Saturday, July 25, 2009

Hidden Risks and Dangers of the Marshall Protocol

An individual made the following post on a Fibro. bulletin board last month, which I found well constructed and inclusive of several citations. This individual was on the MP for a few years and did not have a favorable experience with regards to their Chronic Fatigue Syndrome (CFS). Sadly, this doesn't appear to be an isolated case, and many additional veterans of the protocol are reporting similar unfavorable results by engaging in a protocol designed to restore health that includes radically disobeying the laws of mother nature.
“The human body does not require sunlight, nor foods containing Vitamin D, in order for it to function correctly. The human body can manufacture all the Vitamin D it needs from its own 7-dehydrocholesterol. Clinical medicine is just plain wrong on its understanding of the actions of Vitamin D.” Trevor Marshall (1)

The Marshall Protocol (MP) claims to cure CFS and FM, as as such, is a very polarizing topic. People are either really for it, or really against it. Seduced by the molecular modeling and hope of a cure, I was on the protocol for almost two years. However, after almost landing in ER and experiencing a permanent deterioration in all my CFS symptoms, I have learnt first-hand of the dangers and risks of the MP, none of which I was warned. The MP worsened my existing CFS symptoms such as fatigue, sleep dysfunction, muscle and joint pain and created new symptoms such as neuropathy, parenthesisa, breathing difficulties, cardiac pain and tinnitus which have persisted. Thus I feel that it is my duty to warn others who may be considering the MP, which continues to attract many new patients, of all the hidden risks so that they can make a fully informed decision about whether to undertake this protocol.
To read more, the entire post can be found here: Hidden Risks and Dangers of the Marshall Protocol

The MP > Does Exogenous Vitamin D Really Dock & Deactivate the VDR and Innate Immunity?

Since first discovering the low carb forum I became very interested in vitamin D and became convinced that supplementation was necessary to maintain good health due to the geographic location I reside in (north mid-west U.S.) and the unnatural amount of sunlight I get exposed to on average. Over time I became aware of what is known as the Marshall Protocol (aka the 'MP') and immediately absorbed all of the various information surrounding the protocol and the originator and camp's theories regarding vitamin D and the connection with chronic disease.

In short, one of their main theories is that 'exogenous' (taken in from foods and supplements as opposed to created internally from sun and/or bright light exposure) vitamin D (25OHD, the storage form) is immunsuppressive because it actively binds to, displaces, and deactivates the active form of vitamin D (calcitriol, 1,25OHD3) from the vitamin D (nuclear) receptor (VDR).

These claims by Marshall and the MP camps are only substantiated (to my knowledge) by 'molecular modeling computer simulations' otherwise known as in-silico experiments. There is much controversy around Marshall's theories and people tend to be on polar opposites when concluding whether the theories are valid or not. The in-silico experiments are difficult for many to swallow to adequately justify his theory that 25OHD binds and deactivates the VDR, because they are essentially in-vitro experiments that do not account for many variables that exist when 25OHD exists in a living organism such as a human being.

Being someone who benefits from vitamin D supplementation and believing it to be a vital nutrient for human health and well being, especially when consumed or obtained in synergy with the other fat soluble nutrients like vitamin A and vitamin K2 (Price's once elusive 'X-factor' activator) and especially after reading Weston Price's Nutrition and Physical Degeneration, I began searching for scientific explanations that would dispel Marshall's theory that 25OHD vitamin D shuts down innate immunity in a dose dependent manner and has the ability to directly bind to and deactivate the VDR.
Posted by Josiah Zayner

http://tinyurl.com/ae7hxz

Myself being a molecular biologist and competent in the use of molecular dynamics simulations it is apparent that Mr. Marshall's work is incorrect and he consistently refuses to provide any parameters used in his simulations. See comments on:

http://precedings.nature.com/documents/52/version/1
http://precedings.nature.com/documents/164/version/1

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Originally Posted by Anonymous M.D.

http://tinyurl.com/ae7hxz

I'm an M.D. whose attention was drawn to Trevor Marshall recently. Going to his website, he appears to be an intelligent, somewhat charismatic person who has sold some interesting ideas to a bunch of chronic disease sufferers and in the process has created the usual cult of hopeful pseudoscientists who are drawn to such efforts. There are a few interesting ideas presented there, and in fairness I suspect he may even be onto a few things with respect to sarcoidosis and maybe one or two other conditions that actually are exacerbated by high levels of D/calcium. Otherwise, it's apparent that there's a lot of sloppiness, speculation, and spin, and frankly
I find many of their claims with respect to Vitamin D's harmfulness to be not only unsubstantiated but downright scary and having the potential to do great harm--particularly since he/they have a paucity of evidence for their positions and seem to disdain a great many actual clinical research studies that contradict their thesis that Vitamin D supplementation is generally bad. (A greater value is apparently placed on his 'in silico experiments'. That smacks of just a wee bit of hubris in my book.)

His topics are deep (seeing as how they deal with biochemistry and molecular biology on a level that's too complex to be properly followed by any who aren't versed in those subjects), but despite the richness of detail of his arguments
there are some important errors. For any of his followers who happen to be reading this, one such example would be talking about binding constants and the measured competitive antagonism of calcidiol (aka 25-OHD) on the VDR. Such antagonism may be measurable in vitro, but in vivo it's actually irrelevant. As Marshall's followers all well know, VDRs are NUCLEAR receptors, and as such they aren't directly exposed to circulating (plasma) calcidiol. In the plasma, calcidiol is bound to DBP (D binding protein) and (to a much lesser extent) albumin. Following transport through the plasma, DBP and calcidiol in turn bind to megalin proteins that are expressed on some cell surfaces, which binding in turn triggers clathrin to induce endocytosis. Following endocytosis, calcidiol is released from DBP into the cytoplasm, where it is immediately bound to hsc70 (a constitutively expressed chaperone protein that binds many things, including other D-metabolites such as calcitriol). From there, different metabolites of D appear to be selectively directed to specific intracellular organelles. Most relevantly, hsc70-bound calcitriol (aka 1,25(OH)2D, aka the "active D metabolite") has a higher binding affinity to a nuclear chaperone called BAG-1 than hsc70-bound calcidiol does (see http://jme.endocrinology-journals.o...e2=tf_ipsecsha). This is important because since BAG-1 guides D-metabolites to the VDR, it means that high calcidiol levels won't significantly interfere with VDR binding of calcitriol--and thus Marshall's "in silico"-supported hypothesis that exogenous Vitamin D supplementation interferes with VDR activation turns out to be erroneous. (For his fans, I also don't know what the significance of this VDR-presenting mechanism might be with regard to Marshall's proposed use of Benicar as an artificial VDR agonist. It might or might not be relevant.)

Anyway, history may yet vindicate some of Marshall's other ideas and prove me wrong about him, but for now I see every indication that this guy is well-meaning but dangerously overconfident about the veracity of his theories. If I'm right, then unless/until such theories are thoroughly discredited he will remain an intelligent and articulate person who can convince a lot of other people to join him in his misguided crusade to get the "truth" out about the dangers of Vitamin D. For his fellow co-sufferers of sarcoidosis (and possibly those few other rare conditions exacerbated by high calcium levels) this might be forgivable. For the other 99+% of us, such efforts may have potentially grave consequences. If the thrust of the emerging body of peer-reviewed Vitamin D research is to be believed, a billion people on this planet currently suffer from Vitamin D deficiency, and many of those will enjoy longer and much healthier lives (less cancer, diabetes, hypertension, heart disease, multiple sclerosis, osteoporosis, possibly even asthma and depression) as a result of getting proper Vitamin D3 supplementation. With that at stake, I'd just as soon let people who look up Trevor Marshall know that his ideas are not necessarily as well-respected within the mainstream scientific community as some people here might suggest. He certainly deserves to have a bio, but his claims remain *quite* controversial.
Should you have any additional publications or posts or references that align with this subject, of debunking the MP and the theories they support regarding the danger of vitamin D (specifically exogenous sources of vitamin D), please feel free to comment or contact me via e-mail. I also of course welcome any notes that contradict the information I have provided. I'm simply in search of the unbiased, honest truth on the subject. Thanks in advance.

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One of the claims from Trevor Marshall and the MP camp is that exogenous 25-D from foods and supplements is directly immunosuppressive via it's ability to directly dock to and deactivate the vitamin D nuclear receptor (VDR - an integral nuclear receptor involved in cathelicidin (potent human endogenous antimicrobial agent) gene expression). They support this claim with in-silico computer simulations (which, to my understanding, is not an accurate representation of what is taking place in-vivo, or even in-vitro for that matter.

In a future post I will provide an M.D.'s explanation as to how this claim is incorrect in that there are tight controlling intracellular mechanisms that control conversion & chaperoning of the substrate 25-D and the 1,25OHD active metabolite to the VDR.

Here is a short paper from 2006 that discusses how vitamin D works as a human/mammalian defensin ("Defensin is a generic name reserved for an endogenously synthesized antimicrobial agent") and is integral to the human innate immune system (the branch that targets intracellular pathogens involved in Lyme, Tuberculosis, Chlamydia pneumoniae, mycobacteria, etc.).

Below is an excerpt from the paper that illustrates that in-vitro, limited amounts of the substrate 25-D (which can be obtained exogenously from food and supplements and I believe more indirectly from adequate UV ray exposure) handicap innate immune system components (in this case monocytes & macrophages) from producing the cathelicidin antimicrobial peptide (CAMP) and subsequently killing the mycobacterium tuberculosis.
Vitamin D as a defensin
These data predict that a decrement in the extracellular content of 25-D may be a limiting factor for effective mycobacterium tuberculosis killing. To test this hypothesis Liu and colleagues examined human monocyte-macrophage cathelicidin expression and mycobacterial killing in cells incubated with vitamin D (25-D)-deficient serum from sunlight-deprived African Americans and from a group of vitamin D-sufficient Caucasians. The 25-D-insufficient serum was much less capable of supporting cathelicidin gene expression and bacterial killing than was vitamin D-sufficient serum. However, the significantly diminished cathelicidin and antimicrobial effect of vitamin D-deficient serum on macrophage function could be rescued by restoring the extracellular 25-D levels to normal.
If the hypothesis supported by the MP camp is correct, would we not expect to see reduced CAMP gene expression and reduced mycobaterium killing with the D-sufficient serum? Instead we see the exact opposite; That serum with sufficient (or greater) supplies of 25-D substrate enhances the immune cells' ability to create CAMP and destroy the pathogen, and serum with lower or insufficient supply handicaps the immune cells in battling the pathogen. The 25-D is clearly not binding directly to the VDR and deactivating it, as illustrated by the increased expression of CAMP and pathogen killing, which is dependent on the activated 1,25OHD metabolite, not the 25-D substrate.