Overview
Vitamin D’s importance in maintaining skeletal health is relatively well known, but few people are aware of Vitamin D’s potent role in gene expression and its association with a multitude of chronic diseases. Although excess sun exposure increases our risk for non-melanoma skin cancer, the avoidance of sunshine may actually render us susceptible to vitamin D deficiency, which can lead to serious consequences.
Not only does vitamin D deficiency exacerbate osteoporosis, but growing evidence points to a link between vitamin D deficiency and certain types of cancer, type 2 diabetes, cardiovascular diseases, autoimmune disorders, and neurocognitive decline (1).
The Sunshine Vitamin
Vitamin D, known by many as the “sunshine vitamin,” is a fat-soluble vitamin (meaning, it is absorbed and stored in fat), which actually functions as a hormone in the body. When skin is exposed to direct sunlight, our body produces pre-vitamin D3, which is metabolized in the liver to 25-hydroxyvitamin D3 and then in the kidney to its biologically active form, 1,25-dihydroxyvitamin D3, or Calcitriol. The primary function of Calcitriol is maintenance of serum calcium homeostasis by exerting its effects on the kidneys, small intestine, and bone through both genomic and nongenomic mechanisms of action (2).
Vitamin D Deficiency
Vitamin D deficiency, as measured by 25-hydroxyvitamin D [25(OH)D] serum levels less than 20 ng/ml, is widespread throughout the world. Vitamin D promotes calcium absorption and utilization, with a deficiency traditionally having been associated with rickets in children, and the painful bone disease, osteomalacia, in adults (3, 4). Some experts define a vitamin D insufficiency as 25(OH)D measurements of 21–29 ng/ml, but controversy still exists as to the exact demarcations that constitute a deficiency (5).
Mechanism
The wide distribution of vitamin D receptors (VDR) and the numerous biologic actions reported for 1,25(OH)2D3 may explain how a deficiency could be linked with so many chronic diseases and conditions such as certain cancers, autoimmune diseases, infectious diseases, type 2 diabetes and cardiovascular disease.
Studies have repeatedly shown that Vitamin D supplementation is able to directly or indirectly regulate more than 200 genes, including genes responsible for controlling cellular proliferation, differentiation, angiogenesis, and the modulation of innate and adaptive immune responses.
Researchers theorize that VDR activation directly or indirectly modulates the genetic expression of anywhere from 0.5 to 5% of the total human genome (3).
Risk Factors
Many factors have been implicated in the widespread epidemic of Vitamin D deficiency including:
- Inadequate time in sunlight
- Increasing use of sunscreens
- Malabsorption conditions (Celiac, Crohn’s, Chronic Kidney Disease)
- Pharmaceutical drugs that impair vitamin D absorption by inducing hepatic p450 enzymes to accelerate vitamin D catabolism (i.e., Dilantin)
- Cholesterol-lowering drugs that impair fat soluble vitamin absorption (i.e., cholestyramine)
- Obesity
- Diabetes
- Inadequate dietary intake of vitamin D
- Genetic predisposition to lower vitamin D levels (VDR taq gene polymorphisms)
- Seasonal changes (November through February)
- Geographical location (latitude) relative to equator (6)
Chronic Diseases
Cancer
In an analysis of the 291 genes affected by vitamin D3 supplementation, Hossein-nezhad et al. (2013) demonstrated that a 1.5 fold induction or 1.5 fold inhibition was observed in the gene expression associated with numerous pathways such as cell proliferation, differentiation, and apoptosis (3). With regards to cancer prevention, a 1.5 fold increase was established in the Coatomer Protein Complex, Subunit Beta 2 (COPB2) gene, which is involved in programmed cell death and inhibition of tumor growth (3).
Epidemiologic studies have denoted levels of 25OHD under 20 ng/ml associated with a 30 to 50% increased risk of colon, prostate, and breast cancer, in addition to higher mortality rates from these cancers (1, 7, 20, 21, 22, 23). In a meta-analysis of 18 randomized clinical trials, vitamin D supplementation was reported to significantly reduce all-cause mortality (8).
In another study, Garland et al. (2007) reported that individuals with approximately 52 ng/ml of 25(OH)D serum concentrations had 50% lower risk of breast cancer compared to those with serum levels less than 13 ng/ml (9). The researchers note that Vitamin D intakes of 2,000 IU/day are sufficient to maintain this protective level, and when possible, moderate exposure to sunlight is recommended (9).
In another meta-analysis of 12 studies, Zhang et al. (2015) reported an association between higher serum levels of Vitamin D and lowered risk for lung cancer (10). However, since higher intakes were not significantly associated with reduced risk, more studies are needed to elucidate these findings.
Recently, Timerman et al. (2017) concluded that melanoma patients with vitamin D deficiency and inadequate repletion were significantly associated with worse melanoma-specific mortality. Furthermore, a previous meta-analysis of 19 randomized clinical trials demonstrated a 6% reduction in colorectal cancer risk with every 4 ng/mL increase in vitamin D levels (11).
Cardiovascular Diseases
Vitamin D receptors are located throughout the heart and cardiovascular system and studies have found an association between vitamin D deficiency and cardiovascular diseases.
Vitamin D metabolites have been shown to act on inflammatory, thrombolytic, and the renin angiotensin aldosterone system pathways, exerting a protective effect against heart disease.
Vitamin D exerts its protective effects on endothelial cells, promoting nitric oxide production while suppressing pro-inflammatory cytokines and preventing endothelial cell death. In patients with high blood pressure, low serum vitamin D levels have been associated with a 60% increase in risk for cardiovascular disease (1; 12; 13).
Diabetes
Low serum levels of Vitamin D are associated with impaired insulin sensitivity and beta-cell function among individuals at risk for type 2 diabetes. Diabetic patients are at an increased risk of developing vitamin D deficiency, potentially leading to complications such as kidney damage, cardiovascular disease, and peripheral arterial disease (14).
The incidence of vitamin D deficiency is 33% higher in type 2 diabetic women compared to control subjects, and vitamin D deficiency nearly doubles the risk of developing cardiovascular disease compared to diabetic patients with vitamin D levels in the normal range (15).
Oh et al. (2015) reported the consequences of vitamin D receptor deletion in macrophages of mice. They found augmented macrophage infiltration and cholesterol deposition in the liver and increasing production of cytokines and hepatic glucose – mechanisms, which lead to insulin resistance and acceleration of atherosclerosis (16).
Autoimmune Disorders
Immune cells such as monocytes, macrophages, dendritic cells, T cells and B cells all express vitamin D receptors. Vitamin D plays an important role in immune function and inhibition of inflammatory mechanisms and may help protect against the development of autoimmune diseases. Studies have shown D3 deficiency associated with autoimmunity, such as lupus. In a study by Chen et al. (2007), researchers found that biologically active D3 has powerful effects on B cell responses (17). These effects include suppressing proliferation, generation of class-switched memory B cells, plasma cell differentiation, and immunoglobulin production. This suggests that Vitamin D3 has the potential to be used in the treatment of autoimmune disorders such as lupus by mediating the suppression of B cell over-activity (17; 1).
Neurocognitive & Psychiatric Disorders
Vitamin D receptors are ubiquitous in brain tissues that are in the stage of development, as well as the hypothalamus, pons, basal ganglia, and hippocampus. This signifies Vitamin D’s potential role in brain function and development.
In a systematic review and meta-analysis, researchers found a positive association between vitamin D deficiency and increased rates of depression (18).
Vitamin D deficiency has also been linked to numerous neurological disorders such as epilepsy, multiple sclerosis, neurocognitive decline, dementia and Alzheimer’s disease (1; 24). While it is unclear as to whether this association is causative or circumstantial, evidence has shown vitamin D supplementation to be beneficial to symptom mitigation.
What You Can Do
Get Your Vitamin D Levels Checked
While some doctors routinely run vitamin D tests, others do not. Since a deficiency has been associated with so many conditions and can be incredibly easy to correct, it would be wise to ask your doctor for this simple blood test. Yearly monitoring of serum 25-hydroxyvitamin D concentrations can reveal a deficiency so you can correct it in time.
When getting your vitamin D levels checked, make sure you are getting a blood test to check for levels of 25(OH)D. Tests measuring 1,25(OH)2D can be misleading and should not be used to determine your vitamin D levels. This is because as a person becomes vitamin D deficient and levels of 25(OH)D decrease, levels of 1,25(OH)2D are maintained in the normal range and sometimes are even elevated due to a compensatory increase in parathyroid hormone (PTH) secretion, which stimulates the kidney to produce more 1,25(OH)2D (2).
High-Risk Groups
In those with normal levels of Vitamin D and who are not likely to be deficient, The Food and Nutrition Board recommends a daily intake of 600 IU for children and adults, and 800 IU for those 71 and older (4).
However, according to the NIH (4), certain groups of people may need to be monitored closely for vitamin D deficiency, including:
- Older adults
- Those with darker skin pigmentation
- Diabetic and obese patients
- Those with malabsorption disorders
- Those taking medications that interfere with the absorption of fat soluble vitamins
Supplementation
Holick et al. (2011) suggest that all adults who are vitamin D deficient be treated with 50,000 IU of vitamin D2 or vitamin D3 once a week for 8 weeks or its equivalent of 6,000 IU of vitamin D2 or vitamin D3 daily to achieve a blood level of 25(OH)D above 30 ng/ml, followed by maintenance therapy of 1,500–2,000 IU daily (5).
Sunshine
While it isn’t advisable for anyone to roast themselves in the sun all day (remember the episode of ‘Seinfeld’ when Kramer drenches himself in oil and roasts on the rooftop?), a little dose of sunshine can actually be good for us.
Since sunscreen of SPF 15 has the potential to reduce the capacity of vitamin D3 production by 98%, a mere 10-15 minutes of exposure to the legs, arms, or face (sans sunscreen) 2-3 times a week should be sufficient to keep vitamin D levels in check. With that said, some may need more exposure (those with risk factors, as explained earlier), while people with fair skin or other skin conditions may need to be careful to avoid burning.
Although Vitamin D can be synthesized in the skin from sun exposure, certain individuals homozygous for single nucleotide polymorphisms such as VDR Taq-I may need to supplement with higher doses due to their genetic predisposition for a vitamin D deficiency (19).
Personally, even though I live in Florida, I have to be mindful to supplement with vitamin D since not only do I have both copies of this gene, but I also have malabsorption and micronutrient deficiencies secondary to small intestinal bacterial overgrowth (SIBO). This is yet another example of RDAs not addressing individual needs (do to genetic predisposition, metabolic disorders, environmental insults, or acute/chronic illness which all increase our need for supplementation).
Food Sources
Over 90% of the vitamin D requirement for most people comes from casual exposure to sunlight. Not many foods contain vitamin D naturally.
With that said, dietary sources of vitamin D include fatty fish such as salmon, tuna, and mackerel; beef liver, egg yolks, and cheese; and other fortified foods such as milk, orange juice, breads and cereals (4). Moreover, cod liver oil, which has been considered for over three centuries to be vital for bone health, is an excellent source of vitamin D3 (2).
Bottom-Line
Numerous studies have helped establish the link between vitamin D deficiency and chronic diseases such as autoimmune disorders, diabetes, cardiovascular diseases, neuropsychiatric disorders, and cancer. While it may not be entirely clear whether this association is causal, it is evident that sensible sunlight exposure, dietary and supplemental Vitamin D intakes, and yearly monitoring of serum 25-hydroxyvitamin D levels can significantly mediate such risks and serve as viable preventative options.
References:
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