Deposition of Gadolinium in After Multiple GBCA Injections: Clinical Trial Prospective

Gadolinium-based contrast agents (GBCAs) are indispensable adjuncts to MRI, with numerous studies showing their efficacy in improving the accuracy of MRI studies. Gadolinium deposition in the brains of patients who received multiple doses of GBCAs has recently been reported. Although it is not yet known if there is a clinical implication of brain deposition of gadolinium, concerns for patient safety are of paramount importance. 

Free gadolinium is very toxic and suppression of the reticuloendothelial system, inhibition of phagocytosis, and interruption of the function of smooth and skeletal muscles, have been documented in animal studies. Therefore, gadolinium in GBCAs, is bound to a chelating agent that should remain bound in vivo. 

Based on the chelating agent, GBCAs can be classified as linear and macrocyclic. Macrocyclic GBCAs are more stable than linear agents in terms of in-vivo dissociation of gadolinium from gadolinium-chelate complex. 

The highest degree of dissociation has been observed in nonionic linear chelates (e.g. Omniscan) followed by ionic linear (e.g. Magnevist). All 3 macrocyclic GBCAs (Dotarem, Gadovist and Prohance) remained stable in human serum (1). 

Deposition of gadolinium in humans has been reported in the bones, liver, lung, kidney, heart, eye, and skin of NSF patients but recently, increased signal intensity in the globus pallidus and dentate nucleus associated with multiple GBCA injections (as few as three injections) has been reported. Autopsy studies have confirmed that this increase in signal intensity observed on MRI is due to gadolinium deposition (2). Almost all the publications showed that the increase in signal intensity is related to linear GBCAs and not associated with macrolyclic GBCAs. (3, 4) 

In summary, repeated administration of linear GBCAs can lead to hyperintensity due to gadolinium deposition within the brain. The putative mechanism is the dissociation of the contrast agent into gadolinium and its chelate. To date, no consequences for patient health have been identified. However, this is a rapidly evolving topic. 

Recognizing this, in 2015, the FDA issued a drug safety communications statement regarding the risk for brain deposits with repeated use of GBCAs for MRI. Although, it concluded that the available information does not identify any adverse health effects, caution should be exercised when using GBCAs. Subsequently, in 2016 the NIH has recommended that macrocyclic GBCA should be used instead of linear GBCAs (6). 

Although the long-term impact of deposition of gadolinium in the brain remains unknown, it seems prudent to be careful about the use GBCAs, especially in patients who receive multiple GBCA injections like oncology, neurology and pediatric patients. This new safety concern should also be considered when designing imaging protocols of clinical trials. The protocols of clinical trials should specify type of GBCA that should be used as IRBs may not allow multiple injections of linear GBCAs. 

1. Frenzel T et al. Stability of Gadolinium-based Magnetic Resonance Imaging Contrast Agents in Human Serum at 37 degrees C. Investigative Radiology 2008; 43:817-28. 
2. McDonald RJ. et al. Intracranial Gadolinium Deposition after Contrast-Enhanced MR Imaging.. Radiology. 2015;275(3):772-782. 
3. Kanda T, et al. High Signal Intensity in Dentate Nucleus on Unenhanced T1-weighted MR Images: Association with Linear versus Macrocyclic Gadolinium Chelate Administration. Radiology. 2014; 27:834-841. 
4. Radbruch A, et al Gadolinium Retention in the Dentate Nucleus and Globus Pallidus is Dependent on the Class of Contrast Agent. Radiology. 2015;275(3):783-791 
6. Malayeri A et al. National Institutes of Health Perspective on Reports of Gadolinium Deposition in the Brain. JACR; 2016; 13: 237-241. 

Jenny-Kate Barkin