Gadolinium Toxicity

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Twitter feed of #MRIsafety

The Twitter feed below is about MRI Safety (#MRIsafety). MRI Safety is a larger topic than just the safety of Contrast Agents. Much of it is regarding the strong magnetic fields attracting metallic objects. You will find tweets from people who are concerned about Gadolinium Based Contrast Agents.

#MRIsafety Twitter Feed

Gadolinium Levels in Water Supplies are Increasing: Is That Safe?

The increasing levels of gadolinium found in lakes, bays, rivers, and water supplies around the world correlate with the increased administration of gadolinium-based contrast agents (GBCAs) for MRIs. The gadolinium (Gd) from those GBCAs that gets into our water is called anthropogenic gadolinium since it comes from human activity. Some studies refer to it as a Gd anomaly and note that it is difficult to remove by the usual sewage treatment technology. This is not a new problem, but it is one that requires further investigation to confirm that gadolinium is not absorbed by the GI tract since it could be ingested via drinking water. It seems that might be of even greater concern for infants, children, and pregnant women. Besides being in our drinking water, a 2019 study by Schmidt et al. found anthropogenic gadolinium, in similar concentrations, in tap-water and in a related water-based popular fountain soft drink from two fast food restaurants in six major German cities. That study provided the first evidence that anthropogenic gadolinium in contrast agents enters the human food chain.

A recent study by Inoue et al. reported a significant increase in the Gd anomaly in the rivers in Tokyo, compared to data obtained 22 years ago, depending on the location of the wastewater treatment plants. The amount of Gd had increased by as much as 6.6 times since the assessment 22 years ago. That coincides with the significant increase in the number of MRI scanners in Japan and scans performed with a GBCA. The study notes that common wastewater treatment plants cannot remove gadolinium, so it is released back into the environment. That fact is well-documented in the literature.

A 2020 study by Brünjes and Hofmann found that “contrary to previous assumptions that GBCAs are stable throughout the water cycle, they can degrade.” The authors noted that there is specific concern that “UV end-of-pipe treatment” may enhance the risks posed by GBCAs in drinking water. They noted that increasing GBCA concentrations could become a concern in settings where drinking water is produced from raw water resources with a high proportion of recycled wastewater. They said that during drinking water production, improved water purification would require using expensive reverse osmosis as it is the only efficient way to fully remove GBCAs.  The authors suggested a novel way to reduce the input of gadolinium into the aquatic environment and its potential health risk, and it is to have patients collect urine in leakproof collection bags that include super absorbent polymers for at least 24 hours following administration of GBCAs. Urine would need to be collected not only in hospitals, but also in patients’ homes. It appears that a pilot study by Niederste-Hollenberg et al. was done in Germany in 2018 that had a high level of acceptance by patients.

Is collecting urine after contrast-enhanced MRIs enough to solve the potential problems that might be caused by anthropogenic gadolinium in our drinking water? (more…)

Gadolinium detected in skin of patients with impaired renal function, but no NSF: What does that prove?

Editorial by Sharon Williams
July 2020


If you only look at one specific patient population such as the renally-impaired, for predominantly one specific disease symptom like skin changes, how would you ever expect to know with any certainty whether or not other patient populations are also being harmed by GBCAs? (S. Williams, 2012 Letter to FDA)

 

I have been debating how to present the findings of a study that was published earlier this year, and I decided that the best thing for me to do was to write an editorial about it.

The paper by Kanal et al., Nephrogenic Systemic Fibrosis Risk Assessment and Skin Biopsy Quantification in Patients with Renal Disease following Gadobenate Contrast Administration, says that the study “aimed to analyze any nephrogenic-systemic fibrosis-related risks and quantify skin gadolinium levels in patients with impaired renal function but without nephrogenic systemic fibrosis who had received gadobenate.”

I have read the paper several times and I am still not sure what the study hoped to prove. Is it that half-doses of gadobenate (MultiHance) are safe to use even in renally-impaired patients?  That subclinical NSF does not exist?  That low levels of gadolinium (Gd) in the skin means that the patient has not been adversely affected by retained gadolinium?  With all due respect to the authors, I feel like something is missing.

The study used a screening questionnaire that is geared toward NSF and is primarily about skin changes (Lima et al., 2013). From what we know from the literature about NSF and gadobenate, I am not surprised that so few of the patients screened positive for NSF and that none were found to actually have NSF, especially when, according to the paper, “the vast majority” of them had received half-doses of gadobenate.  As I have said many times about NSF and gadolinium retention, I believe we need to consider what might be happening on the inside of the patient, and not just look at the skin for visible evidence of a problem, and, indeed, not just look for NSF as the only point of concern when it comes to gadolinium retention.

Interestingly, in the 2007 paper by High et al. that was referenced, it said that gadolinium was detected in only 4 of the 13 tissue specimens from 7 NSF patients. However, all 7 patients were included in the NSF Registry.  Perhaps that is why having evidence of Gd in tissue is not part of the Clinicopathological Definition and Workup Recommendations for NSF that was published by Girardi et al. (2010).  Since a patient does not need to have evidence of gadolinium in tissue to be diagnosed with NSF, I would not expect that it would be required in order to prove someone has “subclinical NSF” either. Finding no gadolinium or extremely low levels of gadolinium in dermal tissue does not seem to prove or disprove whether someone has been adversely affected by retained gadolinium.

I understand that there may be situations when undergoing an MRI with contrast might be deemed medically necessary and agreed to by the patient. However, I sincerely hope that, after reading this paper, radiologists and clinicians do not feel there is no concern about using gadobenate as long as it is used in half-doses.  We have to remember that, for inclusion in the study, only a single dose of gadobenate (MultiHance) was required, and the highest gadolinium level was found in a patient with an eGFR of 53 who had 1 MRI with an unspecified amount of contrast.  I think it is still important to consider the cumulative effect of any gadolinium that is retained, and to remember that the damage caused by gadolinium is more than skin deep – it goes to patients’ bones and vital organs as well.  The adverse effects of gadolinium in internal organs will not be visible with the naked eye, but that does not mean it is not happening.

Sharon Williams
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References:
Kanal, E., Patton, T. J., Krefting, I., & Wang, C. (2020). Nephrogenic Systemic Fibrosis Risk Assessment and Skin Biopsy Quantification in Patients with Renal Disease following Gadobenate Contrast Administration. American Journal of Neuroradiology. https://doi.org/10.3174/ajnr.A6448

Williams, S. (2012). Letter to FDA Regarding Gadolinium Toxicity from GBCAs; made public 2016, The Lighthouse Project, GadoliniumToxicity.com. https://gdtoxicity.files.wordpress.com/2016/10/swilliams-2012fda-letter-gdtoxicity1.pdf

Lima, X. T., Alora-Palli, M. B., Kimball, A. B., & Kay, J. (2013). Validation of a Screening Instrument for Nephrogenic Systemic Fibrosis. Arthritis Care & Research, 65(4), 637–642. https://doi.org/10.1002/acr.21877

High, W. A., Ayers, R. A., Chandler, J., Zito, G., & Cowper, S. E. (2007). Gadolinium is detectable within the tissue of patients with nephrogenic systemic fibrosis. Journal of the American Academy of Dermatology, 56(1), 21–26. https://doi.org/10.1016/j.jaad.2006.10.047

Girardi, M., Kay, J., Elston, D. M., Leboit, P. E., Abu-Alfa, A., & Cowper, S. E. (2011). Nephrogenic systemic fibrosis: clinicopathological definition and workup recommendations. Journal of the American Academy of Dermatology, 65(6), 1095-1106.e7. https://doi.org/10.1016/j.jaad.2010.08.041

 

Gadolinium in Ovaries 9.5 Years after GBCA Administration

Editorial by Sharon Williams
May 2020

While being in the middle of the COVID-19 pandemic might not seem like the best time to write an editorial about long-term gadolinium retention, waiting longer was not a good option for me.  I believe that the information I want to share with patients, doctors, and gadolinium researchers needs to be in the public domain.

Anyone who follows our posts knows that none have been made since mid-2019.  I will not go into all the reasons for that, but one of the issues resulted in the removal of my ovaries late last year.  Thankfully, no cancer was found, but something else that should not have been there was – gadolinium.  Testing performed by Doctor’s Data determined that there was gadolinium in both of my ovaries which were removed more than 9.5 years after my last dose of a gadolinium-based contrast agent (GBCA).  I must admit that I was not surprised, since gadolinium was also found in my thyroid tissue that was removed in 2014.

At the time of all my MRIs, I had what the NSF literature refers to as “normal” renal function, meaning an eGFR greater than 60. I have had 5 MRIs with a linear GBCA that is no longer on the market, and my last dose was 10 years ago in March of 2010. I have no history of brain tumors or cancer anywhere in my body. Based on what patients like me have been told, I should not have retained gadolinium from the contrast agent, but I did, and I have proof of long-term gadolinium deposition in my organs. While I understand that deposition alone does not prove causation, I believe it raises serious questions about the long-term effects of gadolinium retention that need to be answered.

You might be wondering if I made the FDA or anyone else aware of the fact that gadolinium was found in my ovarian tissue 9.5+ years after my last dose of a GBCA, and the answer is, yes, I did.  I sent the FDA and more than 20 other doctors and scientists a copy of a document that contained details of my GBCA history and results of testing my blood, urine, and thyroid and ovarian tissue for gadolinium.  While I heard back from the FDA and a few doctors, nothing else has come from it at this time.

Whether the gadolinium level in my tissue was high or not is not the issue since gadolinium should not remain in the body many years after MRIs with a GBCA.  As the FDA noted on page 16 of its Briefing Document for the September 8, 2017, MIDAC public meeting about Gadolinium Retention, “detection of gadolinium weeks or months following GBCA administration is considered abnormal as gadolinium is a trace element and not involved in any physiologic processes.” Sherry et al. (2009) reported that gadolinium is toxic in biological systems that require calcium for proper function due to the very similar radius of the Gd3+ and Ca2+ ions.  Surely, based on what we have learned about gadolinium (Gd) and Nephrogenic Systemic Fibrosis (NSF), no one can honestly think that patients who retain toxic gadolinium for many months or years will not be harmed by it in some way at some point in time.

Until mid-2015, the FDA had not recognized that patients with normal renal function were retaining gadolinium from GBCAs administered for MRIs. While the FDA and Radiology community now acknowledge that everyone who has an MRI with a GBCA likely retains gadolinium from each dose of contrast they receive, so far, they continue to say that they have seen no evidence that retained gadolinium causes harm. I find that statement hard to reconcile with what we know already from the published facts about NSF, GBCAs, and the toxic effects of gadolinium.

While some may think the long-term effects of gadolinium retention are still unknown, I cannot believe it is a benign substance since I continue to experience symptoms of gadolinium toxicity more than 10 years later. It seems clear that a gadolinium study to evaluate patients like me is urgently needed. In my opinion, the issue is not about the toxic effects of gadolinium when it is retained in the human body since the NSF-related literature already informed us about that. The problem is no one understands what it is doing to patients with normal renal function when less gadolinium may have been retained.

As we have said many times before, Gadolinium Toxicity is a “Disease of Degrees” with NSF being the worst manifestation of it when large amounts of gadolinium are retained.  However, based on the published facts about gadolinium and GBCAs, we see no reason to think that retained gadolinium will cause full-blown NSF or nothing at all.

It is my belief that the medical community will not fully-appreciate the scope of the problems related to gadolinium retention until symptomatic patients with normal renal function are interviewed, examined, and tested. If all patients retain some gadolinium from every dose of contrast that they receive, why is it that only a small percentage of people report having symptoms of toxicity? Could asymptomatic patients who have retained Gd go on to develop gadolinium-induced health issues later?  Why are patients who have received macrocyclic agents for their MRIs experiencing intense symptoms; could they be retaining the intact macrocyclic GBCA?

There are many unanswered questions about the long-term effects of gadolinium retention, and I believe patients who have been affected by the toxic effects of gadolinium are key to finding some of those answers.  What you learn from patients like me might help guide new research.

Researchers interested in conducting a study with me or other patients with normal renal function who have evidence of gadolinium retention and symptoms of gadolinium toxicity, should email me at Sharon@GadoliniumToxicity.com.  I sincerely hope that researchers contact me since this problem is not going away.

Sharon Williams

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References
9/8/2017 FDA Briefing Document for Medical Imaging Drugs Advisory Committee Meeting about Gadolinium Retention.  https://www.fda.gov/media/107133/download

Sherry, A. D., Caravan, P., & Lenkinski, R. E. (2009). Primer on gadolinium chemistry. Journal of Magnetic Resonance Imaging : JMRI, 30(6), 1240–1248. Retrieved from http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2853020&tool=pmcentrez&rendertype=abstract

7/27/15 FDA Safety Announcement – https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-fda-evaluating-risk-brain-deposits-repeated-use-gadolinium-based

5/22/2017 FDA Safety Communication –  https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-fda-identifies-no-harmful-effects-date-brain-retention-gadolinium

12/19/2017 & 5/16/2018 FDA Safety Announcements can be found here:
https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-fda-warns-gadolinium-based-contrast-agents-gbcas-are-retained-body

 

Study finds GBCAs induce Mitochondrial Toxicity and Cell Death

A preclinical study by Bower et al. found that gadolinium-based contrast agents (GBCAs) have a toxic effect on mitochondrial respiratory function and cell viability in human neurons.  The study, Gadolinium-Based MRI Contrast Agents Induce Mitochondrial Toxicity and Cell Death in Human Neurons, and Toxicity Increases with Reduced Kinetic Stability of the Agent, was published online ahead of print in Investigative Radiology.  For the study, neurons modeling a subset of those in the basal ganglia were tested, because the basal ganglia region is one of two brain regions that displays the greatest T1-dependent signal hyperintensity changes.  Multiple studies have shown that T1-signal intensity changes in the brain are the result of gadolinium deposition.  The authors noted that there is increasing evidence that all agents (linear and macrocyclic) remain in human brain tissue for some period of time, where they may be taken up into various cell types, including glia and neurons.

Reports of possible clinical symptoms experienced by patients after a contrast-enhanced MRI have been published. However, until this study, it was unknown whether GBCAs induce toxic effects on the cellular function of human neurons.  This study provides the first definitive evidence that GBCAs induce mitochondrial toxicity and cell death in cultured human neurons.  The authors said that the “magnitude of the measured toxicity broadly increases as the kinetic stability of the contrast agent decreases, and the lower stability agents induce toxicity at concentrations that fall within the range detected in some autopsy patients”.  “For all agents, the magnitude of the toxicity increases with concentration.” (more…)

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