Re-equilibration. A deeper look into the subject of Gd movements following chelation.

Re-equilibration is the process in which a system rebalances itself (I will describe with Gd but all metals can be substituted when some element (Gd) is removed from locations in which it is more loosely bound, and as everything strives for equilibrium, the subsequent process Gd moving from locations of tighter bonding to those locations of looser bonding (where proportionately more Gd had been removed), to restore a balance, an equilibrium. This is le Chatelier's principle.

Removal of Gd (or any other heavy metal, occurs either through primary (direct) removal or re-equilibration removal. When it can be achieved, primary removal is a prefered method, because it is much more efficient and involves much less dwell time of Gd remaining in the body. However in some specific scenarios, which usually reflects the tightness of bonding of heavy metal in a particular location, re-equilibration removal may be the only form that works well. For example, DTPA is able to achieve primary removal of Gd from bone (to a modest extent, because of the tightness of bond of Gd in bone), but weaker chelators DMSA) can only remove Gd through the re-equilibration process, and EDTA use although minimal Gd is achieved by primary removal, the great majority is by re-equilibrium removal..

Describing Gd in subjects with GDD,, DTPA chelation results in removal of Gd from the loosely bound reservoirs of skin and soft tissue organs (and skin being the largest reservoir of this, but muscle may be the second largest), and then over time Gd moves from the most tightly and largest reservoir of Gd, bone, back to these organs and skin, to re-establish an equilibrium, of maintaining proportional amounts of Gd in the various locations/reservoirs.

In a relatively reproducible fashion, individuals with relatively few GBCA injections (< 3) experience re-equilibration Flare (essentially their GDD symptoms suddenly worsening again) at 3 weeks time following chelation. The greater the number of GBCA injections the shorter the interval between chelation and onset of re-equilibration symptoms. > 10 GBCA injections re-equilibration symptoms may arise at day 10 post chelation.

Re-equilibration however occurs on additional regional levels between organs and within organs. There is also the as yet unknown balancing of intra- and extracellular localizations Gd, which may be exclusively achieved through re-equilibration.

The example of probable intra-organ re-equilibration and resultant Flare, occurred to me when I was contacted by an individual who had received a drip technique of DTPA administration, and not the standard bolus injection of DTPA. They described a second peak of Flare at day 7. In my opinion this early re-equilibration Flare may be secondary to Gd moving from the extracellular matrix  (ECM, also termed interstitial space) back to the endothelial space.

This requires the explanation of what Gd is removed with DTPA chelation by bolus technique and by drip technique.

To begin with bolus technique is performed by rapid injection (bolus injection) into a port in the iv line. The great majority of MR facilities in the developed world use a machine power injector when bolus injecting GBCA. Hand bolus injection is generally done with chelators for simplicity and cost reasons, but achieves a comparable effect. Drip technique describes the GBCA or chelator injected into the iv bag of normal saline, creating a dilution effect, and the chelator is administered in diluted form over the course of the injection (30 - 60 minutes).

With the bolus injection of DTPA, which is what I use and prefer, we emulate how the GBCA was administered in the first place, by rapid injection. Rapid injection forces a large proportion of the GBCA into the ECM . So maybe 30% of the deposited Gd is in the ECM, and 50% in the endothelial space of the vessels (so vessel surface Gd). If we had administered Gd by drip technique, then I anticipate that 80% of the Gd would be deposited in the endothelium and only 10% in the ECM. This also reflects why GBCAs are always administered at a rapid pace: it drives the GBCA into the ECM and by so doing improves the intensity of enhancement of normal organs and the great majority of diseases. So as a whole the great majority of diseases are much more visible if rapid bolus injection is performed compared to drip technique..

So with a drip technique, the chelator stays largely in the vascular space and therefore removes almost only Gd that is deposited in the endothelial space, and leaves largely untouched Gd in the ECM. Less Flare is observed with this drip approach, because the majority of the Gd that causes symptoms is in the ECM. But everything does follow le Chatelier's principle, so I consider it very likely that removing Gd in the endothelium, must also result in shift of Gd from the ECM to the endothelium to restore balance. This type of rebalancing would occur at a shorter interval than movement from bone back to skin and soft tissue organs. For two reasons: it is shifting from two soft tissue locations (hence less tightly bound), and secondly it is also a very local shift of millimeters. So re-equilibration of this type we would expect re-equilibration Flare to have a much earlier onset, hence 7 days rather than 3 weeks. I do not believe this local redistribution is as effective at removing ECM Gd compared to direct removal with bolus injection of DTPA. Re-equilibrium removal is always a more prolonged course requiring more chelations, and is less efficient

It may be that a drip technique may be useful in some individuals with extreme reaction to the presence of Gd, to at least start the chelation process to avoid massive Flare, then convert over time to the bolus technique.

Primary localization of heavy metal is important to understand (as described above with Gd). When Gd though re-equilibrates to skin and soft tissue organs, that movement is not forceful, so not like bolus injection, but is more analogous to drip injection. Hence primary location Gd is 50% endothelium and 30% ECM, re-equilibrated Gd is essentially 80% endothelial, less than 5% ECM, and the remainder probably in macrophages. So re-equilibrated Gd has a much different localization than primary deposition of Gd. This also suggests that after multiple iv bolus injections of DTPA, the majority of the Gd remaining is Gd re-equilibration in location, so that techniques like drip infusion of DTPA, or better still oral intake of chelator (such as HOPO) becomes of near-equivalent effectiveness at continued Gd removal

So, with bolus-injected GBCA (which is essentially all GBCAs) in the early stages of serial chelation with bolus DTPA injection technique, it starts out with Gd having the pattern of distribution from the original injection, and the primary locations are 50% Gd in endothelium and 30% in the ECM. As the primary localization changes to the post chelation distribution, the post distribution Gd localization will have a progressive shift of less Gd in the ECM (from primary removal)

It is interesting to me that a number of centers may use the drip technique with DTPA solely because it is described in the product insert to chelate with this approach. So how did the manufacturer decide to come up with this approach of drip infusion? The explanation is that DTPA was originally approved for use with Plutonium toxicity. Plutonium would have been acquired through the lungs and skin, hence neither had the forceful delivery into the ECM as observed with GBCAs and iv injection. Therefore most deposited Plutonium would be located close to where it was taken in (lung parenchyma and dermis of skin) and the great majority of Plutonium that entered the vascular system would be trapped in the endothelial tissue and not penetrated into the ECM. It is critical to understand the route of acquisition and the rate of the toxic heavy metal. Plutonium acquired by inhalation, much of the plutonium would be deposited along the major airways and secondarily the small airspaces of the alveoli. Passage into the vascular system would be not forced but a slow process, hence intrabody Plutonium would largely be trapped along the endothelium of small vessels. Primarily in the lungs and secondarily throughout the remainder of the body. The extent of skin entry of Plutonium would be important to know from the perspective of optimal treatment, and also important to know the amount acquired through the digestive tract as well.

As an aside, the occurrence of the Flare reaction was unknown to the chelator manufacturers, so they were amazed when I described Flare of GDD symptoms with DTPA chelation, which I described to them in my early days of chelation of patients with GDD. Why did they not know about Flare? Because plutonium toxicity was a disease of direct toxicity of radiation to the body, whereas GDD is also an immunological reaction. This begs the question well can Plutonium also cause an immunological T cell dysregulation like Gd? Yes this likely would also occur, and likely with a similar incidence as GDD, 1 in 10,000 Plutonium sufferers. So all Plutonium sufferers experience the direct toxic effect of radiation and only 1 in 10,000 would have the prospect of immunologic/ toxicity. The symptoms of immunologic toxicity would also be masked by the radiation toxicity, the latter being a far greater toxicity.

Re-equilibration removal in my opinion is likely the principle method of removal with DTPA of Gd from other tightly bound locations, like vitreous humor in the posterior chamber of the eye. Also to the extent that Gd is in an intracellular location, removal from within cells would also be re-equilibration: DTPA removing extracellular Gd, and subsequent movement of intracellular Gd to extracellular location to re-achieve balance (re-equilibration).

In conclusion, re-equilibration is a fascinating process. It is important to understand it, to make use of it to achieve decrease of total Gd content by depleting all the various reservoirs.

Richard Semelka, MD