No matter what issues the imaging community has to face in regard to contrast media, the one topic that remains top of the list of priorities is understanding the link between gadolinium-based agents and NSF. Medical Imaging Technology takes stock of the situation and looks at what regulatory bodies are doing.
Periodically, there are headlines that hint at new challenges in the area of contrast media, with the shortage of barium recently taking centre stage. Nevertheless, there is one story that continues to dominate, namely the role of gadolinium-based contrast agents in the development of nephrogenic systemic fibrosis (NSF) in some patients.
Though this issue has been around for years, it still remains the biggest talking point, not least because of the rash of lawsuits that have broken out in the US in the years since a link between contrast agents and NSF was established.
Following the clearance of imaging contrast agent Gadovist, also known as gadobutrol, by the US Food and Drug Administration (FDA) in 2011, and this year’s recognition of Dotarem (gadoterate meglumine), the number of approved gadolinium-based contrast agents for use in MRI scans of the central nervous system (CNS) in adults and children over two years of age rose to seven, the others being Magnevist, MultiHance, Omniscan, Ablavar, OptiMARK and ProHance.
The potential benefits of such contrast agents in diagnostic procedures are worthy of note. Gadovist, for example, is cited by the FDA as a particularly effective contrast agent for CNS imaging because it enables radiologists to more easily identify lesions or wounds that disturb the cells and could potentially detach the brain from the blood stream, which would result in serious medical conditions.
At the time of approval, the FDA noted: "Gadovist MRI scans were found viable to identify out and envisage blood circulation/supply of the central nervous system, as it has been found to have improved the revelation of lesions in the nervous system, when equated to MRI scans without the use of contrast agents/media."
Lanthanide gadolinium is used in MRI contrast media because of its paramagnetic properties. It alters the relaxation properties of water protons during imaging, which results in changes in tissue contrast. The use of gadolinium-based contrast media has, however, become inextricably linked with the risks they pose for some patients in regard to the potential development of NSF, although they are recognised as powerful tools in the diagnosis of abnormalities in the brain, spinal cord, blood vessels, liver and kidneys.
The NSF connection
Guidance from the UK Medicines and Healthcare Products Regulatory Agency (MHPRA) indicates that NSF develops over a period of days to several weeks, presenting as red or dark patches or papules on the skin. The skin on the patient’s limbs, and sometimes the trunk, thickens and develops a texture like orange peel, and there can be associated sensations of burning, itching or severe sharp pains in the affected areas. The hands and feet might also swell and develop blister-like lesions.
In severe cases, NSF can restrict joint movements, and may result in contractures and immobility. Furthermore, it can affect internal organs including the lungs, liver and heart as well as muscle fibre. Around 5% of patients develop a rapid progressive disease development, sometimes resulting in death. NSF is, therefore, a debilitating and, in a very few rare cases, fatal disease.
1996 saw the first publication of an article stating that gadolinium-based contrast media were not nephrotoxic, which set them apart from iodine-based alternatives. Thereafter, there was a notable switch to gadolinium-based agents in patients with reduced renal function (see table 1, above), who were referred for enhanced MRI. Gadolinium-based contrast media were also used for computed tomography (CT) and conventional angiography.
NSF was first recognised the following year, after cases emerged in California of skin lesions that could not be identified with any recognised skin disease. In 2000, a report by Cowper examined this new scleromyxoedemalike disease characterised by fibrotic changes in the skin in renal dialysis patients. Nevertheless, it took until 2006 for a clear association to be made between the condition and gadolinium-based contrast agents, which had for a long time been considered to be the safest contrast agents around, adverse reactions to which had been extremely rare.
In 2006, a report by Grobner proposed that there was a link between the development of skin lesions in five out of nine patients with end-stage renal disease who had been exposed to gadodiamide contrast media during MR angiography. In August of the same year, Marckmann et al reported 13 more cases in similar patients, and in the following two years other reports in peer-reviewed journals contributed to the momentum that led to the naming of the condition NSF.
Understanding the effects of gadolinium
Free gadolinium is highly toxic to tissues in the human body. The liver is the most susceptible to the toxic effects of free gadolinium, which causes hepatocellular necrosis. Free gadolinium is sequestered in skeleton, where uptake is stable, and the liver, where uptake is labile.
The toxicity of gadolinium is due to the fact that the ionic radius of Gd3+ is similar to that of Ca2+, which results in gadolinium becoming an inorganic blocker of voltage-gated calcium channels, as noted by Idée J-M, Port M, Dencausse A, Lancelot E, Corot C (2009).
The blocking of these channels impairs physiological processes that depend on the influx of Ca2+. These processes include the contraction of smooth, skeletal and cardiac muscle, and the activity of enzymes including dehydrogenases and kinases, as noted by Palasz and Czekaj (2000), and Adding, Bannenberg and Gustafsson (2001). It has also been observed that calcium-sensing receptors on hepatocytes, renal cells and fibroblasts may also be activated by gadolinium.
Gadolinium acts as an inhibitor of the reticuloendothelial system, with gadolinium chloride accumulating in the lysosomes of the Kupffer cells, inhibiting their phagocytic capacity, which causes them to die.
The toxicity of free gadolinium has long been understood, which is why it has been administered to patients in a chelated form. The first gadolinium-based contrast agents used the tried and tested diethylene triamine penta-acetic acid (DTPA) as the chelating agent, which performed well in animal studies. Recent studies show that of the different molecular structures of contrast agents, those with a macrocyclic structure, as opposed to a linear structure, result in less gadolinium retention. Dotarem has a molecular charge and a cyclical structure and is seen as the least likely to release free Gd3+ into the body.
The reasons why some contrast agents may come with a higher risk than others are multiple and complex. According to the UK MHPRA, contrast agents such as Omniscan and OptiMARK that carry no molecular charge and are arranged in a linear structure with excess chelate seem to be more likely to release free gadolinium ions (Gd3+) into the body. Yet the exact mechanism by which free gadolinium ions that might be deposited in tissues and organs can stimulate NSF is still unknown.
Kidney impairment is certainly a key factor, given that NSF develops only in patients with advanced kidney dysfunction. The MHPRA points out that Omniscan, for example, is excreted from the body via the kidneys, so patients with impaired renal function are less able to efficiently clear the contrast agent from the body.
Today, it has been recognised that the patients who are most at risk of NSF after use of gadodiamide contrast media are those who have had or are waiting to have liver transplants, as well as neonates and children the age of one whose kidneys are not fully developed. There have so far been no known cases of NSF in patients with normal kidney function.
The European Medicines Agency (MDA) has devised classifications for the seven gadolinium-based agents approved by the FDA based on the level of risk they pose as contrast media for end-stage renal disease patients undergoing MRI (See Table 2, above). The least likely to release free gadolinium ions (Gd3+) are Dotarem, Gadovist and ProHance, while the most likely are those with a linear non-ionic structure, namely Omniscan and OptiMARK.
As it stands, however, all gadolinium-based contrast agents are seen as having the potential to trigger NSF and, therefore, all carry the relevant FDA warning. Furthermore, the FDA has prohibited the use of some contrast agents in patients with severe renal conditions – specifically those with a glomerular filtration rate (GFR) below 30 – with Omniscan, the worst offender in cases of NSF, bring hardest hit by this stricture.
Nevertheless, research so far has shown that the number of patients affected is very small. Many contrast agents may come with mild side effects like nausea, vomiting and minor skin reactions. Gadovist, for instance, is among the agents with the lowest risk classification for NSF, but patients have still reported headaches and nausea as common adverse reactions, and some cases of mild to severe hypersensitivity. Despite its relative rarity, the severity of NSF, however, means that those few cases must be considered with the utmost gravity and that the process of gauging the risk factors associated with specific contrast agents must, though challenging, be pursued with vigour.
Standing orders
It is clear that the understanding of the link between gadolinium-based contrast agents and NSF has improved significantly over the years, but there is clearly more work to be done. The important question, therefore, concerns what guidance should be given to radiologists who have to administer these agents.
Best practice is for radiologists to recognise the current indicators, no matter what gadolinium-based contrast agent is being used, and ensure that all risks have been thoroughly evaluated before any imaging process is performed. Detailed evaluation of a patient’s renal function is essential, followed by a careful balancing of the benefits and risks of using a gadolinium-based contrast agent for a specific patient.
In the vast majority of cases, it is likely that this analysis will favour the use of the contrast agent, given that its value in terms of achieving the correct diagnosis will usually have more weight than the very small risk of NSF. However, in some patients that distinction may be less clear, and the risk must be carefully considered and screened for.
Radiologists should use the safest contrast agent possible, which means staying on top of the latest research and looking at guidance from regulators as the understanding of NSF evolves.