Advertisement

Journal of Medical Toxicology

, Volume 15, Issue 1, pp 36–44 | Cite as

Evaluating the Patient with Reported Gadolinium-Associated Illness

  • Tatyana Lyapustina
  • Charlotte Goldfine
  • Sean Rhyee
  • Kavita M. Babu
  • Matthew K. GriswoldEmail author
Review
First Online:

Abstract

Introduction

Gadolinium-based contrast agents (GBCAs) have been increasingly used in clinical practice since their introduction in the 1980s. Recently, increased public attention has been given to patients who report new symptoms following GBCA exposure. This review details the current knowledge surrounding GBCAs, with a focus on the known and proposed disease states that may be associated with GBCAs. Recommendations for the appropriate clinical workup of a patient suspected of having symptoms attributable to gadolinium exposure are included.

Discussion

GBCAs are known to precipitate the disease state nephrogenic systemic fibrosis (NSF), a syndrome characterized by skin thickening in patients with preexisting renal disease. An additional syndrome, termed gadolinium deposition disease, has been proposed to describe patients with normal renal function who develop an array of symptoms following GBCA exposure. While there is a potential physiologic basis for the development of this condition, there is no conclusive evidence to support a causal relationship between GBCA administration and the reported symptoms yet. Clinical evaluation revolves around focused history-taking and physical examination, given the absence of a reliable link between patient symptoms and measured gadolinium levels. There are no recommended treatments for suspected gadolinium deposition disease. Chelation therapy, which is not approved for this indication, carries undue risk without documented efficacy.

Conclusions

The extent to which GBCAs contribute to clinically relevant adverse effects remains an important and evolving field of study. NSF remains the only proven disease state associated with GBCA exposure. Additional data are required to evaluate whether other symptoms should be attributed to GBCAs.

Keywords

Gadolinium Gadolinium deposition disease Nephrogenic systemic fibrosis Gadolinium-based contrast Magnetic resonance imaging 
This is a preview of subscription content, log in to check access.

Notes

Funding Source

The authors received no sources of funding for this research.

Compliance with Ethical Standards

Previous Presentations

This research has not previously been presented in any form.

Conflict of Interest

None

References

  1. 1.
    Knopp MV, Balzer T, Esser M, Kashanian FK, Paul P, Niendorf HP. Assessment of utilization and pharmacovigilance based on spontaneous adverse event reporting of gadopentetate dimeglumine as a magnetic resonance contrast agent after 45 million administrations and 15 years of clinical use. Investig Radiol. 2006;41(6):491–9.Google Scholar
  2. 2.
    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):834–41.PubMedGoogle Scholar
  3. 3.
    Weberling LD, Kieslich PJ, Kickingereder P, Wick W, Bendszus M, Schlemmer H-P, et al. Increased signal intensity in the dentate nucleus on unenhanced T1-weighted images after gadobenate dimeglumine administration. Investig Radiol. 2015;50(11):743–8.Google Scholar
  4. 4.
    Errante Y, Cirimele V, Mallio CA, Di Lazzaro V, Zobel BB, Quattrocchi CC. Progressive increase of T1 signal intensity of the dentate nucleus on unenhanced magnetic resonance images is associated with cumulative doses of intravenously administered gadodiamide in patients with Normal renal function, suggesting dechelation. Investig Radiol. 2014;49(10):685–90.Google Scholar
  5. 5.
    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):479–88.PubMedGoogle Scholar
  6. 6.
    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. Investig Radiol. 2006;41(3):272–8.Google Scholar
  7. 7.
    Murata N, Gonzalez-Cuyar LF, Murata K, Fligner C, Dills R, Hippe D, 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. Investig Radiol. 2016;51(7):447–53.Google Scholar
  8. 8.
    McDonald RJ, McDonald JS, Kallmes DF, Jentoft ME, Murray DL, Thielen KR, et al. Intracranial gadolinium deposition after contrast-enhanced MR imaging. Radiology. 2015;275(3):772–82.PubMedGoogle Scholar
  9. 9.
    Kanda T, Fukusato T, Matsuda M, Toyoda K, Oba H, Kotoku J, 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):228–32.PubMedGoogle Scholar
  10. 10.
    Jensen EC. Technical review, types of imaging, part 4-magnetic resonance imaging. Anat Rec 2nd ed. 2014;297(6):973–8.Google Scholar
  11. 11.
    Zamora CA, Castillo M. Historical perspective of imaging contrast agents. Magn Reson Imaging Clin N Am. 2017;25(4):685–96.PubMedGoogle Scholar
  12. 12.
    Idée J-M, Port M, Raynal I, Schaefer M, Le Greneur S, Corot C. Clinical and biological consequences of transmetallation induced by contrast agents for magnetic resonance imaging: a review. Fundam Clin Pharmacol. 2006;20(6):563–76.PubMedGoogle Scholar
  13. 13.
    Rogosnitzky M, Branch S. Gadolinium-based contrast agent toxicity: a review of known and proposed mechanisms. Biometals. 2016;29(3):365–76.PubMedPubMedCentralGoogle Scholar
  14. 14.
    Cacheris WP, Quay SC, Rocklage SM. The relationship between thermodynamics and the toxicity of gadolinium complexes. Magn Reson Imaging. 1990;8(4):467–81.PubMedGoogle Scholar
  15. 15.
    Runge VM, Clanton JA, Lukehart CM, Partain CL, James AE. Paramagnetic agents for contrast-enhanced NMR imaging: a review. AJR Am J Roentgenol. 1983;141(6):1209–15.PubMedGoogle Scholar
  16. 16.
    OECD. OECD Health Data: Health care resources. Paris: OECD Publishing; 2016. p. 1–1.Google Scholar
  17. 17.
    Shankar PR, Parikh K, Davenport MS. Financial implications of revised ACR guidelines for estimated glomerular filtration rate testing before contrast-enhanced MRI. J Am Coll Radiol. 2018;15(2):250–7.PubMedGoogle Scholar
  18. 18.
    Bellin M-F, Van Der Molen AJ. Extracellular gadolinium-based contrast media: an overview. Eur J Radiol. 2008;66(2):160–7.PubMedGoogle Scholar
  19. 19.
    Davenport MS. Choosing the safest gadolinium-based contrast medium for MR imaging: not so simple after all. Radiology. 2018;286(2):483–5.PubMedGoogle Scholar
  20. 20.
    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. 2016;37(7):1192–8.PubMedGoogle Scholar
  21. 21.
    Food and Drug Administration. Magnevist (gadopentetate dimeglumine) injection label. 2010;:1–10.Google Scholar
  22. 22.
    Food and Drug Administration. MultiHance (gadobenate dimeglumine) Injection and MultiHance Multipack (gadobenate dimeglumine) Injection. 2018;:1–34.Google Scholar
  23. 23.
    Food and Drug Administration. Omniscan (gadodiamide) injection label. 2010;:1–8.Google Scholar
  24. 24.
    Anderson A. NDA 022090 Eovist Gadolinium Warning 27Dec2017 USPI DRAFT. 2018;:1–15.Google Scholar
  25. 25.
    Ersoy H, Rybicki FJ. Biochemical safety profiles of gadolinium-based extracellular contrast agents and nephrogenic systemic fibrosis. J Magn Reson Imaging. 2007;26(5):1190–7.PubMedPubMedCentralGoogle Scholar
  26. 26.
    Haneder S, Kucharczyk W, Schoenberg SO, Michaely HJ. Safety of magnetic resonance contrast media: a review with special focus on nephrogenic systemic fibrosis. Top Magn Reson Imaging. 2015;24(1):57–65.PubMedGoogle Scholar
  27. 27.
    Cochran ST, Bomyea K, Sayre JW. Trends in adverse events after IV administration of contrast media. AJR Am J Roentgenol. 2001;176(6):1385–8.PubMedGoogle Scholar
  28. 28.
    Bottinor W, Polkampally P, Jovin I. Adverse reactions to iodinated contrast media. Int J Angiol. 2013;22(3):149–54.PubMedPubMedCentralGoogle Scholar
  29. 29.
    Murphy KJ, Brunberg JA, Cohan RH. Adverse reactions to gadolinium contrast media: a review of 36 cases. AJR Am J Roentgenol. 1996;167(4):847–9.PubMedGoogle Scholar
  30. 30.
    Nelson KL, Gifford LM, Lauber-Huber C, Gross CA, Lasser TA. Clinical safety of gadopentetate dimeglumine. Radiology. 1995;196(2):439–43.PubMedGoogle Scholar
  31. 31.
    Cowper SE, Robin HS, Steinberg SM, Su LD, Gupta S, LeBoit PE. Scleromyxoedema-like cutaneous diseases in renal-dialysis patients. Lancet. 2000;356(9234):1000–1.PubMedGoogle Scholar
  32. 32.
    Grobner T. Gadolinium--a specific trigger for the development of nephrogenic fibrosing dermopathy and nephrogenic systemic fibrosis? Nephrol Dial Transplant. 2006;21(4):1104–8.PubMedGoogle Scholar
  33. 33.
    Kribben A, Witzke O, Hillen U, Barkhausen J, Daul AE, Erbel R. Nephrogenic systemic fibrosis: pathogenesis, diagnosis, and therapy. J Am Coll Cardiol. 2009;53(18):1621–8.PubMedGoogle Scholar
  34. 34.
    Joffe P, Thomsen HS, Meusel M. Pharmacokinetics of gadodiamide injection in patients with severe renal insufficiency and patients undergoing hemodialysis or continuous ambulatory peritoneal dialysis. Acad Radiol. 1998;5(7):491–502.PubMedGoogle Scholar
  35. 35.
    Frenzel T, Lengsfeld P, Schirmer H, Hütter J, Weinmann H-J. Stability of gadolinium-based magnetic resonance imaging contrast agents in human serum at 37 degrees C. Investig Radiol. 2008;43(12):817–28.Google Scholar
  36. 36.
    Abraham JL, Thakral C, Skov L, Rossen K, Marckmann P. Dermal inorganic gadolinium concentrations: evidence for in vivo transmetallation and long-term persistence in nephrogenic systemic fibrosis. Br J Dermatol Wiley/Blackwell (10.1111); 2007 Dec 7;158(2):273–80.Google Scholar
  37. 37.
    Broome DR. Nephrogenic systemic fibrosis associated with gadolinium based contrast agents: a summary of the medical literature reporting. Eur J Radiol. 2008;66(2):230–4.PubMedGoogle Scholar
  38. 38.
    Leiner T, Kucharczyk W. NSF prevention in clinical practice: summary of recommendations and guidelines in the United States, Canada, and Europe. J Magn Reson Imaging. 2009;30(6):1357–63.PubMedGoogle Scholar
  39. 39.
    Zou Z, Zhang HL, Roditi GH, Leiner T, Kucharczyk W, Prince MR. Nephrogenic systemic fibrosis. JACC Cardiovasc Imaging. 2011;4(11):1206–16.PubMedGoogle Scholar
  40. 40.
    Bennett CL, Qureshi ZP, Sartor AO, Norris LB, Murday A, Xirasagar S, et al. Gadolinium-induced nephrogenic systemic fibrosis: the rise and fall of an iatrogenic disease. Clin Kidney J. 2012;5(1):82–8.PubMedPubMedCentralGoogle Scholar
  41. 41.
    Altun E, Martin DR, Wertman R, Lugo-Somolinos A, Fuller ER, Semelka RC. Nephrogenic systemic fibrosis: change in incidence following a switch in gadolinium agents and adoption of a gadolinium policy--report from two U.S. universities. Radiology. 2009;253(3):689–96.PubMedGoogle Scholar
  42. 42.
    Semelka RC, Ramalho J, Vakharia A, AlObaidy M, Burke LM, Jay M, et al. Gadolinium deposition disease: initial description of a disease that has been around for a while. Magn Reson Imaging. 2016;34(10):1383–90.PubMedGoogle Scholar
  43. 43.
    Semelka RC, Commander CW, Jay M, Burke LMB, Ramalho M. Presumed gadolinium toxicity in subjects with Normal renal function. Investig Radiol. 2016;51(10):661–5.Google Scholar
  44. 44.
    Roberts DR, Lindhorst SM, Welsh CT, Maravilla KR, Herring MN, Adam Braun K, et al. High levels of gadolinium deposition in the skin of a patient with Normal renal function. Investig Radiol. 2016;51(1):280–9.Google Scholar
  45. 45.
    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. Pediatrics. 2015;136(6):e1637–40.PubMedGoogle Scholar
  46. 46.
    Semelka RC, Ramalho M, AlObaidy M, Ramalho J. Gadolinium in humans: a family of disorders. AJR Am J Roentgenol. 2016;207(2):229–33.PubMedGoogle Scholar
  47. 47.
    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):503–10.PubMedGoogle Scholar
  48. 48.
    Kasahara S, Miki Y, Kanagaki M, Yamamoto A, Mori N, Sawada T, et al. Hyperintense dentate nucleus on unenhanced T1-weighted MR images is associated with a history of brain irradiation. Radiology. 2011;258(1):222–8.PubMedGoogle Scholar
  49. 49.
    Hill AB. The environment and disease: association or causation? Proc R Soc Med. 1965;58(5):295–300.PubMedPubMedCentralGoogle Scholar
  50. 50.
    Thakral C, Abraham JL. Nephrogenic systemic fibrosis: histology and gadolinium detection. Radiol Clin N Am. 2009;47(5):841–53–vi–vii–53.PubMedGoogle Scholar
  51. 51.
    Food and Drug Administration. FDA identifies no harmful effects to date with brain retention of gadolinium-based contrast agents for MRIs; review to continue. 2017;:1–4.Google Scholar
  52. 52.
    Girardi M, Kay J, Elston DM, LeBoit PE, Abu-Alfa A, Cowper SE. Nephrogenic systemic fibrosis: clinicopathological definition and workup recommendations. J Am Acad Dermatol. 2011;65(6):1095–7.PubMedGoogle Scholar
  53. 53.
    Leikin JB, Mycyk MB, Bryant S, Cumpston K, Hurwitz S. Characteristics of patients with no underlying toxicologic syndrome evaluated in a toxicology clinic. J Toxicol Clin Toxicol. 2004;42(5):643–8.PubMedGoogle Scholar
  54. 54.
    Naranjo CA, Busto U, Sellers EM, Sandor P, Ruiz I, Roberts EA, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther. 1981;30(2):239–45.PubMedGoogle Scholar
  55. 55.
    Burke LMB, Ramalho M, AlObaidy M, Chang E, Jay M, Semelka RC. Self-reported gadolinium toxicity: a survey of patients with chronic symptoms. Magn Reson Imaging. 2016;34(8):1078–80.PubMedGoogle Scholar
  56. 56.
    Christensen KN, Lee CU, Hanley MM, Leung N, Moyer TP, Pittelkow MR. Quantification of gadolinium in fresh skin and serum samples from patients with nephrogenic systemic fibrosis. J Am Acad Dermatol. 2011;64(1):91–6.PubMedGoogle Scholar
  57. 57.
    Aime S, Caravan P. Biodistribution of gadolinium-based contrast agents, including gadolinium deposition. J Magn Reson Imaging. 2009;30(6):1259–67.PubMedPubMedCentralGoogle Scholar
  58. 58.
    TEST ID: GDU [Internet]. mayomedicallaboratories.com. [cited 2018 Jun 3]. Available from: https://www.mayomedicallaboratories.com/test-catalog/2011/Clinical+and+Interpretive/89301. Accessed 3 June 2018.
  59. 59.
    Telgmann L, Sperling M, Karst U. Determination of gadolinium-based MRI contrast agents in biological and environmental samples: a review. Anal Chim Acta. 2013;764:1–16.PubMedGoogle Scholar
  60. 60.
    Silberzweig JI, Chung M. Removal of gadolinium by dialysis: review of different strategies and techniques. J Magn Reson Imaging. 2009;30(6):1347–9.PubMedGoogle Scholar
  61. 61.
    Mendoza FA, Artlett CM, Sandorfi N, Latinis K, Piera-Velazquez S, Jimenez SA. Description of 12 cases of nephrogenic fibrosing dermopathy and review of the literature. Semin Arthritis Rheum. 2006;35(4):238–49.PubMedPubMedCentralGoogle Scholar
  62. 62.
    Basak P, Jesmajian S. Nephrogenic systemic fibrosis: current concepts. Indian J Dermatol. 2011;56(1):59–64.PubMedPubMedCentralGoogle Scholar
  63. 63.
    Williams S, Grimm H, editors. Treatment possibilities for gadolinium toxicity. 2014. Available from: https://gadoliniumtoxicity.com/help/treatments/. Accessed 3 June 2018.
  64. 64.
    Liu H, Yuan L, Yang X, Wang K. La3+, Gd3+ and Yb3+ induced changes in mitochondrial structure, membrane permeability, cytochrome c release and intracellular ROS level. Chem Biol Interact. 2003;146(1):27–37.PubMedGoogle Scholar
  65. 65.
    Rees JA, Deblonde GJP, An DD, Ansoborlo C, Gauny SS, Abergel RJ. Evaluating the potential of chelation therapy to prevent and treat gadolinium deposition from MRI contrast agents. Sci Rep. 2018;8(1):4419.PubMedPubMedCentralGoogle Scholar
  66. 66.
    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):309–11.PubMedPubMedCentralGoogle Scholar
  67. 67.
    Greenberg SA. Zinc transmetallation and gadolinium retention after MR imaging: case report. Radiology. 2010;257(3):670–3.PubMedGoogle Scholar
  68. 68.
    Centers for Disease Control and Prevention (CDC). Deaths associated with hypocalcemia from chelation therapy—Texas, Pennsylvania, and Oregon, 2003-2005. MMWR Morb Mortal Wkly Rep. 2006;55(8):204–7.Google Scholar
  69. 69.
    Hamenl Pharmaceuticals Package Insert - Instructions for use: Pentetate calcium trisodium injection [Internet]. [cited 2018 Jun 16]. Available from: https://orise.orau.gov/reacts/documents/calcium-dtpa-package-insert.pdf. Accessed 3 June 2018.

Copyright information

© American College of Medical Toxicology 2018

Authors and Affiliations

  1. 1.University of Connecticut Medical SchoolHartfordUSA
  2. 2.University of Massachusetts Medical SchoolWorcesterUSA
  3. 3.Department of Emergency MedicineHartford HospitalHartfordUSA

Personalised recommendations

Cite article

Buy options