What are the physiologically-active forms of Gd in the body?
An important question not yet answered is: what are the physiologically active forms of Gd in the body?
Already understood and broadly accepted:
for NSF, as linear agents almost exclusively cause this disease, fully intact GBCAs should not be able to cause it.
for acute hypersensitivity reactions, these come on as early as instantly following GBCA injection, so fully intact GBCAs are able to cause it.
for visible Gd on MRI in brain tissues, this is (effectively) only observed with linear agents.
It is important to also add into the above the following information from recent/relatively recent literature on GBCAs:
1. There are generally 3 forms (species) of Gd that are observed following injection. In a recent article the Frenzel team nicely categorized them as: i) small water-soluble (intact GBCA); ii) small water-insoluble (Gd salts: Gd-carbonate, Gd-phosphate, etc), and large water-soluble (Gd bound to protein macromolecules).
2. small water insoluble should not result in MR signal.
3. My interpolation of these categorizations is that the high T1 signal on MR images secondary to multiple exposures to linear agents (approximately 5 injections within 2 years) reflects the effect of species iii) Gd bound to macromolecules. We know from MR physics and Gd- contrast agent design, protein macromolecules cause increased tumbling on T1, and shorter T1 (hence brighter on T1 weighted images).
4. animal studies that have used either DTPA-type chelators or HOPO chelator have found that despite the use of chelation, a substantial amount of Gd is still left in the body of animals.
Critical unknowns in humans:
1. what species of Gd is physiologically active? The title of this blog.
2. can immune cells in GDD patients cleave or partially cleave macrocyclic GBCAs to release or better expose the Gd atom?
1. in general most conventional physicians want to disregard the existence of GDD (some form of fear and loathing, previously discussed, not part of this blog).
2. experts who have studied chelators in animal models, estimate that chelation that number in the tens, probably still leaves a lot of Gd left in the body.
3. knowledgeable patients, and some experts, have calculated their total body content of Gd, and the amount that appears to be removed by chelation, and have come up with figures that greater than 100 or 1000 chelations are needed to remove all the Gd. This ignores several extremely important points: i) there is a constant spontaneous elimination of Gd by kidneys (which is dependent on kidney function, so this has to be factored in); ii) there is constant elimination by other organ systems (skin the most important, fecal route very minimal [and I do not want to consider that/measure that, etc, .. this comes up from some patients aksing me: that is my answer) and lung very minimal. SO kidneys probably 85% skin 14%, feces (except for fecal eliminated Gd eg: eovist/primovist (mainly), multihance, ablavar) and lung both <1%. So these estimates may be off by 100 times the actual events... but that is not so bad as we now learn that the estimates by experts about the incidence of COVID infection may also be off by 100 times.
1. experts who use DTPA to chelate Gd in GDD patients find that chelation improves patients. In fact in my current clinical experience individuals who have received 1, and even up to 3-4, can be effectively 'cured' with only a few chelations sessions... Others, and these are the majority at present, take more chelations, and still will have residual disease based on the current approaches.
How then can one reconcile the points above in the 'SO' section and the 'YET' section? The answer was also illustrated in the recent reported that patients who were hospitalized, even intubated experienced much higher survival if they were also administered dexamethasone - a steroid immune suppressor. I would like to add in that I do not think there is anything special about dexamethasone, it was probably cheaper and right at hand.
In my opinion, 'SO' and 'YET' are reconciled because we are not removing all the Gd, but doing two most important processes:
1. removal of the physlologically-active Gd,
2. most importantly dampening/controling the host immune response. The broader community have learned, or should have learned about COVID-19 that a primary cause of injury/death is the host response - this is certainly true from the ages of 10-65.
As I have written in prior blogs, whereas with COVID19 it may be difficult to understand at present in which individual host response is the primary source of injury, and in which it is direct effects of the virus. The question is much simpler with GDD:
In GDD the entirety of the disease process relates to host immune response. Hence two treatments are always essential:
1. removing some/much of the physiologically active Gd,
2. controlling the host response.
Treatment is not based on removing all the Gd, it is based on achieving a combination of both of the above points. The best metric for determining when enough is enough treatment therefore is not with a measure of Gd elimination (eg: urine pre- and post- chelation) although this should be considered, but on how the patient feels. As I have written before, I am aiming for 80-90% feeling 'back to being themselves', and letting their immune system calm down the rest of the way. The primary treatment is then to never get another GBCA injection again.
So, I have had to educate the community of patients and general community of physicians on the entity of GDD... but it is also critical to educate scientists who look at efficacy of chelators in removing Gd in animals: the aim of therapy is not to remove all the Gd..
What is also critical to realize therefore with all chelators, and perhaps especially with effective chelators (eg: likely HOPO will be effective). Effective chelation alone, without concurrently addressing the host immune response is a recipe for disaster. Effective remobilzation of Gd in GDD patients likely will create a situation of constant Flare- and the more effective the chelation, the stronger the Flare. Hence chelation will appear not only to be ineffective, but also 'dangerous'. This is ofcourse different for patients with GSC, chelation without immune system dampening is sufficient.
Finally, what are the physiologically active forms of GDD:
1. based on the similarity between GDD and acute hypersensitivity reaction (AHR), that macrocyclic agents can, like linear agents, cause AHR; and that stable macrocyclic agents cause GDD as well: intact GBCA is physiologically active.
2. it is most likely that Gd in protein macromolecules is physiologically active. This, of the three species, is likely the species that is most effectively removed by chelation. Increased urine Gd values chelating a linear agent are in the range of 15-30 fold, whereas with macrocyclics in the range of 5-10 fold.
3. it is possible that Gd salts are the least physiologically active, and this may be part of the host defence developed over 1 million years, to bind noxious antigens to molecules to create salts. Somewhat ironically, linear agents result in Gd-salts, macrocyclcis generally do not (the Gd remains in fully intact GBCAs).
Early on, I recognized concurrent FRAME drugs is 100% essential in early stage GDD and in complex advanced GDD, but the reality is, some level of immune modulation, even minimal, is essential in 100% of GDD patients to accomplish 'cure'.
Richard Semelka MD Consulting Stay tuned on the latest advancements: