Gadolinium Toxicity

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Study finds more Gadolinium in Bone than Brain Tissue

A recent study by Murata et al, “Macrocyclic and Other Non-Group 1 Gadolinium Contrast Agents Deposit Low Levels of Gadolinium in Brain and Bone Tissue: Preliminary Results from 9 Patients with Normal Renal Function”, adds to the mounting evidence of gadolinium deposition and retention in patients with normal renal function.  The study, published online ahead of print in Investigative Radiology, found that “Gadolinium deposition in normal brain and bone tissue occurs with macrocyclic and linear protein interacting agents in patients with normal renal function”.  The authors noted that, “Deposition of Gd in cortical bone occurs at much higher levels compared with brain tissue and shows a notable correlation between the two”.

The linear gadolinium-based contrast agents (GBCAs) most frequently associated with NSF were designated as Group 1 agents by the FDA in 2010.  Those agents are gadodiamide (Omniscan), gadoversetamide (OptiMARK), and gadopentetate (Magnevist).  The linear protein binding agents include gadobenate dimeglumine (MultiHance), gadoexetate (Eovist), and gadofosveset (Ablavar).  (more…)

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 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.

(more…)

MRI brain signal changes reported in a child

The November 2015 issue of Pediatrics includes a case study by Miller et al.  The article, MRI Brain Signal Intensity Changes of a Child During the Course of 35 Gadolinium Contrast Examinations, describes the quantitative signal intensity changes in the brain of a pediatric patient who had 35 MRIs with a linear gadolinium-based contrast agent (GBCA) between the ages of 8 and 20 years.  The authors report that progressive increases were the most evident in the dentate nuclei, the globus pallidus, and the thalamus.  They noted that the pattern of regional brain hyperintensity observed is consistent with findings from recent adult studies.

High signal intensity in the dentate nucleus and globus pallidus on unenhanced T1-weighted images was first reported by Kanda et al in late 2013 and has been found to be the result of gadolinium deposition in the brain.

Sharon Williams

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Miller, J. H., Hu, H. H., Pokorney, A., Cornejo, P., & Towbin, R. (2015). MRI Brain Signal Intensity Changes of a Child During the Course of 35 Gadolinium Contrast Examinations. Pediatrics, peds.2015–2222–. http://doi.org/10.1542/peds.2015-2222

Kanda, T., Ishii, K., Kawaguchi, H., Kitajima, K., & Takenaka, D. (2013). High Signal Intensity in the Dentate Nucleus and Globus Pallidus on Unenhanced T1-weighted MR Images: Relationship with Increasing Cumulative Dose of a Gadolinium-based Contrast Material. Radiology, 131669. http://doi.org/10.1148/radiol.13131669

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