Matthew Regulski, D.P.M., C.M.E.T., F.A.P.W.C.A., F.A.P.W.H. (c)
Vitamin D (cholecalciferol) should be considered a nutritional substrate that must be ingested or synthesized in sufficient amounts for further synthesis of the very important regulatory steroid hormone (D hormone), especially in patients with pediatric rheumatic diseases.
Vitamin D insufficiency or deficiency was shown to be pandemic and associated with numerous chronic inflammatory, and malignant diseases and even with increased risk of mortality.
The discovery that most tissues and cells in the body have the vitamin D receptor and that several possess the enzymatic machinery that can burn the parameter circulating form of vitamin D, 25-hydroxyvitamin D, to the active form of 1,25-dihydroxyvitamin D, has provided new insights into the function of this vitamin. Of great interest is the role it can play in decreasing the risk of many chronic illnesses, including common cancers, autoimmune diseases, infectious diseases, and cardiovascular disease.
One century after its discovery and three Noble prizes award for discoveries in this topic, we have clear evidences that this so called vitamin D is in fact a pleiotropic steroid hormone similar to other steroid hormones.
Sources Metabolized Vitamin D
Humans get vitamin D from exposure to sunlight, from their diet, and from dietary supplements (Holick, et al, 2006, Garabedian et al, 2006, Boullion et al, 2001, and DeLuca et al, 2004). A diet high in oily fish prevents vitamin D deficiency. Solar ultraviolet B radiation (wave length, 290, 2315 mm) penetrates the skin and converts 7-dihydrocholesterol to pre-vitamin D3, which is rapidly converted to vitamin D3. Because any excess pre-vitamin D3 or vitamin D3 is destroyed by sunlight, excessive exposure to sunlight does not cause vitamin D intoxication (Holick, MF, Garabedian M. 2006).
Few foods naturally contain or are fortified with vitamin D. The “D” represents D2 or D3. Vitamin D2 is manufactured through the ultraviolet irradiation of ergosterol from yeast, and vitamin D3 for the ultraviolet irradiation of 7-dehydrocholesterol from lanolin. Both are used in over-the-counter vitamin D supplements, but the form available by prescription in the United States is vitamin D2.
Vitamin D from the skin and diet is metabolized in the liver to 25-hydroxyvitamin D, which is used to determine a patient’s vitamin D status; 25-hydroxyvitamin D is metabolized in the kidneys by the enzyme 25-hydroxyvitamin D-1 Alpha-hydroxylase (CYP27B1) to its active form, 1,25-dihydroxyvitamin D (Holick, et al, 2006, Garabedian et al, 2006, Boullion et al, 2001, and DeLuca et al, 2004).
The renal production of 1,25-dihydroxyvitamin D is tightly regulated by plasma parathyroid hormone levels and serum calcium and phosphorus levels. Fibroblast growth factor 23, secreted from the bone, causes the cilium-phosphate co-transporter to be internalized by the cells of the kidney and small intestine, and also suppresses 1,25-dihydroxyvitamin D synthesis (Hruska KA, 2006). The efficiency of the absorption of renal calcium and of additional calcium phosphorus is increased in the presence of 1,25-dihydroxyvitamin D.
It also induces the expression of the enzyme 1,25-dihydroxyvitamin D-24-hydroxylase, (CYP24), which metabolizes both 25-hydroxyvitamin D and 1,25 dihydroxyvitamin D into biologically inactive, water-soluble, calcitroic acid.
Vitamin D Hormone Biological Activity
For many years, it was believed that the regulation of calcium homeostasis in the body with a positive influence on bone turnover were the only crucial roles for this hormone. These roles were why it was considered to be a vitamin critical for bone health. This tenet remains correct, but it is now understood that all monocyte-macrophage red cells, including those present in many tissues and various epithelia, are able to express 1Alpha hydroxylase and to synthesis calcitriol locally (Adams JS, Hewison et al, 2010).
Synthesized D hormone can act on cells and in the tissues and in an autocrine or paracrine manner, and the synthesized D hormone, calcitriol serves as a connection between extra cellular stimuli and genomic response of the cells (Mora, Iwata et al, 2008).
It is recognized that the 1ALPHA 25-dihydroxyvitamin D, has high infinity by vitamin D receptor (VDR) due to the presence of a OH group at the 1ALPHA position. The VDRG shows its expression in tissues with high metabolic activity, such as kidneys, bone, and gut, but has low to moderate expression in nearly all other human tissues. VDR when down to hormone, heterodimerizes with the retinoic acid-X-receptor (RXR) and this complex binds to the vitamin D responsive element (VDRE) acting as a transcriptional to enhance or repress gene transcription (Carl Burg C, Campbell JM 2013).
It has been estimated that at least 200 tissues and as many as 2,000 genes are directly or indirectly controlled by this transcriptional complex (Norman AW, 2006). Only high doses of D hormone can induce genetic effects, including immunomodulatory actions while physiologic actions have to be mediated in the genetic and epigenetic regulatory actions of the VDR transcriptional complex (Carl Berg C, Campbell JM 2013, Norman AW, 2006).
VDR protein has been detected both in the cytosol (associated with sarcoplasmic reticulum calcium 2+-ATPase) and in plasma membranes. This ubiquitous presence of the VDR protein may explain some of the rapid nongenomic actions of 1,25-dihydroxyvitamin D, such as calcium uptake, that are related to calcium homeostasis and bone mineralization (H Takangas, et al, 2004).
The seemingly pathways of all steroid hormones, of which vitamin D is very closely related to cholesterol (glucocorticoids and sex hormones, occur through cellular and nuclear hormone receptors) (Sundar KS, et al, 2011).
All of these hormones influence bone formation and immune regulation. Steroid nuclear receptors, when bound to their agonist hormone, under control of co-regulators, catalyzer or metachromatin remodeling, epigenetic modifications, receptor recycling, and ultimately gene expression (Haussler MR, et al, 2013).
Gene regulation appears to be modulated by dual modifications of histone acetylation and DNA methylation. The 1,25-dihydroxyvitamin D hormone has been shown to be a potent genetic and epigenetic regulator. This could be explanation for the possible pathogenic role of low vitamin D status in immune-mediated diseases (Cutolo et al, 2014 and Sundar et al, 2011).
Using this same signaling pattern of 1,25-dihydroxyvitamin D, locally produced in the tissues, exerts its effects on several immune cells, including macrophages, dendritic cells, T and B cells.
Macrophages and dendritic cells constituently express vitamin D receptor (VDR), whereas VDR expression in K cells is upregulated after activation (Margolis et al, 2010). In macrophages and monocytes, 1,25-dihydroxyvitamin D positive influences its own effects by increasing expression of VDR in the cytochrome P450 protein, CYP27B1. Toll-like receptor TLR-mediated signals can also increase the expression of VDR. The 1,25-dihydroxyvitamin D hormone also induces monocyte proliferation and production of interleukin-1 (IL-1) and cathelicidin (a very powerful antimicrobial peptide) by macrophages, thereby contributing to innate immune response (Prue et al, 2011, Adams et al, 2008). The 1,25-dihydroxyvitamin D hormone decreases dendritic cell maturation, inhibiting upregulation of the expression of MAC class II, CD48, CD80, and CD 86. In addition, it decreases interleukin-12 production of dendritic cells and induced production of interleukin-10.
In T cells, 1,25-dihydroxyvitamin D2 decreases the production of interleukin-2, IL-2, IL-17, and gamma interferon and attenuates the cytotoxic activity and proliferation of CD4+ and CD8+ T cells (Liu et al, 2006). The 1,25-dihydroxyvitamin D hormone might also promote the development of the forked box protein (FOXP3, regulatory T cells and IL-10 producing T regulatory type TR1, cells).
Finally 1,25-dihydroxyvitamin D blocks B cell proliferation, plasma cell differentiation, and immunoglobulin production (Dirosa et al, 2011).
It is clear that D hormone exerts its effects on many crucial, important, immunoregulatory proteins and cells. Some of them are recognized as possible causative immune factors for the development of chronic inflammatory diseases. Some of them are recognized as possible causative immune factors for the development of these arthrities. Due to the D hormone’s apparent capability to induce tolerogenic immune response, improved impaired T and B cell function, and enhance a immunity response, in deficiency or insufficiency of D hormone, may well have causative risk factors in several chronic inflammatory diseases (Prietl et al, 2013).
Optimal D Hormone Levels
The best method to determine a person’s vitamin D status is to measure the circulating level of 25 (OH) D. Serum levels of 1,25-dihydroxyvitamin D are often normal or even elevated in both children and adults who are vitamin D deficient due to its very short half life and tight physiologic control by PTH, parathyroid hormone, which can increase renal production of calcitriol (by stimulating 1-alpha-hydroxylase activity). The vitamin D hormonal form is synthesized and accumulated to a large degree in the tissues but there it cannot be measured (Holick, 2007).
For a long time, there has been no consensus on the optimal concentrations of serum 25 (OHD). Most authors have used the cut-off values of 10 to 15 ng/ml to define vitamin D deficiency. In 2010, the Institute of Medicine (IOM) concluded that vitamin D deficiency should be defined as a 25 OHD level of less than 20 ng/ml for children and adults (Institute of Medicine, IOM, National Academies Press, 2011).
The Endocrine Clinical Practice Guidelines Committee of the Endocrine Society proposed a new definition of vitamin D insufficiency and sufficiency. Vitamin D deficiency is now defined as a 25 OHD less than 25 ng/ml, vitamin D insufficiency is 21 to 29 ng/ml and vitamin D sufficiency is greater than 30 ng/ml for both children and adults. It is suggested that the maintenance of a 25 OHD level between 40 and 60 ng/ml is ideal and up to 100 ng/ml is safe (Holick MF et al, 2011, Haney RP, 2003).
In adults, it was shown that the supplementation of 1,000 IU (international units) of cholecalciferol per day increases 25 OHD level by 7 to 10 ng/ml and is believed that 100 IU can increase 25 OHD levels by as much as 2 to 3 ng/ml when serum 25 OHD is below 15 ng/ml (Borden et al, 2008).
With the use of such definitions, it has been estimated that one billion people worldwide have vitamin D deficiency or insufficiency (Holick, 2006, Bischoff-Ferrari et al, 2006, Malaban et al, 1998, Thomas KK, 1998, Chapuy et al, 1997, Holick M et al, 2005). According to several studies, 40 to 100% of US and European elderly men and women still living in the community, not in nursing homes, are deficient in vitamin D (Holick, 2006, Bischoff-Ferrari et al, 2006, Malaban et al, 1998, Thomas KK, 1998, Chapuy et al, 1997, Holick M et al, 2005). More than 50% of postmenopausal women taking medications for osteoporosis had suboptimal levels of 25-dihydroxyvitamin D – below 30 ng/ml (Holick, 2006, Bischoff-Ferrari et al, 2006, Malaban et al, 1998, Thomas KK, 1998, Chapuy et al, 1997, Holick M et al, 2005).
Calcium, Phosphorus, and Bone Metabolism
Now vitamin D, only 10 to 15% of bacteri calcium and about 50% of phosphorus are absorbed (Holick et al, 2006, Boullion et al, 2001, DeLuca, 2004). The interaction of 1,25-dihydroxyvitamin D with the vitamin D receptor increases the efficiency of intestinal calcium absorption to 30 to 40% and phosphorus absorption to approximately 80% (Holick et al, 2006, Boullion et al, 2001, DeLuca, 2004, Haney et al, 2003).
In one study, serum levels of 25-dihydroxyvitamin D were directly related to bone mineral density in white, black, and Mexican-American men and women, with a maximum density achieved when the 25-dihydroxyvitamin D level reached 40 ng/ml or more (Bischoff-Ferrari, 2006). When the level was 30 ng/ml or less, there was a significant decrease in intestinal calcium absorption that was associated with increased parathyroid hormone (Thomas et al, 1998, Chapuy et al, 1997).
Parathyroid hormone enhances the tubular reabsorption of calcium and stimulates the kidneys to produce 1,25-dihydroxyvitamin D. Parathyroid hormone also activates osteoblast which stimulate the transformation of preosteoclast into mature osteoclasts (Holick et al, 2006, Garabedian et al, 2006, Bouillon, 2001). Osteoclast dissolve the mineralized collagen matrix in bone, causing osteopenia and osteoporosis and increasing the risk of fracture (Holick et al, 2006, Bischhoff-Ferrari et al, 2006, Chapuy et al, 1997, Boonen et al, 2006, Chapuy et al, 1992).
The deficiencies of calcium and vitamin D in-uterine and childhood may prevent the maximum deposition of calcium in the skeleton (Cooper et al, 2005). As vitamin D deficiency progresses, the parathyroid glands are maximally stimulated, causing secondary hyperparathyroidism. Hypomagnesemia blunts this response which means the parathyroid hormone levels are often normal when 25-dihydroxyvitamin D levels fall below 20 ng/ml (Shota et al, 2006).
Parathyroid hormone increases the metabolism of 25-dihydroxyvitamin D to 1,25-dihydroxyvitamin D, which further exacerbates the vitamin D deficiency. Parathyroid hormone also causes phosphaturia, resulting in a low-normal or low serum phosphorus level. Without an adequate calcium-phosphorus product, mineralization of the collagen matrix is diminished, leading to classic signs of rickets in children and osteomalacia in adults (Pettifor et al, 2005, Aaron et al, 1974, Holick et al, 2006).
Whereas osteoporosis is associated with bone pain, osteomalacia has been associated with isolated or generalized bone pain. The cause is thought to be hydration of the demineralized gelatin matrix beneath the periosteum; the hydrated matrix pushes outward on the periosteum, causing throbbing, aching pain (Holick et al, 2006).
Osteomalacia can often be diagnosed by using moderate force to press the thumb on the sternum or anterior tibia, which can elicit bone pain (Holick et al, 2006, Melabanan et al, 1998).
One study showed that 93% of persons down to 65 years of age who are admitted to a hospital emergency department with muscle aches and bone pain and who had a wide variety of diagnoses, including fibromyalgia, chronic fatigue syndrome, and depression, were deficient in vitamin D (Plotnikoff et al, 2003).
Muscle Strength and Falls
Vitamin D deficiency causes muscle weakness. Skeletal muscles have a vitamin D receptor and may require vitamin D for maximal function (Holick et al, 2006, Garabedian et al, 2006, Bouillon, 2001, Holick et al, 2006, Bischoff-Ferrari et al, 2006). Performance, speed, and proximal muscle strength are markedly improved when 25-dihydroxyvitamin D increased from 4 to 16 ng/ml and continue to improve as the levels increase to more than 40 ng/ml (Bischoff-Ferrari et al, 2006).
On meta-analysis by randomized, controlled trials (with a total of 1,237 subjects) revealed that increased vitamin D intake reduced the risk of falls by 22% (pools corrected OLS ratio 0.87; 95% CI, 0.64 to 0.92) as compared with only calcium or placebo (Bischoff-Ferrari, 2006).
The same meta-analysis exam of the frequency of falls suggests that 400 IU of vitamin D3 per day was not effective in preventing falls, whereas 800 IU of vitamin D3 per day plus calcium reduced the risks of falls (corrected pooled OLS ratio 0.65; 95% CI, 0.42 to 1.0).
In a randomized controlled trial conducted over a five month period, nursing home residents receiving 800 IU of vitamin B2 per day plus calcium had a 72% reduction in the risk of falls as compared with the placebo group (Broe et al, 2007).
Non-Skeletal Actions of Vitamin D
Brain, prostate, breast, and colon tissues, among others, as well as AIM cells have a vitamin D receptor and respond to 1,25-dihydroxyvitamin D, the active form of vitamin D (Holick et al, 2006, Holick and Garabedian et al, 2006, Bouillon et al, 2001, DeLuca et al, 2004). In addition, some of these tissues and cells express the enzyme 25-dihydroxyvitamin D, 1 Alpha-hydroxylase.
Directly or indirectly, 1,25-dihydroxyvitamin D controls more than 200 genes, including genes responsible for the regulation of safe proliferation, differentiation, apoptosis, and angiogenesis (Nagpal et al, 2005). It decreases cellular proliferation of both normal cells and cancer cells and induces their terminal differentiation (Nagpal et al, 2005).
One practical application is the use of 1,25-dihydroxyvitamin D3 and its active analogs for the treatment of psoriasis (Holick et al, 1998, Kragballe et al, 1998).
1,25-dihydroxyvitamin D is also a potent immuno modulator (Penna et al, 2005). Monocytes and macrophages exposed to a lipopolysaccharide or to mycobacterium tuberculosis help regulate the vitamin D receptor gene in the 25-hydroxyvitamin-1Alpha-hydroxylase gene. Increased production of 1,25-dihydroxyvitamin D3 results in synthesis of cathelicidin, a peptide capable of destroying mycobacterium tuberculosis as well as other infectious agents.
When serum levels are 25-hydroxyvitamin D fall below 20 ng/ml, the monocyte or macrophage is prevented from initiating this innate immune, which explain why black Americans, who are often vitamin D deficient, are more prone to contracting tuberculosis than whites, and tend to have a more aggressive form of the disease (Liu et al, 2006).
When 25-dihydroxyvitamin D inhibits burning synthesis, increases insulin production, and increases myocardial contractility (Li et al, 2003, Chiu et al, 2004, Sittermann et al, 2006).
People living in higher latitudes are at increased risk for Hodgkin’s lymphoma as well as colon, pancreatic, prostate, ovarian, breast, and other cancers and are more likely to die from these cancers as compared to people who are living at lower latitudes (Apperly, 1941, Gorham et al, 2005, Hanchette et al, 1992, Grant, 2002, Giovannecci et al, 2006, Ahonen et al, 2000).
Perspective and retrospective epidemiologic studies indicate the levels of 25-hydroxyvitamin D below 20 ng/ml are associated with a 30 to 50% increased risk of incident of colon, prostate, and breast cancer, along with higher mortality from these cancers (Feskanich et al, 2004, Holick, 2006, Luscombe et al, 2001, Garland et al, 2006, Chang et al, 2005).
An analysis from the Nurses Health Study Cohort (32,826 subjects) show that the odds for colorectal cancer were inversely associated with the medium serum levels of 25-hydroxyvitamin D (the OHS ratio at 16.2 ng/ml was 1.0 and the OHS ratio at 39.9 ng/ml was 0.53; P less than or equal to 0.01. Serum 1,25-dihydroxyvitamin D levels were not associated with colorectal cancer. A perspective vitamin D intake and the risk of colorectal cancer in ?____(@34:49) are in direct relationship (with a relative risk of 1 when the vitamin D intake was 6 to 94 IU per day and a relative risk of 0.53 when the intake was 233 to 652 IU per day, with P less than 0.05) (Gorham et al, 2005).
Participants in women’s health initiative who at baseline had a 25-hydroxyvitamin D concentration of less than 12 ng/ml had a 253% increase in the risk of colorectal cancer over a followup period of eight years (Holick, 2006).
Children and young adults were exposed to the most sunlight had a 40% reduced risk of non-Hodgkin’s lymphoma (Chang et al, 2005). No reduced risk from death from malignant melanoma once it develops, as compared with those who had the least exposure to sunlight (Berwick et al, 2005).
The question here is that since the kidneys tightly regulate the production of 1,25-dihydroxyvitamin D, serum levels do not rise in response to increased exposure to sunlight or increased intake of vitamin D. Furthermore, in a vitamin D insufficient state, 1,25-dihydroxyvitamin D levels are often normal or even elevated.
The likely explanation is that colon, prostate, breast, and other tissues express 25-hydroxyvitamin D-1Alpha-hydroxylase, and produce 1,25-dihydroxyvitamin D locally to control genes that help to prevent cancer by keeping cellulitic proliferation and differentiation in check (Nagpal et al, 2005, Gorham et al, 2005, Grant, 2002).
It has been suggested that if a cell becomes malignant, 1,25-dihydroxyvitamin D can induce apoptosis and prevent angiogenesis, thereby reducing the potential for the malignant cell to survive (Holick and Garabedian, 2006, Boullion, 2001, Holick, 2006, Mentell et al, 2000).
Once 1,25-dihydroxyvitamin D completes these tasks, it initiates its own destruction by stimulating the CYP24 gene to produce the inactive calcitroic acid. This guarantees that 1,25-dihydroxyvitamin D does not enter the circulation to influence calcium metabolism. This is a plausible explanation for why increased sun exposure and higher circulating levels of 25-hydroxyvitamin D are associated with a decreased risk of deadly cancers Holick and Garabedian, 2006, Boullion, 2001, Holick, 2006, Mentell et al, 2000, Gorham 3t al, 2005, Hanchette, 1992, Grant et al, 2002, Giovannecci et al, 2006, Ahonen 2000, Feskenanich, 2004, Holick, 2006, Lescombe, 2001, Garland et al, 2006, Chang et al, 2005).
Autoimmune, Osteoarthritis, and Diabetes
Living at higher latitudes increases the risk of type I diabetes, multiple sclerosis, and Crohn’s disease (Cantora et al, 2004, Ponsonby, 2002). Among white men and women the risk of multiple sclerosis decreases by 41% for every increase of 20 ng/ml in 25-hydroxyvitamin D above the approximately 24 ng/ml (OHS ratio 0.59; 95% CI, 0.36, 20.97; P=0.04) (Munger et al, 2006).
Women who ingested more than 400 IU’s of vitamin D per day had a 42% reduced risk of developing multiple sclerosis. Similar observations have been made for rheumatoid arthritis and osteoarthritis (Merlino et al, 2004, McAlindon et al, 1996). Several studies have suggested that the vitamin D supplementation in children reduce the risk of type I diabetes. Increasing vitamin D intake during pregnancy reduces the development of islet autoantibodies in offspring (Chiu et al, 2004).
For 10,366 children in Finland who were given 2000 IU of vitamin D3 per day during their first year of life and were followed for 31 years, the risk of type I diabetes was reduced by approximately 80% (relative risk 0.22; 95% CI, 0.05 to 0.89) (Hypponen, 2001). Among children with vitamin D deficiency, the risk was increased by approximately 200%, (relative risk 3.0; 95% CI, 1.0 to 9.0)
In another study, vitamin D deficiency increased insulin resistance, decreased insulin production, and was associated with metabolic syndrome (Chiu et al, 2004).
Living at higher latitudes increases the risk for hypertension and cardiovascular disease (Rosten B, 1997). A study of patients with hypertension who were exposed to ultraviolet B radiation three times a week for three months, 25-hydroxyvitamin D levels increased by approximately 180% and blood pressure became normal (both systolic and diastolic). Blood pressure reduced by 6 mm of mercury (Kraus, 1998).
Vitamin D deficiency is associated with congestive heart failure and blood levels of inflammatory factors, including C-reactive protein and interleukin-10, IL-10 (Zitterman, 2006, Zitterman, 2003).
Causes of Vitamin D Deficiency
There are many causes of vitamin D deficiency, including reduced skin synthesis and absorption of vitamin D and acquired and inheritable disorders of vitamin D metabolism and its responsiveness. If we have reduced skin synthesis, such as sunscreen use, deficiencies in skin pigment, aging, season, latitude, and time of day, can also influence our ability to produce and absorb vitamin D (Holick, 2004).
There can be decreased bioavailability, such as malabsorption syndromes (cystic fibrosis, celiac disease, Whipple’s disease, Crohn’s disease, bypass surgery (Lo et al, 1985, Aris, 2005).
There could be cases of increased catabolism that we see with patients that are on anticonvulsants, glucocorticoids, AIDS treatment, antirejection medication, – binding to the steroid enzyme biotic receptors on the pregnanex receptor (Zhou, 2006).
Patients that are breastfed that have poor vitamin D contact in human milk, thereby poor breast feeding can increase infant risk of vitamin D deficiency when breast milk is a sole source of nutrition (Hollis et al, 2004). Other examples could be decreased synthesis of 25-hydroxyvitamin D that we see in patients who have liver failure which then causes malabsorption of vitamin D but production of 25-hydroxyvitamin D is possible (Gascon-Barre, 2005).
There could also be increased urinary loss of 25-hydroxyvitamin D, as in the case of nephrotic syndrome which leads to substantial loss of 25-hydroxyvitamin D bound to vitamin D binding protein within the urine (K/DOQI Clinical Practice Guidelines for Bone Metabolism in Disease and Chronic Kidney Disease, 2003).
Also there may be decreased synthesis of 1,25-dihydroxyvitamin D that is seen in chronic kidney disease. Stage II and III, as well as hyperphosphatemia increases fibroblast growth factor 23, which decreases 25-hydroxyvitamin D-1Alpha-hydroxylase activity.
Stages IV and V, when glomerular filtration rate is less than 30, and the inability to produce adequate amounts of 1,25-dihydroxyvitamin D. These will result in decreased fractional excretion of phosphorus and decreased serum levels of 1,25-dihydroxyvitamin D, as well causing hypercalcemia, secondary to hyperparathyroidism, and renal bone disease (Shimada et al, 2004, Brown, 2001, Holick, 2005, Ritter et al, 2006, Dusso et al, 2006).
Vitamin D Requirements and Treatment Strategies
Recommendations from the Institute of Medicine for adequate daily intake of vitamin D are 200 IU for children and adults up to 50 years of age, 400 IU for adults 51 to 70 years of age, and 600 IU for adults 71 years of age or older (Standing Committee on Scientific Evaluation, Dietary Reference Intakes, Food and Nutrition Board, 1999). However, most experts agree that without adequate sun exposure, children and adults require approximately 800 to 1000 IU per day (Glerup et al, 2000, Boonen et al, 2006, Larsen et al, 2004, Tangpricha et al, 2003, Haney 2003).
Children with vitamin D deficiency should be aggressively treated to prevent rickets (Shah et al, 1994, Thatcher et al, 1999, Markestad et al, 1984).
Since vitamin D2 is approximately 30% effective as vitamin D3 in maintaining serum 25-hydroxyvitamin D levels, up to three times as much vitamin D2 may be required to maintain sufficient levels.
A cost effective method of correcting vitamin D deficiency and maintaining adequate levels is to get patients a 50,000 IU capsule of vitamin D2 once a week for eight weeks, followed by 50,000 IU of vitamin D2 every two to four weeks thereafter (Holick, 2006, Holick 2006, Malabanan, 1998). Alternatively, either 1000 IU of vitamin D3 or 3,000 IU of vitamin D2 per day is effective.
Strategies for Patients with Chronic Kidney Disease
In patients with any stage of chronic kidney disease, 25-hydroxyvitamin D should be measured every three months, and the levels should be maintained at 30 ng/ml or higher, as recommended in the Kidney Disease Outcome Quality Initiative Guidelines from the National Kidney Foundation. It is a misconception to assume that patients taking an active vitamin D analog have sufficient vitamin D: many do not. Levels of 25-hydroxyvitamin D are inversely associated with parathyroid hormone levels, regardless of the degree of chronic renal failure (Brown, 2001, Holick, 2005, Ritter et al, 2006, Dusso et al, 2006).
The parathyroid gland converts 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D, which directly inhibits parathyroid hormone expression. Patients with stage IV or V chronic kidney disease and an estimated glomerular filtration rate of less than 30 ml/minute, the body surface area, as well as those on chronic dialysis, are unable to make enough of 25-hydroxyvitamin D and need to take 1,25-dihydroxyvitamin D3 or one of its less calcemic analogs to maintain calcium metabolism and to decrease parathyroid hormone levels and the risk of renal bone disease.
Sunlight and Artifical Ultraviolet B Radiation
Sensible sun exposure can provide an adequate amount of vitamin D3, which is stored in body fat and released during the winter, when vitamin D3 cannot be produced (Jones et al, 1998, Reid et al, 1986, Sato et al, 2005).
Exposure of arms and legs for five to thirty minutes, depending on time of day, season, latitude, and skin pigmentation, between the hours of 10 am and 3 pm twice a week is often adequate (Jones et al, 1998, Reid et al, 1986, Sato et al, 2005).
Exposure to one minimal erythemal dose while wearing only a bathing suit is equivalent to ingestion of approximately 20,000 IU of vitamin D2 (Jones et al, 1998, Reid et al, 1986, Sato et al, 2005).
The skin has a great capacity to make vitamin D3, even in the elderly, to reduce the risk of fracture (Reid et al, 1986, Sato et al, 2005, Chel et al, 1998).
Vitamin D Intoxication
Vitamin intoxication is extremely rare but can be caused by inadvertent or intentional ingestion of excessively high doses. Doses of more than 50,000 IU per day raise levels of 25-hydroxyvitamin D to more than 150 ng/ml and are associated with hypercalcemia and hyperphosphoremia (Adams et al, 1997, Koutkia et al, 2001, Kreter, 2000).
Doses of 10,000 IU of vitamin D3 per day for up to five months, however, do not cause toxicity (Vieth et al, 2004). Patients with chronic granulomatous disorders, such as sarcoidosis, are more sensitive to serum 25-hydroxyvitamin D above 30 ng/ml because of macrophage production of 1,25-dihydroxyvitamin D which causes hypercalcuria and hypercalcemia (Adams et al, 2006).
In these patients, however, 25-hydroxyvitamin D levels need to be maintained at approximately 20 to 30 ng/ml to prevent vitamin D deficiency and secondary hyperparathyroidism (Adams et al, 2006).
Undiagnosed vitamin D deficiency is more common and 25-hydroxyvitamin D is the best test for measuring the vitamin D status (Kreiter et al, 2000). Serum 25-hydroxyvitamin D is not only predictor of bone health, but is also an independent predictor of the risk for cancer and other chronic diseases.
The report that postmenopausal women who increase their vitamin D intake by 1,100 IU of vitamin D3 reduce the relative risk of cancer by 60 to 77%. This is a compelling reason to be vitamin D sufficient (Lappe et al, 2007).
There are several different ways and different tests for measuring 25-hydroxyvitamin D, and reports and values sometimes can differ. As long as the combined total is 30 ng/ml or more, the patient has sufficient vitamin D (Vieth, 2004). The 1,25-dihydroxyvitamin D assay should never be used for detecting vitamin D deficiency because levels will be normal or even elevated as a result of secondary hyperparathyroidism. Because the 25-hydroxyvitamin D assay is costly, it may not always be available, providing children and adults with approximately at least 800 IU of vitamin D3 per day or its equivalent should guarantee vitamin D sufficiency unless there are mitigating circumstances.
Much evidence suggests that recommended adequate intakes are actually adequate. They need to be increased to at least 800 IU of vitamin D3 per day. Unless a person eats oily fish frequently, it is very difficult to obtain that much vitamin D3 on a daily basis from dietary sources. Excessive exposure to sunlight, especially sunlight that causes sunburn, will increase risk of skin cancer. Thus, sensible sun exposure or ultraviolet B irradiation and the use of supplements are needed to fulfill the body’s vitamin D requirement.
This was a good description of vitamin D deficiency and a good understanding of its metabolism and how it functions in several tissues throughout the body.
In the second part of my presentation, I will present upon how vitamin D can affect the innate and the adapted immune response, as well as affecting wound healing in patients particularly with diabetic foot ulcers and venous leg ulcers. Please be aware that we will be presenting a second part to this future on just that topic.