Vitamin D: a natural wonder drug we’re all avoiding?

This essay was written by Anna K Coussens and was first published in the 2011/12 Mill Hill Essays.

If you were told that there was one very cheap pill you could take every day that would help prevent cancer, diabetes, mental health problems, and multiple sclerosis while dramatically boosting your immune system, most of us would waste little time in popping out to the nearest pharmacy. In recent years, vitamin D has been shown to have a protective role in all of these diseases, yet at the same time the worldwide incidence of vitamin D deficiency is on the increase. You may have heard in the news that the incidence of rickets in children is on the increase, but did you realise that this is due to severe vitamin D deficiency and that a third of British children are thought to be vitamin D deficient? You may also remember the cases of ‘shaken baby syndrome’ where parents were accused of killing their children, but it turned out it was caused by weak bones due to vitamin D deficiency.

If you are unaware of the beneficial effects of vitamin D, you’re not the only one and it probably isn’t your fault as a recent study has shown that more than 50% of healthcare workers are also unaware of the benefits of vitamin D. In an attempt to combat this general lack of awareness clinicians and scientists have been pushing governments and advisory bodies to promote the benefits of vitamin D and increase their daily intake guidelines. In reply, the Chief Medical Officer for England, Dame Sally Davies, has recently advised that some groups, particularly pregnant women and the under-fives, should take a daily vitamin D supplement.

We all know that calcium is essential for bone growth, but fewer know that we need vitamin D for calcium adsorption. In fact, vitamin D is also essential for bone growth. However, vitamin D is not only essential for controlling calcium and phosphate levels, to maintain healthy bones. There is also growing scientific evidence that vitamin D is responsible for a whole host of other health benefits, including maintaining a healthy heart and brain, preventing cancer and diabetes and boosting your immune system.

One reason for its wide-ranging effects is that, unlike other vitamins, the major product of vitamin D, commonly called calcitriol, is actually a hormone. Whereas other vitamins, like vitamin C, need to be obtained from food and act as antioxidants or co-factors in enzymatic reactions, being a hormone means calcitriol is produced by specific cells to act as a messenger to tell other cells what to do. Calcitriol works by binding to the vitamin D receptor made by a certain cell, in the same way that a key fits its lock. Together they form a molecule which can help to turn on and turn off more than 900 genes in that cell. These genes control a diverse range of functions and it is therefore by acting as a key for this lock that the product of vitamin D, calcitriol, has an important role in maintaining a properly functioning body.

Vitamin D is obtained in two forms
Figure 1.

Vitamin D is obtained in two forms D2 (plant–derived) and D3 (UV/ animal-derived). Vitamin D is converted by cytochrome P450 (CYP) enzymes into calcidiol and calcitriol. Calcitriol controls the levels of CYP enzymes to make sure too much calcitriol isn’t produced. The blue line indicates inhibition, the red lines indicate activation.

It used to be thought that vitamin D was converted into calcitriol by two specific enzymatic reactions (Figure 1). The first step, occurring in the liver, produces calcidiol. This is the major form of vitamin D found in the blood and is what is measured to determine if someone is vitamin D deficient. The second step occurs in the kidney to convert calcidiol into calcitriol, through the action of the enzyme cytochrome 27B1 (CYP27B1). Low levels of calcium cause the parathyroid gland to increase production of the parathyroid hormone and this increases CYP27B1 production by the kidney, thereby increasing calcitriol levels. To make sure that too much calcitriol is not produced, calcitriol decreases parathyroid hormone production in order to limit CYP27B1 and its own synthesis.

In 1981, however, it was discovered that CYP27B1 and calcitriol could also be produced by a particular kind of immune cell, called macrophages. These cells act as the body’s rubbish collectors, ingesting and disposing of things the body doesn’t want, such as bacteria during an infection, debris from dying cells, or cancer cells. This was the first evidence that during an infection cells require high levels of calcitriol for optimum functionality. When macrophages sense bacteria they produce their own CYP27B1 so that they can make calcitriol, potentially at higher levels than they can get from the blood. This helps them turn on the genes they need to fight the infection. However, in order that the body doesn’t make too much calcitriol, calcitriol also activates the gene that makes another enzyme (called CYP24A1) which begins to degrade calcitriol. It is now known that many cell types will produce CYP27B1 in response to a range of stimuli. Consequently, vitamin D is now recognised to regulate numerous aspects of cell function, including cell growth, development, activation and death.

If it’s so good, how do we get it?

Vitamin D exists in two forms: vitamin D3 (cholecalciferol) and vitamin D2 (ergocalciferol) (Figure 1). Vitamin D3 is the predominant form in humans and is primarily obtained through skin exposure to UV irradiation from the sun. This converts a substance in the skin (which comes from lanolin) into vitamin D3. It is generally thought that between 5–30 minutes of midday sun exposure (10am-3pm) at least twice a week to the face, arms, legs, or back, without sunscreen, is required to maintain sufficient levels of vitamin D. You get the same amount of vitamin D whether you have 30 minutes exposure or 8 hours, as the heat generated in the skin by the UV will degrade any excess vitamin D produced. A very specific wavelength of UV (UVB) is required for vitamin D production. How close to the equator you live, the season, time of day, cloud cover and smog can all affect the wavelength you are exposed to. Skin colour (determined by the amount of the pigment melanin in your skin) and sunscreen use can also affect the amount of UV radiation that your skin cells receive. Therefore, if you have darker skin you need longer exposure to the sun in order to make the same about of vitamin D3 as someone who has pale skin. Vitamin D3 can also be obtained from dietary sources such as oily fish and eggs and their derived products like cod liver oil. Vitamin D2 is obtained from plant sources, primarily fungus and yeast exposed to UV irradiation, or from nutritional supplements (see historical note).

Where you live is one of the major factors that influences how much vitamin D you get. Equatorial countries, which are sunnier, have a greater steady state of vitamin D than countries at northern or southern latitudes, where seasonal variation in daylight hours is greatest. Even within the UK, if you live in Scotland you are three times more likely to be vitamin D deficient than someone in the southeast of England, as Scotland has a lot less daylight throughout the year (Figure 2). There is growing evidence for associations between geographical vitamin D levels and neurological conditions such as multiple sclerosis (MS), depression and brain development. There is an association between the season during which a pregnant woman has her third trimester and the neurological development of her baby, summer being optimal to maximise vitamin D levels. The severity of MS symptoms can also vary by season.

Older adults are particularly at risk of developing vitamin D deficiency because as they age, their skin cannot synthesize as much vitamin D. Other populations at risk include those who cover their entire body in clothing, indoor dwellers, night workers and people with inadequate intake of vitamin D rich foods, particularly fatty fish. This latter point is of particular note for expectant mothers who are advised to avoid certain seafoods during pregnancy, but total seafood avoidance will increase their risk of vitamin D deficiency. Furthermore, as vitamin D is a fat soluble molecule, calcidiol is stored in fat and its release into circulation is altered by excess stores of body fat. Consequently, obesity is another risk factor for vitamin D deficiency.

UK average annual sunlight duration per day varies.
Figure 2.

UK average annual sunlight duration per day varies according to latitude and corresponds to the gradient of vitamin D deficiency throughout the country.

The ability to tan has been shown to be inversely proportional to vitamin D synthesis. This is because the skin pigment (melanin) blocks UV from penetrating deep within the skin. Many researchers now worry that excessive use of sunscreen, which was encouraged to prevent UV-induced DNA damage and skin cancer, is leading to an epidemic of vitamin D deficiency – particularly in a country like the UK, where UV exposure is moderate in comparison to Australia where the recommendations for sunscreen originated. In support of this idea, reports are emerging from sunny countries that the risk of a second primary cancer after having a non-melanoma skin cancer (the less aggressive form) is lower for nearly all cancers investigated. This is because non-melanoma skin cancers reflect cumulative sun exposure, whereas melanoma (the most aggressive form) is more related to sunburn. Consequently, extended sun exposure, without burning has been shown to prevent melanoma.

How does vitamin D affect so many functions of the body?

We now know that outside the kidney, calcitriol can be made by a range of other cell types including lung, skin, colon, pancreatic, brain, breast and various immune cells (Figure 3). For a cell to respond to calcitriol it needs to make a vitamin D receptor. However, to be an active receptor the vitamin D receptor must also bind to the vitamin A receptor. Binding of calcitriol to these two receptors forms an active molecule called a transcription factor which can bind to a gene’s specific DNA sequence and cause it to be turned on. By controlling the activation of genes, calcitriol affects a wide range of processes within a cell. However, vitamin D metabolites are not the sole activators of the two receptors. Retinoic acid (a form of vitamin A) in combination with calcitriol has been shown to regulate genes in macrophages which help them to kill intracellular bacteria and inhibit their ability to ingest bacteria. This suggests that maintaining physiological levels of both vitamin D and vitamin A may be important for correct functioning of the receptor complex.

The main function of vitamin D is to maintain healthy bones by controlling blood calcium levels. However, calcium is also required for muscle function and deficiency can lead to low muscle strength, again which can be associated with falls and secondary fractures. Conversely, excess calcitriol causes high calcium levels, which can lead to kidney stones, kidney failure and cardiac failure. Luckily this can be prevented if detected early enough.

One of the ways calcitriol helps the body’s immune system to fight infection is by turning on genes which make small proteins called antimicrobial peptides, particularly one called cathelicidin. This small protein has been shown to kill many different pathogens, including bacteria such as M. tuberculosis, Staphylococcus aureus and E. coli, fungi such as Candida albicansand viruses such as herpes simplex virus type 1, influenza and human immunodeficiency virus type 1 (HIV-1). The mechanisms of killing are not completely understood, but it is known that cathelicidin kills bacteria by punching holes in their cell wall. So far we know that cells in the skin, lung, eye, colon, as well as many immune cells all make cathelicidin when sufficient vitamin D is available.

Calcitriol, the active form of vitamin D, affects the function of many organs in the body.
Figure 3.

Calcitriol, the active form of vitamin D, affects the function of many organs in the body.

Paradoxically, despite its ability to induce antimicrobial activity, calcitriol also inhibits many pro-inflammatory signalling molecules (called cytokines and chemokines) which activate and recruit other immune cells and induce anti-inflammatory signals from various immune cells. In general, immune cells make pro-inflammatory cytokines to help activate the immune response during an infection. Recruiting and activating other cells at the site of disease results in the inflammation and raised temperature we all associate with being sick. In many chronic infections, however, excess inflammation can lead to tissue damage. It is believed that calcitriol limits the inflammatory immune response to prevent excess tissue damage at the same time as having direct antimicrobial activity to kill the invading pathogen.

It is via its anti-inflammatory effects that vitamin D is also thought to help in various autoimmune diseases which develop due to inappropriate chronic inflammation, including type 1 diabetes, inflammatory bowel disease (ulcerative colitis and Crohn’s disease), rheumatoid arthritis and asthma. Excess inflammation is also thought to be a damaging factor in neurological conditions where the degree of inflammation is proportional to the severity of symptoms, as occurs in MS. Vitamin D has been shown to reduce inflammation caused by repeated trauma to peripheral nerves in chronic regional pain syndrome and reduce the risk of vascular dementia. However, this link to dementia may also be due to the beneficial effects of vitamin D on the cardiovascular system. As vitamin D limits inflammation and tissue destruction, it also has a positive effect on preventing the thickening of arterial walls which is the main cause of cardiovascular disease and stroke. Vitamin D deficiency is associated with increased blood pressure and severely deficient newborns can have heart failure.

Another way vitamin D can limit tissue damage is by controlling the expression of matrix metalloproteinases (MMPs): enzymes which are capable of degrading all components of the tissue within which cells live. MMPs are generally produced by cells to help repair damaged tissue. Long term MMP activity can cause tissue destruction in chronic inflammatory conditions, such as tuberculosis TB, psoriasis, eczema and asthma, while it also allows cellular migration in metastatic cancers. In work carried out at NIMR, it has been shown that the levels of various MMPs are increased in the blood of tuberculosis (TB) patients and that supplementation with vitamin D during anti-TB therapy significantly reduces the levels of MMPs along with many other pro-inflammatory signals. This is interpreted as good evidence that vitamin D helps to resolve the pathological inflammation which destroys the lung during TB. Lung destruction is what causes TB patients to cough up blood, an image forever linked with the consumption epidemics of the 17th and 19th centuries.

While vitamin D can play a role in limiting cancer metastasis through limiting tissue destruction, it may also control cancer by stopping cell growth, as has been shown for breast cancer cells. However, the majority of evidence for a role of vitamin D in cancer comes from studies showing that vitamin D deficiency and low sun exposure are associated with increased risk of cancer incidence and mortality. Cancers linked to vitamin D deficiency include breast, colon, ovarian, pancreatic, prostate, oesophageal, gall bladder, gastric, rectal, renal and vulvar cancer, melanoma and Hodgkin’s and non-Hodgkin’s lymphoma. In the UK, prostate cancer risk is inversely proportional to the extent of UV exposure, skin colour and sunbathing on holiday. Contrary to links between UV exposure and cancer, childhood sunburn was found to be protective against prostate cancer in UK males. There are also many studies which show no correlation between UV exposure and cancer. The difficulty in finding conclusive evidence for the role of vitamin D in cancer is complicated by the multiple environmental and genetic factors involved (including diet, geographical location, skin colour and genetic predisposition) and the length of time over which cancer develops.

Vitamin D also plays a vital role in maternal health during pregnancy and lactation, particularly during the second and third trimesters. Children born in spring have been shown to have the highest rates of mental disorders (such as depression and schizophrenia) and autoimmune diseases (such as type 1 diabetes and asthma) and expectant mothers are at highest risk of vitamin D deficiency during this time. Higher doses of vitamin D supplementation during pregnancy have been shown to reduce infections and the risk of preeclampsia in mothers, and to increase the bone and muscle strength of their children. Vitamin D deficiency is also associated with the severity of polycystic ovary syndrome symptoms and fertility rates can be enhanced by vitamin D supplementation.

How much vitamin D do we really need?

So if that’s what we currently know about the benefits of vitamin D and the risks of vitamin D deficiency, are we giving people the right advice about vitamin D intake? Because circulating calcidiol levels may not always be indicative of what is occurring within a cell, determining adequate vitamin D levels based solely on blood calcidiol is difficult. The level you choose to define ‘deficiency’ will depend on what physiological process you are trying to maintain. An individual’s requirement will also depend on how well they can actually metabolise vitamin D, transport it to where it is required and how active their vitamin D receptor is. All of these factors can vary between individuals due to their genetic variation. The highest levels of vitamin D are required to maintain optimal functionality of all processes which vitamin D is thought to be involved in. Lower levels will only maintain the vital roles of vitamin D in controlling calcium and bone health.

Determining recommended daily intakes (RDI) also depends on an individual’s sun exposure, sun screen use, ability to tan and skin colour. Therefore, determining an RDI that suits everyone is difficult. The fact that sunlight can provide a huge burst in vitamin D levels suggests that supplementation can be carried out at higher levels than currently recommended and still remain safe. There is more evidence pointing to the health benefits from higher concentrations of vitamin D than to deleterious effects. Two internationally recognised bodies have recently published revised supplementation guidelines. A panel of clinicians from the USA Institute of Medicine (IOM) published one report, and a group of scientists and clinicians from the Endocrine Society published a reply to that report. The conclusions of the two studies are conflicting, with regard to RDI for optimal health outcome. The first is cautionary, underplaying the evidence, the second is realistic in recommending levels not greater than can be obtained naturally from the sun. The major difference was the definition of vitamin D deficiency categorised by the two studies: the IOM specified 20 mg/L as the level based predominantly on benefits to bone health, while the second study categorised people between 20-30 mg/L as being insufficient and more than 30 mg/L as sufficient. However, the later study also suggested that 40-50 mg/L will promote optimal health benefits, with regard to non-bone related functions.While you may not understand what these numbers represent, the fact that the second study recommended double the amount of vitamin D for optimal health, highlights the present conservatism of some advisory bodies. The IOM set their RDI at 600 units per day, while the Endocrine Society paper recommended at least 600 units per day to prevent deficiency and 1500-2000 units per day for optimal health. Higher levels were also recommended for the elderly and obese people in both studies. The upper limit set by the two studies was 4,000 units per day and 10,000 units per day, respectively.

So why was the IOM so cautious in their recommendations? What’s bad about too much vitamin D? Historically, dangerously high levels were prescribed, inducing extremely high levels of calcium which in some cases resulted in kidney failure and cardiac failure. This made clinicians cautious in overprescribing supplements. However, these original studies used extraordinarily high doses, hundreds of times higher than the upper levels which are in dispute by these two studies. Moreover, no toxic effects have been associated with levels of 10,000 units/day, even in patients with an illness. Moreover, when an adult wearing a bathing suit is exposed to the amount of UV which will result in a slight pinkness in the skin, the amount of vitamin D produced is equivalent to ingesting between 10,000 and 25,000 units.

I am Australian and I love the sun. However, being of British heritage means I am blessed with pale, sunburn-prone skin and as such I am cautious when it comes to sun exposure. Despite this, I spent my first summer after moving to London making sure I got out in the sun on the weekends as much as possible, while ensuring I did not get sunburnt. Towards the end of summer, I had my vitamin D measured and was happily surprised to find I had a calcidiol level of 43.6 mg/L – the optimal level recommended by the Endocrine Society. Thus even in an English summer, with only intermittent sun exposure I had reached a level more than double what the IOM has now classified as sufficient. So, if you can naturally make more than 40 mg/L in an English summer, is this level really bad for you? With growing evidence suggesting there are multiple beneficial effects of having calcidiol levels more than 40 mg/L and few negative effects, perhaps we should encourage higher levels in order to promote greater health benefits and a preventative health care policy, rather than recommending levels at the bottom end of healthy, based predominantly on one physiological system (i.e. maintaining healthy bones)? I, for one, trust nature to deliver what I need. If regular sun exposure can give me 43.6 mg/L in summer, then I will take supplements to give me that level when I have limited sun exposure in winter. I wait in anticipation for the revised NICE guidelines for vitamin D. I hope you look out for them too!

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