Residents' Section
Clinical Perspective
Gadolinium in Humans: A Family of Disorders
Audio Available | 
Share
OBJECTIVE. The literature informs us that gadolinium can cause health issues. At least four major gadolinium disorders, including the two well-recognized nephrogenic systemic fibrosis and severe acute adverse event, have been identified.
CONCLUSION. We propose naming the histopathologically proven presence of gadolinium in brain tissue “gadolinium storage condition,” and we describe a new entity that represents symptomatic deposition of gadolinium in individuals with normal renal function, for which we propose the designation “gadolinium deposition disease.”
Keywords: gadolinium, MRI, toxicity
Gadolinium-based contrast agents (GBCAs) have been used extensively since their introduction into clinical practice in 1988. More than 200 million doses are estimated to have been administered worldwide [1]. All GBCAs approved for clinical use have been considered extremely safe when used at low doses (0.1–0.3 mmol/kg) in patients with normal renal function. The accumulated safety record is excellent, with serious adverse reactions occurring in roughly 0.03% of all administrations [2, 3]. However, despite the lack of clinical findings, evidence of in vivo gadolinium deposition has long been recognized [4–7]. The first major study reporting gadolinium deposition in patients with renal failure was published in 1998 [4]. In that study, 25% of administered gadodiamide (Omniscan, GE Healthcare) was not recovered. The first report regarding gadolinium deposition in patients with normal renal function came in 2004, when Gibby et al. [5] described the presence of gadolinium in resected femoral head specimens after administration of both gadodiamide and gadoteridol (ProHance, Bracco), with the greater amount seen after administration of gadodiamide.
The first serious side effects seen after gadolinium administration were only reported 18 years after GBCAs were approved by the U.S. Food and Drug Administration (FDA) when nephrologists connected the administration of GBCAs to nephrogenic systemic fibrosis (NSF) [8, 9]. NSF is a debilitating condition observed in patients with renal failure. Most reported cases have been associated with the administration of nonionic, linear gadodiamide (Omniscan), although reports also described numerically important incidents with another nonionic linear agent, gadoversetamide (OptiMARK, Mallinckrodt Imaging), and with an ionic linear agent, gadopentetate dimeglumine (Magnevist, Bayer HealthCare) [10–15]. To our knowledge, no new cases of NSF have been reported since 2009, which we suspect reflects use of more stable GBCAs and limitation of use of GBCAs in patients with renal failure [16]. As a result, from 2009 to 2014, confidence in the safety profile of GBCAs has been largely restored, with the exception of less stable chelates used in patients with advanced renal failure.
In early 2014, an investigation by Kanda et al. [17] described the development of high signal intensity in brain tissue on T2-weighted images of patients with normal renal function after repeated administrations of a GBCA (Omniscan, Magnevist, or both). This caught many radiologists by surprise, as many had thought that deposition of gadolinium could not occur in patients with normal renal function. This deposition results in signal-intensity increase on unenhanced T1-weighted images in different regions of the brain, primarily in the dentate nucleus (DN) and globus pallidus (GP). As with NSF, the agent most associated with this finding is Omniscan [17–20]. To our knowledge, neither the bone deposition first reported by Gibby et al. [5] nor the brain deposition first reported by Kanda et al. [17] have been associated with recognized disease. We propose to name these storage entities “gadolinium storage condition.”
Along a separate avenue of inquiry, patient advocacy groups have formed, with an online presence in which individual members report that they have experienced severe disease following the administration of GBCAs [21]. Some of these patients have reported persistent presence of gadolinium in their systems, as shown by continued elevated gadolinium in their urine. All experience a variety of symptoms including pain in both the torso and the extremities; the latter location is associated with skin thickening and discoloration. These physical features are similar, but lesser in severity, to those reported for NSF [22]. Our preliminary investigation has convinced us that this phenomenon is a true disease process, which we propose naming “gadolinium deposition disease.”
| Nephrogenic Systemic Fibrosis |   |
|---|
NSF is the best known and most written about of the gadolinium-induced disease entities. NSF is a debilitating and potentially life-threatening disease characterized by widespread progressive tissue fibrosis that predominantly involves the skin and subcutaneous tissues. Initial symptoms typically involve the distal arms and legs, including skin thickening, skin reddening, woody texture of the skin and subcutaneous tissue, and occasionally pruritus. Symptoms and signs may develop and progress rapidly, with some affected patients developing contractures and joint immobility. Onset of NSF symptoms occurs within days to months after injection of GBCA in most patients [8, 9, 11, 13, 23, 24]; however, in rare cases, symptoms have appeared years after the last reported exposure [25, 26].
Two factors are critical to the development of NSF: severe renal failure and IV administration of the GBCA. Most unconfounded, also termed “solitary use,” cases have been reported after exposure to Omniscan, Opti-MARK, and Magnevist, which are responsible for most cases of NSF. We prefer to use the trade names Omniscan rather than gadodiamide because Omniscan is formulated with 5% free diamide ligand and OptiMARK rather than gadoversetamide because OptiMARK is formulated with 10% free versetamide ligand. Both of these agents are linear chelates, and Omniscan and OptiMARK are nonionic, which further lessens their stability. GBCAs that are more stable chelates by virtue of macrocyclic design (gadoteridol [ProHance, Bracco], gadobutrol [Gadavist, Bayer HealthCare], and gadoterate meglumine [Dotarem, Guerbet]) or that have additional hepatobiliary elimination while being ionic linear agents (gadoxetate disodium [Eovist, Bayer HealthCare; Primovist, Bayer Schering Pharma; MultiHance, Bracco]) have been associated with few to no cases of NSF with solitary use.
Stability of the chelate seems to be the factor critical to avoiding NSF. A recent article reported that patients with poor renal function or renal transplantation who received MultiHance did not develop NSF subsequent to MRI [27]. NSF occurs most commonly in patients who have received high doses of GBCA, either as a single administration or cumulatively in multiple administrations over months to years [13, 26, 28]. The reason why some patients with severe acute or chronic kidney diseases develop NSF following exposure to GBCAs while others do not is not known [26].
The most commonly held theory for the pathophysiology of NSF is that gadolinium ions dissociate from their chelating ligands while the agent is in the interstitial space because of the combination of prolonged retention of gadolinium in the body from decreased renal elimination and the greater opportunity for dechelation because of decreased elimination. The released (also termed “free”) gadolinium then binds with native anions such as phosphate, and the resulting insoluble precipitate is deposited in various tissues [29, 30]. A fibrotic reaction is stimulated, involving the activation of circulating fibrocytes (cluster of differentiation 34–positive fibroblasts) [30, 31]. This concept is supported by the greater presence of gadolinium in affected tissues relative to unaffected tissues in patients with NSF [32].
To date, successful treatment has been elusive. Renal transplant and the resultant improved renal function may stabilize the condition and perhaps result in some improvement. The fact that only 3% of patients in the worst category of renal failure (stage V) and receiving the weakest chelate (Omniscan) experience this condition belies the notion that host immunologic factors are important in the disease [16]. Avoiding the use of weak chelates and limiting the number of gadolinium-enhanced studies in individuals with poor renal function has largely eliminated this condition since 2009.
| Severe Acute Adverse Event | |
|---|
Acute adverse events can be categorized as either allergiclike or physiologic and organized according to severity (mild, moderate, or severe). The adverse event rate for GBCAs administered at clinical doses (typically 0.1–0.2 mmol/kg of body weight) ranges from 0.07% to 2.4%. Most reactions are mild and physiologic, including coldness, warmth, or pain at the injection site; nausea with or without vomiting; headache; paresthesia; and dizziness. Allergiclike reactions are uncommon and vary in frequency from 0.004% to 0.7%. The manifestations of an allergiclike reaction to a GBCA are similar to those of an allergiclike reaction to an iodinated contrast medium. Severe life-threatening anaphylactic reactions occur [33–39] but are exceedingly rare (0.001–0.01%) [26, 38, 40, 41]. Severe anaphylactic reaction that results in death has been reported in approximately 1 in 300,000 administrations of GBCAs, with 40 deaths per 51 million administered GBCA doses reported between 2004 and 2009 [42, 43]. Such rates are about one-third as common as reaction rates recorded with nonionic iodine-based contrast agents. Patients with asthma and various allergies may have a mildly increased risk for an allergiclike reaction to GBCAs compared with the general population, as may patients who have had immediate hypersensitivity reactions to MRI contrast media [42]. The frequency of severe anaphylactic reaction resulting in death is comparable and extremely low for all GBCAs. The reason why the frequency of such events is lower for GBCAs than for iodine-based contrast agents is unclear but may be attributable to difference in volumes administered for the two types of media (typically, 15 vs 100 mL, respectively). Allergiclike reactions occur immediately to within 24 hours of GBCA administration, with the most occurring within minutes of the injection, suggesting an immune response to the entire GBCA or part of it. The acuity of the onset reflects that this is an acute immunologic event, but the exact pathogenesis is unclear [26].
| Gadolinium Storage Condition | |
|---|
“Gadolinium storage condition” is the term we propose for gadolinium tissue deposition. Even in patients with normal renal function, in vivo clinical exposure to gadolinium chelates results in gadolinium incorporation into body tissues such as bone matrix [5–7] or brain tissues [44, 45]. As early as 1991, Rocklage et al. [46] noted the potential for minute amounts of chelated or unchelated metals to remain in the body for an extended period as well as the potential for a toxic effect.
Multiple recent reports that observe deposition in the DN and GP represent the largest body of literature on gadolinium storage condition. As mentioned above, the most commonly reported GBCA to result in this condition has been Omniscan, but it has also been seen with Magnevist [17, 47, 48]. The more stable macrocyclic GBCAs, such as ProHance [47] and Dotarem [48, 49], were not associated with significant MRI changes, supporting the concept that gadolinium accumulation varies depending on the stability of the agent used. MultiHance, a more intermediate stable agent but with additional hepatobiliary elimination, was associated with lesser MRI changes when compared with the linear Omniscan and only appreciated in the DN [20]. Recently, Weberling et al. [50] suggested that this agent releases less gadolinium than Magnevist but more than Dotarem.
In two studies published in March and April 2015, McDonald et al. [44] and Kanda et al. [45] showed in cadavers that gadolinium deposition within the brain tissue causes the reported increased signal intensity on T1-weighted images. Confirming human studies, an animal study [49] also found that repeated administration of Omniscan to healthy rats was associated with progressive and persistent signal hyperintensity on T1-weighted images in the DN and with histologic gadolinium deposits in the cerebellum; no such effects were seen in subjects who received Dotarem.
As is the case with NSF, the least stable GBCAs appear to be most likely to result in gadolinium storage condition, and stable agents either do not cause it or cause it at a very low level. On the basis of anecdotal reporting, ProHance, a macrocyclic agent, may deposit as a fully intact chelate in bone, as opposed to the dechelated deposition seen with Omniscan [3, 51]. It should not be surprising that simple storage should be predominantly based on how likely the chelate is to release the gadolinium atom.
The clinical significance of gadolinium tissue deposition remains incompletely understood. As stated in the recent FDA safety announcement regarding brain deposit of gadolinium: “[i]t is unknown whether these gadolinium deposits are harmful or can lead to adverse health effects” [52]. The FDA recommends that “health care professionals should consider limiting GBCA use to clinical circumstances in which the additional information provided by the contrast is necessary” [52]. It may be imperative to consider gadolinium retention potential when deciding which GBCA to administer.
| Gadolinium Deposition Disease | |
|---|
“Gadolinium deposition disease” is the name we propose for a disease process observed in subjects with normal or near normal renal function who develop persistent symptoms that arise hours to 2 months after the administration of GBCAs. In these cases, no preexistent disease or subsequently developed disease of an alternate known process is present to account for the symptoms.
Some of these patients are likely to have coexistent gadolinium storage condition, as described above, but gadolinium deposition disease is also described after a single administration of GBCA. The causal relationship has not been fully established, but it is under investigation. The aforementioned MRI gadolinium-toxicity support group has reported symptoms that they considered to be consistent with the known toxic effects of gadolinium. In a recent survey performed in 17 patients, an association between chronic effects and GBCA exposure was suggested [21]. Their internal investigation of members showed that the symptoms appeared within 1 month after the last contrast-enhanced MRI, and pain in the lower arms and legs persisted to the present time without resolving [53].
In our experience, symptoms of gadolinium deposition disease are similar but not identical to those observed in NSF. Typical clinical features include persistent headache and bone and joint pain. Patients often complain of clouded mentation that many describe as a “brain fog.” More distinctive features are comparable with those observed in NSF but of lesser severity; patients often experience subcutaneous soft-tissue thickening that clinically appears somewhat spongy or rubbery without the hardness and redness observed in NSF. Tendons and ligaments in a comparable distribution may also be painful and have a thickened appearance. Patients may complain of tightness of the hands and feet that resembles the feeling of being fitted with extremely tight gloves or socks. Patients may experience excruciating pain, typically in a distal distribution, of the arms and legs but that may also be in the torso or generalized in location. This pain is often described as feeling like sharp pins and needles, cutting, or burning.
As with NSF, it is unknown why only some patients have symptoms after gadolinium administration. From previous experience with NSF, we assume that less stable GBCAs are more likely associated with symptoms, but this assumption needs further validation. Host factors such as genetic susceptibility, adaptive immune response, or both may determine whether patients with gadolinium storage condition will develop gadolinium deposition disease.
The extent of overlap between patients with gadolinium deposition disease and subjects who have shown gadolinium storage condition in the brain is not known; further research is needed. Other areas of research interest include whether different tissue gadolinium deposition results in different symptoms and whether different immune cell components cause different symptoms. Additionally, a greater range of GBCAs may cause gadolinium deposition disease compared with NSF or gadolinium storage condition. The contribution of acute immune effects may explain why this condition may also be observed even with more stable agents.
Our opinion at present is that gadolinium deposition disease is likely uncommon. We believe that radiologists and clinicians must be attentive to the development of NSF-like disease in patients with normal renal function and not dismiss patients with severe symptoms after GBCA administration. Our opinion is that in patients who describe symptoms that suggest the diagnosis of gadolinium deposition disease, confirmation of the presence of gadolinium is necessary to establish the diagnosis. We recommend 24-hour urine testing for gadolinium, 30 days or more after the most recent GBCA administration. Early recognition will facilitate early treatment of the disease before it becomes more chronic and likely less responsive to therapy.
A recent report described “gadolinium-associated plaques” [54]. Sclerotic bodies (eosinophilic, collagenous, round or ovoid bodies) thought to be pathognomonic for NSF were found in histopathologic examination of the skin of patients exposed to Omniscan without NSF or even renal disease. We would put this condition under the rubric of gadolinium deposition disease if the patients have normal or near normal renal function and show symptoms from the lesions.
| Future Directions | |
|---|
It is important to improve the understanding of the family of disorders related to gadolinium in humans. Genetic testing may hold the key to predict who is likely to have NSF, severe acute adverse event, gadolinium storage condition, or gadolinium deposition disease, but it is uncertain if such testing will occur or be practical. As genetic testing is not currently a reality to prevent these diseases, early detection and treatment are the focus of management.
A number of adverse processes occur from the presence of gadolinium in humans. Because of mounting concern from health care workers and patients, agents that are the least likely to cause harm should be used. Because macrocyclic agents are more stable than linear agents and have been shown to have fewer instances of disease or deposition states, it would be prudent to employ predominantly macrocyclic agents in children and in subjects for whom multiple studies are anticipated (e.g., patients with Crohn disease or multiple sclerosis). Roles still exist for linear agents that possess properties of hepatobiliary elimination (Eovist, MultiHance) or prolonged intravascular dwell time (MultiHance), but continuing to use linear agents that are purely nonspecific and extracellular may be unjustified.
| References | |
|---|
