will anybody learn from the debacle?
or some months I have been following with interest the uproar about the finding of gadolinium deposits in brain tissue of some patients after serial MR examinations with nonspecific gadolinium agents.
The news broke when some radiologists saw high signal intensity stemming from the pituitary gland on T1-weighted MR images – on nonenhanced images. However, the patients had undergone several enhanced studies earlier in their life [1-3].
It is not clear whether gadolinium is still bound to the chelate of a contrast agent, whether it is elemental, or in another, newly formed compound; the latter seems most likely. There is strong evidence that the deposit of gadolinium can be traced back to the linear agents gadodiamide (Omniscan) and gadopentetate dimeglumine (Magnevist). Both of these compounds have already been involved in the NSF scandal ten years ago but are still on the market .
As early as 1988, at one of the first big and independent meetings on contrast agents development for MR imaging, Michael F. Tweedle pointed out that Magnevist could become unstable in vivo and release free gadolinium whereas macrocyclic compounds such as Gd- DO3A (ProHance) and Gd- DOTA (Dotarem) remain stable . At the same meeting researchers from the company producing Gd-DOTA presented similar results and stressed the importance of macrocyclic compounds “to minimize the in vivo dissociation process and avoid[s] potential biological disturbances produced by the presence of free species.” 
What happens to free gadolinium in the human body?
During the early preclinical development of Magnevist, Weinmann and his co-authors  compared the pharmacokinetics of Gd-DTPA and of gadolinium trichloride in rats. 80% of Gd-DTPA was excreted from the organism in urine within three hours, after seven days 90% of the dose was recovered in urine, another 7% in the feces. Less than 0.3% was found in the body, with 0.08% detected in the liver and 0.1% in the kidneys.
Only two percent of free gadolinium was excreted after seven days. The rest remained all over the body …
In the case of free gadolinium (i.e., gadolinium trichloride) only 2% was excreted after seven days. The rest remained all over the body, mostly in the liver and in the spleen, one sixth elsewhere. The conclusion was that chelates such as DTPA can be extremely effective to remove the highly toxic but diagnostically very helpful gadolinium from the body.
However, if the chelate doesn't work properly, patients might be at risk.
A major review on metal ion release from paramagnetic chelates (entitled What is tolerable?) published in late 1991 ended with the sentence :
"Although MRI contrast agents are unlikely to be administered repeatedly in patients, which could result in accumulation of metal ion, the long-term effects of such potential deposition have yet to be demonstrated."
Two years later, the results of animal experiments were published :
“Although intended for single administration in patients, gadodiamide injection has been studied extensively in a range of subchronic studies in rats and monkeys. The compound was well tolerated in monkeys even when administered at doses up to 1.25 mmol/kg daily for 28 consecutive days. In rats, significant toxicity occurred only at high doses ... the pattern of toxicity (involving the stomach, testes, and skin) suggested a disturbance of zinc metabolism.”
However, only rats injected with 50-fold the recommended clinical dose three times a week for three weeks developed severe lesions.
The amount of gadolinium one needs to enhance contrast in pathologies on T1-weighted MR images is minimal – particularly compared to the amounts of iodine needed for x-ray contrast agents. Nearly everybody believed what they were told: There were hardly any acute side effects; in general, “gado” is safer that iodinated x-ray contrast agents – which is true. As always with drugs, the dose and the galenics make the distinction between poison and remedy.
My first encounter with what would become Magnevist happened more than 30 years ago. At that time independent researchers at universities were more interested in the performance of such agents than in their safety, in particular because the safety was guaranteed by the manufacturers. We trusted the characteristics of, e.g., the Gadolinium-DTPA complex that were presented to us. The challenge was how to apply the compound within the given limits – which was worked out step by step.
Soon the new compounds were used for all conceivable kinds of examinations. One outstanding example is the follow-up of treatment of multiple sclerosis patients – in some instances MS patients underwent contrast enhanced studies once a month for two or three years. The general attitude for all medical or not-so-medical indications was: “Gado is a dye and can be used repetitively as often as possible.”
I still remember people in R&D, even companies' leading scientists, complaining that their hints and proposals were pushed aside by the marketing department and the management: "Off-label use is the responsibility of the doctors."
The recommended dose, best enhancement,
and MR angiography
On some of the first MR images in animals and in humans parts of the body were highlighted after the injection of Gd-DTPA, but others turned black. The pituitary gland became bright like a streetlight, the bladder dark. The question was: why; the answer was the correct dose to be injected.
Here the manufacturer of Magnevist was cautious and finally agreed upon 0.1 mmol/kg body weight. All other manufacturers followed this recommendation. This dose provides excellent enhancement at low and medium magnetic fields.
The reason is easily visible on the animated simulation shown in this figure (link).
A dose increase beyond the recommended dose may lead to loss of contrast. This is because a T2 shortening remains and can take over primary influence upon image contrast.
Parallel to the nonspecific gadolinium agents, angiographic blood pool agents were being developed because non-enhanced imaging technologies did not fulfill the requirements for high-resolution angiography. The manufacturers anticipated a substantial market because contrast-enhanced MR angiography was to cut a big slice out of the conventional and CT angiography cake. Yet, the development of the blood pool agents was slow and plagued by setbacks.
Then, suddenly a group of doctors proposed the use of the existing nonspecific agents together with special patented techniques and hardware to perform MR angiography. They all underlined that high-dose gadolinium chelates (up to 0.3 mmol/ kg) were significantly less nephrotoxic than iodinated contrast agents . In a textbook of contrast enhanced MR angiography, Martin R. Prince, Thomas M. Grist and Jörg F. Debatin stated in 2003:
“From an image quality point of view, generally the more contrast the better… Gadolinium compounds have no clinically detectable nephrotoxicity. They can be used safely at the maximum dose in patients with renal failure.” 
Already in a US patent applied for in 1993, one finds the following description:
“The dose of the gadolinium chelate may be within the range of 0.05 millimoles/kilogram body weight to 0.7 millimoles/kilogram body weight depending upon the time required to obtain the image. It should be noted that the dose of the contrast should not be too high such that there may be undesirable toxicity or T2 effects.” 
Since the companies involved neglected the patents, multimillion dollar lawsuits by the patent holders, then license, patent and consultancy agreements with numerous pharmaceutical and hardware companies followed .
Then, early in 2006, there was an outbreak of a new disease in Austria: Nephrogenic fibrosing dermopathy, later called Nephrogenic Systemic Fibrosis (NSF). Single cases had been described earlier, but not attributed to gadolinium:
“NFD was unknown before March 1997 and some authors suggest that the sudden occurrence of the disease in the last 8 years makes it likely that a new agent or technique of examination causes NFD/NSF” . All cases were related to Omniscan.
Among others, Martin R. Prince did an about-face and reacted with a paper describing fifteen patients who developed NSF after high-dose gadolinium-enhanced MR imaging compared to no patient with the standard dose. The conclusion of the paper included the following sentence :
“We recommend using no more than a standard dose of GBCA (0.1 mmol/ kg).”
Shortly after the publication of this article, a letter reached the editor of Radiology and was published. The author stated :
“The finding that all patients who developed NSF had received a high dose of a gadolinum-based contrast agent (GBCA), but none of the 74,124 who had received a standard dose (0.1 mmol per kilogram of body weight) developed NSF, irrespective of renal function, is of particular interest …
“Perhaps it is linked to the development of techniques that require the use of higher doses of GBCA, such as contrast agent-enhanced magnetic resonance (MR) angiography. For better visualization, especially of distal and small vessels, double or triple doses of GBCA are often advocated …
“This temporal coincidence may only be incidental, but it is nonetheless suggestive and may help to explain the somewhat mysterious timing of the appearance of NSF.”
This seemed not to be a serious problem for the manufacturers of Magnevist or Omniscan. These contrast agents are still available on the market today.
More so, the reaction of the US-American manufacturer of Omniscan against the publication of yet another NSF outbreak in a Danish trial consisted in an attempt to silence the radiologist in charge. He had presented the late side effects of the trial, i.e., death or mutilation of twenty patients. This was brought to the light by articles in Pro Publica and the Sunday Times .
As the English newspaper The Guardian reported, GE Healthcare dropped the libel action in 2010:
"Lawyers for leading Danish radiologist Henrik Thomsen said today: 'He will be obviously relieved. Now he won't have to worry about his future financial position, and won't have to keep looking over his shoulder before he says anything.' In agreed statements released today, Thomsen said: 'I stand by my publicly expressed opinion, based on my experience and research on published papers, that there is an association between the chemical formulation of gadolinium-based contrast agents and NSF.' He added: 'It was not my intention to suggest on the basis of the evidence then available to me that GE Healthcare had marketed Omniscan knowing that it might cause NSF.'" 
Still, more than ten years after the identification of the culprits, those responsible evade or dismiss the moral challenge they are confronted with, however plunge headfirst into new ones: gadolinium deposits in the brain.
Gadolinium deposits don't belong in the brain.
Admittedly nowadays one finds the following warning in the package insert: “Do not exceed the recommended dose of … and allow a sufficient period of time for elimination of the drug from the body prior to any readministration.” Yet, the positions of the US-American Food and Drug Administration and their European counterparts leave conflicting impressions, to say it politely; why don't they stop the sale of Omniscan and Magnevist to protect possible future victims?
The vultures are already circling in the air and the ambulance chasers flood the Internet with their websites: the lawyers are coming in great number. The motto is: “Are you gadolinium toxic? If yes, contact us.” They are rather clever and business minded. And they will soon find the arguments with which they will milk the manufacturers, the radiologists – and, most of all, their clients. They will argue like this:
Lack of background knowledge of the radiologists and their incredible trust in pharmaceutical companies; the almighty dollar sign; and use of an inappropriate and unsafe drug, too high a dose, too many serial studies, too close a study after another, examinations too often without proper indication; and, finally, off-label use.
Debacle is as good a word as any to describe what has happened here; and many of the parties involved try to sweep the problem under the rug: manufacturers, radiologists, and supposedly supervising administrations.
What is the clinical significance of gadolinium deposits in the brain and elsewhere? Nobody really knows. However, it doesn't belong there although at present there is no proof that it is harmful. NSF was a new iatrogenic disease. The (unlimited?) storage of gadolinium in the human body could be but a continuation of this disease. Already the idea attracts all hypochondriacs in town.
The recent events coincide with descriptions of the sudden appearance of gadolinium as anthropogenic contamination in tap water . The cause is the use of MR contrast agents; gadolinium cannot be removed by water treatment plants.
What I am afraid of are possible long-term consequences for all of us.
Important Note: Contrast enhanced MR examinations have life-saving benefits. I fully support the intravenous application of gadolinium-based contrast agents for diagnostic purposes. This is not an article against contrast enhanced MR imaging. However, please apply macrocyclic contrast agents and/or agents excreted by both the liver and the kidneys. Even they should only be used if a clear diagnostic advantage for the patient can be expected.
1. 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: 834–841.
2. 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: 803–809.
3. Radbruch A, Weberling LD, Pascal J, et al. Gadolinium retention in the dentate nucleus and globus pallidus is dependent on the class of contrast agent. Radiology 2015, 275: 783-791.
4. Rinck PA. Radiologists meet with heavy collateral damage. Rinckside 2008; 19,3: 7-10.
5. Tweedle MF. Work in progress toward nonionic macrocyclic gadolinium (III) complexes. in: Rinck PA (ed). Contrast and contrast agents in magnetic resonance imaging. Proceedings of Contrast and Contrast Agents in Magnetic Resonance Imaging – A Special Topic Seminar; Trondheim, Norway; 12-13 September 1988. Trondheim and Mons: The European Workshop on Magnetic Resonance in Medicine (EMRF). 1989. 65-73.
6. Meyer D, Schaefer M, Doucet D. Physico-chemical properties of the macrocyclic chelate Gadolinium-DOTA. in: Rinck PA (ed). Contrast and contrast agents in magnetic resonance imaging. Proceedings of Contrast and Contrast Agents in Magnetic Resonance Imaging – A Special Topic Seminar; Trondheim, Norway; 12-13 September 1988. Trondheim and Mons: The European Workshop on Magnetic Resonance in Medicine (EMRF). 1989. 33-43.
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11. Prince MR, Grist TM, Debatin JF. 3D contrast MR angiography. Berlin, New York: Springer Publishers. 3rd ed., 2003. 22-23.
12. Magnetic resonance arteriography with dynamic intravenous contrast agents. Inventor: Martin R. Prince, 202 Delafield St., Ann Arbor, Mich. 48105 [U.S.A.]. United States [of North America] Patent; Patent Number 5,417,213. Patent filed: 7 June 1993; patent granted: 23 May 1995.
13. Ersoy H, Zhang HL, Prince MR. Peripheral MR Angiography. Journal of Cardiovascular Magnetic Resonance. 2006; 8: 517–528.
14. Grobner T. Gadolinium – a specific trigger for the development of nephrogenic fibrosing dermopathy and nephrogenic systemic fibrosis? Nephrol Dial Transplant (2006) 21: 1104–1108. Important erratum: Nephrol Dial Transplant (2006) 21: 1745.
15. Prince MR, Zhang H, Morris M et al. Incidence of nephrogenic systemic fibrosis at two large medical centers. Radiology 2008; 248: 807–816.
16. Gossner J. Letter to the Editor (concerning Prince MR, et al. Radiology 2008; 248: 807-816) and response by Prince MR, et al. Radiology 2009; 251: 612-613.
17. Gerth J (ProPublica) and Ungoed-Thomas J (The Sunday Times). GE suit hushes scientist critical of Omniscan. www.propublica.org/article/ges-omniscan-lawsuit-ratchets-up-volume-in-british-libel-debate-1219; and: The Sunday Times, 19 December 2009.
18. Leigh D. US drug firm drops libel action against scientist. The Guardian. 18 February 2010. www.theguardian.com/science/2010/feb/18/ge-healthcare-henrik-thomsen-libel.
19. Tepe N, Romero M, Bau M. High-technology metals as emerging contaminants: Strong increase of anthropogenic gadolinium levels in tap water of Berlin, Germany, from 2009 to 2012. Applied Geochemistry 2014; 45: 191-197.