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New Studies Question Safety of MRI Contrast Agents

(10.04.2016)


Background:
Gadolinium based MRI contrast agents (GBCAs) are used to enhance the images and allow physicians interpreting the exam to distinguish blood vessels from nearby tissue. Safety claims for the GBCAs are based on the high stability of the agents and the high solubility leading to rapid excretion in an intact state. However, a first safety issue was recognized several years ago, when it was found that fast and complete excretion is hindered among patients with impaired kidney function. Development of adverse health conditions such as nephrogentic systemetic fibrosis (NSF) under conditions of impaired excretion has been reported. Yet, it was previously widely believed that GBCAs are rapidly and completely excreted from the human body in patients with normal kidney function.

A year ago, a study published in the medical journal Radiology examined the brains of cadavers and found that those who had received gadolinium injections had deposits in the brain, while those who had not received such injections did not. In June 2015, a study by European researchers in the journal Investigative Radiology found similar deposits in the brains of rats injected with Omniscan, a GBCA (gadolinium-based contrast agent) made by GE Healthcare. The rats developed significant, persistent MRI abnormalities over time, and high levels of gadolinium were found deep in the rats’ brains. Since then, the FDA, and the EMA, are reviewing whether those deposits are harmful.

The new study:
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."

According to their literature review, the reasons for this accumulation—and the potential  negative consequences  for patients—are still largely unknown, due in part to limited existing clinical data regarding the mechanisms of gadolinium toxicity. “Unequivocal data regarding the effects of multiple GBCA exposure are limited,” they wrote. “However, the information regarding the thermodynamic stability constants for GBCAs, in vitro, animal, and human data, and the emerging data regarding gadolinium tissue accumulation in those with normal kidney function indicate that the potential toxicity associated with GBCA must be seriously and urgently considered.”

Rogosnitzky and Branch cite findings from various recent studies into gadolinium toxicity, including a patient-advocacy group survey in which former patients with repeated exposure to GBCAs reported experiencing neurological, musculoskeletal, or dermal symptoms, including pain (100 percent), muscle symptoms (88 percent) and ocular symptoms (76 percent).

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 that time, the FDA also claimed that available information did not identify any adverse health effects so far. "In the face of the information contained in our study, we believe this position is no longer tenable,” Rogosnitzky said.

Finally, the authors conclude, that the potential toxicity associated with GBCA must be seriously and urgently considered and addressed with more research including retrospective and prospective cohort studies.


Sources: Medical Xpress; April 6, 2016; and BioMetals; April 6, 2016.




The cited study:

Moshe Rogosnitzky, Stacy Branch, Gadolinium-based contrast agent toxicity: a review of known and proposed mechanisms, BioMetals (2016). DOI: 10.1007/s10534-016-9931-7



Related studies (newest first):

Henrik S Thomsen, T1 hyperintensity in the brain after multiple intravenous injections of gadolinium-based contrast agents, Acta Radiol., 57/4 (2016) 389-391. DOI: 10.1177/0284185115626479

James E. Huckle, Ersan Altun, Michael Jay, Richard C. Semelka, Gadolinium Deposition in Humans When Did We Learn That Gadolinium Was Deposited In Vivo?, Invest. Radiol., 51/4 (2016) 236-240. DOI: 10.1097/RLI.0000000000000228

Ashkan A. Malayeri, Kristina M. Brooks, L. Henry Bryant, Robert Evers, Parag Kumar, Daniel S. Reich, David A. Bluemke, National Institutes of Health Perspective on Reports of Gadolinium Deposition in the Brain, J. Am. Coll.  Radiol., 13/3 (2016) 237–241. DOI: 10.1016/j.jacr.2015.11.009

Donna R. Roberts, Kenton R. Holden, Progressive increase of T1 signal intensity in the dentate nucleus and globus pallidus on unenhanced T1-weighted MR images in the pediatric brain exposed to multiple doses of gadolinium contrast, Brain Dev., 38/3 (2016) 331–336. DOI: 10.1016/j.braindev.2015.08.009

Philippe Robert, Xavier Violas, Sylvie Grand, Stéphane Lehericy, Jean-Marc Idée, Sébastien Ballet, Claire Corot, Linear Gadolinium-Based Contrast Agents Are Associated With Brain Gadolinium Retention in Healthy Rats, Invet. Radiol., 51/2 (2016) 73-82. DOI: 10.1097/RLI.0000000000000241

Dragan A. Stojanov, Aleksandra Aracki-Trenkic, Slobodan Vojinovic, Daniela Benedeto-Stojanov, Srdjan Ljubisavljevic, Increasing signal intensity within the dentate nucleus and globus pallidus on unenhanced T1W magnetic resonance images in patients with relapsing-remitting multiple sclerosis: correlation with cumulative dose of a macrocyclic gadolinium-based contrast agent, gadobutrol, Eur. Radiol., 26/3 (2016) 807-815. DOI: 10.1007/s00330-015-3879-9

Bruno Beomonte Zobel , Carlo Cosimo Quattrocchi, Yuri Errante, Rosario Francesco Grasso, Gadolinium-based contrast agents: did we miss something in the last 25 years?, Radiol. Med., 2016. DOI: 10.1007/s11547-015-0614-1

J. Ramalho, R.C. Semelka, M. Ramalho, R.H. Nunes, M. AlObaidy and M. Castillo, Gadolinium-Based Contrast Agent Accumulation and Toxicity: An Update, Am. J. Neuroradiol., 2016. DOI: 10.3174/ajnr.A4615

Joana Ramalho, Mauricio Castillo, Mamdoh AlObaidy, Renato H. Nunes, Miguel Ramalho, Brian M. Dale, Richard C. Semelka, High Signal Intensity in Globus Pallidus and Dentate Nucleus on Unenhanced T1-weighted MR Images: Evaluation of Two Linear Gadolinium-based Contrast Agents, Radiology, 276/3 (2015) 836-844. DOI: 10.1148/radiol.2015150872

Philippe Robert, Stéphane Lehericy, Sylvie Grand, Xavier Violas, Nathalie Fretellier, Jean-Marc Idée, Sébastien Ballet, Claire Corot, 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, Invest. Radiol., 50/8 (2015) 473-480. DOI: 10.1097/RLI.0000000000000181

Emanuel Kanal, Michael F. Tweedle, Residual or Retained Gadolinium: Practical Implications for Radiologists and Our Patients, Radiology, 275/3 (2015) 630-634. DOI: 10.1148/radiol.2015150805

Robert J. McDonald, Jennifer S. McDonald, David F. Kallmes, Mark E. Jentoft, David L. Murray, Kent R. Thielen, Eric E. Williamson, Laurence J. Eckel,  Intracranial Gadolinium Deposition after Contrast-enhanced MR Imaging, Radiology, 275/3 (2015) 772-782. doi: 10.1148/radiol.15150025

Alexander Radbruch, Lukas D. Weberling, Pascal J. Kieslich, Oliver Eidel, Sina Burth, Philipp Kickingereder, Sabine Heiland, Wolfgang Wick, Heinz-Peter Schlemmer, Martin Bendszus, Gadolinium Retention in the Dentate Nucleus and Globus Pallidus Is Dependent on the Class of Contrast Agent, Radiology, 275/3 (2015) 783-791. DOI: 10.1148/radiol.2015150337

Tomonori Kanda, Marie Osawa, Hiroshi Oba, Keiko Toyoda, Jun’ichi Kotoku,  Takahiro Haruyama, Koji Takeshita, Shigeru Furui, High Signal Intensity in Dentate Nucleus on Unenhanced T1-weighted MR Images: Association with Linear versus Macrocyclic Gadolinium Chelate Administration, Radiology, 275/3 (2015) 803-809. DOI: 10.1148/radiol.14140364

Tomonori Kanda, Toshio Fukusato, Megumi Matsuda, Keiko Toyoda, Hiroshi Oba, Jun’ichi Kotoku, Takahiro Haruyama, Kazuhiro Kitajima, Shigeru Furui, 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, 276/1 (2015) 228-232. DOI: 10.1148/radiol.2015142690

Daniel Xia, Richard L. Davis, Judith A. Crawford, Jerrold L. Abraham, 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 Radiol., 51/10 (2010) 1126-1136. DOI: 10.3109/02841851.2010.515614

Steven A. Greenberg, Zinc Transmetallation and Gadolinium Retention after MR Imaging: Case Report, Radiol., 257/3 (2010) 670-673. DOI: 10.1148/radiol.10100560

Hubertus Pietsch, Philipp Lengsfeld, Gregor Jost, Thomas Frenzel, Joachim Hütter, Martin A. Sieber, Long-term retention of gadolinium in the skin of rodents following the administration of gadolinium-based contrast agents, Eur. Radiol., 19 (2009) 1417–1424. DOI: 10.1007/s00330-008-1259-4

Thomas H. Darrah, Jennifer J. Prutsman-Pfeiffer, Robert J. Poreda, M. Ellen Campbell, Peter V. Hauschka, Robyn E. Hannigan, Incorporation of excess gadolinium into human bone from medical contrast agents, Metallomics, /6 (2009) 479–488, DOI: 10.1039/b905145g

Gregory W. White, Wendell A. Gibby, Michael F. Tweedle, 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, Invest. Radiol., 41/3 (2006) 272-278. doi: 10.1097/01.rli.0000186569.32408.95 

Wendell A. Gibby, Krissa A. Gibby, W. Andrew Gibby, Comparison of Gd DTPA-BMA (Omniscan) versus Gd HP-DO3A (ProHance) Retention in Human Bone Tissue by Inductively Coupled Plasma Atomic Emission Spectroscopy, Invest. Radiol., 39/3 (2004) 138-142. doi: 10.1097/01.rli.0000112789.57341.01



Related information

FDA: July 27, 2015: FDA evaluating the risk of brain deposits with repeated use of gadolinium-based contrast agents for magnetic resonance imaging (MRI)
EMET: March 8, 2016: PRAC reviews gadolinium contrast agents used in MRI scans



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Related EVISA News

August 13, 2015: FDA investigating risk of gadolinium contrast agent brain deposits
March 4, 2015: Detection of Gd-based contrast agent in the skin of a patient eight years after administration
October 29, 2012: Identification and quantification of potential metabolites of Gd-based contrast agents 
September 15, 2010: US FDA Announces Gadolinium-Based MRI Contrast Agent Warning
March 25, 2010: Publication on the separation of Gd-based contrast agents awarded
May 4, 2009: Gadolinium speciation analysis in search for the cause of nephrogenic systemic fibrosis (NSF)


last time modified: April 10, 2016










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