I noticed DrK tweeted on this and suggested that I have a look. The implications are that a middling amount is beneficial, but too much vitamin D is bad for you because it affects calcium levels in T cells. This may be lapped-up, because no doctors would think that you should be eating vitamin D capsules like smarties (Sugar coated chocolate sweets).
Of course one says No s**t Sherlock, we already know not to take too much vitamin D, especially with calcium, but do you know the mechanism?
Some vitamin D is good of you, but we want to ensure that you are vitamin D replete for bone health and get any extra benefit possible. we want you to carry on with those trials so we get a result. Having just read the vitamin D council website . It is there in black and white that too much vitamin D is not inert and problems can start above 250nmol/L. This is the concentration aimed for in the mouse study and they report an adverse effect. Therefore, why would you aim for something in animals that you are advised against in humans? Is that 3Rs?
That said there are people taking vitamin D tablets like smarties and levels above 250nmol/L are found in humans.
I am sure you know what’s coming. Should I do the fluffy approach and say we are all amazing and we are all made out of stardust? Or do you want the warts and all?.
Want Fluffy?…Stop here, save yourself for another day. You don’t need to read this.
Accept not so fluffy? Go get a cup of tea, sit back, relax and don’t let your blood pressure rise.
Before I start..You say
“I’m just jealous”…I say .”Paper in the journal Brain, why not be jealous?” However, I have just got back from a meeting, with a session on reading papers and one from this group cropped up and took a bit of a battering concerning interpretation. So let’s continue with the Journal Club.
So here goes. Remember Don’t shoot the messenger:-). Mr. Grumpy was asked for an opinion.
High dose vitamin D exacerbates central nervous system autoimmunity by raising T-cell excitatory calcium. Häusler D, Torke S, Peelen E, Bertsch T, Djukic M, Nau R, Larochelle C, Zamvil SS, Brück W, Weber MS. Brain. 2019 Jul 13. pii: awz190. doi: 10.1093/brain/awz190. [Epub ahead of print].
The abstract says “Poor vitamin D status is associated with a higher relapse rate and earlier disability in multiple sclerosis. Based on these associations, patients with multiple sclerosis are frequently supplemented with the vitamin D precursor cholecalciferol, although it is unclear whether this regimen is of therapeutic benefit”. (After all we have only done thirty clinical studies (check clinical trial.gov) in people with multiple sclerosis and countless other trials in other conditions. The meta analysis Effectiveness of Vitamin D Supplementation in the Management of Multiple Sclerosis: A Systematic Review. Berezowska M, Coe S, Dawes H. Int J Mol Sci. 2019 Mar 14;20(6). pii: E1301 says 3/10 had a positive result. I suppose that is unclear).
If it is unclear after ten trials, and remember this is just MS and every disease has done these studies, I think the answer is clear…It ain’t that effective.
However, is this really where vitamin D acts?
Is the effect earlier in life, like in the womb, to shape your immune repertoire that predisposes you to autoimmunity as the epidemiological data suggests or is it really a therapeutic thing?. The data point to the former not the latter. This is “streetlight science”. We do the trials that are easiest, not the trials that need to be done. These trials are prevention.We are going to the same place with microbiome trials. That’s a prediction. Let’s see whose right the trials have started.
Perhaps it may say why bother with the approach?. However, before you chuck your tablets away. I must say there are other supportive studies where the data supports the words. However, it is probably one of those incremental things where it is beneficial to be vitamin D replete. It is going to have major effects..I think the answer is no, because it doesn’t have the side effects. I have always thought this and that is why I don’t like bandwagon science where stuff is done without any thought. An opinion leader says something and we should all follow like Lemmings. I think not. A strong non-specific inhibition of the immune response should equate to more infection. This is simple biology. You don’t get one without the other.
However, there are lots of papers were a clear benefit has and can be seen
Anyway back to the paper
The authors argue that because of the “perception of harmlessness, the current practise to supplement with vitamin D, [often leads to] an excessively high dose”. But 37 in 20,000 is surely not often see below (source vitaminD council)
The lab lesson is do your reading before your writing.
In “view of lack of clear therapeutic benefit in a therapeutic trial in MS” the authors investigated the prophylactic effect (Give the treatment before disease development) of vitamin D supplementation in mice.
Anyway, to model consequences of this common practice, mice were fed for more than 3 months with a low, medium or high dose of cholecalciferol (Vitamin D3), representative of vitamin D deficiency, modest and disproportionally high supplementation, respectively, in people with MS. Compared to vitamin D-deprived mice, its moderate supplementation reduced the severity of subsequent experimental autoimmune encephalomyelitis (Really? I mean Really?)
Does it pass the Smack you in the eye test? Is the red line (Low) different vs= versus from the black (Std = standard) line dose. “ns” means “not significantly different”?)
Clearly, this means to me a Big No Effect. This is why DrK has got me going with his tweet. This was his carrot, he knows I’m the donkey and am now chomping on it.
Aging mice show poor recovery, but what is the normal disease course as there is no difference between the low and standard dose and no vitamin D deficient diet
If we were thinking about translation to human biology what does this study say?
The standard dose (black) has one non-susceptible animal and so it will drop the line graph, however there is no-significant (ns) difference even according to the authors own analysis! Yet in the abstract and elsewhere in the paper it says the opposite. I am truly, truly shocked by the level of review.
Essentially all animals got an attack and so if viewed from a translational prespective it would say whatever dose you use…you are going to have an attack, therefore you shouldn’t bother pursuing further clinical trials with vitamin D as it won’t work. Now I will counter this saying there are other mouse studies where the data for a vitamin D-mediated effect is more compelling. However, no wonder I am a Grumpy.
However, if we accept this and say nothing, how can we educate the next generation to loose bad practise and do better?
In contrast to the “no effect” seen in the graph above, the text states otherwise, and this why it is so important to read the data not what authors write about their own data. One questions whether the authors (ten of them) and referees really all saw the same data before it was written/reviewed.
I know this is rather harsh, and I apologise for my bad behaviour. It will do me no favours, but “come-on people! Stop giving me bad examples that I use on teaching slides on how to read papers!” Use of EAE is a severe disease. In this study a grade 4 means animals have hindlimb paralysis. If we do not strive to have certain standards, the end of its use will be hastened even more than it already is.
I know many of you say good, but there is good stuff out there and you need ideas, to help future treatments
What was the reason for this? No… not the over interpretation…the effect (which wasn’t there) in animals.
Direct exposure of mouse or human T cells to vitamin D metabolites inhibited their activation. So we have the mechanism of how vitamin D works. ,….Oh and an incresase in Tregs, best not forget dogma.
Oh EK, which bit is increased?. It clearly says that disease is inhibited and T regs do up. Where is the data? Maybe if we had the raw data we could see if there is a statisitical difference. But is there a biological difference?.
Do the T regs go down when there is no disease control as seen with the high dose? Well not really. So much for that idea then. If you create a story the information all needs to fit.
Next up the bomb shell, vitamin D maybe bad for you!
“In contrast, mice with 25-(OH) vitamin D levels above 200 nmol/l developed fulminant EAE with massive CNS infiltration of activated myeloid cells, Th1 and Th17 cells”
If there is worse disease as claimed with the high dose, you expect to see more infiltrates more Gamma interferon IL-17 etc, etc and more damage in the histology. They reported that and so I can buy the difference. Therefore be warned. Importantly, however, the histology supports the view there is no difference between the low and the standard dose, reinforcing the view that there is overinterpretation of the data.
So “When dissecting this unexpected outcome, we observed that high, but not medium dose vitamin D had caused mild hypercalcaemia, which rendered T cells more prone to pro-inflammatory activation. Exposing murine or human T cells to equivalent calcium concentrations in vitro enhanced its influx, triggering activation, upregulation of pro-inflammatory gene products and enhanced transmigration across a blood-brain barrier model. These findings suggest that vitamin D at moderate levels may exert a direct regulatory effect, while continuous high dose vitamin D treatment could trigger MS disease activity by raising mean levels of T-cell excitatory calcium”.
There you have it. Calcium is the problem. So now we go in vitro, where we should be wondering about the 30nmol/L (Low), 100nmol/L and 250nmol/L (high) doses levels . The more vitamin D (0-1000nM) metabolites the less T cell divisions notably on CD4 cells in the mouse and maybe CD8 T cells. The effect on human cells looked rather marginal (a statistical effect, however is it biologically meaningful?) effect. Then they add calcium and there is a bit more proliferation. As you smacking yourself in the eye. What do you see?
They then went back to the animals and induced increased calcium levels in the body and there was an increase in T cell activation markers (CD69 on T cells) in the lymph glands, but not in the spleen. So calcium can do this in the absence of vitamin D. So there is the mechanism. Surprisingly though, they did not show that this increased EAE.
Maybe the result was not going to be clear cut. I wonder?
Hypercalcemia produced by parathyroid hormone suppresses experimental autoimmune encephalomyelitis in female but not male mice. Meehan TF, Vanhooke J, Prahl J, Deluca HF. Arch Biochem Biophys. 2005 Oct 15;442(2):214-21
However they did report that increased calcium allowed human T cells to cross an artificial blood brain barrier. We also know that calcium is important in T cell proliferation
Calcium dependence of T cell proliferation following focal stimulation.Schwarz EC, Kummerow C, Wenning AS, Wagner K, Sappok A, Waggershauser K, Griesemer D, Strauss B, Wolfs MJ, Quintana A, Hoth M.Eur J Immunol. 2007 ;37(10):2723-33.
Calcium signalling in T cells.Trebak M, Kinet JP. Nat Rev Immunol. 2019;19(3):154-169.
We have had salt and EAE, what next milk and EAE? I know…. only joking.…Actually we’ve been there already:-( (Lactobaccillus,Butyrophhilin, etc)
Therefore they conclude that “secondary hypercalcaemia occurring upon high-dose vitamin D treatment could enhance migration of pro-inflammatory effector T cells into the affected CNS”.
So you have a mechanism, a warning and a suggestion that we need larger clinical trials to demonstrate efficacy. Based on the animal work, I would ask the question: Do we really?
The past animal studies supporting vitamin D use were questioned in this report, based on their short duration of study. This study was longer, but surprisingly the referees never questioned whether vitamin D supplementation was of any benefit at all. Based on the data presented the answer was no. I guess this is what DrK saw.
However, animals are not humans and mice are adapted to living in the dark, humans are snoozing when this happens and live in the light and get much of their vitamin D from sunlight. The human experiment is what is needed, and the question arises whether the animal studies have highlighted a problem that does not exist in humans?
The question therefore is does high dose vitamin D cause triggering of disease activity?.
You can argue there have been reports of effects of vitamin D and calcium on T cell cytokines, but you could play Devil’s advocate and argue if the B cells are important, so what. Who cares about T cells…Only joking:-)
Importantly what is the evidence for clinical worsening in humans? This the central question
Humans have been consuming large amounts of vitamin D. Does this exascerbate MS? So before you start munching on vitamin D tablets. Read this:
The vitamin D council recon that 50nMol/L is desirable. Although a vitamin D level of 30 ng/ml (75 nmol/l) is typically considered adequate, the Vitamin D Council recommends maintaining levels of 40–80 ng/ml (100–200 nmol/l), and states that anything over 100 ng/ml (250 nmol/l) may be harmful.
Despite the fact that more people are now taking vitamin D supplements, it’s rare to find someone with very high blood levels of this vitamin.One recent study looked at data from more than 20,000 people over a 10-year period. It found that only 37 people had levels above 100 ng/ml (250 nmol/l). Only one person had true toxicity, at 364 ng/ml (899 nmol/l)
The vitamin D council recommend 1000 IU /day, Adults 5,000IU/day this is lower from the Food and Nutrition Board in USA (infants 400-800 seniors) which is arguably not enough)
Very high levels of 25(OH)D can develop if you:
- take more than 10,000 IU/day (but not equal to) everyday for 3 months or more. However, vitamin D toxicity is more likely to develop if you take 40,000 IU/day everyday for 3 months or more.
- take more than 300,000 IU in a 24 hour period.
So what happens in humans?
Safety and T cell modulating effects of high dose vitamin D3 supplementation in multiple sclerosis. Smolders J, Peelen E, Thewissen M, Cohen Tervaert JW, Menheere P, Hupperts R, Damoiseaux J. PLoS One. 2010 Dec 13;5(12):e15235.
BACKGROUND: A poor vitamin D status has been associated with a high disease activity of multiple sclerosis (MS). Recently, we described associations between vitamin D status and peripheral T cell characteristics in relapsing remitting MS (RRMS) patients. In the present study, we studied the effects of high dose vitamin D3 supplementation on safety and T cell related outcome measures.
METHODOLOGY/PRINCIPAL FINDINGS:Fifteen RRMS patients were supplemented with 20,000 IU/d vitamin D3 for 12 weeks. Vitamin D and calcium metabolism were carefully monitored, and T cell characteristics were studied by flowcytometry. All patients finished the protocol without side-effects, hypercalcaemia, or hypercalciuria. The median vitamin D status increased from 50 nmol/L (31-175) at week 0 to 380 nmol/L (151-535) at week 12 (P<0.001). During the study, 1 patient experienced an exacerbation of MS (Would this of happened anyway?) and was censored from the T cell analysis. The proportions of (naïve and memory) CD4+ Tregs remained unaffected. Although Treg suppressive function improved in several subjects, this effect was not significant in the total cohort (P=0.143). An increased proportion of IL-10+ CD4+ T cells was found after supplementation (P=0.021). Additionally, a decrease of the ratio between IFN-γ+ and IL-4+ CD4+ T cells was observed (P=0.035).
CONCLUSION/SIGNIFICANCE: Twelve week supplementation of high dose vitamin D3 in RRMS patients was well tolerated and did not induce decompensation of calcium metabolism. The skewing towards an anti-inflammatory cytokine profile supports the evidence on vitamin D as an immune-modulator, and may be used as outcome measure for upcoming randomized placebo-controlled trials.
However, before I feel too smug read this:
Unfavorable outcomes during treatment of multiple sclerosis with high doses of vitamin D. Fragoso YD, Adoni T, Damasceno A, de Albuquerque Damasceno CA, Ferreira ML, Finkelzstejn A, Gomes S, Goncalves MV, Grzesiuk AK, Lins S, Mendes MF, de Oliveira FT, Parolin MF, Rocha CF, Tauil CB. J Neurol Sci. 2014; 346(1-2):341-2
Treatment of multiple sclerosis (MS) with high doses of vitamin D has never been proven effective or safe. Attracted by the option of a “natural” and “curative” treatment for MS, some patients abandon their conventional therapy in order to try this highly desirable alternative.
Here, we report on a series of cases that presented neurological or systemic complications while high doses of vitamin D were being used. Since this treatment has attracted attention from the Brazilian media for some time now, it is possible that the experience that we report here might be the future experience of others, should this treatment become equally fashionable elsewhere.
The 21 cases reported here reflect the authors’ daily practice with patients with relapsing remitting MS who were exposed to high doses of vitamin D. These patients sought private consultations with doctors who are known to use high doses of vitamin D supplementation for treatment of MS. In 19 cases, the treatment proposed for these patients consisted of complete immediate withdrawal of disease-modifying drug (DMD) therapies and the start of high doses of vitamin D. Three patients continued on their DMD with one doctor while taking high doses of vitamin D recommended by another doctor.
For these 21 patients with relapsing remitting MS, the daily doses of cholecalciferol varied from 8000 IU to 150,000 IU (average 87,000 IU, median 100,000 IU/day). The average period of use was one year (range: one month to three years). Seventeen patients presented worsening of their neurological condition (remember they were not been treated with a DMT so was it the vitamin D or the lack of an effective DMT), with new relapses and new lesions on magnetic resonance imaging, and the disability worsened in ten patients (> 1 point on EDSS). Interestingly, 64% of these neurological manifestations were related to cervical or brainstem lesions. Apart from the failure to control MS, some of these patients’ treatments with vitamin D were correlated with other signs and symptoms: one patient presented severe gastric symptoms, one patient progressed with pseudo-brain tumor and seizures, two patients presented tonic–clonic seizures and five patients presented severe hypercalcemia. There were three cases of kidney failure, two cases of nephrolithiasis and three cases of nephrocalcinosis. Patients with kidney complications presented serum levels of ionic calcium between 13.8 mg/mL and 16.8 mg/mL (reference values up to 10 mg/mL). Three patients required a few days in intensive care units in order to stabilize their clinical condition. There were no fatal cases and the serum levels of vitamin D were typically 150 ng/mL. Exclusive or complimentary treatment of MS with any doses of vitamin D is an emerging concept that, so far, lacks scientific evidence. However, we take the view that the treatment that these 19 patients underwent was neither proven safe nor proven efficient. In conclusion, treatment with high and very high doses of vitamin D has not been properly tested for efficacy and safety in MS and should not be used in medical practice.
Remember these people were not on a DMT and they relapsed cause and effect or lack of treatment? However, they were taking vitamin D pills like smarties. Stop it..they are not sweets!!!
There have been loads of vitamin D studies what do they say? This is DrRuths and ProfG territory, so I will let them answer.
CoI I am not a Doctor and do not recommend any supplement. One needs to be particularly careful about not adding extra calcium supplementation. Maybe ProfG will comment on this but avoid being extreme with complementary medicines. There is no evidence it is benefit and may be harmful. Yes I will be sent to the DogHouse for this outburst. There you go..too much Blogging will be bad for my scientific career It’s the same with medicines. Take the recommended dose.
If this mouse study warns you of this then it has done a good job.
Want it in a bite sized chunk read it here (open access)
Vitamin D Supplementation in Central Nervous System Demyelinating Disease-Enough Is Enough. Häusler D, Weber MS. Int J Mol Sci. 2019;20(1). pii: E218
I’m off to take a chill pill, ready for the abuse that may come my way