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The Vitamin D Controversy

The vitamin D controversy: An interview with Professor Michael Holick

Professor Michael Holick, the world's leading expert on vitamin D research, responds to some of the more recent negative studies that seem to be so readily picked up by the media.

He then goes on to provide a roundup of some of the exciting, upcoming trials of this vitally important nutrient.

Covered in this episode

[00:20] Welcoming Michael Holick
[00:34] Introducing today’s topic: new controversial evidence on Vitamin D
[01:16] Discussing the Vital D Study
[04:18] Discussing the validity of the Bolland and Reid review and vitamin D’s effect on bone health in the elderly
[07:47] Discussing the D Health Study and the importance of measuring baseline levels of vitamin D
[10:27] Vitamin D supplementation in overweight and obesity
[12:39] Continuing the discussion on baseline and treatment level measurements during a vitamin D study
[14:44] Why do we do poorly designed trials that we know will fail
[17:07] Vitamin D dosing and toxicity
[19:43] Safe sun exposure
[23:11] Vitamin D and the prostaglandin cascade
[25:50] Clinical signs of vitamin D toxicity
[27:19] Discussing genomics of vitamin D and immunity study 
[30:41] Vitamin D actions of autoimmune disorders
[35:58] Vitamin D interventions for various disorders
[40:37] Medications that affect vitamin D levels


Andrew: This is FX Radio. I'm Andrew Whitfield-Cook. And with me on the line today is none other than the esteemed Professor Michael Holick, truly the world expert in vitamin D. So welcome, Michael.

Michael: Pleasure to be always with you, Andrew.

Andrew: Thank you. Michael, there's been some quite controversial papers being published just recently regarding vitamin D. So what I'd like to do today is to do a sort of roundup of some of the upcoming trials and maybe some of the previous trials that have happened and we'll talk more about this vitamin D controversy, the sort of really taking the wind, very interesting that the media always takes the negative aspect on this, it’s like a tall poppy syndrome. But you've got some very exciting things coming up in the future that might sort of change that viewpoint. But let's go through some of these upcoming trials around the world that I've sort of been reading about. 

First thing, the Vital D study where they're giving, you know, 2000 IU plus, sorry, or omega-3 fatty acids and there are sort of four arms here. Can you give a wrap up of what that study is looking at and your opinion of whether you think it's going to have a positive or negative outcome?

Michael: Yeah, that's a good question. I'm a consultant for this activity and also in the process of applying for an ancillary grant to look at some specific issues regarding some of the subjects that are getting the 2000 units of vitamin D. But the long story short is that Dr. Manson, Joanne Manson applied for this grant, this very large grant, and it's going to be where they're going to be sending out to people throughout the United States, and these are adults over the age of 50, either 2000 units of vitamin D a day, a placebo, and/or omega-3 fatty acids and asks the question, does taking omega-3 fatty acids really have any impact on reducing risk of cancer and heart disease? And the same is with vitamin D.

Andrew: Yeah.

Michael: One of the issues, however, is that because the Institute of Medicine has recommended for adults over the age of 70 that they could take up to 800 units a day as their RDA, the placebo group could take up to 800 units of vitamin D a day.

Andrew: Right.

Michael: And therefore, the question will be is that if enough of the placebo group has already taken a vitamin D supplement, you know, will you be able to see a significant difference of 800 versus 2000 units a day? And my understanding is that a majority of the subjects, in fact, are not taking a vitamin D supplement. The good news is that they're going to be measuring baseline and study over the period of time of this next five years blood levels of 25-hydroxyvitamin D so that they'll be able to at least look at these different outcomes, which is colon cancer and various other cancers and heart disease, stroke, hypertension, bone health and relate it to their baseline 25-hydroxyvitamin D and if there's any improvement whatsoever to their, you know, mid-study or end of study, 25-hydroxyvitamin D level. 

They're also going to be measuring bone formation, bore reabsorption markers. They're going to be measuring markers of inflammation. So there should be a huge amount of information that could flow from the study. And now that they're going to have blood levels of 25-hydroxyvitamin D, they may be able to put it all together.

Andrew: Yeah.

Michael: But like I said, the concern, of course, is the placebo group could take up to 800 units a day…

Andrew: Yeah.

Michael: …and that in itself is likely to have an effect.

Andrew: Yeah, yeah. That's a really interesting thing that you mentioned about high potential, we’ll talk about that a little bit later. But when we last spoke, we were talking about the review that Bolland and Reid did in New Zealand, and they basically trounced vitamin D just saying there's no point in looking at it further for bone health and things like that. But I think you said that they didn't do prior and in-study measurements of vitamin D levels.

Michael: Correct.

Andrew: Yeah.

Michael: So that's part of the problem I mean, not that they didn't do it. But what they did was they did basically an analysis.

Andrew: They did an analysis.

Michael: They did not do a new study, which is kind of what the press implied.

Andrew: Yeah.

Michael: But they simply looked at previous studies, most of those studies were using 400 units of vitamin D a day, so an inadequate dose of vitamin D. And they didn't really do a very good job in measuring baseline or end-of-study 25-hydroxyvitamin D, didn't measure bone absorption and inflammation markers. So there are a whole host of reasons why just putting a bunch of studies together and saying that, "In some, these studies don't demonstrate benefit," well, not a surprise. I mean, they weren't getting the kind of vitamin D that we think you need to satisfy your body's vitamin D requirement even for bone health.

Andrew: Yeah. One of the other things I pulled out looking at their data was they had one of the trials that used a higher dose of vitamin D as having a negative outcome and put it in the negative box if you like. But that trial was the one where they gave 500,000 IU once a year and looked at falls and they had an increase in falls. Well, it's not actually the case where that's necessarily negative. What it shows is that vitamin D works very, very, very quickly on muscle and it can't work quickly on bone. Do you remember that study?

Michael: Exactly. Yeah, these are elderly nursing home residents that probably don't see the light of day, all of a sudden they're vitamin D deficient and they're now getting this energy boost of vitamin D…

Andrew: Yeah.

Michael: …and feeling a heck of a lot better, being more active, and therefore, more likely to be at risk of falling and therefore fracturing.

Andrew: Yeah.

Michael: Now, if you look at the data set, they showed that there's a 31% increased risk for fracture at three months, but no significant increase risk for fracture and falling at about six months.

Andrew: Later on. Yeah.

Michael: So, you have to wonder about that data set, and I agree with you that it was probably the likelihood that they corrected the osteomalacia, aches and pains in bones and muscles and muscle weakness. Proximal muscle weakness is a classic example for vitamin D deficiency. People feel better, so they're going to be more active, they're likely to fall. They're elderly, they have low bone mass, and so they're going to fracture.

Andrew: And it's really interesting that watching the sort of fallout from that study and the comments from other people around the world, and then they answer those comments and they basically try and trounce each comment. It's very, almost vitriolic.

Michael: Yeah. And also, you know, there are other studies that were done way before they did the study in Scandinavian countries and they showed that 500,000 units twice a year in nursing home residents definitely maintain bone density and reduce risk of falling and fracture.

Andrew: Wow. There's a lot more that needs to come out about the results from that meta-analysis, that's for sure. 

One other study that I've picked up on recently is a local one to me, it's in Queensland and it's called the D Health Study, run by the Queensland Institute of Medical Research. Can you give us a wrap up on what that trial is going to be looking at and what your forecast is for the future of it?

Michael: Yeah, I mean, I think that, you know, they're interested in giving these high doses of vitamin D. I think the intervention is 100,000 units, right, every 3 months for a year. So it's about 1100 units a day. And they looked at, you know, blood pressure markers, you know, and various other issues regarding cardiovascular disease, and basically concluded that there wasn't any significant benefit. But yet, when they looked more carefully at the data, those that had the lowest blood levels of 25-hydroxyvitamin D, it appeared to be a risk factor for hypertension.

And so herein lies the problem with these studies. You really need to look at the baseline 25-hydroxyvitamin D levels. If your vitamin D sufficient, you know, and now you're giving vitamin D, you're less likely to see a significant benefit. There are a lot of studies out there where individuals that are significantly vitamin D deficient if you improve their vitamin D status, that they did quite well.

Andrew: Yeah. And I think this is, I guess, a bit of a caveat in, you know, testing baselines. What we need to do in these trials is looking at baseline studies of vitamin D compared to treatment levels. But we don't need to do that in practice every day. We need this data so that we can pull out the effects. But when we're looking at a clinical application of it, we're testing way too much. We need to be asking more simple questions like, "Do you go out into the midday sun for five minutes?" Is that right?

Michael: Amen. Yeah, and not only that, but you know, I think that, to me, it's a little bit ingenuous to think that, you know, you've been vitamin D deficient for a very long period of time and you really increase your risk for many of these chronic illnesses and then expect to just start taking vitamin D for a couple of months or even a year or two and expect to see a dramatic reversal, you know, many of these outcome measures.

Andrew: Yeah.

Michael: And that's why we continue to promote adequate vitamin D from birth until death because we think it really does play a role in maintenance of good health.

Andrew: Yeah. One of the other things that I have a question about these trials where they're using, you know, what we would term up to be appreciable levels of vitamin D for most people or for many people, but unfortunately, the sad fact of our Western society, particularly in America and Australia, is that we are way overweight. So when we're looking at 2000 IU as an intervention, a daily intervention, in obese people, we may have to times that by 3 to 5 times to get the same sort of effect as in somebody of a normal body mass index. So, again, when we're looking at these trials when you're looking at a larger population, half of them at least are going to be way overweight. Can you just take out half of those, are they going to be non-responders, or like how do you answer that question with this sort of dose?

Michael: Right. So that is absolutely an issue. And as you probably are aware, there was this very interesting New England Journal article that came out by Dr Powe looking at blood levels of 25-hydroxyvitamin D and the vitamin D binding protein and then relating it to the bioavailable 25-hydroxyvitamin D. 

Andrew: Right.

Michael: And you know, all of that probably is playing a role as well but like you said, we know that if you have a BMI of greater than 30 that you have a marked decrease in your blood level of 25-hydroxyvitamin D and to be able to treat and maintain Vitamin D sufficiency, they need too up to five times more vitamin D. So you're right, we think that a good dose of vitamin D is 2,000 to 3,000 units a day. That's what I have all my patients on. I personally take 3000 units a day. Blood level in the range of 100 to 125 nmol/L. And if you're obese, you may need to be on 6,000 to 8,000 units up to 10,000 units of vitamin D a day, just to raise your blood level into this range that we think is the healthy range. And most studies don't take that into account.

Andrew: So again, in a trial situation, it's really important to do baseline and treatment levels. And maybe some of these trials should be looking at the effects that are seen when you raise the serum level of vitamin D to a certain level.

Michael: Exactly.

Andrew: Yeah. Is there any trials coming up looking at that?

Michael: And that a baseline level of 25-hydroxyvitamin D, and, you know, probably mid-course study to be sure that they're compliant and that you're getting the desired level of 25-hydroxyvitamin D and certainly at the end of the study…

Andrew: Yeah.

Michael: …to be sure that level is in what we consider to be the healthy range, which the Endocrine Society recommends is about 100 to 150 nmol/L.

Andrew: Yeah, it'd be very interesting to look at that as an intervention. But I also take that point that you made previously and you make again is that the review by Bolland didn't even look at the measurements and so you can't even be sure that people actually took the supplements. It's a big issue with compliance, as we know.

Michael: Exactly. The two largest studies that have looked at vitamin D and bone health, one is the RECORD study out of Great Britain, and the other is the Women's Health Initiative. And both of those studies they didn't have baseline and end-of-study 25-hydroxyvitamin D levels, and they admitted that probably upwards of 50% to 60% of the time these people weren't taking what they were supposed to be so that their compliance rate was very low.

Andrew: Yeah, in fact, I also read in one of the studies, there was a negative study recently, and it might have been the one looking at hypertension with no effect and they said...even in the abstract, they say that this study has got limitations by the adherence to take the active.

Michael: Yeah, I mean, you have to kind of wonder why these things get published.

Andrew: Yeah.

Michael: But if you don't take it, why would you expect it to work?

Andrew: So I have to ask this next question. And you know, it's a very cynical question to ask, but I have to ask it. If investigators continued to use these low doses in trials...we know that we've got issues with obesity. They're not measuring by baseline nor treatment levels, surely they've got a fair idea that they're going to have, you know, a poor outcome or a negative outcome in the trial. Why do they continue to churn out these trials?

Michael: Well, part of the reason is that the IRBs had been very concerned that if the Institute of Medicine recommends 600 units for most children and adults, 800 units for adults over the age of 70, with a safe upper limit of 4000 units, a nd before 2010, the safe upper limit was 2000 units. So the IRBs were reluctant to give approval to be giving these higher doses. And furthermore, there continues to be this issue that if you get a blood level of 25-hydroxyvitamin D that's above 115 nmol/L they have what's called a U-shaped curve.

Andrew: Yeah.

Michael: So that whereas everybody agrees that if you increase your Vitamin D intake, if you're vitamin D deficient, you reduce your risk for mortality and you maintain that lower risk. But then all of a sudden at around 150 nmol/L they say that now all of a sudden mortality risk is going up, or that risk for cardiovascular disease is going up, or cancer is going up. So, people have been reluctant to be giving higher doses getting much above 150 nmol/L, which is where we think people should be at between 100 and 150 nmol/L to have the beneficial effects of the vitamin D.

Andrew: Right. So it's more of sort of erring on the side of being scared or, you know, caution, rather than looking at therapeutic side of things.

Michael: Exactly. Yeah, I think that's the major issue and that many of these trials, a lot of the investigators don't have very much clinical experience with vitamin D, and they're new to the field, and so they're not really sure exactly what they're doing. And so, as a result, they kind of, you know, use the Institute of Medicine's recommendations and, you know, they feel comfortable in doing so.

Andrew: Okay, so just to, if you like, answer a bit of a whimsical question on that safety aspect. With your vast expertise in using vitamin D over decades in patients, many hundreds and hundreds of patients, where do you see toxicity being an issue?

Michael: Yeah, I typically give all my patients, and we published two papers on this now, up to 6 years I've done this, is to give 50,000 units once a week for 8 weeks, that's equivalent to about 6,000 units a day, fill up the empty vitamin D tank. 

Andrew: Yep.

Michael: Even if they're vitamin D sufficient, I give them 50,000 units once a week for 8 weeks, they may raise their blood level to maybe from about 50 nmol/L or 60 nmol/L up to about 80 nmol/L to 100 nmol/L. No consequence, no toxicity. I then put my patients on 50,000 units every 2 weeks forever, which is basically equivalent of 3,000 units a day. 

Andrew: Yep.

Michael: And again, we published a paper, Archives of Internal Medicine, 2009, and showed that there was no toxicity, and that everybody was able to maintain healthy blood levels above 75 nmol/L, most around 100 to 150 nmol/L.

Andrew: Right. Okay, so if I can, not a devil's advocate question, but just to sort of check you on that. So you tend to give larger bolus doses less frequently. And some trials are sort of saying, well, some investigators are asking the question, is it reasonable that we give higher doses less frequently or should be looking at lower dosages more frequently, which obviously, you've got an issue with compliance doing that. What do you find to be more effective in your practice?

Michael: Sure. Well, the reason I do this is because in the United States, the only pharmaceutical form, believe it or not, is 50,000 units.

Andrew: Right.

Michael: And so, as a result, because I give it as a prescription, and because patients want it as a prescription, they're more likely to take it and be compliant with it. And the pharmacy will also call them on a monthly basis to tell them, "By the way, pick up your prescription," that it's very effective.

Andrew: Right.

Michael: However, with those that wish to take a supplement, I just tell them, go to your local pharmacy and to get a 2000-unit supplement and then to supplement that with a multivitamin that contains 1000 units of vitamin D. So they're getting about 3000 units a day, and it works identically.

Andrew: Yeah. And I think that there's one huge thing in my book is that we need to also advocate to patients and that is the safe sun exposure policy.

Michael: No question about it. I mean, you know, there was a study done in Africa where they showed that Maasai warriors that are outside all the time, their blood levels, on average, were about 115 nmol/L, which really tells us evolutionary, I think, where we all should be. We developed an app, dminder.info, that is for free. You can use it now in Australia or anywhere on the globe and it'll tell you how much vitamin D you're making based on your skin type, time of day, season, and your latitude. So, and I usually recommend, always protect your face, most sun-exposed, most sun-damaged, but arms, legs, abdomen, and back, it's perfectly fine. And that the amount of skin that you expose, the more vitamin D that you make, so the less time you need to be outside.

Andrew: That's right. I've got to say, I use that DMinder app and, you know, as you know, I live in Queensland, Australia, so we get scorching sun up there, and also, along with that, we have the highest incidence of melanoma in Queensland as well, which is genetically linked. But this DMinder app is very useful because you can put in your skin type. And that's what I find really, really unique about this app is that so people are various...let's say the fairer skin types who have got, you know, fair skin, red hair, freckles, and who are at increased risk of melanoma, then they can put that into the app and it will tell them to decrease the amount of time that they get sun exposure.

Michael: Exactly. So we built into that app a warning sign so that we say, "You've made this amount of vitamin D, you now have had enough sun exposure, wear sun protection or get out of the sun."

Andrew: Yeah, yep. I love that safety aspect it's brilliant. I'm a really big advocate because, you know, this is the thing about sunlight is we get it for free. We evolved as beings on this earth, not salamanders, we should be, you know, exposing our bodies to sunlight. But obviously, with the fairer skin types that have evolved over millennia, and now we're encroaching on the hotter climates, which is not where we evolved the fairer skin types.

Michael: No question about it. I mean, even neanderthals, they now know from the genetic analysis that they had a mutation of their melanocyte-stimulating hormone receptor, and therefore, were likely to be Celtic and redheaded.

Andrew: Oh, really?

Michael: Yeah. So they believe now these dark-haired neanderthals that we've always been brought up to believe, you know, were these, kind of, hairy creatures, they could never have existed in Europe…

Andrew: Ah.

Michael: …they would have died early because of vitamin D deficiency and inability to procreate. And so they lost their skin pigment in order to be able to survive.

Andrew: Yeah. And I remember in your talk just about that inability to procreate, there was also a skeletal change in that, wasn't there, in the hips, in the pelvic canal? Yeah.

Michael: Yeah, if a child is vitamin D deficient during the first couple of years of life, female, they have a flat form pelvis, a small pelvic outlet. So they have a difficult, if not impossible, time with childbirth.

Andrew: Wow, interesting, interesting stuff. So let's move on now to a recent trial, and this one was co-authored by you. This was the Vitamin D favourably alters the cancer-promoting prostaglandin cascade paper. Can you explain and elucidate what happened with that trial, please?

Michael: Sure. What we did was Dr Ed Sauter, who's a surgeon and very, very good at this, was taking cells from the breast, and these are the cells that typically can develop into cancer, they're the most likely cells to develop into cancer, and what they did was to incubate them with 25-hydroxyvitamin D, 1,25 dihydroxyvitamin D, and also celecoxib, which is, as you know, an anti-inflammatory agent.

Andrew: Yeah.

Michael: And to see whether or not the combination of the two they have further anti-inflammatory activity, which may be a precipitating factor for inducing the cells to become malignant. And what was found, curiously, was that the vitamin D component, did not find it to be additive or synergistic, but the effect with the celecoxib demonstrated that the PGE2 and Cox-2 levels decreased in the breast of women that were treated first in these cultured cells and then when these women were given 2,000 units of vitamin D plus celecoxib and these cells were taken out and looked at that they had a significant impact on the inflammatory activity. So this could be one of the explanations for why vitamin D may be of some value in reducing risk for breast cancer.

Andrew: Right. And I do remember a paper that was talking about using 10,000 IU per day in oestrogen negative and positive breast cancer patients. I'm just wondering if I got that paper...have you read that paper? Because that's sort of seems...

Michael: I don't remember the details.

Andrew: Right, that seems to tie in with that, you know, whether they were giving this vitamin D because the patients were indoors, I don't know. So in other words, they were just merely correcting a vitamin D deficiency, but they were using 10,000 IU per day, I remember that.

Michael: Yeah, and getting back to that issue of how much vitamin D causes toxicity. I mean, literally, you have to take tens of thousands of units of vitamin D a day…

Andrew: Yeah.

Micheal: …for least a half a year before you even have to begin to worry about toxicity. And typically, you'd have to get above about 500 nmol/L before you even have to worry about toxicity. So there's a big latitude in terms of how much vitamin D you can take and worrying about the toxic side effects. 

Andrew: Yeah.

Micheal: And just for your listeners, vitamin D toxicity does not mean an elevated blood level of 25-hydroxyvitamin D because I see a lot of docs referring their patients to me with a blood level, say, of 200 nmol/L and they're saying that the patient's vitamin D toxic. No. What you have to really see is suppression of PTH and elevation of the serum calcium and often the serum phosphate, those are kind of pathognomonic for vitamin D intoxication.

Andrew: Right. So they look at measuring the calcium levels, their corrected calcium score, and alkaline phosphatase, their parathyroid hormone, is that correct?

Michael: Yeah, alkaline phosphatase is usually normal.

Andrew: Right.

Michael: But the PTH is suppressed because of the calcium is up.

Andrew: Got you.

Michael: And then if you really want to be absolutely sure, you can not only correct the calcium with your albumin but also, you get ionised calcium.

Andrew: Right. Okay, thanks for that. That's great. All right, so another one, trial was on the genomics of vitamin D, and this has you as the primary author. This one's very interesting. Can you talk about the conclusions of that trial, please, Michael?

Michael: Sure. So, long story short is that, you know, there are a lot of studies underway of mostly in vitro studies suggesting that vitamin D may have an immunologic effect. So what we decided to do is to take healthy adults...and these are principally medical students and graduate students at our institution. We know from our past experience that they're all vitamin D deficient or insufficient, their blood levels are usually in the range of about 45 to 50 mol/L. And we gave them either 400 or 2000 units of vitamin D a day for 3 months. And what we did was we collected, obviously, blood, not only to measure baseline and end-of-study 25-hydroxyvitamin D levels to be sure that they were compliant and that we had the desired effect of raising their vitamin D status, but we also got their white blood cells.

And we isolated the RNA from the white blood cells, and then did broad gene expression analysis of over 22,500 genes and asked the question “at baseline for this individual, compared to taking 2000 units of vitamin D a day, after 3 months and getting another blood...and isolating their white blood cells, was there any significant change in the genes that may be controlling a whole variety of metabolic processes?” And we were pleasantly surprised to find that the 2,000 units a day had influenced over 200 genes, about 271 genes. And when we looked at the functions of these genes, they controlled up to 80 different metabolic processes.

And that includes regulating auto-oxidation, which of course, is a very important component now of inflammation as well as for malignancy, altering immune function, altering DNA repair, and the list goes on. So I think what we've demonstrated for the first time is this non-calcemic benefit, this direct non-calcemic benefit of simply increasing your vitamin D intake for a period of 3 months, raising your blood level from about 45 to 50 nmol/L up to about 75nmol/L to a 100 nmol/L, and by doing so, remarkably improved the expression of genes that are important for immunologic health as well as overall health and well being.

Andrew: And this ties in with recent research that was looking at vitamin D's use in helping people with lupus. So, you know, admittedly, things like cancer, we're talking about a decades-long progression to disease, same with cardiovascular disease. So as you said earlier, it can be quite hard when you're saying “I will let you take vitamin D for 12 weeks and see if it will decrease your risk of cancer,” which develops over the last 30, 40 years. 

It’s a little bit hard, maybe the track in a short time, but with autoimmune diseases, hard as they are to treat, sometimes you can have a dramatic effect on dampening the inflammatory response. So can you go through the action of vitamin D in autoimmune disorders and what the recent research is revealing in that aspect?

Michael: Sure, but to get back originally to this concept of cancer and the issue regarding how long it takes to develop and the role of vitamin D. 

Andrew: Yep.

Micheal: But there are now several studies that have demonstrated that patients with cancer, if they improve their vitamin D status, that they have decreased risk for morality from the cancer.

Andrew: Right. Actually, yes, you're right. I remember the melanoma paper.

Michael: Yep, yep. And even breast cancer nowadays, they've been able to show it. And so regarding the immune effects, it was shown over 30 years ago that inactivated B and T lymphocytes have no vitamin D receptor, but monocytes did. And we now understand a little bit more about this process. When you activate a T or B lymphocyte, all of a sudden these lymphocytes start expressing a vitamin D receptor. So now you know that these active B and T lymphocytes are now going to be wanting to see some active vitamin D. And we now also realise that monocytes will now convert 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D, which interacts with the receptor, not only in the monocyte but we think that the monocyte may even, in fact, release the 1,25 D locally to activate the T and B lymphocytes to control their function.

So in macrophages and monocytes, it was demonstrated by Adams and Modlin and Liu that one of the first things that gets turned on in a macrophage, let's say, infected with TB. So, the lipopolysaccharide component of TB interacts with toll-like receptor is that the cell is told to increase production of the active form of vitamin D 1,25-dihydroxyvitamin D, it now goes back into the nucleus, interacts with its vitamin D receptor, and now increases the expression of cathelicidin, which is a defensive protein that specifically can lyse and kill infective agents like TB.

Andrew: Yep.

Michael: So we think that it plays a very important role in helping to fight infectious diseases, acute infectious diseases. But on the other side, T and B lymphocytes, B lymphocytes, the active form of vitamin D down-regulates immunoglobulin synthesis. Now, you may think, oh my gosh, if you do that, you're now increasing your risk for infection. But the other side of the coin is what if, in fact, and we believe that this is true, that 1,25 D is actually modulating immunoglobulin synthesis? And that if you were to develop, say, a slow viral infection that may be responsible for causing type 1 diabetes or multiple sclerosis and now all of a sudden you're mounting an immune response, 1,25-dihydroxyvitamin D, by modulating immunoglobulin synthesis, may be reducing the risk for developing autoimmunity to these infectious diseases and reducing risk for both MS as well as type 1 diabetes.

Andrew: Right.

Michael: I think the same may be true for rheumatoid arthritis, as well as for even Crohn's disease.

Andrew: Right.

Michael: T lymphocytes, we now know that the T1 to T2 ratio is significantly changed when 1,25-dihydroxyvitamin D interacts with these lymphocytes making them more prone to be favourable lymphocytes, less likely to be reactive to its host, i.e. to cause autoimmune disease but yet help to fight infection and inflammatory processes.

Andrew: So that can also answer the way that macrophages get hijacked by cancers, basically to propagate cancer rather than kill them, the tumour-associated macrophages.

Michael: Correct. And we think that, you know, that this happens in granulomatous disorders, even like sarcoid…

Andrew: Yeah.

Micheal: …that these macrophages are coming in, they're trying to do their thing, they may not be as successful, but they're definitely producing 1,25-dihydroxyvitamin D, which is kind of the driver for the engine to help the macrophage do its thing is to help the macrophage function…

Andrew: Yeah.

Micheal: …and be able to affect either malignant cells and/or infectious processes.

Andrew: Right. So as an intervention in let's take autoimmune diseases, disorders for a category. If we looked at things like well, firstly, lupus where there was some recent positive trials with using vitamin D, but also the caveats that are associated with things like sarcoid, which you just mentioned previously, can you talk to us about what sort of interventional levels you'd use of vitamin D in the various disorders and, you know, how quickly you'd expect them to work or what sort of outcomes you'd expect?

Michael: It depends on the circumstance. And so what we always do with all my patients, I alert them, is that they definitely need to monitor their calcium to 25-dihydroxyvitamin D, corrected calcium for sure, and maybe even 24-hour urine calcium to be sure that you're not having any side effects. With that said, we know, typically, that 90% of patients with sarcoid have hypercalciuria, 10% can develop hypercalcemia and the major reason is because these macrophages produce 1,25-dihydroxyvitamin D which enters the circulation and then has effects on your calcium metabolism, both the intestines and bone. So for sarcoid patients, I usually caution them and I only put them on an amount of vitamin D that gets their blood levels in the range of about 50 nmol/L to about 65 or 70 nmol/L. In that range, they can be basically vitamin D sufficient for themselves because of the sarcoid activity…

Andrew: Yep.

Micheal: …and not cause hypercalcemia or significant hypercalciuria. The other side of the coin though is for patients with lupus who aren't necessarily having activated macrophages making 1,25-dihydroxyvitamin D is that we will give them more vitamin D as I've given my now MS patients more vitamin D, even my rheumatoid arthritis patients more vitamin D, see if I can improve muscle function for MS patients, maybe improve the honeymoon period for rheumatoid arthritis patients, some of them tell me that they feel better by being on higher doses of vitamin D.

So some of them are on 10,000 up to 20,000 units of vitamin D a day. But I watch very carefully making sure that their total calcium, ionised calcium, and corrected calcium are normal. I often will do a 24-hour urine calcium. If I don't see any change, PTH doesn't change, I know that I can maintain their 25-hydroxyvitamin D level, even around 300 nmol/L and possibly have some anti-inflammatory activity for these chronic illnesses while not causing toxicity.

Andrew: And I think to tie this in, if you like, to the comments that we made right at the beginning regarding testing that for most people, it's not appropriate, but for these conditions and for those people who are at risk, then obviously testing a baseline and your various measures of toxicity and those predisposed people that these are the relevant group to be testing in.

Michael: Exactly. And to put this into perspective, because I know that this testing is becoming very controversial because it's the most ordered test in the United States. My understanding is in Australia, somewhere around $80 million to $100 million Australian is being spent on an assay. So you're right, we do not recommend testing. Sensible sun exposure, getting the amount of vitamin D that I've been recommending, the Endocrine Society's been recommending 1,000 units for children, 2,000 to 3,000 units for adults, and more if you're obese. But think about it, is that if you have rheumatoid arthritis or multiple sclerosis, some of these medications are incredibly expensive.

Andrew: Yeah.

Michael: And toxic. And so if you need to increase your vitamin D intake, and yes, you have to monitor their vitamin D status, and their 24-hour urine calcium and the like, the expense for that, and also the relative safety of this is so much better than many of these immunologic agents that are being used for treating rheumatoid arthritis and multiple sclerosis, you know, is cost effective.

Andrew: And that's just such a perfect point for the appropriate testing of vitamin D levels. So Michael, just as a wrap-up point, can you go through, for the listeners, those medications that actually decrease vitamin D or have issues with vitamin D metabolism?

Michael: Sure, I think that the one that is well known, of course, are anti-seizure medications like Dilantin and Tegretol. It was well documented over 40 years ago by Dent in England that children institutionalised on multiple anti-seizure medications had rickets and vitamin D deficiency and that they had a resistance to vitamin D. And it's all because these drugs specifically increase the metabolism of 25-hydroxivitamin D, and it's easy to overcome, is to simply increase the vitamin D intake, monitor their 25-hydroxide vitamin D levels. Usually they need about three to five times more vitamin D when they're on an anti-seizure medication. Prednisone will do the same thing. And so as a result, people that are on prednisone, A, they should increase their calcium intake by a little bit more from about 1000 milligrams a day to 1500 milligrams a day because prednisone decreases the efficiency of intestinal calcium absorption but it also increases the destruction of 25-hydroxyvitamin D. So often patients need about two to three times more vitamin D in order to satisfy their vitamin D requirement. 

Also rifampin. Even St. John's Wort has been shown to increase the destruction of 25-hydroxyvitamin D. So there are various medications out there that can decrease your vitamin D status by increasing the destruction of 25-hydroxyvitamin D. Also, if you're on cholestyramine, this will bind vitamin D so it won't permit you to absorb it. And some of these other products that are on the market to help prevent fat absorption or cholesterol absorption, they also prevent vitamin D absorption. So you need to take your vitamin D several hours before or several hours after taking these type of medications.

Andrew: Michael, perfect points and practice points for those practitioners that are listening today. Thank you so much for giving us the truth about what's happening really in the research with vitamin D. I thank you once again, Professor Michael Holick.

Michael: Thank you very much and have a delightful day.

Andrew: This is FX Radio. And I'm Andrew Whitfield-Cook.


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Prof. Michael Holick