Narrative literature analysis (see also Introduction)

Gadolinium Deposition in the Brain – Extracellular Linear GBCA

The use of linear extracellular GBCA led to visible changes in signal intensity (SI) ratios and measurable Gd depositions in the rat, dog, and human brain (Davies, 2021; De Bevist, 2020; El Hamrani, 2020; Fretellier, 2019; Grahl, 2021; Koiso, 2019; Minaeva, 2020; Richter, 2020; Wang, 2019a) and in the anterior pituitary gland (Mallio, 2019). Most depositions were in perivascular foci in the DN and GP (Davies 2021), with evidence of co-localization to parenchymal iron (Minaeva, 2020).

The amount of deposition in rat brains occurred independent of age or sex (Fretellier, 2019). Local blood-brain barrier disruptions (e.g., radiotherapy) did not lead to an increase in deposition (Jost, 2019). Active inflammation showed higher Gd concentration in inflamed areas in mouse brains (Wang, 2019a), while the presence of diabetes led to lower brain concentrations (Wang, 2019b). There was a decrease in concentration over time in all brain regions, but long-term retention over 1 year occurred preferentially in the rat DN (El Hamrani, 2020).

The use of intra-articular gadopentetate did not lead to visible Gd-deposition in human brains (Bunnell, 2021).

Gadolinium Deposition in the Brain – Hepatobiliary Linear GBCA

The use of linear GBCA such as gadobenate and gadoxetate has been limited in the EU to hepatobiliary MRI indications. The approved standard dose of gadobenate is 0.05 mmol/kg, less than the dose of linear extracellular GBCA. However, outside the EU gadobenate is used for total body indications, in doses up to 0.1 mmol/kg. Use of gadobenate led to visible SI changes in human brain (Barisano, 2019; Nguyen, 2020). Neuroinflammation led to higher Gd concentrations in the rat brain after gadobenate use (Damme, 2020).

In human cadavers, the mean Gd concentration in brain was 3-6x higher for gadobenate compared to gadoterate, but washed out over time (Kobayashi, 2021). In sheep, the level of Gd retention 10 weeks after a single dose injection was 14-fold higher for gadobenate than for gadoterate (Radbruch, 2019).

A meta-analysis on Gd deposition of gadoxetate showed significant bias of the 5 included studies, and therefore presently available data on gadolinium deposition for gadoxetate is still incomplete (Schieda, 2020).

Gadolinium Deposition in the Brain – Macrocyclic GBCA

The administration of cumulative doses of macrocyclic GBCA did not lead to visible changes in T1 signal intensity (SI) or to changes in T1 relaxation times in rat and human brains in most studies (Bennani-Baiti, 2019; Deike-Hoffmann, 2019, Forslin, 2019, Fretellier, 2019, Hannoun, 2020; Neal, 2020), but not in all (Splendiani, 2020).

Quantitative susceptibility mapping showed a relation of susceptibility changes with the number of gadobutrol injections, but only for the GP (Choi, 2020).

In rat brains macrocyclic GBCA led to measurable Gd concentrations 1-5 weeks after administration, which were lower for gadoteridol compared to gadoterate and gadobutrol. The GBCA wash-out over time led to a 3-5-fold reduction from 1 to 5 weeks and was more rapid for gadoteridol. The levels at 5 weeks were in the order of 0.14-0.30 nmol Gd/g tissue (Bussi, 2020 and 2021).

Speciation of Gadolinium deposition in the brain

In speciation analyses in rat brains, the macrocyclic GBCA gadoterate was present exclusively as the intact GBCA. For the linear GBCA gadobenate and gadodiamide a combination of intact GBCA, complexes of dissociated Gd³⁺ bound to ferritin, and Gd³⁺ bound to other macromolecules was present. Incomplete column recovery suggested presence of labile complexes of dissociated Gd³⁺ with endogenous molecules. In addition, Gd was present in insoluble amorphous spheroid structures of 100-200 nm. Gadolinium was consistently co- localized with calcium, phosphate, and oxygen, suggesting the structures composed of mixed Gd/Ca-phosphates (Strzeminska, 2021 and 2022).

Gadolinium Deposition in the Abdominal Organs

Like in the brain, administration of linear GBCA led to increased Gd concentrations in abdominal organs, like kidney and liver. In sheep, concentrations were 3-21x higher than for macrocyclic GBCA: for kidney 502 vs. 86 ng/g tissue, for liver 445 vs 21 ng/g tissue, and for spleen 72 vs 4 ng/g tissue. Gadodiamide concentrations were 879, 780 and 137 ng/g, gadobenate concentrations 179, 157 and 16 ng/g, and gadobutrol 86, 35 and 6 ng/g tissue, respectively. However, no tissue alterations were detected (Richter, 2021).

In the abdominal organs Gd was least retained after administration of gadoxetate, followed by gadobutrol and gadodiamide when clinically recommended doses were administered.

Most of the retained gadolinium was excreted within 4 weeks after GBCA administration (Oh, 2020).

Administration of macrocyclic GBCA led to measurable Gd concentrations in liver and kidney 4 weeks after administration, which were lower for gadoteridol compared to gadoterate and gadobutrol. The levels for liver ranged 0.36-1.22 nmol Gd/g tissue and for kidney 39-294 nmol Gd/g tissue (Bussi, 2020 and 2021).

Gadolinium Deposition in the Bone and Skin

In rat skin, macrocyclic GBCA led to measurable Gd concentrations 1-5 weeks after administration, which were lower for gadoteridol compared to gadoterate and gadobutrol. The levels in skin where initially high, but after washout levels at 5 weeks were in the order of 0.31-0.53 nmol Gd/g tissue (Bussi, 2020 and 2021).

In human cadavers, 80 days after last GBCA exposure the mean Gd concentration in bone and skin was 2.9-4.4x higher for gadobenate compared to gadoterate. Bone was the primary Gd retention site with levels of 23-100 ng/g tissue/mmol GBCA. Gadolinium elimination rate was high for skin (Kobayashi, 2021).

Potential clinical symptoms of Gd deposition

Despite the retention of Gd in various tissues, no histopathologic changes in rat brains could be found (Ayers-Ringler 2022), nor tissue alterations in MS patients (Kühn, 2022).

In addition, no effect on sensorimotor or behavioural functions could be demonstrated for either linear or macrocyclic GBCA in mice (Akai 2021) or humans (Vymazal, 2020). Gadolinium retention was not related to symptom worsening in relapsing MS patients (Cocozza, 2019).

However, for linear GBCA, pain hypersensitivity has been seen in rats (Alkhunizi, 2020). In MS patients, increased relaxation was associated with lower information-processing speed (Forslin, 2019) or may result in mild effects on cerebellar speech or verbal fluency (Forslin, 2019; Kühn, 2022).

Self-reported symptoms of gadolinium deposition

The ACR Committee on Drugs and Contrast Media has suggested alternative nomenclature for patients with a spectrum of self-reported symptoms and signs. These include neurologic, cognitive, musculoskeletal, and other non-specific complaints, and different cytokine levels. They suggest terming these Symptoms Associated with Gadolinium Exposure (SAGE), to standardize reporting. SAGE will need to replace older terms such as gadolinium deposition disease (GDD), gadolinium storage disease (GSD), and gadolinium storage condition (GSC) (McDonald, 2022).