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FDA identifies no harmful effects to date with brain retention of gadolinium-based contrast agents for MRIs


While many studies have given evidence that all GBCAs may be associated with some gadolinium retention in the brain and other body tissues, up to now such retention could not be linked to any adverse health effects. Accordingly, the FDA will not restrict the use of GBCAs, but it will continue to study their safety and will organize  a public meeting to discuss this issue in the future, the agency said in a news release.

The FDA further affirms its recommendations from July 2015 for health care professionals where it was already said that clinicians should limit their use to cases in which additional information yielded by the contrast agent is necessary and reassess the need for repetitive MRIs with GBCAs.

There are two different types of GBCAs, having linear or macrocyclic ligands. A review of the studies related to retention of GBCAs in different organs has reveled that that linear GBCAs retain more gadolinium in the brain than macrocyclic GBCAs. However, FDA's review did not identify adverse health effects related to this brain retention.

Gadolinium, a heavy metal, can be retained not only in the brain but also in other parts of the body such as in bone and skin. To date, the only identified adverse health effect related to gadolinium retention is a rare condition called nephrogenic systemic fibrosis (NSF) that occurs in a small subgroup of patients with pre-existing kidney failure that is responsible for limited excretion of GBCAs. FDA is also reviewing studies reporting of patients with normal kidneys who developed NSF after receiving GBCAs for an MRI. Some of these patients had retained gadolinium in their brains as well.

In order to support the ongoing review process, the FDA is urging  patients and health care professionals to report side effects involving GBCAs or other medicines to the FDA MedWatch program, using the information in the “Contact FDA” box at the bottom of the page:https://www.accessdata.fda.gov/scripts/medwatch/medwatch-online.htm.

Related studies (newest first)

Jennifer S. McDonald, Robert J. McDonald, Mark E. Jentoft, Michael A. Paolini, David L. Murray, David F. Kallmes, Laurence J. Eckel, Intracranial Gadolinium Deposition Following Gadodiamide-Enhanced Magnetic Resonance Imaging in Pediatric Patients: A Case-Control Study, JAMA Pediatr. (2017). doi: 10.1001/jamapediatrics.2017.0264.
[Epub ahead of print].

S. Bae, H.J. Lee, K. Han, Y.W. Park, Y.S. Choi, S.S. Ahn, et al. Gadolinium deposition in the brain: association with various GBCAs using a generalized additive model, Eur. Radiol. (2017)  Jan 12. doi: 10.1007/s00330-016-4724-5. [Epub ahead of print].

S. Ichikawa, U. Motosugi, Y. Omiya, H. Onishi, Contrast agent-induced high signal intensity in dentate nucleus on unenhanced T1-weighted images: comparison of gadodiamide and gadoxetic acid. Invest. Radiol.,  2017 Feb 11. doi: 10.1097/RLI.0000000000000360. [Epub ahead of print].

J. Kahn, H. Posch, I.G. Steffen, D. Geisel, C. Bauknecht, T. Liebig, Is there long-term signal intensity increase in the central nervous system on T1-weighted images after MR imaging with the hepatospecific contrast agent gadoxetic acid? a cross-sectional study in 91 patients. Radiology, 282 (2017) 708-716. doi: 10.1148/radiol.2016162535

H.H. Hu, A. Pokorney, R.B. Towbin, J.H. Miller, Increased signal intensities in the dentate nucleus and globus pallidus on unenhanced T1-weighted images: evidence in children undergoing multiple gadolinium MRI exams. Pediatr. Radio., 46 (2016) 1590-1598. doi: 10.1007/s00247-016-3646-3

D.R. Roberts, K.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 (2016) 331-336. doi: 10.1016/j.braindev.2015.08.009

N. Maximova, M. Gregori, F. Zennaro, A. Sonzogni, R. Simeone, D. Zanon, Hepatic gadolinium deposition and reversibility after contrast agent-enhanced MR imaging of pediatric hematopoietic stem cell transplant recipients. Radiology, 281 (2016) 418-426. doi: 10.1148/radiol.2016152846

N. Murata, L.F. Gonzalez-Cuyar, K. Murata, C. Fligner, R. Dills, D. Hippe, K.R. Maravilla, 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. Invest. Radiol., 51 (2016) 447-453. doi: 10.1097/RLI.0000000000000252

N. Murata, K. Murata, L.F. Gonzalez-CuyarF, K.R. Maravilla, Gadolinium tissue deposition in brain and bone. Magn. Reson. Imaging, 34 (2016) 1359-1365. doi: 10.1016/j.mri.2016.08.025

D.R. Roberts, S.M. Lindhorst, C.T. Welsh, K.R. Maravilla, M.N. Herring, K.A. Braun, B.H. Thiers, W.C. Davis, High levels of gadolinium deposition in the skin of a patient with normal renal function. Invest. Radiol., 51 (2016) 280-289. doi: 10.1097/RLI.0000000000000266

L.M. Burke, M. Ramalho, M. AlObaidy, E. Chang, M. Jay, R.C. Semelka, Self-reported gadolinium toxicity: A survey of patients with chronic symptoms. Magn. Reson. Imaging, 34 (2016) 1078-1080. doi: 10.1016/j.mri.2016.05.005

R.C. Semelka, J. Ramalho, A. Vakharia, M. AlObaidy, L.M. Burke, M. Jay, M. Ramalho, Gadolinium deposition disease: initial description of a disease that has been around for a while. Magn. Reson. Imaging, 34 (2016) 1383-1390. doi: 10.1016/j.mri.2016.07.016

R.C. Semelka, M. Ramalho, M. AlObaidy, J. Ramalho, Gadolinium in humans: A family of disorders. AJR Am. J. Roentgenol., 207 (2016) 229-233. doi: 10.2214/AJR.15.15842

R.C. Semelka, C.W. Commander, M. Jay, L.M. Burke, M. Ramalho, Presumed gadolinium toxicity in subjects with normal renal function: a report of 4 cases. Invest. Radiol., 51 (2016) 661-665. doi: 10.1097/RLI.0000000000000318

A.A. Malayeri, K.M. Brooks, L.H. Bryant, R. Evers, P. Kumar, D.S. Reich,  D.A. Bluemke,  National Institutes of Health perspective on reports of gadolinium deposition in the brain. J. Am. Coll. Radiol., 13 (2016) 237-241. doi: 10.1016/j.jacr.2015.11.009

R.M. Gathings, R. Reddy, D.S. Cruz, R.T. Brodell, Gadolinium-associated plaques: a new, distinctive clinical entity. JAMA Dermatol., 151 (2015) 316-319. doi: 10.1001/jamadermatol.2014.2660

J.H. Miller, H.H. Hu, A. Pokorney, P. Cornejo, R. Towbin, MRI brain signal intensity changes of a child during the course of 35 gadolinium contrast examinations. Pediatrics, 136 (2015) e1637-40. doi: 10.1542/peds.2015-2222

T. Kanda, T. Fukusato, M. Matsuda, K. Toyoda, H. Oba, J. Kotoku, T. Haruyama, K. Kitajima, S. 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.20151452690

R.J. McDonald, J.S. McDonald, D.F. Kallmes, M.E. Jentoft, D.L. Murray, K.R. Thielen, E.E. Williamson, L.J. Eckel,  Intracranial gadolinium deposition after contrast-enhanced MR imaging. Radiology, 275/3 (2015) 772-782. doi: 10.1148/radiol.15150025

M. Girardi, J. Kay, D.M. Elston, P.E. Leboit, A. Abu-Alfa, S.E. Cowper SE. Nephrogenic systemic fibrosis: clinicopathological definition and workup recommendations. J. Am. Acad. Dermatol., 65 (2011) 1095-1106. doi: 10.1016/j.jaad.2010.08.041

Related information

EMA: European Medicines Agency. Gadolinium-containing contrast agents
EMA: March 10, 2017: PRAC concludes assessment of gadolinium agents used in body scans and recommends regulatory actions, including suspension for some marketing authorisations
EMA: March 8, 2016: PRAC reviews gadolinium contrast agents used in MRI scans

FDA: Information on Gadolinium-Based Contrast Agents
FDA: July 27, 2015: FDA evaluating the risk of brain deposits with repeated use of gadolinium-based contrast agents for magnetic resonance imaging (MRI)

Related EVISA Resources

Brief summary: Speciation analysis for the study of metallodrugs and their biomolecular interactions
Link Database: Toxicity of Gadolinium compounds
Link database: Use of Gadolinium in pharmaceuticals
Materials Database: Gadolinium Materials
Link page: All about Mass Spectrometry: Resources related to Mass Spectrometry

Related EVISA News

March 11, 2017: European Medicines Agency recomments to pull linear Gadolinium-based MRI contrast agents from market 
April 10, 2016: New Studies Question Safety of MRI Contrast Agents
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: May 24, 2017


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