Analytical Interference in Serum Iron Determination Reveals Iron Versus Gadolinium Transmetallation With Linear Gadolinium-Based Contrast Agents

Fretellier, Nathalie; Poteau, Nathalie; Factor, Cécile; Mayer, Jean-François; Medina, Christelle; Port, Marc; Idée, Jean‐Marc; Corot, Claire

doi:10.1097/rli.0000000000000081

Cited by 10 publications

(11 citation statements)

References 26 publications

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“…36,37 The interference observed in the measurement of serum calcium by the linear GBCAs was demonstrated to be due to transmetallation, which was subsequently reported as well in the colorimetric measurement of serum iron. 37,38 Despite the recommendation in the 1995 publication that colorimetric kits should not be used for determination of serum calcium in blood within 24 hours after gadodiamide injection, in the United States other analytical methods were generally not employed. This led eventually to a report in 2003 documenting inappropriate intravenous calcium administration in 7 patients, due to the incorrect diagnosis of critical hypocalcemia from blood samples obtained soon after gadodiamide injection.…”

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confidence: 99%

“…39 Subsequently, it has also been shown that linear agents in general interfere with the analytical determination of serum iron and that the macrocyclic agents do not. 38 The world of MR owes thanks to Thomas Grobner for his identification of the link between nephrogenic systemic fibrosis (NSF) and intravenous GBCA administration. 40 In a report published January 23, 2006, Dr Grobner described 5 patients in his dialysis unit who underwent contrast-enhanced MR angiography and then developed, within 2 to 4 weeks, thickening and induration of the skin, starting in the lower extremities and progressing to the trunk and upper extremities (with concomitant pain).…”

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confidence: 99%

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Safety of the Gadolinium-Based Contrast Agents for Magnetic Resonance Imaging, Focusing in Part on Their Accumulation in the Brain and Especially the Dentate Nucleus

Runge

2016

Investigative Radiology

144

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The established class of intravenous contrast media for magnetic resonance imaging is the gadolinium chelates, more generally referred to as the gadolinium-based contrast agents (GBCAs). These can be differentiated on the basis of stability in vivo, with safety and tolerability of the GBCAs dependent upon chemical and biologic inertness. This review discusses first the background in terms of development of these agents and safety discussions therein, and second their relative stability based both on in vitro studies and clinical observations before and including the advent of nephrogenic systemic fibrosis. This sets the stage for the subsequent focus of the review, the current knowledge regarding accumulation of gadolinium in the brain and specifically the dentate nucleus after intravenous administration of the GBCAs and differentiation among agents on this basis. The information available to date, from the initial conception of these agents in 1981 to the latest reports concerning safety, demonstrates a significant difference between the macrocyclic and linear chelates. The review concludes with a discussion of the predictable future, which includes, importantly, a reassessment of the use of the linear GBCAs or a subset thereof.

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confidence: 99%

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confidence: 99%

Safety of the Gadolinium-Based Contrast Agents for Magnetic Resonance Imaging, Focusing in Part on Their Accumulation in the Brain and Especially the Dentate Nucleus

Runge

2016

Investigative Radiology

144

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“…The interference seen after gadodiamide and gadoversetamide administration has been concluded to be due to the dissociation of these gadolinium chelates, with macrocyclic chelates not producing any interference with analytical methods. 24 For example, in the presence of OCP (used for the calcium colorimetric assay), it has been shown that gadodiamide disappears and the free ligand and a new complex Gd-OCP appear. 24 In the case of circulating angiotensin-converting enzyme, an effect of the added free ligand, with gadodiamide and gadoversetamide, is likely.…”

Section: Interference With Analytical Testsmentioning

confidence: 99%

“…24 For example, in the presence of OCP (used for the calcium colorimetric assay), it has been shown that gadodiamide disappears and the free ligand and a new complex Gd-OCP appear. 24 In the case of circulating angiotensin-converting enzyme, an effect of the added free ligand, with gadodiamide and gadoversetamide, is likely. 22 In regard to the determination of serum iron and problems therein principally with gadodiamide and gadoversetamide, the situation would most likely arise only shortly after contrast administration or in patients with renal impairment.…”

Section: Interference With Analytical Testsmentioning

confidence: 99%

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Dechelation (Transmetalation)

Runge¹

2018

Invest Radiol

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The issue of dechelation (transmetallation) in vivo after administration of the linear gadolinium-based contrast agents, and potential safety concerns, is considered on the basis of an extensive, focused literature review. Early indications of potential problems included the high level of excess ligand used in the formulation of 2 agents (indeed the 2 least stable thermodynamically) and interference with laboratory tests when blood was drawn from patients relatively soon after administration of these same agents. The advent of nephrogenic systemic fibrosis in the late 2000s raised additional major concerns.The correlation in 2014 of dentate nucleus hyperintensity on precontrast T1-weighted scans with multiple prior injections of linear gadolinium chelates, in patients with normal renal function, has driven subsequent research concerning dechelation of these agents in vivo. Unexpectedly high levels of gadolinium in the bone, skin, and liver have been found long term after administration, in animal models and in humans, although the latter data are limited. Bone may serve as a long-term reservoir, with a residual excretion phase for gadolinium after intravenous injection of the linear agents due to a subsequent slow release from bone. Many different patient populations could be vulnerable and potentially later develop clinical symptoms, although at this stage there are only limited data and small retrospective uncontrolled studies. Possible vulnerable populations include children, menopausal women, patients with osteoporosis (who are predisposed to fractures and often slow to heal or heal poorly), those receiving multiple doses, those with proinflammatory conditions, moderate renal dysfunction, or an undefined genetic predisposition. Of particular concern would be nephrogenic systemic fibrosis-like symptoms-including particularly pain and skin/joint symptoms, or disease related to the incorporation of gadolinium in hydroxyapatite in bone, in small subgroups of patients with a not yet defined propensity and/or cofactor. These concerns have led to withdrawal of the linear agents from the largest clinical market, Europe, with the exception of the hepatobiliary agents for delayed liver imaging, an indication that cannot be fulfilled by the current macrocyclic gadolinium chelates (for which these concerns do not apply).

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