Vitamin D is produced primarily by the action of sunlight on 7-dehydrocholesterol in the skin. It is metabolised to 25-hydroxyvitamin D (25D) in the liver and then to 1,25-dihydroxyvitamin D (1,25D) in the kidney. This active form of vitamin D acts on distal tissues to promote absorption of calcium and phosphate. This is the endocrine function of vitamin D.

It is now known that many tissues can convert 25D to 1,25D and they also have the receptor for active vitamin D. This includes components of the immune system, such as macrophages and T-cells. Intracrine (within the same cell) responses and paracrine responses to vitamin D underpin a much wider role for vitamin D than was previously understood.

Vitamin D acts in both the innate and adaptive arms of the immune system. In the innate arm it promotes non-specific antibacterial and antiviral responses to infection. In the adaptive arm vitamin D appears to act on T-cells to suppress the normal inflammatory responses to an infection. Although inflammation is a normal response to infection, inappropriate continued inflammation may be at the root of auto-immune disease. It is postulated that if 25D levels are low, then less is available to macrophages, dendritic cells and T-cells, which, in turn, are able to make less activated 1,25-dihydroxyvitamin D (1,25D) and suppression of inflammation by the adaptive immune system is reduced.

Association studies have linked low levels of vitamin D with the presence of autoimmune disease such as type 1 diabetes, Crohn’s disease or multiple sclerosis.

There is, as yet, no universal agreement about the levels of vitamin D that are ‘normal’ and ‘deficient’. However, recent studies suggest that 50 nmol/ml 25-hydroxyvitamin D is a threshold level for deficiency.

Vitamin D deficiency occurs even in sunny parts of the world, such as Saudi Arabia and California, if people have limited exposure to sunlight. People with darker skin (who need more sunlight to produce vitamin D), those who routinely cover their skin and housebound people are at risk of vitamin D deficiency. In addition, people who live in countries in the far North (e.g. the UK) or South of the globe receive insufficient sunlight during the winter months to make adequate amounts of vitamin D. “During the winter months, absolutely, I think everybody should be given vitamin D supplements”, says Professor Hewison.

Striking a balance between sufficient skin exposure to make vitamin D and too much skin exposure leading to the risk of skin cancer is another important consideration. One approach that might help here is fortification of foodstuffs, as occurs in some countries.

A recent prospective study has shown that vitamin D supplementation has a “strongly positive effect” in reducing the incidence of rheumatoid arthritis. This large trial involved nearly 26,000 participants over a five-year period. “Over the first three years there was no real difference between the vitamin D arm and the placebo arm, in terms of effects on prevention of autoimmune disease, but once it went beyond the three years you did see a very strongly significant effect. There’s actually something like a 22 percent decrease …. in the reports of autoimmune disease in these individuals”, says Professor Hewison.

Many people are vitamin D deficient and given the strong link between low vitamin D levels and a wide range of human health issues” and vitamin D is a relatively cheap and relatively safe agent, then there is at least a good rationale behind improving the vitamin D levels for individuals”, says Professor Hewison.

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Autoimmune diseases are commonly treated with glucocorticoids such as prednisolone, prednisone and dexamethasone. Although these are successful in treating the inflammation of autoimmune disease, they also have side effects, including osteoporosis. “Vitamin D just acts in a very similar fashion and it doesn’t really have that downside when it comes to your bone function”, says Professor Hewison. It might be possible to combine vitamin D with glucocorticoids to treat autoimmune disease because they work well to raise the levels of regulatory T-cells. “These are areas of potential vitamin D function that we’re trying to explore here at Birmingham – new ways of potentially utilising vitamin D in combination with other treatments as a treatment rather than a preventative agent for autoimmune disease”, he adds.

Summarising the current position Professor Hewison makes the following points:

• Many people are vitamin D deficient and given the “strong link between low vitamin D levels and a wide range of human health issues” and “vitamin D is a relatively cheap and relatively safe agent, then there is at least a good rationale behind improving the vitamin D levels for individuals”.
• Further studies will clarify the causative role of vitamin D deficiency in some disorders but in the meantime “the message will be that [supplementation] probably has little benefit for those who already have plenty of vitamin D but it has potentially important benefits for people who are vitamin D deficient – and I think that would include quite a lot of people in the UK”.
• Food fortification will be an important way to combat vitamin D deficiency generally.
• Targeted supplementation will still be important for some groups. Frontline health care practitioners should identify people who are at risk of vitamin D deficiency (dark-skinned individuals, those who are housebound or who keep their skin covered at all times) and suggest vitamin D supplements

“Hopefully, 100 years after vitamin D was discovered [we will] finally cure rickets in the UK “, he concludes.

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The recognition that low vitamin D levels were linked with increased risks of a variety of health issues, including common cancers and autoimmune disease, prompted calls for prospective, randomised, controlled trials of vitamin D supplementation. The rationale for this was that systematic supplementation with vitamin should reduce the risk of developing such diseases. Such studies need to be continued for long periods and may fail to show any effects if the participants are vitamin D-replete at the outset rather than vitamin D deficient.

“Essentially, many of the trials have been null studies – they haven’t really shown any specific effect of vitamin D. Sometimes in subgroups, for example, if you look at people who are …… vitamin D deficient at start versus those who [have] sufficient that’s where you may see in an effect of vitamin D – in the vitamin D-deficient people”, explains Professor Hewison.

However, the VITAL trial,¹ has recently shown that “there is some potential for vitamin D protecting against autoimmune disease”, he says.

The trial involved nearly 26,000 participants. The treatment group received vitamin D 2000 IU per day over a five-year period. The initial results showed that vitamin D supplementation had no effect on cardiovascular disease or common cancers but when the incidence of autoimmune disease was examined, a different picture emerged.  “Over the first three years there was no real difference between the vitamin D arm and the placebo arm, in terms of effects on prevention of autoimmune disease, but once it went beyond the three years you did see a very strongly significant effect. There’s actually something like a 22 percent decrease …. in the reports of autoimmune disease in these individuals”, says Professor Hewison.

The trial targeted an older age group (over 50 years of age) and so provided no information about younger people who might be at risk of type 1 diabetes or multiple sclerosis.  “But nevertheless, this was a very strongly positive effect showing that vitamin D can help to potentially prevent the onset of autoimmune disease in a more elderly population. So, the message was really, if you can increase your vitamin D level when you get a bit older then you have the potential to protect against some forms of autoimmune disease”, he says.

“It’s interesting to know that when they broke down the autoimmune diseases into the different types …… it was primarily rheumatoid arthritis that vitamin D in this study protected against so it has most positive effect on that particular form of autoimmunity”, he adds.

The next important question will be whether vitamin D has any benefits in established auto-immune disease, i.e. as a treatment to reduce inflammation. This is likely to present a number of challenges.  Professor Hewison explains:

“We know that once autoimmune disease sets in the immune system almost tries to circumvent the effects of vitamin D. We know, for example, that memory immune cells that are produced in autoimmunity, in your synovial joints for example, are less sensitive to vitamin D than T-cells, immune cells ….. in your general circulation. So, the idea is that when the autoimmune disease sets in, it almost makes it harder for agents like vitamin D to work. So, you need higher levels of vitamin D to achieve an effect once the diseases become established. So, that’s another problem that we have to face … if somebody already has autoimmune disease do we have to increase vitamin D levels still further in order to get a positive effect?”

Reference

1. Hahn J et al. Vitamin D and marine omega 3 fatty acid supplementation and incident autoimmune disease: VITAL randomized controlled trial. BMJ 2022;376:e066452

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One reason for low levels of vitamin D is limited exposure to sunlight and countries in the far North or South of the globe receive considerably less sunlight during the winter months. “You can only really be assured of getting a lot of sunlight access if you live … around the Equator, so, yes, it could be simple geography”, says Professor Hewison.

Another important factor is skin colour. “You need more photons of sunlight to create the same amount of vitamin D if you have dark darker skin pigmentation. So, if somebody has darker skin pigmentation living in a country like the UK there’s always going to be a greater risk of vitamin D deficiency whereas if they lived in the tropics that probably wouldn’t apply”, he says.

“You do need to have your arms and face exposed to sunlight in order to make adequate amounts of vitamin D in any country”, explains Professor Hewison. Factors that prevent this level of skin exposure such as a dress code that requires complete skin coverage, using a large amount of sunscreen or simply living and working indoors all the time can lead to vitamin D deficiency.  Even in a sunny place this can happen.

Professor Hewison recalls:

“I worked for 10 years in California in Los Angeles. When I was checked for my vitamin D levels – and I’d been there for a few months …. I was vitamin D deficient and that was principally because I was working so hard I would get into the car, drive to work, to a covered parking lot ….. and I was rarely outside and so I wasn’t making as much vitamin D as you might suppose living in a very sunny place.”

A similar pattern is seen in Saudi Arabia where low vitamin D levels are common because people routinely cover their skin.

In 2015 the Science Advisory Council on Nutrition admitted that the UK was vitamin D deficient as a nation and that it could not be guaranteed that everyone would maintain adequate levels of vitamin D on their own. The period between October and April is when there is least sunlight – often easily remembered as the period between when the clocks go back (to GMT) and when the clocks go forward (to British Summer Time).  “That’s really the time when you should be actively supplementing with vitamin D.  … During the winter months, absolutely, I think everybody should be given vitamin D supplements”, he says.

Striking a balance between sufficient skin exposure to make vitamin D and too much skin exposure leading to the risk of skin cancer is another important issue. Professor Hewison says, “It’s important to recognize that we are aware of potential damage that can be done to our skin by being in in sunshine and that’s really why the supplement story has become quite prominent”.

Vitamin D deficiency is less common North America and that is partly because much of the continent is further south than the UK but also because milk and orange juice are routinely fortified with vitamin D. In addition, there is greater awareness of the risks of vitamin D deficiency and so many people also take supplements, especially the elderly. “But in North America there is still a high prevalence of vitamin D deficiency in African-American communities where darker skin pigmentation means that it’s it is more difficult to make vitamin D. So, it’s not the whole of the North America that is vitamin D replete – there are communities where there is still a significant problem”, he says.

One approach to this has been food fortification – an approach that has worked well in Finland where several common foodstuffs were fortified.

Professor Hewison says: “We’re making, I think, good inroads in the UK in trying to approach this issue.  I think it’ll become more prominent in the next few years principally because the technology to put vitamin D into foodstuffs has improved. So previously, like in North America, it used to be in orange juice and milk, for example, but not all communities use those products so something that may be more accessible is flour. If you can put vitamin D into flour, most communities use flour regularly and that could be a better way of getting a more even supplementation ….. of vitamin D in the general population.”

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Vitamin D acts in both the innate and adaptive arms of the immune system. In the innate arm it promotes non-specific antibacterial and antiviral responses to infection. In the adaptive arm vitamin D appears to act on T-cells to suppress the normal inflammatory responses to an infection.  The inflammatory response to infection is normal but a problem arises when there is a sustained and inappropriate inflammatory response that persists after the initial infection has abated and can damage tissues.

Professor Hewison explains:

“That’s where vitamin D has its … second function which is to dampen down inappropriate inflammatory responses and it does this by suppressing the T-cells that are known to be associated with this. These are Th1 (T helper type 1) and T helper 17 T-cells. It dampens them down but also importantly increases [the] expression of cells which are known as regulatory T-cells or T-regs and they … adapt the immune system and calm it down quite a bit. So, it’s promoting the good guys in inflammation and dampening down the bad guys – and in this way vitamin D could be quite an important factor in terms of just generally keeping your inflammation down and potentially protecting against this inappropriate response that can lead to autoimmune disease”.

Thus, if 25D levels are low, then less is available to macrophages, dendritic cells and T-cells, which, in turn, are able to make less activated 1,25-dihydroxyvitamin D (1,25D) and suppression of inflammation by the adaptive immune system is reduced.

To date, evidence for a link between vitamin D and autoimmune disease has come from association studies where people have looked at the levels of vitamin D in healthy individuals and compared them to levels in individuals who’ve got various autoimmune diseases, such as type 1 diabetes, Crohn’s disease or multiple sclerosis – and found that those individuals tend to have lower levels of 25D. Such associations are not necessarily evidence of causality.

It has been difficult to demonstrate a causal effect for vitamin D deficiency in autoimmune disease, Professor Hewison acknowledges.  “Essentially what you have to have is a randomized, controlled trial in which people are receiving higher levels of vitamin D to correct that vitamin D deficiency and then look to see whether they’re going to develop autoimmune disease – which is not easy to do given that it can take many years to develop something like multiple sclerosis or type 1 diabetes”, he explains.

What is a normal vitamin D level?

Much of this work hinges on achieving a normal vitamin D (25D) level. However, this is not straightforward because different levels of 25D are accepted as ‘normal’. Furthermore, there can be some confusion over the units that are used; some centres use nanomoles per litre (nmol/L) and others using nanograms per ml (ng/ml).

A large study by the National Academy of Medicine in North America in 2010 recommended a level of 50nmol/L (20ng/ml), but this was based exclusively on the effects of vitamin D on bone health and protection against rickets. If this were used as the threshold level (i.e. above 50nmol/L – healthy; below 50nmol/L – unhealthy) most people in the UK would be classified as vitamin D deficient, says Professor Hewison. The Science Advisory Council on Nutrition (SACN) in the UK therefore recommended that vitamin D levels should not fall below 25 nmol/L or 10 ng/ml.  However, many clinicians in North America, would say that neither of those two levels is really optimal – we should be aiming for an optimal level which would be higher than 75 nmol/L.  “Really, it’s unclear what is the best approach to take and certainly it’s very difficult when you’re carrying out randomised, controlled supplementation trials”, he says.  In many trials that are carried out in North America, participants often have baseline levels of vitamin D as high as 75 nm/L and supplementation studies take the levels higher still. A similar trial in the UK would start from a lower baseline level.

Mendelian randomisation studies might throw more light on this. Professor Hewison explains:

“I think there are some interesting studies that just come out recently which have involved something called Mendelian randomisation. Without going into greater detail, this is a way of saying that, …. as well as sunlight access and various foods, everybody has a genetic component to their vitamin D levels.  That’s genetic variations in the enzymes that metabolise vitamin D, the proteins that carry it around and so on…….. Some people will always be predisposed to having slightly higher vitamin D than others and if you use this tool on a wide range of people – hundreds of thousands of individuals – you can begin to link that genetic level of vitamin D to diseases and get some idea of the sort of level where you get better health effects. ……It seems very likely that 50 nmol/ml 25-hydroxyvitamin D is a threshold level for vitamin D. Really, I think we should be trying to get everybody above 50nmol/L.  Whether you need to go higher – I think that’s a matter for discussion, but certainly people less than 50 nmol/L – they do appear to be more strongly linked with disease risk than people who are over 50 nmol/L.”

Two recent studies have used a non-linear approach based on the notion that being supplemented with vitamin D means much more to somebody who’s deficient than it does to somebody who’s already got sufficient. “If you’re already at 75 nmol/L going up to 100, which is what some of the U.S trials have done, doesn’t give you a great advantage but if you’re down at 10 nmol/L and you go up to 35 that’s a big improvement. ….. I think that’s something we really need to get over – is the idea that the major beneficiaries of any vitamin D will be people who are deficient and there are plenty of them in the UK”, says Professor Hewison.

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For the past 30 years Professor Hewison has been engaged in a wide spectrum of vitamin D research ranging from aspects of clinical usage to intricate details of molecular biology. Important projects have included the development of new assays to measure the status of vitamin D in individuals and work on vitamin D in type 1 diabetes. This year (2022), he notes, is the 100^th anniversary of the discovery of vitamin D as a substance that could prevent the bone disease rickets (childhood osteomalacia). A recent review described what is currently understood about the broad range of vitamin D functions, including its interconnections with autoimmune disease.

Vitamin D is produced primarily by the action of sunlight on 7-dehydrocholesterol in the skin. “I know it’s difficult to believe in a country like the UK, but we still do”, says Professor Hewison. Additional sources of vitamin D include fatty fish, such as mackerel and herring, mushrooms and, in some countries, from foods that have been fortified with vitamin D. In the USA, for example, vitamin D is added to milk and orange juice.

Whatever the source of vitamin D it has to be converted into its active form and this is a two-step process.  First, 25-hydroxyvitamin D (25D) is produced in the liver and then a further hydroxylation in the kidney results in 1,25-dihydroxyvitamin D (1,25D), the hormonal form of vitamin D. Professor Hewison explains: “It’s released from the kidneys in very small amounts and acts on distal tissues and that’s primarily its function – to help you bring calcium and phosphate minerals from your diet into your bloodstream. That’s how vitamin D protects against rickets – it brings calcium in from our diet – and that’s the principal function of vitamin D when it’s a hormone, when it’s acting in an endocrine fashion. So, for many years, of course, that was how vitamin D was perceived but we now know that there are other actions of vitamin D as well”.

Over the past 20 years there has been much interest in the extra-renal metabolism of vitamin D. It is now known that many tissues can convert 25D to 1,25D and they also have the receptor for active vitamin D.

“So outside of the classical bone-protection, endocrine system there are many tissues that can both make active vitamin D and respond to it. One of the major areas where this is seen is in the immune system where cells such as macrophages and dendritic cells are able to make the active form of vitamin D and they can respond to it as well – and that can modulate immune responses in that individual. So, the idea here is, of course, if you supplement vitamin D you may be able to enhance those immune responses and, conversely, of course if you’re vitamin D deficient it may be that you have an impaired immune function”, he explains.

When everything takes place within the same cell it is known as an intracrine response.  Thus, if a macrophage produces active vitamin D and then responds to it and creates a specific immune response, that is an intracrine response. If the macrophage releases the active vitamin D to act on other cells in the in proximity, e.g. a T-cell (activated T-cells express the vitamin D receptor), then that is known as a paracrine response; “Something that happens by one cell producing a little bit of active vitamin D then acting on a an another cell in the locality”, adds Professor Hewison.

“Essentially, what these intracrine and paracrine responses are saying is that it’s possible to have a fully-fledged vitamin D system outside of the kidney/endocrine system and that … then creates a whole other spectrum of potential responses for vitamin D beyond its effects in protecting against rickets”, he says.

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