Gadolinium Deposition Disease: A Short Recap on Chelation, Flares, and Mitochondria
I am amazed that there is still so much misunderstanding about GDD, Chelation Treatment, Flares, and Mitochondrial Injury.
I was contemplating writing a long review piece, but I am in the process of doing that to submit it for publication in the peer-reviewed literature, and I don't want to see a peer-reviewed article jeopardized because it basically repeats what I have blogged. So instead I will strike briefly on the high-points- and make the points quite clear.
At the present time optimal treatment for GDD is chelation with DTPA. I have modified my approach since descriptions I have published in the literature, so although I don't like pre-empting an article in the literature, and thereby jeopardizing it.... it seems I have to.: I always now start with our standard oral steroid/antihistamine regimen (this is published, so look for it there) which begins 2 days before chelation.. I always for the last 1-1.5 years start the firstt chelation with one day chelation with reduced amount of 1 of the DTPAs, and always give iv steroid. From there I progress to giving more chelator and less steroids over future chelation sessions. Change is based on the tolerance of the individual to keep them at a Flare rating of 3-5/10 severity. At times of doing cytokine research I have had to break from this approach, so as not to alter cytokine response due to presence of steroids and to see maximal cytokine release.
Full dose Ca-DTPA/ full dose Zn-DTPA even with concurrent steroids can result in Flares of 8/10 or higher. A number of subjects will not tolerate that, and stop chelating if the Flare is too high. So now, knowing that I cannot predict who can tolerate severe Flare (even if they say they can) I ease everyone into chelation with a low chelator dose/ high steroid dose so they are not frightened by the chelation process. 3-4 years ago I had performed the full dose regimen from the start, with the concept that mist people want Gd out of their bodies as quickly as possible, but some people can not tolerate that... even if they tell me they can.
So this is how I always start.
2. Repetition of chelation should be done no longer than 4 weeks apart. If there is too much time between chelations then re-equilibration Flare may be too strong, and some patients refuse to continue chelation because the re-equilibrium Flare is too strong. I use when the re-equilibration phase starts becoming intense to gauge when the schedule of chelations should be. Many individuals are ok with 4 week intervals, where re-equilibration starts becoming prominent at 3.5 weeks. I will elaborate more below.
3. Gd removal Flare (AKA treatment Flare) is adjusted by varying/adjusting the amount of chelator and amount of steroid/antihistamine used. Subjects should be able to understand that the Gd removal Flare can be adjusted that way, so they don't freak out about early post chelation Flare being too strong... it can be brought down. This Flare can be brought under control. Do not freak out.
4. Re-equilibration Flare is diminished by shortening the interval between chelation sessions. In general the more Gd that is removed (either because the individual has had multiple GBCA injections or they have received linear GBCA agents or Gadavist) or the particularity of that individuals severity of immune reaction to GBCAs. Subjects should be able to understand that the re-equilibration Flare is diminished by decreasing the interval between chelations to every 2 weeks or to every week. This is a simple correction. Do not freak out. It alwasy works.
5. I do not use and do not advocate the use of chelators with weaker binding to Gd than DTPA. So I do not advocate EDTA, DMSA, DMPS, etc. The reason is that they result in Gd removal Flare and Gd re-equilibration Flare, which powerful chelators do, but also Gd redistribution Flare. which powerful chelators do not do The redistribution Flare should always be avoided, because there is no value to it, only injury. An easy way to think of it, one would never administer as a GBCA, Gd-EDTA, Gd-DMSA, or Gd-DMPS, that would be criminally negligent.... what is true for the chelator in a GBCA is also equally true for the chelator in decorporation. Flare is useful because it confirms the diagnosis of GDD and also shows that chelation is working and Gd is being removed. Gd- re-equilibration Flare is of value as it indicates that Gd is being moved from bone back to skin (primarily). Skin Gd can be readily removed in large quantity, bone Gd cannot, so this re-equilibration is a very good thing.
There are 4 categories of Flare: disease activity, Gd removal, Gd redistribution, Gd re-equilibration.
Disease activity. As with any disease, and typically with autoimmune disease, symptoms can show periods of dramatic intensification (Flare) often because of a provocative event, stress is a common provocative event.
Gd removal. If a substantial amount of Gd is removed and you have the immune mediated inflammatory disease state of GDD then there will be a Flare reaction to its removal. It occurs when a treatment is effective at removing Gd, and won't occur if the treatment is not effective There is a tendency to confuse Gd removal Flare as bad, and no Gd Removal Flare as good. In fact the exact opposite is true: Gd removal Flare is the most specific finding to show that a subject has GDD and that Gd is being removed in significant amounts. No Flare (to an effective chelator) means no GDD. The trick in treatment is to keep the Flare manageable. No Gd Removal Flare means: either you do not have GDD or you are not removing any appreciable amount of Gd. The timeline for this Flare is generally 1-7 days immediately following chelation
Gd redistribution. Gd redistribution is the phenomenon that Gd is picked up in the tissues and quickly released by the chelator and redistributed to another site.. For example Gd picked up in skin and then re-released and can go to other tissues, like brain, or back to skin. This serves no useful purpose and can contribute to worsening. Hence I never recommend using weaker chelators.. The stability constant is the critical piece of knowledge to let one know how effective a chelator will be. The stability constant of DTPA with Gd is something like 300,000 times greater than that of EDTA, and much greater still compared to DMSA and DMPS. The stability constant of HOPO is better than that of DTPA, so in principle HOPO should be a preferable agent to chelate compared to DTPA. My estimates for redistribution are 1% with DTPA, 30% with EDTA, and 50% with DMSA and DMPS. The timeline for this Flare is identical to Gd removal, 1-7 days.
Gd re-equilibration. Gd re-equilibration refers to the property of le Chateliere's principle that substances strive to be in equilibrium. Gd re-equilibrium can be generally avoided entirely if chelation is done daily, daily chelation can be done with Zn-DTPA, since Zn- is bound much more tightly to DTPA than all others of the native metals, so it will not put native metals in imbalance. Ca-DTPA will put daily metals in imbalance if performed daily, hence for Gd removal I would never recommend daily Ca-DTPA, this would be dangerous. Now for Plutonium or other radioactive metals I may prefer Ca-DTPA over Zn-DTPA , even daily, because it will achieve greater Plutonium removal. For heavy metals where the major repository is bone, like Gd and lead, I actually prefer a strategy that incorporates some re-equilibration, Gd and lead are much more difficult to remove from bone than from skin, because bone binds it more tightly, hence since we want to deplete the total body content of Gd, incorporating re-equilibration bone removal with direct chelation bone removal makes good sense. In subjects who received 1-4 GBCA agents, chelation schedules every 3-4 weeks is appropriate with some noticeable re-equilibration Flare occurring at 3.5 weeks. More than 10 GBCA injections then the greater amount of Gd removal with each chelation will likely require shorter intervals, such as chelation every 2 weeks, so severe Gd re-equilibration has not developed. Re-equilibration likely begins in at 1 week and can become noticeable at 2 weeks, with at 3.5 week definitely perceived Gd re-equilibration Flare is evident in everyone with GDD. Re-equilibration Flare continues to progress to 3 months and then plateaus, and about 1/3 of times still progresses, 1/3 of times plateaus, and 1/3 decreases. The fewer number of GBCA injections the more likely it will decrease from 3 months. So in individuals who have received 1-3 GBCA injections if they freak out due to severe Flare after 1 GBCA injection, > 50% of individuals, perhaps 75% ,will show progressive decrease in symptoms. Many tend to attribute this improvement, to "thank God I stopped chelating' when in fact what has happened is that even with just 1 chelation they removed enough Gd that over time their body's immune system could calm down and manage with the lesser amount of Gd left in them. I never recommend stopping well performed chelation (what I describe above) after 1 chelation due to severity of re-equilbration Flare. Even though I use Gd removal Flare as the specific diagnostic criteria for establishing GDD, Gd re-equilbration Flare symptoms are even more accurate as a means to diagnose a Deposition Disease state. Here is why, it is not rare that people who get an injection of anything, even normal saline (that is simple sterile salt water at blood salt content level)- just even due to the stress of getting a catheter inserted, It is conceivable this nonspecific reaction could be misinterpreted as Gd removal Flare. But sudden development at 3 weeks following chelation of GDD symptom worsening can only occur in the setting of GDD (or other heavy metal deposition diseases). Also I use in judging when a subject can stop chelating altogether, is have them pause from chelation for 3 months, and if the symptoms progressively get worse and not tolearblae they can simply return to chelation with no harm done by the pause.
Articles on mitochondrial injury have been in the literature for a few decades on other heavy metals, such as lead, mercury, Cadmium, Chromium, based on biomarkers of mitochondria being observed in these patients, and absent in 'normals'. Over the last few years mitochondrial injury has been reported following GBCA injection or in GDD subjects. It has not been firmly established how the mitochondria are injured. Many lay people assume that it is from the heavy metal actually entering the cells.. and many worry about the brain... My theory is, it is most often not this, but due to cytokines that have been stimulated to be released from Tcells that interact with cell surface membranes to generate this internal cellular injury, or the cytokines or other polypeptides entering the cells to cause injury.
This is the basis of my theory: 1. the majority of GBCAs are created as nonspecific extracellular agents,, meaning they do not enter cells, 2. some of them are macrocyclics that are almost certainly fully intact, therefore no dissociated Gd entering cell, when serum mitochondrial biomarkers are evident, 3.scanning electron microscopy images show Gd containing molecules in interstitial tissue and not intracellular, to date, 4. The only agents that do enter cells are multihance, eovist, and ablavar, and the only cells this is thought to occur in is hepatocytes, and not brain cells.
My opinion why it is just cytokines:. 1. Normal subjects (GSC) who have received GBCAs do not show symptoms of neurological disease, and if it is a pure metabolic process of the GBCA entering the cell, then it should occur in GSC as well as GDD. At the present time, there is no evidence to suggest that there is a difference in the amount of Gd retention in the body between GSC and GDD.. Whereas there is a difference in cytokine profile between GSC and GDD.
In the standard resting disease state of GDD the cytokines probably are a combination of systemic circulating cytokines, and local brain interstitium T cell generated cytokines. In the dynamic states of Gd removal and Gd re-equilibration, where a lot of Gd is being pulled out of tissues throughout the body, I suspect that the greatest amount of cytokines perturbing the brain, are in the systemic circulation and not locally generated in the brain. This also explains why cognitive impairment resulting from chelation readily resolves with further chelation, the cause of the cognitive impairment is more transient and peripheral, rather than durable and central.
Overall probably the greatest cause globally of poor results of chelation is that chelation is performed poorly by inexperienced practitioners. The most common reason is that many practitioners use EDTA to remove lead and extrapolate that to Gadolinium Deposition Disease. Most people with lead in them have Lead Storage Condition, (LSC) analogous to GSC, there is then no immune reaction to removal of lead in LSC, as there is no immune reaction in GSC subjects to the removal of Gd. Subjects with LSC, who number in the 350 million range in the USA (ie: everyone minus 100,000 with LDD) then dirty removal of lead with EDTA works fine... this also true of GSC, dirty removal of Gd with EDTA is also fine, there is just a lot of re-equilibration in the mean-time with both of them. Removal of Gd in GDD, and lead in LDD, is highly nuanced and absolutely requires careful thought and the use of steroids, until the time of a more specific immune dampening agent is developed.
So dirty chelation probably accounts for 90% of failures.
Perhaps 1%, as I have written before, have some type of (possibly unique) additional T cell dysregulation that chelating Gd out has an adverse effect on that underlying disease state.
The last 9% of failures is either ideally performed chelation (with DTPA) that for various reasons resulted in too much Flare for the person to tolerate (as I write above) either the Gd removal Flare most often, or the Gd re-equilibration Flare, or too much chelator, or too long intervals between chelation. This 9% are a true tragedy, because if they continued chelation the great majority would have excellent response, as severe Flare means a lot of Gd is moving in the right directions we want it to move in. If done right it is simple changes to make the Flares more acceptable: 3-5/10 rather than 8-10/10. I am baffled why these individuals do not continue chelation, when at least a few of them I have told them exactly what is going on. I think it is simply the irrational fear of intense Flare that they think will be permanent, and will accept the concept of being in their status quo of extremely sick for the rest of their lives than take even the smallest chance of being even sicker- even when an expert, even the world expert ,tells them this will almost certainly not happen. This is a great tragedy, and I suffer thinking of it and trying to do something about it.... it is analogous to the irrational fear and the resultant hating of people who may be essentially identical to you but differ in one small way.
Richard Semelka, MD