Safety assessment of gadolinium-based contrast agents (GBCAs) requires consideration of long-term adverse effects in all human tissues

Determination of the clinical importance of gadolinium (Gd) deposition must include the entire body. The benefit/risk assessment of only cerebral Gd deposition is not sufficient. The conclusion from the study of Schlemm et al., ‘Dentate nucleus T1 hyperintensity is not associated with gadobutrol’, suggests the authors’ confidence in administration of the macrocyclic agent gadobutrol. The statement ‘since long-term clinical effects of cerebral Gadolinium (Gd) deposition are still unknown, the indication for GBCA administration should be strict’ is incomplete, and in reality, far from clinical practice. The focus after administration of GBCAs must be on patients with frequent applications, particularly patients with multiple sclerosis (MS). The detection of disease activity in MS, defined as new/enlarging T2 lesions on brain magnetic resonance imaging (MRI), has been proposed as a biomarker in MS and is also possible in principle without GBCA. The number of GBCA administrations is crucial, since each can result in Gd deposition. Participants in this study received no more than three doses of gadobutrol, but in daily practice, in 1 year alone, a single control MRI study in MS patients means two to three GBCA doses (one for brain, one to two for spinal cord (cervical spine and thoracic spine on 2 days)), and this can occur for many years. It is important to recognize, however, that Gd is not only being retained in the brain. There seem to be three cases of nephrogenic systemic fibrosis (NSF) following the prior unconfounded administration of gadobutrol. Although this number is exceedingly small, the fact remains that since it is a macrocyclic agent, it is not clear why the incidence is not zero. In a rat study by Robert et al., although the Gd concentration in the brain after repeat linear GBCA administration was 14 times greater than after repeat macrocyclic GBCA administration, Gd from the macrocyclic was not zero. With lower levels of Gd deposition from macrocyclic agents such as gadobutrol, it is unlikely that all side effects will be detected and published by physicians; there are probably a number of undetected cases.