So why am I talking about an iceberg on the Gadolinium Toxicity website? Let me explain.
Not long after I started researching NSF and Gadolinium in early 2010, I saw a reference to an editorial by Dr. Henrik Thomsen of Denmark that had been published in 2008. The title was, Is NSF Only the Tip of the “Gadolinium Toxicity” Iceberg? The title caught my attention and really made me think. It took me a while, but I finally managed to find the editorial. After reading it, I had more questions than answers.
It seems that in the early 1990s, there was already concern about the stability of the nonionic linear GBCAs, and the macrocyclic agents were found to be significantly more stable in serum. It was known that transmetallation with other metal ions in the body was more apt to occur with the DTPA-based chelates, and when transmetallation occurs it results in the toxic Gadolinium ion remaining in the body. Dr. Thomsen asked, “Why were nonionic linear chelates chosen instead of macrocyclic chelate?” That is a very good question.
For those of us in the U.S., a better question might be, why did it take the FDA longer to react than the European Medicines Agency (EMEA) and the Japanese authorities? In 2007, the EMEA determined that Omniscan, Magnevist, and OptiMARK shouldn’t be used in patients with an eGFR <30 and it recommended that these agents should be used with caution in patients with moderately reduced kidney function (eGFRs 30-60). The Japanese authorities took the same position. Although the FDA required a boxed warning be included on all GBCA product labeling in 2007 to warn about the risk of NSF in patients with severe renal disease, it wasn’t until September of 2010 that the FDA announced that those same three linear agents (Omniscan, Magnevist, and OptiMARK) would be described as “inappropriate for use among patients with acute kidney injury or chronic severe kidney disease”.
Restricting the use of the linear agents in those with severe kidney disease or acute kidney injury was definitely the right thing to do. However, if the linear agents were found to be significantly less stable and more likely to undergo transmetallation, wouldn’t that also pose some degree of risk to patients with normal kidney function as well?
Dr. Thomsen noted that Gadolinium “accumulates in the bone of patients with normal kidney function” and that four times more accumulates after a less stable nonionic linear agent than a nonionic macrocyclic agent. He pointed out that nowadays patients undergo multiple contrast-enhanced MRI. He mentioned women with increased risk of breast cancer, but MS patients and those with certain types of brain tumors or cancers also have multiple contrast procedures. He said that “after each examination some Gadolinium will accumulate in the bone (and probably other tissues) and it will stay there for many years”.
Dr. Thomsen asked, “What will happen when the Gadolinium is released” from the bone? Since Gadolinium is known to deposit primarily in bone, how much will be released back into the body during periods of increased bone turnover? Interestingly, he said that “the release of high amounts of Gadolinium over a short period might cause the classic symptoms of Gadolinium Toxicity rather than NSF.” We believe that patients who retain less Gadolinium, like those with normal kidney function might do, also experience symptoms of Gadolinium Toxicity rather than NSF.
Thomsen said, “Long-term observation (e.g., 20 years) will be necessary before we can conclude anything about the safety of Gadolinium-based Contrast Agents, in particular those with lowest stability.” He said that “based on both the older and the most recent literature, it is possible that with NSF we have only seen the tip of the ‘Gadolinium Toxicity’ iceberg.”
He wrote that editorial in 2007-2008, and since then there has been additional evidence of Gadolinium retention in patients with normal kidney function. There is evidence that the macrocyclic agents also deposit in bone and other tissues of study animals, even in the absence of NSF-like skin lesions. And there are now cases of NSF linked to macrocyclic agents. I think that NSF is probably the worst manifestation of Gadolinium Toxicity, but nothing I have read in the literature makes me believe it will be the only one.
Some of us, including those with normal kidney function, are already on a collision course with that “Gadolinium Toxicity iceberg” that Dr. Thomsen mentioned, but it isn’t too late to save others from being harmed by it too. I believe there is ample evidence of a problem out there, now it’s time for someone to step up and do something about it.
Patient Access to Dr. Thomsen’s editorial can be obtained here: http://onlinelibrary.wiley.com/doi/10.1002/jmri.21478/pdf