The fact that we produce vitamin D in our skin in the presence of sunlight signifies how necessary it is to our health. Even though it seems easy enough to get, according to recent data published in the European Journal of Clinical Nutrition, vitamin D deficiency is prevalent in 24% of Americans, 37% of Canadians and 40% of Europeans . Data from 2012 indicate that 50% of the world’s population are vitamin D insufficient. A deeper look reveals that vitamin D deficiency and insufficiency vary by age, sex, ethnicity and geographic location, with reduced time spent outdoors and insufficient consumption of vitamin D-rich foods having the greatest impact on suboptimal levels . The medical community is certainly testing more than it did in the past, naturally picking up on more deficiencies, and providing us with the opportunity to address this key biomarker of good health. This blog discusses sources of vitamin D, contributors to vitamin D deficiency, and its role in chronic and acute disease, especially its association with comorbidities that predict an increased risk of complications and poor outcomes to COVID-19.
Sources of Vitamin D
There are 2 forms of vitamin D – D3 (cholecalciferol) which is found in animal-based foods, and D2 (ergocalciferol) which is found in plant-based and fortified foods. The richest sources of vitamin D3 are foods such as fatty fish, cod liver oil, egg yolk, pork, lamb, and beef. Vitamin D fortified foods like cereals and dairy products may contain D2 or D3. Mushrooms are the only plant-based food that are a rich source of vitamin D as they contain ergosterol that is converted to vitamin D2 upon exposure to ultraviolet light . Mushrooms, much like humans, need to have exposure to UV light, in particular UVB rays, to enhance their production of vitamin D. A 1-cup serving of mushrooms can provide the recommended daily allowance of vitamin D2 and can be an excellent source for vegans and vegetarians .
Aside from food, the best sources of vitamin D are sunlight and supplementation. To produce enough vitamin D through sunlight, we need to safely expose our skin to unfiltered sunlight for 15-20 minutes 3-4 times a week. Sunscreen and air pollution filter out UVB rays which are needed for vitamin D production, and people with darker skin need more time in the sun to produce the same amount of vitamin D as a high concentration of pigment in the skin from melanin slows production. Vitamin D produced through sunlight and from the diet or supplements can be stored in the liver and adipose tissue. These stores of inactive vitamin D can be drawn upon for later use if sun exposure or diet are insufficient during the winter months.
Vitamin D – Nutrient or Hormone?
While vitamin D is not officially a nutrient, we can get it through food in its inactive form. Vitamin D more appropriately qualifies as a pro-hormone in that its structural backbone is that of a steroid hormone. We can produce Vitamin D in our skin through sunlight-activated photoconversion of 7-dehydrocholesterol to D3, which is released into the bloodstream and transported to various cells and tissues. There it binds to the vitamin D receptor (VDR) to influence gene expression. Once inactive vitamin D is formed from sunlight or consumed in foods, it is converted in the liver to 25-hydroxycholecalciferol (25(OH)D) then to its active form of 1,25-dihydroxycholecalciferol (1,25(OH)2D) in the kidney. Vitamin D is the prohormone, while 25(OH)D is the major circulating and storage form that can be measured in serum or dried blood spot. While 1,25(OH)2D is the hormonally active form of Vitamin D, it is less stable and not more clinically relevant than 25(OH)D regarding its relationship to health benefits.
Vitamin D and Bone Health
Vitamin D is necessary for the absorption of calcium and phosphorus from the intestines and for bone formation through activation of osteoclasts and osteoblasts. The active form of vitamin D produced in the kidneys increases intestinal absorption of calcium by 30-40% and phosphorus by 80% . Active vitamin D also increases bone resorption of calcium, which together with increased calcium absorption from the intestines results in an increase in blood calcium levels. The increase in blood calcium decreases the production of parathyroid hormone (PTH), which is responsible for mobilizing body stores of calcium when blood levels get too low. Low PTH and adequate blood calcium increases calcitonin which deposits calcium back into the bone . Getting enough dietary calcium and vitamin D, either from food or sunlight, reduces bone resorption and contributes to a healthy balance between breakdown (osteoclastic) and formation (osteoblastic) of bone. Too much vitamin D without adequate calcium may contribute to accelerated bone resorption to increase blood calcium levels, with the net result of bone loss. Elevated blood calcium can lead to calcification of arteries and soft tissues and potentially contribute to kidney stones .
A 2019 article reported a double-blind, randomized clinical trial which evaluated the bone density effects of 3 different vitamin D dosages in 311 participants over a 3-year period. The participants ranged in age from 55-70 years and none of the participants had osteoporosis. Baseline serum values of 25(OH)D ranged between 30-125 nmol/L. The vitamin D dosages given to the 3 groups within the study were 400 IU, 4000 IU, and 10,000 IU daily for 3 years. Calcium supplementation was also provided to those who received less than 1200 mg per day from food sources. Bone density scans were done at the end of the 3-year period. The group that received the highest dosage of vitamin D had lower total volumetric radial and tibial bone mineral density than the other 2 groups . These results show that daily vitamin D supplementation at these doses result in an inverted U-shaped distribution where optimal dosing appears to be in the 4000 IU range. Too little vitamin D results in poor calcium and phosphorus absorption which can lead to lower bone density. Likewise, too much vitamin D can result in increased bone resorption which can also lead to lower bone density, especially if dietary or supplemental calcium are inadequate.
Systemic Effects of Vitamin D
Outside of the bone and kidneys, the hydroxylase enzyme that is responsible for the conversion of inactive vitamin D to active vitamin D is expressed in multiple epithelia, the placenta, the intestines, platelets, beta cells of the pancreas, the prostate, and various immune cells . Most tissues throughout the body have VDRs indicating the broad range of biological actions of this pro-hormone. Once bound to tissue-specific VDRs, vitamin D can influence the modulation of cell growth, support neuromuscular functions, influence immune system response, inhibit angiogenesis, stimulate insulin production, inhibit the renin-angiotensin-aldosterone system, and reduce inflammation . Deficiencies in vitamin D have been associated with heart disease, hypertension, type 1 and type 2 diabetes, obesity, depression, fractures and falls, autoimmune disease, influenza, cancer, and cognitive impairment .
Vitamin D and the Immune System
Vitamin D can modulate the innate and adaptive immune response, and deficiency has been associated with increased autoimmunity and increased susceptibility to infections. Vitamin D receptors are expressed on B cells, T cells and antigen-presenting cells, which are all capable of producing the active form of vitamin D. Within the immune system, production of the hydroxylase enzyme that converts inactive vitamin D to active vitamin D may be induced by the presence of cytokines such as IFN-gamma, IL-1, and TNF-alpha.
The conversion of inactive Vitamin D to its active form by B and T cells in the presence of inflammatory mediators occurs as a localized reaction to enhance immune activity against infections while controlling excessive inflammation. This localized reaction functions independently of feedback controls related to vitamin D and bone homeostasis. Vitamin D inhibits B and T cell proliferation and differentiation, shifts the immune response from a Th1 to a Th2 phenotype, and facilitates the production of T regulatory cells to moderate inflammation . Vitamin D also decreases the production of inflammatory cytokines (IL-17, IL-21) while increasing the production of anti-inflammatory cytokines such as IL-10 . Several cells involved in immune function express VDR and hydroxylase enzyme; this suggests that the active form of vitamin D influences immune function in both innate and adaptive responses.
Vitamin D and COVID-19 Comorbidities
Supplementation, food sources, and sun exposure to improve vitamin D status are important considerations in those who live with obesity, type 2 diabetes, cardiovascular disease and hypertension, as these comorbidities are associated with a poor COVID-19 prognosis and deficiency of vitamin D tends to be high in these populations. Accumulating data suggest that serum vitamin D is inversely related to metabolic syndrome . In fact, there is a strong relationship between vitamin D deficiency and the degree of obesity, particularly central adiposity. Decreased outdoor activities and sun exposure along with an increase in sedentary lifestyle are the obvious contributors; however, there are certain biochemical dynamics that may also contribute to the relationship between vitamin D deficiency and obesity which can be the precursor to metabolic syndrome, type 2 diabetes, and cardiovascular disease.
In vitro studies on murine, porcine, chicken and human adipocyte cell lines revealed that vitamin D interferes with the adipocyte differentiation process which inhibits adipogenesis . VDR expression in adipose tissue, food intake, and exercise levels also seem to be associated with vitamin D deficiency in obese individuals. The master regulator of adipogenesis is peroxisome proliferator-activated receptor gamma (PPARγ). This regulator of adipogenesis and VDR share a common binding partner, retinoid X receptor (RXR). A higher presence of VDR competitively inhibits the binding of PPARy to RXR, which decreases the chance of adipogenesis-related gene expression . It is also suspected that an increase in adipose tissue will tend to sequester vitamin D, keeping it from entering the circulation and binding to receptors.
Hypertension and cardiovascular disease are also associated with vitamin D deficiency. Vitamin D deficiency and insufficiency have been observed to upregulate the renin-angiotensin-aldosterone system (RAAS) resulting in hypertension, as there is a direct link between vitamin D deficiency and upregulation of this system. A pioneering study at the University of Chicago in 2002 proved vitamin D to be an antihypertensive agent. VDR knockout mice have elevated blood pressure, cardiac hypertrophy and increased activation of the RAAS. Vitamin D acts as a potent suppressor in renin biosynthesis which initiates the activation of the RAAS .
The cardiovascular benefits of adequate vitamin D may be related to its ability to decrease vascular calcification, reduce immune-associated inflammation, improve cardiac contractility, and support healthy cardiac tissue . The mechanisms by which vitamin D may protect against cardiovascular disease have yet to be fully elucidated, but the fact that the heart and vascular system have VDRs reveals the potential necessity of vitamin D for healthy cardiovascular function. Most of the available evidence includes large observational studies and smaller randomized trials that are lacking in their ability to evaluate cardiovascular outcomes as primary endpoints. A recent meta-analysis of randomized clinical trials that included more than 83,000 participants found that vitamin D supplementation was not associated with reduced risks of major adverse cardiovascular events, myocardial infarction, stroke, cardiovascular disease mortality, or all-cause mortality, compared with placebo .
It is important to note that cardiovascular disease develops in humans as a result of many confounding factors, and to isolate a single pro-hormone as the ‘one thing’ that contributes to or prevents a disease process is impossible. While it is difficult to create an absolute cause and effect relationship between low vitamin D and cardiovascular disease, retrospective analyses have shown an association. The reality is, we cannot expect to prevent or reverse cardiovascular disease with a single supplement even though it may contribute to key biochemical functions that are supportive of good health. A single compound is a small part of a much larger whole and many lifestyle factors that contribute to cardiovascular disease may also contribute to vitamin D deficiency.
Vitamin D and COVID-19 Infection and Recovery
In the presence of COVID-19, blood levels of vitamin D can be a potential predictor of outcome as it relates to the balance between proinflammatory and anti-inflammatory mediators, vascular stability, and the ability to fight the infection. During respiratory viral infection, inactive vitamin D can be converted to active vitamin D by the alveolar epithelial cells increasing production of cathelicidin and defensins, which reduce the survival and replication of viruses . Cathelicidin and defensins are anti-microbial peptides found in neutrophils, epithelial cells, and macrophages, and are activated by the presence of bacteria, viruses, fungi and the active form of vitamin D. A recent article in The Lancet states that vitamin D favorably modulates host responses to severe acute respiratory syndrome induced by SARS-CoV-2, both in the early viremic and the later hyperinflammatory phase of COVID-19 . Though there are no current conclusive studies on vitamin D status and outcomes for COVID-19, there is enough data on the basic functions of active vitamin D and its effects on the immune system to come to the reasonable conclusion that in the presence of any bacterial, viral or fungal infection, adequate vitamin D levels can be supportive of recovery and lessen the duration and severity of disease by supporting a healthy and balanced immune response.
As stated above, vitamin D has a regulatory effect on the renin-angiotensin-aldosterone system (RAAS) which is involved in controlling blood pressure. The SARS-CoV-2 virus enters cells through the ACE2 receptor. ACE2 is the enzyme that converts angiotensin II, a vasoconstrictor, to angiotensin I-7, a vasodilator. The binding of the virus to the ACE2 receptor results in a downregulation of ACE2 leading to an increase in angiotensin II causing vasoconstriction and increased blood pressure. An increase in angiotensin II can result in acute respiratory distress syndrome (ARDS), myocarditis and cardiac injury . Renin is a positive regulator of angiotensin II, meaning that increased renin leads to increased angiotensin II. Vitamin D is a potent inhibitor of renin; therefore, low vitamin D status can lead to increased activation of the RAAS and an increase in angiotensin II . The effect of SARS-CoV-2 on the ACE2 receptor and its consequent downregulation are further compounded in the presence of a vitamin D deficiency. Supplementation with vitamin D in those who are deficient can suppress the release of renin, which is the first step in the activation of the RAAS, and thereby decrease the release of angiotensin II and possibly decrease the potential to advance to ARDS.
Causes of Vitamin D Deficiency
Severe Vitamin D deficiency manifests as rickets in children and osteomalacia in adults. Over a decade ago, Vitamin D deficiency was considered an epidemic with over a billion people worldwide at deficient or insufficient levels. Too much time spent indoors, advancing age, having darker skin or never exposing the skin to natural sunlight, and living at latitudes that are far north or south of the equator, are the main contributors to vitamin D deficiency; however, malabsorption from chronic intestinal inflammation as in Crohn’s disease and ulcerative colitis, poor digestive capacity, biochemical and genetic disorders, and certain medications can prevent absorption and activation of vitamin D.
Medications that may interfere with vitamin D status activate the pregnane X receptor which plays a crucial role in the detoxification of xenobiotics and drugs. When activated, the pregnane X receptor increases a specific hydroxylase enzyme that degrades active and inactive vitamin D, converting them into physiologically inactive metabolites that are eventually excreted from the body. Pregnane X receptor is also very similar in structure to the VDR and binds to elements associated with VDRs, interfering with key processes associated with the biochemical actions of vitamin D .
Classes of medications that activate the pregnane X receptor include antiepileptic drugs such as phenytoin and carbamazepine, antineoplastic drugs such as tamoxifen, Taxol and cyclophosphamide, antihypertensives such as nifedipine and spironolactone, antiretrovirals such as ritonavir and saquinavir, antibiotics such as clotrimazole and rifampicin, endocrine medications such as cyproterone acetate, and the anti-inflammatory, dexamethasone . Polypharmacy is a common problem especially amongst the elderly population and those with chronic illness. Medications that affect vitamin D status can have far-reaching consequences that extend beyond bone density. It is a good idea to evaluate 25(OH)D status at least twice a year and supplement with vitamin D to help to avoid complications of deficiency associated with medications.
Supplementing with Vitamin D
Daily supplementation with vitamin D should be part of a regular supplement program, especially for those who live at higher latitudes and spend more time indoors, as it can take several months of supplementation and moderate sun exposure to bring vitamin D to optimal levels. Vitamin D3 has a higher affinity for binding proteins and a longer half-life than D2, so it is usually recommended for supplementation. Both D2 and D3 are effective at raising circulating levels of 25(OH)D; however, vitamin D2 tends to be less bioactive so must be given at higher dosages. It has also been noted that vitamin D2 is somewhat less stable than D3 and is not the preferred form of vitamin D by the hydroxylase enzymes in the liver that convert D2 or D3 to 25(OH)D .
The RDA recommendation for vitamin D supplementation is 600-800 IU/day ; however, for those who have little sun exposure and low levels of 25(OH)D as measured in serum or dried blood spot, supplementing with 2000-4000 IU/day may be warranted to bring up baseline values to an optimal range. Food sources of vitamin D are also high in vitamin A and the 2 nutrients may act synergistically together to support a balanced immune response. Using 1 tablespoon of high-quality cod liver oil daily is a rich source of both nutrients in a whole food form.
Measuring Vitamin D Status
In the past decade, we have developed a deeper appreciation for the role that vitamin D can play in our health from bone support to immune function. Testing vitamin D levels has become a standard in annual blood work and vitamin D supplementation is readily available and affordable. The normal range as defined by the Endocrine Society is 20-80 ng/mL; however, according to the Vitamin D Council, optimal levels would be somewhere between 40-80 ng/mL. ZRT Laboratory offers an easy at home finger-stick dried blood spot test measuring vitamins 25(OH)-D2 and 25(OH)-D3. Both forms of vitamin D are measured because some people supplement with D2, especially when dosing at a higher concentration less frequently, as is often recommended in a primary care setting. By measuring both forms of vitamin D, ZRT provides a comprehensive view of vitamin D status. Vitamin D is offered as a single test as well as being included in our Weight Management, Wellness Metrics, Fitness Metrics, and Elite Athlete Metrics profiles.
As we face the current coronavirus pandemic, knowing our baseline level of vitamin D and supplementing appropriately has never been more important. Assuring that we have a healthy and balanced immune response that can effectively reduce viral load and suppress uncontrolled inflammation is crucial for prevention and recovery. Spending time outdoors and exposing our skin to a little bit of sunshine is also good for the body and mind.
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