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Study is first to report Gadolinium Toxicity in Patients with Normal Renal Function
“Presumed Gadolinium Toxicity in Subjects with Normal Renal Function – A Report of 4 Cases”, is a landmark paper which documents the first presumed cases of gadolinium toxicity. Richard C. Semelka, MD, Radiologist at the University of North Carolina at Chapel Hill, and his colleagues are the authors. This is the first study to describe a series of patients with normal renal function who developed symptomatology lasting beyond the immediate post-injection period after the administration of a gadolinium-based contrast agent (GBCA).
Two subjects were assessed at 2 months and at 3 months after GBCA administration (early stage), and 2 subjects were assessed at 7 years and 8 years after GBCA administration (late stage). Clinical features were similar between subjects, and included central torso pain (all), peripheral arm and leg pain (all), clouded mentation (2), and distal arm and leg skin thickening and rubbery subcutaneous tissue (one early and both late subjects). All subjects had evidence of gadolinium retention ranging from one month up to 8 years after disease development.
Regarding clinical findings, the authors note that “these 4 individuals showed features that resemble and are observed in NSF patients”. “Specifically, the glove-and-sock pattern of pain (seen in all patients) is essentially universally seen in NSF, and central torso pain (seen in 3 patients) is seen with some frequency, but not universally, in NSF patients. Skin thickening and doughiness of the hands was seen in the 2 subjects with late-stage disease and is also described as a feature that progressively develops with NSF.” They also noted that “headache and clouded mentation are vague and non-specific clinical symptoms; but they had new onset in 2 subjects”. While numerous recent studies report gadolinium deposition in the brain, no histopathological changes have been documented yet. They point out that a compound may be neurotoxic without being associated with histopathological signs.
These clinical features are comparable to the symptomatology reported by Burke et al, in which the most common self-reported symptoms included bone/joint pain and head/neck symptoms including headache, vision change, and hearing change (77.6% each). (more…)
More evidence of gadolinium deposition in children’s brains
Three recent retrospective studies have reported finding evidence of increased signal intensities in the brains of pediatric patients who had undergone multiple MRIs with a gadolinium-based contrast agent (GBCA). The studies by Hu et al, Roberts et al, and Flood et al, add to the mounting evidence of gadolinium deposition in the brain of both children and adults exposed to GBCAs.
The study by Hu et al involved 21 patients, each of whom received multiple MRI exams with a GBCA over the course of their medical treatment. The number of exams ranged from 5 to 37 (19 out of 21 had more than 6 serial GBCA MRI exams), and the duration of treatment from first to most recent exam ranged from 1.2 to 12.9 years. The patients were between 0.9 and 14.4 years of age at the time of their first GBCA exam. Signal intensity ratios in the dentate nucleus and globus pallidus increased between the first and most recent MRI exam in all 21 patients receiving a GBCA.
The authors concluded that the data provided supports the growing evidence of potential gadolinium deposition in the brain. The observation of signal intensity increases in the dentate nucleus and the globus pallidus on unenhanced T1-weighted images are consistent with prior studies in adults. They noted that “additional studies are warranted to determine whether intracranial gadolinium deposition is the source responsible for these hyperintense structures and whether changes in standard practice of care are needed”.
Hu, H. H., Pokorney, A., Towbin, R. B., & Miller, J. H. (2016). Increased signal intensities in the dentate nucleus and globus pallidus on unenhanced T1-weighted images: evidence in children undergoing multiple gadolinium MRI exams. Pediatric Radiology, 1–9. http://doi.org/10.1007/s00247-016-3646-3
Roberts et al found that the number of prior gadolinium-based contrast agent doses in pediatric patients is significantly correlated with progressive T1-weighted dentate hyperintensity. Sixteen pediatric patients were included for analysis. The patient ages ranged from 2 months to 14 years at the time of the first contrast dose. The number of doses before the last brain MR imaging examined ranged from 4 to 16. Hyperintensity was visible within the dentate nucleus on unenhanced images in the patients who had received at least 7 prior doses of GBCA.
The authors note that “pathologic evaluation of the brain in patients with normal renal function who were administered GBCAs has shown that gadolinium is deposited not only in the dentate nucleus but throughout the brain, including the frontal lobe white matter and frontal cortex”. “While the clinical significance of the long-term retention of gadolinium in the brain is unknown, it is particularly concerning for pediatric patients, who are undergoing neurodevelopment.” (more…)
New Study calls for FDA action on Gadolinium-based Contrast Agents
Details of a new article about gadolinium-based contrast agent safety concerns were posted to EurekAlert! by MedInsight Research Institute. The article, “Gadolinium-Based Contrast Agent Toxicity – A Review of Known and Proposed Mechanisms”, by Rogosnitzky and Branch, was published in the Springer journal BioMetals.
Of special interest to us is the fact that the authors referenced the Lighthouse Project and results from our 2014 paper, Gadolinium Toxicity: A Survey of the Chronic Effects of Retained Gadolinium from Contrast MRIs. As we have done, the authors called for FDA action on Gadolinium-Based Contrast Agents.
The following release can be found at http://www.eurekalert.org/pub_releases/2016-04/mri-srq040616.php
EurekAlert!
PUBLIC RELEASE: 6-APR-2016
Study raises questions about the safety of MRI contrast agent; authors call for FDA action
MEDINSIGHT RESEARCH INSTITUTE
APRIL 6, 2016, Ariel, Israel – An article published today in the Springer journal BioMetalsraises serious questions about the safety of the gadolinium-based contrast agents that are used in about 30 percent of magnetic resonance imaging (MRI) scans. In their literature review, researchers from MedInsight Research Institute and Israel’s Ariel University analyzed studies detailing the known and proposed mechanisms of retained gadolinium toxicity. According to lead author Moshe Rogosnitzky, “Although gadolinium is bound to chelating agents designed to flush out the rare metal following an MRI, it has been found to deposit in the brain, bone, and other organs.”
Rogosnitzky said that this finding contradicts the longstanding belief that patients with normal kidney function are not at risk for gadolinium accretion. In 2007, the U.S. Food and Drug Administration (FDA) ordered a black box warning for gadolinium-based contrast agents following the discovery that patients with kidney disease were developing nephrogenic systemic fibrosis (NSF) due to the inability to clear gadolinium from their bodies. In July 2015, the FDA announced it was evaluating the risk of brain-deposits in patients who undergo repeated exposure to gadolinium-based contrast agents. “At the time, FDA claimed that available information did not identify any adverse health effects. In the face of the information contained in our study, we believe this position is no longer tenable,” said Rogosnitzky.
Study author and toxicologist Dr. Stacy Branch underscored the urgent need for the FDA to take action. “Given the ever-growing toxicological and gadolinium tissue retention data, it is vital that the FDA promptly leads efforts, including retrospective and prospective clinical studies, to better define the connection between GBCA-exposure and adverse health events,” she said. “This is needed to guide the choice of preventive methods, achieve accurate diagnoses, implement effective treatment approaches, and spark research for the design of safer contrast agents and imaging protocols.”
Rogosnitzky, who heads the Center for Drug Repurposing at Ariel University, called upon the scientific community to quickly develop treatments for gadolinium overload. “Our literature review did not reveal a single suitable drug to swiftly remove gadolinium from the body,” he said. “In one study, the authors estimated it might take up to 156 years to remove a patient’s stored gadolinium using a particular drug.” Rogosnitzky believes that a good first step is to study existing chelator drugs used for other metal toxicities in order to assess their possible utility in gadolinium accumulation.
The published article sounds the alarm about the gap in scientific knowledge about treatment for gadolinium toxicity. “With the ominous discovery that gadolinium is retained in healthy patients, there is a critical shortage of scientific information regarding how to assess gadolinium toxicity, and perhaps most importantly, how to treat it,” Rogosnitzky said.
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The article, “Gadolinium-Based Contrast Agent Toxicity – A Review of Known and Proposed Mechanisms,” can be accessed at http://link.springer.com/article/10.1007/s10534-016-9931-7.
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Gadolinium Deposition in Humans is Not Something New
Since early 2014, there have been numerous articles published that report finding evidence of gadolinium deposition in the brain within the dentate nucleus (DN) and globus pallidus (GP) in patients with normal renal function. The findings seem to have come as a surprise to some radiologists, but a review article by Huckle et al indicates that no one should be surprised by the findings. The article, Gadolinium Deposition in Humans – When did we learn that Gadolinium was deposited in vivo?, takes a retrospective look back at gadolinium-based contrast agents (GBCAs) to describe the historical evidence of gadolinium (Gd) deposition in vivo. According to the authors, it “shows that deposition in the basal ganglia should come as no surprise”.
The article notes that deposition of gadolinium in animals with normal renal function has been described in the peer-reviewed literature since at least 1984 when Weinmann et al reported that although gadolinium elimination in rats was largely complete 7 days after administration of Gd-DTPA, a small fraction (0.3%) was retained. Other animal studies confirmed gadolinium retention that was proportional to the dose. Gadolinium was found in bone, skin, and other organs in animals.
The higher stability of macrocyclic GBCAs compared to the linear agents has been confirmed in published animal studies. However, while higher levels of gadolinium were detected in the skin and bones of animals injected with linear agents, the studies demonstrated that “quantifiable levels of gadolinium” are deposited after administration of all GBCAs – linear and macrocyclic agents.
Gadolinium Toxicity 