Why should patients undergoing a routine medical procedure like an MRI know about a rare heavy metal with a name that sounds more like something out of an X-Men comic than a substance found in a doctor’s office? Read more to find out.
What is Gadolinium?
Gadolinium is a chemical element with atomic number 64 and symbol Gd. Named for the mineral gadolinite (which itself was named for the Finnish chemist and mineralogist Johan Godalin), gadolinium was not discovered until the 1880s, when Swiss chemist Jean Charles de Marignac used spectroscopy to first detect the element in its oxidized form.
By appearance, gadolinium is a light silver color, and, among other properties, gadolinium is malleable and ductile. Too reactive to exist on its own except in a laboratory, gadolinium is found in nature in oxide form, often contained in minerals such as monazite and bastnasite, both of which are used in gadolinium production. It is estimated that gadolinium’s prevalence in the earth’s crust is equivalent to approximately 6.2 milligrams per kilogram, or 0.00062%.
In its ion form, gadolinium is highly toxic to mammals. The median toxic dose in humans is 100-200 mg/kg.
What is Gadolinium used for?
While gadolinium lacks the major industrial uses of some elements, it is used in a variety of highly specialized applications as far ranging as nuclear energy production, medicine, and color-television tubes.
Gadolinium in Nuclear Energy Production
Gadolinium possesses qualities that make it ideal for certain uses in nuclear energy production. Due to its high neutron cross-section, gadolinium has been widely included in the shielding material that insulates the cores of nuclear reactors. In some reactors—particularly CANDU reactors—gadolinium also is used as an emergency shutdown measure. Further, gadolinium often plays a role in the propulsion of nuclear-powered marine vessels such as submarines and battleships, where it is used in the nuclear reactor as a so-called “burnable poison” to help control excess fuel reactivity.
Gadolinium in Healthcare
In healthcare, also due to its high neutron cross-section, gadolinium frequently is used in neutron therapy that targets tumors, as well as in several varieties of medical imagery, from neutron radiology to certain x-ray systems, where it is included in the phosphor layer that converts x-rays into light.
However, the use most likely to impact everyday people—albeit a use of which most people remain unaware—is the role of gadolinium in magnetic resonance imagery (MRI). As opposed to neutron radiology and x-rays, in which gadolinium is used in devices that remain external to the patient’s body, during an MRI scan, a compound that includes gadolinium—called a gadolinium-based contrast agent, or GBCA—often is injected intravenously directly into the patient’s body in order to produce an “enhanced” image. The use of a GBCA allows healthcare professionals to better observe internal organs, bloods vessels, and tissues, which, in theory, should improve the accuracy of diagnoses. GBCAs are most frequently used to help identify health problems such as cancer, infections, or internal bleeding.
This use of gadolinium in GBCAs during MRI raises several important questions, not the least of which are: Do people who get MRIs know that they are being injected with a chemical element that is also used in nuclear reactors? What are the potential health risks of such a practice, and are these risks worth the benefits derived from an “enhanced” image? Are healthcare professionals adequately informed of these risks, and are they weighing the risks appropriately against the benefits?
Gadolinium is used in a variety of industrial and medical applications including:• Shielding nuclear reactors
• Providing emergency shutdown capabilities for nuclear reactors
• Acting as a “burnable poison” on nuclear-powered marine vessels
• Helping convert x-rays to light in certain x-ray systems
• Enhancing MRI imagery when injected directly into a patient’s bloodstream as a gadolinium-based contrast agent (GBCA)
What is a gadolinium-based contrast agent (GBCA), and what does it have to do with me?
If you are one of the millions of Americans who have undergone an MRI, you may have been injected with a gadolinium-based contrast agent (GBCA). GBCAs have been used for decades to “enhance” the image provided in an MRI, but new evidence is casting doubt on whether GBCAs are as low-risk as once thought.
Known Effects of Gadolinium Exposure
While it is known that gadolinium is highly toxic as a free ion, it has been believed that gadolinium is safe in humans when chelated, or bonded to other molecules or ions. As a free ion, the median lethal dose of gadolinium in mammals is estimated to be approximately 100-200 mg/kg, but, based on experiments with rodents, the median lethal dose of chelated gadolinium is believed to be up to 100 times higher. However, with over a dozen different chelated gadolinium compounds having been approved as intravenous contrast agents around the world, there still exists a concerning lack of clinical research exploring the safety of these various products, both as a class and individually, particularly when one considers that all of these compounds contain an element known to be toxic in ion form.
Health risks associated with exposure to gadolinium-based contrast agents (GBCAs) during MRI include:
• Nephrogenic Systemic Fibrosis (NSF) in patients suffering from impaired kidney function
• Anaphylactic shock and other acute reactions
• Potential for chronic and delayed manifestations of toxicity due to gadolinium accumulation in the body
Have you or a loved one suffered an adverse health reaction following GBCA exposure during an MRI scan? Contact the expert attorneys at TheLawFirm.com now for a free legal consultation.
What is Nephrogenic Systemic Fibrosis (NSF), and what does it have to do with GBCAs?
According the National Institutes of Health (NIH), Nephrogenic Systemic Fibrosis (NSF) is a serious condition potentially impacting numerous body parts but which typically affects the skin most severely. Symptoms of NSF are similar to those of scleroderma and include a tightening or swelling of the skin, itchiness or other skin discomfort resulting therefrom, and contracture, or the shortening and hardening of tissue. Some patients with NSF suffer from contractures so severe that it causes their arms and legs to become rigid to the point of immobility.
For over a decade there has been a growing body of evidence indicating a link between the administration of gadolinium-based contrast agents (GBCAs) and the onset of NSF in patients with preexisting kidney problems. This connection was established as far back as 2006, and subsequent research has identified potential explanations as to why this might be the case. While hypotheses vary somewhat, they all focus on the potential harm caused when gadolinium ions become dissociated from the chelated compound contained in the GBCA (Recall that, while gadolinium is considered much less toxic when chelated, or bonded, it becomes highly toxic when in ion form). It is suspected that, because patients suffering from renal impairment process the GBCA through their kidneys more slowly than patients with healthy kidneys, it expands the amount of time the GBCA spends in their system, thereby increasing their exposure to highly toxic dissociated gadolinium ions.
What are the symptoms of Nephrogenic Systemic Fibrosis (NSF)?
• Tightening and/or swelling of the skin
• Itchy skin
• Contracture (the shortening and hardening of tissue)
• Red and/or dark patches on the skin
• Joint and muscle pain
• Rigidity of the arms and legs
• Fibrosis of internal organs
Note: There is no known effective treatment for NSF.
Does gadolinium stay in the body after a GBCA injection?
Yes. While early theories surrounding the use of GBCAs postulated that the chelated gadolinium would pass through the kidneys and be out of the body before any dissociated gadolinium ions would be released into the patient’s body, a growing body of evidence now suggests otherwise.
Alarmingly, recent reports have shown signs of gadolinium retention in the bones, kidneys, livers, and even the brains of otherwise healthy patients who have been subject to GBCA injections in conjunction with MRI scans. Perhaps even more shocking than the accumulation of gadolinium in the tissue of vital organs, however, is the fact that we know very little about what this means for the health of affected patients.
In a 2016 study on GBCAs, researchers in Israel and Maryland urged further investigation into this important area, noting:
“Despite the observation of gadolinium accumulation in tissues regardless of renal function, very limited clinical data regarding the potential for and mechanisms for toxicity is available.” Later, the authors added ominously, “[T]he clinical significance of gadolinium tissue accumulation in patients without renal impairment is not fully known.”
In other words, we know that gadolinium is highly toxic in ion form, and we now also know that gadolinium remains in vital human tissue—including brain tissue—long after the injection of a GBCA. But healthcare professionals know very little about what this means or how dangerous it is.
FDA-Approved Gadolinium-Based Contrast Agents (GBCAs):
Do some GBCAs result in greater accumulation of gadolinium in the body than others?
Yes. According to the United States Food and Drug Administration (FDA), the gadolinium-based contrast agents (GBCAs) Dotarem (gadoterate meglumine), Gadavist (gadobutrol), and ProHance (gadoteridol) resulted in the lowest gadolinium levels remaining in the body, while the GBCAs Omniscan (gadodiamide) and OptiMARK (gadoversetamide) resulted in the highest gadolinium levels.
Why the different amounts of gadolinium retention among the various GBCAs? Despite the GBCAs each containing roughly the same amount of gadolinium, the difference in retention most likely has to do with the different compounds from which they are derived. One might recall from a previous section that the gadolinium in GBCAs is chelated, that is, bonded with another ion or molecule, in order to render it much less toxic to humans.
However, over time, these bonds break apart, and gadolinium ions dissociate. To put it simply, different compounds used in GBCAs have bonds of varying strength, with weaker bonds resulting in more dissociated gadolinium ions being released into the body. The GBCAs featuring compounds with bonds more likely to break therefore are associated with higher levels of gadolinium retention in patients.
GBCAs are divided into two different groups based on their chemical structure: linear and macrocyclic. According to the FDA, “Linear GBCAs result in more retention and retention for a longer time than macrocyclic GBCAs.”
Which GBCAs are associated with the highest and lowest levels of gadolinium retention in the body?
• Omniscan (gadodiamide)
• OptiMARK (gadoversetamide)
Lowest Gadolinium Retention Levels:
• Dotarem (gadoterate meglumin
• Gadavist (gadobutrol)
• ProHance (gadoteridol)
Do we know what effects gadolinium accumulation will have on the human body?
Unfortunately, the answer for the most part is no. As recently as December 2017 the United States Food and Drug Administration (FDA) issued a safety announcement conceding the necessity of further investigations to evaluate the health impact of gadolinium retention in the body. The FDA stated:
“To date, the only known adverse heath 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. We have also received reports of adverse events involving multiple organ systems in patients with normal kidney function. A causal association between these adverse events and gadolinium retention could not be established.”
Did you know…
…that a landmark 2016 study appearing in the American Journal of Roentgenology, in addition to identifying the increased risk of nephrogenic systemic fibrosis (NSF), also noted a strong association among exposure to GBCAs and acute adverse events? According to the study, these “adverse events” ranged from mild responses such as coldness, warmth, and pain at the injection sight to severe life-threatening anaphylactic reactions.
The study also proposed two new terms, “Gadolinium Storage Condition” (GSC) and “Gadolinium Deposition Disease” (GDD) to describe combinations of symptoms observed in certain patients who had been exposed to GBCA. The study’s authors define “Gadolinium Storage Condition” (GSC) as the retaining of gadolinium deposits within the body’s tissue. They define “Gadolinium Deposition Disease” (GDD) as “a disease process observed in subjects with normal or near normal renal function who develop persistent symptoms that arise hours to 2 months after the administration of GBCAs,” noting that in cases of GDD “no preexistent disease or subsequently developed disease of an alternate known process is present to account for the symptoms.”
The study describes the symptoms of GDD being like those of NSF, though less severe. Those suffering from GDD showed “subcutaneous soft-tissue thickening” similar to NSF, though without the characteristic tightness and redness. Other symptoms of GDD frequently included muscle pain, joint pain, and intense headaches. Patients have also described feeling a tightness in the hands and feet, as if “being fitted with extremely tight gloves or socks.” Patients also complained of “excruciating pain” in the arms, legs, or torso, which they compared to the feeling of “sharp pins and needles, cutting, or burning.” Citing the need for further research, the study’s authors state, “As with NSF, it is unknown why only some patients have symptoms after gadolinium administration.”
Why are gadolinium ions so toxic?
In its ion form, gadolinium is highly toxic due to its interference with the numerous important bodily functions dependent on calcium-ion channels. Calcium-ion channels are essential to the functioning of so-called “excitable” cells, such as muscle cells, glial cells, and neurons.
Populations having a higher risk for gadolinium retention include:
• Those receiving multiple doses of gadolinium-based contrast agents (GBCAs) in a lifetime
• Pregnant women
• Patients with inflammatory conditions
• Patients with kidney problems
Why is the chelated gadolinium contained in GBCAs presumed to be safe for humans, while gadolinium in ion form is considered toxic?
The chelated gadolinium in GBCAs was believed to be safe for humans because, in theory, the chelated compounds would pass through the kidneys and be flushed out in the urine before the toxic gadolinium ions had a chance to dissociate and enter the patient’s tissue. More recent evidence, however, suggests that gadolinium remains in a patient’s body months or even years after the original exposure a GBCA.
“Gadolinium Deposition Disease (GDD)”
Gadolinium Deposition Disease (GDD) is the name proposed by the authors of a 2016 study for a condition similar to NSF but which, unlike NSF, occurs in patients having previously healthy kidneys. The symptoms of GDD arise from as soon as hours after GBCA exposure to up to two months later.
These symptoms include:
• Muscle pain
• Joint pain
• Tightness in the hands and feet
• Extreme pain in the arms, legs, or torso
• Generalized pain
Have you suffered the symptoms of GDD following exposure to a GBCA during an MRI scan? Contact the expert attorneys at TheLawFirm.com now for a free consultation.
How is gadolinium produced?
Gadolinium is isolated from surrounding materials through a complex chemical process that involves mining certain minerals before crushing them and bathing them in various acidic compounds to produce salts.
After the mining of a mineral such as monazite or bastnasite—mostly likely in a major gadolinium-producing country such as China, the United States, Australia, Sri Lanka, or Brazil—the minerals are then crushed and processed in a bath of either hydrochloric acid or sulfuric acid, which transforms the insoluble oxides into soluble chlorides or sulfates. After the acidic filtrates have been neutralized by a caustic soda with a low pH, the mix is treated with ammonia oxalate and then heated, converting the rare earth metals into oxides.
Next, the oxides are treated again in an acid bath, this time of nitric acid, which separates out cerium, as cerium is insoluble in nitric acid. Magnesium nitrate is then applied to the solution of nitric acid and dissolved rare earth metals, resulting in crystallization and the formation of salts consisting of gadolinium, samarium, and europium, which are then sorted via ion exchange chromatography.
Gadolinium is extracted from the salts by placing the salts with calcium in an argon atmosphere and collectively heating the elements to 1450 degrees Celsius.
History of FDA Notices Regarding Gadolinium-Based Contrast Agents (GBCAs)
December 2010 Acknowledging a scientifically established connection between GBCA exposure and the development of nephrogenic systemic fibrosis (NSF) in patients with preexisting kidney impairments, the FDA mandated changes to the GBCA labels warning of the risk. The FDA further instructed healthcare professionals to screen patients for acute kidney injury prior to administering a GBCA and to avoid the use of the GBCAs Magnevist, Omniscan, and Optimark in patients with acute kidney injury or chronic kidney disease.
July 2015 The FDA announced an investigation into the potential health impacts of gadolinium deposits in the brain left behind after repeated exposure to GBCAs during MRIs. Citing the need for more information, the FDA did not mandate any changes to the labels of GBCAs. While acknowledging that recent publications had reported GBCA retention in the brains of individuals having undergone four or more MRI scans using GBCA injections, FDA stated, “It is unknown whether these gadolinium deposits are harmful or can lead to adverse health effects” while recommending that healthcare professionals “consider limiting GBCA use to clinical circumstances in which the additional information provided by the contrast is necessary.”
May 2017 In announcing the results of its investigation into the potential health impacts of gadolinium retention in the brain following exposure to GBCAs, the FDA declared that “[a]ll GBCAs may be associated with some gadolinium retention in the brain and other body tissues. However, because FDA 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.”
December 2017 The FDA released a new Safety Announcement stating that it will require a new class warning as well as additional safety measures for all GBCAs. Specifically, the FDA required “several actions to alert health care professionals and patients about gadolinium retention after an MRI using a GBCA.”
Have there been lawsuits filed by patients who alleged they were harmed by exposure to gadolinium-based contrast agents (GBCAs)?
Yes. The vast majority of the lawsuits to date have been brought by patients suffering from preexisting kidney problems who developed nephrogenic systemic fibrosis (NSF), a serious condition with no cure that can possibly result in death. Thankfully, a change in practice has resulted in fewer patients with severe kidney impairment being exposed to GBCA, and there have been few if any documented cases of NSF resulting from GBCA exposure taking place after 2010.
However, recently, GBCA-related lawsuits have begun to reappear over what some have called “gadolinium poisoning.” Most famously, in November 2017, action-film star Chuck Norris and wife Gena brought suit against a number of companies involved in the manufacturing and distribution of GBCAs, alleging that Gena had suffered a host of serious health problems since being exposed to GBCAs approximately 5 years earlier. Among the conditions allegedly caused by Gena’s GBCA exposure were “cognitive defects; body pain and burning; kidney damage; loss of energy and mobility; and difficulty breathing due to rib damage.” As a result, the Norrises claimed, Gena continued to require stem cell therapies and other costly medical treatments. The couple sought over $10 million in damages from a total of 11 defendants, including reimbursement for millions of dollars in out-of-pocket medical expenses. In a statement, the Norrises declared:
“Unfortunately, litigation is the only course of action we can take to hold the drug companies accountable for threatening the lives of so many innocent people who undergo MRIs. These companies continue to say that there is no link between gadolinium and adverse events, even though the evidence is overwhelming that this heavy metal stays in the body for years, rather than hours.”
We at TheLawFirm.com could not agree more. Unfortunately, in our broken healthcare system, patients injured by dangerous medications or defective medical devices all too often must resort to the legal system to have any chance of holding large corporations to account. Although we would prefer that Big Pharma simply start putting patient outcomes ahead of quarterly profits and shareholder value, we know that is unlikely to happen any time soon. That’s why the expert attorneys at TheLawFirm.com are here when you need us. Contact us now for a free consultation.
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Sources: US National Library of Medicine, MedlinePlus, “Canagliflozin” Forbes.com AuntMinnie.com Source: American Journal of Roentgenology, “Gadolinium in Humans: A Family of Disorders” Source: National Institutes of Health (NIH) – US National Library of Medicine National Institutes of Health (NIH) – Genetic and Rare Diseases Information Center (GARD) United States Food and Drug Administration Source: United States Food and Drug Administration (FDA) National Institutes of Health—US National Library of Medicine, “Gadolinium-based contrast agent toxicity: a review of known and proposed mechanisms”