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Could Sugar replace Gadolinium-Based Contrast Agents used for MRIs?
Animal studies have shown that D-glucose is a potential biodegradable MRI contrast agent for imaging glucose uptake in tumors. According to findings reported by Xu et al in “Dynamic Glucose-Enhanced (DGE) MRI: Translation to Human Scanning and First Results in Glioma Patients”, dynamic glucose-enhanced (DGE) imaging is feasible in humans. Chemical exchange saturation transfer (CEST) MRI was used to image dynamic signal changes in the human brain at 7 Tesla (7T) during and after infusion of D-glucose (sugar).
DGE image data from 4 normal volunteers and 3 glioma patients showed strong signal enhancement in blood vessels, while the enhancement varied spatially over the tumor. The authors noted that the areas of enhancement differed spatially between DGE and conventional Gd-enhanced imaging, suggesting complementary image information content for these two types of agents.
The researchers concluded that it was possible to detect water signal changes in the human brain induced by infusion of D-glucose. They said that the signal changes are due to glucose uptake in vessels, the brain and tumor tissue areas, and are related to the kinetics of delivery, transport and metabolism of D-glucose. They noted that an interesting finding is that different tumor areas showed varying times of enhancement, which suggests that the dynamic time curves may contain information about blood-brain barrier (BBB) permeability.
According to the study authors, a larger human study is needed, and for DGE to become relevant clinically, it would have to be possible at 3 Tesla and preferably also at 1.5 Tesla.
Why this is important for patients – (more…)
Gadolinium Deposition Disease – Part of a Family of Disorders
Important News for Patients who have retained gadolinium –
A recently published article by UNC Radiologist Dr. Richard Semelka and his colleagues proposes naming the histopathologically proven presence of gadolinium in brain tissue “gadolinium storage condition”, and it describes a new entity that represents symptomatic deposition of gadolinium in individuals with normal renal function, for which they propose the designation “gadolinium deposition disease”. The article titled: Gadolinium in Humans: A Family of Disorders, was published in AJR online.
The article is not freely available to the public at this time. Because of that, I will provide some important information from the article for patients and their doctors below.
Gadolinium Storage Condition –
“Gadolinium storage condition” is the term proposed for gadolinium tissue deposition. The authors said, “Even in patients with normal renal function, in vivo clinical exposure to gadolinium chelates results in gadolinium incorporation into body tissues such as bone matrix or brain tissues.” (See references below.)
It appears that gadolinium accumulation varies depending on the stability of the agent used. As with NSF, the least stable GBCAs appear to be most likely to result in gadolinium storage condition, and stable agents either do not cause it or cause it at a very low level. The clinical significance of gadolinium tissue deposition remains incompletely understood.
Gadolinium Deposition Disease –
“Gadolinium deposition disease” is the name proposed for a disease process observed in subjects with normal or near normal renal function who develop persistent symptoms that arise hours to 2 months after the administration of gadolinium-based contrast agents (GBCAs). In these cases, no preexistent disease or subsequently developed disease of an alternate known process is present to account for the symptoms.
The authors note that some of these patients are likely to have coexistent gadolinium storage condition, as described above, but gadolinium deposition disease is also described after a single administration of GBCA. The causal relationship has not been fully established, but it is under investigation.
The article references our MRI Gadolinium-Toxicity support group and notes that the group has reported symptoms it considers to be consistent with the known toxic effects of gadolinium. They also cite the results of our 2014 Symptom Survey which suggests an association between chronic effects and GBCA exposure.
The authors said, in their experience, “Symptoms of gadolinium deposition disease are similar but not identical to those observed in NSF”. They said that their preliminary investigation has convinced them that this phenomenon is a true disease process. (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.
Disclaimer: AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert system.
Toxicity of Gadolinium Deposition from MRI Contrast Agents
A recent review article by Ramalho et al summarizes the literature on gadolinium-based contrast agents or GBCAs that are administered for contrast-enhanced MRIs, and it ties together information on agent stability, and animal and human studies. The article, “Gadolinium-Based Contrast Agent Accumulation and Toxicity: An Update”, also emphasizes that the low-stability agents are the ones most often associated with brain deposition of gadolinium that has been reported in the literature since 2014.
Since the article has Open Access at AJNR.org, I will not go into all of the details of it. However, there are some facts contained in the paper that I want to present here that are relevant to why GadoliniumToxicity.com exists. In 2014, Hubbs Grimm and I created this website as a way to alert people to a problem that was not yet recognized by the FDA and medical industry. That problem was gadolinium retention in patients with normal renal function. We knew the facts were in the published literature, but they just had not been seen by the right people yet. Thankfully, that has now begun to change.
Nephrogenic Systemic Fibrosis (NSF)
No review of GBCAs would be complete without some background information on NSF.
In 2006, the association between the administration of GBCAs and the development of Nephrogenic Systemic Fibrosis (NSF) in patients with severe renal disease was reported by Grobner and then by Marckmann et al. NSF predominantly involves the skin, but it is a systemic disease that may also affect other organs such as the lungs, liver, heart, and muscles. The exact pathophysiology of NSF remains unknown, but as the review states, the dissociation of gadolinium ions from their chelating ligands has been accepted as the primary etiology. That is more likely to occur in patients with renal failure than in those with normal renal function since the excretion rate is reduced in those with renal failure. The article indicates that most cases of NSF reported in the literature have been associated with the administration of nonionic, linear gadodiamide (Omniscan, GE Healthcare), nonionic, linear gadoversetamide (OptiMARK, Covidien), and with ionic, linear gadopentetate dimeglumine (Magnevist, Bayer HealthCare Pharmaceuticals).
After limiting the use of GBCAs in patients with renal failure and using more stable GBCAs, there have been no new cases of NSF reported since mid-2009. According to the paper, from 2009 to 2014, confidence in the safety of GBCAs had been largely restored. However, since 2014, numerous studies have been published that reported finding evidence of gadolinium deposition in neural tissues in patients with normal renal function. (more…)
Gadolinium Toxicity 