What is Vitamin D?
It was known in the 19th century that fish oil and sunlight helped cure rickets (a disorder characterized by impaired mineralization of bone tissue and growth plates). However, it wasn’t until the 20th century that it was determined that rickets was caused by a deficiency of a vitamin. After rickets was experimentally induced in rats, it was understood that the compound in fish oil that treats rickets was not vitamin A, but another fat-soluble compound. In 1922, McCollum isolated Vitamin D after deactivating vitamin A in fish oil, and in 1924, it was demonstrated that some foods, when exposed to ultraviolet light, gained the ability to cure rickets. This is how Vitamin D was discovered.
Vitamin D is a fat-soluble vitamin.
It is not just a vitamin, but also a hormone. Vitamin D can be taken into the body either as Vitamin D itself or by converting its precursor in body tissues through ultraviolet light into Vitamin D. Vitamin D is found in insignificant amounts in foods other than fish oil.
Very few foods naturally contain Vitamin D (fatty fish like sardines, herring, tuna, mackerel, salmon, cod liver oil, egg yolks, liver, and organ meats). Therefore, after ultraviolet radiation, dermal synthesis remains the primary way to obtain Vitamin D. A distinguishing feature of Vitamin D is that it can be synthesized in the body through sunlight.
Functions of Vitamin D
Its main function is to maintain the balance of calcium in the body. It is involved in calcium and phosphorus metabolism, plays a role in their absorption, and increases their reabsorption from the kidneys. It also helps store them in bones. In the absence of Vitamin D, calcium absorption is 10-15%, while in its presence, it rises to 30-80%. Vitamin D is essential for bone formation and works together with Vitamins A and C to perform this function.
Vitamin D and Bone Health
Despite being uncommon in developed countries, severe Vitamin D deficiency can cause rickets in infants or children and osteomalacia in adults. However, subclinical Vitamin D deficiency, which shows no symptoms, is more common and is associated with osteoporosis and a higher incidence of falls or fractures.
Bone mineral accumulation begins during pregnancy, especially in the third trimester. Bone mass increases about 40 times from birth to adulthood, and 90% of bone mass is achieved by the end of the second decade of life. Childhood and adolescence are critical periods for bone mineral accumulation. A public health assessment conducted in 2010 concluded that calcium supplementation in healthy children did not significantly reduce fracture incidence. A healthy and balanced diet that meets the recommended calcium intake was more effective than routine calcium supplementation. However, due to limited natural Vitamin D sources and inadequate sun exposure in most children and adolescents, Vitamin D supplementation is necessary.
Can Vitamin D Prevent Falls and Fractures?
Since Vitamin D is necessary for calcium balance and bone metabolism, Vitamin D supplementation and its potential to prevent falls and fractures is worth discussing. However, evidence is conflicting. Various meta-analyses have shown that after supplementation of 700-1000 IU of Vitamin D per day, the risk of falls in elderly individuals decreased, especially those with low Vitamin D levels. A meta-analysis conducted in 2007 concluded that a combination approach (800 IU of Vitamin D + 1200 mg of calcium daily) was more effective in reducing hip fractures and death in hospitalized patients. However, later reviews indicated that neither Vitamin D alone nor in combination with calcium significantly reduced the risk of falls and fractures in adults living in the community. Moreover, combination treatment with Vitamin D and calcium may increase the frequency of kidney stones. High doses of Vitamin D (a single high dose of 500,000 IU per year, resulting in chronic serum 25(OH)D >40 ng/mL) have been found to increase the risk of falls and fractures, so intermittent high doses should be avoided.
Vitamin D and the Immune System
Vitamin D has direct effects on both innate and acquired immunity. It also plays a role in cell differentiation. The relationship between Vitamin D and certain diseases is discussed below.
Tuberculosis
There is a relationship between Vitamin D deficiency and tuberculosis. In 2008, it was reported that ultraviolet B radiation had a positive effect on tuberculosis treatment. However, one study concluded that Vitamin D supplementation did not show significant improvement in clinical outcomes.
Respiratory Infections
There is an inverse relationship between 25(OH)D levels and the risk of upper respiratory infections. Newborns with 25(OH)D <20 ng/mL had six times higher risk of bronchiolitis associated with respiratory syncytial virus at the age of 1 compared to those with 25(OH)D >30 ng/mL. A recent meta-analysis of 25 studies in 2017 showed that in patients with severe Vitamin D deficiency (<10 ng/mL), Vitamin D supplementation reduced the incidence of acute respiratory infections.
Asthma
Vitamin D intake during pregnancy may be associated with an increased risk of wheezing attacks in children later in life. A cross-sectional study observed the 25(OH)D levels in asthma and healthy groups. The study showed that Vitamin D concentrations were directly related to vital capacity (FEV1/FVC) ratio and that lower 25(OH)D levels were associated with worse asthma conditions.
Atopic Dermatitis
One study showed that serum 25(OH)D levels were lower in patients with atopic dermatitis. A small randomized clinical trial found beneficial effects of Vitamin D supplementation in children with winter-associated atopic dermatitis. In contrast, another systematic review in 2012 did not find significant benefits in clinical outcomes (itching, sleep loss, frequency of flare-ups) following Vitamin D intervention.
However, since reports on the relationship between Vitamin D status and these diseases are conflicting, supplementation is not currently recommended.
Vitamin D and Other Systemic Effects
Vitamin D plays a vital role in cellular function and differentiation, influencing a wide range of health outcomes. It has been associated with various diseases such as cancer, cardiovascular diseases, psoriasis, multiple sclerosis (MS), type 1 diabetes, and inflammatory bowel diseases. Research suggests that vitamin D deficiency increases the risk of MS, and supplementation has been shown to reduce the frequency of attacks in MS patients.
Vitamin D deficiency has also been linked to hypertension, cardiovascular events, increased cancer incidence, musculoskeletal pain, migraines, and neuropsychiatric disorders like schizophrenia, dementia, and depression. However, current evidence on the role of vitamin D intervention in treating or preventing these conditions remains insufficient.
Summary of Vitamin D’s Benefits:
- Regulates calcium and phosphorus metabolism.
- Plays a key role in bone formation.
- Prevents osteoporosis.
- Supports the immune system.
- Helps prevent skin tumors.
- Has been shown to improve psoriasis.
Vitamin D Deficiency
The best indicator of vitamin D status in the human body is serum 25(OH)D concentration. The Institute of Medicine (IOM) suggests that an optimal level for skeletal health is 20 ng/mL, while the Endocrine Society (ENDO), International Osteoporosis Foundation (IOF), National Osteoporosis Foundation (NOF), and American Geriatrics Society (AGS) recommend at least 30 ng/mL to prevent diseases.
| nmol/L | ng/mL | Diagnosis |
|---|---|---|
| <30 | <12 | Vitamin D deficiency |
| 30-50 | 12-20 | May be insufficient for some individuals, risky levels |
| >50 | >20 | Sufficient for 97% of the population |
Symptoms of Vitamin D Deficiency
Deficiency of vitamin D primarily manifests in the skeletal system. Diseases related to skeletal symptoms include rickets, osteomalacia, and osteoporosis.
- Rickets
- Osteomalacia
- Osteoporosis
- Autoimmune diseases
- Hypertension and cardiovascular diseases
- Rheumatoid arthritis
- Certain cancers (prostate, colon, breast)
- Central nervous system disorders
Risk Factors for Vitamin D Deficiency
- Reduced dermal synthesis of Vitamin D: Darker skin (high melanin content) reduces the skin’s ability to synthesize Vitamin D from sunlight.
- Infants and growing children
- Elderly individuals: Age decreases the skin’s ability to synthesize Vitamin D.
- Obesity: Increased fat tissue retains vitamin D, leading to a higher risk.
- Reduced exposure to ultraviolet-B (UVB) radiation: Limited exposure to sunlight due to factors like covering up, living in buildings, or sunscreen use can significantly reduce Vitamin D synthesis. SPF 30 sunscreen can decrease Vitamin D production by up to 95%.
- Geographical factors: Higher latitudes, winter seasons, and higher altitudes can reduce UVB exposure. Pollution and cloud cover also limit sunlight exposure.
- Inadequate dietary intake: Poor nutrition or conditions that impair absorption, such as celiac disease, Crohn’s disease, and others, can contribute to Vitamin D deficiency.
Synthesis of Vitamin D
Vitamin D synthesis is dependent on the duration and intensity of sunlight exposure. During the summer months, when the sunlight is more direct, Vitamin D formation is higher, while in winter, sunlight is less effective. UVB radiation is most prevalent between 10:00 AM and 3:00 PM. In fair-skinned individuals, just 10-15 minutes of sun exposure on the arms and face can provide enough Vitamin D. However, individuals with darker skin may require longer sun exposure.
Vitamin D deficiency is a particular concern in infants and adolescents due to rapid skeletal growth, making them more vulnerable to diseases like rickets. Research has shown that breastfed infants are at higher risk, especially when their mothers have low Vitamin D levels.
The elderly are also at higher risk due to reduced Vitamin D synthesis and response to the vitamin, making deficiency more likely.
In summary, adequate Vitamin D is crucial for various body functions, and its deficiency can lead to significant health issues. It is important to monitor Vitamin D levels, especially for those at higher risk.
Vitamin D Requirements
The dietary reference intake (DRI) for calcium and vitamin D is shown in the table below (Institute of Medicine-IOM).
| Age | Calcium (mg/day) | Upper Intake Level (mg/day) | Vitamin D (IU/day) | Upper Intake Level (IU/day) |
|---|---|---|---|---|
| 0-6 months | 200 | 1000 | 400 | 1000 |
| 6-12 months | 260 | 1500 | 400 | 1500 |
| 1-3 years | 700 | 2500 | 600 | 2500 |
| 4-8 years | 1000 | 2500 | 600 | 3000 |
| 9-18 years | 1300 | 3000 | 600 | 4000 |
| 19-50 years | 1000 | 2500 | 600 | 4000 |
| 51-70 years (men) | 1000 | 2000 | 600 | 4000 |
| 51-70 years (women) | 1200 | 2000 | 600 | 4000 |
| >70 years | 1200 | 2000 | 800 | 4000 |
| 14-18 years (pregnant/lactating) | 1300 | 3000 | 600 | 4000 |
| 19-50 years (pregnant/lactating) | 1000 | 2500 | 600 | 4000 |
For infants under 12 months, the recommended daily intake (RDA) for vitamin D is 400 IU, and for children aged 1-18 years, it is 600 IU. Maternal vitamin D can help create fetal stores, but even infants born to mothers with vitamin D deficiency may experience a deficiency after 8 weeks of life if supplementation is not provided. It has been reported that babies can get adequate vitamin D by being exposed to sunlight for 30 minutes per week while wearing only a diaper or 2 hours per week while fully clothed. However, the American Academy of Pediatrics recommends that infants under 6 months should not be exposed directly to sunlight due to concerns over skin cancer risks and recommends obtaining vitamin D through natural food or supplements. Consequently, both the American Academy of Pediatrics and the Pediatric Endocrine Society recommend that exclusively or partially breastfed infants require daily supplementation of 400 IU of vitamin D starting in the first few days of life. Obese children or those on chronic medications may require 2-4 times the usual dose.
In 2010, the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN) updated its guidelines, recommending 800-1000 IU of vitamin D, 110-130 mg of calcium, and 55-80 mg of phosphorus daily for premature infants to support bone health. By the end of 2013, the American Academy of Pediatrics issued a report recommending 200-400 IU of vitamin D daily for very low birth weight preterm infants (<1500g) and 400 IU for those weighing over 1500g. These lower dosages are adjusted based on the smaller size of premature infants, and relatively lower vitamin D intake is necessary to reach adequate serum levels of 25(OH)D.
Vitamin D Sources
Vitamin D needs are primarily met through sunlight. Dietary sources are quite limited.
- Rich sources: Cod liver oil, fatty fish, liver
- Moderate sources: Egg yolk
- Low sources: Milk, cheese, butter
Vitamin D Supplementation
Vitamin D supplementation for adults depends on the serum 25(OH)D concentration and absorption capacity. In patients with normal absorption, serum 25(OH)D levels can increase by 0.7-1.0 ng/mL for every 100 IU of vitamin D3. The increase is more prominent in patients with lower baseline 25(OH)D levels.
When vitamin D deficiency is identified, treatment dosages have been established. Children and adolescents under 18 years can be treated with 2000 IU/day (or 50,000 IU weekly) for 6 weeks, after which maintenance at 600-1000 IU daily is recommended. For adults with deficiency, a treatment regimen of 6000 IU/day (or 50,000 IU weekly) for 8 weeks, followed by 1500-2000 IU daily, is advised. Obese individuals or those on medications affecting vitamin D metabolism may need higher doses for effective treatment.
Vitamin D Supplementation for Deficiency
| 25(OH)D Level | Vitamin D Supplementation |
|---|---|
| <10 ng/mL | 50,000 IU weekly for 6-8 weeks, then 800 IU/day |
| 10-20 ng/mL | 800–1000 IU/day |
| 20-30 ng/mL | 600-800 IU/day |
| Malabsorption | 10,000-50,000 IU/day |
Serum 25(OH)D should be monitored after 3 months of treatment. If the target level is not reached, higher doses may be required.
Vitamin D Toxicity and Complications
Vitamin D toxicity is generally not a concern under normal conditions. It usually occurs due to excessive vitamin D supplementation, especially with serum 25(OH)D levels above 100-150 ng/mL.
The acceptable upper limits for vitamin D intake are as follows:
- Infants under 6 months: 1000 IU
- 7-12 months: 1500 IU
- 1-3 years: 2500 IU
- 4-8 years: 3000 IU
- 9-18 years: 4000 IU
- Adults: 10,000 IU
Long-term excessive sun exposure does not lead to vitamin D toxicity because of the conversion of previtamin D3 and vitamin D3 to inactive metabolites.
Acute vitamin D toxicity typically presents with symptoms such as confusion, headache, polydipsia, polyuria, anorexia, vomiting, and muscle weakness due to hypercalciuria and hypercalcemia. Chronic toxicity can lead to nephrocalcinosis, bone demineralization, and pain.
Vitamin D and COVID-19
Currently, there is no specific vaccine or treatment for COVID-19, and elderly individuals with underlying comorbidities are at higher risk for severe disease. The outbreak and rapid spread of SARS-CoV-2 is a global health threat with destabilizing consequences worldwide. Therefore, it is important for most people to know how to strengthen their immune system to prevent SARS-CoV-2 infection or how to control the severity of the disease to avoid fatal outcomes in future waves of the COVID-19 pandemic.
Although there is no clear evidence that vitamin D supplementation prevents the severity and mortality of COVID-19, increasing data suggest that it may potentially be effective in preventing and treating the disease. Data show that there is an inverse relationship between vitamin D levels and outcomes of COVID-19, including its severity and mortality.
Vitamin D modulates both innate and acquired immunity and may potentially prevent or reduce complications associated with acute respiratory infections. Vitamin D could help prevent SARS-CoV-2 infection through immune modulation. Studies support the potential role of vitamin D in reducing the risk of COVID-19 infections and mortality. It has been shown that vitamin D supplementation is safe and effective in preventing acute respiratory infections. New data report the antiviral effects of vitamin D, which can directly inhibit viral replication and also act in an anti-inflammatory and immunomodulatory way.
In COVID-19 patients, underlying diseases can enhance some of the characteristics of vitamin D deficiency, such as immune-modulatory effects. This may make these patients more sensitive to the effects of vitamin D deficiency compared to others. It is still unclear how vitamin D balances functional immune responses with antiviral conditions in these patients. Additionally, the role of insufficient local vitamin D production in the lungs due to SARS-CoV-2 infection in COVID-19 patients is unclear.
Vitamin D supplementation has shown protective effects against respiratory infections, so individuals at higher risk of vitamin D deficiency during this global pandemic should consider taking vitamin D supplements to maintain circulating 25(OH)D levels at optimal levels (75-125 nmol/L). A recent review recommended loading doses of vitamin D in 50,000 IU capsules, ranging from 200,000-300,000 IU, to reduce the risk and severity of COVID-19. The primary treatment target, due to insufficient evidence, is to ensure that 25(OH)D levels are >50 nmol/L or 20 ng/mL.
Despite conflicting data, current evidence suggests that supplementation with multiple micronutrients, which play roles in supporting the immune system, can modulate immune function and reduce the risk of infection. The micronutrients with the strongest evidence for immune support are vitamin C, vitamin D, and zinc.
There is insufficient evidence regarding the relationship between vitamin D levels and the severity and mortality of COVID-19. Therefore, randomized controlled trials and large-scale cohort studies are needed to test this hypothesis.
Vitamin D is not only essential for bone health but also beneficial for many other systems as a key nutrient, vitamin, and hormone.
The American Academy of Dermatology has declared that UV radiation from sunlight or artificial sources is a known carcinogen. Therefore, obtaining vitamin D through sun exposure may not be safe or efficient. Doctors should inform patients at high risk for vitamin D deficiency on how to obtain adequate dietary or supplemental vitamin D.
Research is ongoing to evaluate the effects of vitamin D supplementation and determine the optimum serum levels of 25(OH)D. Other recommendations for vitamin D supplementation should be personalized accordingly.
In our country, during the winter season, adults can meet their vitamin D requirements by ensuring adequate and balanced nutrition, along with daily direct exposure to sunlight for about 30 minutes on the head, face, hands, arms, feet, and legs. Consumption of one egg, 2 glasses of full-fat milk or dairy products daily, and fatty fish 1-2 times a week can meet their vitamin D needs. For those unable to achieve these conditions, vitamin D supplementation at the recommended levels should be provided. Vitamin D3 is typically available in 50,000 IU bottles, with 3 drops providing 400 IU of vitamin D. If multivitamins or calcium supplements enriched with vitamin D are taken, the contents should also be accounted for.
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