Gadolinium Based Contrast Agents - the Side Effect Risks

Tags: Gadolinium, GBCA, MRI, contrasting agency

Gadolinium Based Contrast Agents: Benefits and Risks

Recent stories in the media (http://www.newsweek.com/what-gadolinium-chuck-norris-claims-it-poisoned-his-wife-704647) have highlighted an existing but not well-known concern: that MRI is not a risk-free procedure. This has to do with one of the MRI imaging techniques that is based on the injection of a contrast agent. The most widely used contrast agent for prostate cancer detection is gadolinium, or more precisely, chelated gadolinium that is marketed in various forms under numerous brand names, but known collectively as gadolinium based contrast agents (GBCA’s).

Gadolinium is a rare earth metal whose paramagnetic properties are the reason for its use as a contrast agent.  Since it is toxic to the body, it is chelated with an organic compound that allows it to be rapidly excreted from the body through the kidneys. Other materials have also been used for enhancing con-trast – all have known toxicities.

To understand the importance of GBCA’s in cancer detection (and hence the tension that exists between their benefits and risks) requires a basic understanding of how MRI works. A reader already familiar with this subject or perhaps time limited can skip over the next few paragraphs to the section titled “GBCA Risks”.

How MRI Works

The following description is taken from https://en.wikipedia.org/wiki/Magnetic_resonance_imaging. In MRI, the person is positioned within an MRI scanner and an oscillating magnetic field is temporarily ap-plied at the appropriate resonance frequency. The excited hydrogen nuclei (protons) in various tissues within the magnetic field emit a radio frequency signal which is measured by a receiving coil. The radio signal may be made to encode position information by varying the main magnetic field using gradient coils. As these coils are rapidly switched on and off they create the characteristic repetitive noise of an MRI scan. The contrast between different tissues is determined by the rate at which excited atoms re-turn to the equilibrium state. This is called relaxation. Exogenous contrast agents may be given to the person to make the image clearer. That’s where GBCA’s come into play.

The technique that makes use of GBCA is called dynamic contrast enhancement (DCE). But before get-ting into that, the reader should know that the two commonly used imaging techniques – T1 weighted imaging and T2-weighted imaging, have limitations, because the contrast between types of tissue (the basis for reading the images) is not tissue-specific. T1-weighted imaging results in bright signals for fat tissue and low signals for what could be tumor but also might be edema, inflammation, infection, he-morrhage or calcification. T2-weighted imaging results in bright signals for tumor but also for inflamma-tion or infection and low signals for fat, air or calcification. Thus the radiologist reading either image is seeing contrasting tissue but not knowing precisely what is tumor and what is other kinds of benign tissue.

DCE helps him make a more informed decision. The spin polarization used to form the T1 image decays with a characteristic time constant known as the T1 relaxation time. The hydrogen protons in different tissues have different T1 values, which is the main source of contrast in MR images. GBCA’s shorten the T1 relaxation time of nearby hydrogen protons thereby enhancing the contrast in the image. One of the important ways DCE helps to guide the radiologist is by enhancing vascularity. The injected GBCA tends to concentrate more in blood vessels and in the intrastitial space between the blood vessels. Since tu-mors are characterized by increased vascularity, areas of enhanced signal immediately after injection could be tumor sites. An area that projects a bright signal on a T2 weighted image, which could be a tu-mor, but does not enhance on a T1-weighted image with DCE may not be a tumor. The radiologist has another tool that helps him make the final decision – diffusion weighted imaging.

The use of all the tools of MPMRI (including DCE) is especially warranted when scanning a prostate that has been treated, either by radiation or by any of the focal therapies, because scarring and inflammation can make reading the scans tricky. Unfortunately, some post-treatment protocols and most forms of ac-tive surveillance require MRI at regular intervals forever, thus the concerns about gadolinium are of spe-cial importance for those men for whom the probability of toxicity is greatly increased by repeated MRIs.

GBCA Risks

The following is taken in part from https://en.wikipedia.org/wiki/Gadolinium#Safety

As a free ion, gadolinium is highly toxic due to interference with a number of calcium-ion channel de-pendent processes. The influx of calcium ions into the cell can initiate a myriad of calcium-dependent processes including muscle contraction, gene expression, and secretion. Thus gadolinium should not be allowed in the body in its free state. GBCA’s are chelated compounds considered safe enough to be used in most persons. However, it is known that gadolinium can dissociate from its chelate before being eli-minated from the body.

There are two main types of GBCA, linear and macrocyclic. They differ in the way gadolinium is bound to the chelate. The macrocyclic chelates bind the gadolinium much more strongly, which minimizes the possibility of dissociation. On March 10, 2017, the committee of the European Medicines Agency (EMA) recommended the suspension of marketing authorizations for four linear GBCAs used for MRI scans be-cause of concerns about small amounts of gadolinium from administered GBCAs being deposited in the brain. At the completion of its year-long review of GBCAs, the EMA’s Pharmacovigilance and Risk Assess-ment Committee (PRAC) “found convincing evidence of accumulation of gadolinium in the brain from studies directly measuring gadolinium in brain tissues and areas of increased signal intensity seen on MRI scan images many months after the last injection of a gadolinium contrast agent”. Linear agents recommended for suspension by the PRAC are:

Gadobenic acid, marketed as MultiHance by Bracco Diagnostics Inc.

Gadodiamide, marketed as Omniscan by GE Healthcare

Gadopentetic acid, marketed as Magnevist by Bayer HealthCare Pharmaceuticals

Gadoversetamide, marketed as OptiMARK by Mallinckrodt Inc.

Dr. Barentsz, who is considered by many to be the leader in the field of clinical MRI, uses a macrocyclic GBCA, called Gadovist, which is considered the safest agent.

Unfortunately, in the USA radiologists are still using the banned linear GBCA's. Among them is my radio-logist, Dr. Busch in Chattanooga, TN. He uses MultiHance which, though not the worst, is still a linear agent on the banned list. I understand that using the most effective agent is important, especially when scanning a prostate that has been treated, however, as post-treatment protocol demands repeated MRIs, there is a significant risk of incurring toxicities for which at present there are no known cures. MPMRI is becoming standard of care for initial diagnosis and for follow-up, therefore the number of men being scanned is rising, so that the probability of gadolinium toxicity is rising too.

What to Discuss with your Radiologist before an MRI

Based on recent findings, it makes sense to discuss the need for contrast with the radiologist. Ask if it is really necessary. There is growing awareness of the toxicity problem among the radiological community, and as a result contrast is being used less frequently, especially in men who have not been treated. BTW, multiple biopsies may be one reason for using contrast, as scar tissue makes reading the scans more difficult… another reason to get an MRI first, before biopsy.

Before an MRI with contrast, be confident that your kidney function is normal (GFR > 60 ml/min) At a minimum, ask him/her to use a macrocyclic GBCA.

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