MRI Contrast Agent, Gadolinium

What is Gadolinium?

Gadolinium is one of the 17 rare-earth elements, and is part of the “lanthanide” series of metals. Most rare-earth metals are toxic to humans. Gadolinium has paramagnetic properties – that means that when it moves through a magnetic field (such as an MRI), its temperature increases slightly. This makes it useful to enhance the image quality in MRI scans.

Gadolinium is highly toxic to humans. While gadolinium has no known biological properties, and is not found naturally in the human body, its molecules are similar in size and shape to calcium, which has many biological functions. Because free gadolinium ions mimic calcium in the body, it interferes with the effects of calcium-dependent processes. Gadolinium can cause a host of toxic effects, including inflammation, oxidative stress, neurological damage, and damage to our genes, or DNA. The damage to cells from gadolinium is exacerbated by exposure to the magnetic fields of MRI scanners1.

Gadolinium as an MRI or MRA contrast agent

If a gadolinium ion is chelated, or “caged” within an organic molecule (called a ligand), it is assumed to become safe as the organic molecule acts as barrier between the gadolinium and human cells. This is how gadolinium contrast agents are manufactured. These contrast agents are injected intravenously into patients who are undergoing an enhanced MRI or MRA scan. In patients with healthy kidneys, much of the gadolinium is excreted from the body within a few hours of the scan.

Is gadolinium completely excreted after a scan?

While originally it was thought that all injected gadolinium contrast is quickly excreted from the body, this was later discovered to be incorrect. Gadolinium retention was first identified in patients with kidney disease who underwent MRI scans with gadolinium contrast. Subsequent research has shown that gadolinium accumulates in patients with normal kidney function too2,3,4,5. This is thought to happen due to dissociation between the “chelating agent” and the gadolinium molecule, that causes a release or “spillage” of the gadolinium metal into the body tissues.

Gadolinium has been found to be retained in many tissues including bone and skin, but it also crosses the blood brain barrier (BBB) where it accumulates in highly sensitive brain tissue.

First reports of gadolinium contrast toxicity

First reports of gadolinium being associated with a fatal disorder called Nephrogenic Systemic Fibrosis (NSF), were published in April 20066. In 2007, the FDA requested gadolinium contrast manufacturers to place a “black box warning” on all gadolinium contrast products. A black box warning is the strongest warning that the FDA uses in pharmaceutical packaging, indicating that a particular-product poses a serious health risk. At that time, in 2007, the risk was only thought to affect patients with existing kidney disease or damage.

What is Nephrogenic Systemic Fibrosis (NSF)?

NSF, also known as nephrogenic fibrosing dermopathy (NFD), is a serious disease that causes tissue thickening and fibrosis of joints, diaphragm, thigh muscles, lung vessels and lower abdomen. Skin lesions can also appear. The disease causes a loss of joint mobility and can be fatal.

NSF is a disease whose sole cause is the exposure to gadolinium contrast agents during MRI scans. It occurs only in patients who have renal insufficiency (kidney damage) which results in limited excretion of gadolinium from the body7.

New evidence of gadolinium accumulation comes to light

Reports of long-term gadolinium accumulation in patients with normal kidney function, following gadolinium enhanced MRI scans, first appeared in 2009. It was shown that gadolinium could be found in the bones of patients who underwent gadolinium MRI scans even 8 years later8. Since 2009, many new reports began appearing in the medical literature showing that gadolinium accumulates not only in bones, but also in particular areas of the brain. In all these cases, the patients tested had normal kidney function.

In 2016, a review article by MedInsight researchers was published in the journal BioMetals, that consolidated all the known and assumed toxic effects of gadolinium9. This article reviewed studies showing that gadolinium was toxic to kidneys, liver, brain, and white blood cells, and damages DNA.

“Gadolinium Deposition Disease” announced

In 2016, a landmark article10 was published by Dr. Richard Semelka and colleagues of University of North Carolina. Dr. Semelka, long considered amongst the greatest experts in MRI contrast safety, coined the term “gadolinium deposition disease”.

According to the authors, “gadolinium deposition disease” is the name proposed for 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 gadolinium-based contrast agents (GBCAs). In these cases, no preexistent disease or subsequently developed disease of an alternate known process is present to account for the symptoms11.”

“Typical clinical features of “gadolinium deposition disease” include persistent headache, bone and joint pain, clouded mentation often described as “brain fog”, and soft-tissue thickening under the skin. Patients may complain of tightness of the hands and feet that resembles the feeling of being fitted with extremely tight gloves or socks.”

“Patients may experience excruciating pains of the arms and legs but that may also be in the torso or generalized in location. This pain is often described as feeling like sharp pins and needles, cutting, or burning.”

The researchers concluded12: "We propose naming the histopathologically proven presence of gadolinium in brain tissue 'gadolinium storage condition,' and we describe a new entity that represents symptomatic deposition of gadolinium in individuals with normal renal function, for which we propose the designation 'gadolinium deposition disease’."

FDA makes an announcement

In 2015, the FDA announced that it was evaluating the risk of gadolinium accumulation in the brains of patients who have undergone repeated exposure to gadolinium-based contrast agents. As of March 2017, almost two years later, the FDA has not updated their guidance about using gadolinium in MRI scans.

European Medicines Agency takes action

With new research that demonstrates that gadolinium can accumulate in body tissues after MRIs that use gadolinium-based contrast agents, the European Medicines Agency (EMA) launched its own investigation. In March 2017, a committee of the EMA recommended the suspension of the marketing authorizations for four gadolinium-based contrast agents (GBCAs) used for MRI scans because of concerns about residual gadolinium in the brain.

Following a year-long review of gadolinium based contrast agents, 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”.

The EMA committee recommended the suspension of use of the following four “linear” gadolinium contrast agents:

  • MultiHance® (Gadobenic acid)
  • Omniscan® (Gadodiamide)
  • Magnevist® (Gadopentetic acid)
  • OptiMARK® (Gadoversetamide)

The EMA procedures now allow the companies marketing these contrast agents an opportunity to appeal this recommendation. Afterwards, the committee’s final recommendations will be sent to the Committee for Medicinal Products for Human Use (CHMP) for its opinion.

The committee did not recommend halting the use of the “non-linear” or “macrocyclic” gadolinium contrast agents, since they are more stable and have a much lower propensity to release gadolinium. Nevertheless the committee recommended that they be used at the lowest dose that enhances images sufficiently to make diagnoses and only when unenhanced body scans are not suitable.

Is gadolinium contrast really needed?

Due to the widely-held assumption that gadolinium contrast poses no risks, it has become widely overused in adults, and even in young children. A critical landmark study published in 2016 by Stanford University MRI experts questioned the necessity of gadolinium contrast in children with cancer.

In the study of 66 boys and 53 girls suffering from benign and malignant metastatic tumors, the researchers had three experienced radiologists independently and blindly review the MRI images of these children. They found that the gadolinium-enhanced scans provided no increased diagnostic benefit compared to MRI scans without gadolinium or PET scans13.

Is there a cure for gadolinium toxicity?

There is no currently known cure for gadolinium toxicity. The treatment most commonly used is chelation, where a chelating agent is introduced to the body, either intravenously or orally. The chelating agent binds to heavy metals in the body which are then excreted, usually through the kidneys. Although chelation has not been shown to completely remove gadolinium from the body, many patients anecdotally report lessening in the severity of their symptoms.

New chelating agents are being developed to specifically treat gadolinium toxicity.

Preventing gadolinium toxicity

The first thing that you can do, should you need an MRI scan, is to question whether the gadolinium contrast is necessary. Your doctor may explain that it will help deliver much higher-quality images. You should question whether the enhanced images will alter the treatment decisions in any way. If the answer is that it will not, you should refuse the gadolinium injection.

If it is clear to you that the gadolinium is necessary to make treatment choices that cannot be made without it, you can still take proactive action. Ask your doctor to measure your blood or urine gadolinium levels before the scan, and do so again at least one week AFTER the scan. This will help you to know if you have retained any gadolinium from the scan, and help you in making future decisions about using gadolinium in future scans.

What to do if you suspect gadolinium toxicity

If you suspect you have gadolinium toxicity, the first step is to determine whether you have retained gadolinium in your body. This can be achieved through either a blood test, a urine test, or both. To obtain an up-to-date list of laboratories that perform gadolinium testing, complete this form.

If the tests reveal elevated gadolinium levels, you should contact a medical toxicologist to discuss the steps available to monitor and treat it. You may also subscribe here for our free alerts of new ways to treat gadolinium toxicity and important updates about this topic.

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    Help yourself and help others too

    The issue of gadolinium toxicity has surfaced thanks to courageous grassroots efforts by people who were unfortunately affected by gadolinium toxicity. These efforts led to the creation of two important resources, The Lighthouse Project and the Gadolinium Toxicity Facebook page. You can help yourself and help others by signing this petition to stop the damage and find a cure for victims of MRI contrast toxicity. The petition will be sent to health regulatory authorities of major countries.

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