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Accumulation of rare earth elements in human gallstones: a perspective from dietary and human health

BMC Gastroenterology volume 24, Article number: 324 (2024) Cite this article

Abstract

Background

Gallstone disease poses a global threat to human health and is strongly linked to environmental factors. However, there is currently no data on the presence of rare earth elements (REEs) in human gallstones. This paper investigates the concentration and distribution of REEs in gallstones for the first time, aiming to explore the environmental implications on human health.

Methods

A total of 25 gallstone samples were collected in Shanghai and the content of REEs was measured by Inductively coupled plasma-Mass Spectrometry (ICP-MS) to explore the distribution of REEs in gallstones.

Results

The concentration of REEs in gallstones ranged from 4.89 to 190.8 ng/g (mean 39.21). In most of the gallstone analyses, REEs have been detected and generally attributed to environmental exposure or food contamination. The Y/Ho ratio of gallstones was lower than that of continental rocks, similar to that in the blood, indicating limited fractionation during fluid transport processes in the gallbladder.

Conclusions

The upper continental crust (UCC)-normalized REEs pattern in gallstones showed depletion of light REEs, while most showed enrichment of heavy REEs. Positive Gd anomalies were found in most samples, while few samples suggested anthropogenic influence. Whether exogenous inputs or in vivo biofractionation lead to changes in REEs fractionated patterns require further analyses.

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Introduction

Rare earth elements (REEs) refer to the lanthanides in the periodic table, ranging from lanthanum (La) to lutetium (Lu), which share similar physicochemical properties [1]. Moreover, REEs are usually divided into light REEs (LREEs, La to Nd), medium REEs (MREEs, Sm to Ho), and heavy REEs (HREEs, Er to Lu) due to their different chemical properties [2]. The key difference lies in their ionic radii and ability to form stable complexes; LREEs have larger ionic radii and tend to be more electropositive, while HREEs have smaller ionic radii and are more likely to form stable complexes with ligands, and MREEs are intermediates in size and reactivity between LREEs and HREEs. In recent decades, REEs have been widely used in agriculture, industry and medicine, high-tech industry, and others [3, 4]. The increasing use of REEs poses a higher risk of environmental exposure to humans, as REEs are non-essential elements for living systems [5,6,7]. Higher REE concentrations have previously been observed in water, soil, and plants in REE mining areas [8, 9]. The enrichment of gadolinium (Gd) has been detected in human bone by contrast agents for medical use in magnetic resonance imaging (MRI) [10]. REEs can induce decreased total serum protein, albumin, globulin, serum triglycerides and immunoglobulin, but increased blood cholesterol [11]. Additional intake of REE can reduce the intelligence quotient of children and chronically hinder the central nervous system conduction of adults, even at low doses [12]. Therefore, the biological effects and distribution patterns of REEs in the human body should be investigated.Gallstone disease is a common clinical condition characterized by abnormal masses consisting of a solid mixture of cholesterol crystals, mucin, calcium bilirubinate and cholecalciferol [13]. Among the predisposing factors for biliary tract cancer, gallstones are considered as the predominant risk factor (more than 60% of biliary tract cancer patients have gallstones) [14]. More than 20% of adults develop gallstones, and some of patients develop symptoms or complications [15]. Regarding the complex predisposing factors of gallstones, medical prevention and treatment of the disease remain unindicated. In general, the main pathogenic factor is bile cholesterol oversaturation caused by hepatic metabolic defects [16]. A high-cholesterol diet, obesity, genetic predisposition, and environmental factors contribute to an increased risk of gallstone formation [17]. However, due to individual differences in lifestyle habits, we have a limited understanding of the elemental variations in gallstones. Early studies of gallstone disease revealed some information about composition, mineralogy, structure, formation process, and geo-environmental factors [18, 19]. However, to the best of our knowledge, there is a lack of epidemiological data to study gallstones in humans from a geochemical perspective associated with REEs. It is, therefore, necessary to monitor and conduct toxicological investigation of REEs, not only from an environmental or industrial hygiene point of view but also from a medical treatment point of view. Whether long-term exposure to or ingestion of REEs has other effects on gallstones, and how REEs potentially accumulate in the gallstones remain unclear.

Biliary tract tumors were the fastest-rising malignant tumors from 1972 to 1994 and showed a continuous increase in Shanghai [20,21,22]. Regional biliary tract cancer and gallstone disease have been reported to have a higher incidence rate in Western countries and parts of Asia [13, 17, 23]. The average prevalence in adults in Europe, the Americas, Africa and Asia is estimated to be 3%, 5%, 10%, and 15%, respectively [23]. As one of the thriving cities in China, Shanghai occupies a higher standard of living and medical care, and the dietary pattern has become more westernized in recent years [22]. In addition, in modern urban areas with a developed economy, there may be a higher risk of exposure to REEs due to the high levels of REEs in the surrounding environment (i.e. river water, soil, and atmospheric dust) [24,25,26]. In addition to teeth and bones, previous analyses of REE concentration levels have focused on tissues (i.e., brain, lymph node, and skin) or fluids (i.e., blood, urine, and colostrum) [9, 11, 27, 28]. Few studies have discussed the concentration of REEs in human gallstones and their health effects. Shanghai Sixth People’s Hospital is a Grade 3 A general hospital, that receives the largest number of gallstone patients every year. Systematic analysis of the chemical properties of REEs on the incidence of gallstone disease in Shanghai is essential to provide guidance for other regions. This study focused on the characteristics of gallstones in Shanghai Sixth People’s Hospital, China. The aims of this study were to (1) report for the first time the geochemical composition of REEs in the gallstones, and (2) report the distribution patterns of REEs to reflect the impact of the environment on humans.

Materials and methods

Sample preparation and measurement

The gallstone samples (DJS-1 to DJS-25) were surgically obtained from 25 patients admitted to Shanghai Sixth People’s Hospital (China), the project was approved by the hospital’s Ethics Review Committee, and the patients’ informed consent. Gallstone samples were mostly yellow or yellowish-brown, and some appeared dark brown (Fig. 1). A total of 25 gallstone samples were rinsed with distilled water, dried at room temperature, and stored in PFA beakers. Subsequently, all samples were totally digested using the HF-HNO3-HClO4 method (3 ml HF, 1 ml HNO3 and 0.5 ml HClO4, followed by heating at 120 °C for 48 h) in a Class 100 high-efficiency particulate air filter hood in a Class 1000 cleanroom [29, 30]. As the solution evaporated, 1 ml HNO3 and 3 ml HCl were added to the beakers which were then placed on a hotplate at 120 °C for 24 h for the samples to digest again. Finally, samples were re-dissolved in distilled 2% HNO3 ready for measurements. All pre-treatment of gallstone samples was accomplished at the Nu Surficial Environment and Hydrological Geochemistry Laboratory (Nu-SEHGL) at China University of Geosciences (Beijing). The content of REEs was measured on an ICP-MS (Elan DRC-e, Perkin Elmer, Waltham, MA, USA) at the Institute of Geographic Sciences and Natural Resources Research, Chinese Academy of Sciences. Quality control was conducted using procedural blanks and standard reference materials (GBW-27;GBW-07120). The recovery values ranged within ± 10% and were presented in Table S1, including detection limit and precision.

Fig. 1
figure 1

Pictures of some of the gallstone samples used in this study

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Data analysis and calculation

Body mass index (BMI) is a measure of whether a human body is healthy, and the formula is as follows [31]:

$$\:BMI=\:W/{H}^{2}$$

where W stands for weight and H stands for height. The BMI unit used in this study was kg/m2.

The normalized REEs pattern is used to eliminate the Oddo − Harkins effect between neighboring REE concentrations (the concentration of an element with an even atomic number is always higher than that of an element with an odd atomic number in the vicinity) [32]. The upper continental crust (UCC) was chosen to normalize measured REE concentrations, as the food consumed by humans originates from the UCC [11, 33]. In general, REEs exist in the form of REE3+ in the natural environment. However, due to their unique atomic structure, some REEs can be oxidized or reduced (such as Ce3+ to Ce4+ and Eu3+ to Eu2+) with significant fractionation compared to neighboring REEs [2]. In addition, extreme Gd positive fractionation has also been found in the environment due to anthropogenic input [34,35,36]. In this study, the anomalies for Ce, Eu, and Gd were calculated as follows [37, 38]:

$$\begin{gathered}\:\delta \:\:Ce\: = \:C{e_{sample}}\:/\:C{e_{UCC}}/ \\ \:(0.5 \times \:L{a_{sample}}/\:L{a_{UCC}} + \:0.5 \times \:P{r_{sample}}/\:P{r_{UCC}})\: \\ \end{gathered}$$
$$\begin{gathered}\:\delta \:Eu\: = \:E{u_{sample}}/\:E{u_{UCC}}\:/\: \\ (0.67 \times \:S{m_{sample}}/\:S{m_{UCC}}\: + \:0.33 \times \:T{b_{sample}}/\:T{b_{UCC}} \\ \end{gathered}$$
$$\begin{gathered}\:\delta \:Gd\: = \:G{d_{sample}}/\:G{d_{UCC}}\:/\: \\ (0.33 \times \:S{m_{sample}}/\:S{m_{UCC}}\: + \:0.67 \times \:T{b_{sample}}/\:T{b_{UCC}}) \\ \end{gathered}$$

where values below or above 1.0 indicate negative or positive anomalies of REEs, respectively. Notably, a Gd anomaly with a δGd value below 1.1 is induced by natural processes, while a δGd value above 1.5 indicates the anthropogenic input [36, 39].

Results

Gallstones can be divided into cholesterol, pigmented and mixed stones [40]. In general, cholesterol stones are mainly composed of cholesterol, and their pathogenesis is the supersaturation of cholesterol in the gallbladder bile [19]. The results of gallstone component analysis showed that all samples in this study were cholesterol stones. Gallstone samples were roughly oval in shape with weights ranging from 15.14 mg to 790.09 mg. Patients with gallstones were between the ages of 25 and 71 (72% were over 50 years old), with males and females each accounting for about half in this study. Men and women weighed 57.0 kg to 97.0 kg and 50.0 kg to 88.1 kg, respectively.

The average concentration of total REEs (ΣREEs) in gallstones was 39.21 ng/g, which was lower than that in the blood (644.74 ng/g), hair (705.34 ng/g), urine (3867.1 ng/g), and urinary stones (346.00 ng/g) [9, 11, 27, 41]. The exposure of REEs to humans was demonstrated by their accumulation in urine [42], which is one of the primary methods of excretion of elements. REEs can enter the human body through hair follicles [43, 44], carried into bloodstream throughout the body via circulation system [42, 45]. Compared with the ΣREEs concentration of gallstones in males (4.89 ng/g to 190.81 ng/g, mean: 41.44 ng/g), those in females showed a narrower range of ΣREEs concentrations and lower levels (7.66 ng/g to 64.91 ng/g, mean: 28.47 ng/g) (Table S2). This difference may be linked to the bile acid synthesis and cholesterol metabolism influenced by sex hormones [46]. Estrogen, which is more prominent in females, increases cholesterol saturation in bile and decreases gallbladder motility, which caused higher incidence of gallstones in women [47]. The concentrations of LREEs (20.80 ng/g) and MREEs (106.35 ng/g) accounted for an average of 65% and 27% of the ΣREEs concentrations in gallstones, respectively, higher than those of HREEs (2.86 ng/g). Among all REEs, La, Ce, Nd, and Gd had the highest concentrations. The coefficient of variation (CV) of almost all REEs in all samples was generally close to 1, except for Gd (4.27) and Yb (2.99) which had much higher CV values. Results suggested substantial fluctuation in Gd and Yb concentrations of gallstone samples.

Discussion

Effects of diet on the concentration of REEs in gallstones

Dietary rare earth elements vary widely (Fig. 2a), and dietary intake may affect cholesterol levels and bile composition, potentially affecting gallstone formation. the ΣREE concentrations of most gallstones (75% samples) were below 50 ng/g and both male and female showed similar enrichment with regards to the distribution of LREE, MREE and HREE (Fig. 2b), specifically showing that higher concentrations of LREEs and lower concentrations of HREEs (except for DJS-3 and DJS-22, which had high concentrations of MREEs with Gd/ΣREEs > 90%). This distribution is probably attributed to the dietary intake of terrestrial and aquatic species, which gradually transfer REEs [8, 48,49,50]. Firstly, long-term consumption of a diet high in fat and protein may also increase the incidence of gallstones [13, 17, 23]. Consumption of a high-calorie diet, which is more common in the West, is clearly a key factor in gallstone disease [18]. Similarly, gallstone patients from Shanghai may also have been on a high-calorie diet, as elevated triglyceride and cholesterol levels were observed in half of the patients. As for water intake, the concentration of REEs in drinking water was at an extremely low level with negligible risk of exposure after treatment [27]. Secondly, the agricultural products inherited REE-fertilizers with LREEs enrichment [7, 51, 52], displaying preferential absorption and bioaccumulation of LREEs. Therefore, the LREE enrichment in gallstones may be affected by the dietary intake. For the REEs exposure risk to gallstone patients, some aquatic products and Chinese traditional tea may accumulate high concentrations of REEs, posing a high risk of exposure to human health. Chana et al. suggested that tea consumption is positively correlated with cholelithiasis, i.e., consumers who drink more than one cup of tea per day have a higher risk of developing gallstones [53]. Wang et al. suggested that the REE distribution pattern of fish is similar to that of suspended particulate matter and sediments, which inherit the REE characteristics of the regional aquatic environment [54]. In contrast, fruits show lower REE concentrations, suggesting negligible risk of exposure. Compared with the ΣREE concentrations in edible products, those in the gallstones are relatively low. The transport of REEs in the matrix is usually in the soluble form, while fewer REEs remain in the solid form [55]. As a result, a large part of the ingested REEs may be removed through metabolism. Notably, residual REEs in gallstones may represent an unmetabolized fraction, which may be more farsighted in the human system.

The ΣREE concentration was negatively correlated with gallstone weight, while the BMI of the patient was weakly correlated with ΣREE concentration and gallstone weight (Fig. 2c). It may indicate that the REEs do not precipitate with other components (i.e., bilirubinates, carbonates and phosphates), whereas when the mass of gallstones reaches 200 mg, they are continuously released and converge to a constant value. Typically, calcium-sensitive ions will complex with carbonate anion and precipitate into the main components distributed in gallstones [56]. Although REEs are thought to bind readily to carbonates or phosphates, the complexions are restricted by the pH of the surrounding environment [57]. Further analyses are needed to explain the causes of the release of REEs in gallstones.

Fig. 2
figure 2

ΣREE concentration and related parameters. (a) comparison of ΣREE concentrations in various edible products and gallstones, (b) Mass ratio of LREE, MREE, HREE to ΣREE in gallstones, (c) Relationship between gallstone weight and ΣREE concentration Data from: [8, 48,49,50,51, 58,59,60]

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Distribution patterns of REEs in gallstones

In general, REE patterns in edible products (crops and animals) showed enrichments of LREEs with higher concentrations [8, 48,49,50, 58]. Although food consumption is a primary source of REEs in humans, the pattern of REEs in gallstones showed limited variation compared to edible products. The UCC-normalized REE pattern in gallstones showed depletion of LREEs, with most showing enrichment of HREEs and some showing enrichment of MREEs (Fig. 3a). Most samples showed greater fluctuation between each REEN value in light gallstones, while a relatively flat pattern of REEs was found in heavier gallstones. There may be further bio-fractionation between each REE during gallstone formation. A comparison of REEs in various parts of the human body (Fig. 3b) showed that the concentration of REEs in hair and bone was higher than that in gallstones, while the concentration of REEs in blood and urine was lower than that in gallstones [11, 61,62,63]. Compared to the hair, the rest of the human body showed stronger absorption of REEs in the mining polluted environment. In addition to the enrichment of LREEs in human hair, REEs in blood, urine, bones, and gallstones were enriched in MREEs or HREEs. Gd anomalies were only found in three gallstone samples (Fig. 3b). Gd anomaly has also been found in human bones, caused by the residual Gd from MRI contrast agent [63].

Fig. 3
figure 3

UCC-normalized patterns of REEs for gallstones (data shown in Fig. 3b are the average values of each matrix)

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Values of (La/Yb)N and (La/Sm)N lower than 1 indicate enrichment of LREEs, while values higher than 1 indicate enrichment of HREEs and MREEs, respectively; a value of (Sm/Yb)N lower than 1 indicates enrichment of HREEs, and a value higher than 1 indicates enrichment of MREEs [2, 64]. The ratios of normalized-REEs, such as (Yb/La)N, (Sm/La)N, and (Sm/Yb)N, were calculated to explore the enrichment and depletion of the REEs in gallstone samples (Fig. 4). Almost all samples showed enrichment of HREEs and depletion of LREEs. Similarly, kidney stones also showed an enrichment pattern of HREEs ( [41]. Only four samples (DJS-9, DJS-10, DJS-19, DJS-23) had values of (Yb/La)N and (Sm/La)N lower than 1, which may have resulted from higher La concentrations. Patterns of the normalized-REEs of the four samples showed an upward trend from Ce to Lu, indicating the enrichment of HREEs.

Fig. 4
figure 4

The fractionation among REEs and molar ratios of Y/Ho in gallstones

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The chemical behavior between Y and Ho is closely related due to similar ionic radii, while Y and Ho exhibit great differences in their covalent bonding abilities [65, 66]. In general, Ho preferentially complexes with organic compounds (similar to the complexation between LREEs and organic matters) or HCO3−, and Y has a stronger adsorption capability for solid particles [67]. The fractionation between Y and Ho indicates an interaction between aquatic biomass and solids in the system [68, 69]. The Y/Ho ratio of gallstones ranged from 10.20 to 20.41, with an average value of 14.62 (Fig. 4b). All samples showed medium levels of Y/Ho values in gallstones: lower than those in continental rocks, but higher than those in urine and similar to those in blood [61, 62, 70]. Blood is the most widely distributed in the human body, carrying a large flow of materials, and is an important supplier of gallbladder components. The similar characteristics of the Y/Ho ratio in blood and gallstones may indicate limited REEs fractionation during transport in the human system.

REE anomalies under human influence

δCe values lower than 1.0 indicate a negative Ce anomaly (Fig. 5a). Most samples had δEu values higher than 1, except for 6 samples with values lower than 1. δCe values ranged from 0.25 to 1.04 with an average value of 0.74, while δEu values ranged from 0.79 to 1.78 with an average value of 1.16 (Table S2). In general, natural Ce anomalies are induced by valence changes in the system (such as dissociative Ce3+ to Ce4+), which is susceptible to the redox environment [25]. Under oxidative conditions, Ce3+ can be oxidized to Ce4+ and further complexed with HCO3− or CO32− in alkaline media [71]. The pH of the gallbladder in a normal person is about 7.4, with an alkaline environment [56]. However, this study found depletion of Ce in gallstone samples, which may indicate that Ce exists in the trivalent form in a reducing environment and that fewer Ce4+ remains in gallstones. The behavior of Eu essentially inherits from the original source, which may explain the slightly negative Eu anomalies (δEu: 0.79 to 0.96) in a few gallstones. Eu anomalies are also strongly influenced by changes in redox conditions, where Eu3+ will be reduced to Eu2+ and replace Ba2+ or Ca2+ in minerals [72]. Therefore, the positive Eu anomalies in gallstones can be attributed to the substitution by Eu2+. Ce and Eu anomalies are widely used to indicate redox conditions in the environment [71, 73, 74]. Similarly, Ce anomalies can also be caused by changes in redox conditions within the human body. The combined analyses above suggest that the gallbladder may be in a reducing environment.

Fig. 5
figure 5

REEs anomalies in gallstones samples

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The δGd value showed noticeable fluctuations (0.8 to 327.55). Gd positive anomalies (δGd > 1.1) were found in more than 1/3 of the samples (Fig. 5b). Gd is applied to clinical and diagnostic medical imaging due to its paramagnetic nature with potent (long) T1 relaxing mechanisms [75]. Gadolinium-based contrast agents (GBCAs) are widely used to enhance image contrast in magnetic resonance imaging procedures [76]. In general, most stable hydrophilic GBCAs (73% ~ 90%) are excreted from the body, but studies have revealed that a small fraction of Gd does not clear the body following the application of Gd-based contrast agents and is incorporated and retained in the human body for several years [10]. For quite some time, it was generally accepted that the use of GBCAs was safe. However, free Gd3+ is a toxic lanthanide heavy metal that is similar in size to Ca2+. This similarity may lead to competitive inhibition of biological processes requiring Ca2+ and cause toxicity [35]. As a result, Gd3+ can be rapidly incorporated into gallstones by substituting Ca2+, and incorporation through this process would result in rapid accumulation of Gd in gallstones. In general, Gd-EDPA injections are considered to be a non-negligible factor affecting Gd concentrations in the human body [34, 77]. However, the modern medical diagnostic process of gallstones prefers the application of computed tomography (CT) over MRI, without the participation of Gd-based comparison [78, 79]. Positive δGd may not only be induced by exogenous inputs, but may also be caused by Gd enrichment in the human body, with a pathological mineralization process.

Limitations and future suggestions

This study firstly reported the REEs contents and distribution patterns of gallstones but was limited by the small size of gallstone samples and lack of detailed pathological information and environmental information. The future research should involve a larger sample size and control group. In addition, exploring the potential sources of REEs exposure and fractionation processes in vivo may provide insights into how REEs are metabolized in the human body.

Conclusions

This study is the first to report data on REEs in gallstones and use them to track the bioavailable REEs in gallstones from patients in Shanghai. Generally, drinking water and topsoil (representing food sources) have contributed most of the bioavailable REEs for gallstones. However, significant HREEs enrichment has been found in gallstones, which is contrarian to the REEs pattern in most foods (LREEs enrichment). The negative Ce anomalies and positive Eu anomalies were widely found in most samples, indicating the reducing environment in the human gallbladder. Additionally, positive Gd anomalies (δGd > 1) were found in most samples, while few samples suggested anthropogenic influence (δGd > 1.5). The enrichment of Gd in the gallbladder is possibly affected by a combination of bio-accumulation and GBCAs ingestion. Gallstones characterized by positive Gd anomalies may suggest that more residual Gd remains in the human body than has been estimated previously. This study has preliminarily applied the use of REEs to trace the connection between humans and the surrounding environment, indicating that REEs have great potential at the intersection of life and environmental sciences.

Data availability

Data is provided within the supplementary information files.

Abbreviations

REEs:

Rare earth elements

LREEs:

Light REEs, La to Nd

MREEs:

Medium REEs, Sm to Ho

HREEs:

Heavy REEs, Er to Lu

MRI:

Magnetic resonance imaging

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Funding

This study was supported by the National Natural Science Foundation of China (Nos. 41661144029, 82200710, and 82374215).

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Authors and Affiliations

  1. Digestive Endoscopic Center, Shanghai Sixth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China

    Shuang Shen, Zhixia Dong, Shan Wu & Xinjian Wan

  2. Central Lab, School of Medicine, Shanghai Sixth People’s Hospital, Shanghai Jiao Tong University, Shanghai, 200233, China

    Shuang Shen

  3. State Key Laboratory of Biogeology and Environmental Geology, China University of Geosciences (Beijing), Beijing, 100083, China

    Guilin Han, Shunrong Ma & Ziyang Ding

  4. Frontiers Science Center for Deep-time Digital Earth, Institute of Earth Scineces, University of Geosciences (Beijing), 100083, Beijing, China

    Guilin Han, Shunrong Ma & Ziyang Ding

  5. Nu Instruments, Wrexham Industrial Estate, 74 Clywedog Road South, 13 9XS, Wresham, LL, UK

    Ye Zhao

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  1. Shuang Shen
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  7. Ye Zhao
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  8. Xinjian Wan
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Contributions

Conceptualization was performed by G. H and X. W.; data curation by G. H.; formal analysis by S. M. and Z. D.; Funding acquisition by G. H. and X. W.; investigation by X. W., S. S., Z. D. and S. W.; Writing-original draft by G. H., Y. Z. and S. M.; writing-review & editing by G. H., S. M., Y. Z.; all authors have read and agreed to the submitted version of the manuscript.

Corresponding authors

Correspondence to Guilin Han or Xinjian Wan.

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The study was approved by the ethics committee of Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine (protocol code 2022-YS-126, 24 February, 2022). Written informed consent for participation was waived by the Ethics Committee of Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine.

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Shen, S., Han, G., Dong, Z. et al. Accumulation of rare earth elements in human gallstones: a perspective from dietary and human health. BMC Gastroenterol 24, 324 (2024). https://doi.org/10.1186/s12876-024-03426-1

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BMC Gastroenterology

ISSN: 1471-230X

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