Gadolinium Toxicity

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Television Coverage of Gadolinium Toxicity on Full Measure

Sharyl Attkisson, five-time Emmy Award winner, and recipient of the Edward R. Murrow investigative reporting award, featured Gadolinium Toxicity in her June 11 edition of Full Measure.  Chuck Norris and his wife Gena Norris both talked about her struggle with her related symptoms that resulted in them spending over $1,000,000 on special care.

Our own Sharon Williams was also featured in the segment, both for her own symptoms and for her advocacy including letters to the FDA in starting in 2012 and the maintenance of this website..

Y0u can see a video of the program and read the dialogue here:
http://fullmeasure.news/news/cover-story/mri-06-11-2017

European Medicines Agency takes action on Linear Gadolinium-based Contrast Agents

On July 21, 2017, the European Medicines Agency (EMA) confirmed previous recommendations to suspend the use of three linear gadolinium-based contrast agents (GBCAs) used for MRIs, citing potential risks from brain deposition of gadolinium.  The use of one other linear GBCA will be restricted to liver scans.

The 3 suspended agents are Magnevist (gadopentetic acid), Omniscan (gadodiamide), and OptiMark (gadoversetamide).  The agent restricted to liver scans is MultiHance (gadobenic acid).

Read the article on Aunt Minne about this action here:
http://www.auntminnie.com/index.aspx?sec=ser&sub=def&pag=dis&ItemID=117859

The official announcement from the EMA can be found here:
http://www.ema.europa.eu/docs/en_GB/document_library/Referrals_document/gadolinium_contrast_agents_31/Opinion_provided_by_Committee_for_Medicinal_Products_for_Human_Use/WC500231824.pdf

Additional information on the EMA website can be found here:
http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/referrals/Gadolinium-containing_contrast_agents/human_referral_prac_000056.jsp&mid=WC0b01ac05805c516f

We are encouraged by the EMA’s action and believe that the FDA should take a similar stance.

Patients and their doctors should report all adverse events and clinical symptoms to the FDA or the appropriate governing authority in their country.  Chronic symptoms that develop soon after MRIs with contrast could be manifestations of the harm done by gadolinium deposition in the brain, bones, and elsewhere in the body.

FDA indicates no effects found yet from retained gadolinium in the brain

On Monday, May 22, 2017, the FDA issued its second Safety Announcement about gadolinium retention in the brain. The following text is the FDA’s complete announcement.

FDA Drug Safety Communication: FDA identifies no harmful effects to date with brain retention of gadolinium-based contrast agents for MRIs; review to continue

This is an update to the FDA Drug Safety Communication: FDA evaluating the risk of brain deposits with repeated use of gadolinium-based contrast agents for magnetic resonance imaging (MRI)issued on July 27, 2015.

Safety Announcement

[ 5-22-2017]

A U.S. Food and Drug Administration (FDA) review to date has not identified adverse health effects from gadolinium retained in the brain after the use of gadolinium-based contrast agents (GBCAs) for magnetic resonance imaging (MRI). All GBCAs may be associated with some gadolinium retention in the brain and other body tissues. However, because we identified no evidence to date that gadolinium retention in the brain from any of the GBCAs, including GBCAs associated with higher retention of gadolinium, is harmful, restricting GBCA use is not warranted at this time. We will continue to assess the safety of GBCAs and plan to have a public meeting to discuss this issue in the future.

Our recommendations for health care professionals and patients remain unchanged from July 2015 when we informed the public that we were investigating this potential risk with GBCAs. As is appropriate when considering the use of any medical imaging agent, health care professionals should limit GBCA use to circumstances in which additional information provided by the contrast agent is necessary, and assess the necessity of repetitive MRIs with GBCAs. Patients, parents, and caregivers should talk to their health care professionals if they have any questions or concerns about the use of GBCAs with MRIs. Retention of gadolinium affects only GBCAs, and does not apply to other types of scanning agents used for other imaging procedures, such as those that are iodine-based or radioisotopes.

GBCAs contain gadolinium, a type of heavy metal, that is linked to a carrier molecule. MRIs are a way to scan the body for problems such as cancer, infections, or bleeding. GBCAs are injected into a vein to enhance the quality of the MRI images of internal organs, blood vessels, and tissues, which helps health care professionals diagnose medical conditions. There are two types of GBCAs based on their chemical structures, linear GBCAs and macrocyclic GBCAs.

We evaluated scientific publications1-17 and adverse event reports submitted to FDA. Some human and animal studies looked at GBCA use over periods longer than a year. These publications and reports show that gadolinium is retained in organs such as the brain, bones, and skin. The publications show that linear GBCAs retain more gadolinium in the brain than macrocyclic GBCAs. However, our review did not identify adverse health effects related to this brain retention.

To date, the only known adverse health effect related to gadolinium retention is a rare condition called nephrogenic systemic fibrosis (NSF) that occurs in a small subgroup of patients with pre-existing kidney failure. NSF is a painful skin disease characterized by thickening of the skin, which can involve the joints and cause significant limitation of motion within weeks to months. Recent publications report cases of reactions involving thickening and hardening of the skin and other tissues in patients with normal kidney function who received GBCAs and did not have NSF; some of these patients also had evidence of gadolinium retention.3, 12, 16 We are continuing to evaluate such reports to determine if these fibrotic reactions are an adverse health effect of retained gadolinium.

The manufacturer of OptiMARK (gadoversetamide), a linear GBCA, updated its label with information about gadolinium retention in various body organs such as the brain, skin, and other organs. We are reviewing the labels of other GBCAs to determine if changes are needed.

A recent review by the Pharmacovigilance Risk Assessment Committee (PRAC) of the European Medicines Agency (EMA) also identified no adverse health effects with gadolinium retention in the brain, but that Committee recommended suspending the marketing authorization of certain linear GBCAs because they cause a greater retention of gadolinium in the brain compared to macrocyclic GBCAs. The Committee’s recommendation is currently undergoing an appeal, which will be further reviewed by the PRAC and subsequently by the EMA’s Committee for Medicinal Products for Human Use.18

We are continuing to assess the safety of GBCAs. FDA’s National Center for Toxicological Research (NCTR) is conducting a study on brain retention of GBCAs in rats. Other research is also being conducted about how gadolinium is retained in the body. We will update the public when new information becomes available and we plan to have a public meeting to discuss this issue in the future.

We urge patients and health care professionals to report side effects involving GBCAs or other medicines to the FDA MedWatch program, using the information in the “Contact FDA” box at the bottom of the page.

The list of approved GBCAs and References included with this FDA Communication can be found here: https://www.fda.gov/Drugs/DrugSafety/ucm559007.htm

The link to MedWatch can be found on the Contact FDA page.
https://www.fda.gov/AboutFDA/ContactFDA/default.htm

New Study Reports Gadolinium Retention in 70 Cases with Normal Kidney Function

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.

Final Thoughts

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

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