Gadolinium Deposition in Tissues: Current Evidence

Patients increasingly request information on risks related to contrast administration. Presentations by three experts in the field of gadolinium-based contrast agents (GBCAs) and a Q&A gave some answers.

Participants:

  • Olivier Clément, Hôpital Européen Georges-Pompidou, Paris/France (Chairman)
  • Uwe Karst; University of Muenster/Germany
  • Alexander Radbruch; German Cancer Research Center, Heidelberg/Germany
  • Henrik S. Thomsen; Copenhagen University Hospital/Denmark

 Stability of Gadolinium Chelates and Chelation Therapy

Uwe Karst, chemist at the University of Muenster, Germany, addressed

  • the thermodynamic stability of GBCA, which is not directly dependent on linear or macrocyclic GBCA structure and is of less importance when discussing Gd deposition in tissues.
  • the kinetic stability indicating the speed of dissociation of the Gd-complex. Macrocyclic GBCAs show significantly higher kinetic stability compared to linear GBCAs. “The importance of kinetic stability depends upon exposure time”, said Karst with regard to patients with renal disease.

Karst also talked about “chelation therapy” as an approach for removing remaining gadolinium (Gd) from the body: it targets re-dissolving “insoluble” Gd-species. Chelation therapy is an established concept for intoxications with other heavy metals such as mercury. For chelation therapy, DTPA (diethylenetriaminepentaacetic acid) or Zn-DTPA is used. However, there might be dedicated risks associated with Gd remobilization or iron removal, he said.

Is Gadolinium Deposition a Real Disease?

Alexander Radbruch from the German Cancer Research Center in Heidelberg critically reviewed the paper about “Gadolinium deposition disease” by Richard Semelka et al. (Magn Reson Imaging 2016): The pain symptoms Semelka et al. described are not very specific (central pain, peripheral pain, headache, bone pain), the number of cases is small (n=42), and patients have not been examined thoroughly, but filled in questionnaires only.

A recent paper (Invest Radiol 2018) by Semelka et al. reported the use of intravenous calcium (Ca)-/zinc (Zn)-DTPA for the treatment of 25 symptomatic patients diagnosed with “gadolinium deposition disease”. “I am very skeptical about chelation therapy”, said Radbruch, “as all we know is based on questionnaires and there was no control group.” Future research should better focus on concrete symptoms like skin changes instead of vague symptoms such as ‘brain fog’. “We radiologists need to guide this debate”, he demanded.

‘Gadophobia’ and Recommendations for Radiologists

“Never deny a patient a clinically well-indicated enhanced MRI examination”, pled Henrik S. Thomsen from Copenhagen University Hospital, Denmark. The risk associated with developing ‘gadophobia’ could be worse than the risk related to indicated macrocyclic GBCAs “because you may overlook for example a cancer or a vascular lesion if you don’t give the contrast medium”, said Thomsen. He reminded the audience to always use the smallest amount of contrast medium needed for diagnostic results. Finally, the brand name and dose of the administered contrast agent should always be recorded in the patient report.

Public Discussion

Cases of ‘Gadolinium deposition disease’?

Chairman Olivier Clement from Hôpital Européen Georges-Pompidou, Paris, asked the audience to raise their hands if anybody had ever encountered a patient with symptoms of ‘Gadolinium deposition disease’ as described by Semelka et al. Nobody in the audience responded, except a radiologist who reported “We do have patients who are afraid of receiving contrast”.

Patients’ fear

“Has anybody had patients who refused to receive GBCAs?” asked Clement.

  • Participant from Germany: “We hear this question from patients three times per week on average.”
  • Participant from Finland: “We had a patient assigned for breast MRI who had been warned by a doctor to never accept any type of contrast.”
  • Participant from Denmark: “I have more patients coming up with very specific questions on whether receiving contrast agent is dangerous or not. And I am still struggling with giving these patients an answer.”

Risk Stratification

In order to classify the risk related to Gd retention, Clement said: “The most serious risk of contrast is the risk of developing a shock. I had one fatal case with an anaphylactic shock three years ago. This risk is as small as one to a few hundred thousands – and that is much higher than any risk related to Gd retention. Going home by bicycle has a much higher risk than receiving contrast.”

Gd-Detection is Extremely Sensitive

Karst: “We can detect extremely low concentrations of gadolinium. We are talking about a few parts per billion. In every person who has ever had chemotherapy with platinum-based drugs, you can detect platinum for his life-time. With gadolinium things are similar. Furthermore, there is a natural background burden of gadolinium. You will find nobody with no gadolinium at all. However, we can’t discriminate gadolinium deposition induced by contrast administration from deposition caused by the natural background burden.”

Radbruch: “We could start looking for other substances and we would also find deposition of those in the human brain. My impression is that we focus too much on Gd deposition. And we will never be able to demonstrate that there is no side effect of Gd deposition, even if we put all our resources in that for ten years.”

Giving GBCA to Children

Question from a participant: “Has there been any research on Gd deposition in pediatric patients?”

Radbruch answered: “We have to perform risk assessment in these patients. I would assume that pharmacokinetics work similar in children: The longer you wait after contrast administration, the more contrast has been eliminated. If clinically necessary, I do not hesitate giving Gd-based contrast to children.”

Thomsen: “We do not administer contrast media to healthy people, but to patients only. Overlooking a pathology might be more dangerous.”

How to Communicate Risk to Patients

Question from the auditorium: “Should the unknown risk of gadolinium deposition be part of the information leaflets that we routinely hand out to patients? Or should we communicate this only to patients who explicitly ask about it? We don’t give this information in our leaflets up to now. But we do inform about many other risks.”

Radbruch: “This is a difficult question. In the United States they do have it in their leaflets. I don’t want to give you advice on that.”

Participant from Switzerland: “I know of one case in which a patient sued his doctor because he was not given any information on potential Gd deposition. The situation is different in different countries.”

Thomsen: “We should not forget: Patients can develop the same symptoms without receiving any contrast.”

Registry for Gd Deposition Disease?

Clement asked whether it would it be an option to report cases of suspected “Gd Deposition Disease”.

Thomsen answered: “We would have big problems with reporting these cases because the symptoms are so unspecific.”

Presentation Title: Gadolinium deposition in tissues: current evidence and alternatives
Presentations
Speaker: Olivier Clément, Hôpital Européen Georges-Pompidou, Paris/France (Chairman)Date: March 2nd  , 2019
Session code: #A-0904, A-0905, A-0906