Abstract
Despite the impressive safety of gadolinium (Gd)-based contrast agents (GBCAs), a small number of patients report the onset of new, severe, ongoing symptoms after even a single exposure—a syndrome termed Gadolinium Deposition Disease (GDD). Mitochondrial dysfunction and oxidative stress have been repeatedly implicated by animal and in vitro studies as mechanisms of Gd/GBCA-related toxicity, and as pathogenic in other diseases with similarities in presentation. Here, we aimed to molecularly characterize and explore potential metabolic associations with GDD symptoms. Detailed clinical phenotypes were systematically obtained for a small cohort of individuals (n = 15) with persistent symptoms attributed to a GBCA-enhanced MRI and consistent with provisional diagnostic criteria for GDD. Global untargeted mass spectroscopy-based metabolomics analyses were performed on plasma samples and examined for relevance with both single marker and pathways approaches. In addition to GDD criteria, frequently reported symptoms resembled those of patients with known mitochondrial-related diseases. Plasma differences compared to a healthy, asymptomatic reference cohort were suggested for 45 of 813 biochemicals. A notable proportion of these are associated with mitochondrial function and related disorders, including nucleotide and energy superpathways, which were over-represented. Although early evidence, coincident clinical and biochemical indications of potential mitochondrial involvement in GDD are remarkable in light of preclinical models showing adverse Gd/GBCA effects on multiple aspects of mitochondrial function. Further research on the potential contributory role of these markers and pathways in persistent symptoms attributed to GBCA exposure is recommended.
Highlights
With excellent general safety profiles, gadolinium (Gd)-based contrast agents (GBCAs) are a mainstay for medical imaging
Plausible health risks prompted the European Medicines Agency to recommend the discontinuation of several gadolinium-based contrast agents (GBCAs) [2], and Gadolinium Deposition Disease (GDD) was proposed as a new clinical entity following increasing reports of severe, persistent, post-exposure symptoms concomitant with ongoing Gd excretion [3,4]
GBCA excretion rates may be significantly lower than originally estimated in individuals with apparently normal renal function [27], patient urinary Gd at 1–7 months post-MRI
Summary
With excellent general safety profiles, gadolinium (Gd)-based contrast agents (GBCAs) are a mainstay for medical imaging. Safety exceptions emerged initially with the discovery of Nephrogenic Systemic Fibrosis (NSF) in patients with pre-existing renal compromise [2]. Gd-induced necrosis and apoptosis of diverse cell types and fibrotic chemokine/cytokine activity are reported in various preclinical models [3]; no clinical histological evidence or relationship between GBCA dosing and neurological outcomes has been reported [3]. Plausible health risks prompted the European Medicines Agency to recommend the discontinuation of several GBCAs [2], and GDD was proposed as a new clinical entity following increasing reports of severe, persistent, post-exposure symptoms concomitant with ongoing Gd excretion [3,4]
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