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Overlap Gadolinium Toxicities

Overlap conditions are very common in diseases, and often with autoimmune diseases. A condition I am very familiar with is actually called Overlap Syndrome, in which a patient has more than one of: Autoimmune hepatitis, Primary sclerosing cholangitis, and Primary biliary cirrhosis.

Conditions can also be founded upon the specific genetic mutation, regardless of organ of origin (eg: kidney cancer, lung cancer, can be related based on the specific mutation) which then correlates with the best treatment strategy. This is a relatively new concept in cancer treatment: treatment according to genetic mutation and not organ of origin.

The gadolinium toxicities can be grouped according to the primary immune cell (PIC) involvement: (note that it almost never is the case that only 1 type of immune cell is involved).

Anaphylactoid acute hypersensitivity reaction(AAHR) : PIC > Mast Cell (direct activation). General consensus.

Gadolinium Deposition Disease: PIC > T-cell/T-cell dysregulation. Our working theory.

Nephrogenic Systemic Fibrosis (NSF) : PIC> CD 34+ circulating fibrocytes. General agreement. Part of bone marrow cell infiltrates (our working theory).

The most common overlap is AAHR which persists as GDD. Clinically this is shown by a patient who within minutes of GBCA injection develops AAHR symptoms: hives, skin flushing; additional symptoms though that overlap with GDD such as throat swelling and difficulty breathing. It is the hives which is the classic AHR finding not seen in 'pure' GDD. Simple AAHR resolves then with treatment within 24-48 hours and the patient remains well. In AAHR/GDD overlap classic GDD symptoms then persist and prevail: brain fog, bone pain, classic skin findings, fasciculations, etc.

I will muse on the fact that since most imaging patients are not followed up, what percentage of patients end up having overlap AAHR/GDD. I suspect it is not a small %. I am very hesitant in treating overlap very severe AAHR (near death)/ GDD as GDD - as the Flare may provoke another near-fatal AAHR. These patients likely need to be treated in a hospital setting where advanced resuscitation is available. (ie: it is right there).

Overlap AAHR/ NSF I have not heard cases of, but I suspect they exist.

Overlap GDD/ NSF. Many of the symptoms are very similar, as previously written, just that NSF tends to be more severe. For example not pinkish skin with doughy skin thickening (GDD) but red skin with woody hardness (NSF). Overall, fibrosis in GDD is fortunately a mild and uncommon event, whereas in NSF it is severe and the typical event. I have not seen one, but I suspect they can co-exist. Unlike pure GDD, I think in this overlap likely the patient must have features of having received a weaker linear chelate and having advanced renal failure. In a related fashion, GDD in advanced renal failure also likely exists. This may be seen, and not accurately described, in subjects with advanced renal failure, and toxicity that looks more like GDD (less aggressive and more additional central symptoms) than NSF. Renal failure subjects with less aggressive NSF may have GDD. GDD would also be suspected if the agent used is one that is not associated with GDD (such as Dotarem or Prohance). since all GBCAs result in GDD, and only select less stable result in NSF.

Full house: Overlap AAHR/ GDD/ NSF. Again, I have not seen this but am sure it should exist.

Treatment for all these conditions should be about the same- although this has not yet been explored with NSF. This is what we are doing for GDD: remove Gd while simultaneously dampening the host immune reaction. Incidentally fundamentally the same treatment strategy for severe Covid-19.

Richard Semelka, MD

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