Vitamin D: the 'sunshine vitamin', its role and the effects of deficiency

Abstract

This article, the third in our series on vitamins and minerals, explores the biosynthesis of vitamin D metabolites, the role of vitamin D in the body and the effects of deficiency and overdose on human health.

Citation: Andrade M et al (2024) Vitamin D: the 'sunshine vitamin', its role and the effects of deficiency. Nursing Times [online]; 120: 4.

Authors: Maria Andrade is honorary associate professor, John Knight is associate professor and Zubeyde Bayram-Weston is senior lecturer; all at the School of Health and Social Care, Swansea University.

• This article has been double-blind peer reviewed
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Introduction

Vitamin D refers collectively to a group of structurally related, fat-soluble molecules, which are essential to human health and physiology. In this third article in our vitamins and minerals series, we examine the nature and diverse physiological roles of vitamin D, as well as pathological effects associated with its deficiency.

Nature and sources of vitamin D

All forms of vitamin D are derived from cholesterol or the structurally related molecule ergosterol. Two major forms of vitamin D are important in humans:

• Vitamin D2 (ergocalciferol) - primarily synthesised by fungi, but also found in small amounts in plants colonised or infected by fungi and obtained preformed in the diet;
• Vitamin D3 (cholecalciferol) - synthesised by animals and either obtained preformed in the diet (for example, from meat, dairy products or eggs) or synthesised in the human
  
  body (Fig 1).

Biosynthesis in the skin

Vitamin D is often called the 'sunshine vitamin' because the skin can photosynthesise it when exposed to sunlight (Holick, 2023). The lipid molecule 7-dehydrocholesterol functions as a vitamin D precursor molecule. It is found in the cell membranes of the keratinocytes (skin cells) of the epidermis (outer skin layer) and fibroblasts in the dermis (lower skin layer). Exposure of skin to ultraviolet components of sunlight with a wavelength of 280-320 nanometres (UVB) causes conversion of 7-dehydrocholesterol into pre-vitamin D3 (Fig 2).

Pre-vitamin D3 is thermodynamically unstable at normal body temperature (37°C); within eight hours around 80% of photosynthesised pre-vitamin D3 will have changed form (isomerised) into vitamin D3 (cholecalciferol), which has a much higher thermal stability (Janoušek et al, 2022).

Food sources and supplements

From late March to the end of September, most people in the UK should be able to make all the vitamin D they need from skin exposure to sunlight, with an estimated 90% of vitamin in the body photosynthesised by the skin (Taylor and Davis, 2019). However, in the autumn and winter, when exposure to radiant sunshine is limited, and UVB levels much reduced, vitamin D levels must be boosted through dietary intake. Vitamin D rich foods include:

• Oily fish, including sardines, herring and mackerel;
• Red meats;
• Liver;
• Egg yolks;
• Mushrooms;
• Fortified foods, such as some breakfast cereals and fat spreads.

Vitamin D is commonly measured in micrograms (µg) or international units (IU) where 1µg is equal to 40 IU. Adults and children from one year require 10µg (400 IU) of vitamin D daily (NHS, 2020).

Current UK government advice is that everyone should consider taking a vitamin D supplement in the autumn and winter months (NHS, 2020). A daily supplement throughout the year of 10µg (400 IU) is also recommended for adults, and children over the age of four, who:

• Wear clothes covering most of their skin when outdoors;
• Spend limited time outdoors (for example, if frail or housebound);
• Reside in an institution such as a care home.

People of Asian, African or African-Caribbean heritage are also advised to consider taking a daily 10µg supplement as increased skin pigmentation may reduce the skin's ability to manufacture sufficient vitamin D at northern European latitudes.

Babies from birth to one year if breastfed or consuming <500ml of formula milk should have a daily supplement of 8.5-10µg, while children 1-4 years of age should have a daily supplement of 10µg throughout the year (NHS, 2020).

"The best known role of vitamin D is in enhancing the absorption of dietary calcium and phosphate in the gut"

Transport of vitamin D

Vitamin D3 that has left skin cells, and vitamin D2 and D3 absorbed from food or dietary supplements, rapidly binds to blood plasma proteins for transport around the body. Approximately 15% of vitamin D metabolites bind to albumin, the most abundant plasma protein; the remaining 85% bind to vitamin D binding protein (VDBP), which has a much higher affinity for vitamin D (Bickle and Schwartz, 2019).

VDBP is produced by the liver and is structurally related to albumin; it has a single binding site, which can bind to and transport all the vitamin D metabolites. VDBP functions as an efficient circulating reservoir, which can be drawn upon as required, providing buffering against sudden vitamin D depletion (Bouillon et al, 2020).

Metabolism in the liver and kidneys

Vitamins D2 and D3 are biologically inactive, requiring two further structural changes to become active molecules capable of eliciting physiological effects:

• Conversion by the liver cells (hepatocytes) into calcidiol, the main circulating form of vitamin D (Fig 2). Calcidiol has a relatively long half-life of around 2-3 weeks and is the form measured to assess people's vitamin D status (Chang and Lee, 2019). There is no consensus on the optimal or desirable concentration of calcidiol, but 32ng/mL (80nmol/L) or higher is considered sufficient to maintain normal physiology and ensure health (Janoušek et al, 2022);
• Conversion of calcidiol by the kidneys into biologically active calcitriol, which crosses into target cells to elicit its diverse biological effects (Bouillon et al, 2020). The enzymes involved here depend on magnesium, so magnesium deficiency can significantly reduce levels of biologically active vitamin D (Uwitonze and Razzaque, 2018).

As calcitriol levels rise, many cell types produce the enzyme CYP24A; this progressively deactivates calcitriol, which is converted into calcitroic acid for eventual elimination in the bile (Janoušek et al, 2022). Calcitriol has a relatively short half-life of around 4-6 hours (Chang and Lee, 2019). This enzymatic inactivation is an important homeostatic mechanism for regulating levels of active vitamin D.

Vitamin D as a steroidal hormone

Technically vitamin D is not a true vitamin because it can be synthesised by the body (endogenously) after exposing the skin to sunlight (Demer et al, 2018). Rather, it is often seen as a steroid hormone, whose lipid nature allows it to diffuse freely across cell membranes and bind to specific cell receptors to exert its effects (Knight et al, 2020). As vitamin D receptors are universally present in all nucleated human cells (Chang and Lee, 2019), almost all cells can respond to vitamin D metabolites.

The bulk of the active form of vitamin D (calcitriol) circulates throughout the body in the plasma bound to VDBP. However, small amounts (0.4%) circulate unbound or become free by disassociating from VDBP; it is this that allows it to exert its physiological effects (Bickle and Schwartz, 2019).

Free calcitriol rapidly diffuses across the cell membranes of target cells into the aqueous fluid (cytosol) of the cytoplasm. Here it binds with high affinity to the vitamin D receptor (VDR). Once bound it crosses into the cell nucleus and binds with a second receptor, the retinoid X receptor (RXR) (Fig 3).

Collectively, this conjugated complex forms a functional dimer (two units); this can bind to the vitamin D response elements on target genes to either activate or deactivate them (Stoffers et al, 2022). It is thought VDREs are associated with hundreds of human genes and binding serves to either enhance or suppress the transcription of specific messenger ribonucleic acid (mRNA) molecules. This either increases or decreases the production of proteins that can influence various human physiological processes (Demer et al, 2018).

Effects on calcium and phosphate absorption

Probably the best-known role of vitamin D is enhancing absorption of dietary calcium and phosphate in the gut. Vitamin D deficiency is recognised as the most under-diagnosed and undertreated nutritional deficiency, affecting around one billion people worldwide; vitamin D insufficiency affects half the world's population (Kiran et al, 2020). People deficient in vitamin D may only be able to absorb around 10-15% of dietary calcium, compared with 20-40% when vitamin D levels are normal (Janoušek et al, 2022).

Vitamin D activates genes that increase production of calcium channel proteins in the enterocytes (cells lining the small intestine). It also enhances pumping of calcium ions across the gut wall. These effects allow efficient calcium uptake as food is digested (Fleet, 2022).

Vitamin D also enhances production of calcium channel proteins in distal convoluted tubules of the nephrons (kidney tubules). This ensures calcium is efficiently absorbed from the renal filtrate instead of being lost in the urine (Janoušek et al, 2022). This contributes to calcium homeostasis, which ensures adequate and stable calcium levels in the blood.

Normal blood calcium levels are maintained at around 2.1-2.6mmol/l (Bazydlo and Needham, 2014). The range is narrow because calcium is vital to so many physiological processes, including:

• Maintaining bone and tooth health and density;
• Blood coagulation;
• Muscle contraction;
• Normal cell division;
• Secretion from glands;
• Release of neurotransmitters at synapses (Knight et al, 2021).

Effect on immune function

Vitamin D enhances immunity through several mechanisms, including:

• Enhancing mechanical barriers to infection - upregulating (increasing the expression of) genes responsible for the synthesis of proteins that form tight junctions between epithelial cells, which enhances the robustness of tissues such as the skin, gut, respiratory and urinary tracts;
• Increased antimicrobial activity - enhancing production of cathelicidin by monocytes (largest white blood cells), skin, lung, gut and placental cells. Cathelicidin acts as a potent antimicrobial peptide (small protein) with a broad range of activity against various bacterial and viral pathogens (Holick, 2023);
• Enhanced killing of pathogens - increasing production of highly reactive oxygen-free radicals by monocytes, enhancing their killing capability;
• Suppressed production of inflammatory mediators and autoimmune responses - reducing synthesis of inflammatory cytokines (such as interleukin 2, 12 and 17 and interferon gamma) while stimulating populations of T-regulatory cells (Tregs) that are known to suppress inflammation. This may explain why vitamin D may be beneficial in certain autoimmune diseases, for example, multiple sclerosis (MS) (Janoušek et al, 2022).

Vitamin D deficiency and supplementation

Bone health

Vitamin D deficiency is particularly detrimental to bone health as the body will always prioritise maintaining blood calcium concentration over maintaining skeletal integrity (Janoušek et al, 2022). Vitamin D deficiency is associated with rickets in children and osteomalacia in adults.

In both diseases, vitamin D deficiency results in hypocalcaemia (low blood calcium). This leads to secondary hyperparathyroidism as the parathyroid glands increase secretion of parathyroid hormone (PTH) to try and increase and normalise blood calcium concentration (Uday and Högler, 2018). Elevated PTH enhances the activity of bone-digesting cells called osteoclasts, resulting in varying degrees of bone demineralisation (Knight et al, 2020). PTH also increases elimination of phosphate (the other mineral component of bone) in the urine, leading to hypophosphataemia (reduced blood phosphate). This further contributes to the development of rickets and osteomalacia (Uday and Högler, 2020).

Since the mineral components of bone (calcium phosphate) impart hardness and rigidity to the skeleton, demineralisation can lead to the progressive softening of the bones.

Rickets

In rickets, reduced availability of calcium and phosphate means the soft cartilaginous growth plates in the long bones of children cannot fully ossify (convert to calcified bone). This leads to progressive bone deformity, whereby the weight of the body causes bending of the load-bearing bones of the lower limbs (Fig 4); hence leg bowing is common in children with severe rickets (Uday and Högler, 2020). Other symptoms of rickets can include:

• Thickening of the ankles, wrists and knees;
• Soft skull bones;
• Potential spinal deformities;
• Pain in affected bones that can lead to reluctance to walk;
• A change in gait (walking pattern) with waddling often present;
• Increased risk of fractures;
• Poor skeletal growth preventing children from attaining their full height potential;
• Dental problems, including tooth cavities, thin enamel layers and teeth failing to erupt normally;
• Problems outside of the skeletal system caused by low blood calcium, including: muscle cramps, muscle fasciculation (twitching), and tingling in the hands (NHS, 2021).

Rickets was once so common in the UK that it was referred to as 'the English disease'. At the beginning of the 20th century, around 80-90% of children living in industrialised cities were affected (Holick, 2023). Causes included a combination of poor diet and pollution (smog) leading to vitamin D deficiency (Newton, 2022). By reducing pollution levels, introducing vitamin D-fortified foods and offering cod liver oil (rich in vitamin D) as a dietary supplement to pregnant women and infants, rickets was all but eliminated in the UK. However, it has since made a return, especially in the expanding Black, Asian and minority ethnic populations, who are particularly susceptible to vitamin D deficiency at the UK's northern latitude (Uday and Högler, 2018).

Globally today, rickets in low-income countries is primarily due to dietary deficiency of calcium and vitamin D, while in the UK and other high-income countries it is more commonly associated with inadequate sun exposure. Contributing factors in the UK include its northern latitude combined with increasing racial diversity, and cultural factors, such as people covering up in the sun and using high-factor sunscreens due to greater skin cancer awareness (Uday and Högler, 2018). These effects can be mitigated by increasing dietary intake of vitamin D-rich foods or use of supplements as recommended (NHS, 2020).

Although modern epidemiological studies on rickets in the UK are scarce, research in 2001 on children under five revealed an incidence of around 7.5 cases per 100,000 (Callaghan et al, 2006). Recent estimates are much lower, suggesting an incidence of 0.48 cases per 100,000 in children under 16 years, rising to 1.39 cases per 100,000 in the under-fives (Julies et al, 2020). These figures almost certainly under report the true number of children affected by rickets as milder cases can be asymptomatic, so go unrecorded.

"Large doses of vitamin D, particularly long-term, can lead to vitamin D toxicity"

Osteomalacia

Despite being commonly referred to as the adult form of rickets, osteomalacia has some key differences. While rickets primarily affects the ossification of the growth plates, osteomalacia occurs after the growth plates have fused. Like rickets, osteomalacia is most commonly due to vitamin D deficiency. However, it is characteristically associated with reduced bone replacement during normal dynamic bone turnover. The term osteomalacia means 'soft bones', highlighting the demineralisation that occurs as the disease progresses.

Symptoms are similar to those of rickets, including:

• Varying degrees of bone pain;
• Muscle fasciculation/weakness;
• Altered gait;
• Increased risk of fracture;
• Potential for spinal deformity in chronic osteomalacia (Zimmerman and McKeon, 2022).

As with rickets, cases of osteomalacia are probably massively under-reported and many may be misdiagnosed as the more common disease, osteoporosis. Although accurate figures for the incidence of osteomalacia in the UK are currently unavailable, post-mortem analysis of adult bone tissues suggests an incidence of up to 25% in some northern European adult populations (Zimmerman and McKeon, 2022; Uday and Högler, 2018).

Role in other acute and chronic diseases

Epidemiological studies have also implicated deficiency of vitamin D in many acute and chronic diseases. These include acute respiratory diseases, diabetes, rheumatoid arthritis, MS, cardiovascular disease and various neurological disorders (Holick, 2023). While much research is incomplete and often contradictory, some key findings are briefly highlighted below.

Covid-19 and other infections

Because vitamin D is so intimately involved in modulating immune responses, its potential role in Covid-19 infection was examined early in the pandemic. Although findings from multiple studies are often contradictory, the general consensus is that low levels of vitamin D are associated with increased infection risk, severity of disease and mortality for Covid-19. It is suggested that supplementation to restore normal levels of vitamin D in the early stages of Covid-19 infection could reduce or prevent severe disease progression and reduce mortality (Jordan et al, 2022). However, the effectiveness of vitamin D in treating Covid-19 still needs to be fully established using the gold standard of randomised control trials (RCTs) (Janoušek et al, 2022).

Previous studies have already highlighted that vitamin D supplements can protect against a variety of other acute respiratory tract infections (ARIs) potentially by enhancing immune responses. Likewise, vitamin D deficiency is associated with increased susceptibility to many ARIs, including influenza and common cold viruses (Jolliffe et al, 2021; Martineau et al, 2017).

In patients infected with HIV, vitamin D supplementation for 12-48 weeks increased T-helper counts (depleted by HIV) and reduced viral loads (Santos et al, 2023).

Autoimmune diseases

MS is an autoimmune disease where the immune system attacks and destroys the myelin sheath (insulation) that surrounds neurons, preventing efficient conduction of nerve impulses. Vitamin D deficiency appears to increase the risk of MS, with the disease more prevalent in higher latitude countries where photosynthesis of vitamin D in the skin is naturally lower, making deficiency more likely. That deficiency could be a risk factor is supported by other studies suggesting that boosting vitamin D levels could reduce the risk of MS (Nipith and Holick, 2020). It has been speculated that deficiency creates an environment conducive to autoimmunity and autoinflammation, increasing the chances of the myelin sheath being attacked (Nipith and Holick, 2020).

Type 1 diabetes mellitus (T1DM) accounts for around 10% of cases of diabetes mellitus and occurs when the immune system attacks and destroys the insulin-producing β (beta) cells of the pancreas (Knight et al, 2017). Like MS, the incidence of T1DM is greater in higher latitudes, suggesting a possible link with vitamin D. This is supported by evidence from Finland where incidence of T1DM decreased after fortifying certain foods with vitamin D (Harvey, 2023). This may be due to vitamin D acting as a general suppressant of autoimmune reactions (Harvey, 2023)

Psoriasis is a common autoimmune skin disorder characterised by over-proliferation of epidermal skin cells. Treatment with stable topical vitamin D analogs, such as calciptriol, can be as effective as traditional topical steroids without the steroidal side-effects, although the mechanism remains unclear (Bouillon et al, 2018).

Cancer

Cancers occur due to uncoordinated cell division. Many studies suggest vitamin D is involved in controlling cell division cycles, implicating deficiency with increased risk of cancer and poorer prognosis: in four randomised control trials involving 44,492 patients, cancer mortality was moderately reduced by vitamin D supplementation (Bouillon et al, 2022). Meta-analysis studies, which systematically assess previous research studies, have revealed an association between higher levels of vitamin D and decreased mortality and better prognosis in prostate cancer patients (Santos et al, 2023).

A recent review of vitamin D's role in cancer by Seraphin et al (2023) found deficiency was linked to higher grades of breast cancer, reduced survival of melanoma (the deadliest skin cancer) and increased risk of squamous cell carcinoma. High vitamin D levels/supplementation was associated with a 38% lower risk of ovarian cancer, suppression of colorectal cancer stem cells and reduced risk of developing melanoma. The study highlighted vitamin D's positive anti-cancer effects, but further research is needed to understand more (Seraphin et al, 2023).

Cardiovascular disease

Human studies suggest decreased levels of vitamin D may increase the risk of cardiovascular disease/events, including hypertension, cardiomyopathies, congestive heart failure, ischaemic cardiac events, stroke and cardiovascular mortality. However, many studies are small scale with multiple possible confounding factors. Furthermore, a recent analysis of 21 RCTs involving more than 80,000 patients suggested no effects of vitamin D supplementation on major cardiovascular events (Bouillon et al, 2022).

Type 2 diabetes

Type 2 diabetes mellitus (T2DM) is characterised by insulin resistance and is the most common form of diabetes mellitus, accounting for around 90% of patients (Knight et al, 2017). That many T2DM patients are deficient in vitamin D is not surprising considering the prevalence of deficiency in the general population. However, a recent study of 116 patients with T2DM in India found 74.1% were vitamin D deficient (Vijay et al, 2023).

Potential links between deficiency and the aetiology of T2DM remain poorly understood and RCTs have not confirmed that vitamin D supplements can prevent T2DM (Bouillon et al, 2022). However, some studies suggest regular vitamin D supplements can help prevent disease complications (Vijay et al, 2023).

Neurological conditions

Vitamin D supplementation may limit neuroinflammation in Parkinson's disease, potentially reducing neural damage and improving neurological outcomes as the disease progresses (Plantone et al, 2023). It also appears to reduce the number and frequency of migraine attacks but is less useful in reducing perceived pain intensity (Plantone et al, 2023).

Many studies have highlighted that vitamin D deficiency is associated with a greater risk of developing Alzheimer's disease, however, vitamin D supplements do not seem beneficial (Plantone et al, 2023). In addition, while low vitamin D levels may be associated with increased symptoms of anxiety and depression (Akpınar and Karadağ, 2022), currently, there is insufficient evidence for using vitamin D supplementation to treat depression (Guzek et al, 2023).

Vitamin D overdose

With growing awareness of the importance of vitamin D to human health, combined with greater commercial availability of supplements, it is important to ensure that no one exceeds recommended limits. The UK recommended maximum doses a day are:

• 100µg (4000 IU) for adults, breastfeeding women and children aged 11-17;
• 50µg (2000 IU) for children aged 1-10;
• 25µg (1000 IU) for infants under 12 months (NHS, 2020).

Large doses of vitamin D, particularly long-term, can lead to vitamin D intoxication. Although rare, this is a potentially life-threatening condition characterised by multisystemic signs and symptoms. Many of these are linked to the hypercalcaemia triggered by elevated vitamin D levels. Signs and symptoms include:

• Hypertension;
• Arrhythmias (with characteristic ECG changes such as S-T segment changes or shortened Q-T intervals);
• Poluria (increased urination);
• Hypercalciuria (increased calcium in the urine and potential calcium deposition in renal tubules);
• Potential renal failure;
• Dehydration;
• Polydipsia (increased thirst);
• Abdominal pain, pancreatitis, vomiting, peptic ulceration, constipation.
• Neurological dysfunction, psychosis, confusion, depression, stupor, apathy, drowsiness and, potentially, coma (Alkundi, 2022).

Treatment includes discontinuing the vitamin D supplement, a low calcium diet, rehydration (using isotonic saline) and steroids (Alkundi, 2022). If necessary, calcitonin and bisphosphonates can be prescribed. Calcitonin allows osteoblasts (bone-forming cells) to direct excess calcium into the bones and stimulates the kidneys to excrete excess calcium in the urine.

Bisphosphonates inhibit osteoclasts (bone-digesting cells); this prevents release of additional calcium into the blood while simultaneously allowing the osteoblasts to deposit excess calcium in the skeleton. Using calcitonin with bisphosphonates enhances its effects (Asif and Farooq, 2023).

Conclusion

Vitamin D is essential to bone health and normal levels are required for a healthy immune system. Vitamin D deficiency has been associated with a wide range of human diseases but, aside from rickets and osteomalacia, its role in most other diseases remains poorly elucidated.

Key points

• Vitamin D is a group of fat-soluble vitamins with active forms functioning as steroid hormones
• Most vitamin D in humans is photosynthesised by the skin, with small amounts coming preformed in food
• Deficiency of vitamin D can cause rickets in children and osteomalacia in adults
• Vitamin D is essential for normal immune function
• Vitamin D deficiency has been linked to many human diseases including cancer, autoimmune and infectious diseases, and neurological conditions

• The next article in this series explores vitamins E and K.

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