A 41-year-old woman has a rapidly growing wrist mass that does not seem typical for a ganglion. Her orthopaedic surgeon recommends a contrast-enhanced magnetic resonance imaging (MRI) scan to evaluate for a potential mass. However, the patient explains that she does not want to get “gadolinium poisoning.” How do you address her concerns?

MRI creates exquisitely detailed images of the body using a combination of a strong magnetic field, radiofrequency excitations, and advanced mathematics. Millions of MRI examinations are performed safely each year, and oftentimes the addition of intravenous or intra-articular contrast can add valuable clinical information for many orthopaedic indications. In this brief update, we will summarize key recent developments in safety of gadolinium-based contrast agents (GBCAs).

GBCAs have been in common clinical use since 1988 and have been safely administered millions of times. Pure gadolinium is a heavy metal that decreases T1 relaxation time, thereby appearing “bright” on T1-weighted images. Gadolinium is toxic in elemental free form, and the free metal ion must be “chaperoned” in an organic ligand to be safely administered, where the compound can pass through the vasculature, soft tissues, and ultimately out of the body via renal excretion. Health risks to the patient may occur if the free gadolinium ion dissociates from the chaperone molecule before the GBCA is excreted from the body.

A total of seven GBCAs are licensed for clinical use in the United States (Table 1) and can be categorized into three different structural classes: linear ionic, linear nonionic, and macrocyclic. Each of these structural types appears to have a different safety profile; the macrocyclic molecules offer the greatest stability (least free gadolinium dissociation) and the linear nonionic has the least stability.

Jpn J Radiol

Clinical use of GBCAs
For orthopaedic indications, intravenous administration of GBCAs can provide valuable clinical information for pre- or postoperative assessment of tumors, suspected infection of the spine or peripheral joints (in both native and postsurgical indications), and evaluation of rheumatologic disorders. Depending on the specific contrast agent and weight of the patient, between 5 mL to 20 mL of contrast is injected intravenously, and imaging is obtained after a brief delay.

In addition to the intravenous route, direct intra-articular injection of diluted GBCAs can be performed for MR arthrography, which allows detailed assessment of the intra-articular structures, typically in the clinical setting of sports-related injuries. In comparison to intravenous GBCA administration, much less contrast (0.05 mL–0.1 mL of GBCA) is administered into a joint. The GBCA is diluted in saline and/or iodinated computed tomography (CT) contrast and then injected by the radiologist under fluoroscopic or ultrasound guidance prior to the MR arthrogram.

It should be noted that none of the commercially available GBCAs have been approved by the U.S. Food and Drug Administration (FDA) for intra-articular administration in the United States, and thus an MR arthrogram is therefore an “off-label” use. In a patient who can appropriately receive GBCAs, however, an MR arthrogram is generally very safe and use of the GBCA produces no known risks to intra-articular structures.

Overview of GBCA adverse effects
Despite their widespread use, there are important safety considerations to be aware of with respect to GBCAs. Adverse effects of GBCAs can be broadly classified into three categories: nephrogenic systemic fibrosis (NSF), tissue gadolinium deposition, and acute adverse event. It should be noted that these adverse effects have been largely described for intravenous (rather than intra-articular) administration.

NSF
NSF, the most-studied GBCA complication, is a systemic fibrosing disorder that involves the skin, subcutaneous tissues, and internal organs. It is a progressive disease with no known cure that may result in severe disability or death. Clinically, NSF manifests with skin thickening, joint flexion contractures, and fibrosis of the connective tissues of internal organs. The correlation between previous GBCA administration and NSF was first published in 2006, and since that time more than 800 cases have been reported in the peer-reviewed literature, almost exclusively occurring in patients with severe renal impairment, with an estimated glomerular filtration rate (eGFR) of < 30 mL/min/1.73 m2.

Nearly all cases of NSF are associated with three linear GBCAs: gadopentetate dimeglumine, gadodiamide, and gadoversetamide, which are thought to be less stable than their macrocyclic counterparts. The number of new cases of NSF has declined to near zero after knowledge of the disease became well known and strict eGFR screening guidelines were implemented. Additionally, many radiology departments have transitioned to administering macrocylic GBCAs. In patients with renal failure, the utility of dialysis after GBCA administration remains to be determined, but is generally recommended.

In summary, the linear GBCAs gadodiamide, gadopentetate dimeglumine, and gadoversetamide should not be given to patients with acute or chronic renal failure. Further studies would be required to determine the safety of macrocyclic GBCAs or the linear GBCA gadobenate dimeglumine in patients with renal disease or on dialysis.

Tissue gadolinium deposition
There is now imaging-based and histological evidence of gadolinium deposition within the dentate nucleus and globus pallidus in patients with a prior exposure to linear-type GBCAs, even those with normal renal function. There is also evidence of gadolinium deposition within the proximal femora, as seen on proximal femoral specimens from patients undergoing total hip arthroplasties. Both linear and macrocyclic GBCAs may be implicated in tissue gadolinium deposition, although the amount deposited by macrocyclic GBCAs is much less than linear GBCAs. Importantly, the clinical significance of these deposits remains unclear.

Acute adverse event to GBCA
Acute adverse effects to GBCAs are rare, with reported rates between 0.004 percent and 0.7 percent of GBCA administrations and occur much less commonly than reactions to iodinated CT contrast media. Adverse effects to GBCAs may mimic an acute allergic reaction, with symptoms consisting of hives, rash, throat swelling, shortness of breath, or anaphylaxis. Severe life-threatening anaphylactoid reactions are exceedingly rare, occurring in less than 0.01 percent of GBCA administrations. In contrast to a true allergic reaction, antigen-antibody responses are not always identified. Regardless of the etiology, however, these reactions are treated in a similar manner to true allergic-type reactions.

Summary: What do we tell our patient?
With respect to the woman in our clinical vignette who was concerned about potential “gadolinium poisoning,” it can be helpful to mention that in properly screened patients (with normal renal function), the risk of a serious gadolinium-related fibrosing disease (NSF) is near zero. Additionally, asymptomatic tissue deposition of gadolinium has been demonstrated to occur in some patients with normal renal function, predominantly with certain types of contrast agents that are falling out of favor. Although this finding has raised concern among the medical community, as well as the media, the clinical significance of this tissue deposition remains to be determined.

It can be helpful to discuss with our patient that the clinical implications of an untreated and potentially life-threatening orthopaedic problem, such as a neoplasm or infection, may outweigh any less-defined risk of potential gadolinium-related adverse event. For instance, the real risk of missing a potential neoplastic mass may have more impact on the patient’s life than the undefined risk of potential gadolinium deposition.

We recommend emphasizing that the decision to receive a gadolinium-based contrast agent ultimately lies with the patient. Even though multiple studies have shown that intravenous contrast improves diagnostic performance for many inflammatory, infectious, and neoplastic conditions, helpful information may nonetheless be able to be obtained even without contrast. Additionally, there are certain noncontrast MRI sequences that can be helpful, such as diffusion-weighted imaging (DWI). DWI can image regions where there is restricted Brownian motion, and this information can be helpful to distinguish tumor from granulation tissue, or abscess from seroma.

If a patient has more detailed questions about receiving gadolinium contrast, he or she should always feel free to speak directly with a radiologist.

After consideration, our fictional patient did decide to receive contrast (Fig. 1), which allowed optimal diagnosis and treatment of her wrist mass.

Jacob C. Mandell, MD, is a staff radiologist in the division of musculoskeletal imaging and intervention at Brigham and Women’s Hospital. Charles H. Cho, MD, MBA, is a staff radiologist in the department of radiology at Brigham and Women’s Hospital.

References:

1. Kanda T, Oba H, Toyoda K, Kitajima K, Furui S. Brain gadolinium deposition after administration of gadolinium-based contrast agents. Jpn J Radiol. 2016;34(1):3–9.
2. Kanda T, Osawa M, Oba H, Toyoda K, Kotoku J, Haruyama T, et al. High Signal Intensity in Dentate Nucleus on Unenhanced T1-weighted MR Images: Association with Linear versus Macrocyclic Gadolinium Chelate Administration. Radiology. 2015;275(3):803–9.
3. White GW, Gibby WA, Tweedle MF. Comparison of Gd(DTPA-BMA) (Omniscan) versus Gd(HP-DO3A) (ProHance) relative to gadolinium retention in human bone tissue by inductively coupled plasma mass spectroscopy. Invest Radiol. 2006;41(3):272–8.
4. Stojanov D, Aracki-Trenkic A, Benedeto-Stojanov D. Gadolinium deposition within the dentate nucleus and globus pallidus after repeated administrations of gadolinium-based contrast agents—current status. Neuroradiology. 2016;58(5):433–41.
5. Semelka RC, Ramalho M, AlObaidy M, Ramalho J. Gadolinium in humans: A family of disorders. Am J Roentgenol. 2016;207(2):229–33.