Gadolinium Deposition Disease: Theories on Mechanisms of Disease
There is considerable interest on many fronts of what are the mechanisms of disease for GDD. There is a perception that exact knowledge of this is critical to have the disease accepted as a real entity.
As prologue to this subject, it has to be understood by the reader, that exact knowledge of mechanisms of disease and mechanisms of drug action is incomplete for essentially all diseases and all drugs, and many such as psychiatric diseases and drugs have only recently been moderately understood. There are still to this day some extremely common drugs, most notable acetaminophen, where the mechanisms of antipyresis (fever control) and pain-killing effects remain unknown, despite decades of use and multibillion dollars in sales. Acetaminophen also does not have anti-inflammatory effects, unlike aspirin and NSAIDs (eg: ibuprofen) - no idea why.
It is common also to accept and limit the use of drugs even if the mechanism is unknown - thalidomide and phocomelia (deformed small arms and legs in children when the mom's took the drug thalidomide in pregnancy for nausea).
Furthermore, acute hypersensitivity reaction (AHR) has been recognized for atleast 5 decades for Radiology contrast agents (iodine agents and GBCAs), and yet the mechanisms are not fully known. Still we manage patients for them, and with drugs where their effect is not fully known. Ofcourse the similar entity fibromyalgia (and in my opinion most 'diagnosed' cases represent toxicities to metals, which present day may be frequently Gd, and the disease is actually GDD) the mechanism is not known, but it is an accepted entity. Though, as with GDD, after decades of denying its existence.
That the mechanisms for GDD not fully known, hence the disease does not exist, is a false assertion. This knowledge is incomplete for virtually everything in medicine, and absent for a number of prominent diseases or drugs. As I have written GDD is closely related to AHRs, so the theories written below also address a subject not understood for 5 decades of knowing that it exists.
Mechanisms of Disease.
There are multiple mechanisms of disease for GDD. Probably the two most common are: 1) Gd substituting for Ca in many biological actions and 2) stimulation of cytokine release in immune cells. Gd also can substitute for other cations, such as sodium, which accounts for sweat smelling metallic, and for eye-tearing issues. It would not be surprising if Gd also inserts in place of other cations in other physiologic processes: Mg, Mn, iron, copper, etc.
Individual symptoms and my theory for their explanation are as follows:
Brain Fog. Theories on this are among the most conjectural, but I start with this anyways. Brain fog is also seen in lead poisoning, and with other heavy metals. This has been recognized with lead for decades, and no explanation established. Gd has been shown in animal models to insert in place of calcium at neural synapsis. Brain fog may be a direct central cerebrum neural synapse malfunction from Gd/Ca substitution, likely in the frontal complex. Release of cytokines and other inflammatory products either systemically or focally in the brain likely also plays a role. A direct toxic effect on brain cells is possibly also occurring.
Burning skin pain. The Transient Receptor Potential Vanilloid 1 (TRPV1) channels are responsible for the symptom of burning pain from entities like bee stings, nettles, capsaicin (hot ingredient in chili peppers). TRPV1 also termed capsaicin receptor and the vanilloid receptor 1. TRPV1 is primarily located in peripheral nerves but also central nerves. TRPV1 are also cation channels, so substitution of Gd as the cation may also play a role. Cytokine release from immune cells (and probably other cells, eg: dermis cells) probably is a major factor in stimulated the TRPV1 hyperactivity.
Bone Pain. Bone pain likely reflects local cytokine release from immune cells situated in bones, due to Gd depositing in bone.
Pins and Needles. Pins and needles are likely primarily small fiber neuropathy. Primarily this may reflect Gd/Ca substitution in peripheral nerve synapses.
Muscle fasciculations. Muscle fasciculations likely primarily reflects Gd/Ca substitution. Muscle contraction depends on Ca entering into muscle cells creating the environment for actin and myosin to bind causing myocyte (muscle cell) contraction. Gd entering into the system is like having broken teeth in gears, such as in a watch, causing irregular muscle firings.
Skin thickening and discoloration. The composite of inflammatory cell infiltration and release of inflammatory substances is likely the dominant factor.
Vision problems. This likely reflects a few processes all occurring simultaneously. The dry eyes likely reflects Gd/Sodium substitution in tears. Muscle dysfunction as mentioned above in optic and periorbital muscles. Possible central nerve abnormality either in the optic nerve and/or occipital brain.
Tinnitus. Ear ringing (tinnitus) likely arises from improper function of muscles and nerves in the structures of the inner ear from Gd/Ca substitution.
Imbalance/ataxia. This likely involves a combination of muscle dysfunction, peripheral nerve dysfunction, and possibly direct central dysfunction in the cerebellum, all reflecting Gd/Ca substitution.
Cardiac arrhythmia. Direct Gd/Ca substitution in cardiac nerves, and SA and Av nodes, are likely the principle factor. Direct Gd/Ca substitution in myocardial cells also likely plays a role.
Gastrointestinal Disorders. The intestinal wall is composed of smooth muscle (leiomyocytes) which are not under our direct cognitive control, unlike striated muscles (rhabdomyocytes) which are under our cognitive control. Nonetheless, the same components of muscle contraction occurs to propel intestinal contents through the GI tract by peristalsis. Gd/Ca substitution also occurs through the GI tract, and amongst the most devastating is small bowel stasis (essentially paralysis and dilation), that not only causes functional blockage but also bacterial overgrowth, and complications from that (sepsis and death being the most serious). Innervation of bowel also acts as the mechanism to cause bowel to contract and propel contents. As with other peripheral nerves, Gd/Ca substitution also occurs in bowel. This contributes to all the same abnormalities of muscle dysfunction. Gastric stasis and vomiting. Small bowel stasis, colon stasis, etc.
Unanswered important questions.
Other less common symptoms can be explained in a similar fashion. Although it can be clearly understood that if in some individuals GBCAs cause a significant cytokine release in immune cells, then symptoms such as skin burning and bone pain can be explained to occur in only GDD patients and not patients with Gadolinium Storage Condition (GSC). The immune system has a highly variable function between individuals probably largely due to genetic effects.
However it is not as clear, that if many of the symptoms that occur in GDD reflect a simple Gd/Ca substitution then why don't everyone experience this, as likely GSC subjects contain as much Gd in their bodies as those with GDD, as likely a very similar amount of Gd is present in both, determined essentially by the amount of GBCAs they have received.
Why do GDD patients alone, and not GSC subjects, experience the symptoms resulting from Gd/Ca and Gd/Na substitution, if they both have about the same amount of Gd retained? Shouldn't a simple metabolic effect have the same effect in everyone?
It may be that the immune system possess a regulatory effect on access the permeability of all cell membranes, or perhaps even an intracellular effect, such as on mitochondria. Toll-like receptors (TLRs) are critical receptors on cell membranes, primarily on innate immune cells (macrophages - which is the cell I favor as being integral in GDD), but these receptors also are present on the adaptive immune system cells (B-cells, T-cells) and other cells. These receptors are responsible for recognizing pathogens (such as bacteria) and thereby stimulation of reaction to them; in GDD, Gd is acting as the pathogen. It may be membrane channels related to/acting in concert with TLRs, respond by either preventing passage of cations that are not Ca, along Ca channels (which would be the circumstance in the 'normal' setting, such as with GSC subjects); or alternatively rendering Ca (and Na) channels more patent/less selective and allowing Gd to also enter them (the circumstance in GDD patients).
Is it Gd, the ligand, or the fully intact chelate that stimulate AHR and GDD. As AHR often reacts to GBCA injection immediately, and frequently GDD does as well, these entities arise when all GBCAs are fully intact. Gadavist/Prohance/Dotarem certainly should be fully intact when GDD initiates by 24 hrs post-injection, and maybe with Dotarem and Prohance even when it initiates at 1 month. Unlike with NSF, intact GBCA certainly causes GDD; but likely also unchelated Gd causes GDD as well, maybe rarely with AHR.
So fully intact GBCA is the culprit in virtually all cases of AHR, and many cases of GDD. Some have wondered if the ligand could be responsible. I consider it very unlikely, if for no other reason than GDD has virtually the identical symptom complex as lead toxicity- so the symptoms are heavy metal reaction. My theory is that many immune cells (beyond just neutrophils and macrophages, which both are known to adopt amoeba-like configurations, from their baseline round shape, to engulf entities as their mechanism of destroying them) recognize the presence of Gd in a molecule by probing the surface, whether Gd is in a linear or macrocyclic configuration. Gd is never far from the surface of the GBCA, so it can be detected. My opinion is that likely many immune cells can partially coat invading entities (like a star-fish), so they are able to recognize that Gd is present when it resides in a small molecular structure, no matter how it is configured. So I am also theorizing the unknown critical aspect of AHR, as a bonus in this blog.
Richard Semelka MD Consulting Stay tuned on the latest advancements: