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. 2024 Mar 8;10(6):e27419. doi: 10.1016/j.heliyon.2024.e27419

Gadolinium deposition in the liver and brain in a rat model with liver fibrosis after intravenous administration of gadoxetate disodium

Peiying Wei a,b,1, Qiuhui Hu b,1, Chengbin He b,1, Peng Hua c, Di Yang d, Chang Shao e, Lesi Xie e, Zhijiang Han a, Xiaoxuan Zhou b,⁎⁎, Zhongxiang Ding a,⁎⁎⁎, Hongjie Hu b,⁎
PMCID: PMC10966456  PMID: 38545226

Abstract

Objectives

To investigate gadolinium deposition in the liver and brain in a rat model with liver fibrosis (LF) after intravenous administration of gadoxetate disodium (GD) and the histological effects of gadolinium deposition in the liver and brain.

Methods

Adult male Sprague–Dawley rats were randomly assigned to one of the three groups: 1) LF group received intraperitoneal injection of carbon tetrachloride (CCl4) for 9 weeks alone; 2) LF&GD group received CCl4 and intravenous administration of GD (for 5 consecutive days); 3) GD group received olive oil and GD. Seven days after the final injection of GD, the deep cerebellar nuclei (DCN) and liver were excised to determine gadolinium concentrations via inductively coupled plasma mass spectrometry, and histologic staining was performed. Bonferroni's post-hoc test and Wilcoxon rank sum test were used to compare the differences between the three groups.

Results

The concentrations of retained gadolinium in the liver in the LF&GD group (2.18 ± 0.44 μg/g) were significantly greater compared to the LF group (0.02 ± 0.01 μg/g, P < 0.001) and GD group (0.37 ± 0.11 μg/g, P < 0.001). Also, the concentrations of retained gadolinium in DCN were increased in the LF&GD group (0.13 ± 0.06 μg/g) compared to the LF group (0.01 ± 0.00 μg/g, P < 0.001) and GD group (0.06 ± 0.02 μg/g, P = 0.019). No histopathological alterations were detected in the liver and DCN between LF&GD group and LF group.

Conclusions

LF aggravated gadolinium deposition in the liver and DCN after administration of GD. However, no significant acute histological alterations were observed due to gadolinium deposition.

Keywords: Gadolinium-based contrast agent, Gadoxetate disodium, Gadolinium deposition, Liver fibrosis, Deep cerebellar nuclei

1. Introduction

Liver fibrosis (LF), resulting from various chronic liver diseases, can eventually proceed to cirrhosis and even hepatocellular carcinoma [1,2]. Patients frequently undergo multiple contrast-enhanced MRI examinations throughout the course of LF development. However, the use of gadolinium contrast agents (GBCAs) has raised significant public concerns regarding the deposition of gadolinium in the body. Since Kanda et al. [3] in 2014 first reported that high signal intensity of the dentate nucleus and globus pallidus on unenhanced T1-weighted images was associated with repeated administrations of GBCAs, multiple studies on similar evidence have been emerging [[4], [5], [6], [7], [8]]. Accumulating evidences confirmed by inductively-coupled plasma mass spectrometry (ICP-MS) further showed that gadolinium retention was found in the brain, cerebrospinal fluid, and several other organs after repeated administration of GBCAs, even in humans and animals with normal renal function [6,[9], [10], [11], [12], [13], [14]]. These findings are mainly shown in linear GBCAs compared to macrocyclic GBCAs [6,[8], [9], [10],[14], [15], [16]]. Although there is no clear evidence that gadolinium retention causes any clinical symptoms [15,[17], [18], [19]], the potential toxicity of GBCA exposure and free gadolinium warrant safety concerns regarding the application of GBCAs. Consequently, in 2017, the European Medicines Agency (EMA) recommended the suspension of the marketing authorizations for three linear GBCAs: gadodiamide (Omniscan®), gadoversetamide (Optimark®), and gadopentate dimeglimine (Magnevist®) [20].

As a linear GBCA, gadoxetate disodium (GD) can improve the detection rate and characterization of liver lesions due to its specific hepatobiliary stage imaging, which has not been suspended by the European Medicines Agency and is still widely used for liver assessment [21]. However, several clinical studies have shown increased signal intensity in dentate nucleus after GD administration, probably due to gadolinium deposition [21,22]. Animal experiments further confirmed gadolinium deposition in organs after the administration of GD [23]. However, to the best of our knowledge, only a few studies have been conducted to investigate gadolinium deposition after GD exposure in disease models [24,25].

Only one previous study based on a rat model showed that LF did not result in increased gadolinium deposition in the liver and skin after the administration of GD [24]. However, as far as we know, there is no further evidence, and no study has been conducted to explore the effect of LF on the deposition of gadolinium in the brain, given that studies have confirmed that LF may cause blood-brain-barrier damage [26]. In addition, residual gadolinium in the brain can be used as a critical indicator to reflect gadolinium deposition in the whole body [14]. Therefore, further investigation of gadolinium deposition in the brain and liver in the presence of LF is essential.

Hence, the present study aimed to conduct quantitative analysis of gadolinium deposition following GD exposure (0.625 mmol/kg for 5 consecutive days) in the liver and brain of rats with LF, and to determine whether there were any histological alterations due to gadolinium deposition in the liver and brain.

2. Materials and methods

2.1. Animals

Twenty-five healthy male Sprague-Dawley rats (8 weeks old, 200–220 g) were obtained from the Experimental Animals Institute of Zhejiang University. The rats were housed in a specific-pathogen-free environment with an ambient temperature of about 22 ± 2 °C, air humidity of 40–70% and a 12:12 light/dark cycle for 1 week. The experimental model used was a well-accepted rat model of carbon tetrachloride (CCl4) – induced LF [27,28]. A total of 18 rats were used to induce LF. For CCl4 injections, a 1:1 mixture of olive oil and CCl4 was injected intraperitoneally at a dose of 1 mL/100 g of body weight twice per week for 9 weeks [28]. During this 9-week induction period, 5 rats died. After the last day of CCl4 injections, the remaining 13 rats were randomly assigned to two groups: LF Group (n = 6) received no further administrations, and LF&GD group (n = 7) received 0.625 mmol/kg of GD (Eovist; Bayer Health-care) via the tail vein in 0.25–0.5 mL/s once a day for 5 consecutive days starting on the final day of CCl4 injection, 5 h after the administration of CCl4. The GD group (n = 7) received intraperitoneal injection of olive oil and intravenous administration of GD, with the same injection volume and time point as the LF&GD group. Five days after the final day of CCl4 injection or after the last administration of GD, blood (0.6 mL) was withdrawn from the tail vein of each rat, and alanine aminotransferase (ALT), aspartate aminotransferase (AST), creatinine, total bilirubin (TB), albumin, uric acid (UA), urea, γ-glutamyl transferase (γ-GT) levels were measured using the corresponding enzyme-linked immunosorbent assay kit (Elabscience) according to the manufacturer's protocols. All rats were sacrificed 7 days after the final injection of GD. Immediately after euthanasia, two samples of liver and DCN tissue were harvested: one was stored at −80 °C, and one was fixed in formalin. Disposable equipment was used to avoid cross-contamination.

In this prospective study, all animal experiments were approved by the institutional ethical committee of animal experimentation of our hospital (NO. SRRSH20220427) and were performed in accordance with the guide for the care and use of laboratory animals.

2.2. MRI acquisition and analysis

MRI examination was acquired at both baseline and 7 days after the final injection of GD. MRI was performed on a clinical 3.0 T MRI (Discovery 750 w 3.0 T GE Healthcare system) using a dedicated two-channel rat coil before the first administration of GD and euthanasia. During the MRI scan, rats were anesthetized with isoflurane (Butler Schein Animal Health) (induction, 3.5% vol/vol; maintenance, 1.5–2% vol/vol). T1-weighted MRI was performed using a fast-spin echo sequence with the following parameters: repetition time (TR)/echo time (TE) = 500 ms/16 ms; field of view (FOV) = 6.0 cm; phase FOV = 0.75 cm; echo train length = 3; bandwidth = 14.71 kHz; matrix = 192 × 192; slice thickness = 1.2 mm; number of excitations (NEX) = 7. Finally, 11 slices were acquired to provide coverage from the olfactory bulb to the cerebellum.

The image analysis was performed by two experienced readers in a blinded way for each experimental group. T1 signal intensity was measured by positioning the regions of interest over the bilateral deep cerebellar nuclei (DCN) and brain stem (BS) according to the anatomy of the rat brain [29]. The DCN-to-BS signal intensity ratio (SIR) was calculated by dividing the mean signal intensity of the DCN by that of the BS.

2.3. Total gadolinium quantification

The homogenized cryopreserved tissue (liver weighed approximately 200 mg, DCN weighed approximately 20 mg) was mixed with 1 mL concentrated nitric acid (65% for analysis, Merck) and heated to 80 °C until complete digestion. After further dilution, samples were spiked with rhodium ICP-MS standard solution (Agilent7800), according to standard protocols. The gadolinium concentrations were determined by external calibration. The instrumental limit of quantification was 0.5 ng/g, considering all dilution steps. The concentrations inferior to the limit of quantification were treated conservatively as equivalent to 0.5 ng/g, when needed.

2.4. Histological analysis

Tissues were fixed in 10% neutral-buffered formalin for 24 h and then stored in 70% alchool, embedded in paraffin, and sliced into 5-μm-thick sections. Hematoxylin-eosin staining was performed on all the tissues, while the liver was stained with Masson's trichrome and Sirius Red staining, and the brain was subjected to Nissl staining according to standard procedures. The images of the liver and brain slides were acquired with a NanoZoomer S60 digital pathology slide scanner (Hamamatsu Photonics, Hamamatsu City, Japan). The LF stage was determined by a veterinary liver pathologist (9 years of experience) using the 0–6 Ishak staging system [30]. Additional slides were reviewed independently by a board-certified pathologist (14 years of experience) blinded to sample provenance.

2.5. Statistical analysis

Statistical analysis was performed using SPSS 27.0 (IBM Co., Armonk, NY, USA) and GraphPad Prism 9.0.0 software (GraphPad Software Inc, San Diego, CA). Quantitative data were tested for normality using Kolmogorov-Smirnova's test with data being normally distributed if P > 0.05. Continuous variables with normal distribution (ALT, creatinine, TB, albumin, UA, urea, γ-GT, DCN-to-BS SIR, and gadolinium quantification) were presented as mean ± standard deviation, and variables with nonnormal distribution (AST and UA) were expressed as median (interquartile range). Comparison of all three groups (LF group, LF&GD group, GD group) was performed by using One-way factorial analysis of variance followed by Bonferroni's post-hoc test (for normal distribution data) or Kruskal-Wallis test with post-hoc correction (for nonnormal distribution data). The difference in DCN-to-BS SIRs between baseline and 7 days after the last GBCA injection was analyzed using paired t-test. Individual data that were five-fold lower or higher than other data of the group were considered outliers and excluded. For all tests, P < 0.05 was considered a statistically significant difference.

3. Results

3.1. Serological indexes for each experimental group

ALT and AST were higher in the LF group (both P < 0.05) and LF&GD group (both P < 0.01) than in the GD group. TB was higher in LF&GD group than in the GD group (P = 0.020), but no significant difference was observed between the LF group and GD group (P = 0.097). Albumin was lower in the LF group (P = 0.031) and LF&GD group (P = 0.017) than in the GD group. UA was higher in the LF group than in the GD group (P = 0.007), and no significant difference was detected between the LF&GD group and GD group (P = 0.092). In addition, no significant difference was observed in ALT, AST, TB, albumin, and UA between the LF group and LF&GD group (all P = 1.000). Creatinine, urea, and γ-GT did not differ significantly between the three groups (all P > 0.100) (Table 1).

Table 1.

Serological indexes for each experimental group.

Index LF group (1)
(n = 6)		 LF&GD group (2)
(n = 7)		 GD group (3)
(n = 7)		 P value Pairwise comparisons (P value)
1 vs 2 1 vs 3 2 vs 3
ALT (U/L) 191.71 ± 60.23 233.12 ± 129.80 47.49 ± 9.18 0.004 1.000 0.026 0.004
AST (U/L) 268.06 ± 103.21 276.54 ± 64.65 140.65 (136.26, 154.40) 0.004 1.000 0.028 0.006
Creatinine (umol/L) 43.26 ± 7.25 42.34 ± 4.82 37.21 ± 6.65 0.236 1.000 0.356 0.543
TB (umol/L) 10.47 ± 1.12 11.49 ± 3.56 7.39 ± 1.19 0.018 1.000 0.097 0.020
Albumin (g/L) 29.17 ± 1.96 29.45 ± 1.20 32.26 ± 1.72 0.010 1.000 0.031 0.017
γ-GT (U/L) 3.36 ± 1.86 2.23 ± 0.51 4.10 ± 1.52 0.103 0.563 1.000 0.112
UA (umol/L) 92.88 ± 27.52 68.63 (58.84, 94.96) 47.26 ± 11.46 0.008 1.000 0.007 0.092
Urea (mmol/L) 5.06 ± 0.49 4.92 ± 0.32 4.88 ± 0.46 0.767 1.000 1.000 1.000
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Values are expressed as mean ± standard deviation or median (interquartile range). GD, gadoxetate disodium; LF, liver fibrosis; ALT, alanine aminotransferase; AST, aspartate aminotransferase; TB, total bilirubin; UA, uric acid; γ-GT, γ-glutamyl transferase.

3.2. Histological findings

Masson's trichrome and Sirius red-stained sections demonstrated LF in LF&GD group and LF group (Fig. 1), and the fibrosis stage did not differ significantly between the two groups (Ishak stage 5). In the GD group, there was no evidence of LF (Ishak stage 0). No other histopathological difference was observed between the LF GD group and LF group in the liver and DCN (Fig. 1, Fig. 2). Besides, compared with GD group, both LF&GD group and LF group had degenerative changes in the DCN, that is, the density of neurons was reduced, and the neuropil was mottled and degenerated.

Fig. 1.

Fig. 1

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Example images of liver stained with hematoxylin-eosin (H&E), Masson trichrome, and Sirius red for the three groups.

Fig. 2.

Fig. 2

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Example images of DCN stained with H&E and Nissl for the three groups.

3.3. DCN-to-BS SIRs for each experimental group

No data were excluded. Fig. 3 shows the representative images of the cerebellum containing the DCN for each experimental group before and after repeated GD administration. DCN-to-BS SIRs increased in the LF&GD group (P = 0.005 for left; P = 0.011 for right) and GD group (P = 0.019 for left; P = 0.032 for right), 7 days after the last GD injection compared to those at baseline MRI. No significant difference was observed in DCN-to-BS SIR between baseline and before euthanasia in the LF group (P = 0.278 for left; P = 0.322 for right). Among the three groups, no significant differences were detected in the left and right DCN-to-BS SIR at baseline (P = 0.076 for left, P = 0.426 for right) or 7 days after the last administration of GD (P = 0.277 for left, P = 0.784 for right) (Fig. 4, Table 2).

Fig. 3.

Fig. 3

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Representative T1-weighted images of the cerebellum containing the DCN for the three groups before and after repeated intracisternal administration of GD.

Fig. 4.

Fig. 4

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Signal intensity evaluation of DCN on unenhanced T1-weighted magnetic resonance images. (A) Comparison of left DCN-to-BS SIR between baseline and 7 days later in three groups. (B) Comparison of right DCN-to-BS SIR between baseline and 7 days later in three groups. Significance was assigned to P ≤ 0.05 (*), P ≤ 0.01 (**), and P ≤ 0.001 (***).

Table 2.

Left and right DCN-to-BS SIRs for each experimental group.

Treatment group Left DCN
 Right DCN
SIRPre SIRPost P value SIRPre SIRPost P value
LF group (n = 6) 0.97 ± 0.03 1.00 ± 0.04 0.278 0.98 ± 0.05 1.02 ± 0.05 0.322
LF&GD group (n = 7) 0.92 ± 0.04 1.03 ± 0.04 0.005 0.96 ± 0.04 1.03 ± 0.02 0.011
GD group (n = 7) 0.94 ± 0.03 1.00 ± 0.03 0.019 0.96 ± 0.03 1.02 ± 0.04 0.032
P value 0.076 0.426 0.277 0.784
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Values are expressed as mean ± standard deviation. DCN, deep cerebellar nuclei; BS, brain stem; SIR, signal intensity ratio; SIRPre, SIR at the pre-injection time point; SIRPost, SIR at the post-injection time point; GD, gadoxetate disodium; LF, liver fibrosis.

3.4. Concentration of gadolinium in tissues after GD exposure

One gadolinium concentration (0.32 μg/g) in DCN in the GD group was excluded because of a five-fold difference with the other data in their group. The concentrations of retained gadolinium in the liver in LF&GD group were significantly greater compared to the LF group (P < 0.001) and GD group (P < 0.001), but no significant difference was detected between the LF and GD groups (P = 0.093). The concentrations of retained gadolinium in DCN in the LF&GD group were significantly greater compared to the LF group (P < 0.001) and the GD group (P = 0.019), but no significant difference was observed between the LF and GD groups (P = 0.139) (Fig. 5, Table 3).

Fig. 5.

Fig. 5

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Gadolinium concentrations in liver and DCN measured by inductively coupled plasma mass spectrometry. (A) Comparison of gadolinium concentration in liver among three groups. (B) Comparison of gadolinium concentration in DCN among three groups. Significance was assigned to P ≤ 0.05 (*), P ≤ 0.01 (**), and P ≤ 0.001 (***).

Table 3.

Mean concentration of gadolinium in tissues after GD exposure.

Tissue LF group (1)
(n = 6)		 LF&GD group (2)
(n = 7)		 GD group (3)
(n = 7)		 P value Pairwise comparisons (P value)
1 vs 2 1 vs 3 2 vs 3
Liver 0.02 ± 0.01 2.18 ± 0.44 0.37 ± 0.11 <0.001 <0.001 0.093 <0.001
DCN 0.01 ± 0.00 0.13 ± 0.06 0.06 ± 0.02 <0.001 <0.001 0.139 0.019
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Values are expressed as mean ± standard deviation (gadolinium, in μg/g). GD, gadoxetate disodium; LF, liver fibrosis; DCN, deep cerebellar nuclei.

4. Discussion

In the present study, we used a rat model of LF to investigate the effect of LF on gadolinium deposition in the liver and brain 7 days after administration of GD and the histological effects of gadolinium deposition on the liver and brain. Our results revealed for the first time that LF led to increased deposition of gadolinium in the liver and DCN after administration of GD, and the existence of gadolinium did not cause tissue damage.

Currently, only a few studies have evaluated gadolinium deposition after the administration of GD, and the results are divergent in both clinical and animal studies. Although Conte et al. [31] and Ichikawa et al. [32] demonstrated that multiple administrations of GD were not associated with increased signal in dentate nucleus and globus pallidus on unenhanced T1-weighted images, subsequent reports have shown the opposite results [21,22,33]. An autopsy study by Murata et al. [34] used ICP-MS and confirmed that gadolinium deposition occurred in the brain of a decedent with normal kidney function who had been administered GD. Early animal studies also showed the opposite results. Mühler et al. [35] did not show any gadolinium retention in the liver and negligible presence in the brain after repeated administration of GD. Another study showed retained gadolinium in the liver at a concentration higher than that measured in the other organs [36]. A recent study investigated gadolinium deposition in rat abdominal organs after administration of GD compared to gadodiamide and gadobutrol; the results showed that residual gadolinium was minimal in all tissues after administration of GD but higher than that in the control group [23]. Therefore, additional evidence is needed for gadolinium deposition after injection of GD.

Only a few studies have focused on the effect of disease status on gadolinium deposition after the administration of GD [24,25]. In 2012, Hope et al. [24] demonstrated that the administration of GD in a rat model of active LF did not result in increased gadolinium deposition in the liver or increased fibrosis. Conversely, our results showed that LF aggravated gadolinium deposition in the liver. We speculated that the reason for different findings might be related to different grades of LF and injection schemes of GD. In 2015, Sato et al. [25] found that gadolinium deposition was significantly greater in the kidney, spleen, and liver of hepatorenally-impaired rats than that in renally-impaired rats after GD exposure. However, LF was not analyzed as a single factor in Sato et al.’s study [25], given the interaction of the urinary and biliary excretion mechanism of GD. In addition, we investigated for the first time the effect of LF on gadolinium deposition in the brain after administration of GD, and showed positive evidence. Congruent with previous nonclinical histological studies and clinical studies on other GBCAs [9,17,37,38], no histopathological changes caused by gadolinium deposition were observed. Additionally, gadolinium deposition in the liver after administration of GD did not aggravate LF, consistent with the finding of Hope et al. [24].

Inflammation in the liver causes capillarization and dysfunction of sinusoidal endothelial cells in the setting of LF, resulting in increased vascular permeability [24,39]. Thus, LF may result in increased gadolinium in the liver, as approximately 50% of GD is taken up by hepatocytes and excreted through bile [21,40]. While LF aggravated gadolinium deposition in the DCN, it might be related to its effect on the permeability of the blood-brain-barrier [26]. However, we did not find any evidence of LF resulting in increased signal intensity in the DCN on unenhanced T1-weighted magnetic resonance images and speculated that the increased deposition of gadolinium caused by LF was not sufficient to alter the T1 relaxation rate. However, the results showed that LF&GD group was significantly higher compared to LF group, which was consistent with previous studies [23].

Due to the high protein-binding properties in the blood, GD has a higher longitudinal relaxation than other GBCAs. Thus, the recommended dose of GD is only a quarter of that of other GBCAs [23]. Therefore, the injected dose of GD taken in this study was 0.625 mmol/kg, based on the dose of 2.5 mmol/kg taken for other GBCAs in previous studies [18,41,42]. This dose was also determined with reference to the set-ups reported previously [25]. Although the dose used in our study was larger than that used clinically (0.025 mmol/kg), a higher dose was used to increase the possibility that aggravation of gadolinium deposition caused by LF would be visualized if present.

Our studies present several limitations. First, only male rats were used in this study. A dedicated study was needed to account for potential sex variability. Second, different grades of LF may lead to different concentrations of retained gadolinium, necessitating additional studies. Third, the present study aimed to investigate the effect of LF on gadolinium deposition in the liver and DCN after administration of GD. Thus, further studies are essential for the deposition of other organs, such as the skin, kidney, and spleen. Fourth, although there was a statistical difference in DCN-to-BS SIR between baseline and 7 days after the last GD injection, this difference may not be very obvious on the magnetic resonance images we provided. We speculated that it might be related to insufficient image resolution and contrast, as well as the use of a clinical 3.0 T MRI for scanning. Finally, only one GBCA was used in this study, and GD should be compared to other linear GBCAs or macrocyclic GBCAs for final validation.

In conclusion, LF aggravated gadolinium deposition in the liver and brain in rats following repeated injections of GD, and gadolinium deposition in the liver and brain did not cause corresponding histological alterations.

Funding statement

This work was supported by the National Natural Science Foundation of China (82071988), the China Postdoctoral Science Foundation (2020M681889), the Zhejiang Provincial Medical and Health Technology Project (2021RC024, 2023RC181).

Data availability statement

Data will be made available on request.

Additional information

No additional information is available for this paper.

CRediT authorship contribution statement

Peiying Wei: Writing – review & editing, Writing – original draft, Visualization, Validation, Supervision, Software, Project administration, Methodology, Investigation, Funding acquisition, Data curation, Conceptualization. Qiuhui Hu: Writing – review & editing, Visualization, Validation, Software, Project administration, Methodology, Data curation. Chengbin He: Writing – review & editing, Visualization, Validation, Supervision, Software, Methodology, Investigation. Peng Hua: Visualization, Validation, Software. Di Yang: Writing – review & editing, Visualization, Validation, Supervision, Methodology. Chang Shao: Writing – review & editing, Visualization, Validation, Software, Methodology, Investigation, Data curation. Lesi Xie: Visualization, Validation, Software, Methodology, Investigation, Data curation. Zhijiang Han: Writing – review & editing, Supervision, Project administration, Investigation, Formal analysis. Xiaoxuan Zhou: Writing – review & editing, Visualization, Resources, Funding acquisition, Formal analysis, Data curation, Conceptualization. Zhongxiang Ding: Writing – review & editing, Resources, Project administration, Formal analysis, Data curation, Conceptualization. Hongjie Hu: Writing – review & editing, Validation, Resources, Project administration, Funding acquisition, Formal analysis, Data curation, Conceptualization.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Contributor Information

Xiaoxuan Zhou, Email: zhouxiaoxuan@zju.edu.cn.

Zhongxiang Ding, Email: hangzhoudzx73@126.com.

Hongjie Hu, Email: hongjiehu@zju.edu.cn.

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