1 ng/mL [9, 54, 55, 56, 60]. This is also explanation for why giving 1000 IUs of vitamin D daily to an adult who has a blood level of approximately 18–20 ng/mL is not effective in raising blood levels of 25(OH)D above 30 ng/mL .
Obese adults with a BMI >30 require 2–3 times more of vitamin D to both treat and prevent vitamin D deficiency [9, 64, 65]. This is because vitamin D being fat soluble gets diluted in the body fat and is not bioavailable. Patients with inflammatory bowel disease and gastric bypass surgery are less efficient in absorbing the fat soluble vitamin D and often need higher doses to treat and prevent vitamin D deficiency. In some cases where vitamin D cannot be absorbed in the gastrointestinal tract exposure to sunlight or artificial sunlight i.e. a UVB lamp such as the Sperti lamp or a tanning bed that emits UVB radiation can be an effective alternative to treat and prevent deficiency [34, 35, 66, 67, 68].
Neonates should receive 400 IUs of vitamin D daily as soon after birth as possible especially for breast fed infants since human breast milk contains very little, if any, vitamin D unless the mother is ingesting approximately 6400 IUs of vitamin D daily [9, 69]. To quickly correct infantile vitamin D deficiency infants can receive 2000 IUs of vitamin D daily for 6–8 weeks [9, 70]. For infants where there is concern that they might not be seen again, the infants can receive Stoss therapy which is very high dose usually 250,000 IUs of vitamin D intramuscularly to prevent infantile rickets [71, 72]. Toddlers and children who are vitamin D deficient can be treated with 50,000 IUs of vitamin D once a week for 6 weeks or 2000 IUs of vitamin D daily without concern for toxicity [9, 70].
Some healthcare professionals who have available to them active vitamin D i.e. 1,25(OH)2D3 (calcitriol) or its active analog 1-alpha-hydroxyvitamin D3 believe that giving these analogs is an effective way to treat vitamin D deficiency. However these analogs not only have a relatively short half-life but can cause hypercalciuria and hypercalcemia and should not be used to treat vitamin D deficiency. These active forms of vitamin D however are effective in treating inborn and acquired disorders in the metabolism of 25(OH)D to 1,25(OH)2D especially in patients with severe chronic kidney disease .
5 Vitamin D toxicity
Vitamin D intoxication is extremely rare. One cannot become vitamin D toxic from sun exposure because excess vitamin D is destroyed by the sun . The only cause is due to nonintentional or intentional ingestion of excessively high quantities of vitamin D for a prolonged period of time. [73, 74, 75, 76] Examples include a misunderstanding of the difference between micrograms and milligrams and a manufacturer putting in 1000 times more vitamin D than was on the label which was 1000 IUs in a capsule. The consumer of this product was advised to take 4 capsules a day for a total of 4000 IUs. However consumers were taking 4 million IUs daily for several months to more than a year . A Canadian manufacturer did not dilute the crystalline vitamin D and the consumer who took 2 teaspoons a day believing that he was taking 2000 IUs daily had received more than 1 million IUs a day for more than a year . A small dairy in Massachusetts inadvertently was adding up to 250,000 IUs of vitamin D in 8 oz of milk. Some of these consumers presented with overt vitamin D intoxication including a serum calcium as high as 16 mg/dL (normal range 8.6–10.6 mg/dL) and an elevated serum phosphate level in the range of 5–6 mg/dL (normal range 2.7–4.5 mg/dL). Their blood levels of 25(OH)D were in the range of 350–550 ng/dL .
6 Concerns about the J-curve and U-curve regarding blood levels of 25(OH)D
The IOM in its report raised concerns about raising blood levels of 25(OH)D above 50 ng/mL . The IOM panel members agreed that vitamin D deficiency is associated with an increased risk for mortality especially from cardiovascular disease. The IOM panel members plotted a few studies reporting the relationship of mortality with blood levels of 25(OH)D. They showed a significant decline in mortality until the blood level of 25(OH)D approached 30 ng/mL and then showed a slight increase that was apparent at 50 ng/mL. The IOM panel members concluded that there should be concern about a potential increased risk for mortality if the blood level of 25(OH)D is above 50 ng/mL. This is known as J-curve or U-curve effect. However one of the studies that they plotted actually concluded that there continued to be at decreased risk for mortality from men above 50 ng/mL and that only in women there was a possibility of a slight increased risk for mortality . Several publications have appeared challenging the concept of the so-called J-U-curve. [78, 79] First and foremost very few of these subjects in any of the studies had blood levels above 50 ng/mL. However more importantly the question that was never asked was how was it that some individuals in these studies had a blood level of 25(OH)D above 50 ng/mL. One possible explanation was that these individuals were actually vitamin D deficient and being treated for vitamin D deficiency. To confirm this possibility Kroll et al.  reported on 3.8 million blood samples collected in the United States in adults over a two-year period of time. Because vitamin D2 is routinely used the treat vitamin D deficiency the samples were analyzed by liquid chromatography tandem mass spectroscopy for the presence of 25(OH)D2. Remarkably 57% of samples that had a total 25(OH)D of 50 ng/mL or greater had detectable levels of 25(OH)D2. This suggested that these individuals were being treated for vitamin D deficiency and therefore would be more likely to be at higher risk for mortality due to their previous chronic vitamin D deficiency .
There continues to be contentious debate about what blood level of 25(OH)D is considered to be deficient and sufficient [7, 9, 10, 79, 80, 81]. It is in part based on the definition of vitamin D deficiency as to how much of vitamin D is required to be vitamin D sufficient. The IOM used a population model and determined that 400, 600 and 800 IUs daily is all that is required for neonates up to one year, children and adults up to 70 years and adults over 70 years respectively to achieve a 25(OH)D of 20 ng/mL in 97.5% of the population . The IOM recommendations were not intended to provide guidance for the treatment and prevention of vitamin D deficiency. It was up to professional associations to make those recommendations. The Endocrine Society, National and International Osteoporosis Foundations and the American Geriatric Society chose to define vitamin D sufficiency as the blood level of 25(OH)D of at least 30 ng/mL [9, 12]. They also considered a blood level up to 100 ng/mL as perfectly safe. The Endocrine Society recommend a preferred range of 40–60 ng/mL. This is the range that likely our hunter gatherer forefathers achieved while being exposed to sunlight on a daily basis. The body has a huge capacity to produce vitamin D. Exposure of half an adult body to about 50% of the amount of sunlight that would cause a mild sunburn 24 h later is equivalent to ingesting approximately 5000 IUs of vitamin D daily [34, 35]. This is consistent with the observation made in Maasai herders who maintained blood levels of 25(OH)D of 40–50 ng/mL . To achieve and maintain this level would require an adult to ingest 4000–5000 IUs daily of vitamin D [60, 62]. Therefore the recommendations for vitamin D intake of 400–1000 IUs, 600–1000 IUs and 1500–2000 IUs daily for children under one year, children 1–18 years and all adults respectively to treat and prevent vitamin D deficiency by the Endocrine Society is reasonable . Teenagers however should be treated as adults and should also be receiving at least 1500–2000 IUs a day . The IOM recommended the upper limit for most children and adults be at 4000 IUs daily. The Endocrine Society agreed that 4000 IUs daily is reasonable as the upper limit for children but for adults 10,000 IUs daily is more reasonable especially since obese people require 2–3 times more vitamin D to treat and prevent recurrent vitamin D deficiency [9, 62].
There are a multitude of studies relating the health benefits of vitamin D and sun exposure for reducing risk for many chronic illnesses including deadly cancers, autoimmune diseases including multiple sclerosis, rheumatoid arthritis, Crohn’s disease in type 1 diabetes, cardiovascular disease, neurocognitive dysfunction, type 2 diabetes and infectious diseases. [1, 25, 34, 35, 84, 85].
The abstinence message of avoiding all direct sun exposure without sun protection by many dermatology societies  has not resulted in a significant decline in the incidence of the most deadly form of skin cancer, melanoma . This is expected since most melanomas occur on the least sun exposed areas and occupational sun exposure decrease decreases the risk for melanoma [88, 89]. Furthermore obesity has been linked to an increased risk for both melanoma and nonmelanoma skin cancer . Excessive sun burning increases risk not only for the deadly melanoma but also for non-melanoma skin cancer [88, 89]. Felton et al.  reported that people with skin type II living in the UK and exposed to UV radiation that would be expected to be received in the summer, did as expected, have increased DNA damage in the epidermis. This exposure also significantly increased their blood level of 25(OH)D. At the end of the study an evaluation of the epidermis revealed a marked decline in DNA damage that was reflected by a decrease in urinary DNA metabolites. This demonstrated that the Caucasian skin type II that evolved as people migrated north and south of the equator not only permitted a more efficient production of vitamin D but at the same time developed mechanisms to overcome the DNA damage that was associated with being exposed to the vitamin D-UVB solar radiation . Recently the World Health Organization has recognized on its website that sensible sunlight does provide health benefits including the production of vitamin D. However it is hard to define sensible sun exposure since time of day, season, latitude, altitude and skin pigmentation all can dramatically influence how much vitamin D is produced in the skin when exposed to sunlight [34, 35]. As a result an app dminder.info which is free for the android and apple formats has been developed to provide a user with information as to when and how much vitamin D can be produced during sun exposure anywhere on the planet anytime of the year for all skin types . It also advises a user when they’ve been exposed to enough sunlight and to seek sun protection so that they do not acquire a sunburn.
With all of the mounting evidence for a wide variety of health benefits associated with vitamin D sufficiency there is no downside to be improving everyone’s vitamin D status. The goal should be to have a blood level of 25(OH)D of at least 30 ng/mL; the preferred range being 40–60 ng/mL. This can be achieved by increasing everyone’s vitamin D supplementation to the levels recommended by the Endocrine Society  as well as obtaining sensible sun exposure [34, 90, 91, 92, 93, 94]. There is no need to be screening every one for the vitamin D status [7, 9]. It is much more cost effective to increase food fortification with vitamin D [34, 90, 91, 92, 93, 95, 96] and encourage vitamin D supplementation and sensible sun exposure. However those individuals with fat malabsorption syndromes, those who had had gastric bypass surgery or have other risk factors or inborn or acquired disorders in vitamin D metabolism do require screening with followup measurements of 25(OH)D [1, 9, 62].
Compliance with ethical standards
This is a review and therefore there are no issues regarding compliance and ethical standards.
Conflict of interest
The author declares that he is a consultant for Quest Diagnostics, Ontometrics Inc. and is on speaker’s Bureau for Sanofi Inc.
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