Letter to the Editor: “Gadolinium in brain – more indicator than main tissue at risk?”

by Helena Radbruch, Ahmed H. El-Khatib, Carmen Infante Duarte, Eyk Schellenberger (eyk.schellenberger@charite.de)

This Letter to the Editor refers to two articles published in European Radiology:

1. Gadolinium deposition within the paediatric brain: no increased intrinsic T1-weighted signal intensity within the dentate nucleus following the administration of a minimum of four doses of the macrocyclic agent gadobutrol
2. Repeated intravenous administration of gadobutrol does not lead to increased signal intensity on unenhanced T1-weighted images—a voxel-based whole brain analysis

Dear Professor Menu,

With great interest we read the recent articles by Young et al. [1] and Langer et al. [2] that reported no detectable T1-signal changes in patients that received several doses of macrocyclic gadolinium-based contrast agents (GBCA) before. This is in accordance with highly sensitive measurements using inductively coupled plasma mass spectrometry (ICP-MS) of post mortem samples that reported lower depositions of macrocyclic GBCA in comparison to linear GBCA. [3]

Interestingly, GBCA depositions imaged by laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS) by Fingerhut et al. [4] and El-Khatib et al. [5] did not cause obvious histopathological signs of brain alterations in the area of gadolinium depositions, while the exclusion of subtle brain alterations need further research. These results are in accordance with a recent experimental study that demonstrated GBCA with lower kinetic stability causing mitochondrial toxicity and cell death in human neuronal cells at gadolinium concentrations similar to those measured in human brain samples. The more stable, macrocyclic GBCA demonstrated similar effects, but only at higher concentrations, revealing comparable mechanisms of toxicity. [6]

Remarkably, one of the patients investigated by LA-ICP-MS by Fingerhut et al. had suffered from nephrogenic systemic fibrosis (NSF) that is a known severe side effect of GBCA in patients with impaired kidney function [7] and this patient even died from the consequences of GBCA. [4] Since even this patient did not show obvious histopathological signs in brain, the GBCA depositions in brain were far less dramatic to this patient in comparison to the multiple severe fibrotic alterations in other organs caused by GBCA, e.g. in heart! Therefore, the brain is – at least in patients with intact blood brain barrier – likely not the most endangered organ despite the reported second highest GBCA concentrations besides bones. [3, 4]

In conclusion, although brain toxicity remains an important aspect in particular in patients with chronic neuroinflammation, for which higher gadolinium depositions have been shown experimentally, [8] gadolinium deposits in other organs and especially in cells of the immune system [9] should be in the special focus of further research on GBCA safety.