Vitamin D, explained by Prof. Adrian Martineau: the full interview

Adrian, thank you so much for joining us. My first question is: what levels of vitamin D are optimal in the blood?

I guess the first question to think of here is: what are you measuring? Essentially there are three major forms of vitamin D. What I call parent vitamin D: that's what we make in our skin in response to sunlight, or what we eat in the diet, primarily in oily fish. Then there's the major circulating metabolite, that's 25-hydroxyvitamin D, or calcidiol. And then there's the active hormonal form of vitamin D, which is 1,25-dihydroxyvitamin D. There are others, but those are the three main players. The parent form has got a very short half-life, so it's not very good as a biomarker of vitamin D status. And the active form is very, very tightly regulated according to your blood calcium levels, by a hormone called parathyroid hormone and various other factors. So the compound we measure when we look at vitamin D levels is the middle of those, the 25-hydroxyvitamin D, which has got a half-life of around one to two months.

But it's a big controversy about how much of that should be in the circulation for optimal human health, and there's a huge range of answers that you get from different people. The most conservative people would say that 25 nanomoles per litre is enough. I should just highlight that these levels are expressed in two different kinds of units, which can introduce some confusion. In the UK we tend to use nanomoles per litre. In the US people tend to talk about nanograms per mil. And they can convert quite easily between each other by multiplying or dividing by 2.5. So 10 nanograms per mil is the same as 25 nanomoles per litre. As I was just saying, you wouldn't find many people who say you need less than 25 nanomoles per litre. But the people who are more enthusiastic about vitamin D might say you need as high as 75, or even 100 nanomoles per litre, for optimal human health. There's a lot of controversy in the field about which is best.

So even in the research field, it's not exactly clear.

Absolutely. There's a lot of controversy. I think everyone's agreed you need at least 25 nanomoles per litre. But there are those who believe that you'll get significant extra benefits by going up above 50, or above 75, whereas other people might not agree so much. In general, the UK is the most conservative in terms of governmental advice, with the recommended level being that low, at 25 nanomoles per litre. Most European countries state a level of 50 nanomoles per litre. And then over in the US, you might find more people recommending levels a bit higher, 75 nanomoles per litre, the same as 30 nanograms per mil.

Is there a reason why people are more concerned about going higher? Is there risk there?

Absolutely. But it's not at that level of 75. The thing about vitamin D that distinguishes it, say, from vitamin C, is that it's a fat-soluble vitamin. With vitamin C, if you just took a big dose, you would basically wee it out within 24 hours. But with vitamin D and other fat-soluble vitamins, it's stored in the body. So you can get vitamin D toxicity if you take too much. The lowest level at which toxicity has been reported is around about 220 nanomoles per litre. But you do occasionally get people who have an underlying medical condition that renders them vitamin D hypersensitive. Somebody who's got sarcoidosis, a rare autoimmune condition, or somebody who's got undiagnosed hyperparathyroidism, could even become hypercalcaemic with a normal dose of vitamin D. That's pretty rare, but it does occur.

Because it's fat-soluble, does that mean it's stored in fat cells?

Fat and muscle.

So would someone who's more overweight be able to, or need to, take more? Or is it not weight-dependent at all?

There's a very strong association, actually, between having a higher body mass index, being overweight, and having lower circulating vitamin D. That's thought to be a sort of reservoir issue: basically, if you have a higher amount of adipose tissue, then more of your bodily vitamin D will be sequestered into that, and that will then take it away from the circulation. That's the thinking.

So it could even be that we need a recommendation for different body masses.

Well, it's well recognised that you need different doses to achieve a given serum level of 25-hydroxyvitamin D in somebody who's thin versus somebody who's fatter.

What do most people get wrong about vitamin D? What's the big mistake people make?

I guess one issue is around safety. People might say that you can take as much as you like and it won't harm you, and that's not right. If you take more than 4,000 units a day as an adult on a regular basis, then you could be at risk of having too much vitamin D, and that can then basically push up your blood calcium, which can have adverse consequences, particularly for your renal function. The second thing you see online is the perception that vitamin D is a kind of panacea for all ills. Maybe 20 years ago we had more optimism about that being the case, but there are more and more clinical trials coming out now that suggest that perhaps some of that optimism wasn't justified.

We've spoken about the effects of it being too high. What if it's too low?

That's certainly bad for your health as well, and the impacts on human health really depend on how low it goes. You can have situations where vitamin D levels are undetectable, and in children that can actually cause death. One of the key functions of vitamin D is to support calcium absorption. So particularly for infants who are being 100% breastfed by mums who are vitamin D deficient, they can have extremely low vitamin D levels, and that can result in seizures due to low calcium levels in the blood, or heart problems, hypertrophic cardiomyopathy, which basically arises because the heart muscle can't contract, because you don't have enough calcium circulating, and you need calcium to support muscle contraction. That can cause a fatality. So at its most extreme, vitamin D deficiency can actually cause death.

If you then go up the age groups a little bit, to toddlers, the classic manifestation of vitamin D deficiency is rickets. That rickets phenotype can be rescued by having enough calcium in the diet, so usually young children have rickets because they've got a combination of very low vitamin D levels and low calcium. That basically causes problems with development of the growth plates, and can cause classic skeletal deformities, knock knees or bow legs and various other classical deformities, and that can ultimately lead to failure to grow and develop joints in a healthy way.

As you get older, the main complication of vitamin D deficiency relates to thinning of the bone: osteopenia, osteoporosis. Again, this reflects the key role of vitamin D in supporting absorption of calcium from the diet. If you can't do that, you end up less able to mineralise your bone, and that puts you at risk of fractures. And then the final one to mention is osteomalacia. That's a condition caused by low vitamin D levels in which you can't get enough mineralisation of bone. You can get what are called pseudo-fractures, and in extreme cases you can get problems with your proximal muscle strength, again because you need vitamin D to absorb calcium and you need calcium for optimal muscle function. People who have that rather extreme manifestation of vitamin D deficiency would have problems, for example, standing up out of a chair. They have a classic sort of waddling gait. That's the rather extreme end of the vitamin D deficiency spectrum. These are all recognised as what I call classical complications of vitamin D deficiency.

There's another whole group of so-called non-classical effects of vitamin D, which is a bit more controversial. These are really based around basic science research showing the presence of the vitamin D receptor, and the one-alpha-hydroxylase enzyme which activates vitamin D, in a whole load of tissues that aren't related to calcium: in the brain, in the gut, in the lung. For several decades now there's been a big research effort to try and elucidate these non-classical effects of vitamin D on the immune system, on cancer risk, on diabetes risk. Although epidemiological studies have shown associations between low vitamin D status and increased risk of diabetes, of particular cancers, of multiple sclerosis and other immune-mediated disorders, clinical trials certainly haven't shown a benefit consistently for prevention of cardiovascular disease or hypertension. So a lot of those other disease associations are a bit more controversial. Although I'd say the evidence around multiple sclerosis is quite strong, and the evidence around some autoimmune diseases is also quite strong.

So it's growing in the less-researched areas. I remember seeing studies during COVID as well, how vitamin D might influence that, but that's much newer research, right?

There have been several of these so-called mega-trials: big population-based randomised controlled trials where adults are randomised to receive vitamin D supplements or dummy tablets. Most of those haven't shown benefits for the major outcomes that they were powered to look at, cardiovascular disease and cancer incidence. There are a few smaller trials that have possibly shown a benefit for prevention of progression of colonic polyps to colon cancer. There's a little bit of evidence from one of the larger trials, VITAL in the US, that vitamin D might have benefits in terms of reducing risk of autoimmune disease. But otherwise the results have been largely disappointing. I think this has driven a contraction of interest from governments and funders in funding larger research studies into vitamin D.

How does vitamin D from sunlight differ from supplements?

Basically there are two forms of parent vitamin D: vitamin D3 and vitamin D2. Vitamin D2 has got an extra methyl group, an extra CH3, and that comes basically from fungal and plant sources. Whereas vitamin D3 is the stuff that we make in our skin when sunlight shines on it, and it's also the stuff that we eat when we ingest oily fish. In fact, fish make their vitamin D by eating plankton, who get theirs from the action of sunlight. So basically all of it originally comes from sunlight. The vitamin D you make in your skin will always be D3. The vitamin D in your diet might be D3 or might be D2, particularly with supplements. Most supplements are vitamin D3, because the 25-hydroxy form of that has got a slightly longer half-life than 25-hydroxy D2. But some supplements are intentionally D2, because that's the vegetable source that's appropriate for vegans. Actually most of the D3 comes from sheep's wool, so it's not appropriate for vegans, but it's fine for vegetarians. So that's one thing: the chemical composition of the vitamin D might vary between sunshine and diet, if you're taking a lot of D2 in the diet, because you get D3 on the skin.

The other big difference relates to the pharmacokinetics. That's basically the pattern of 25-hydroxy D in your bloodstream that you get in response to ingesting something versus having it made in your skin. With vitamin D made in your skin, you're not going to get very precipitous rises or falls in your 25-hydroxy D level. And if you take a daily supplement, or you just have it in your diet on a regular basis, you simply will have a steady-state vitamin D. By contrast, if you take intermittent, very large doses of vitamin D, which is sometimes used in medical practice to help people who might forget their daily tablet, you can just give a big injection or a single large dose, that does result in a quite steep increase in 25-hydroxy D level followed by a gradual decline. And there's a growing body of evidence that that's not the best way to get your vitamin D, because it can have unanticipated negative effects on vitamin D metabolism outside of your kidneys and your gut. So basically, if you take a daily supplement of vitamin D3, it will be roughly similar to having a daily dose of sunshine on your skin.

Do you know the dose people should take in order to get to those optimal levels? We said at the start, it depends which "optimal" you go for.

Speaking of adults: if you're aiming to get to 25 nanomoles per litre, 10 nanograms per mil, which is the lowest recommended level, and you don't have an extraneous source of vitamin D, so you're not exposed to the sun and you don't have much in your diet, then 400 units, or 10 micrograms, a day. That's another useful conversion factor. When you talk about the amount of vitamin D that you take, there are again two units of measurement, the microgram and the international unit. 10 micrograms is the same as 400 international units. If you wanted to get your level above 75 nanomoles per litre, 30 nanograms per mil, then you probably need to take around about 2,000 units, that's 50 micrograms, obviously depending on your body mass index. And if you're trying to get to 50 nanomoles per litre, 20 nanograms per mil, you take around about 1,000 per day. You shouldn't take over 4,000 units per day; that's the maximum recommended amount. All those doses apply to adults, so you have to scale them down for kids. Basically, you're never going to go wrong by taking 400 units per day. Even small children can take that dose of 400 units per day. It's just that if you want to get higher than 25 nanomoles per litre as an adult, you would need to take a bit more.

What would be cool is if we made a calculator where you could enter your body weight or BMI and it could tell you the optimal dose to take. Maybe that's over-complicating it.

You could build a model, but you'd have to put in a few other variables as well. Genetics has actually got a bigger influence on this. The main protein in your body that binds to vitamin D is called vitamin D binding protein. Depending on which form you've inherited from your mum and dad, you can see two or three times higher levels in response to supplementation than somebody with a different form.

So it's essentially a gene, you have one or the other, and one will mean you're much more responsive to vitamin D supplementation?

It's not binary; there are actually six different forms. But yes, if you look at the extremes, the one that's associated with the tightest binding versus the one associated with the loosest binding, then you do see about a two- to threefold difference in the 25-hydroxy D response to supplementation.

Is it possible to match up a dose of 4,000 IU in a supplement to an amount of time in the sunlight?

That is tricky. And the reason it's tricky is because not all sunlight is the same. It's the ultraviolet B in sunlight that stimulates synthesis of vitamin D in your skin. It's the same stuff that makes you tanned. So if you're getting tanned, you're making vitamin D; that's a very rough rule of thumb. But the amount of UV that you get from the sun depends on a number of factors. The first one is latitude. If you're at higher latitude, further away from the equator, that sunshine has got to cut through a lot more atmosphere before it hits the Earth's surface, and that filters out UVB. So even if you went up to the Arctic at the moment, you'd have a really long day, but you wouldn't necessarily make much vitamin D, because the sunlight's coming in at such a shallow angle. The second factor is the time of day. Around the middle of the day the sun's more vertical, so it's got less atmosphere to travel through, so there's a higher UVB amount. A third factor is how much of your body is exposed. If it's just face and hands, you obviously make a lot less than if you've got a T-shirt on, or even if you take your T-shirt off.

And then a fourth factor relates to skin pigmentation. The human body makes a pigment, melanin, which is basically designed to reduce the damage that ultraviolet light can cause to your DNA. At equatorial latitudes, the risk of getting skin cancer is high because of the very intense sunshine, and your risk of becoming vitamin D deficient is low because of the intense sunshine. So natural selection would favour people with more pigmented skins. Whereas if you're living at either pole, the opposite is the case: your risk of skin cancer is rather low because the UV's not very intense, but your risk of vitamin D deficiency is rather high. That's probably natural selection; it explains why people toward the poles have got paler skins and people toward the equator have got darker skins. But if you've got a darker skin and you're living in a northern or southern climate, away from the equator, that means you're less able to make vitamin D for a given amount of sunshine. And that's why we see people of African or South Asian origin being at higher risk of vitamin D deficiency here in the UK.

So the plot thickens, from body mass to also skin colour, in how much you might need to take.

What about blood work? Should people measure their vitamin D and then supplement in response to that?

That's a tricky one. From the perspective of the National Health Service, it's expensive, and probably difficult to justify in terms of health economics, the amount you spend on that as a health service versus the health benefit. Obviously, if people have got their own personal funds and they want to measure it, then it is one way to be able to accurately titrate the dose you're taking against your target concentration, particularly if you've got a target concentration in mind. I would say, though, that there are quite a range of assays out there, and if you're going to do that, then you should use a reputable one. A good way of finding out if it's reputable is to look at the method that's used, and a method that involves mass spectrometry, liquid chromatography tandem mass spectrometry, is going to be more accurate than other ones. There are some tests out there that will measure a blood spot: you can just put a blood spot on a piece of paper, send it off in the post, and they will use this high level of technology, and it can give you quite an accurate answer. But it will cost you 25 quid.

I suppose what you've really got to think about is what else would that money go towards. You can probably buy years' worth of vitamin D supplements for that. Would that just be a better spend for the population?

So there are these rules of thumb. 400 units will get you above 25 nanomoles per litre. 1,000 will get you to 50. 2,000 will get you around 70 to 75, roughly. And so you could just use those. The only time you would want to measure it from a medical perspective, and you'd also want to measure calcium, is if you have one of these underlying conditions that makes you sensitive: sarcoidosis, or hyperparathyroidism.

Do you know how long it would take to get to those optimal levels on those doses? Or is it the same for everyone?

As a rule of thumb, it's about three half-lives to reach steady state with a daily dose. So if you're taking a daily dose, it might take you two to three months to get to your target concentration. There's a shortcut: you can take a big bolus dose, a loading dose, and then take a daily dose after that. That would get you up there in a week. But as I said before, taking those doses does give you these rather unphysiological fluctuations in 25-hydroxy D. So unless you were doing that under medical supervision, I wouldn't recommend it.

And that's when the risks you talked about earlier come in, when you're way above the blood levels you should be?

I think the risk is best described in people who take these intermittent bolus doses long-term. Somebody who once every two months takes a whacking dose of vitamin D: we know that's not the best way to have it. Under medical supervision, if you were found to have a very low vitamin D level, your doctor might well prescribe you a single loading dose to get you back up to where you need to be, and then a daily maintenance dose. That would be completely appropriate.

It's about having the regular up and down. And if you just take a supplement every day, you're basically at consistent levels.

Yes. You'd then be at steady state.

For people that are inside all day, or in the winter here, that's really the most appropriate time for a vitamin D supplement. Do people need it in the summer?

Guidance from the UK Department of Health is that all UK residents should consider taking 400 units a day over winter and spring, because we know that's when deficiency is pretty common. But if you're in a risk group for vitamin D deficiency, then there is a recommendation to consider taking that all year round. Those risk groups are people who don't get out in the sun, so people living in institutions where they don't get outside; pregnant women; and people of South Asian or African ethnic origin, people who have got more melanised skin, will be at higher risk of deficiency through the year and might want to consider taking a supplement through the year.

I assume you can't get too much vitamin D from the sun; your skin just stops making it?

That's right. The whole process is regulated quite tightly, so you can't get vitamin D toxic from the sun.

It's only taking it orally that you can take too much.

Or if you have a big injection.

Do you take a vitamin D supplement, and if so, at what dose?

I think, when I remember, during the winter, 400 units. Not in the summer or the autumn.

Does time of day matter with vitamin D? I've seen something online that says, because you get it from sunlight typically, your body would expect it more in the morning.

No. The half-life's long enough for that not to matter.

So it's essentially absorbed at an even pace?

Well, you'd absorb it; it's very well absorbed, actually, so you absorb it within an hour or two of ingesting it. But your circulating level of vitamin D metabolites will maintain a steady state, so you're not going to have a trough. It's not like an antibiotic that's got a short half-life of six hours or something. You won't get a trough in vitamin D concentrations if you miss two days.

Was there any vitamin D misinformation you've seen online that you're just like, that is so wrong?

I guess just those two things that I mentioned earlier.

What research has not yet been done on vitamin D that you would like to see done?

I mentioned earlier these so-called mega-trials, big population-based trials looking at effects of vitamin D on these non-classical outcomes. One of the limitations of those is that they tend to have been done in populations where baseline deficiency wasn't that common. A lot have been done in the US, New Zealand, Australia, where many of the participants already had 25-hydroxy levels above 50 or even 75 nanomoles per litre. I think ultimately some of their null results might be explained by the fact that there weren't many deficient people in those trials. We and others have tried to get a very large population-based randomised trial funded here in the UK, but we haven't been successful. I think that is a gap. It's possible that if similar studies to those done in the US, Australia and New Zealand were done in the UK, the results might be different, simply because there's a lot more deficiency at baseline.

Or somewhere like Sweden or Norway?

You might think that, but actually they've got some of the best vitamin D status in Europe. Culturally they have a lot of oily fish in the diet, and there's a big culture of taking cod liver oil supplements. Paradoxically, if you look at the map of Europe, some of the best vitamin D status is actually up in Scandinavia.

I remember when I went to Sweden I saw a lot of vitamin D ads everywhere, so I thought they must clearly be on it.

And there's a big tradition of having cod liver oil supplements as well. That contains vitamin D, vitamin A and omega-3s.

What do you think about vitamin K2 being added to vitamin D supplements?

There's a lot of interest in this at the moment, and there's a biological rationale for it on first principles, because vitamin K2 is involved in the carboxylation of a protein called osteocalcin, which is part of the pathway of bone mineralisation. Basically, vitamin D supports the absorption of calcium; vitamin K2 helps to activate some of the factors that then allow that calcium to be deposited in bone. So there is a theoretical basis for it. However, I'm not aware that there's a lot of vitamin K2 deficiency out there. And the only randomised controlled trial I know to have compared vitamin D alone versus vitamin D plus K2 on bone outcomes did show a small effect on carboxylated osteocalcin, but didn't have any downstream effects on measures of bone mineral density. So I think it's more of a theoretical benefit that hasn't really been borne out in the randomised controlled trials conducted to date.

Is it only the one trial, or are there multiple?

I think there are other studies, but that's the largest one that I'm aware of.

Based on your research, if we got everyone's vitamin D levels to the optimal level, what impact do you think that would have on the country as a whole?

Based on my research, not much, because I spent about 20 years showing that vitamin D didn't do too much in terms of boosting your immunity to various different respiratory pathogens. But my research aside, and looking at that of others, I think what would definitely happen is that if you could find a way to improve vitamin D status, particularly in groups at high risk of deficiency, you'd be able to eliminate rickets. There are over 100 diagnoses of rickets in the UK every year, so that would be a major public health benefit straight off. Around bone health, most of the evidence from randomised controlled trials suggests that the benefits of vitamin D on bone mineralisation are best seen when you take calcium as well, alongside the vitamin D. So giving vitamin D on its own might not necessarily have that marked an effect on fracture rates, but it might have a subtle effect.

And then there are these other two indications around immune function. The evidence around vitamin D for multiple sclerosis prevention: there never will be a randomised controlled trial, because the outcome is too rare, so we have to rely on less direct evidence, Mendelian randomisation studies that look at genetic factors, and observational studies alongside basic science studies. All of those are quite strong; they all point in the same direction with MS, that vitamin D is likely to have a benefit in terms of preventing that. And then the last one, unproven but looking reasonably optimistic, is some other autoimmune diseases as well. Those are a little bit more speculative. The benefits in terms of preventing rickets and osteomalacia are unequivocal, and will be a big public health benefit.

That's everything. Thank you very much, I really appreciate it.