Current Insights On The Effects Of Vitamin D Deficiency

With a review of the literature, this author takes a closer look at how a deficiency of vitamin D affects patients in regard to bone health, diabetes, arthritis and other areas.

The active form of Vitamin D is a pleiotropic steroid hormone that has multiple biological effects. It is integral to the regulation of calcium homeostasis and bone turnover. The active form of vitamin D also has antiproliferative, pro-differentiation, antibacterial, immunomodulatory and antiinflammatory properties within the body in various cells and tissues. 

One should consider vitamin D (cholecalciferol) a nutritional substrate that patients must ingest or synthesize in sufficient amounts for further synthesis of the very important regulatory steroid hormone (D hormone), especially in patients with pediatric rheumatic diseases.

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 vitamin D’s discovery and three Nobel Prize awards for discoveries in this topic later, we have clear evidence that this so-called vitamin D is in fact a pleiotropic steroid hormone similar to other steroid hormones. 

What Are The Sources Of Metabolized Vitamin D?

Humans get vitamin D from exposure to sunlight, diet and dietary supplements.^1–3 A diet high in oily fish prevents vitamin D deficiency. Solar ultraviolet B radiation (wavelength, 290 nm, 2315 mm) penetrates the skin and converts 7-dehydrocholesterol to pre-vitamin D3, which rapidly converts to vitamin D3. Since sunlight destroys any excess pre-vitamin D3 or vitamin D3, excessive exposure to sunlight does not cause vitamin D intoxication.^1,2

Few foods naturally contain or are fortified with vitamin D2 or D3. Vitamin D2 is manufactured through the ultraviolet irradiation of ergosterol from yeast and vitamin D3 from the ultraviolet irradiation of 7-dehydrocholesterol from lanolin. Both vitamins D2 and D3 are available in over-the-counter vitamin D supplements, but the form available by prescription in the United States is vitamin D2. 

The liver metabolizes vitamin D from the skin and diet to 25-hydroxyvitamin D, which determines a patient’s vitamin D status. 25-hydroxyvitamin D metabolizes in the kidneys by the enzyme 25-hydroxyvitamin D-1 alpha-hydroxylase (CYP27B1) to its active form 1,25-dihydroxyvitamin D.^1–3 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 calcium phosphate cotransporter to be internalized by the cells of the kidney and small intestine, and also suppresses 1,25-dihydroxyvitamin D synthesis.⁴ The efficiency of the absorption of renal calcium and of additional calcium phosphorus is higher 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. 

A Closer Look At Vitamin D Hormone Biological Activity

For many years, we believed that the regulation of calcium homeostasis in the body and a positive influence on bone turnover were the only crucial roles for vitamin D. These roles were why we considered this hormone to be a vitamin critical for bone health. This tenet remains correct but now we understand that all monocyte-macrophage red cells, including those present in many tissues and various epithelia, are able to express 1-alpha hydroxylase and synthesize calcitriol locally.⁵

Synthesized D hormone can act on cells, in the tissues and in an autocrine or paracrine manner. The synthesized D hormone, calcitriol, serves as a connection between extra cellular stimuli and genomic response of the cells.⁶

We recognize that the 1-alpha 25-dihydroxyvitamin D has high infinity by vitamin D receptor due to the presence of a OH group at the 1-alpha position. The vitamin D responsive element 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.

Researchers have estimated that at least 200 tissues and as many as 2,000 genes are directly or indirectly controlled by this transcriptional complex.⁷ 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 vitamin D receptor transcriptional complex.⁷

Steroid nuclear receptors, when bound to their agonist hormone, under control of co-regulators, catalyzer or meta chromatin remodeling, facilitate epigenetic modifications, receptor recycling, and ultimately gene expression.⁸

Gene regulation appears to be modulated by dual modifications of histone acetylation and DNA methylation. Research has shown the 1,25-dihydroxyvitamin D hormone is a potent genetic and epigenetic regulator. This could be explanation for the possible pathogenic role of low vitamin D status in immune-mediated diseases.⁹

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 whereas vitamin D receptor expression in natural killer cells is upregulated after activation.¹⁰ In macrophages and monocytes, 1,25-dihydroxyvitamin D positive influences its own effects by increasing expression of vitamin D receptor in the cytochrome P450 protein CYP27B1. Toll-like receptor mediated signals can also increase the expression of vitamin D receptor. 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.¹¹ The 1,25-dihydroxyvitamin D hormone decreases dendritic cell maturation, inhibiting upregulation of the expression of major histocompatibility complex class II, CD48, CD80 and CD86. In addition, the 1,25-dihydroxyvitamin D hormone decreases interleukin-12 production of dendritic cells and induces 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.¹² 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 1 (TR1) cells.

Finally, 1,25-dihydroxyvitamin D blocks B cell proliferation, plasma cell differentiation and immunoglobulin production.¹³

It is clear that D hormone exerts its effects on many crucial immunoregulatory proteins and cells.¹⁴ Some of these effects are recognized as possible causative immune factors for the development of chronic inflammatory diseases. Some effects are recognized as possible causative immune factors for the development of these arthritides. Due to the D hormone’s apparent capability to induce tolerogenic immune response, improved impaired T and B cell function, and enhance an immunity response, in deficiency or insufficiency of D hormone, may well have causative risk factors in several chronic inflammatory diseases.

What Are 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 parathyroid hormone, which can increase renal production of calcitriol (by stimulating 1-alpha-hydroxylase activity). To a large degree, the tissues synthesize and accumulate the vitamin D hormonal form but one cannot measure it in the tissues.¹⁵

For a long time, there has been no consensus on the optimal concentrations of serum 25(OH)D). Most authors have used the cutoff values of 10 to 15 ng/mL to define vitamin D deficiency. In 2010, the Institute of Medicine defined vitamin D deficiency as a 25(OH)D level of less than 20 ng/mL for children and adults.¹⁶

The Endocrine Clinical Practice Guidelines Committee of the Endocrine Society proposed new definitions of vitamin D insufficiency and sufficiency.¹⁷ The definition of vitamin D deficiency is now a 25OHD 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. The guidelines suggest that the maintenance of a 25OHD level between 40 and 60 ng/mL is ideal, and up to 100 ng/mL is safe.

With the use of such definitions, studies have estimated that 1 billion people worldwide have vitamin D deficiency or insufficiency.^1,18–21 According to several studies, 40 to 100 percent of elderly men and women in the United States and Europe still living in the community, not in nursing homes, are deficient in vitamin D.^1,18–21 More than 50 percent of postmenopausal women taking medications for osteoporosis had suboptimal levels of 25-dihydroxyvitamin D: below 30 ng/mL.^1,18–21

Pertinent Insights On Calcium, Phosphorus And Bone Metabolism

The interaction of 1,25-dihydroxyvitamin D with the vitamin D receptor increases the efficiency of intestinal calcium absorption to 30 to 40 percent and phosphorus absorption to approximately 80 percent.^1,3

In one study, serum levels of 1,25-dihydroxyvitamin D were directly related to bone mineral density in Caucasian, African-American and Mexican-American men and women with a maximum density occurring when the 25-dihydroxyvitamin D level reached 40 ng/mL or more.18 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.²⁰

The parathyroid hormone enhances the tubular reabsorption of calcium and stimulates the kidneys to produce 1,25-dihydroxyvitamin D. Parathyroid hormone can stimulate the transformation of preosteoclast into mature osteoclasts.^1–3 Osteoclasts dissolve the mineralized collagen matrix in bone, causing osteopenia and osteoporosis and increasing the risk of fracture.^{1,18,20,22,23}

The deficiencies of calcium and vitamin D in utero and in childhood may prevent the maximum deposition of calcium in the skeleton.²⁴

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.^1,25,26

Whereas osteoporosis is associated with bone pain, osteomalacia has been associated with isolated or generalized bone pain. Researchers believe the cause to be hydration of the demineralized gelatin matrix beneath the periosteum; the hydrated matrix pushes outward on the periosteum, causing throbbing, aching pain.¹ One can often diagnose osteomalacia by using moderate force to press the thumb on the sternum or anterior tibia, which can elicit bone pain.^1,19

One study showed that 93 percent of people up to age 65 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.²⁷

How Vitamin D Affects Muscle Strength And Fall Risk

Vitamin D deficiency causes muscle weakness. Skeletal muscles have a vitamin D receptor and may require vitamin D for maximal function.^1,2,3,18 Performance, speed and proximal muscle strength markedly improved when 25-dihydroxyvitamin D increased from 4 to 16 ng/mL and continued to improve when the levels increased to more than 40 ng/mL.¹⁸

One meta-analysis of randomized controlled trials (with a total of 1,237 patients) revealed that increased vitamin D intake reduced the risk of falls by 22 percent in comparison in comparison with only calcium or placebo.¹⁸ The same meta-analysis 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.¹⁸

What The Research Reveals About The Non-Skeletal Actions Of Vitamin D

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.²⁸ Vitamin D decreases the cellular proliferation of both normal cells and cancer cells and induces their terminal differentiation.

The 1,25-dihydroxyvitamin D is also a potent immunomodulator.²⁹ Monocytes and macrophages exposed to a lipopolysaccharide or mycobacterium tuberculosis help regulate the vitamin D receptor gene in the 25-hydroxyvitamin-1-alpha-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 of 25-hydroxyvitamin D fall below 20 ng/mL, it prevents the monocyte or macrophage from initiating this innate immunity. This may explain why African-Americans, who are often vitamin D deficient, are more prone to contracting tuberculosis than Caucasians, and tend to have a more aggressive form of the disease.¹²

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.^{1–3,30–38}

How Vitamin D Affects The Autoimmune System, Osteoarthritis And Diabetes

Among Caucasian men and women, the risk of multiple sclerosis decreases by 41 percent for every increase of 20 ng/mL in 25-hydroxyvitamin D above the approximately 24 ng/mL.³⁹

Women who ingested more than 400 IU of vitamin D per day had a 42 percent reduced risk of developing multiple sclerosis. Authors have made similar observations for rheumatoid arthritis and osteoarthritis.^40,41 Several studies have suggested that vitamin D supplementation in children reduces the risk of type I diabetes. Increasing vitamin D intake during pregnancy reduces the development of islet autoantibodies in offspring.⁴²

For 10,366 children in Finland who consumed 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 percent.⁴³ Among children with vitamin D deficiency, the risk of diabetes was higher by approximately 200 percent.

What Are The 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.⁴⁴ There can be decreased bioavailability in patients with malabsorption syndromes due to cystic fibrosis, celiac disease, Whipple’s disease, Crohn’s disease or bypass surgery).⁴⁵

There could be cases of increased catabolism that we see with patients who are on anticonvulsants, glucocorticoids, AIDS treatments, immunosuppressants, to the steroid enzyme receptors on the pregnane X receptor.⁴⁶

There are poor vitamin D levels in human milk so poor breastfeeding can increase an infant’s risk of vitamin D deficiency when breast milk is a sole source of nutrition.⁴⁷ Other examples of vitamin D deficiency could be decreased synthesis of 25-hydroxyvitamin D that we see in patients who have liver failure, which causes malabsorption of vitamin D even though production of 25-hydroxyvitamin D is possible.⁴⁸

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.⁴⁹

There may also be decreased synthesis of 1,25-dihydroxyvitamin D in patients with chronic kidney disease. Stage II and III kidney disease as well as hyperphosphatemia increases fibroblast growth factor 23, which decreases 25-hydroxyvitamin D-1-alpha-hydroxylase activity.

Stages IV and V kidney disease indicate a glomerular filtration rate of less than 30 mL/min 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.^28,50–53

Current Insights On 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.⁵⁴ However, most experts agree that without adequate sun exposure, children and adults require approximately 800 to 1,000 IU per day.^55–57

A cost-effective method of correcting vitamin D deficiency and maintaining adequate levels is for patients to take 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.^1,19 Alternatively, either 1000 IU of vitamin D3 or 3,000 IU of vitamin D2 per day is effective. 

In patients with any stage of chronic kidney disease, one should measure 25-hydroxyvitamin D every three months and patients should maintain the level at 30 ng/mL or higher as recommended in the Kidney Disease Outcome Quality Initiative Guidelines from the National Kidney Foundation.^28,51–53 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.^28,51–53

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.^58–60 Exposure of arms and legs for five to 30 minutes, depending on time of day, season, latitude and skin pigmentation, between the hours of 10 a.m. and 3 p.m., twice a week is often adequate.^58–60 Exposure to one minimal erythemal dose of sunlight while wearing only a bathing suit is equivalent to ingesting approximately 20,000 IU of vitamin D2.^58–60

What You Should Know About Vitamin D Intoxication

Vitamin intoxication is extremely rare but can result from 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.^61,62

In Conclusion

Undiagnosed vitamin D deficiency is common and 25-hydroxyvitamin D is the best test for measuring the vitamin D status.64 Serum 25-hydroxyvitamin D is not only a predictor of bone health but is also an independent predictor of the risk for cancer and other chronic diseases.

Researchers noted 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 percent. This is a compelling reason to be vitamin D sufficient.⁶⁵

There are several different ways and different tests for measuring 25-hydroxyvitamin D, and reports and values can sometimes differ. As long as the combined total is 30 ng/mL or more, the patient has sufficient vitamin D.⁶³ Never use the 1,25-dihydroxyvitamin D assay for detecting vitamin D deficiency because levels will be normal or even elevated as a result of secondary hyperparathyroidism. Since 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 of vitamin D are actually inadequate. I have found levels need to increase 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 the 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. 

Dr. Regulski is the Director of the Wound Institute of Ocean County, NJ. He is a partner of Ocean County Foot and Ankle Surgical Associates, and a member of the American Podiatric Medical Association.

This article originally appeared at https://www.abmsp.org/news_info_archive_content.php?post_id=330 . It has been adapted for Podiatry Today with the permission of the American Board of Multiple Specialties in Podiatry.

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