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.

The authors note that this deposition was first seen as progressively increased signal intensity in the globi pallidi and/or dentate nuclei (DN) on unenhanced T1-weighted images in patients with normal renal function that had multiple administrations of GBCAs.  The increased signal intensity is also referred to as T1 hyperintensity.

A 2015 study by McDonald et al was the first to document that the high signal intensity in the neural tissues was from deposited gadolinium.  The brain specimens were from postmortem examinations of 13 subjects who underwent at least 4 MRIs with gadodiamide (Omniscan).  They showed a dose-dependent relationship between intravenous gadodiamide administrations and subsequent neural tissue deposition that was independent of renal function.  Kanda et al confirmed neural tissue deposition in brain tissues obtained at autopsy in 5 patients with normal renal function who had received Magnevist, Omniscan, or ProHance (Bracco Diagnostics) in varying combinations.

A 2015 animal study by Robert et al also demonstrated that repeated administrations of Omniscan to healthy rats was associated with progressive and persistent T1 signal hyperintensity in the DN and with histologic gadolinium deposits in the cerebellum.  There were no effects observed in rats that received the macrocyclic agent gadoterate meglumine (Dotarem, Guerbet).

The article provides information about other recent studies that report increased signal intensity and gadolinium deposition in the brain.  Study findings support the concept that gadolinium accumulation varies depending on the stability of the agent used, and suggest that all GBCAs should be evaluated individually, despite their molecular structure.

In-vitro stability, pharmacokinetics, and biodistribution of GBCAs are also included in the article.  There appear to be many factors that can result in dissociation of the Gd³⁺ ion from its ligand that have nothing to do with the patient’s renal function.   “The dissociation is an equilibrium process defined by 2 distinct and independent parameters: kinetic and thermodynamic stabilities.”  “Other factors, including the concentration of competing ions or ligands and the interaction times between the gadolinium chelates and the competitors, contribute to the stability of GBCAs.”

Gadolinium Toxicity
The information contained in this section of the review article includes many facts that are covered on this website.  The toxic effects of gadolinium are extensive and we believe explain many of the symptoms reported by affected patients.

The paper notes that most of the known toxicity of the free Gd³⁺ ion is related to 2 properties: its insolubility at physiologic pH, resulting in very slow systemic excretion; and an ionic radius close to that of Ca²⁺ that allows Gd³⁺ to compete biologically with Ca²⁺.

The authors state that because gadolinium is a well-known blocker of many types of voltage-gated calcium channels at very low concentrations, it can inhibit physiological processes such as contractions of smooth, skeletal, and cardiac muscles; transmission of nerve impulses; and blood coagulation.  It also inhibits the activity of certain enzymes, some dehydrogenases and kinases, and glutathione S-transferases.  Gadolinium may increase the expression of some cytokines, inhibit mitochondrial function, and induce oxidative stress.

Spencer et al found that major lesions related to single-dose administration of gadolinium chloride in rats consist of mineral deposition in capillary beds, phagocytosis of minerals by macrophage-like cells, hepatocellular and splenic necrosis followed by dystrophic mineralization, decreased platelet numbers, and increased coagulation times.  Other studies determined that gadolinium is a potent inhibitor of the reticuloendothelial system.  All GBCAs and gadolinium chloride have been found to stimulate fibroblast proliferation in tissues taken from healthy subjects.  It is noted that this last process may be a major factor responsible for NSF because proliferation of CD34+ fibroblasts is the hallmark histologic feature of this disease.

Gadolinium Retention and Tissue Deposition
The authors note that even in patients with normal renal function, in vivo clinical exposure to GBCAs results in gadolinium incorporation into body tissues such as bone matrix or brain tissues.  As early as 1991, Rocklage et al stated, “Minute amounts of chelated or unchelated metals are likely to remain in the body for an extended period of time and could possibly result in a toxic effect.”

Incorporation of gadolinium into human bone removed from patients with normal renal function was reported by Gibby et al (2004), and confirmed by White et al (2006); the patients had received gadodiamide (Omniscan) or gadoteridol (ProHance) no less than 3 days and not more than 8 days before they underwent total hip arthroplasty.  Darrah et al (2009) confirmed that gadolinium incorporates into bone and is retained >8 years; the study also involved the linear agent Omniscan and the macrocyclic agent ProHance.  Other researchers have estimated that approximately 1% of the injected gadolinium from each dose of contrast could be released from the GBCA and deposited in the bones, including in patients with normal kidney function.

Xia et al (2010) reported gadolinium deposition within brain tumor tissues that had blood-brain barrier disruption; the deposition occurred in patients without severe renal disease.  Deposition of gadolinium in the cerebellum was also reported in a patient who developed NSF.  Gadolinium deposition in neural tissues in patients with an intact blood-brain barrier and normal renal function was only recently established by McDonald et al, followed by Kanda et al.

The paper states that in bone and other tissues, gadolinium deposition can be explained, in part, by the presence of fenestrated capillary systems, in combination with the analogous nature of Gd and Ca.  However, neural tissue deposition with an otherwise intact blood-brain barrier as reported by McDonald et al and Kanda et al is not clearly understood.

Clinical Significance of Gadolinium Deposition
This section of the paper caught our attention since it includes data from our “Survey of the Chronic Effects of Retained Gadolinium from Contrast MRIs”.

As the authors said, the retention of gadolinium is important clinically.  Gadolinium has no known biological use in the human body, and heavy metals are known to be toxic.

“The risks associated with the administration of weaker chelate GBCAs to patients with severely impaired kidney function are well-documented, and NSF is the result.  As described in this review, the published literature, most of which is recent, indicates that some gadolinium from each dose given may remain in the body of all patients regardless of their renal function.  The long-term and cumulative effects of retained gadolinium are, at present, unknown in patients with normal renal function.”

As many recent studies involve gadolinium deposition in the brain, I believe it is important to remember that there is proof of gadolinium toxicity in the brain when administered by the intraventricular route in rats (Ray et al, 1998), and also by the intravenous route after blood-brain barrier disruption (Roman-Goldstein et al, 1991).

In 2014, 17 members of our MRI-Gadolinium-Toxicity Support Group participated in our Symptom Survey.  A summary of the results can be found on page 5 of the review article.  All of the participants had normal renal function, and evidence of gadolinium retention a month or more after their last contrast-enhanced MRI.  All 17 reported having Chronic Pain.  Interestingly, 11 of 17 reported having Cognitive Symptoms such as brain fog and difficulty concentrating.  It was the second highest prioritized symptom, with 3 selecting it as their highest priority.  I believe that may be evidence of the toxic effects of gadolinium deposition in the brain.

“Recent literature confirms that gadolinium deposition occurs in the human brain after multiple gadolinium contrast administrations, despite an intact blood-brain barrier and normal renal function.”  “The ultimate significance of this deposition in subjects with normal renal function, in their brain and elsewhere, remains to be determined.  Careful evaluation, especially in children, is recommended when administering GBCAs”.

My Thoughts
The paper states, “It is conceivable that patients may be adversely affected by retained gadolinium, especially in the brain.”  Based on my interactions with other affected patients, I believe it is more than conceivable – it is happening.

Patients are not retaining a benign substance; they are retaining a toxic metal that has the potential to adversely affect all body systems.  One only has to review the NSF-related literature to understand what retained gadolinium can do to the inside of the human body.

This review article, along with the review article by Huckle et al, do an excellent job of covering the facts related to gadolinium deposition, GBCA stability, and gadolinium toxicity.  However, I believe gadolinium retention likely occurs far more frequently than many might think.

You can access the review article by Ramalho et al here: http://www.ajnr.org/content/early/2015/12/10/ajnr.A4615.full.pdf+html

Additional information can be found in the Background Section of our website.

Sharon Williams

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Reference information reflects only those works mentioned in my post about the Review Article by Ramalho et al.  

Ramalho, J., Semelka, R. C., Ramalho, M., Nunes, R. H., AlObaidy, M., & Castillo, M. (2015). Review Article: Gadolinium-Based Contrast Agent Accumulation and Toxicity: An Update. AJNR Am J Neuroradiol, (10.3174/ajnr.A4615). Retrieved from http://www.ajnr.org/content/early/2015/12/10/ajnr.A4615.full.pdf+html

Huckle, J. E., Altun, E., Jay, M., & Semelka, R. C. (9000). Gadolinium Deposition in Humans: When Did We Learn That Gadolinium Was Deposited In Vivo?. Investigative Radiology, Publish Ah. Retrieved from http://journals.lww.com/investigativeradiology/Fulltext/publishahead/Gadolinium_Deposition_in_Humans__When_Did_We_Learn.99255.aspx

Grobner, T. (2006). Gadolinium–a specific trigger for the development of nephrogenic fibrosing dermopathy and nephrogenic systemic fibrosis? Nephrology, Dialysis, Transplantation : Official Publication of the European Dialysis and Transplant Association – European Renal Association, 21(4), 1104–8. Retrieved from http://ndt.oxfordjournals.org/content/21/4/1104.full

Marckmann, P., Skov, L., Rossen, K., Dupont, A., Damholt, M. B., Heaf, J. G., & Thomsen, H. S. (2006). Nephrogenic Systemic Fibrosis: Suspected Causative Role of Gadodiamide Used for Contrast-Enhanced Magnetic Resonance Imaging. J Am Soc Nephrol, 17, 2359–2362. Retrieved from http://jasn.asnjournals.org/content/17/9/2359.full.pdf

McDonald, R. J., McDonald, J. S., Kallmes, D. F., Jentoft, M. E., Murray, D. L., Thielen, K. R., … Eckel, L. J. (2015). Intracranial Gadolinium Deposition after Contrast-enhanced MR Imaging. Radiology, 150025. http://doi.org/10.1148/radiol.15150025

Kanda, T., Fukusato, T., Matsuda, M., Toyoda, K., Oba, H., Kotoku, J., … Furui, S. (2015). Gadolinium-based Contrast Agent Accumulates in the Brain Even in Subjects without Severe Renal Dysfunction: Evaluation of Autopsy Brain Specimens with Inductively Coupled Plasma Mass Spectroscopy. Radiology, 142690. http://doi.org/10.1148/radiol.2015142690

Robert, P., Lehericy, S., Grand, S., Violas, X., Fretellier, N., Idée, J.-M., … Corot, C. (2015). T1-Weighted Hypersignal in the Deep Cerebellar Nuclei After Repeated Administrations of Gadolinium-Based Contrast Agents in Healthy Rats: Difference Between Linear and Macrocyclic Agents. Investigative Radiology, 50(8). Retrieved from http://journals.lww.com/investigativeradiology/Fulltext/2015/08000/T1_Weighted_Hypersignal_in_the_Deep_Cerebellar.1.aspx

Spencer, A. J., Wilson, S. A., Batchelor, J., Reid, A., Pees, J., & Harpur, E. (1997). Gadolinium Chloride Toxicity in the Rat . Toxicologic Pathology , 25 (3 ), 245–255. http://doi.org/10.1177/019262339702500301

Rocklage, S. M., Worah, D., & Kim, S.-H. (1991). Metal ion release from paramagnetic chelates: What is tolerable? Magnetic Resonance in Medicine, 22(2), 216–221. Retrieved from http://doi.wiley.com/10.1002/mrm.1910220211

Gibby, W. A., Gibby, K. A., & Gibby, W. A. (2004). Comparison of Gd DTPA-BMA (Omniscan) versus Gd HP-DO3A (ProHance) retention in human bone tissue by inductively coupled plasma atomic emission spectroscopy. Investigative Radiology, 39(3), 138–42. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/15076005

White, G. W., Gibby, W. A., & Tweedle, M. F. (2006). Comparison of Gd(DTPA-BMA) (Omniscan) versus Gd(HP-DO3A) (ProHance) relative to gadolinium retention in human bone tissue by inductively coupled plasma mass spectroscopy. Investigative Radiology, 41(3), 272–8. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/16481910

Darrah, T. H., Prutsman-Pfeiffer, J. J., Poreda, R. J., Ellen Campbell, M., Hauschka, P. V, & Hannigan, R. E. (2009). Incorporation of excess gadolinium into human bone from medical contrast agents. Metallomics : Integrated Biometal Science, 1(6), 479–488. Retrieved from http://pubs.rsc.org/en/content/articlehtml/2009/mt/b905145g

Xia, D., Davis, R. L., Crawford, J. A., & Abraham, J. L. (2010). Gadolinium released from MR contrast agents is deposited in brain tumors: in situ demonstration using scanning electron microscopy with energy dispersive X-ray spectroscopy. Acta Radiologica (Stockholm, Sweden : 1987), 51(10), 1126–36. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/20868305

Ray, D. E., Holton, J. L., Nolan, C. C., Cavanagh, J. B., & Harpur, E. S. (1998). Neurotoxic potential of gadodiamide after injection into the lateral cerebral ventricle of rats. American Journal of Neuroradiology, 19(8), 1455–1462. Retrieved from http://www.ajnr.org/content/19/8/1455.full.pdf+html

Roman-Goldstein, S. M., Barnett, P. A., McCormick, C. I., Ball, M. J., Ramsey, F., & Neuwelt, E. A. (1991). Effects of gadopentetate dimeglumine administration after osmotic blood-brain barrier disruption: toxicity and MR imaging findings. AJNR. American Journal of Neuroradiology, 12(5), 885–90. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/1950917