Measuring Gd in Humans. A brief revisitation and comprehensive overview on the subject.

I recently heard from 2 separate patients that they wanted to get an MRI of the brain to identify whether Gd was present. I realized that they have not understood what I had written in a much earlier blog. So this blog will be brief, but much more comprehensive. This is an overview of Gd detection in humans.

Physical detection of Gd. The physical detection of Gd in the body requires tissue sampling. The easiest tissue to sample, and also is one of the two largest reservoirs is skin. A skin bopsy is the most straightforward. Deep skin biopsies have been the traditional method to detect Gd, and has been the standard for the diagnosis of NSF (GISF).. Any tissue can be evaluated for the presence of Gd. A number of commercial labs perform detection on a wide range of tissues. To the present time, the only commercial lab that will evaluate bone for Gd presence is Doctors Data. Attention should be addressed to Dean Bass, PhD who is in charge of special projects at Doctors Data. Note a couple of things, a separate sample section of any of the tissues, from the sample that the hospital is looking at for histology, for the various reasons of looking at histology, for example presence of fibrosis or presence of cancer cells. The separate sample prepared as directed by the lab the tissue is being sent to, to look for Gd. The other critical point, presently they just test for if Gd is present or not, but do not evaluate what form the Gd is in (that is also called speciation of Gd: is Gd still in the original GBCA, is it bound to phosphate, protein or anything else). Speciation of course would be important to know, but currently not done by labs

Gadolinium can be detected in hair, nails, sweat. Hair and nail detection is used for many other lab detections, alcohol and diabetes (A1C) detection are two common applications. The problem is it describes what has been happening over prior months, maybe up to a couple of weeks ago. My interest in treating subjects is what is happening now, so I don't use them.

Detection of Gd by MRI. The classic detection of Gd on MR studies is to look for the presence of high signal on noncontrast T1 weighted image (NCT1)s, and the structures looked at are the Dentate Nucleus and Globus Pallidus, as they accumulate more metal than other regions, classically more iron, but this includes more Gd.

The critical points are: this does not detect all species of Gd, so fully intact GBCAs interestingly, are not in high enough concentration to generate high signal. This extrapolates from the observation that very tightly bound Gd in the macrocyclic agents Prohance Dotarem/Clariscan are not visible as high signal on NCT!, despite the fact that we now know that it is deposited there. The same cast of characters associated with NSF are the most likely to be observed in the brain, with an expanded list of lesser stability MR contrast agents. My team and I have written a number of papers on this subject, so I know it extremely well. I will cut to the chase.

My theory is that the Gd detected has been dislodged from the GBCA and is bound to proteins. Why? GBCAs that exhibit protein binding have the shortest T1 relaxivity (brightest signal on T1) of all MR contrast agents. As such they are also administered in lower dose. So Multihance and Eovist (and the now now used Ablavar) all have protein binding, all have higher T1 relaxivity, and all can be administered in lower dose to achieve adequate enhancement. I have not yet made the time to study the newest FDA approved MR contrast agent, the macrocyclic agent Gadopiclenol (trade names Vueway and Elucirem) which has much higher T1 relaxivity than other agents and then can be administered in lower dose. I am assuming it is due to protein binding that it has such a high T1 relaxivity. Why does protein binding result in higher signal > increased tumbling rate. Just accept that for now.

So based on publications by others and our own, these are my estimates for the number of GBCA injections needed to generate high signal on NCT1, based on the type of GBCA. . Some agents I have extrapolated.

Omniscan : 5 injections.

Optimark: 5 or 6 injections

Magnevist: 10 injections.

Mutihance: 20 injections.

Gadavist: 30 injections (estimate)

Prohance, Dotarem/Clariscan, Gadopiclenol: > 100 injections (estimate).

The timeline for the repetition of injections and for the collective injection time span is unknown, but my estimate is 4 years. Also these agents can be mixed and matched. So 3 Omniscan and 15 Multihance likely combines to generate high signal.

Realistically then, for the great majority of GDD subjects, there will not be high signal in the brain. Thoise most likely to achieve this are those who received 5 injections of Omniscan, just because it is more likely to have undergone 5 MRIs with GBCAs than 10 0r 20. In short, for the great majority, forget the notion that getting an MRI will show show Gd in the brain.

Also on standard MRI studies only the brain has shown evidence of the presence of Gd... even though Gd is everywhere throughout your body.

There are investigational MR sequences that apparently can detect Gd in other tissues, and hence presumably in the brain (without having to conform to the list above). But they have been individual reports. I like to see 3 separate groups describing something before I can ascribe to it... So it is possible in the near future that Gd will be detected more broadly on MRI.. The other problem, is that it seems no other radiologist, other than me, may be interested in this.

Detection of Gd by X-ray Fluorescence (XRF). Gadolinium detection by XRF has been performed and reported by a few groups. The usual location used for detection is the tibia (lower leg). This is because this bone is very superficial and is large in size. Extra superficial tissue will interfere with the process, this is described as attenuation of the Gd x-rays leaving the tissue. This is described as a noninvasive approach. Scientifically this is very interesting, as all metals will have a different frequency of x-rays that they will generate. Also appealing is unlike what I describe for Gd in the brain, that MR only shows Gd bound to protein (for the present time) this technique detects Gd regardless of the speciation. Newest systems can achieve data in 30 minutes, which is a great improvement.

So it is best used to look at Gd in the tibia. But here is the point that makes me nervous, that is buried in the description of the technique. It is a radioactive process... New scanners to achieve the shorter imaging time use 5 GBq (gigabecquerel) of radioactivity as the source. So as with nuclear and PET imaging, I am always very nervous about these (yes more nervous than Gd) and often times they gloss over or don't report the amount of radioactivity involved. So I would not really describe this is noninvasive.. However the one positive aspect of the radiation story, is that the distal legs are relatively resistant to developing cancer from radioactivity, compared to the central body - largely because there are no organs that are relatively rapidly creating new cells. So this technique could detect Gd in the skull (the bones) but not likely the brain tissue.

For now XRF should be used just on the tibia.

Future direction: The future direction of detecting Gd in actual tissue in the body is with the development of novel MR techniques for this specific purpose.

Gadolinium in blood and urine: In my opinion Gd in blood and urine are the most important lab tests. To cut to the ending 24 hr urine is by far the most important test. Blood testing is interesting. In the native state Gd in detected in blood certainly for atleast 1 week following GBCA injection, whereas Gd is detected in urine, especially 24 hr urine, for atleast 3 months in everyone. Notice I describe this as native presence, also termed unprovoked, as with chelation Gd will be detected in blood and usine in an elevated fashion, for the above described timelines, but proportionately shorter depending on the GBCAs and the number of injections... this is a separate discussion.. The difference between a blood sample and 24 hr urine: a blood sample tells you how much Gd is present in motion in the body at that very second the sample it take. 24 hour urine describes Gd in motion over an entire 24 hour period So beyond 1-4 weeks (depending on the sensitivity of detection) at that split second of a blood draw detectable amounts of Gd is not shown. . I don't think I need to elaborate further on that. Its like panning for gold.

Above is the state of the knowledge Dec 2024 on Gd detection.

I always, and only use 24 hour urine to detect Gd, and when I do chelation for Gd (or for every other heavy metal) I always combine recent (within 3 days) prechelation urine values with post chelation 24 hour urines. Post chelation always starts immediately (starting after the first post-chelation urination) after chelation for approximately 24 hours. A slight range based on when chelation is performed the next day. So I never continue urine collection for that postchelation sample to include the chelation session performed day 2. In essentially everything is science it is critical to be standardized. So when I say always about 24 hour, and about timing of pre and postchelation, this means always.

Detection of Gd by tissue sampling can be useful for various research purposes, and for supporting documentation of the presence of Gd, when that supporting evidence is deemed crucial.

Richard Semelka, MD