Gadolinium in Humans Revisited: Emphasis on Gadolinium Deposition Disease - Part 1

In this second perspective I write for my web-site, I will revisit the subject that I have achieved recent notoriety on. Notoriety traditionally has meant fame and recognition, but more recently its use focuses on the tinging with scandal. I am using this second definition, but not because of me and this subject, but because of the perception of stakeholders nervous of this subject. There is nothing to be nervous of, and I will explain why below. In my previous version of this work published in the American Journal of Roentgenology, I separated the discussion into 4 types: 1) acute hypersensitivity reactions, 2) gadolinium depositing in the body that is apparently asymptomatic: gadolinium storage condition (GSC), 3) gadolinium toxicity: Gadolinium Deposition Disease (GDD), and 4) chronic gadolinium toxicity in renal failure patients: Nephrogenic Systemic Fibrosis. As this is a non-peer-reviewed perspective piece I am now unfettered to say what I actually think, without having to moderate descriptions to soothe the feelings of reviewers. I will point out areas where currently I express my opinion, that has not (yet) been scientifically proven. As I have gone into greater depth and with references in the earlier publication, I will focus more on unchartered territory in this piece, to give the reader my concept of where the future lies. Acute Hypersensitivity Reactions Acute hypersensitivity reactions occur with essentially everything that we encounter in our bodies, especially substances entering from the outside. Perhaps the most famous and well recognized of these reactions are the reactions to peanuts and to bee stings. A thought I have when critics tell me why have I not flushed out the immunology of GDD better, I have to muse on the fact that with 60 years of formal learning in immunology, there are more things being learned still with peanuts and with bee stings. Acute hypersensitivity reactions are generally divided into 3 categories: mild, moderate, and severe. For those of us who do not like minutia of detail, but larger pictures: a small nuisance not likely to kill you (a few hives), a definitely bothersome situation with only minimal likelihood of killing you (lots of hives, trouble breathing), and a situation that is very distressing and could well kill you (major breathing problems, cardiac problems, vascular collapse). Acute hypersensitivity reactions are mediated by products elaborated by cells, so I term this polypeptide-based. The well known products are histamine and antibodies. But there are a whole host of other products, that who knows what all they do: like cytokines, chemokines, growth hormone, and anti-tumor necrosis factors. Well trained immunologists probably have identifireed atleast 20 products, which tells me that there are probably at least 100. Mild reactions probably occur in 5% or so of patients, and with gadolinium based contrast agents (GBCAs) severe reactions occur in 1 in 1,000, with truly life-threatening severe reactions occuring in 1 in 100,000 to 300,000. This acute adverse reaction rate compares favorably with even the safest of over the counter (OTC) drugs. Considerable attention has been spent in Radiology to prevent (prophylaxis) and treat acute hypersensitivity reactions. Pre-treatment with a steroid regimen often over a 12 hour period is most frequently performed with patients considered at high risk: asthmatics, history of allergic reactions, in particular history of reactions to prior radiology contrast agents. Steroid treatment is recognized as likely having good effect at prevent mild acute hypersensitivity reactions, but has not been shown to prevent severe life-threatening reactions. In other words, all the time, expense and danger (of other drugs) of steroid pretreatment likely prevents reactions that are no big deal, but may not prevent reactions that are a really big deal. Here is where I differ from orthodoxy: I believe steroid pretreatment as currently done is a waste of time and money. Probably the only smart pretreatment is with drugs termed antihistamines, where benadryl is the classic drug used, given 1 hour prior to receiving the radiologic contrast agent. Probably the most sense though is just rapid recognition of hypersensitivity reaction and immediate treatment with an antihistamine. Here is the other thing, I am quite sure benadryl is not the best drug for this. Other drugs that have a wider suppressing effect on a greater range of acute hypersensitivity products released (cytokines, chemokines, etc). I do not have the knowledge or experience in this area, but probably agents such as claritin or singulair may be more appropriate agents: antihistamine action is not enough. The other point in which I differ from orthodoxy is I believe we are looking at the wrong types of patients as the at risk subjects. I agree that asthmatics and patients with prior severe reaction, especially to the type of contrast used, are high risk. The unrecognized high risk population is young (20-50 years), otherwise healthy white females. A few years back I embarked upon a study to examine who are the patients who actually die from acute hypersensitivity reactions from GBCAs. I identified 1 patient in the USA, 1 patient in the Netherlands, and 1 patient in Italy. All of them were relatively young females, otherwise apparently healthy, received the contrast agent, then died, even in hospital settings. I believe the factors in this case are that these women had very healthy immune systems, but hyper-reactive, what I term selective immune system hyper-responsiveness. In writing this I do not intend to cause panic in women in this category (which may represent essentially 90% of the readers of this article). You form the same group who would have this type of reaction to essentially any drug and any food type, etc, so it is impossible to cocoon yourself away from any harm. This awareness I direct really at health care providers: the patients now who I am most worried about who develop breathing rpoblems after a GBCA-enhanced study are youngish otherwise healthy individuals. Perhaps one of the reasons that they have died is that natural assumption is that since they are young and healthy they will quickly recover from this doubt of breathing or blood pressure issue. My opinion is their immune system is so robust that once it starts on a course of reaction it can quickly escalate out of control. Pay careful attention to young females who are showing considerable distress following a GBCA administration: treat early with an antihistamine, and treat earlier, than you would otherwise think necessary, with epinephrine. For all the patients out there - remember this is exceedingly rare, and may happen with anything, not just GBCAs. I mention this in some detail, because these patients are the same type who are most at risk for GDD (in my opinion at present). I also believe that acute hypersensitivity reactions are closely related to GDD in many other respects. Another similarity they share is that all types of GBCAs may result in both conditions. Gadolinium retained in the body: Gadolinium Storage Condition (GSC)

Essentially everyone who undergoes a GBCA-enhanced study is retaining some gadolinium in their body. After a single dose, the amount retained from a linear agent is atleast 4 times greater than from a macrocyclic agent. This may become more of an issue when more GBCA-enhanced studies are performed in the same individual, especially with linear agents. Brain deposition in the basal ganglia is a marker for significant retention of gadolinium, and most studies have shown that after 5 studies enhanced with linear agents, the presence of gadolinium is visible as bright tissue in the basal ganglia. There are a few things that I have found remarkable about gadolinium retention. Perhaps the most striking of which is that we all have historically believed, and I have consistently written in papers of mine, that 'free' gadolinium is toxic. If it is so toxic, why is it that, if we do the math, 300 million GBCA does have been administered, maybe this means 200 million patients have undergone GBCA administration, and of that 200 million perhaps 50 million have received multiple GBCA enhanced studies, so will have substantial gadolinium retained in their body, why are the great majority of these 50 million perfectly fine? This is one critical point to diminish public hysteria on gadolinium, for the great majority of us (which includes myself) gadolinium retained in the body is not making us sick. This would also be true for other heavy metals, in the modern era, likely the majority of us living in developed nations have some amount of retained heavy metals in our bodies: lead, mercury, chromium and arsenic to name a few. Yet even with those other heavy metals, ostensibly we are not sick from them. Clearly though, sickness is likely a dose-dependent phenomenon, but even more important is our host reaction to the presence of these heavy metals, again returning to my concept of selective immune system hyper-responsiveness. So my first point, is that we should not be in a panic about gadolinium left in our body : GSC. At the same time, it is reasonable to think that we should minimize the amount of gadolinium retained in our body, and this is where the decision of the European Medicines Agenecy to remove linear agents off the market is not an unreasonable position to take. After all, even though we may not be sick from the gadolinium now, what will happen when there are substantial physiologic changes in our body and gadolinium released from tissues where they are stored: bone in particular. Puberty, pregnancy, major injury, osteoporosis, to name the most common major physiologic changes. The great majority of the radiologic literature has focused on gadolinium retained in the brain. The short summary is: linear agents, especially if more than 5 studies enhanced with them have been performed, will result in visibly detectable gadolinium in the brain, agents that are progressively more stable deposit progressively less gadolinium. So an intermeidtae stability agent like Multihance probably becomes visible after 15-20 doses, and an extremely stable agent like Dotarem may not achieve significant enough retention in the body to be visible even after 50 studies. Studies by Gibby, White and most recently by Ken Maravilla's group have shown that by far the greater concentration of gadolinium is found in bone, maybe at least 20 times the concentration, than in brain. From Nephrogenic Systemic Fibrosis, and animal studies we know that skin also has a high concentration of gadolinium retained in it and in skin tissue substrate. If we then take concentration into consideration and combine this with the actual total size of the tissues: so total size of bone tissue vs skin tissue vs brain. From the concentration and size of these organs we can estimate what the actually quantity of gadolinium is in each of these structures. My estimates are that the percent amount of gadolinium in each of these organs is 40% for bone, 40% for skin and substrate, and probably not more than 2% for brain. My estimates for other organs includes 5% for spleen and 5% for liver. So all the attention on brain and yet the percent total of gadolinium in the brain is likely no more than 2%. The vast majority of gadolinium is in the bone and in the skin/skin substrate. This explains why most of the severe symptoms in sufferers of GDD are in these two tissues.

The third break from orthodoxy is that traditionally radiologists have considered that essentially all the gadolinium from the administered dose of GBCA is eliminated by the body after 24 and certainly after 48 hours, we now know this is not true. One obvious study that needs to be performed is to determine for each of the different agents individually: what is the 24 hour urine gadolinium content (the metric I prefer for determining mobilizable gadolinium in the body) over time. This is necessary to determine what the differences are between GSC patients and GDD patients, if any. The fourth subject is: can gadolinium be removed from the body once it is retained there? The answer we determined scientifically is: yes. We have reported in the peer-reviewed literature that chelation with Ca-/Zn-DTPA results in 10 to 20 fold increase in urine gadolinium content, compared to prior to chelation.

The wild card for GSC is what may happen to the individual if gadolinium is released at a time of major physiologic change? That is perhaps why, especially patients who have undergone multiple GBCA enhanced studies with linear agents, may consider chelation therapy to remove at least some or most of it. Read the continuation of this blog post -> Gadolinium Toxicity: Gadolinium Deposition Disease