| Section |
Description |
Last update |
| #00-intro | Introduction. |
2023-06-23 |
| #01-higher | Higher
than normal 25-hydroxyvitamin D levels to suppress chronic inflammatory
disorders: the (Cicero) Coimbra, (Patrick) McCullough and (Pete) Batcheller
protocols. |
2023-06-23 |
| #02-helminths | Lack
of intestinal worm infections leads to self-destructively strong immune
responses, including auto-immune disorders and much greater risk of
severe COVID-19. |
2021-10-02 |
| #03-ra | Other mechanisms related to rheumatoid arthritis and other autoimmune disorders. |
2021-10-02 |
| #04-novel | Compounds beyond D3, 25OHD and 1,25(OH)2D which are in the early stages of being researched. |
2021-08-24 |
| #05-25ohdreg | Regulation of 25-hydroxyvitamin D levels. |
2021-08-24 |
| #06-dau |
Review articles concerning vitamin D and autoimmune diseases |
2021-10-19 |
Brazilian patients with psoriasis and vitiligo were given 0.975 mg 35,000 IU of vitamin D3 a day, for 6 months. 25-hydroxyvitamin D levels rose for two months and then stabilised. For the psoriasis patients, the mean baseline was 14.9 ng/mL, rising to a mean of 106.3 ng/mL. For the vitiligo patients, the mean baseline was 18.4 ng/mL, rising to 132.5 ng/mL. No calcium supplements were allowed. Patients were instructed to avoid foods rich in calcium, and to drink 2.5 litres of water a day. No other nutrients were mentioned, but existing medications for the conditions were continued.
The treatment benefited all 16 psoriasis patients and 14 of the 16 vitiligo patients.
The researchers state that with sufficiently restricted calcium intake, there are no problems with bloodstream calcium levels rising excessively. Serum calcium levels need to be within a narrow range since most or all cells rely strongly on the concentration of calcium, sodium and potassium ions internally and in the extracellular fluid, which may be the bloodstream. ("serum" broadly means the liquid, plasma, part of the blood.)
They acknowledge that high circulating 25-hydroxyvitamin D levels cause excessive osteoclast [WP] activity, though they do not provide a mechanistic explanation for this. I guessed that this is due to 25-hydroxyvitamin D (calcifediol) molecules, which have a lower affinity for the vitamin D receptor molecule than 1,25-dihydroxyvitamin D (calcitriol) but nonetheless may activate VDR molecules in osteoclasts if the 25-hydroxyvitamin D level is high enough.
I later found confirmation of this important mechanism:Vitamin D-Mediated Hypercalcemia: Mechanisms, Diagnosis, and Treatment
Peter J. Tebben, Ravinder J. Singh, and Rajiv Kumar
Endocrine Reviews 2016-09-02
https://academic.oup.com/edrv/article/37/5/521/2567097
The ingestion of excessive amounts of vitamin D3 (or vitamin D2) results in hypercalcemia and hypercalciuria due to the formation of supraphysiological amounts of 25-hydroxyvitamin D [25(OH)D] that bind to the vitamin D receptor, albeit with lower affinity than the active form of the vitamin, 1,25(OH)2D, and the formation of 5,6-trans 25(OH)D, which binds to the vitamin D receptor more tightly than 25(OH)D.
(They discuss this 5,5 trans
isomer - a different shape of the same molecule - in the article. They
researched it in rats. To what extent this is important in humans
was unknown. See here for the article in which they report this, and articles which cite it.)
Osteoclasts are cells which destroy bone calcification.
Osteoblasts [WP] build bones, in part by raising calcium levels (mainly as
calcium hydroxyapatite) in bone. Healthy bone requires continual and
finely balanced activity of both osteoclasts and osteoblasts.
I do not understand how the combination of low calcium intake with increased osteoclast activity does not risk long-term de-mineralisation (weakening, due to less calcium compounds) of bone. It takes years for this to occur and precise testing of an individual's bone mineral density requires special techniques, with the same X-ray machinery, in precisely the same piece of bone, over multiple years.
I regard this potential long-term bone weakening as a serious concern. Hopefully many people will find their autoimmune inflammatory disease suppressed without pushing 25-hydroxyvitamin D levels as high as to cause significant loss of bone mineral density.
This article from the Calgary Vitamin D Study:
Adverse Effects of High‐Dose Vitamin D Supplementation on Volumetric Bone Density Are Greater in Females than Males
Lauren A Burt, Emma O Billington, Marianne S Rose, Richard Kremer, David A Hanley, Steven K Boyd
Journal of Bone and Mineral Research 2020-08-10
https://asbmr.onlinelibrary.wiley.com/doi/abs/10.1002/jbmr.4152 (Paywalled.)
https://sci-hub.se/10.1002/jbmr.4152
reports that while bone mineral density falls with age, that post-menopausal women who took 4000 IU vitamin D3 a year for 3 years, and those who took supposedly 10,000 IU a day for three years (but the content diminished, so they had less in the later part of the trial, and their 25-hydroxyvitamin D levels were only somewhat above those of the 4000 IU/day subjects after 3 years) had a greater rate of bone mineral density decline than those women who took 0.01 mg 400 IU a day.
The researchers were not expecting
this. These were the results of a very careful trial, with
precise X-rays of exactly the same part of the bones, with the same
X-ray machine. Bone strength was computed from the detailed
structure of the bone, and this showed no such decline in the higher
vitamin D3 intake subjects with respect to that of the women taking 400
IU a day. No such discrepancies were found in men of the same 55
to 70 age group.
(I have studied this in some detail but not yet written up what I found. There has been some discussion of this research - and there are citing articles.
I would like to follow this up more, but it takes days and weeks to
thoroughly research material like this - and I am an electronic
technician and computer programmer, not someone who is earns their
living for such work.)
The authors suggest 300 ng/mL circulating 25 hydroxyvitamin D is safe for
most people. This may be the case, but they acknowledge the need for
long-term research studies to assess the impact on bone and on other
so-far unknown potential ill effects.
Their theoretical framework is of higher 25-hydroxyvitamin D levels compensating for genetically determined "vitamin D resistance" in particular individuals, such as due to genetically determined inefficiencies in the 1-hydroxylase enzyme which converts 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D. I am not sure to what extent such differences have been found, but it is well established that genetic variations in the vitamin D receptor and the vitamin D binding protein are correlated with a large number of disease conditions.
See below for my critique of their theoretical framework.
While they mention vitamin D based intracrine and paracrine conversion of 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D in immune cells, they do not explain this as internal, and to nearby cell, signaling systems, which are completely distinct from hormonal signaling, both of which enable the cells to respond to particular circumstances and which are only activated when the cell detects those circumstances.
They repeatedly state, as most vitamin D researchers do, that
"vitamin D" "regulates" the immune system, immune responses and/or
immune cells. A proper understanding of vitamin D based intracrine and
paracrine signaling shows that this is absolutely not the case. High
circulating levels of 25-hydroxyvitamin D, diffusing into immune cells,
enable the cells to work properly by
producing the required amount of 1,25-dihydroxyvitamin D when required
- this is what activates the vitamin D receptors in the same, or in
nearby, cells and so changes their behaviour. This causes immune
responses to be better regulated.
The theoretical framework here seems to exclude genetic
variations, includes acquired difficulties in the metabolism of the
three vitamin D compounds and adds to - or perhaps expands on - this, by
mentioning "insufficient biological activity" of 1,25-dihydroxyvitamin
D:
Underlying the CP is the hypothesis of the non-hereditary, but acquired form of vitamin D resistance and insufficient biological activity of 1,25(OH)2D3, which both may be overcome by high doses of vitamin D3, compensating the resistance.
This article reports:
a retrospective analysis of almost 300 patients monitored with respect to their treatment according to the CP as well as an analysis of gene polymorphisms (SNPs) [WP] of the vitamin D metabolism in a subgroup of patients.
They outline the Coimbra protocol, including their starting
vitamin D3 doses for different conditions - something which was not
mentioned at https://coimbraprotocol.com.
1000 IU/kg body weight for MS; 300 - 1000 IU/kg body weight for the majority of other autoimmune diseases, such as rheumatoid arthritis, psoriatic arthritis, connective tissue diseases, plaque psoriasis, inflammatory bowel diseases; and 150–300 IU/kg body weight for autoimmune inflammation of the thyroid gland. The latter dosage was usually the starting dose in children for all diagnoses.
I get the impression that MS is the toughest disease they generally deal with, and that their aim is not to push for the highest possible 25-hydroxyvitamin D levels, at least initially, for many of the other diseases they treat. They provide a partial list of diseases they treated in their 319 patients in Germany, Austria and Switzerland:
36% vitiligo
23% multiple sclerosis
15% other diseases
7% alopecia areata, psoriasis
2% scarring alopecia, rheumatoid arthritis, atopic dermatitis, ulcerative colitis, autoimmune thyroditis
1% Crohn's disease, "psoriasisarthritis"
In
the long term, the mean vitamin D3 dose was 52,955 IU/day for MS
patients and 29,791 IU/day for patients with all other diseases.
(I use the term "supplemental intake" for vitamin D general nutrition,
but these are medicinal doses intended to suppress or cure disease.)
These doctors do not require that 25-hydroxyvitamin D levels be
tested. However they present some data from such tests done by the
patients' primary care doctors.
440 values of 25(OH)D in 186 different patients with a mean of 141.4 ± 75.6 (SD) ng/mL (data not shown). The maximum value of 806 ng/mL 25(OH)D in a single female patient with MS was not paralleled by abnormal results in renal function or serum and urinary calcium levels.
This 806 ng/mL a much higher level than any I recall reading about. The Endocrine Society 2011 recommendations include these statements, including an arbitrarily derived 100 ng/mL threshold - but there is no account for bodyweight or obesity:
Although it is not known what the safe upper value for 25(OH)D is for avoiding hypercalcemia, most studies in children and adults have suggested that the blood levels need to be above 150 ng/ml before there is any concern. Therefore, an upper limit UL of 100 ng/ml provides a safety margin in reducing risk of hypercalcemia.
In addition to a low calcium diet, and 2.5 litres of water a day, patients are required to "manage stress" (This always makes me wonder - such an instruction is just another stressful constraint! "Meditation, yoga, qigong, tai chi, and psychotherapy" are recommended. I think they should tell people to minimise or eliminate caffeine and go easy on the dark chocolate.)
In order to avoid osteopenia or osteoporosis following strict calcium restrictions, frequent and regular exercise (jogging and walking) or where physically applicable daily use of a vibration plate was strongly recommended as prophylaxis.
(A "vibration plate" is a strongly vibrating platform which
supposedly increases the benefit of exercise including holding muscles
taut, by cyclic increases in tensile stress on these muscles.)
They prescribe magnesium, a form of vitamin A and vitamin K2. (I will write about vitamin K2 after I have read more research on it - there are multiple forms of it, and it occurs already in some plant foods.)
In addition to exercise, they use vitamin K2 to reduce the degree to which high 25-hydroxyvitamin D levels may weaken bones:
Vitamin K2 (menaquinone) has been described as a protective factor for bones (cofactor for mineralization in synergy with vitamin D and vitamin A), the circulatory system and endothelium (cofactor for demineralization, also in synergy with vitamin D and vitamin A). In addition, antioxidative effects have been described. As recently shown, MS patients have much lower blood levels of vitamin K2 than healthy controls. Since high doses of vitamin D may increase the risk of artery calcification following the elevation of serum calcium, we add vitamin K2 to the CP in daily concentrations between 100 µg and 800 µg depending on the starting dose of vitamin D3 and the levels of serum calcium and urinary calcium excretion.
Further dietary supplements depend on many different aspects, such as type and disease activity, blood analysis, degree of inflammation, oxidative and nitrosative stress, results from gut microbiome analysis and many others.
Further to a bunch of tests I won't list here, there is additional monitoring of bone and kidney health:
Depending on baseline levels, bone densitometry as well as bone metabolizing parameters (such as bone-specific alkaline phosphatase, P1NP or osteocalcin, and urine for serum crosslinks) should be monitored individually. Additionally, ultrasound examination of the kidneys once a year is very valuable.
I assume they are concerned about kidney stones. Supplemental boron would probably reduce or eliminate the risk of this. See the research of M. R. Naghii https://aminotheory.com/cv19/#boron-kidney-stones .
(I am yet to identify, read and analyse the best research on kidney stones and vitamin D.)The results and safety analysis they present are too detailed to
summarise here, but they found no problems with hypercalcemia (excessive
calcium in the bloodstream) or with kidney function. They did not
mention any detailed, precise, long-term measurements of bone mineral
density. The article was finished in March 2022, four years after they
began using the Coimbra protocol.
. . . increases in dosages are - under appropriate doctoral supervision - only moderately correlated with the subsequent serum and urinary calcium measurements.
However, with respect to all single measurements in 319 patients in over 3.5 years, we temporarily stopped vitamin D3 only in 27 situations, when calcium excretion exceeded more than 10 mmol/24 h (normal values: 2.50–8 mmol Calcium/24 h). In almost all cases, the dietary calcium intake was reviewed with the patient with emphasis on reducing calcium intake to less than 500 mg daily and they were encouraged to increase fluid intake. As a result, the patients were restarted on the CP four-to-eight weeks later without any further disruptions in their treatment.
In 16 cases (13 f, 3 m, mean age 39.1 years), the CP treatment was stopped due to different reasons (e.g., non-compliance, no clinical effect, increase in symptoms, food supplements too expensive, diet too complex, daily fluid intake too stressful, pregnancy, familial hypocalciuric hypercalcemia, and significant increase in parameters of bone metabolism).
They analysed the prevalence of various gene mutations in their patients.
We strongly recommend that CP is always used in the hands of qualified and experienced physicians and strongly advise against the use of CP by patients themselves based on Internet information.There are links to 113 pages (August 2022), each a testimony with
photographs of a person who benefited from the Coimbra protocol.
The diseases include:
71 Multiple sclerosis
7 Rheumatoid arthritis
7 Atopic dermatitis
4 Myasthenia gravis
3 Vitiligo
3 Psoriasis
2 Neuromyelitis Optica (NMO) or Devic's disease
2 Lupus
2 Lyme disease
2 Sjogren's syndrome
1 Spongiotic dermatitis
1 Fibromyalgia
1 Alopecia
1 Schleroderma
1 Sjogren's syndrome
1 Psoriatic arthritis
1 Idiopathic thrombocytopenic purpura
1 Type 1 diabetes (This is extraordinary.)
1 Autoimmune polyneuropathy
1 Ichtyosis
1 Crohn's disease
It is worth reading some of these, such as from Ludi Caneiro, with MS:
"When I first got sick I had so many symptoms; weakness, fatigue, tingling, and several others that I do not even remember after my treatment. I'm so grateful to Dr. Coimbra for seeing me right away despite his busy schedule, I went to his office with a heart full of hope, and once I met him in person, I knew I was following the right path.
Today, five years later, I have a completely normal life and two beautiful children, I've had two easy, great pregnancies without the need to interrupt my treatment. My children are so strong, healthy and beautiful. The only memory I have of MS is a slight weakness in my left leg, which does not prevent me from doing anything; walking, running, jumping, practicing sports and lifting weights, everything I used to do before my diagnosis.
Today I take 60,000 IU a day and live a normal, healthy life."
These reports are a good contrast to reading all the relatively bleak academic journal articles.
A German site devoted to the Coimbra protocol, which is run by some of the doctors who co-wrote Amon et al. above, has 58 testimonials:
This link is to the Google Translate version so following the links leads to English translations of each report, such as this one on Crohn's disease.
(This subsection added 2023-06-23.)
This is a simple and - I think - robust critique of the hypothesis presented by Dr Coimbra and other doctors using his protocol, as just described, which, in summary, is that the etiology of auto-immune diseases is primarily or wholly due to genetic and/or acquired "vitamin D resistance".
Many of the diseases which the Coimbra protocol is effective for treating can also be successfully treated by helminthic therapy: introducing a relatively benign intestinal worm infection, without any other intervention regarding vitamin D3 or other nutrients.
Crohn's disease patients have gone into remission after treatment with pig whipworm: PMC1774382
https://helminthictherapywiki.org/wiki/Special:AllPages
Lupus patient abandons wheelchair to run nine miles a week after getting hookworms
fibromyalgia, IBS and rheumatoid arthritis
13 years of remission for Crohn's disease and IBD-related arthritis
* This leads to a video reporting success in suppressing Parkinson's disease and an article PMC5626019 about
cytotoxic T cells recognising alpha-synuclein in PD patients. I
guess that such activity might drive disease progression - such as by
breaking up single agglomerations into multiple smaller agglomerations
which continue to grow - and be amenable to better regulation by
helminthic therapy and/or higher 25-hydroxyvitamin D levels. An article
in a non-PubMed-indexed journal collates reports of helminthic therapy
being effective for dozens of illnesses, though I suspect some of these
reports are spurious.
Since there is no reason to believe that helminthic therapy significantly alters the operation of the three vitamin D compounds, and the results are the same, it follows that the fundamental etiology of these diseases cannot be due to problems with vitamin D compounds.
I propose, as in my summary above, that while genetic variations of many types - including those affecting vitamin D - play some role in the etiology of all these disorders, the primary problem is lack of helminths. As described below, our immune system evolved to cope with helminthic compounds which downregulated the inflammatory, indiscriminate cell-destroying, immune responses which tackle these parasites. So, in general, our inflammatory responses are stronger than what would be most healthy for us, in the absence of those down-modulatory compounds. Most people in developed countries are not infested with helminths.
Helminthic therapy is not out of the question for any deadly and supposedly untreatable disease. Ideally, we would be able to use helminthic compounds as pharmaceuticals and so downmodulate our excessive inflammatory responses to any degree we choose, without actual helminths. However, none are currently available for use, and I am not sure to what degree they are being used in human trials.
For reasons unknown, very high 25-hydroxyvitamin D levels are highly capable of down-modulating excessive inflammatory responses even in the absence of helminths - but we must remember that this also enables much stronger innate and adaptive responses than are possible with the typically low, 25 ng/mL or less, 25-hydroxyvitamin D levels most people have today, without proper vitamin D3 supplementation.
Daily oral dosing of vitamin D3 using
5000 TO 50,000 international units a day in long-term
hospitalized patients: Insights from a seven year experience
Patrick J McCullough, Douglas S Lehrer and Jeffrey Amend.
Journal of Steroid Biochemistry and Molecular Biology 2019-01-04
https://www.sciencedirect.com/science/article/abs/pii/S0960076018306228
(Paywalled.)
https://sci-hub.se/10.1016/j.jsbmb.2018.12.010
Please also see: https://aminotheory.com/cv19/#helminthsgone
As best we know, our ancestors, going
back tens of millions of years, were ubiquitously infected with
helminths (intestinal worms) which evolved to exude compounds which
down-modulate the inflammatory immune responses which mammals evolved
to destroy multicellular parasites. Antibodies and macrophages
(adaptive responses) and the innate responses which work well against
viruses, bacteria and fungi are no use against multicellular
parasites.
Inflammatory immune responses involve
large-scale, indiscriminate, destruction of multiple cells - ideally
those of the parasite but also, unavoidably, our own. There
are several mechanisms, but one example is regulatory lymphocytes
secreting pro-inflammatory cytokines (immune system signaling
molecules) into the area where the parasite is located, which
attracts eosinophils [WP]
to the site. Eosinophils are the suicide bombers of the immune
system. Once activated (by appropriate cytokines) the eosinophil
disintegrates, releasing a variety of compounds from its
vacuoles. These destroy proteins, DNA, RNA and disrupt cells in
other ways, such as with reactive oxygen species. They also
release cytokines which affect the behaviour of other immune
cells.
Inflammatory responses can also play a role in fighting some viral infections. See McGregor et al. 2020 https://aminotheory.com/cv19/icu/#2020-McGregor
for Th1 regulatory lymphocytes responding to SARS-CoV-2 infection in
the lungs by emitting a pro-inflammatory mix of two-cytokines in their
startup program (a lot of a pro-inflammatory cytokine and a little of
an anti-inflammatory cytokine). After some time (hours, I
guess) the Th1 lymphocyte detects changes in other parts of the immune
system in its vicinity (a high level of a complement protein [WP])
which causes it to switch to an anti-inflammatory shutdown program, by
producing a little of the pro-inflammatory cytokine and more of the
anti-inflammatory cytokine. This is presumably a healthy response
to this infection. However, if the TH1 lymphocyte does not have enough 25-hydroxyvitamin D, then it cannot make this transition, and remains stuck indefinitely in its pro-inflammatory program.
McGregor et al. observed this failure to transition to the anti-inflammatory shutdown program in Th1 cells from the lungs of severe COVID-19 patients. It is reasonable to assume that the lack of 25-hydroxyvitamin D caused these Th1 cells to produce the (pro-inflammatory) cytokine storm which causes widespread destruction of endothelial cells, especially in the lungs, leading to hypoxia and tissue damage which cause microembolisms and larger clots in the lungs, brain, heart and all other organs: harmful and possibly deadly severe COVID-19.
It is also reasonable to assume similar
processes are at work in other acute hyper-inflammatory immune
dysregulation disorders which are to a large extent caused by
inadequate levels of 25-hydroxyvitamin D: sepsis (GS), Kawasaki disease (Stagi et al. 2015), Multisystem Inflammatory Syndrome (Fekatea et al. 2020) and pre-eclampsia [GS] .
However, for most people in many or most countries since (very
approximately) the early 20th century, an additional problem drives
excessive inflammatory responses: due to not having helminth
infections, our inflammatory immune responses are far stronger than
what would be healthy, because the genetic instructions which create
the immune system evolved over tens of millions of years in which the
base level responses had to be stronger than whatever strength is most
healthy, to compensate for the weakening effects of the
immunomodulatory compounds (we assume there are more than one) exuded
by likely several species of helminths.
The combination of nearly ubiquitous lack of helminths (leading to
overly strong inflammatory responses, differing from one individual to
the next according to genetic variation) AND the very widespread lack
of sufficient (such as 50ng/ml) 25-hydroxyvitamin D, is the setting
which gives rise to vast amounts of auto-immune disorders AND to the
acute hyper-inflammatory dysregulated immune responses which drive
sepsis, severe COVID-19 etc.
As we see from the previous section, for some or many people who
experience auto-immune problems with common (lower than 50ng/ml)
25-hydroxyvitamin D levels, and with 50ng/ml, it is frequently possible
to suppress the pathologically hyper-inflammatory immune responses
which cause their conditions by higher than normal (well above 50ng/ml)
25-hydroxyvitamin D levels. As far as I know, there is no
detailed research on the mechanisms which cause this.
In this context, I was not surprised to find this important new research:
Ethiopian COVID-19 patients with active helminth infections were found to have a 77% lower chance of severe COVID-19 compared to those without such infections. (p < 0.0001)
11 of the 257 patients without helminth infections died. None of the 284 patients with helminth infections died. (p = 0.009).
Helminths-based bi-functional molecule, tuftsin-phosphorylcholine (TPC), ameliorates an established murine arthritis
Miri Blank, Tomer Bashi, Jordan Lachnish, Dana Ben-Ami-Shor, Ora Shovman, Mati Fridkin, Miriam Eisenstein, Alexander Volkov, Iris Barshack and Yehuda Shoenfeld.
PLoS One 2018-08-08
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0200615
Some people find relief from autoimmune disorders by the introduction of helminths: https://helminthictherapywiki.org . This is a highly significant research article:
Trichuris suis therapy in Crohn’s disease
R W Summers, D E Elliott, J F Urban Jr, R Thompson and J V Weinstock Gut 2005 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1774382/
871 Google Scholar citations.