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Evaluating the Patient with Reported Gadolinium-Associated Illness

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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.

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References

  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.

    Article  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  10. Jensen EC. Technical review, types of imaging, part 4-magnetic resonance imaging. Anat Rec 2nd ed. 2014;297(6):973–8.

    Article  Google Scholar 

  11. Zamora CA, Castillo M. Historical perspective of imaging contrast agents. Magn Reson Imaging Clin N Am. 2017;25(4):685–96.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  13. Rogosnitzky M, Branch S. Gadolinium-based contrast agent toxicity: a review of known and proposed mechanisms. Biometals. 2016;29(3):365–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  16. OECD. OECD Health Data: Health care resources. Paris: OECD Publishing; 2016. p. 1–1.

    Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  18. Bellin M-F, Van Der Molen AJ. Extracellular gadolinium-based contrast media: an overview. Eur J Radiol. 2008;66(2):160–7.

    Article  PubMed  Google Scholar 

  19. Davenport MS. Choosing the safest gadolinium-based contrast medium for MR imaging: not so simple after all. Radiology. 2018;286(2):483–5.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  21. Food and Drug Administration. Magnevist (gadopentetate dimeglumine) injection label. 2010;:1–10.

  22. Food and Drug Administration. MultiHance (gadobenate dimeglumine) Injection and MultiHance Multipack (gadobenate dimeglumine) Injection. 2018;:1–34.

  23. Food and Drug Administration. Omniscan (gadodiamide) injection label. 2010;:1–8.

  24. Anderson A. NDA 022090 Eovist Gadolinium Warning 27Dec2017 USPI DRAFT. 2018;:1–15.

  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.

    Article  PubMed  PubMed Central  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  28. Bottinor W, Polkampally P, Jovin I. Adverse reactions to iodinated contrast media. Int J Angiol. 2013;22(3):149–54.

    Article  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  30. Nelson KL, Gifford LM, Lauber-Huber C, Gross CA, Lasser TA. Clinical safety of gadopentetate dimeglumine. Radiology. 1995;196(2):439–43.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  39. Zou Z, Zhang HL, Roditi GH, Leiner T, Kucharczyk W, Prince MR. Nephrogenic systemic fibrosis. JACC Cardiovasc Imaging. 2011;4(11):1206–16.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  49. Hill AB. The environment and disease: association or causation? Proc R Soc Med. 1965;58(5):295–300.

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Thakral C, Abraham JL. Nephrogenic systemic fibrosis: histology and gadolinium detection. Radiol Clin N Am. 2009;47(5):841–53–vi–vii–53.

    Article  PubMed  Google Scholar 

  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.

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  57. Aime S, Caravan P. Biodistribution of gadolinium-based contrast agents, including gadolinium deposition. J Magn Reson Imaging. 2009;30(6):1259–67.

    Article  PubMed  PubMed Central  Google Scholar 

  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. 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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  PubMed Central  Google Scholar 

  62. Basak P, Jesmajian S. Nephrogenic systemic fibrosis: current concepts. Indian J Dermatol. 2011;56(1):59–64.

    Article  PubMed  PubMed Central  Google Scholar 

  63. Williams S, Grimm H, editors. Treatment possibilities for gadolinium toxicity. 2014. Available from: https://gadoliniumtoxicity.com/help/treatments/. Accessed 3 June 2018.

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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.

    PubMed  PubMed Central  Google Scholar 

  67. Greenberg SA. Zinc transmetallation and gadolinium retention after MR imaging: case report. Radiology. 2010;257(3):670–3.

    Article  PubMed  Google Scholar 

  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. 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.

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Lyapustina, T., Goldfine, C., Rhyee, S. et al. Evaluating the Patient with Reported Gadolinium-Associated Illness. J. Med. Toxicol. 15, 36–44 (2019). https://doi.org/10.1007/s13181-018-0689-x

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