Advanced vitamin D topics - some people need much more D3 than normal, to suppress rheumatoid arthritis, multiple sclerosis, psoriasis, cluster headaches, migraines etc.; Newly discovered vitamin D compounds; The impact of lack of helminths on inflammatory responses, including severe COVID-19

This page is a work in progress..

../ To the main page of this site.

Robin Whittle rw@firstpr.com.au  02 October 2021    Twitter: https://twitter.com/RobinWhittle3
(First established 2021-07-16.)

Disclaimer:

You are reading the best efforts of an electronic technician and computer programmer.   What I write will hopefully help you understand the research, but should not be mistaken for medical advice.  Medical advice is what you get after a doctor has examined you.  Even if I was a doctor, I haven't examined you!

Don't take my word for anything.  Please read the research articles I cite - or at least their abstracts and my summaries.  If you don't understand them, please ask your doctor or other healthcare professional to read them and advise you. 


Before reading this page, please familiarise yourself with the research articles I link to and discuss at:

What every MD should know about vitamin D and the immune system
https://vitamindstopscovid.info/05-mds/

For an overview of vitamin D, COVID-19 and early treatment for this, and how these are being ignored in the current global push for vaccination, without early treatment, as the sole solution:  https://nutritionmatters.substack.com/p/vitamin-d-and-early-treatment-vs


This page assumes a strong interest in biology and treatment arrangements which go not only beyond many MD's limited knowledge of vitamin D, but also beyond a properly informed knowledge of the needs for most people for D3 supplementation to enable the immune system to work well, as described in the above-mentioned page.

If you have this strong interest, a reasonable knowledge of biology and the ability to make your own decisions, even tentatively so, about your own and your family's health, then you might like to join the Nutrition for Immune System Health (NISH) email discussion list: https://NISH.groups.io .  This is a high-signal-to-noise ratio discussion group with MDs and nurses (only one so far), leading vitamin D researchers (many of whom are MDs), nutritionists, as well as autodidacts such as myself with no formal qualifications.

On 2021-10-02 I added mention of new research on helminths (intestinal worms) including how active helminth infections in Ethiopia are associated with a 77% reduction of incidence of severe COVID-19.  This is really interesting and makes good sense once the evolutionary history of helminth infections and the immune system is understood.

Contents

Section
Description
Last update
#00-intro Introduction.
2021-08-24
#01-higher Higher than normal 25-hydroxyvitamin D levels to suppress chronic inflammatory disorders.
2021-08-24
#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





#00-intro

00 Quick intro and some articles of interest

The articles linked to from the  ../05-mds/ page are broadly sufficient to understand everyone's need for circulating 25-hydroxyvitamin D levels of 50ng/ml 125nmol/L or more, in order that the immune system can work properly.  This is normally best achieved with supplemental vitamin D3, though in emergencies, a single, small, oral dose of calcifediol repletes these levels in about 4 hours.  Calcifediol is the name most commonly used for 25-hydroxyvitamin D as a pharmaceutical: https://vitamindstopscovid.info/04-calcifediol/ .

These discussions apply directly to humans - and generally to companion and agricultural non-human animals, who - without proper supplementation - may not be getting the D3 they need to be healthy.

This page concerns:
I can't write about all this yet, since I need to carefully read the articles first!


#01-higher

01 Higher than normal D3 intakes to suppress autoimmune overly-inflammatory conditions:

#cc

The Coimbra Protocol

This was developed by Dr Cicero Coimbra in Brazil to suppress MS (Multiple Sclerosis) and potentially other autoimmune diseases.   I know two people who have used this approach to successfully suppress extremely debilitating rheumatoid arthritis.

https://www.coimbraprotocol.com/the-protocol-1

https://www.grassrootshealth.net/blog/dr-coimbras-protocol-multiple-sclerosis/


#pm

Patrick McCullough and colleagues in Ohio

Dr McCullough takes 1.25mg 50,000IU D3 a day to suppress psoriasis.  He and his colleagues research healthy D3 intakes for most people, and the much higher intakes which (with suitable medical supervision) suppress a variety of auto-immune diseases.

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


Oral and Topical Vitamin D, Sunshine, and UVB Phototherapy Safely Control Psoriasis in Patients with Normal Pretreatment Serum 25-hydroxyvitamin D Concentrations: A Literature Review and Discussion of Health Implications

Patrick J McCullough, William McCullough, Douglas Lehrer, Jeffrey Travers and Steven Repas.
Nutrients 2021-04-27
https://www.mdpi.com/2072-6643/13/5/1511

#pb

Pete Batcheller - cluster headaches and migraine

The above two MDs are world leaders in clinical research regarding higher than normal D3 intakes to suppress MS, rheumatoid arthritis, psoriasis etc. - all of which are well known to be caused by excessive inflammation.

Pete Batcheller (Washington State, USA) is another such pioneer, though he has no medical qualifications.  He has a chemistry degree and is a retired US Navy fighter pilot and commander.  His research and outreach was prompted by his own debilitating cluster headaches.   He used oxygen as an abortant (to stop the CH attack within minutes or tens of minutes) and after some years noticed that he had little trouble with CHs in summer - the time of peak vitamin D, since he spent a great deal of summer outdoors. 

By experimentation, very extensive reading of prior research literature, and work with now thousands of sufferers, Pete Batcheller has developed a detailed, reliable, protocol which greatly reduces and for some people eliminates the occurrence of these frightening, exceedingly painful, cluster headaches.

He has helped over 5000 cluster headache and migraine sufferers (personal conversation, 2021-08-22) suppress their symptoms with a protocol which resembles that of Dr Coimbra - with whom he has corresponded.   

The link between excessive inflammation and his own cluster headaches was made clear in after he cleared the windscreen of his pickup truck of a layer of pollen which had settled there.  His D3, boron and other nutrients protocol had kept the CHs in abeyance for years, but they returned with a vengeance within hours of this gross pollen insult to his immune system.   Illness can reduce circulating 25-hydroxyvitamin D levels and so cause CHs to occur again - so extra D3 and/or first generation antihistamines (which cross the blood-brain barrier) can be used to counter this.

Pete Batcheller's success in largely suppressing these awful conditions, with the help of people who he communicates with via his website, shows that there are significant human health problems which are not yet solved by MDs and professional researchers, but which are amenable solution to imaginative, highly motivated people who lack medical qualifications.   His website is:

http://www.clusterheadaches.com

His Protocol is available as a PDF (Download the CH Preventative Treatment Protocol . . .) at:

Suggested Preventative Treatment Protocol for Neurologists, Pain Specialists, and Primary Care Physicians using the Anti-Inflammatory Regimen to Treat Patients with Cluster Headache
Pete Batcheller, CDR USN (Ret.) January 15, 2017 
https://vitamindwiki.com/Cluster+headaches...

This guidance for primary care physicians and neurologists has been used successfully and without adverse outcomes by over 5000 cluster headache (and migraine) sufferers in the past 4 years.    It includes suggested testing frequency for 25-hydroxyvitamin D levels, and for total calcium and parathyroid hormone levels, the latter two which should be monitored every 6 or 12 months to ensure they remain within their reference ranges.

Although directed at the needs of cluster headache sufferers, and to the similar needs of those suffering from migraine, I think this document is an excellent reference for people who are suffering from other systemic hyper-inflammatory disorders, including all those mentioned in the title of this page.

It is not an RCT or a peer-reviewed journal article.  It is the product of years of research and working with hundreds of people by the time it was written.  The subsequent thousands of successful interventions (according to self-reported survey responses) and the absence of reports of problems - to the researcher / sufferer who is unusually well connected with thousands of sufferers - indicate that this Protocol contains valuable guidance.

The mean 25OHD of CH sufferers before commencing the protocol was 22.8ng/ml.  Typical daily D3 intakes were of the order of 0.25mg 10,000IU - along with omega 3 fatty acids, particular forms of vitamin K2, boron, zinc, magnesium and B vitamins as well as other vitamins and minerals.

The optimum pain-free 25-hydroxyvitamin D serum concentration was 83.4ng/mL = 208.5nmol/L.
 
A handful of CHers under physician’s supervision, have reported sustained
serum 25(OH)D concentrations above 100 ng/mL, (250 nmol/L) some as high as 198 ng/mL.  They also reported total calcium serum concentrations were within normal reference ranges and PTH concentrations at the low end of the reporting range with no other symptoms other than a cessation of their CH.  

Mechanisms by which higher than normal D3 intakes might help suppress auto-immune hyper-inflammatory diseases:

Vitamin D Resistance as a Possible Cause of Autoimmune Diseases: A Hypothesis Confirmed by a Therapeutic High-Dose Vitamin D Protocol
Dirk Lemke, Rainer Johannes Klement, Felix Schweiger, Beatrix Schweiger and Jörg Spitz
Frontiers in Immunology 2021-04-07
https://www.frontiersin.org/articles/10.3389/fimmu.2021.655739/

#02-helminths

02 Helminths downmodulate inflammatory responses

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:

Effect of co-infection with intestinal parasites on COVID-19 severity: A prospective observational cohort study
Dawit Wolday et al.
EClinicalMedicine  2021-09-01
https://www.thelancet.com/journals/eclinm/article/PIIS2589-5370(21)00334-5/fulltext

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).

These two highly significant results are strong arguments for the causality being from helminth infections to protection from hyper-inflammatory immune responses.  However, two other mechanisms come to mind, which I guess are of limited or no significance:
  1. it is possible that a secondary cause might be people with poorer sanitation and so living conditions (who are more prone to helminth infections) may spend more time outdoors and so have higher 25-hydroxyvitamin D levels.  Unfortunately these levels were not measured.

  2. Assuming there is significant variation in the strength of the immune response (in the absence of helminths) between individuals, as is surely the case, then perhaps those with the stronger inflammatory immune responses are less likely to be infected with helminths - and these same people are  more likely to develop severe COVID-19 because of that stronger inflammatory response.

The researchers attribute their observations to the patients having a "different, more activated" immune response as a result of helminth infection.  However, there's no reason to believe that helminth infections lead to better immune responses. For this to occur, they would either have to produce anti-viral compounds which the human immune system had not evolved, or somehow stimulate a greater antiviral response than the human immune system would generate on its own.  These mechanisms can't be ruled out, but a more likely explanation for most or all of the observed differences in outcome is as just mentioned, especially in the context of the research by Miri Blank and colleagues mentioned below.

Helminth infections cannot reasonably be introduced to fight severe COVID-19, because they would take too long to develop.  However, these observations are most informative when trying to understand all the factors which affect COVID-19 disease progression.

Ideally, I think, we would have one or more of the immunomodulatory compounds exuded by helminths (at least one is currently known) available as pharmaceutical treatments to suppress autoimmune disorders AND sepsis, severe COVID-19 etc.

This little known field is fascinating and potentially as important for the health of humans and our companion and agricultural animals as vitamin D.

As best I can tell, the helminth researchers and vitamin D researchers have little or no contact or knowledge of each other's work.   They  should compare notes more!

Here is one of the research articles concerning a helminthic compound which down-modulates inflammatory immune responses.  Ideally I would have time to research this field more thoroughly.  This page is an early work in progress. 

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.

An older Crohn's disease article.  I want to find some more recent ones too. See the articles which cite this one:

Therapeutic Effect of Vitamin D Supplementation in a Pilot Study of Crohn's Patients
Linlin Yang; Veronika Weaver; Jill, Smith; Sandra, Bingaman; Terry, Hartman and Margherita Cantorna
Clinical and Translational Gastroenterology 2013-01-13
https://journals.lww.com/ctg/...Therapeutic_Effect....aspx

176 Google Scholar citations.

Here are two other articles concerning helminths and COVID-19:

Helminth coinfection and COVID-19: An alternate hypothesis
Russell Hays, Doris Pierce, Paul Giacomin, Alex Loukas, Peter Bourke and Robyn McDermott.
PLOS Neglected Tropical Diseases 2020-08-17
https://journals.plos.org/plosntds/article?id=10.1371/journal.pntd.0008628

26 Google Scholar citations.

Old friends meet a new foe: A potential role for immune-priming parasites in mitigating COVID-19 morbidity and mortality
Tara J Cepon-Robins, Theresa E Gildner
Evolution, Medicine & Public Health  20201-10-20
https://academic.oup.com/emph/article/2020/1/234/5930904

9 Google Scholar citations.

There are other articles of interest in these citation lists.

#03-ra

03 Connections between Rheumatoid Arthritis (RA), psoriasis and potentially other conditions - and some cell-biology hypotheses of contributing causes

Regarding RA, please also see my earlier material on boron: https://aminotheory.com/cv19/#08-boron .

Perhaps there is a way of connecting tenuous knowledge of:
These are all deep and developing fields.  I expect my rabbit-hole alarm to go off frequently.  Hopefully I will find something interesting without being lost interminably in the warrens.

Citrullination [WP] involves an enzyme modifying an arginine amino acid when it is part of a protein.  An NH ketamine group is replaced with an O ketone group, both doubly bonded to the molecule.  This changes the arginine into citrulline, which is not a protein building amino acid.  The behaviour of the whole protein changes in several ways, and this can trigger the production of antibodies and then those antibodies attaching to said proteins, triggering a cell-destroying (inflammatory) response.

The articles below also concern some aspects of the HLA-DR [WP]  which may be involved in both RA and worse outcomes in COVID-19.  (I am yet to read these articles, except the last: Martin et al. 2021.)

How citrullination invaded rheumatoid arthritis research
Walther J van Venrooij & Ger JM Pruijn
Arthritis Research & Therapy 2014-01-29
https://arthritis-research.biomedcentral.com/articles/10.1186/ar4458


Functional and Structural Characterization of a Novel HLA-DRB1*04:01-Restricted α-Enolase T Cell Epitope in Rheumatoid Arthritis
Christina Gerstner, Anatoly Dubnovitsky, Charlotta Sandin, Genadiy Kozhukh, Hannes Uchtenhagen, Eddie A. James, Johan Rönnelid, Anders Jimmy Ytterberg, Jennifer Pieper, Evan Reed, Karolina Tandre, Mary Rieck, Roman A. Zubarev, Lars Rönnblom, Tatyana Sandalova, Jane H. Buckner, Adnane Achour and Vivianne Malmström
Frontiers in Immunology 2016-11-14 
https://www.frontiersin.org/articles/10.3389/fimmu.2016.00494


Progression on Citrullination of Proteins in Gastrointestinal Cancers
Shuzheng Song and Yingyan Yu
Frontiers in Oncology 2019-01-23
https://www.frontiersin.org/articles/10.3389/fonc.2019.00015


The influence of HLA genotype on the severity of COVID-19 infection
David J. Langton, Stephen C. Bourke, Benedicte A. Lie, Gabrielle Reiff, Shonali Natu, Rebecca Darlay, John Burn and Carlos Echevarria
HLA Immune Response Genetics 2021-04-19
https://onlinelibrary.wiley.com/doi/10.1111/tan.14284


Association between psoriasis and rheumatoid arthritis in a nationally representative population in the United States
Amylee Martin, Akshitha Thatiparthi, Jeffrey Liu, Jashin J. Wu.
Journal of the American Academy of Dermatology  Letter 2021-07-15
https://www.jaad.org/article/S0190-9622(21)01945-9/ (Paywalled.)

(Dr Wu has kindly sent me a copy of this article.)

A carefully conducted survey found that 8.1% of people with psoriasis reported a history of RA, while such a history was reported by only 4.0% of people without  psoriasis.  The OR for these findings varied from 2.82 for subjects aged 20 to 49 and 1.64 for subjects aged 50 and above.  The authors write:

This association may be attributed to a similar pathophysiology, with
tumor necrosis factor-alpha and interleukin 17 implicated in both the disorders.  Interestingly, tumor necrosis factor-alpha inhibitors have been reported to paradoxically induce and/or worsen psoriasis, most commonly, in individuals with RA or Crohn disease.


#04-novel

Recently discovered - or at least little known to MDs - but potentially significant vitamin D compounds

Add a hydroxyl group to the 20th carbon in D3 and . . .

20S-Hydroxyvitamin D3, a Secosteroid Produced in Humans, Is Anti-Inflammatory and Inhibits Murine Autoimmune Arthritis
Arnold E. Postlethwaite, Robert C. Tuckey, Tae-Kang Kim, Wei Li, Syamal K. Bhattacharya, Linda K. Myers, David D. Brand, and Andrzej T. Slominski
Frontiers in Immunology 2021-06-30
https://www.frontiersin.org/articles/10.3389/fimmu.2021.678487/

Sulphated 25-hydroxyvitamin D is prevalent in the circulation:

The serum vitamin D metabolome: What we know and what is still to discover
Robert C. Tuckey, Chloe Y.S. Cheng, Andrzej T.Slominski
Journal of Steroid Biochemistry and Molecular Biology  2018-09-04
https://www.sciencedirect.com/science/article/abs/pii/S0960076018302206 (Paywalled.)
https://sci-hub.se/10.1016/j.jsbmb.2018.09.003
60 Google citations.


#05-25ohdreg

05 Regulation of circulating 25-hydroxyvitamin D levels by enzymes which degrade it, at rates approximately proportional to its concentration, forming a negative feedback system which makes it harder to raise higher levels than lower levels


I have a general idea that this works, but would like to know a lot more about the mechanisms and to what extent they are affected by and affect D3 levels - and more broadly conversion of D3 to 25OHD in cells outside the liver.

See the above-mentioned article: The serum vitamin D metabolome . . . .


© 2021 Robin Whittle   Daylesford, Victoria, Australia