Gadolinium Retention Updates & Resources
 

Since late 2013, the field has begun to recognize high signal changes in specific brain regions, previously observed and attributed to specific pathologies, are actually signs of Gadolinium accumulation following the use of
gadolinium based contrast agents (GBCA).

Notably these observations are made in patients with renal function that allows the use of GBCA generally or of specific agents, and does not offend the FDA and international warnings put in place to deal with the role of GBCA in Nephrogenic Systemic Fibrosis (NSF) during the late 1990s.

As can be expected, our understanding of the situation is evolving with new experimental data and consideration of existing material on the biochemical behaviour of Gadolinium chelates and ionic forms, such that Radiology is actively considering the relevance of this to clinical practice.

In July 2015, the FDA issued a Safety Communication advising Radiologist and clinicians to make a number of specific considerations in their medical practice, and recommendations to patients. In summary (quotation of source listed below):

  • Health care professionals should consider limiting GBCA use to clinical circumstances in which the additional information provided by the contrast is necessary.
  • Health care professionals are urged to reassess the necessity of repetitive GBCA MRIs in established treatment protocols.
  • Patients, parents, and caregivers should talk to their health care professionals if they have any questions about the use of GBCAs with MRIs.
  • Healthcare professionals and patients are encouraged to report adverse events or side effects related to the use of these products to the FDA’s MedWatch Safety Information and Adverse Event Reporting Program: www.fda.gov/MedWatch/report

The FDA referred the matter to its National Center for Toxicological Research, to work with industry and the research community to understand the mechanisms and any potential adverse health effects. To this point the group has not reported.

The following links are provided to help locate the range of opinion and scientific reports on this evolving topic.

Some material is Open Access, some requires relevant subscriptions to journals, and some may be accessible to ResearchGate members

 

FDA Announcements
2015 July 27 2015 U.S. Food & Drug Administration. Safety Alert for Human medication. Drug Safety Communication – Gadolinium-based Contrast Agents.
http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm456012.htm OPEN ACCESS
 
Previous Reports Attributed to Pathologies, Now Considered Signs of Gadolinium Accumulation
2009 Roccatagliata L, Vuolo L, Bonzano L, Pichiecchio A, Mancardi GL.
Multiple sclerosis: hyperintense dentate nucleus on unenhanced T1-weighted MR images is associated with the secondary progressive subtype.
Radiology 2009;251(2):503-510.
http://pubs.rsna.org/doi/pdf/10.1148/radiol.2511081269 OPEN ACCESS
 
2011 Kasahara S, Miki Y, Kanagaki M, et al.
Hyperintense Dentate Nucleus on Unenhanced T1-weighted MR Images Is Associated with a History of Brain Irradiation.
Radiology 2011;258(1):222-228.
http://pubs.rsna.org/doi/pdf/10.1148/radiol.10100508 OPEN ACCESS
   
Observations of Brain High Signal Attributed to Gadolinium Accumulation
2014

Kanda T, Ishii K, Kawaguchi H, Kitajima K, Takenaka D.
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 2014;270(3):834-841
http://pubs.rsna.org/doi/pdf/10.1148/radiol.13131669 OPEN ACCESS

Errante Y, Cirimele V, Mallio CA, Di Lazzaro V, Zobel BB, Quattrochi CC.
Progressive increase of T1 signal intensity of the dentate nucleus on non-enhanced magnetic resonance images is associated with cumulative doses of Gadodiamide.
Invest Radiol 2014;49:685-690.
http://www.ncbi.nlm.nih.gov/pubmed/24872007 Abstract Open Access. Article, subscription required.

2015

Kanda T, Osawa M, Oba H, et al.
High Signal Intensity in Dentate Nucleus on Unenhanced T1-weighted MR Images: Association with Linear versus Macrocyclic Gadolinium Chelate Administration.
Radiology 2015;275(3):803-809.
http://pubs.rsna.org/doi/10.1148/radiol.14140364 Abstract Open Access. Article, subscription required.

Quattrocchi CC, Mallio CA, Errante Y, et al.
Gadodiamide and Dentate Nucleus T1 Hyperintensity in Patients With Meningioma Evaluated by Multiple Follow-Up Contrast-Enhanced Magnetic Resonance Examinations With No Systemic Interval Therapy.
Invest Radiol 2015;50(7):470-472.
http://www.ncbi.nlm.nih.gov/pubmed/25756685 Abstract Open Access. Article, subscription required.

Radbruch A, Weberling LD, Kieslich PJ, et al.
High-Signal Intensity in the Dentate Nucleus and Globus Pallidus on Unenhanced T1-Weighted Images: Evaluation of the Macrocyclic Gadolinium-Based Contrast Agent Gadobutrol.
Invest Radiol 2015;50(12):805-810.
http://www.ncbi.nlm.nih.gov/pubmed/26523910 Abstract Open Access. Article, subscription required.

McDonald RJ, McDonald JS, Kallmes DF, et al.
Intracranial Gadolinium Deposition after Contrast-enhanced MR Imaging.
Radiology 2015;275(3):772-782.
http://www.ncbi.nlm.nih.gov/pubmed/25742194
http://pubs.rsna.org/doi/pdf/10.1148/radiol.15150025 OPEN ACCESS

Kanda T, Fukusato T, Matsuda M, et al.
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 2015;276(1):228-232.
http://www.ncbi.nlm.nih.gov/pubmed/25942417
http://pubs.rsna.org/doi/pdf/10.1148/radiol.2015142690 Subscription Required

McDonald RJ, McDonald JS, Kallmes DF, et al.
Intracranial Gadolinium Deposition after Contrast-enhanced MR Imaging.
Radiology 2015;275(3):772-782.
http://pubs.rsna.org/doi/pdf/10.1148/radiol.15150025 Open Access

Robert P, Lehericy S, Grand S, et al.
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 2015;50(8):473-480.
http://www.ncbi.nlm.nih.gov/pubmed/26107651 Abstract
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4494686/ OPEN ACCESS

Ramalho J, Castillo M, AlObaidy M, et al.
High Signal Intensity in Globus Pallidus and Dentate Nucleus on Unenhanced T1-weighted MR Images: Evaluation of Two Linear Gadolinium-based Contrast Agents.
Radiology 2015;276(3):836-844.
http://pubs.rsna.org/doi/abs/10.1148/radiol.2015150872 Abstract Open Access. Article, subscription required.

Quattrocchi CC, Mallio CA, Errante Y, et al.
Gadodiamide and Dentate Nucleus T1 Hyperintensity in Patients With Meningioma Evaluated by Multiple Follow-Up Contrast-Enhanced Magnetic Resonance Examinations With No Systemic Interval Therapy.
Invest Radiol 2015;50(7):470-472.
http://www.ncbi.nlm.nih.gov/pubmed/25756685 Abstract Open Access. Article, subscription required.

Stojanov DA, Aracki-Trenkic A, Vojinovic S, Benedeto-Stojanov D, Ljubisavljevic S.
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 2015.
http://link.springer.com/article/10.1007%2Fs00330-015-3879-9 Abstract Open Access. Article, subscription required.

Critique of Stojanov 2015
Agris J, Pietsch H, Balzer T.
What Evidence Is There That Gadobutrol Causes Increasing Signal Intensity within the Dentate Nucleus and Globus Pallidus on Unenhanced T1W MRI in Patients with RRMS?
Eur Radiol 2015:1-2. OPEN ACCESS

Weberling LD, Kieslich PJ, Kickingereder P, et al.
Increased Signal Intensity in the Dentate Nucleus on Unenhanced T1-Weighted Images After Gadobenate Dimeglumine Administration.
Invest Radiol 2015;50(11):743-748.
http://www.ncbi.nlm.nih.gov/pubmed/26352749 Abstract Open Access. Article, subscription required.

Adin ME, Kleinberg L, Vaidya D, Zan E, Mirbagheri S, Yousem DM.
Hyperintense Dentate Nuclei on T1-Weighted MRI: Relation to Repeat Gadolinium Administration.
AJNR Am J Neuroradiol 2015;36(10):1859-1865. (online Aug 20 2015)
http://www.ncbi.nlm.nih.gov/pubmed/26294649 Abstract Open Access. Article, subscription required.

Miller JH, Hu HH, Pokorney A, Cornejo P, Towbin R.
MRI Brain Signal Intensity Changes of a Child During the Course of 35 Gadolinium Contrast Examinations. (Case Study)
Pediatrics 2015;136(6):e1637-1640.
http://www.ncbi.nlm.nih.gov/pubmed/26574593 Abstract Open Access. Article, subscription required.

Kanda T, Oba H, Toyoda K, Furui S.
Recent Advances in Understanding Gadolinium Retention in the Brain.
AJNR Am J Neuroradiol 2015 ahead of print
http://www.ajnr.org/content/early/2015/10/22/ajnr.A4586.long Open Access

Roberts DR, Holden KR.
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 2015. Ahead of print
http://www.ncbi.nlm.nih.gov/pubmed/26345358 Abstract Open Access. Article, subscription required

2016 Robert P, Violas X, Grand S, et al.
Linear Gadolinium-Based Contrast Agents Are Associated With Brain Gadolinium Retention in Healthy Rats.
Invest Radiol 2016;51(2):73-82.
http://www.ncbi.nlm.nih.gov/pubmed/26606549 Abstract Open Access. Article, subscription required.
   
Scientific Papers on Gadolinium Accumulation in Other Tissues
Bone  
2006 White GW, Gibby WA, Tweedle MF.
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 2006;41(3):272-278.
http://www.ncbi.nlm.nih.gov/pubmed/16481910 Abstract Open Access. Article, subscription required.
 
2009 Darrah TH, Prutsman-Pfeiffer JJ, Poreda RJ, Ellen Campbell M, Hauschka PV, Hannigan RE.
Incorporation of excess gadolinium into human bone from medical contrast agents.
Metallomics 2009;1(6):479-488.
http://pubs.rsc.org/en/content/articlelanding/2009/mt/b905145g/unauth#!divAbstract FREE ACCESS available with registration
Skin  
2010 George SJ, Webb SM, Abraham JL, Cramer SP.
Synchrotron X-ray analyses demonstrate phosphate-bound gadolinium in skin in nephrogenic systemic fibrosis.
Br J Dermatol 2010;163(5):1077-1081
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4334379/pdf/nihms219438.pdf Open Access
 
2012 Haylor J, Schroeder J, Wagner B, et al.
Skin Gadolinium Following Use of MR Contrast Agents in a Rat Model of Nephrogenic Systemic Fibrosis. Radiology 2012;263(1):107-116.
http://pubs.rsna.org/doi/pdf/10.1148/radiol.12110881 Open Access
 
2014 Gathings RM, Reddy R, Santa Cruz D, Brodell RT.
Gadolinium-associated plaques: A new, distinctive clinical entity.
JAMA Dermatology 2014.
http://www.ncbi.nlm.nih.gov/pubmed/25389795 Abstract Open Access. Article, subscription required.
   
Scientific Papers on GBCA Stability
 
Scientific reviews Regarding Gadolinium & GBCA Biochemistry
2001 Adding LC, Bannenberg GL, Gustafsson LE.
Basic experimental studies and clinical aspects of gadolinium salts and chelates.
Cardiovasc Drug Rev 2001;19(1):41-56.
http://www.ncbi.nlm.nih.gov/pubmed/11314600
http://onlinelibrary.wiley.com/doi/10.1111/j.1527-3466.2001.tb00182.x/epdf OPEN ACCESS
 
2008

Frenzel T, Lengsfeld P, Schirmer H, Hutter J, Weinmann HJ.
Stability of gadolinium-based magnetic resonance imaging contrast agents in human serum at 37 degrees C.
Invest Radiol 2008;43(12):817-828
http://www.ncbi.nlm.nih.gov/pubmed/19002053 Abstract Open Access, Article subscription required

Morcos SK.
Extracellular gadolinium contrast agents: differences in stability.
Eur J Radiol 2008;66(2):175-179.
http://www.ncbi.nlm.nih.gov/pubmed/18343072 Abstract Open Access. Article subscription required

2008

Perazella MA.
Tissue deposition of gadolinium and development of NSF: a convergence of factors.
Semin Dial 2008;21(2):150-154
http://onlinelibrary.wiley.com/doi/10.1111/j.1525-139X.2007.00403.x/abstract Abstract Open Access. Article, subscription required.

Sieber MA, Lengsfeld P, Frenzel T, et al.
Preclinical investigation to compare different gadolinium-based contrast agents regarding their propensity to release gadolinium in vivo and to trigger nephrogenic systemic fibrosis-like lesions.
Eur Radiol 2008;18(10):2164-2173.
http://link.springer.com/article/10.1007%2Fs00330-008-0977-y Open Access

2009

Idee JM, Port M, Robic C, Medina C, Sabatou M, Corot C.
Role of thermodynamic and kinetic parameters in gadolinium chelate stability.
J Magn Reson Imaging 2009;30(6):1249-1258.
http://onlinelibrary.wiley.com/doi/10.1002/jmri.21967/abstract Abstract Open Access. Article, subscription required

Leung N, Pittelkow MR, Lee CU, Good JA, Hanley MM, Moyer TP.
Chelation of gadolinium with deferoxamine in a patient with nephrogenic systemic fibrosis.
NDT Plus 2009;2(4):309-311.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4421246/ Open Access

Sherry AD, Caravan P, Lenkinski RE.
Primer on gadolinium chemistry.
J Magn Reson Imaging 2009;30(6):1240-1248.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2853020/ Open Access

2010

Panesar M, Boateng F, Patel SS, et al.
Transmetallation and gadolinium: do low iron stores prevent the development of nephrogenic systemic fibrosis in high-risk end-stage renal disease patients?
Hemodial Int 2010;14(3):289-294.
http://www.ncbi.nlm.nih.gov/pubmed/20662951 Abstract Open Access. Article, subscription required.

Greenberg SA.
Zinc Transmetallation and Gadolinium Retention after MR Imaging: Case Report.

Radiology 2010;257(3):670-673
http://pubs.rsna.org/doi/pdf/10.1148/radiol.10100560 OPEN ACCESS

2014 Fretellier N, Poteau N, Factor C, et al.
Analytical interference in serum iron determination reveals iron versus gadolinium transmetallation with linear gadolinium-based contrast agents.
Invest Radiol 2014;49(12):766-772.
http://www.ncbi.nlm.nih.gov/pubmed/24943092 Abstract Open Access. Article, subscription required.
   
Review Papers & Opinion Pieces
2015

Kanal E, Tweedle MF.
Residual or Retained Gadolinium: Practical Implications for Radiologists and Our Patients.
Radiology 2015;0(0):150805.
http://pubs.rsna.org/doi/pdf/10.1148/radiol.2015150805 Open Access

Herbert Y. Kressel, MD, Editor of Radiology, Alexander Radbruch, MD, JD, Robert J. McDonald, MD, PhD, Emanuel Kanal, MD, and Michael F. Tweedle, PhD,
Radiology Podcast discussing gadolinium-based contrast media
https://www.youtube.com/watch?v=gmgv6EvGw0o Open Access

RSNA.
Gadolinium may remain in the brain after contrast MRI. RSNA; 2015. (Press Release)
https://www2.rsna.org/timssnet/media/pressreleases/PDF/pressreleasePDF.cfm?ID=810 Open Access

Huckle JE, Altun E, Jay M, Semelka RC.
Gadolinium Deposition in Humans: When Did We Learn That Gadolinium Was Deposited In Vivo?
Invest Radiol 2015;Publish Ahead of Print.
http://www.ncbi.nlm.nih.gov/pubmed/26588463 Abstract Open Access. Article, subscription required.

Karabulut N. Gadolinium deposition in the brain: another concern regarding gadolinium-based contrast agents.
Diagn Interv Radiol 2015;21(4):269-270
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4498420/pdf/dir-21-4-269.pdf Open Access

Semelka R.
Working definition of Gadolinium deposition disease.
November 2015
http://gadoliniumtoxicity.com/2015/11/01/gadolinium-deposition-disease-gdd-in-patients-with-normal-renal-function/

Ramalho J, Semelka RC, Ramalho M, Nunes RH, AlObaidy M, Castillo M.
Gadolinium-Based Contrast Agent Accumulation and Toxicity: An Update.
AJNR Am J Neuroradiol 2015 (Dec 10 2015, ahead of print)
http://www.ajnr.org/content/early/2015/12/10/ajnr.A4615.long Open Access

   

Gadolinium: Environmental Studies
2010 Lawrence MG.
Detection of anthropogenic gadolinium in the Brisbane River plume in Moreton Bay, Queensland, Australia.
Mar Pollut Bull 2010;60(7):1113-1116.
http://www.sciencedirect.com/science/article/pii/S0025326X10001384 Abstract Open Access. Article, subscription required.
 
2011 Kulaksız S, Bau M.
Anthropogenic gadolinium as a microcontaminant in tap water used as drinking water in urban areas and megacities. Applied Geochemistry 2011;26(11):1877-1885.
http://www.sciencedirect.com/science/article/pii/S0883292711003222 Abstract Open Access. Article, subscription required.
 
2015 Lindner U, Lingott J, Richter S, Jiang W, Jakubowski N, Panne U.
Analysis of Gadolinium-based contrast agents in tap water with a new hydrophilic interaction chromatography (ZIC-cHILIC) hyphenated with inductively coupled plasma mass spectrometry.
Anal Bioanal Chem 2015;407(9):2415-2422.
http://link.springer.com/article/10.1007%2Fs00216-014-8368-5 Abstract Open Access. Article, subscription required.
 
2016 Lingott J, Lindner U, Telgmann L, Esteban-Fernandez D, Jakubowski N, Panne U.
Gadolinium-uptake by aquatic and terrestrial organisms-distribution determined by laser ablation inductively coupled plasma mass spectrometry.
Environmental Science: Processes & Impacts 2016. Ahead of print. Jan 2016
http://pubs.rsc.org/en/Content/ArticleLanding/2016/EM/C5EM00533G#!divAbstract Abstract Open Access. Article, subscription required.