Gadolinium Toxicity: Gadolinium Deposition Disease - Part 2

This is a continuation of my blog post Gadolinium in Humans Revisited: Emphasis on Gadolinium Deposition Disease.

Mechanisms of disease.

Currently the various mechanisms of disease are theoretical in nature. As a result, even my closest working associates have differing opinions than I do. I will focus on my opinions but describe the various elements, that are the cause for varying opinions. My belief is that because both acute hypersensitivity reactions and NSF are immunologic in nature, and GDD is related to them, it stands to reason it is also immunologic. Immune cells are the gate-keepers for response, and also show the greatest variety of responsiveness of all the cell systems in the body. There are a number of papers that have described metabolic pathways that gadolinium interferes with, essentially by substituting in for calcium. Perhaps there are 10 pathways reported on, which tells me that there are probably at least 100 pathways. But, if it were purely a substitution in for calcium phenomenon, then all of the 10 to 50 million subjects with retained gadolinium should be experiencing these metabolic disruptions, but they are not, only 1 in 1,000 or 1 in 10,000 are. My opinion is that the immune system has allowed the various metabolic processes to occur, most likely because it has over-reacted to the presence of gadolinium, although the mechanism is likely more complex than that. Patients with GDD appear also to have direct neurologic disease that probably reflects direct toxicity to nerve cells, heart disease, and vascular calcification. All these multisystem disorders I believe have originated from the immune system dysfunctional handling of gadolinium.

The importance of describing the multisystem nature of the disease, from my perspective, is to avoid chasing down and treating individual symptoms. Treating individual symptoms in a hodge-podge manner likely will do more harm than good. The critical focus should be on treating the global disease process.

Treatment for GDD.

There are at least 3 components to treatment of GDD: 1) removing the gadolinium - the central issue; 2) mediating the acute hypersensitivity response, which likely persists; 3) mediating the late cellular response.

Before addressing the 3 components, it is important to mention, that as treatment for the disease is far from mature, reasonable efforts to avoid making the disease worse should be performed. Of course hopefully for the future there will be genetic testing so that patients at significant risk will not receive GBCAs. However, perhaps the most obvious initial mediator is to stop performing more GBCA enhanced studies on patients who have shown early findings of GDD. We are currently studying the frequency of occurrence of individuals who on initial GBCA-enhanced studies show clinical symptoms of GDD, but go on to receive more GBCA-enhanced studies, tragically not infrequently to investigate the cause of the unknown symptoms - which turn out to be those of GDD. Clearly, once a patient shows evidence of early signs of GDD, they should never receive a GBCA-enhanced MRI again.

What are early symptoms. Head-ache is common but too nonspecific. Prolonged metallic taste or olfactory sensation after the MRI. This is typical for about 30 seconds after the injection for many GBCAs, but sufferers describes this sensation for days or longer. Intense all over burning, but in early stages this may be experienced as unusual all over tingling. Intense focal bone or joint pain. Brain fog in isolation again may be difficult to assign to early GDD, but attention to this is warranted.

Removing Gadolinium.

We have published experience using Ca-/Zn-DTPA for removing gadolinium in the body, and have shown that 24 hr urine gadolinium content increases 10 to 20 fold following use of these agents. At the present time removal with this strategy, which is termed rechelation of gadolinium is the most obvious and best approach. Of the currently available, FDA-approved chelating agents, DTPA is by far the best agent. The thermodynamic stability of gadolinium to DTPA is 300,000 times that of gadolinium to EDTA. Currently EDTA has often been used for this purpose, largely because it was the only agent commonly available, and practitioners are also not trained molecular pharmacists. It turns out the keys for ideal chelating agents for gadolinium (and any other unwanted element) is the measure of thermodynamic (essentially how strong the bonds are) and kinetic (how quickly a molecule comes apart). There are other agents currently in development, an oral version of DTPA and another agent HOPO. It is some time away before these agents will achieve FDA approval, or if they will achieve FDA approval.So in the mean-time, we have to make due of the best agents we have available - which is Ca-/Zn-DTPA. The greater thermodynamic stability of Gd-DTPA versus Gd-EDTA informs me that when the chelator binds Gd it will most likely hold onto the gadolinium until it is removed from the body by kidney elimination, a weaker chelate like EDTA worries me that it may pick up the gadolinium but then frequently redeposit it elsewhere in the body in addition to some promotion of kidney elimination.

Management of Acute Hypersensitivity Features.

The traditional drug used to treat this for acute hypersensitivity reactions is benadryl. My opinion is that this is too old school antihistamine drug, and broader spectrum drugs for the range of acute hypersensitivity polypeptides (cytokines, chemokines, etc) would be preferred. I am not convinced that the best agent(s) are yet known, but better agents are probably claritin and singulair. We have considered a combination of drugs for this purpose.

Management of Chronic Cell Based Features.

Chronic cell based reactions (macrophages, T-lymphocytes, bone marrow cell infiltrates) probably are responsible for the chronic deleterious features of distal arm and leg discoloration, pain and tissue doughiness. My opinion is that in later stages when these morphologic changes are present, chelation alone may not be sufficient to treat the disease fully. The solution are likely either with anti-autoimmune drugs (the archetype is Humira) and/or immune modulation drugs (the least toxic may be cyclosporin). A critical future phase of investigation is to determine if any of these agents show beneficial responce in patients.

Gadolinium Deposition Disease Similarities to Other Heavy Metal Toxicities.

GDD is a fascinating study in multicomponent iatrogenic human disease. One critical aspect of investigating into the genetics, physiology, and treatment of the disease, is that likely the findings and solutions will likely be closely related to what is necessary to know about other heavy metal toxicities. Increasingly it is becoming clear that lead contamination in water and pipes is likely an enormous nation-wide problem. If appreciable gadolinium is present in 10 - 50 million americans, appreciable lead is probably present in 50 to 100 million americans. This is not to mention mercury, chromium, aluminum, and arsenic. If a successful combination therapy is developed for GDD, most likely it can also be applied to sufferers from these other metal toxicities.

Nephrogenic Systemic Fibrosis (NSF).

The disease was first described in the late 1990's, NSF has been recognized as due to gadolinium since 2006. The essential predisposing factors are: administration of less stable GBCAs (almost exclusively linear agents, and primarily nonionic linear agents) and the presence of advanced renal failure, most often stage V chronic renal failure. Since late 2007 when nonionic linear agents and the ionic linear agent magnevist were no longer administered to patients with advanced renal failure, the disease has largely disappeared. The primary cell associated with the condition is CD 34+ fibrocytes. These cells though are likely in the family of bone marrow cells, which are stimulated and released in the setting of chronic inflammatory diseases.

The disease shows onset from 2 weeks - 2 years. The classic clinical picture is distal arm and leg (glove and sock) tissue woodiness, redness, pain and joint contractures. The face is spared.

My break with orthodoxy with this condition are as follows: only 5% of patients with stage V renal failure develop NSF even when given the least stable agent, Omniscan. The variability of acquiring the disease suggests that there must be a genetic propensity, as I have suggested with GDD. It is also worth revisiting with NSF, do patients show other features that are observed in GDD such as brain fog? It is possible that since the findings of the glove and sock disease were so impressive and devastating, other features had been ignored in these patients.

Is NSF, GDD in the setting of advanced renal failure, or is it a separate purely chronic cell-based immunologic disease?

Treatment.

No successful treatments have been found for NSF, although reports described stabilization of disease following kidney transplantation. Based on findings with GDD, consideration should be given to rechelating gadolinium in the body with DTPA combined with dialysis, or just on its own in patients with a functioning renal transplant and an acceptable eGFR.

Consideration should be given in the setting of accidental administration of a linear nonionic GBCA in a patient with advanced renal failure for dialysis within 24 hours, and with a second dialysis session within a day of the first session. In most other settings (administration of a macrocyclic agent) creating a new dialysis port and performing dialysis is not indicated, and may be detrimental.

Safety of 'free' gadolinium.

It does appear surprising that if gadolinium has been described for decades as a toxic metal, how is it that millions of individuals have appreciable gadolinium in their bodies and yet are essentially perfectly well despite its presence? The explanation is that gadolinium is never 'free' in the body, it is always bound to something. The gadolinium either resides in the intact GBCA (most likely almost all gadolinium is in this state with the most stable of the macrocyclic agents), bound to inorganic molecules (phosphates, carbonates, etc) or bound up in large organic macromolecules. So even in the setting where gadolinium may be released inside the body from its chelate (for example from the less tightly bound nonionic linear agents) the gadolinium is quickly picked up by inorganic molecules or large macromolecules, so any 'free' time is measured in fractions of a second.

This host reaction to bind heavy metals to minimize their toxicity is also ongoing with all other heavy metals - lead may be the most prevalent and noteworthy. This also explains why lead is relatively nontoxic in the millions of people with appreciable lead in their bodies.

This completes the document on Gadolinium in Humans. Following blogs are targeted posts to specific aspects on Gadolinium Deposition Disease.