The viewpoints presented here include Gadolinium Toxicity news and thoughts about various aspects of living with the effects of Gadolinium Toxicity. They may just be one person’s idea or an experience that happened to them. These viewpoints are important to share, because someone looking at them from a different viewpoint may be able to tie some things together in a way that we did not see.
March 10, 2017 – A committee of the European Medicines Agency (EMA) has recommended the suspension of the marketing authorizations for four linear gadolinium-based contrast agents (GBCAs) used for MRI scans because of concerns about small amounts of gadolinium from administered GBCAs being deposited in the brain.
At the completion of its year-long review of GBCAs, the EMA’s Pharmacovigilance and Risk Assessment Committee (PRAC) “found convincing evidence of accumulation of gadolinium in the brain from studies directly measuring gadolinium in brain tissues and areas of increased signal intensity seen on MRI scan images many months after the last injection of a gadolinium contrast agent”.
Linear agents recommended for suspension by the PRAC are:
Gadobenic acid, marketed as MultiHance by Bracco Diagnostics Inc.
Gadodiamide, marketed as Omniscan by GE Healthcare
Gadopentetic acid, marketed as Magnevist by Bayer HealthCare Pharmaceuticals
Gadoversetamide, marketed as OptiMARK by Mallinckrodt Inc.
The PRAC’s final recommendations will be sent to the Committee for Medicinal Products for Human Use (CHMP) for its opinion. Further details will be published when CHMP renders its opinion regarding the removal of the four linear agents from the market.
In its press release, the PRAC noted that deposition of gadolinium in other organs and tissues has been associated with rare side effects of skin plaques and Nephrogenic Systemic Fibrosis (NSF). It also noted that “non-clinical laboratory studies have shown that gadolinium can be harmful to tissues”.
The PRAC said that two linear agents will remain available: gadoxetic acid (brand name Eovist), used at a low dose for liver scans, since it meets an important diagnostic need in patients with few alternatives, and a formulation of gadopentetic acid injected directly into joints because its gadolinium concentration is very low. The PRAC indicated that both agents should be used at “the lowest dose that enhances images sufficiently to make diagnoses and only if unenhanced scans are not suitable”.
On July 27, 2015, the FDA issued its first, and so far only, Safety Announcement regarding gadolinium retention in the brain following repeated use of a GBCA for MRIs. It acknowledged that trace amounts of gadolinium may stay in the body long-term, and noted that “recent studies conducted in people and animals have confirmed that gadolinium can remain in the brain, even in individuals with normal kidney function”.
The 2015 announcement said that the FDA, including its National Center for Toxicological Research (NCTR), “will study this possible safety risk further”. As of this writing, the FDA has made no further public safety announcements regarding the use of gadolinium-based contrast agents.
It remains to be seen if the FDA will follow the lead of the EMA and suspend the use of the linear GBCAs. Three of the four suspended agents are linked to the most unconfounded cases of NSF, and they are among the most widely used GBCAs for magnetic resonance imaging (MRI) procedures.
PRAC concludes assessment of gadolinium agents used in body scans and recommends regulatory actions, including suspension for some marketing authorisations. EMA/157486/2017. http://www.ema.europa.eu/docs/en_GB/document_library/Press_release/2017/03/WC500223209.pdf
Full-disclosure, we are reporting on our own retention paper.
Today we have released our fourth research paper on gadolinium retention from Gadolinium-based Contrast Agents (GBCAs) administered for contrast-enhanced MRIs. The paper is titled “Gadolinium Retention from Contrast MRIs in 70 Cases with Normal Renal Function – 24-hour Urine Test Results”.
Drawing on the contrast MRI history and 24-hour gadolinium urine testing results information that we have received from members of the MRI-Gadolinium-Toxicity Support Group, we reported retrospectively on 70 cases with 120 urine test results. We are thankful to the members of our support group for being willing to share their information with us. The participants all had normal kidney function and report having symptoms of gadolinium toxicity. We believe the results reported are dramatic.
About the Gadolinium Retention Study
The number of results presented is up significantly from our last paper in 2014 when we reported on 15 cases and 40 test results. The additional data points allowed us to look at gender as a possible differentiator, but the data showed nearly identical test results for males and females. With information about the number of contrast-enhanced MRIs for each case, we were able to analyze the results in three groups: cases with a single contrast MRI, cases with 2 to 4 contrast MRIs, and cases with 5 or more contrast MRIs. Readers of this site will not be surprised that the analysis showed that for these cases, there was a discernible difference in test results based on these groupings. The 2 to 4 contrast group generally had higher levels of gadolinium in their urine for a longer period of time than those with a single contrast. Likewise, the results for the 5 or more MRIs group were higher longer than the cases in the 2-4 contrast MRIs group. This is consistent with the cumulative effect of multiple contrast-enhanced MRIs that others have reported.
We also provided the raw test results data for each case, enabling other researchers as well as patients to look at the progression of test results over time. Averages for time blocks since the last contrast MRI are also shown to help in understanding the progression of gadolinium urine levels.
A few observations regarding the test results are revealing. 21 cases had urine tests performed in the first month with results that range from 507 mcg Gd/24hr urine specimen 4 days after the contrast MRI to results around 17 mcg Gd/24hr near the end of the first month. All of the results are enumerated in the report. 8 cases had urine test results more than 36 months after their contrast MRI with results as high as 0.6 mcg Gd/24hr more than 7 years after the individual’s last contrast-enhanced MRI. There is no broadly utilized acceptable range for gadolinium in a 24-hour urine collection. Mayo Clinic has established a reference range that was recently updated to be 0.0-0.6 mcg Gd/24-hour urine specimen collected more than 96 hours after administration of a GBCA. 40 cases had urine tests in the first 3 months after their contrast MRI, with the lowest result being 1.74 mcg Gd/24hr, well above the Mayo reference range that is applicable once four days have elapsed since the contrast MRI. Simply stated the results we observed are inconsistent with the clearance times indicated on GBCA product labeling and the understanding of most researchers and clinical practitioners.
To the best of our knowledge, this is the most comprehensive reporting of retained gadolinium as evidenced by urine testing that is available to the public. While the methods we used do not meet the rigor of a clinical trial, and we do not know if similar results would be seen universally, we believe the consistency of the results and the lack of outliers on the low side are justification for concern. We believe that further investigation by researchers, GBCA manufacturers, and licensing agencies is warranted.
This study does not stand alone, but confirms the many recently published research papers that reported unexpected retention of gadolinium from contrast MRIs by people with normal renal function. We encourage stronger action by the FDA and others to inform patients about possible gadolinium retention from contrast-enhanced MRIs and the potential for long-term side-effects.
We urge patients, clinicians, and researchers to read the entire report and share as appropriate with your families, care-givers, and colleagues. Read the Report.
Hubbs Grimm and Sharon Williams
A petition drive to Stop the Damage and Find a Cure for Victims of MRI Contrast Toxicity has been started at change.org. The toxicity comes from the gadolinium that is retained from Gadolinium-Based Contrast Agents (GBCAs) administered for contrast-enhanced MRIs. We hope all of our readers will sign the petition and then tell all their friends who will sign it and then tell all of their friends. With today’s social media, we have a chance to get the attention of the FDA and other decision makers around the world.
The petition was started by MedInsight Research Institute. https://medinsight.org/ and specifically by Moshe Rogosnitzky, the co-founder and Executive Director. He is an established research scientist and medical innovator whose pioneering work has resulted in the development of new treatments for various types of cancer and auto-immune diseases. We have been in touch with Moshe since late 2015 when he first contacted us about gadolinium toxicity issues.
His blog post announcing the petition drive “What price will we pay for the FDA’s faith in Gd?” lays out his case for why various actions regarding the use of Gadolinium-Based Contrast Agents are needed now. He covers many of the points we have raised and brings new insight as to why the FDA, NIH, WHO, and other organizations worldwide must Stop the Damage and Find a Cure for Victims of MRI Contrast Toxicity, the headline for the petition.
Please take action now and show your support by signing this petition at Change.org.
A special issue of the journal Magnetic Resonance Imaging has been published and it is dedicated to “Gadolinium Bioeffects and Toxicity”. The issue starts with a safety overview of GBCAs by MRI Safety expert Dr. Emanuel Kanal, and ends with articles by UNC Radiologist Dr. Richard Semelka. One of the articles provides the initial description of Gadolinium Deposition Disease (GDD) which, while recently named, has been around for a while.
The issue is broken down into 4 sections as shown below. The link will take you to the abstract, but you can access a PDF of the complete paper.
Kanal, E. (2016). Gadolinium based contrast agents (GBCA): Safety overview after 3 decades of clinical experience. Magnetic Resonance Imaging. http://doi.org/10.1016/j.mri.2016.08.017
MRI Findings –
Kanda, T., et al (2016). Gadolinium deposition in the brain. Magnetic Resonance Imaging, 34(10), 1346–1350. http://doi.org/10.1016/j.mri.2016.08.024
Radbruch, A. (2016). Are some agents less likely to deposit gadolinium in the brain? Magnetic Resonance Imaging, 34(10), 1351–1354. http://doi.org/10.1016/j.mri.2016.09.001
Ramalho, J., et al, (2016). Technical aspects of MRI signal change quantification after gadolinium-based contrast agents’ administration. Magnetic Resonance Imaging, 34(10), 1355–1358. http://doi.org/10.1016/j.mri.2016.09.004
Basic Sciences –
Murata, N., et al, (2016). Gadolinium tissue deposition in brain and bone. Magnetic Resonance Imaging, 34(10), 1359–1365. http://doi.org/10.1016/j.mri.2016.08.025
Prybylski, J. P., et al, 2016). Gadolinium deposition in the brain: Lessons learned from other metals known to cross the blood–brain barrier. Magnetic Resonance Imaging, 34(10), 1366–1372. http://doi.org/10.1016/j.mri.2016.08.018
Swaminathan, S., et al, (2016). Gadolinium toxicity: Iron and ferroportin as central targets. Magnetic Resonance Imaging, 34(10), 1373–1376. http://doi.org/10.1016/j.mri.2016.08.016
Tweedle, M. F., et al, (2016). Gadolinium deposition: Is it chelated or dissociated gadolinium? How can we tell? Magnetic Resonance Imaging, 34(10), 1377–1382. http://doi.org/10.1016/j.mri.2016.09.003
Future Directions –
Semelka, R. C., et al, (2016). Gadolinium deposition disease: Initial description of a disease that has been around for a while. Magnetic Resonance Imaging, 34(10), 1383–1390. http://doi.org/10.1016/j.mri.2016.07.016
Prybylski, J. P., et al, (2016). Can gadolinium be re-chelated in vivo? Considerations from decorporation therapy. Magnetic Resonance Imaging, 34(10), 1391–1393. http://doi.org/10.1016/j.mri.2016.08.001
Ramalho, J., et al, (2016). Gadolinium toxicity and treatment. Magnetic Resonance Imaging, 34(10), 1394–1398. http://doi.org/10.1016/j.mri.2016.09.005
Semelka, R. C., et al, (2016). Summary of special issue on gadolinium bioeffects and toxicity with a look to the future. Magnetic Resonance Imaging, 34(10), 1399–1401. http://doi.org/10.1016/j.mri.2016.09.002
My thoughts –
I believe this Special Issue is an important step in moving the discussion about gadolinium retention in patients with normal renal function forward. It seems that everyone now agrees that all patients exposed to gadolinium-based contrast agents retain some gadolinium from each dose of contrast that they receive. However, regardless of what you call it, patients are suffering from the toxic effects of retained gadolinium.
There is no doubt in my mind or the minds of other affected patients that retained gadolinium can cause chronic clinical symptoms of varying severity. Hopefully a large population of affected patients will be interviewed and examined soon. I believe that discussing symptoms with patients might trigger a thought process that leads researchers to uncover the missing pieces of the puzzle that explain the difference between what has been seen in brain tissue that contains gadolinium and the symptoms that patients are experiencing.