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Vitamin D in chronic inflammatory and autoimmune diseases. Reconciling contraditory literature

Discussion in 'General Treatment' started by serg1942, Oct 3, 2018.

  1. serg1942

    serg1942 Senior Member

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    DISCLAIMER: I have no official credentials (i.e. university degrees in science) that would confer on me the recognized scientific expertise to elaborate on and interpret scientific articles. It follows that any conclusions I might have reached do not have validity unless confirmed by someone with appropriate scientific expertise. Lastly, as English is not my first language and the current text has not been reviewed by a qualified translator, I take no responsibility for any
    misunderstandings or misinterpretations that might arise from my grammatical errors. This text must therefore be viewed as a layman’s interpretation of the sources that have been noted.

    Post's author background:
    I'm an industrial engineer and a 5th-year medical student. I suffer from CFS and from chronic Lyme disease.

    Personal notes before reading this post:
    - I am sorry for writing the subject of the post in capital letters. I just copied and pasted the title from my whole article, and didn't even notice it was in capitals letters. I understand this might come somewhat too strong for some people, so I just changed it. Again, I apologized to those who have felt offended in any way.

    - As I have been suggested, I have written down the disclaimer which was in my article, on top of my original post, together with my credentials, so you don't have any doubt about the validity of the article.

    - The article I wrote is very well referenced, with cites properly placed from 58 scientific papers (my background as engineer allows me to know how to do this), which are listed at the end of the article. You can perfectly distinguish what comes from a given paper from those conclusions I reached on my own (which is not much--most things are paraphrased and properly referenced).

    - I have been told that my assertions are too aggressive. I apologize if they came up that way. I just manage in English, so please understand that it is very difficult for me to grasp these nuances... Again, I apologize for this.

    - However, I guess I am allowed to write down conclusions made by scientific papers. Thus, when I say that vitamin D is an immune suppressor as powerful as a glucocorticoid, it is because it has been shown in several studies, which I properly quote in my article. Likewise, when I say that vitamin D might be dangerous, again, I am paraphrasing some authors. And when I state that I think that vitamin D supplementation could be counter-productive for chronic inflammatory diseases, I am making a conclusion based on tents of papers which advice just that. If this is worrisome, well, it actually is, in my humble and layman's opinion, and in some expert's opinions as well, which are properly cited in my text. I have just made a thorough scientific review, and highlighted some of the conclusions reached in some papers. Of course, this is just one of the views, as I extensively show in my article; Many physicians do defend vitamin D supplementation.

    - Now I do hope I have made things clearer. It is up to us to draw conclusions from the available literature, own experiences, etc. etc.

    - Please let me know if I still need to change something. I'll do it gladly. But I won't sugar-coat what some compelling evidence has shown. It would not do any good to anybody, in my opinion, and I guess I am actually allowed to have an opinion on my own, which now I hope it is clear it is just a layman's opinion.




    Hi everybody,

    I have finally finished a comprehensive review on vitamin D and chronic diseases. I embarked in such a big task because the literature was really confusing and contradictory on whether it is advisable to take vitamin D, or whether it could be even dangerous. This is a very important issue for me because I am still placing my hopes on LDI, a treatment that has almost cured my mom (something seems to be impeding that she gets 100% asymptomatic, but she is most of the days), and that has given to me a very significant but transitory improvements, several times in the past. Thing is that LDI is supposed to work when taking very high doses of vitamin D, and therefore I have been supplementing with this hormone for a long time, while racking my brain trying to figure out a reason for the therapy to stop working on me and others over time… Well, interestingly and much to my surprise, I recently came across with some studies showing the powerful immune-suppressive effects of vitamin D (as powerful as any glucocorticoid), and even most worrisome, I read some studies showing that it inhibits the antigen-presentation process of dendritic cells, which lies at the very heart of the LDI mechanism. Actually, given that vitamin D is fat-soluble, it would make sense that it would accumulate in the body over time and that at one point it could prevent the therapy from working, especially taking into account that its immune-suppressive properties seem to be dose-dependent.

    Well, for this reason I have performed a thorough review on vitamin D on chronic inflammatory diseases (such as ME/CFS), that maybe can be also helpful to some of you guys, as I think, after having done this review, that vitamin D supplementation could actually inhibit many therapies we follow.

    Below is the summary of the article. attached is full text.

    I hope it is helpful,
    Best!
    Sergio

    ************************

    ABSTRACT

    Low levels of the pre-hormone 25-hydroxyvitamin D (VD25) are normally shown in many chronic inflammatory diseases, and many studies show symptomatic improvements, lower rates of autoimmune diseases and fewer inflammatory markers, from taking vitamin D supplements. This has led many physicians and governments to argue that low levels of VD25 lie at the core of the pathogeneses of many conditions, and therefore vitamin supplementation is broadly recommended. However, some physicians and researchers defend the so called “alternate hypothesis”, which describes the low levels of vitamin D as a consequence of the chronic inflammation, instead of the cause. If the proponents of the alternate theory were right, vitamin D supplementation could be really dangerous; therefore, it is of imperative importance to review the available evidence and draw a solid conclusion on the matter.

    One of the most important functions of vitamin D is exerted on the immune system. In this regard, when certain Toll-Like-Receptors (TLR) are activated, mainly on monocytes and macrophages, the circulating VD25 is converted into the active form 1,25dihydroxycholecalciferol (VD1,25) by the cells, which in turn induces the expression of antimicrobial peptides (AMPs) by binding to the nuclear vitamin D receptor (VDR). These peptides (mainly cathelicidins and beta defensins) constitute a major component of the innate immune system, showing activity against bacteria, fungi and viruses.

    While the most accepted effect of vitamin D on the immune system is to enhance the innate immune response and to inhibit the acquired immunity, in vitro essays as well as interventional studies show contradictory results. In this vein, VD1,25 has demonstrated to block the conversion of Th1- and Th17- cytokines while promoting the Th2-immune response and the formation of Treg-cells. VD1,25 has also shown to inhibit the maturation and proliferation of dendritic cells (DC), to halter the antigen presentation capacity of DC and other antigen-presenting-cells, and to promote the anti-inflammatory and tolerogenic phenotypes of macrophages and DC. Furthermore, it has shown to induce hyporesponsivity in T cells and in peripheral blood mononuclear cells (PBMC), and to inhibit antibody secretion and autoantibody production by B-lymphocytes. Moreover, and in respect to the innate immunity, it has been reported that VD1,25 inhibits TLR2, TL4 and TLR9 as well as NK-cells.

    There is a significant paradox, in that vitamin D is necessary for an efficient innate response against numerous intracelular pathogens, but at the same time, it has shown to impair both the innate and the Th1-mediated immune responses. In this vein, some of these discrepancies shown in the literature could be explained by the different doses of VD1,25 or VD25 used in the experiments. Thus, the studies using supraphysiological doses are those which show the most immunosuppressant effects of VD1,25, while some studies using physiological doses report, for example, that VD1,25 does not impede the Th1-mediated response or that the TLR and NK-cells are not inhibited by VD1,25 when lower doses are used. In any way, it seems clear after reviewing some of the literature, that the high VD1,25 serum levels found in patients with many chronic inflammatory and autoimmune conditions, can actually suppress significantly the immune system. In this regard, the anti-inflammatory properties and potency of VD1,25
    (in considered physiological doses) and dexamethasone have been shown to be quite similar. Likewise, the inhibitory effect of VD1,25 on DC was shown to be very similar to the effect of glucocorticoids. In anyway, the effects of vitamin D supplementation observed in interventional studies are very useful in elucidating the effects of vitamin D on the immune system. In this regard, vitamin D supplementation in patients with multiple sclerosis, confirmed the promotion of tolerogenic DC, which in turn induced regulatory T cells and produced a shift toward T-helper-type 2 response. In this vein, PBMC responsiveness to disease-associated antigens was significantly reduced, while the signs and symptoms of the disease improved. Likewise, supplementation of vitamin D in patients with cystic fibrosis showed similar results.

    Finally, at the end of this article, the “alternate theory” is described in detailed. This model proposes that, in chronic inflammatory and autoimmune diseases, intracellular microbes invade nucleated cells, inhibiting the VDR. This leads to high levels of VD1,25, low levels of VD25 and low-grade chronic inflammation and autoimmune processes produced by cross-reactivity, what would explain the symptoms of these diseases. When these conditions take place, AMPs cannot be properly expressed, what renders the immune system unable to eradicate the perpetuated infections. Thus, in this proposed-disease-model, extra vitamin D supplementation would be really harmful, as it can displace the VD1,25 from the VDR, blocking this receptor even more. In addition, vitamin D supplementation can further hamper AMPs production, what inhibits the innate response towards the intracellular pathogens even further.

    If the alternate theory is accurate, the vitamin D supplementation in chronic inflammatory and
    autoimmune diseases can be detrimental and dangerous, as it would allow the intracellular pathogens to spread, and the chronic situation would become even worse. Paradoxically, this can lead to transient symptomatic relief, in a way similar to that of many anti-inflammatory drugs.

    Is the alternate theory supported by evidence? After a thorough review, we could conclude that it is. In this respect, low levels of VD25 are clearly associated with a wide variety of conditions; similarly, in many of these diseases the VD1,25 have been found to be elevated. In a similar vein, various pathogens have shown to down-regulate the VDR (including mycobacterium tuberculosis, mycobacterium leprae, aspergillus fumigatus, Epstein–Barr virus, HIV and borrelia burgdorferi). Finally, low levels of AMPs have been reported in some autoimmune conditions.

    In summary, after an exhaustive review of the literature, we can conclude that low levels of VD25 are possibly due to the effects of chronic inflammation, and not the other way around. In this respect, and given the fact that the so called “alternate theory” seems to be well supported by the literature, it seems advisable to be very careful when it comes to vitamin D supplementation, especially in those with chronic inflammatory diseases.
     
    Last edited: Oct 6, 2018
  2. Wolfcub

    Wolfcub Senior Member

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    Thank you. I really appreciate this research @serg1942

    When I first became ill, it was at the end of a particularly hard bitter winter. Vitamin D3 wasn't on my mind. But a few weeks later, desperate for some help, I wondered if vitamin D3 had been very low at the onset of my illness (hadn't had any sun on my body for months.)
    So I thought I'd experiment with supplementing. I started low (400IU) Wary of overdoing it.
    At first -no help and no noted response. So I kept it up for 90 days (that's how many pills were in the box) During that time -plus exposure to quite a lot of sun, I started to feel a little better subtly, and even went into a 3 week remission.
    However given the random nature of my remissions/relapses, I have no idea if vitamin D3 was helping or not. Not clear enough evidence.

    I stopped the vitamin D3 for a while. Thinking I was getting plenty of sun anyway.
    I went downhill a bit during August. Haven't had another notable remission since.
    I started taking 400IU of D3 again about 3 weeks ago but have noticed no benefits at all this time.
    I know that's a low dose but I am wary of taking huge doses.

    It's hard to get blood levels measured frequently on my health system. The last I knew (April) I was told by the doctor that my D levels were "normal" (maybe not optional, but normal.) Beyond that I have no info.
     
  3. xrayspex

    xrayspex Senior Member

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    thanks @serg1942 this is validating because Vitamin d in any dose or type makes me feel worse, dont even like to stay on it a day as I get insomnia and really crabby!
     
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  4. PatJ

    PatJ Forum Support Assistant

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    Thank you for posting the results of your research.

    Vitamin D makes many of my symptoms worse. It leads to increases in light and sound sensitivity, brain fog, and muscle fatigue.

    I've tried very low dose (100IU/day) and very high dose (80K IU/day) for varying periods and have always felt worse.
     
  5. Diwi9

    Diwi9 Administrator

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  6. Shoshana

    Shoshana Northern USA

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    People still might need to make individual decisions, based on their particular health issues, and on multiple sources of info.
     
  7. Murph

    Murph :)

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    I very much appreciate the research by @serg1942. But I'm a lot like @Wolfcub above. I've started and stopped taking Vit D enough times to suspect it helps me. I know I usually feel better in summer, especially late summer, and usually regress in late winter/early spring. While I have 1000 theories for that, Vitamin D is one of the 1000!.

    I now take 10,000 IU a day and am definitely aware that Vit D can poison you at high levels and that unlike Vit C, it is stored in the body. So I'm watching out for symptoms that could be caused by that.

    I'm open minded on whether it is good or bad but I don't think the effect is especially dramatic either way, nor particularly immediate, and people should be able to safely do some self-experimentation.
     
  8. serg1942

    serg1942 Senior Member

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    Thank you so much guys for sharing your thoughts. I will answer in detail in the next days, as my energy allows, as this is a very important topic for me and I think for many of us who have taken or are taking vitamin D. I would like to brain storm with you over this topic, and expand my knowledge from your experience and opinions.

    Just a few things I’d like to point out in advance, after reading your posts:

    - When you take vitamin D, you suppress your immune system at many levels, just as powerfully as with any glucocorticoid (both substances have been compared in a study, and the comparison with glucocorticoids have been established in some papers as well).

    - If you take vitamin D and you get better, this is probably due to the immune suppression. Note that you don't necessarily feel a Herxheimer reaction (that you'd feel by taking almost mots therapies that go close to the heart of the problem), what points to the fact that you are not killing any pathogen, but instead, lowering the inflammation that causes our symptoms. However, this is not a cure, and makes the picture worse in the long term, in my layman opinion.

    - if you take vitamin D and you feel worse, I think this might be a good sign, as the VDR is not as blocked as it is in the very severe cases. Or maybe, this just depends on the virulence of the persisten pathogens we have, which are different for every person...

    Again, I will answer soon! Thank you!
    Sergio
     
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  9. xrayspex

    xrayspex Senior Member

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    @serg1942 I like forward to hearing more when you have time. Certainly we all have to go with our own trials and errors and what we know of our bodies mixed with research. for me I tried D many times and forms like the last 10 years and pretty much reluctantly gave up due to unpleasant symptoms...when I dug around seeing what kind of peers i had I did find some forums of a subset of Lupus folks that had negative symptoms like me--we all also cannot tolerate sun much so seems like that likely could tie in too. I do have Sjogrens diagnosis which can be like Lupus.
     
  10. kangaSue

    kangaSue Senior Member

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    If you have significant GI problems though, low VD,25 and high VD1,25 could just as easily be due to a physiologic hyperparathyroidism (parathyroid levels will be elevated, can be just slightly) secondary to either low calcium or vitamin D intake or intestinal malabsorption issues.

    If you feel worse supplementing vitamin D here then, it can be due to not having enough fat in the diet or possibly having too little in the way of fat stores (malnutrition).

    https://www.aafp.org/afp/recommendations/viewRecommendation.htm?recommendationId=140
     
    Last edited: Oct 4, 2018
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  11. Learner1

    Learner1 Forum Support Assistant

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    ...or being allergic to lanolin, which is where most vitamin D supplements come from

    As for the study, I'm wondering which VDR and other SNPs the participants had, as well as status of other cofactors...

    Low vitamin D levels are linked to many types of cancer.

    It certainly seems that there might be individual variation...

    Interesting topic though. Tell us more...
     
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  12. pamojja

    pamojja Senior Member

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    Also interesting to read the recent previous thread by Serg trying to confirm that there are cases where this hypothesis would have panned out:

    Some questions for those who have been taking vitamin D3

    For example in particular, by trying to find anyone with experience of high 1.25 levels, and continuing the high vitamin D3 intake. Which interestingly found only 1 case, where the opposite as expected to this hypothesis occurred - the addition of even higher intake and co-factors nutrients - brought 1.25 serum levels down very fast to healthy levels.

    Personally feel very at unease having an untested hypothesis in CAPITAL LETTERS posted, because usually almost all do not understanding the difference between an UNTESTED hypothesis to one thoroughly tested. Though one wouldn't expect such at PhoenixRising as much. Considering the bitter fact, that approximately 95% of US adults have lower dietary vitamin D intake than even the ridiculously low RDA.

    Where the vast majority would have sensitivity to vitamin D because of similar rampant deficiencies in nutrient co-factors needed for vitamin D to work properly. And can only hope that the vast majority with real deficiencies does NOT feel satisfied with this untested hypothesis, and therefore out of unfounded fear do without any this potentially lifesaving ESSENTIAL nutrient, to their own future harm.

    I understand @serg1942, you have equal good intentions. And are conscientious to place the following disclaimer at the top of your paper:
    I'm too only a laymen, english is my second language too, and I've become very biased because of reversal of chronic inflammatory conditions (PAD 2, COPD 1, T2D) by maintaining my 25(OH)D serum levels at about 70 ng/ml AND comprehensive supplementation for 10 years. Whereby also a 60% walking disability has been revoked.

    An untested hypothesis has to be tested first. That's what I unintentionally did out of no viable options available through conventional medicine and nothing left to loose. And by experimenting - while always also considering deficiencies of the many co-factors nutrients (Mg, vitamin A, Ks, boron etc.), which scientific papers Serg's is based on, almost never do - maintaining vitamin D serum at relatively high levels has been greatly beneficial for me. This hypothesis has been tested in-vivo and proven to be invalid in my number of 1.

    Vitamin 25(OH) serum levels can of course be low and 1.25 high from chronic inflammation itself, that doesn't contradicts the fact that in the vast majority of about 95% of US adults it is mainly because of insufficient dietary intake of this essential nutrient and it's co-factors.

    My approach if I would feel sensitive to supplemented vitamin D despite having tested vitamin D deficiency, is to test for all co-factor nutrients possible too. And experiment with dietary intake and micro-doses from different companies, equal with all missing co-factors.
     
    Last edited: Oct 5, 2018
  13. Shoshana

    Shoshana Northern USA

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    I didn't see the disclaimer, until @pamojja posted it, (thank you for that! )

    and my guess is that most readers HERE, at PR, cannot read everything, so many likely don't/ didn't see it either.
    My view, my opinion, is that it should be IN the original post, perhaps at the top of it.

    I always like to know any writer's background/credentials, of any of my sources of info, on any topic,
    and if especially if they are posting on PR, very strongly worded conclusions.

    I did not click on the full text, to find the poster's credentials, IF it is there.
    But I did search for author/poster's credentials, and could not locate them.
    The poster's wordings sound very authoritiative, however I always want info about all/any of my sources,
    and I also did not see any footnotes, documenting sources of info used for the conclusions drawn by the writer.
    (Again, perhaps it is in the text I did not expand)

    I respect the writer's opinion and research time and effort spent, and info shared,
    however, I would have appreciated more obvious to all, and more easy access to credentials, if posting in this manner.
    I also agree with above poster that ALL CAPS, in the title, here at PR, was not needed or helpful.

    ******

    It is my own opinion, that some of us have very good reasons to supplement, various things we are very low on, and have no other source for it. (The most ill/disabled of us, cannot get outdoors for any sunlight, or cannot be skin exposed if we do, and have measured extreme low, and cannot digest a variety of foods )

    It is also my opinion, that over the past decades, and likely the future ones,
    the recommendations on Vit D, as well as MANY, and countless foods, vitamins, supplements, activities, lifestyles, and treatments, vascillate and vary, often back and forth over time,
    and different credible sources, even at any one given time, also reach differing conclusions and recommendations,

    so we often do not have available, as definitive exact absolute answer, like the article above seems to imply that we now do.

    These are my own opinions. I am Just sharing them. I made this effort, to write this post, in case it helps someone else, to read my view,
    or to weigh the posted research paper, with their own experiences and their other sources of info.
    Others are free to debate, if helpful for them,
    But for me in my extremely ill state, I personally do not want rebuttals directed at me, and my view debated, but prefer, we each state our own view, and let others ponder what is best for each individual, in their own circumstances.
     
    Last edited: Oct 5, 2018
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  14. Wolfcub

    Wolfcub Senior Member

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    I have to agree @pamojja
    The co-nutrients have such a varied part to play, not only the vitamin D3 intake. There are variables.

    Also I am aware that high doses have greatly helped many people, both with ME/CFS and without. It is a great supplement for people generally if not "overdone".

    My feeling is a vitD3 supplement is definitely needed if someone cannot get sunshine and/or is vegan or vegetarian (a vegan D3 is available). And that would apply to anyone, whether a CFS sufferer or not.

    However I also think that having ME/CFS (the strangest illness indeed!) can mean that unprecedented effects can happen which may not happen to others without this illness.
    I am aware that I for instance can no longer tolerate things I could have done before this illness, or have seemingly random neutral or even negative effects from things which helped me in the past; and even the strange effect that something helps so much when a treatment is first started....only for the benefits to suddenly stop even days later.
    I think many may have a similar experience.
    So that does have to be borne in mind with ME/CFS.
     
    Last edited: Oct 5, 2018
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  15. serg1942

    serg1942 Senior Member

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    Hi guys, I have changed my original post as suggested. Please let me know if now it's everything alright.

    I just came from a conference and I'm worn out, but I thought this was important, so I just made the suggested changes. I will read everything and get back to you soon, I hope this time to discuss science, which is my only goal.

    Best,
    Sergio
     
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  16. serg1942

    serg1942 Senior Member

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    I forgot to add, just to make things clearer, that I have not developed any untested hypothesis. This is an hypothesis defended by Mangin et al, Waterhouse et al, Amy Proal et al, Marshall G et al, among others (I make this point clear in my abstract) , which I have just explained and tried to find literature supporting or contradicting it. I just concluded that this so called 'alternate hypothesis', is well supported by the literature, and I give all the references I have used , so that you can check and make your own mind.

    By the way, this theory is not totally unproven. It is actually supported by direct interventional studies (with a VDR agonist) , as well as by indirect studies, which demonstrate parts of the puzzle conforming this theory.

    Finally, I don't even give my opinion on the partially tested theory, which I think might be incomplete. I only show literature supporting the theory.

    Best,
    Sergio
     
  17. Stretched

    Stretched Senior Member

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    @serg1942 This post replaces my earlier post on your other current thread on Vitamin D3... .

    You might Google Dr. Cicero Coimbra, neurologist in Brazil for his research and studies with Vitamin D3. He’s the guru of its doses and affects. I’ve followed his protocol after reading several other short books on the benefits of D3, and his MS cures using D3.

    I tried his super supplementation of D3 a couple of years ago. My dose was 150,000-200,000 IU daily. I went for about 3 months and it seemed to perk me up. I also followed his advice to use K2, B1, A, and Vitamin E in conjunction with these super high doses, plus lots of water.

    I then casually dropped to 20,000 IU daily and have been on that dose since, along with maintaining the other supplements mentioned. I feel okay with this, as Coimbra postulates that everyone can supplement with benefits using moderately high doses of D3. I suppose I’m convinced he’s right since his research papers tell of remarkable cures using extraordinary high doses of D3. BTW, he had/has? a Facebook page and a You Tube video.

    I have not tested specifically for D3 but all other blood panels are normal.
     
    Last edited: Oct 6, 2018
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  18. serg1942

    serg1942 Senior Member

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    Just to back up my previous statement. Here's a paper explaining the theory I dissect in my article, published by Amy Proal. It also shows the results of some patients following a treatment based on this proposed pathogenesis model. Again, I'm not defending this whole approach. I just described it, and focused on the probable problems arising from either high pathophysiological levels of VD1, 25, or from exogenous VitD supplementation.

    I hope this helps to put things in perspective:
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4076734/#!po=32.1705
     
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  19. jesse's mom

    jesse's mom Senior Member

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    My short lived experience with D vitamin was greatly helped by @serg1942 and @pamojja, in the other thread. I was instructed by my Dr to take a large dose weekly of vit d3 (50,000 IU). The result from one dose, was a dangerous drop in blood pressure and literally fainting while talking with my family. I could not walk on my own for three days. I drank fluids, took an inhaled corticosteroid, and increased my salt intake.

    The experience was scary and I almost went to the ER twice. After my blood pressure began to increase again I tried a tiny lick of a punctured gel cap of 3000. Again my blood pressure dropped to well below a normal low pressure. Determined to try to build up to a higher dose I shopped on amazon for a low dose vit D3. I settled for a children's dose and will try half of that and monitor my blood pressure. I have also ordered a child's dose of vit K and A. I was so amazed at how sensitive I have become to this!

    I am trying to achieve a lower blood pressure long term. My skin, in the last year burns easily, even with sunscreen on in the shade. I was always in the sun before CFS disabled me to bedridden for this past year. My skin browned nicely. One more side note is that I am not a milk drinker, although I do eat cheese and butter.

    Thank you all for your diligent research and reporting it here for us! I will watch this thread closely.
     
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  20. Chiron

    Chiron

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    Is vitamin D immuno suppressive or immune modulatory? I've always wondered this because sometimes vitamin D supplementation objectively increases my immune activity while at other times it seems to lower it.

    Also, are we talking synthetic D3, natural D3 from cod liver oil and such, or vitamin D produced by sunlight?

    What about people with various VDR mutations, how do they factor into this theory?

    If vitamin D is immune suppressive, is that a bad thing per se? I think about how sunlight is inhibitory to things like skin conditions. A lot of people experience improvements in psoriasis and eczema from UV exposure.

    One thing I've learned about hormones in my 2 years of study is that they are incredibly complex and feedback systems are sometimes unpredictable across various genetic phenotypes.

    I can't comment on high doses of D3 (25,000IU/day and above) because to me that is just off the grid.
     
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