Reports of gadolinium accumulation in the brain have surprised many practitioners, and raised questions of potential harm to patients. The FDA & NIH recommend reconsideration of GBCA use while investigations continues. The accumulation calls into doubt a common assumption that existing renal function mediated guidelines are sufficient to avoid significant biological interaction.

This presentation reviews the recent reports and presents literature concerning gadolinium chelate stability, transmetalation, gadolinium interactions in biochemistry, observations of bone and skin accumulation (beyond NSF definitions), and environmental build up to provide a context for a reconsideration, by clinical and research practitioners, of our current GBCA usage.

In 2006, the prevailing perceptions of radiology practitioners about Gadolinium based contrast agent (GBCA) safety received a large shock. The idea that GBCA was pivotal with a disabling, and fatal condition called nephrogenic systemic fibrosis (NSF) (1,2) took many by surprise. Research from the fields of dermatology, nephrology and biochemistry progressively identified GBCA as a trigger to the condition. Work examining the stability of gadolinium chelation agents, led to an appreciation that prolonged renal clearance times allow gadolinium ions and compounds (so called “free” gadolinium) to form in-vivo, and initiate the condition in some way. Consistent guidelines for GBCA use mediated by renal function were published and widely followed. Within these guidelines, the use of GBCA was again considered to have minimal risk of harm, and no potential biological interaction.

In late 2013 radiology received a second surprise regarding GBCA, which again called into question generally held understandings of the behavior of these compounds in-vivo. Kanda et al (3) found an association between high signals in unenhanced T1 imaging of the dentate nucleus and globus pallidus, and previous exposure to GBCA in patients with acceptable renal function. The observation was confirmed by similar reports (4-7), and it was noted that the appearances were previously attributed to specific pathologies (8,9). These observations indicated that the renal function guidelines had not mitigated all undesirable impacts of the contrast agents, and raised questions of potential harm.

In the intervening period investigations have established that the gadolinium is deposited throughout the brain (10,11). Multiple studies have found that the accumulation is more pronounced from contrast agents with lower kinetic stability in-vivo(12). In mid-2015, the US Food and Drug Administration (FDA) announced they would engage with scientists and industry to undertake further investigations and research in to the matter(13). The FDA recommended in the interim that health professionals consider “limiting GBCA to circumstances in which the additional information provided is clinically necessary”, and to particularly reassess the necessity of repetitive GBCA use in established treatment protocols. This year, the US National Institute of Health accepted recommendations to use macrocyclic contrast agents in preference over linear agents, and to use GBCA only when clinically indicated , or approved by the Institutional review Board (14).

Disassociation of gadolinium ions from the contrast agent ligand can occur before complete excretion, thus allowing biochemical interactions (15-17). Gadolinium is a transitional metal with no native biochemical role. It cannot be excreted except when chelated to a suitable exogenous large molecule, leading to accumulation that are progressive with multiple GBCA doses. Due to having a similar size to calcium, but with a higher affinity, ionic gadolinium will attach to calcium binding points in many enzymes, interfering with their function, particularly in RNA replication, and by promoting the formation of free radicals that cause downstream cellular damage (15,18). Accumulation should be considered as iatrogenic toxic contamination. Gadolinium compounds form rapidly in serum and accumulate in the bone, potentially providing a potential slow release pool of marginally soluble ionic gadolinium compounds(19). In addition to patient care concerns, environmental scientists have identified rising gadolinium levels in waste water(20-22), drinking water(23) and in algae and microfauna (24).

Radiology is being asked again to reconsider its understanding of GBCA safety, the characteristics of agents , and the patterns of contrast use, only this time in the absence of scientifically evidenced harm. The FDA has received self-reports of symptoms associated with GBCA exposure, but presently does not find enough commonality to establish a relationship(13), yet patient groups are organizing and becoming vocal around this issue [www.gadoliniumtoxicity.com].

Consideration of the wider literature may help inform clinical decisions regarding GBCA practice in the general and individual case. This second surprise has highlighted a need for more appreciation of the behavior of gadolinium contrast agents, and a more informed view of their safety profile. The situation also highlights that clinical GBCA use, including dosage, frequency and specific or class of agent, are all medical decisions that fall directly within the responsibility of the medical practitioner providing the examination, the MRI radiologist. Informed medical considerations should dominate all contrast related decisions from the selection of agents purchased by an organization, to the documentation of GBCA used in an individual patient’s examination.