Gadolinium Deposition and Chronic Toxicity

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Key points

  • Gadolinium is retained in body tissues; higher concentrations seem to occur in patients with renal impairment and after exposure to the less stable gadolinium-based contrast agents.

  • MR imaging does not detect all the gadolinium deposits present in human tissues; bone deposition is not perceptible with MR imaging.

  • MR imaging changes are seen after administration of linear agents, which may result from decreased imaging sensitivity or variations in the composition of the retained gadolinium.

  • The

Gadolinium-based contrast agents

Gadolinium is a rare earth element in the lanthanide series with powerful paramagnetic properties. Free gadolinium (Gd3+) is toxic in humans and to be used in vivo it must be chelated to organic ligands. Numerous mechanisms of gadolinium toxicity have been proposed, including calcium channel inhibition, production of reactive oxygen species, and induction of apoptosis.13, 14, 15 Gadolinium may also increase the expression of some cytokines16 and inhibit mitochondrial function.17

The chelate is a

Gadolinium storage conditions

It has been considered that GBCAs are eliminated rapidly and almost completely after intravenous injection. However, currently, it is recognized that GBCAs may be retained, undergo dechelation, and induce gadolinium deposition in a range of tissues and organs in patients with normal renal function, a condition recently termed “gadolinium storage condition.” Data from both animal and human studies have so far demonstrated that gadolinium can accumulate in skin, bone, brain, liver, kidney,

How does gadolinium enter the brain?

The mechanism of GBCA accumulation in the brain is still unknown, and several additional related questions remain uncertain, including the initial pathway of entry into the brain, the molecular structure of retained gadolinium, the potential saturation and washout effects, and more important the differences between GBCA classes.

Initially, it was thought that damage to the blood–brain barrier, renal dysfunction, liver disease, or metabolic disorders were the cause of contrast deposition in the

What is the chemical structure of retained gadolinium in the brain after repeated exposure to gadolinium-based contrast agents?

Whether the accumulated gadolinium is dechelated and associated with different molecules or chelated in its original formulation is not completely clear. Although some of the tissue deposits have been identified as gadolinium and phosphorous-containing particles by electron microscopy49, 75 or as intact GBCA (gadoteridol76 or gadobenate and Gd-DTPA36), very little is known about other chemical species of the retained gadolinium. Because the physiologic environment in which the GBCA is present

The Effect of Renal Function on Gadolinium Retention

One of the factors that seems to contribute to the pathogenesis of NSF is the slow excretion of GBCAs in those patients allowing the lower stability gadolinium chelates to dissociate and release gadolinium. Patients with renal failure are exposed to prolonged effects from injected GBCAs because prompt elimination through renal excretion does not occur.78 Impaired renal function is therefore a risk factor for the deposition of gadolinium in tissues, including the brain.79 Recently, Rasschaert

Gadolinium toxicity

A few anecdotal case reports regarding neurologic and nonneurologic gadolinium-induced toxicities without clear evidence of causality from other entities have been published, including GBCA-induced encephalopathy,8, 9 cognitive impairment,10 recurrent pancreatitis,11 and acute tubular necrosis.12

Recently, Ariyani and colleagues116 examined the effect of gadolinium on thyroid hormone (TH) receptor activity and TH-mediated brain development in vitro and found that exposure to specific GBCAs may,

Gadolinium deposition disease

The term gadolinium deposition disease was introduced by Semelka and colleagues122 and refers to a symptomatic disease process observed in individuals with normal renal function that arises within 2 months of GBCA administration and has no other etiologic explanation.

A recent survey among patients who attributed their symptoms to previous GBCA administrations was published describing the most common symptoms of presumed gadolinium deposition disease.123 In a follow-up survey,124 the authors

General guidelines and recommendations

The European Medicines Agency,127 the American College of Radiology,128 and the European Society of Urogenital Radiology129 have not yet proposed guidelines concerning gadolinium deposition. As a general safety recommendation, GBCAs should be administered only when clinically necessary and at the lowest possible dose that still results in diagnostic quality images. Stable chelates, favoring macrocyclic agents, should be preferred, if GBCAs are required.130 Other recommendations include keeping

Summary

The potential toxicity associated with GBCAs is a subject that cannot be ignored. The amount of gadolinium deposition in tissues is likely primarily related to the stability of the GBCA complex. Linear GBCAs are generally less stable and thus result in increased gadolinium deposition in the brain and bone compared with macrocyclic agents, but all GBCAs may result in gadolinium deposition. The mere presence of gadolinium retained in human tissues, recently named gadolinium storage condition,

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