It has been a turbulent decade for the once-unblemished reputation of gadolinium- based contrast agents (GBCAs) — and yet even today it isn’t easy to put one’s finger on exactly what it is about them that has everyone so excited. HealthCare Business News spoke with Dr. Emanuel Kanal, a professor of radiology and the director of MR services at the University of Pittsburgh Medical Center, and an expert on the topics of gadolinium and MR safety, about the developments that have been taking place. He remembers a time — not too long ago — when gadolinium was regarded as “one of the safest drugs there was.”

The trouble started in 2006 when it came to light that administration of at least some of the FDA-approved GBCAs to patients with acute or chronic renal insufficiency could lead to nephrogenic systemic fibrosis (NSF) — an often progressive disease with no known cure in which skin thickening hampers mobility and can limit bending at the joints, among other symptoms.

Then, in 2013, findings surfaced to suggest that gadolinium may accumulate in the brains of patients who undergo multiple examinations with at least some of the FDA-approved GBCAs. It’s a phenomenon that Kanal calls intracranial gadolinium accumulation. “No one told us it would stay in the body,” says Kanal. “They told us it had a half-life of 90 to 120 minutes and after 6 or 9 hours most of it is gone, and we assumed that after a day or two there’s no trace left.”

So what does it mean that this is not actually the case? And if we don’t have scientific evidence that there is anything medically detrimental about this accumulation, what exactly is everyone so worked up about? And how will this impact the way MR scans are ordered in the future?

Not all gadolinium accumulates at the same rate
Here’s what we do know, according to Kanal: Gadolinium is a heavy metal from the lanthanide series. In certain forms it can have significant toxicity, and therefore, it is generally understood that we don’t want to have it in our bodies if it is not needed there. We also know that the two different types of GBCAs — macrocyclic agents and linear agents — appear to cause accumulation at different rates.

There are three macrocyclic GBCAs on the market — Dotarem (Guerbet), Gadavist (Bayer) and ProHance (Bracco) — and although it’s unclear if accumulation happens equally, if at all, among this group, the evidence suggests that accumulation happens less with this group, or perhaps at a slower rate, than with linear agents.

Unlike macrocyclic agents, which form multiple bonds in a ring-like structure, linear agents form single bonds — like two people holding hands. Therefore, the bonds of linear agents break more easily. Among the linear agents, Kanal says the accumulation seems to happen most with Omniscan (GE Healthcare), equaled or followed by Magnevist (Bayer), then likely followed by MultiHance (Bracco). He says other linear agents such as Optimark (acquired by Guerbet when it purchased Mallinckrodt’s contrast business last year) may also accumulate, but these agents have smaller market shares and sufficient evidence has not been collected yet regarding their accumulation behavior.

So why not just swap out linear agents for macrocyclic agents? Unfortunately, that solution oversimplifies the problem. Radiologists must also factor in the relaxivity of an agent — which refers to how much must be administered to adequately produce the desired visual contrast.

“There is no agent, I believe, that is immune to having some retention in the body, it’s just not the way science or math works,“ says Kanal, “but there are significant differences in the amount or rate that they accumulate in a human after a certain number of doses of these agents.” As for the clinical significance of gadolinium accumulation? “As of today we simply do not know,” says Kanal.

Impacting utilizaion patterns
Kanal says his work as an emergency neuroradiology specialist has been drastically impacted by the knowledge that gadolinium can accumulate in the brain. “Every single day of my professional life I now find myself canceling studies that are requested with contrast where I don’t believe or agree that contrast is indicated,” he says.

The number of gadolinium-enhanced MR exams being conducted — both nationally and internationally — is decreasing, he says. When it is being administered, it is sometimes being done at a lower dose, and often affects the choice or what type/brand of agent is to be administered. “Which agents people are using is also changing,” says Kanal. “Just like we saw with NSF, there were massive changes with utilization patterns and which agents were used for what patients. We’re seeing people switching again based on the potential or theoretical concern of retaining more gadolinium in the patient’s bodies with some agents than with others.” As long as there are no good alternatives to gadolinium, however, it remains a vital part of the radiologist’s toolkit and Kanal doesn’t expect that to change any time soon.

More than meets the eye
The gadolinium that we can visualize is visible because it is interacting with water molecules in the brain, thereby shortening the tissue T1 and brightening its signal to become bright. According to Kanal, “That kind of gadolinium is almost across the board water soluble, but we do know there is also water-insoluble gadolinium in biopsies and autopsies — which very likely would not be visible on an MR image.” That means all the data that is being collected from MR images is potentially overlooking an undetectable quantity of retained tissue gadolinium that simply does not register in the scan. Through autopsies and biopsies, Kanal says work is being done to try and shed some light on that possibility.

“And we don’t even know what form it will be in,” says Kanal. “Is it in the form in which it had initially been injected? Did it disassociate and then re-form?” Further, accumulation in the brain is only part of this issue. It has been known for over a decade that gadolinium from at least some GBCAs is retained in the bone of patient recipients, and that the amount retained there is greater for at least some of the linear agents than from at least some of the macrocyclic agents. For now, according to Kanal, there are simply more questions than answers. Defining the medical implications of gadolinium accumulation — if indeed there are any — is a work in progress that researchers continue to chip away at every day.