Elsevier

Magnetic Resonance Imaging

Volume 34, Issue 10, December 2016, Pages 1341-1345
Magnetic Resonance Imaging

Introduction
Gadolinium based contrast agents (GBCA): Safety overview after 3 decades of clinical experience

https://doi.org/10.1016/j.mri.2016.08.017Get rights and content

Abstract

In the past three decades, we have learned much about the potential short-term and long-term safety issues associated with the intravenous administration of gadolinium based contrast agents (GBCAs). Yet, surprisingly, the past few years and even months have been accompanied by new discoveries in this field. This manuscript focuses predominantly on what we have learned – and are continuing to learn – about the long-term potential MR safety issues associated with the administration of the various GBCAs available today and will highlight areas in which they appear to differ from each other at least in a quantitative fashion, if not qualitatively.

Introduction

On June 28, 1988 FDA approval was provided to the first gadolinium-based magnetic resonance (MR) contrast agent for clinical application in human diagnostic magnetic resonance imaging (MRI). With that announcement, the MR industry was irreversibly transformed. Image contrast manipulation in diagnostic MRI, arguably the single strongest characteristic of this fledgling new diagnostic imaging not even five years old at the time, had always been accomplished by manipulating pulse sequence timing parameters and power considerations. TR, TE, TI, flip angle were our most powerful image contrast controls in MRI, as they interacted with the intrinsic tissue magnetization behavior characteristics of hydrogen density, T1, T2, and T2*. Now, for the first time, image contrast could also be modified by effecting changes in the intrinsic tissue magnetization behavior characteristics and constants themselves. We could control not only the imaging technology, but now the tissue magnetization behavior itself was also subject, at least in part, to our diagnostic imaging control, manipulation, and oversight. With its inevitable benefits on diagnostic sensitivity and even specificity, the value of diagnostic MRI grew by leaps and bounds. MRI as a diagnostic modality grew at a rate literally unprecedented by any medical diagnostic imaging tool ever utilized, overshadowing and eclipsing historical rates of growth of such tools as diagnostic x-ray, CT, nuclear medicine, ultrasound, and PET scanning, to name a few.

Following the successful introduction of gadopentetate, the first GBCA to receive FDA approval in the US, other competing agents were subsequently introduced (Table 1). Some were quite similar, from a safety, efficacy, biodistribution, mechanism of action, and pharmacokinetic point of view, to already existing products, while others were introduced with greater relaxivities and/or tissue specificities over the years. Our dependence on these agents has grown to a point where diagnostic MRI today is accompanied by the intravenous administration of a gadolinium based contrast agent in roughly 30% to 45% of all clinical US MR studies today.

Section snippets

Short term GBCA safety issues

Until 2006 the main discussions regarding safety for all GBCA were related to short term adverse reactions. These themselves were divided into two very broad categories: As described by Debatin et al in 1991 [1] regarding iodinated contrast agents and applied to GBCA as well by accepted practice, adverse reactions to GBCA can be broadly divided into two main categories, allergic and non-allergic in nature, the latter now generally being referred to as physiologic reactions. GBCA-related

The role of efficacy in diagnostic contrast enhanced MRI

In 2004, the FDA approved the first contrast agent with a significantly higher relaxivity than the others that had been available in the US until then. At identical administered doses, gadobenate was shown to have superior diagnostic efficacy compared to lower relaxivity agents, and “High Relaxivity” became an integral part of the new GBCA-related terminology – and marketing - in the US. Between 2004 and 2013, all new GBCA approved by the FDA were high relaxivity, including gadobenate,

Longer term adverse effects of GBCA

The beginning of 2006 brought with it the landmark observation by Grobner [8] connecting the administration of GBCA to the eventual development of Nephrogenic Systemic Fibrosis (NSF) in patients with significant renal function impairment. This disease was initially first described by Cowper in 2000 [9] and at that time was referred to as Nephrogenic Fibrosing Dermopathy (NFD). Interestingly, even as early as 2001 Cowper et al conjectured, “…it is possible that a newly introduced agent may

The transmetallation theory

At this point, most subscribe to the transmetallation theory of NSF induction. Also known as the dechelation or dissociation theory, it begins with recognition of the toxic nature of the free gadolinium ion. To decrease toxicity, all GBCA are bound to ligand molecules. Thus bound, these molecules are relatively restricted from toxic interactions, but are also somewhat impeded in their abilities to interact with and potentiate T1 shortening in the hydrogen nuclei of target water molecules. Thus,

Retained intracranial gadolinium

Before the dust could completely settle on NSF and long term gadolinium safety, another potential long term safety issue was revealed to the international MR community. Kanda and co-authors [12] published their observations that, for at least some intravenously administered GBCA, T1 shortening was observed in several locations in the brain, including predominantly (but not only) in the dentate nucleus and globus pallidus. This T1 shortening seemed to respond in an exposure-dependent fashion,

Gadolinium Associated Plaque

In 2014 an electronic report first appeared describing a new dermatologic abnormality in which a characteristic dermatologic histologic finding, known as a sclerotic body, was found in patients who had received specifically gadodiamide, and in whom, in at least one patient, no renal disease was present. Named Gadolinium Associated Plaque [30], this was described as a new condition that can occur wither with or without the presence of renal disease, but was distinct from, and occurred without

www.gadoliniumtoxicity.com

There is a group of patients who over the past few years have gathered together in electronic format and who report sharing in common one attribute: That they believe that since they received a GBCA they have suffered significant health-related deterioration or symptoms that in their opinions are related to the gadolinium administration at least temporally, if not causally. While this is not the place to elaborate on their reported symptoms or this subject in general, it is worth noting that

Increasing levels of gadolinium in our water supply

It has also been noted since 1996 that of all the trace metals, the levels of gadolinium, and specifically gadolinium, in the reservoirs, drinking water supplies, and rivers in and around large metropolitan centers has been markedly increasing [31]. While we do not know the clinical significance, if any, of this finding, it has been traced to medical usage of gadolinium as a contrast agent in diagnostic MRI. Intact undissociated medically administered GBCA chelates have been identified in the

Summary

Following their initial release, GBCA were felt to be among the safest drugs in medical usage at the time. Indeed, short term adverse events remain distinctly uncommon (<2.5%) and the vast majority of these are minor, transient, and require no treatment or intervention. However, the last decade has seen a prominent rise in concern about potential longer term adverse effects of GBCA usage. These are related predominantly to the potential development of NSF in some renally impaired patients

References (33)

  • T. Grobner

    Gadolinium--a specific trigger for the development of nephrogenic fibrosing dermopathy and nephrogenic systemic fibrosis?

    Nephrol Dial Transplant

    (2006)
  • S.E. Cowper et al.

    Nephrogenic Fibrosing Dermopathy

    Am J Dermatopathol

    (2001)
  • P.E. LeBoit

    What nephrogenic fibrosing dermopathy might be

    Arch Dermatol

    (2003)
  • T. Kanda et al.

    High signal intensity in the dentate nucleus and globus pallidus on unenhanced T1-weighted MR images: relationship with increasing cumulative dose of a gadolinium-based contrast material

    Radiology

    (2014)
  • R.J. McDonald et al.

    Intracranial Gadolinium Deposition after Contrast-enhanced MR Imaging

    Radiology

    (2015)
  • Y. Errante et al.

    Progressive increase of T1 signal intensity of the dentate nucleus on unenhanced magnetic resonance images is associated with cumulative doses of intravenously administered gadodiamide in patients with normal renal function, suggesting dechelation

    Invest Radiol

    (2014)
  • Cited by (77)

    • MRI of pelvic vessels

      2023, Magnetic Resonance Imaging of The Pelvis: A Practical Approach
    • Gadolinium based contrast agents (GBCAs): Uniqueness, aquatic toxicity concerns, and prospective remediation

      2022, Journal of Contaminant Hydrology
      Citation Excerpt :

      Admittedly, the clinical significance of retained Gd is not fully known yet; there are only several conflicting expert opinions, there is also lack of sufficiently reliable and mutually agreable data about the safety of clinically administered GBCA. Similarly, the implication of the presence of the anthropogenic Gd in water after a considerable number of years is still largely controversial (Choi and Moon, 2019; Do et al., 2022; Kanal, 2016; Soloff and Wang, 2020). Perhaps the current imbroglio about GBCA safety restrained the environmental or waste/drinking water regulators from establishing a safety limit of Gd–concentration in water.

    View all citing articles on Scopus
    View full text