Gadolinium-based contrast agents (GBCAs) are used in magnetic resonance imaging to increase diagnostic performance. Gadolinium in its elemental form is toxic to humans because the ionic radius of gadolinium is close to that of calcium and, thus, it may act as an inorganic blocker of calcium channels.1 In addition, gadolinium ion substitution for calcium in biological sites may stay bound for long periods due to the +3 charge on the gadolinium ion. To prevent this, gadolinium in contrast agents is administered in a chelated form (ie, incorporated into a ligand), and in this form, it is considered safe.2,3 The first indication for concern with GBCAs came in 2006 with the discovery of nephrogenic systemic fibrosis. Nephrogenic systemic fibrosis is a rare debilitating condition that occurred in patients with renal failure and has been associated with the use of GBCAs,2 primarily certain linear GBCAs that more readily release unchelated gadolinium in vivo.
To further underscore concerns of potential adverse effects from gadolinium use, Kanda et al4 reported an increasing T1-weighted image hyperintensity within the brain in the globus pallidus (GP) and dentate nucleus (DN) related to cumulative doses of linear GBCA, even in patients with normal renal function. This observed hyperintense T1 was confirmed to be associated with retention of small amounts of gadolinium from an autopsy study by McDonald et al.5 A subsequent autopsy study by our group6 demonstrated the variability in retained gadolinium among different contrast agents. Significance of these small amounts of retained gadolinium in human tissue is not fully understood; however, the potential for toxicity remains of great concern. Although several observational studies have failed to show a toxic effect from these small amounts of retained gadolinium, there is a small group of patients who reportedly suffer from various maladies including pain and debilitation, which they attribute to GBCA exposure. Although controversial and, as yet, unproven, these patients have been referred to as having “gadolinium deposition disease” by Semelka et al7 who is currently studying this patient group and continuing to evaluate them.
Although, to date, no proven adverse effect from administered gadolinium exists, there is still considerable detail that is not known regarding GBCAs and their biologic behavior. We do know that small amounts of gadolinium are retained in the human body but we do not know the speciated form(s) of these deposits. We also have evidence that different GBCAs are retained and eliminated at different rates in rats,8 although this is not directly transferable to humans. Bower et al9 showed evidence of GBCA toxicity in neuronal cell culture that was directly related to GBCA concentration and inversely related to kinetic stability of the various agents. In addition, Bower et al pointed out that any clinical effect was likely to be related to factors such as the amount of retained gadolinium, the rate of elimination, and the integral of the amount retained over a long period. Thus, to begin to accumulate these types of data to evaluate for possible subtle long-term effects, a noninvasive method is needed to quantify tissue gadolinium.
A major impediment in evaluating patients with possible gadolinium toxicity is that we lack a reliable method to noninvasively sample, quantify, and monitor gadolinium in humans in vivo. One possible biological material that is known to concentrate heavy metals, is readily accessible, and can be obtained noninvasively is hair. The purpose of this study is to use laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS) to evaluate gadolinium levels in hair obtained from decedents that were exposed to GBCA during life and to determine if there is a possible correlation with concentrations in other body tissues obtained at autopsy including brain, bone, and skin.
MATERIALS AND METHODS
This study was approved by our institution's Human Subjects Review Board for retrospective review of medical records and was Health Insurance Portability and Accountability Act compliant. In addition, autopsy consent from each case granted authorization for use of tissues for research purposes.
Cases were identified, and their electronic medical records (EMRs) were screened when they presented for autopsy between December 2017 and May 2019 at the pathology department in our institution. If they met the inclusion criteria, brain, bone, skin, and hair samples were collected. Inclusion criteria included having complete and accessible medical records, a history of 1 or more GBCA injection(s), exposure to a single type of GBCA, and most recent exposure within 1 year before death. Medical records were thoroughly reviewed, to the best of our ability, to make a determination as to the completeness of those records. The time limitation (ie, 1 year before death) was implemented due to the shorter hair lengths in received samples. For example, an injection 1 year ago would require approximately 12 cm of hair to capture the exposure period. Exclusion criteria included inaccessible or incomplete medical records, and exposure to multiple GBCA types. Initially, a total of 42 cases with gadolinium exposure and 2 controls were identified from the consecutive autopsy review.
Electronic medical records were subsequently more thoroughly searched for exposure to GBCA. The type of GBCA administered, dose, and date of injection for all recorded injections were compiled for all cases with exposure. Subjects documented without exposure to GBCAs were included as controls. Age, sex, and estimated glomerular filtration rate (eGFR) were recorded for all subjects. For subjects with eGFR values above 60, autopsy records report “>60.” For subjects with eGFR values below 60, the actual numeric value is reported.
A tiered screening methodology was used to identify cases that did not meet inclusion criteria. Nine subjects received injections of more than 1 GBCA type, 12 received injections more than a year before their death, 1 had very short hair that was too short to capture the exposure period, 1 did not have a hair sample, and 1 more was missing that required information in the EMR. In total, 24 potential cases were excluded from this initial study group. Eighteen cases with a history of exposure to a single type of GBCA with the most recent injection occurring within 1 year were identified for inclusion. Two of those cases did not have hair long enough to capture the exposure period (eg, hair length representative of 1 month of growth, but exposure period was 6 months prior) and were excluded. Human scalp hair, on average, grows at the rate of 1 cm/month.10 Final inclusion was 16 cases and 2 controls in this study. Table 1 summarizes subject characteristics for the subset included here.
Hair-bearing scalp samples as well as brain sections including the GP, DN, and white matter (WM) were collected for all subjects. Skin and bone (rib) samples were also collected at the time of autopsy for most subjects. Brain, bone, and skin tissue samples were stored in a 10% formalin solution. After receipt from the pathology department, all tissue samples were cut using stainless steel surgical instruments (eg, scalpel blades, scissors), which were cleaned with distilled water and dried between each sample to prevent cross contamination of gadolinium. Brain, bone, and skin tissue samples were cut and weighed using an analytical balance (AG104; Mettler Toledo, Greifensee, Switzerland). Samples underwent microwave-assisted nitric acid digestion before ICP-MS analysis following a modified version of the US Environmental Protection Agency method 6020a (revision 1, 2007).
Hair from the scalp samples were plucked, including the root when possible, using carbon fiber (nonmetal) tweezers and placed in microfuge tubes (1 per subject); these tubes were filled with acetone and the caps closed. Tweezers were cleaned with methanol between subjects to prevent cross contamination. The microfuge tubes with hairs and acetone were sonicated for 30 minutes in water at room temperature. The hairs were then removed from the acetone and placed in Kim Wipe pouches to be dried in an incubator at 37°C for 1 hour. This washing process has been used previously11 and removes exogenous contamination from the hair shaft. The cleaned hairs are then mounted onto glass slides covered in double stick tape, which adheres the hair to the slide without damaging the shaft. The slides were placed on the laser stage along with calibration gels and a glass pellet standard reference material (National Institute of Standards and Technology, 612) with trace metals. The calibration gels were bovine skin–based gelatin amended with selected isotope concentrations between 0 and 2000 μg/g.
For LA analysis, the laser path along each hair was traced as a single line scan from root to tip in the instrument software (Agilent NWR ESI ActiveView). After the material was ablated, it was transported through a Teflon tube to the ICP-MS via a stream of helium for analysis. Between 4 and 18 hairs were analyzed from cases, and 2 hairs were analyzed from the controls. Calibration gels and standard reference material were included in each batch run to assess instrument stability over time. After samples were analyzed, counts per second (cps) data were output from the ICP-MS software (MassHunter).
The instrumentation used for analysis of the hairs included an Elemental Scientific, Inc, New Wave Research 213 (Nd:YAG [neodymium:yttrium aluminum garnet]) laser interfaced to an Agilent 7900 ICP-MS. The laser operated at a 213-nm wavelength.12 The LA instrument was outfitted with a 2-volume sample cell, which minimized material lost during ablation as well as signal broadening. The helium flow through the laser was 800 mL/min with 1.07 L/min of argon makeup gas T-ed in between the laser and ICP-MS. The sampling period for all isotopes and materials was 0.515 seconds and the integration time for 157Gd was 0.4 seconds. The ICP-MS was set to helium mode without collision cell gas and a radiofrequency power of 1550 W. Laser parameters for the hair and gel analysis were as follows: spot size of 30 μm, firing rate of 20 Hz, scan speed of 100 μm/s, and energy of 60%. Brain, skin, and bone tissue were analyzed using the same ICP-MS instrument listed above, except that argon carrier gas flow was 1.03 L/min with no makeup gas.
Data Processing and Analysis
Laboratory-reported gadolinium concentrations were used for the brain (GP, DN, and WM), skin, and bone samples. The time series of m/z157 intensities for each hair profile was processed using a rolling mean centered on 5 values. Similar data reduction techniques (ie, rolling average and/or median) have been used by previous LA-ICP-MS analysis of hair,13 corals,14 and otoliths.15 Mass-based concentrations (ie, microgram per gram) of 157Gd in each hair line scan were calculated using a linear regression calibration curve derived from the gels. The distance along the hair shaft (in millimeters) was derived from the scan speed of the laser (100 μm/s for hair) and the acquisition time of each data point. An example plotted line scan for an individual hair showing a 157Gd peak is provided in Figure 1A; an example of a hair from one of the control subjects with no peak is shown in Figure 1B.
For each hair line scan with an identified peak, the portion along the shaft (excluding the root) that included a 157Gd peak was isolated and the maximum concentration was selected as the representative measure for the individual hair. These maximum values were averaged for all hairs analyzed for a specific subject to generate a representative measure of the hair gadolinium concentration for that subject. Hair from control subjects showed no 157Gd peaks, and the average of the hair line scan was used as the representative concentration for each hair; an average of all hairs analyzed was used as the representative concentration for a control. Concentrations below the LA-ICP-MS method's detection limit (0.05 μg/g) were set to 0.05 μg/g.
Using the “lm()” function in RStudio (version 3.4.0), a linear regression between each tissue type was conducted to assess the relationship between tissue concentrations. Significance was determined as P < 0.05. Due to the small sample size, no adjustments were made (ie, did not use controlling variables).
There were 16 cases with exposure to GBCAs and 2 controls included in this study. Approximately, a third of the cases received linear GBCAs (gadoxetate or gadobenate) and the remaining two thirds received macrocyclic GBCAs (gadobutrol or gadoteridol). There is some variability in the concentration of injectable gadolinium agents. Thus, gadoxetate contains 0.25 mmol/mL, gadobenate and gadoteridol contain 0.5 mmol/mL, and gadobutrol contains 1.0 mmol/mL. Total GBCA dose for each case was calculated as the total number of mL injected multiplied by the GBCA molarity of the agent received. Two cases (subjects 3 and 6) received 3 injections, and the other 14 cases received only 1 injection. For the 2 cases that received multiple GBCA injections, subject 3 received injections at 51, 70, and 75 days before death, and subject 6 received injections at 5, 6, and 106 days before death. Days between the last injection and death were between 2 and 69. For 2 subjects (2 and 3), brain and hair samples were received for analysis, but no skin or bone samples.
Cases had higher 157Gd concentrations than controls by at least a factor of 5 (conservative estimate due to detection limit) and up to a factor of 100. Among the brain tissue samples, the GP results were generally the highest with an average concentration of 0.11 μg/g compared with the DN and WM, which had average concentrations of 0.046 and 0.027 μg/g, respectively. Skin concentrations ranged from 0.0154 to 0.21 μg/g, and bone concentrations ranged from 0.11 to 2.3 μg/g. The highest tissue concentrations were present in the hair samples at 5.3 μg/g for subject 9. This was consistent with previously published articles16,17 noting that metal concentrations in hair can be 1 to 2 orders of magnitude higher compared with other tissues. Summaries of the subjects and tissue concentrations are in Table 2.
Comparison of the different tissues using linear regression revealed good agreement (ie, correlation) between some tissue types. The best model fit was the comparison between WM and hair concentrations (R2 = 0.83; P < 0.0001) followed by the comparison between DN and hair (R2 = 0.72; P < 0.0001), and DN and skin (R2 = 0.70; P < 0.0001). The correlation between DN and hair is shown in Figure 2. The DN is of particular interest as it plays an important role in planning and initiation of voluntary movement, and is also a known location of high gadolinium deposition in the brain.5,6
Increasing hair concentrations correlated significantly with increasing concentrations in DN, WM, and skin tissues. Although the linearity between hair and bone was low (R2 = 0.30), this relationship was still statistically significant at an alpha of 0.05. Figure 3 displays the linear regression results' R2 values and associated P values for all tests.
All regressions that included GP results were generally not linearly related (ie, low R2 values), indicating high variability between GP concentrations and other tissue concentrations. The GP results for subject 7 were almost twice as high as the next highest GP concentration. The other tissue concentrations for this subject did not reflect the same degree of elevated gadolinium concentrations. This result was considered an outlier in the GP results, and if it were to be excluded from the regression analysis, the linearity of the relationship between GP and hair is improved from an R2 of 0.049 (P = 0.19) to 0.22 (P < 0.05). Figure 4 shows the comparison between GP and hair with the outlier.
Gadolinium-based contrast agents are administered intravenously and most are excreted in the urine.3 Two of the GBCAs included in this study, gadoxetate and gadobenate, are not solely excreted in the urine, but also excreted through the liver. There are 2 general types of GBCAs: the first are linear agents in which the structure of the ligand includes an open chain linked to the gadolinium atom, and the second are macrocyclic agents, where the gadolinium atom is enclosed within a cyclic ligand.2 Linear agents are less stable than macrocyclic agents and thus are more likely to release the gadolinium into the body.18 Multiple studies have demonstrated higher levels of retained tissue gadolinium associated with linear compared with macrocyclic agents.6,19
Using T1 hyperintensity in the GP and DN to quantify gadolinium can be unreliable because other metals (eg, iron and copper) can accumulate in these tissues and contribute to T1 hyperintensity.20 The method used to quantify gadolinium in most studies using human autopsy tissue is ICP-MS, which is a destructive process.5,6,21 These studies have found that, compared with cases without exposure to GBCAs, brain specimens including GP and DN with history of GBCA use have statistically significant increased concentrations of gadolinium. The highest levels of retained gadolinium in the brain are found in deep gray nuclei including the GP and DN, although lesser amounts can also be found in other brain structures including WM. It should also be noted that control subjects without exposure to GBCA may still show trace levels of gadolinium but at much lower levels (usually 1 to 2 orders of magnitude lower) compared with exposed patients. This presumably represents accumulation from exogenous background contamination in water or other sources of gadolinium.
As patients continue to receive GBCAs for diagnostic imaging procedures, development of appropriate monitoring strategies is crucial to better understand the natural history and to assess possible toxic effects of the small amounts retained in human tissue. The recent revelation that gadolinium deposition occurs in various tissues, and the limited research on relationships between gadolinium deposition and reported adverse outcomes underscores this need for effective, noninvasive monitoring. The analyses presented here were chosen to include tissues with presumed different gadolinium kinetics (ie, deposition and washout/elimination).
Hair fibers are proteinaceous fibers with an outer cuticle, inner cortex, and sometimes a central medulla.22Figure 5 shows the general anatomy of the 2 primary hair components: the hair shaft (ie, the fiber) and the hair follicle (ie, the structure embedded within the skin). The cortex is the thickest layer of the hair shaft and is largely composed of keratin, which contains sulfhydryl groups of amino acids.17,23 The sulfhydryl groups show high affinity for metals, which can facilitate their deposition into the hair shaft.17 However, the mechanism by which metals are incorporated into hair during fiber synthesis is still not well characterized.17 Concentrations of metals in hair are generally higher (by an order of magnitude or more) than concentrations in blood and urine.16,17 Hair samples are stable and, thus, make storage and transport considerably simpler than other tissue samples. In addition, the noninvasiveness of sample collection is very attractive.17
Recently, techniques linking LA with ICP-MS analysis have been developed to produce highly spatially resolved data of trace metals in biological samples. When a hair is analyzed using LA, the result is that numerous data points are continuously compiling as the hair is ablated and material is sent to the ICP-MS. Depending on the optimized instrument parameters (eg, laser pulse rate) and the length of the hair, each hair may have hundreds to thousands of discrete data points.
High-resolution quantitative elemental distributions with LA-ICP-MS have been produced in brain tissues,24Daphnia magna (planktonic crustaceans) and Danio rerio (zebrafish) embryos,25 skin tissues,26 and at our own University of Washington laboratory in mouse brain tissue27 and nasal rosettes from COHO salmon.28 The application of this microdestructive technique29 has also been used to quantify metal contents in hair. This includes animal and human research on single point and time-resolved temporal frames.13,30–35
Previous studies have used ICP-MS to quantify gadolinium in hair for target subject populations including cancer patients,36 patients receiving GBCAs,37 and residents living near rare earth mining areas.38 The measurement of gadolinium using LA-ICP-MS on the whiskers of mice exposed to GBCAs was recently reported.39 This study used line scan analysis techniques that showed that higher doses of GBCA resulted in higher gadolinium concentrations within the whiskers.
The LA-ICP-MS has been established as a powerful and sensitive analytical technique for trace metal quantification and distribution at micrometer resolution. Unfortunately, this method is destructive and is difficult to use on live tissue. Using this technique on hair strands has allowed monitoring of toxic metals and drugs, and has the potential to monitor gadolinium in patients after administration of GBCAs. However, this technique has not been fully investigated for gadolinium, and no study to date has correlated gadolinium concentrations in hair with other tissues such as brain, bone, and skin.
The measure used for the hair concentration in this study is representative of a maximum signal from a single dose, whereas the brain, skin, and bone concentrations may reflect accumulation from multiple doses for some subjects. Although 2 of our cases were exposed to more than 1 dose of GBCA, there was still a very good correlation between the measured hair concentration, especially in brain WM and DN. However, this was not adequately tested with our small pilot study sample size. In addition, this study tested 1 method of hair concentration quantification using a single maximum signal measure. There are other methods such as analyzing low levels of steady-state hair gadolinium concentration that may be useful but were not tested in this initial study. Independent of the hair measure, other tissue concentrations will presumably be attenuated over time, differentially for each tissue, and based on the tissue-specific excretion kinetics for gadolinium and/or the gadolinium chelates. The effect this will have on the measured tissue correlations with hair remains to be determined.
Other articles19,40,41 have reported higher tissue gadolinium concentrations (either through T1-weighted image or ICP-MS) in humans and animals who received linear GBCAs, compared with macrocyclic GBCAs. However, the data derived from this study did not show a difference in linear regression between these 2 types of GBCA. Although the case study group included roughly two thirds macrocyclic agents and one third linear agents, they defined a single continuous regression line. This likely reflects the fact that, although the 2 different types of GBCA retain gadolinium at different rates, the mechanism of tissue retention, or at least of hair accumulation, is similar for both GBCA types. In a way, this supports the potential for hair analysis because it further suggests the ability to measure gadolinium retention independent of GBCA type or types (in the case of multiple exposures) the patient may have been exposed to.
There are many limitations to this initial pilot study. Gathering relevant autopsy cases is difficult and precludes typical recruitment methods. One is subject to the limitations of which cases come to autopsy and what their history of GBCA exposure is. Thus a small sample size was analyzed. In addition, the GBCA agents studied were limited for similar reasons.
Despite this, we were able to study a reasonable distribution of linear and macrocyclic agents that included 2 cases with multiple exposures. Although we used our best efforts to thoroughly review each subject's medical records, this study was a retrospective one, and thus, there is the potential that some pertinent information was not available. Only 1 LA-ICP-MS hair analysis method was tested in this study and future work with alternative analysis types are being pursued.
This research study shows significant correlation between hair gadolinium concentrations and brain and skin gadolinium concentrations, suggesting that hair may serve as a safe and effective biomonitoring tissue for patients who receive GBCA injections. This was an initial pilot study with a small sample size from a nonideal study population. Nevertheless, the results are promising and should prompt further research.
This work was supported by the National Institute of Environmental Health Sciences (grant number P30ES007033) and in part by a grant from Guerbet, LLC. The content is solely the responsibility of the authors and does not necessarily represent the views of the National Institute of Environmental Health Sciences or Guerbet, LLC.
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