Gadolinium Toxicity

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July 21, 2017 – European Medical Authority takes action on Linear Contrast Agents.  Read all about it.

March 10, 2017 – European group recommends to stop using 4 linear GBCAs Read all about it.

February 27, 2017 – New Study Reports Gadolinium Retention in 70 Cases with Normal Kidney Function. Read all about it.

We have gathered information from hundreds of articles in the published literature related to Gadolinium and NSF which are referenced throughout the Background section.  Here, we will provide some of the highlights of our research findings.

The following information was presented in Appendix 2 of our Symptom Survey Report.

While our Survey of the Chronic Effects of Retained Gadolinium from Contrast MRIs is the first to report Gadolinium Retention in 17 patients with normal renal function, previously published studies also describe patients without severe renal impairment who retained Gadolinium, some for long periods of time.  Based on published literature, the symptoms reported by Survey participants are consistent with what is known about Gadolinium Toxicity.  The long-term effects of retained Gadolinium are unknown.

We have summarized information from related research below.

Gadolinium in Patients with Normal Renal Function

The following published studies found evidence of Gadolinium in brain, bone and skin tissues of patients without severe renal disease:

Gibby (2004) confirmed deposition of Gadolinium in bone tissue from patients with normal renal function 4 days after exposure to a GBCA.[1]

Darrah et al (2009) confirmed that Gadolinium, introduced in chelated form, incorporates into bone and is retained for longer than 8 years post-exposure.[2]

A Mayo Clinic study by Christensen et al (2011) found detectable concentrations of Gadolinium in fresh tissue specimens taken from two control subjects with normal renal function; both patients had previous GBCA exposure, one 8 months and the other 16 months before biopsy.[3]

Xia et al (2010) found Gadolinium-containing deposits present in brain tumor biopsies of patients without severe renal disease.  Insoluble deposits containing Gadolinium were found in 7 biopsies from 5 patients whose estimated GFRs were above 53 ml/min.  In two cases in which more than one biopsy from the same patient was analyzed, the later biopsies after more scans had higher amounts of Gadolinium than the earlier biopsies.[4]

Kanda et al (2013) found that abnormally high signal intensity detected in two regions of the brain on unenhanced T1-weighted images was related to the number of previous Gadolinium-based contrast enhanced MRIs that had been undergone by the population of patients with normal renal function.[5]

Symptoms of NSF Patients

While we could not find a comprehensive catalogue of NSF patient symptoms, articles regarding NFD/NSF describe both symptoms and affected body systems that are similar to those reported in this paper.

Cowper SE [ICNSFR Website on March 13, 2014] reports symptoms and signs of NSF that include swelling and tightening of skin, joint contractures, and skin changes described as reddened or darkened patches, papules, or plaques.  Skin may feel “woody” and resemble the texture of the peel of an orange. There may be burning, itching, or severe sharp pains in involved areas.  Muscle weakness often occurs.  Radiography may reveal calcification of the soft tissue.  Deep “bone pain” has been described in the hips and ribs.  Hand and foot swelling with blister-like lesions has been reported.  Some patients have yellow papules or plaques on or near the eyes.  Rapid, new onset fluctuating hypertension of unknown cause has been described prior to onset of the skin lesions.[6]

Ting et al (2003) report the first case of NFD with systemic involvement.  Autopsy revealed extensive fibrosis and calcification of the diaphragm, psoas muscle, renal tubules, and rete testes.  Also affected were the esophagus, lungs, kidneys, and myocardium of the left ventricle.[7]

Levine et al (2004) report 5 cases of NFD.  Patients had progressive induration and stiffening of limbs.  All had skin changes over affected muscles variably consisting of hyperpigmentation, erythematous patches, thickening, and tightening with a dimpled or furrowed appearance.  Lower limbs were affected in all patients, with pain reported as joint pain, and burning pain in legs and/or feet.  One patient had hardening of the muscles of the neck, back, arms, forearms, thighs and legs.  Jaw opening was affected in two patients.  All had chronic scleral injection (bloodshot eyes).[8]

Mendoza et al (2006) describe symptoms of 12 NFD patients that include: skin sclerosis and puckering, pruritus and burning, extremity swelling, difficulty swallowing, muscle induration, paresthesias or burning pain, aching or cramping, and joint flexion contractures.[9]

Kucher et al (2006) presented an NFD/NSF autopsy with fibrosis of the diaphragm and esophagus.[10]

Swaminathan et al (2008) reported unique cardiac and vascular events in NSF including sudden monocular blindness secondary to posterior ischemic optic neuropathy, limb ischemia, and recurrent cardiac arrhythmias.  They presented the first evidence that NSF is associated with systemic deposition of metals including gadolinium, iron, and aluminum, with the highest quantity of gadolinium deposited in the heart, blood vessels, and skin.[11]

Mayr et al (2009), in describing the clinical spectrum of NSF, write: “In summary, the involvement of subcutaneous structures such as fascia, muscle, tendons, periarticular tissue, and joints by NSF is well established by clinical and histopathology data.” [12]

Koreishi et al (2009) conducted a review of 4 NSF autopsy cases.  Besides cutaneous manifestations of NSF, some had calcification and fibrosis of the dura, thyroid, and heart including cardiac conduction system.  Fibrosis of the thyroid manifested clinically as hypothyroidism.[13]

Kanamalla and Boyko (2002) described progressive gadolinium diffusion into the vitreous and aqueous humors of the ocular globes, perivascular spaces, and the ventricles of the brain seen on fluid-attenuated inversion-recovery (FLAIR) MR imaging in patients with chronic renal failure.[14]

Barker-Griffith et al (2011) evaluated the previously unreported ophthalmic pathologic feature of two autopsy cases of NSF including Gadolinium deposition in the eye.[15]

Edgar et al (2010) report a case of NSF presenting as a progressive myopathy with minimal skin findings.  The patient developed limb stiffness, proximal weakness, and woody muscle texture.[16]

Sanyal et al (2011) conducted an autopsy-based review of one NSF case along with a review of published literature.  Insoluble Gd-phosphate deposits were detected in the skin, liver, lungs, intestinal wall, kidney, lymph node, skeletal muscle, dura mater and cerebellum of the NSF autopsy case, primarily in vascular walls.  The authors believed this to be the first case to document Gadolinium deposition in brain parenchyma in NSF.[17]

Zou and Ma (2011) reviewed 408 biopsy-confirmed cases of NSF.  Clinical features noted include: dermal pain, thickening and hardening, especially in lower extremities; sharp pains, burning or itching in affected areas; joint contractures or limited range of motion; “stiffness” without contractures; scleral plaque or injection.  Over one-third of patients were without contractures or limited range of motion; the authors felt this suggests that these patients had a mild form of NSF.[18]

Toxic Effects of Retained Gadolinium

It is widely recognized that NSF is essentially the manifestation of toxicity of Gadolinium released from Gd-containing contrast agents.[19]

Beyond NSF, little has been published about the toxic effects of Gadolinium retention in the human body.  Most of what is known about Gadolinium Toxicity comes from testing on animals.

Although the free Gadolinium ion is known to be toxic, Gadolinium is not listed as a toxic element by the CDC’s Agency for Toxic Substances & Disease Registry (ATSDR).  However, the symptoms reported in this paper are similar to those known to occur from exposure to other toxic metals.

Gabbiani et al (1966) found that all Rare Earth Elements (REEs) induce connective-tissue calcification at the site of subcutaneous injection.  “The induction of splenic calcification after intravenous administration appears to be typical of lanthanides”.[20] (Gadolinium is a lanthanide).

Spencer et al (1997) report on the toxicity of Gadolinium Chloride (GdCl3) in the rat.  After administration, major lesions consisted of mineral deposition in capillary beds (particularly lung and kidney).  Major toxic effects were also evident in the hematopoietic and lymphoid tissues, liver, and stomach.  Electron microscopy and x-ray microanalysis of the spleen and liver revealed electron-dense deposits in splenic macrophages, Kupffer cells, and hepatocytes composed of gadolinium, calcium, and phosphate.[21]

Adding et al (2001) noted in their review article that the non-complexed gadolinium ion is retained for long periods in the body.  They also note that toxicity studies have indicated that gadolinium can cause several “deleterious effects”.[22]

From A Primer on Gadolinium Chemistry (2009) – Gd3+ (gadolinium) has an ionic radius very nearly equal to that of Ca2+ (calcium).  This is one of the reasons why Gd3+ is so toxic in biological systems – Gd3+ can compete with Ca2+ in all biological systems that require Ca2+ for proper function and, in doing so, Gd3+ binds with much higher affinity.[23]

Vassallo et al (2011) found that mercury, lead and gadolinium, even at low doses or concentrations, affect vascular reactivity.[24]

Feng et al (2010) offered new insights into the mechanism of Gd-induced neurotoxicity. The results suggest that Gadolinium causes neuron cell apoptosis primarily by inhibiting mitochondrial function and inducing oxidative stress.[25]

Xia et al (2011) demonstrated that Gadolinium-induced cytotoxicity in neurons occurs via oxidative injury and endoplasmic reticulum (ER) stress-related signal transduction.[26]

Ibrahim et al (2006) present a review of heavy metal poisoning including clinical presentation. The most commonly involved organ systems include central nervous, gastrointestinal (GI), cardiovascular, hematopoietic, renal, and peripheral nervous systems.[27]

Medscape (2013) provides information on the clinical presentation of Mercury Toxicity including many of the symptoms reported in this paper.[28]

Liu et al (2013) review the neurotoxicity and biomarkers of lead.[29]

 

[1] Gibby, W. A., Gibby, K. A., & Gibby, W. A. (2004). Comparison of Gd DTPA-BMA (Omniscan) versus Gd HP-DO3A (ProHance) retention in human bone tissue by inductively coupled plasma atomic emission spectroscopy. Investigative Radiology, 39(3), 138–42. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/15076005

[2] Darrah, T. H., Prutsman-Pfeiffer, J. J., Poreda, R. J., Ellen Campbell, M., Hauschka, P. V, & Hannigan, R. E. (2009). Incorporation of excess gadolinium into human bone from medical contrast agents. Metallomics : integrated biometal science, 1(6), 479–88. Retrieved from http://pubs.rsc.org/en/content/articlehtml/2009/mt/b905145g

[3] Christensen, K. N., Lee, C. U., Hanley, M. M., Leung, N., Moyer, T. P., & Pittelkow, M. R. (2011). Quantification of gadolinium in fresh skin and serum samples from patients with nephrogenic systemic fibrosis. Journal of the American Academy of Dermatology, 64(1), 91–6. doi:10.1016/j.jaad.2009.12.044

[4] Xia, D., Davis, R. L., Crawford, J. A., & Abraham, J. L. (2010). 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 Radiologica (Stockholm, Sweden : 1987), 51(10), 1126–36. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/20868305

[5] Kanda, T., Ishii, K., Kawaguchi, H., Kitajima, K., & Takenaka, D. (2013). 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, 131669. doi:10.1148/radiol.13131669

[6] Cowper SE. Nephrogenic Systemic Fibrosis [ICNSFR Website]. 2001-2013. Available at http://www.icnsfr.org. Accessed 03/13/2014

[7] Ting, W. W., Stone, M. S., Madison, K. C., & Kurtz, K. (2003). Nephrogenic fibrosing dermopathy with systemic involvement. Archives of Dermatology, 139(7), 903–6. Retrieved from http://archderm.jamanetwork.com/article.aspx?articleid=479394

[8] Levine, J. M., Taylor, R. A., Elman, L. B., Bird, S. J., Lavi, E., Stolzenberg, E. D., McGarvey, M. L., et al. (2004). Involvement of skeletal muscle in dialysis-associated systemic fibrosis (nephrogenic fibrosing dermopathy). Muscle & nerve, 30(5), 569–77. doi:10.1002/mus.20153

[9] Mendoza, F. A., Artlett, C. M., Sandorfi, N., Latinis, K., Piera-Velazquez, S., & Jimenez, S. A. (2006). Description of 12 cases of nephrogenic fibrosing dermopathy and review of the literature. Seminars in arthritis and rheumatism, 35(4), 238–49. doi:10.1016/j.semarthrit.2005.08.002

[10] Kucher, C., Steere, J., Elenitsas, R., Siegel, D. L., & Xu, X. (2006). Nephrogenic fibrosing dermopathy/nephrogenic systemic fibrosis with diaphragmatic involvement in a patient with respiratory failure. Journal of the American Academy of Dermatology, 54(2 Suppl), S31–4. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/16427988

[11] Swaminathan, S., High, W. A., Ranville, J., Horn, T. D., Hiatt, K., Thomas, M., Brown, H. H., et al. (2008). Cardiac and vascular metal deposition with high mortality in nephrogenic systemic fibrosis. Kidney International, 73(12), 1413–8. Retrieved from http://dx.doi.org/10.1038/ki.2008.76

[12] Mayr, M., Burkhalter, F., & Bongartz, G. (2009). Nephrogenic Systemic Fibrosis: Clinical Spectrum of Disease. Journal of magnetic resonance imaging : JMRI, 30(6), 1289–97. doi:10.1002/jmri.21975

[13] Koreishi, A., & et al. (2009). Nephrogenic Systemic Fibrosis A Pathologic Study of Autopsy Cases. Arch Pathol Lab Med, 133(December), 1943–1948. Retrieved from http://www.archivesofpathology.org/doi/pdf/10.1043/1543-2165-133.12.1943

[14] Kanamalla, U. S., & Boyko, O. B. (2002). Gadolinium Diffusion into Orbital Vitreous and Aqueous Humor, Perivascular Space, and Ventricles in Patients with Chronic Renal Disease . American Journal of Roentgenology , 179 (5 ), 1350–1352. Retrieved from http://www.ajronline.org/content/179/5/1350.short

[15] Barker-Griffith, A., Goldberg, J., & Abraham, J. L. (2011). Ocular pathologic features and gadolinium deposition in nephrogenic systemic fibrosis. Archives of Ophthalmology, 129(5), 661–3. Retrieved from http://archopht.jamanetwork.com/article.aspx?articleid=427337

[16] Edgar, E., Woltjer, R., Whitham, R., Gultekin, S. H., Watnick, S., & Cupler, E. J. (2010). Nephrogenic systemic fibrosis presenting as myopathy: a case report with histopathologic correlation. Neuromuscular Disorders : NMD, 20(6), 411–3. Retrieved from http://www.nmd-journal.com/article/S0960-8966(10)00166-5/abstract

[17] Sanyal, S., Marckmann, P., Scherer, S., & Abraham, J. (2011). Multiorgan gadolinium (Gd) deposition and fibrosis in a patient with nephrogenic systemic fibrosis – an autopsy-based review. Nephrology Dialysis Transplant, (0), 1–11. Retrieved from http://ndt.oxfordjournals.org/content/early/2011/03/25/ndt.gfr085.full.pdf

[18] Zou, Z., & Ma, L. (2011). Nephrogenic systemic fibrosis: review of 408 biopsy-confirmed cases. Indian journal of dermatology, 56(1), 65–73. doi:10.4103/0019-5154.77556

[19] Todd, D. J., & Kay, J. (2008). Nephrogenic systemic fibrosis: an epidemic of gadolinium toxicity. Current rheumatology reports, 10(3), 195–204. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/18638427

[20] Gabbiani, G., Jacqmin, M. L., & Richard, R. M. (1966). Soft-tissue calcification induced by rare earth metals and its prevention by sodium pyrophosphate. British Journal of Pharmacology and Chemotherapy, 27(1), 1–9. Retrieved from http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1510795&tool=pmcentrez&rendertype=abstract

[21] Spencer, A. J., Wilson, S. A., Batchelor, J., Reid, A., Pees, J., & Harpur, E. (1997). Gadolinium Chloride Toxicity in the Rat . Toxicologic Pathology , 25 (3 ), 245–255. doi:10.1177/019262339702500301

[22] Adding, L. C., Bannenberg, G. L., & Gustafsson, L. E. (2006). Basic Experimental Studies and Clinical Aspects of Gadolinium Salts and Chelates. Cardiovascular Drug Reviews, 19(1), 41–56. Retrieved from http://onlinelibrary.wiley.com/doi/10.1111/j.1527-3466.2001.tb00182.x/pdf

[23] Sherry, A. D., Caravan, P., & Lenkinski, R. E. (2009). Primer on gadolinium chemistry. Journal of Magnetic Resonance Imaging : JMRI, 30(6), 1240–8. Retrieved from http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2853020&tool=pmcentrez&rendertype=abstract

[24] Vassallo, D., & et al. (2011). Toxic effects of mercury, lead and gadolinium on vascular reactivity. Braz J Med Biol Res, 44, 939–946. Retrieved from http://www.scielo.br/pdf/bjmbr/v44n9/1088.pdf

[25]Feng, X., Xia, Q., Yuan, L., Yang, X., & Wang, K. (2010). Impaired mitochondrial function and oxidative stress in rat cortical neurons: implications for gadolinium-induced neurotoxicity. Neurotoxicology, 31(4), 391–8. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/20398695

[26] Xia, Q., Feng, X., Huang, H., Du, L., Yang, X., & Wang, K. (2011). Gadolinium-induced oxidative stress triggers endoplasmic reticulum stress in rat cortical neurons. Journal of neurochemistry, 117(1), 38–47. doi:10.1111/j.1471-4159.2010.07162.x

[27] Ibrahim, D., Froberg, B., Wolf, A., & Rusyniak, D. (2006). Heavy Metal Poisoning: Clinical Presentations and Pathophysiology – Review 2006. Clin Lab Med 26, 67–97. doi:10.1016/j.cll.2006.02.003

[28] Mercury Toxicity Clinical Presentation. (n.d.). Retrieved March 5, 2014, from http://emedicine.medscape.com/article/1175560-clinical

[29] Liu, K., Hao, J., Zeng, Y., Dai, F., & Gu, P. (2013). Neurotoxicity and biomarkers of lead exposure: a review. Chinese medical sciences journal = Chung-kuo i hsüeh k’o hsüeh tsa chih / Chinese Academy of Medical Sciences, 28(3), 178–88. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/24074621


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