Show me the Gd. Where is the Gd located.
The article by Brent Wagner's team "Safety of Magnetic Resonance Imaging Contrast agents" in Frontiers in Toxicology, the same issue in which our paper on Near-cure of GDD with iv DTPA, brought to attention again a critical aspect of: where is the Gd?
There are basically 3 considerations of where is the Gd, that relates not only to Gd, but to all heavy metals, with each heavy metal having their own distribution of these 3 main considerations:
which organs does Gd go to. i) what are the approximate amounts in each, ii) how durable / persistent are these reservoirs, that each organ represents.
This we have a good sense of from several prior reports in humans, looking at organ deposition either in resected specimens (like femoral heads) or in cadavers. For Gd, the l;argest reservoirs are bone and skin. Gd goes to all other organs and tissues with fat being the smallest reservoir. So this reflects the distribution of a water-soluble metal and metal-complex in a body.
in the organs where is the Gd located?
Gd uniquely of the heavy metals is presently derived from iv administration (less commonly intra-arterial and joint space administration). Secondarily, and also important, is the Gd is delivered as a fast bolus, which serves to force much of the Gd into the interstitial tissue/ extracellular matrix.
This has been shown in one histologic report to represent a lot of the administered Gd being trapped in the blood vessel walls, mainly the endothelium (inner layer) of vessels, perhaps 70%, and 30 % in the extracellular matrix ECM). This also makes sense, based on how and what rate Gd was given. Interestingly, if the Gd was administered by drip technique a much greater percent would be trapped in blood vessel walls, maybe 80-90% and 20-10% in the ECM.
how much of the Gd is intracellular vs extracellular? The third critical point is of importance, and remains largely uncertain in humans. Dr Wagner's paper considered that there is a lot of Gd in the mice model in an intracellular location. They employed scanning electron microscopy. Their observations were of proteins/polypeptides which are nanoparticle markers of intracellular reaction suggestive of direct deposition. But as I read the paper then no direct image or other evidence of Gd in cells, which is essential to demonstrate.
My current opinion is that the great majority of Gd remains extracellular in humans. I base this on the following:
Gd should remain nearly fully extracellular
a) fully intact GBCA agents are termed nonspecific extracellular agents. This means that in the development phase the companies had shown they are extracellular in location.
b) if these agents are truly extracellular in their intact state Dotarem/Clariscan and Prohance should be always fully intact and hence extracellular,, yet GDD secondary to these agents is essentially identical to GDD for the other agents, and these latter agents may be in part or to a great extent disassembled from the manufactured ligand.
c) scanning micrographs shown in the literature show Gd in the ECM and have not shown Gd in cells.
Uncertainty: Gd may in part be intracellular in humans.
a) do we actually trust fully the 3 points above, as there may be conflicts of interest for the companies, and the researchers, who may have received a lot of funding from the companies.
b) we do know that certain MR contrast agents: eovist/primovist, multihance, and ablavar, are taken up by hepatocytes [liver cells], and enter through cell membrane channels in order to be eliminated in part by the biliary system. But this cell entry follows cell surface membrane foci that are (supposedly) unique to hepatocytes But if they are picked up by hepatocytes, are we completely certain that other cells may have at least a few of these same cell membrane channels.
c) macrophages and other similar immunological cells take up foreign antigens by phagocytosis. So these cells at least should have intracellular Gd.
d) it does not seem unreasonable that at least support cells in various organs should take up Gd as a protective mechanism. So endothelial cells of blood vessels, in general throughout the body, absorbing Gd intracellularly, and in the brain glial cells picking up Gd to protect neurons.
e) other metals, example Arsenic, have been shown to be taken up by cells (Calcium mimicry) and in the case of Arsenic deposited in nuclei.
Related points:
Humans are not mice when it comes to cellular activity.
a) when Multihance was initially developed, the manufacturer observed in the mouse model that 50% of the agent was eliminated through the biliary system, which means that the agent has gone through intracellular uptake in hepatocytes. They had initially intended marketing as a hepatobiliary agent in humans. However in human trials they found that only 5% was eliminated by the biliary system. Multihance had however excellent T1 relaxivity and was marketed initially for brain studies. My interpretation of this data of mice vs human, is that there is more cell membrane surface receptors for biliary activity in mice, and/or general increased porosity of the cell surface membrane, and/or less blocking substances elaborated in mice, compared to humans. So unless proven otherwise, based on this finding of differences in biliary elimination, my opinion is that there is increased cell surface membrane porosity in the mice model, which would account for, if it exists, more intracellular Gd in mice than humans.
Does chelation for Gd work in humans?
This issue has been addressed in humans by several papers my team have written on the use of iv DTPA, culminating in the recent paper on Near Cure of Gadolinium Deposition Disease with iv DTPA chelation, and many blogs I have written on the subject. I recommend reading those. In short, the points are: i): Gd is making GDD sufferers sick. ii) Gd is documented to be removed by chelation with pre- and post 24 hr urine studies; iii) patients get the appropriate Flare reactions, iv) sufferers feel better after chelation; iv) with sufficient chelations, properly performed, individuals experience near Cure. There is as much evidence, and in most comparisons, much more evidence, that chelation with iv DTPA achieves successful outcomes for GDD, than essentially most treatments for most diseases.
What is critical, and it still amazes me to have to write this: the chelator used must have high stability constant for the metal that one wants to remove, and effectiveness of the ability of the chelator to remove the metal in vivo must be shown with 24 hr urines, pre- and post-chelation. If chelation is performed with chelators that have lower stability constant, then the treatment does not meet standard of care. The only other chelator in the pipeline currently that meets these criteria is HOPO. A powerful chelator binds with Gd in many speciations for removal, but also where Gd is more tightly bound than DTPA achieves, it tugs the Gd (such as fully intact Dotarem/Clariscan and Prohance) back into the circulation for removal. Weaker chelates cannot achieve either of these activities (bonding or tugging) well, and also importantly results in higher redistribution.
Does chelation work in mice?
Several years ago the Bayer group including the lead researcher Hubertus Pietsch wrote a paper on chelation of iv DTPA in mice, for mice subjected to a linear agent (I believe Omniscan) and the Bayer macrocyclic agent Gadavist. They showed that iv DTPA removed Gd from the brain in mice who received Omniscan, but did not remove Gd in mice who received Gadavist. THey used the latter to show that Gadavist was fully intact. Our experience in humans concurs with their findings with Omniscan, but disagrees with their finding in Gadavist. Urine Gd is ALWAYS elevated, and often 20 times, when chelating Gadavist. This could be easily shown by any MR center, who wants an 'easy' important paper to write. chelate with iv DTPA consecutive individuals who received iv Gadavist at MRI. I have always intended to write this paper myself, so have kept this card in my hand, but since it is important to get it out, I am letting everyone know the paper I want to write, so they can write it instead and take the credit.
So why did iv DTPA not pick up Gd from Gadavist in mice? Probably: i) too short interval in the mice so all Gadavist was fully intact., ii) mice are different than humans; iii) Bayer makes Gadavist.
If Gd is intracellular in humans could chelation still work for the proportion that is intracellular?
Yes it could, here is why:
a) the Bayer study suggests it must, even if Gd is truly intracellular in mice.
b) by the process of le Chateliere principle: re-equilibration.ECM located Gd removed by chelation, then Gd moves from intracellular to extracellular to re-equilibrate, then following chelation removes this once intracellular Gd. We use this explanation for Gd removal bone
c) many cations (positively charged atoms) freely move both ways between the intracellular and extracellular compartments to maintain an equilibrium. This is done more many atoms/molecules, and as examples is essential with Ca+, Sodium (Na)+, and Potassium (K)+, and all the native metals Mg, Mn, Zn, Cu. If this does not occur the individual would soon die. So if this happens with these cations why would it not occur with Gd (forced by le Chaeliere's principle).
Additional uncertainties/ Do not be fooled by:
a) papers describing biliary elimination agents showing intracellular uptake in hepatocytes. This is what they are supposed to do. So ignore these regarding proof of intracellular presence of Gd.
b) assuming intracellular changes necessarily mean Gd is intracellular.
c) Gd demonstrated by scanning electron microscopy, are these individual Gd atoms or clusters of Gd-containing molecules. I think they must be clusters to be that visible. Clustering of Gd molecules may also make them more symptom-generating.
c) studies designed to look at Gd, whether in animals or other models, if they are designed to evaluate Gd in humans from iv GBCA administration, they must also be performed in the way Gd is administered, by rapid iv administration. In this regard I am thinking of earlier papers written on HOPO, the animal models had intraperitoneal administration of Gd. Yes this gives some valuable insight, but to make the most appropriate evaluation of this and all other metals, the route and rate of administration must match how the metal got there to begin with.
Discussion and Summary
The reader should not misinterpret this blog to mean that I am flatly denying Gd is intracellular in location. I am not. But I am uncertain. I would be 100% confident if electron microscopy images were presented that showed Gd within cells. Also whichever labs that have shown other metals like Arsenic in the cell nucleus, should also look at other metals, such as Gd, to see if they are intracellular. Ofcourse I am also a little skeptical of this localization as well, how reliable were techniques in the past to show intranuclear localization. But I have not studied this, so I am just using the wisdom-sense of being skeptical.
I am firmly opposed to the authors of that work stating that since their findings suggest that Gd is intracellular that Gd cannot be chelated, a completely unwarranted assertion. This is a false, irresponsible and, even worse, a dangerous claim. Since they actually did not do chelation in mice, they should know better than not to talk about it, since it was not part of their study. They should know, which the casual lay reader may not know, that conclusions for a paper must be based on what was performed in the study and not some random subject not part of their study. They did not look at chelation, so should not have commented on it. at all. In fact, this unsubstantiated assertion goes against the one study that did look at chelation in mice, the above referenced Bayer study. What this false claim has done is destroyed hope in a number of sufferers that their disease is untreatable. I know this because some have texted me to this effect So now I had to write this lengthy blog to show all sides of the issue (which maybe it was useful for GDD sufferers for me to do anyways). What they should restrict their Discussion and Conclusion to: Our findings have shown surrogate intracellular polypeptides and intracellular changes which are compatible with intracellular localization of Gd in the mouse model. Further investigation is warranted to show direct visualization of intracellular Gd, and whether these findings are also observed in humans.
Do not misinterpret my opposition to this irresponsible claim, that I am somehow denying the possibility that Gd is deposited in an intracelllular location in critical cells (like neurons), I was the first physician to describe the Gd toxicity GDD, which went against the great majority of the work that I had done on Gd previously. Also I was fully aware that this would cause great ire amongst the Radiology community of MR radiologists, of which I was a leader.. So I have shown in this, and other matters, that I am not afraid to speak up about the truth, especially when patient health is at risk. I am not aware of any physician who has done this to the full extent what I have done. Ofcourse the ire is shameful, but it is human nature, so maybe I forgive a number of the skeptics. The point being I really do want to know if Gd is intracellular and in which cells, beyond the ones I mention above. Which cells do experience Gd uptake, and what proportion of retained Gd is intracellular. This is important information. But I do not have a lab that can evaluate this.. Maybe this would be an important request that the FDA makes of the companies themselves,
This would be the request.
In a large animal model analogous to humans, using your MR contrast agent, separately radio-label the Gd and the ligand, and show over the course of 1 year the following: location of Gd in organs, elimination and pattern of elimination over time, in a few animals perform histological evaluation of organs showing the pattern of distribution in cells (perivascular, ECM) with an emphasis if Gd is intracellular, what proportion of Gd is intracellular, where is it located in the cells., While they are at it, perform proper chelation on these animals, and show the change of distribution, and localization of Gd with repeated chelations over time.
I think all of the above should be established, and the companies should be the ones to do so (not only me). Ofcourse if I was given the resources to do this, I could do it as well, and identify and farm out to labs with experience. But this is 10s of millions of dollars. An easier study, would be to look at decedents (corpses), who received Gd, both those not sick from it GSC, and those with GDD, to identify the patterns of distributions of Gd in various organs, and if Gd is intracellular, and what proportion is intracellular.
But the reader should not fear the fact that the above information is unknown. A great deal of things we do in medicine is either frankly unknown (how general anesthetic agents work) or a fair amount of it is unknown (everything else). What I have shown (and a lot of this patient groups have shown prior to me): GDD proof of existence, GDD symptoms, who gets GDD, prolonged presence of Gd in the body (IAKA forever), cytokines associated with Gd administration in normals and GDD, chelation, how chelation should be performed, and that correctly performed chelation results in near Cure in the great majority (and as a highly knowledgeable, ethical and experienced researcher, this is near Cure and not complete Cure),
to end: Correctly performed chelation can achieve near CURE in the majority of patients. where-ever the Gd is or is not located.
Richard Semelka, MD.
Comentários