Route of Entry has Significant Effect on Pattern of Disease in GDD
I watched the movie Dark Waters recently. It turns out we all have PFOA in our bodies. At least as scientifically fascinating that GDD can be so devastating in humans, recognizing the range of injuries Gd has been observed in animal models, is that most humans do not experience these adverse injuries. There clearly is protective measures, such as toll-like receptors, that block Gd from inserting into Ca- driven metabolic pathways. It is likely that the immune system blocks injury from Gd, and many other foreign, pollutant, antigens.
Focusing on route of entry. Most pollutants (including other heavy metals) enter by inhalation or consumption, and a few by skin absorption. Gd somewhat uniquely enters by iv route. This is one of the reasons that even as oral chelators with high stability constant for Gd are developed, iv chelation will likely have to remain an important part of the treatment regimen.
I have mentioned before, the list of toxin symptoms from lead and Gd are virtually identical, except Gd has a prominent component of peripheral arm and leg, glove and sock distribution of injury. This is most marked for NSF. The explanation is: most often lead is acquired through oral consumption, and Gd by iv administration. Blood tends to pool in the most distal locations from the heart - so hand and feet, so Gd toxicity results in this pattern.
I have described it previously that the chelator (DTPA) should follow the path of the injuring substance - so iv route (like cops and robbers). Taken one step further it should also follow a similar delivery approach.
The image I have recently conceived is (and dark waters seems appropriate) imagine a small stream with medium pace of water flow, and there are large pebbles in the bank that one wants to remove. Adding a removal fluid to the stream, if it is administered at a slow rate will primarily just follow the path of the water in the stream. To reflect back to imaging, early on with iodine contrast in CT and also the early experience with GBCA and MRI, iv drip administrations were used. It took a few years to realize with CT that this was a lousy technique compared to dynamic push, because organs (for example, liver and pancreas) did not enhance much with iv drip, hence you could not see solid tumors that well Dynamic power injection was required to observe disease well. So contrast forcibly administered into the interstitial spaces. I have described this before.
So Gd has been forcibly injected into the tissues as the GBCAs were administered by dynamic bolus injection to better visualize disease. Hence in the analogy, the pebbles have been stuck quite firmly into the bed of the stream. In order to remove these pebbles then a forceful injection of chelator has to be shot into the stream. Continuing to explain our technique. If one forceful injection has been performed it is reasonable to consider that a number of pebbles will have been loosened but not removed from the stream bank - hence a short-time follow up of a second forceful injection, to remove the pebbles loosened but not removed with the first bolus. This explains, with an exact analogy, our reasoning for split bolus of DTPA bolus push administration.
It is also clear from this analogy that distribution will be related to how the substance has been administered. I have focused on the glove and sock distribution, but much more comprehensively is the following: toxins administered by iv route should have a significantly larger distribution along the vessel structures. One would anticipate that much of the Gd deposited has an enormous propensity to be within the vascular walls and the perivascular interstitial tissue. So comparing Gd with lead, one would anticipate that Gd should have a vastly greater distribution in a perivascular, especially peri-venular (small veins) space. This is because Gd enters the tissues through arteries, passes into capillaries, exits into the interstitium, and then re-enters into small veins - venules. So likely the largest concentration of Gd in the body is in the perivascular interstitium and especially the peri-venular interstitium.
I had to think of this distribution pattern, from recent discussion with a physician-sufferer with disease, and recent vein clot following chelation. Clotting is likely much more likely with GDD than other heavy metal entities, like lead deposition disease, because a far greater percentage of the heavy metal is located in vessel walls and immediately surrounding interstitium, based mechanistically on the route of administration. Studies reporting Gd in tissues have described this localization of Gd, but I believe this blog is the first written explanation of why this has occurred: because of the
route of administration.