Gadolinium Toxicity

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Possible connection between GBCAs and Small Fiber Neuropathy

A recent study by Radbruch et al. used a mouse model to assess intraepidermal nerve fiber density (IENFD) after injection of gadolinium-based contrast agents (GBCAs). The study, “Is Small Fiber Neuropathy Induced by Gadolinium-Based Contrast Agents?”, was published in Investigative Radiology. Radbruch and his colleagues investigated changes of small fibers in the epidermis of mice as a potential cause of patient complaints about burning pain in their arms and legs after administration of a GBCA.  As a possible additional marker for damage of small fibers, the appearance of terminal axonal swellings (TASs) was assessed. Small fiber neuropathy (SFN) is a disorder of thinly myelinated Aδ-fibers and unmyelinated C-fibers, and it is typically associated with burning pain in the lower arms and legs. The authors noted that the cause of SFN remains unknown in up to 50% of cases.

The study involved 6 groups of 8 mice that were intravenously injected with one dose (1 mmol/kg body weight) of either a macrocyclic GBCA (gadoteridol, gadoterate meglumine, gadobutrol), a linear GBCA (gadodiamide or gadobenate dimeglumine), or saline. Four weeks after injection, the mice were euthanized, and footpads were assessed using immunofluorescence staining. Intraepidermal nerve fiber density (IEFND) was calculated, and the median number of terminal axonal swellings (TASs) per IEFND was determined. They found a significant reduction of IEFND in the footpad of mice for all GBCAs tested compared with the control group.  There was a significantly larger decrease of IEFND for the linear GBCAs compared to macrocyclic GBCAs. They found a significant increase of TAS/IEFND for the linear GBCAs, whereas only a “trend without significance” was found for the macrocyclic agents.

The authors noted that, to the best of their knowledge, the study is the first to investigate a correlation between small fiber degeneration and GBCA exposure. (more…)

Gadolinium Reference Range for those with no GBCA exposure

The article, “Establishing Reference Intervals for Gadolinium Concentrations in Blood, Plasma, and Urine in Individuals Not Previously Exposed to Gadolinium-Based Contrast Agentsby Layne et al., was published in Investigative Radiology earlier this year. Their study set out to determine whether healthy people who have never received a gadolinium-based contrast agent (GBCA) have detectable concentrations of gadolinium (Gd) in their blood and urine, and to then develop a reference range for Gd concentrations in blood and spot urine. A secondary aim of the study was to determine whether spot urine Gd concentrations are equivalent to those in timed 24-hour urine collections.  In the majority (93.3%) of their 120 healthy volunteers, the Gd concentrations were undetectable in blood, plasma, spot urine samples, and 24-hour urine collections. No participants had detectable concentrations of Gd in their plasma. The authors noted that those subjects who did have detectable Gd concentrations in their spot urine samples had considerably lower concentrations than those identified in the reference interval published on the Mayo Clinic web site, which is less than 0.8 mcg/g creatinine.


Proposed Gadolinium Reference Intervals, Layne et al. (2020):
      • Whole blood: <0.008 ng/mL or <0.050 nmol/L
      • Plasma: <0.009 ng/mL or <0.057 nmol/L
      • Spot urine: <0.036 μg/g creatinine or <0.0250 nmol/mmol

More Study Details –

Twenty subjects also did a timed 24-hour urine collection, and urine Gd concentrations were measured in samples from those collections. None of the 24-hour urine collections had detectable Gd concentrations, and those 20 subjects also did not have detectable Gd in their spot urine specimens.

Study participants were recruited from the staff at Guy’s and St Thomas’ NHS Foundation Trust, London, and students from King’s College London who are based at St Thomas’ Hospital. Potential subjects completed a basic health questionnaire to determine suitability for inclusion in the study. Participants had to be 18 years or older with no significant medical history, no history of smoking or vaping within the previous 6 months, and no prior exposure to gadolinium or GBCAs.  All participants had an estimated glomerular filtration rate (eGFR) of 70 or greater.  Of the 120 subjects, 79 (65.8%) were female and 41 (34.2%) were male.  The median age was 29.6 years.

Although no subjects reported having an MRI with a GBCA, detectable concentrations of Gd were found in 10 of the 120 subjects.  Four of those 10 reported undergoing an MRI without contrast in the past, which could not be confirmed, so those 4 were excluded from further data analysis.

The authors noted that it is possible that subjects had a degree of background Gd exposure from anthropogenic gadolinium which is known to be in tap water. (more…)

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 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

 

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