Gadolinium contrast agents are used in 40 to 50 percent of MR scans and, by some estimates, roughly 400 million doses have been administered since it was introduced in 1988.

For most of those years, the agent appeared to have virtually no drawbacks, but over the last decade or so, the medical imaging community has been forced to reexamine that narrative.

In 2006, researchers discovered that the agent put patients with renal insufficiencies at risk of nephrogenic systemic fibrosis. Then, in 2013, findings surfaced suggesting that gadolinium could accumulate in the brain of patients undergoing multiple scans.

Since then, the question that remains unanswered has been: what are the clinical implications for gadolinium accumulation in the brain?

Assessing risks
In March, the Pharmacovigilance Risk Assessment Committee (PRAC) of the European Medicines Agency (EMA) concluded an assessment of gadolinium agents and recommended regulatory actions, including suspension for some marketing authorizations.

Two months later, the FDA weighed in on gadolinium with its own findings. The agency announced that, after a two-year study of the issue, it had not identified adverse health effects from gadolinium retained in the brain after the use of gadolinium-based contrast agents (GBCAs) for MR imaging.

“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,” the agency wrote in a statement. “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.”

Despite those findings, an FDA panel voted in September to add retention warnings to the labeling of gadolinium agents. The group also voted unanimously (15-0) in favor of requiring contrast manufacturers to conduct more studies aimed at understanding the implications of gadolinium retention and any health risks that may accompany it.

Macrocyclic versus linear gadolinium contrast agents
Gadolinium retention rates appear to be lower with macrocyclic agents – such as Dotarem (Guerbet), Gadavist (Bayer) and ProHance (Bracco) – than with linear agents. For that reason, the PRAC recommendations refer to linear agents – such as MultiHance (Bracco), Omniscan (GE Healthcare), Magnevist (Bayer) and Optimark (Guerbet).

Still, in some cases, the PRAC recommended keeping particular linear agents available. For example, it determined that gadoxetic acid (a linear agent marketed by Bayer as Primovist in Europe and Eovist in the U.S.) should remain on the market because it meets an important diagnostic need in patients with few alternatives.

Guerbet, one of the major gadolinium companies, published a statement shortly after the PRAC findings, saying it did not “intend to request a reexamination of the recommendations.”

In April, the American College of Radiology chimed in on the discussion, stating that “although gadolinium accumulation appears to be dose-dependent, there remains no evidence of cellular toxicity, nor is there credible evidence of neurologic sequelae after over 300 million worldwide human doses.”

From that perspective, removing valuable diagnostic contrast agents from the market would be inappropriate without any proof that they were harming patients. The ACR called for more research into the clinical consequences of linear gadolinium accumulation, emphasizing that the contrast agents have “significant and well-documented diagnostic utility,” and in some instances may have benefits over their macrocyclic counterparts.

The ACR also advised that measurement by mass spectrometry has revealed that gadolinium deposition rates for linear and macrocyclic agents vary within a given class and that different chemical forms of gadolinium appear to be depositing within tissues, some of which would be undetectable using MR.

This, it concluded, suggested that while MR signal changes led to the discovery of gadolinium accumulation in the brain, they are less reliable for determining the quantity of gadolinium deposition in general.

Chipping away at the mystery
Unraveling the mystery of gadolinium accumulation is a scientific process and it starts with testing various hypotheses.

One question researchers have had about the risks of gadolinium accumulation concerns which patients are most susceptible to having the contrast agent accumulate in their system. One possibility could be that a compromised blood-brain barrier is more likely to experience accumulation of the agent, but research published in Radiology in June suggests otherwise.

Dr. Robert J. McDonald of the Mayo Clinic and his team examined postmortem neuronal tissue samples from five patients with normal brain pathology who had multiple gadolinium-enhanced MR exams between 2005 and 2015, and 10 patients who underwent MR exams without the contrast agent.

“Our results suggest current thinking with regard to the permeability of the blood-brain barrier is greatly oversimplified, as gadolinium appears to accumulate even among patients with normal brain tissue and no history of intracranial pathology,” McDonald said at the time.

The good news is that the researchers didn't detect any histologic changes that suggest toxicity in patients who were exposed to gadolinium.

Exploring alternatives
While the scientific community is in agreement that gadolinium does more good than harm, some researchers are developing an alternative to gadolinium-based contrast agents. In February, a team from the Massachusetts Institute of Technology published findings in the Proceedings of the National Academy of Sciences suggesting that there may be another option in the pipeline.

The researchers found that similar MR contrast can be produced with small iron oxide nanoparticles that have been treated with a zwitterion coating. Zwitterions are molecules that have areas of positive and negative electrical charges that cancel out and make them neutral.

The new iron oxide nanoparticles, they reported, may be safer for patients with impaired kidney function, for whom gadolinium exposure can increase the risk of nephrogenic systemic fibrosis.