Heisen-Semelka Uncertainty Principles in GDD. Applies to other metal deposition diseases (Pb,Hg,etc)

I believe everyone with a scientific mind loves the concept of the Heisenberg Uncertainty Principle. I like to expand it beyond quantum physics to express that various entities can be two different things at the same time.

So heavy metal toxicity is both an immunogenic (reactogenic) immune system disease and a direct toxic process, and then if the heavy metal is radioactive, a radioactive toxicity process as well. So when is the effect immunogenic and when is it direct toxicity: the short answer is I don't know, and I don't think anyone at this point knows. Hence I co-apted Heisenberg's name (no insult intended, this may be some kind of cultural, certainly intellectual, appropriation) into the Heisen-Semelka Uncertainty Principle.

#1. Mitochondrial damage and oxidative stress secondary to heavy metals has been described for decades, and even over a decade ago atleast 20 enzymatic processes have been recognized as involved in, altered or damaged by heavy metal exposure. Different heavy metals shown to cause injury to different sets of enzymes.

What is causing this mitochondrial damage? Is Gd entering cells and running amok? My opinion is for most cells probably not (Gd will be taken up by a number of white blood cells like macrophages) but substantial uptake by nerve cells in the central nervous system- I am uncertain, but doubt it. No doubt there are enzymatic changes involved, and maybe dozens of them, but if it is pure biochemical reactions, then shouldn't everyone be affected? I think most of these injuries reflect direct activity of host pro-inflammatory cytokines, and lack of sufficient inflammation suppressing cytokines, and possibly cytokines and other proteins that block cell surface receptors that result in intracellular disturbance.

#2. Gd localization in tissues. Illustrated organ: brain. My current opinion is that Gd in the brain is located in the following compartments and in these approximate percentages:

i)interstitial space/extracellular matrix in perivascular distribution (80%); vascular basement membrane cells (8 %); brain located immune cells (4%); nerve supportive cells (glial cells> astrocytes, oligodendrocytes, and microglial cells [5%]); and brain cells (neurons) 1%. I am however not certain and further research on decedents (dead people) with exact localization of Gd by subcellular techniques such as scanning electron microscopy and newer methods. This is readily do-able and should be done.

#3. Mechanism of injury by Gd. What is causing the full range of injuries by Gd, is it 1. direct toxic effect of Gd, 2. the inability of immune cells to block the action of Gd on cell surface membrane, among other locations: internal sub-cellular membranes- mitochondria? Golgi Apparatus? endoplasmic reticulum? or 3. the activity of pro-inflammatory cytokines and other inflammogens? Probably all 3, where I emphasize the third.

I think it is the crucial interplay between the immune system and various cells throughout the body The immune system of the great majority of us inhibits or prevents the potential toxic effects of Gd.

In general, immune effects can arise from very small doses, especially if the dose is contained in a tissue space, so that dendritic cells can readily pick them up in adequate numbers and present them to other cells, principally T cells. This explains why even small amounts injected in joint spaces or from extravascular extravasation can result in GDD. This almost pure immunogenic effect we see in individuals who have received even just 1 MR arthrogram with maybe 1 ml of GBCA, or small volume interstitial injection, still develop GDD from just that.

Direct toxic effects usually are experienced by larger doses of the particular toxin. An excellent example of that is the deterministic effect (dose related) of cataract development following x-ray exposure. Dose dependency is likely involved in many of the symptoms and adverse effects of GDD. Gd insertion in place of Ca in many biological processes reflects that.

#4. Which speciations (molecular forms) of Gd are toxic? If 'free' (unchelated ) Gd is the problem, then why do Dotarem, Clariscan and Prohance cause the same symptom complex as linear agents? These former agents should still be fully intact when GDD develops. I could imagine that Gadavist may degrade over time, but also not sure how much that occurs, and symptoms certainly develop at a time that Gadavist should be fully intact. I believe all speciations of Gd are toxic, and relate to the small size (or surface localization) of all the molecular forms of Gd. The immune cells still recognize Gd is there, in small molecules.

#5. Dynamic Distribution of Gd. Both in the standard condition of post-GBCA injection, and also post Gd chelation. Does it differ for GDD sufferers and GSC individuals? My opinion is that the distribution between sufferers and 'normals' does not differ significantly. Re-equilibration of Gd would be fascinating to observe. This is do-able but would require using a large animal model that also sweats like humans, and GBCAs with separate labelling of Gd and the GBCA ligand.

#6. Mechanism of removal by DTPA (and HOPO). How much of the Gd is transmetallized and how much is Gd in its deposited form being simply tugged back into the circulation by electromagnetic forces. My opinion with weaker GBCAs much of the Gd is transmetallized, and with stable GBCAs they are tugged back from the interstitial space back into the circulation to be eliminated through renal route.

#7. What immunologic mechanisms in normals prevents GBCAs from being toxic, that GDD sufferers lack? Answering this question should provide insights into treating not only GDD, but all metal toxicities, likely all immune mediated inflammatory diseases, and maybe all invading cell type diseases (infections and cancers).

#8. What is the X factor in renal failure that causes less stable GBCAs to result in NSF and not more stable agents? A dark irony that GDD sufferers experience is that most allopathic physicians accept NSF (and acute hypersensitivity reaction [AHR]) but have difficulty believing in GDD. GDD understanding is straightforward: individuals have had a foreign antigen that contains a heavy metal directly injected into their body, bypassing their natural host defences on the skin and GI tract. Why wouldn't a certain number of people experience an immune reaction to it? Duh! It is the entire basis of immunology. In an earlier blog I used the peanut allergy. The concept with GDD is exactly the same as AHR, only the principal cell lines differ. Pure AHR is a Mast cell disease. Pure GDD is a Tcell disease (my theory). Not uncommonly they occur together, starting as AHR and persisting as GDD (MAST cell + Tcell). Pure NSF is a bone marrow cell infiltrate disease, which is for most diseases the last immune cell group to get involved, when everything else has failed. Why in NSF does the immune system jump to the end of the story, avoiding earlier steps, and why with just weaker GBCAs where Gd has been dissociated from its ligand. Both AHR and GDD react to all speciations of Gd, NSF appears to react only to Gd dissociated from its original ligand. It is not so clear why weaker linear agents result in NSF and not more stable and macrocyclic agents. What is the X factor in renal failure? This is far from clear-cut.

So my opinion is that the immune system recognizes Gd either chelated in original contrast agent or unchelated from original contrast agent, because even when chelated the molecule is small and Gd is recognized. This is true for AHR and GDD. At the present time, in the Heisin-Semelka uncertainty principles, I favor many of the deleterious effects as immune system derived, so it is cytokines and maybe additional inflammogens that cause mitochondrial injury, cognitive impairment (often termed brain fog) and many of the other general awful symptoms. Fortunately in GDD the cytokines are pro-inflammatory principally, so well managed chelation with immune system dampening should help the great majority of sufferers return close to full health. This is unlike NSF where a sizable percentage of cytokines are pro-fibrotic, and this is a much more difficult situation to be in, where near complete resolution would be extremely rare, with current drugs available. The additional major problem is poor renal function in NSF sufferers. I have advocated chelation combine with dialysis in these individuals.

The above are just a few of the uncertainties in the Gd and other metal stories. Uncertainty doesn't mean we should be paralyzed into inactivity. Chelation with the best available chelator, and simultaneous immune system dampening, is the appropriate and effective treatment, regardless of the number and variety of enzyme/ cell process interferences Gd causes.

Richard Semelka, MD