Metallomic Profiling of the Human Eye and Its Relevance to Ophthalmic Diseases

Abstract

Levels of micro- and macroelements in the human organism change dynamically and undoubtedly remain critical for human health. Currently, much research is focused on searching for the concentrations of various metals (including toxic ones) in the tissues obtained from patients suffering from various diseases including ophthalmic diseases. However, the knowledge in this matter is still scarce and highly limited. Previous studies related to the changes in the levels of micro- and macroelements within the morphological elements of the eye and visual tract were performed on animal models in most cases, and only for the chosen elements. In addition, the majority of the studies performed on human samples were mostly focused only on the group of patients with chosen ophthalmic diseases such as glaucoma or cataracts. Moreover, usually, the results of the studies are contradictory, and some hypotheses are still unexplained. The understanding of the physiology and pathophysiology of the processes that lead to the changes in the distribution of the levels of micro- and macroelements that are crucial in the etiology of ophthalmic diseases might provide more effective prevention and better therapeutic strategies, or even improvements in the treatment of chosen ophthalmic diseases. In this paper, we summarized the current knowledge regarding the metallomic analysis of the human organ of vision and its relationship with chosen ophthalmic diseases.

1. Introduction

Metallomics is a branch of science that focuses on the research of metals, including biometals and biometalloids, with a particular emphasis on the interactions and functional connections between the ions of different metals and various biomolecules, such as metabolites or proteins.

Metallomics is an interdisciplinary field of science that involves the systematic identification, quantification, and functional analysis of all metal and metalloid species in cells, tissues, or organisms. It integrates techniques from chemistry, biology, and analytical science to explore the roles of essential and toxic metal ions in biological systems [1]. For example, metallomics may investigate how transition metals like iron (Fe), zinc (Zn), or copper (Cu) participate in enzymatic catalysis or contribute to oxidative stress when dysregulated. Biometalloids, on the other hand, refer to metalloids—elements with intermediate properties between metals and nonmetals—that are involved in biological processes. Examples include arsenic (As) and selenium (Se). While selenium (Se) is an essential trace element incorporated into selenoproteins with antioxidant roles, arsenic (As) is primarily recognized as a toxicant, although it has been shown to influence signal transduction and gene expression at subtoxic concentrations [2,3]. The application of metallomics in medical research, especially in the context of toxicology and ophthalmic diseases, provides critical insights into metal homeostasis, transport, accumulation, and toxicity mechanisms.

It is commonly known that micro- and macroelements are responsible for the proper functioning of numerous biochemical and metabolic processes. However, their uneven distribution in the organism leads to significant differences in nutrient concentrations in tissues and bodily fluids [4]. This is proof of the fact that particular organs, for proper physiological functioning, need only specific amounts of chosen elements, while the others might occur only in trace amounts [5]. The concentrations of micro- and macroelements continually fluctuate. In order to provide the measurements of the concentrations of the elements in the biological samples, it is necessary to perform the mineralization process as well as the use of the advanced analytical techniques such as inductively coupled plasma mass spectrometry (ICP-MS), inductively coupled plasma atomic emission spectroscopy (ICP-AES), AAS (atomic absorption spectroscopy), and laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS) (

Table 1. Comparison of analytical techniques used in ocular metallomic studies.

Analytical Technique	Advantages	Limitations	Applications in Ocular Studies
ICP-MS (Inductively Coupled Plasma Mass Spectrometry)	High sensitivity (ppt level); multi-element detection; isotopic analysis possible	Expensive instrumentation; complex sample prep; potential contamination	Widely used for aqueous humor, lens, and retina; enables trace metal profiling
AAS (Atomic Absorption Spectroscopy)	Relatively simple and cost-effective; good for single-element quantification	Low throughput; less sensitive than ICP-MS; cannot do multi-element at once	Used in postmortem retina and optic nerve studies (e.g., Al, Fe, Zn levels)
TXRF (Total Reflection X-ray Fluorescence)	Minimal sample prep; simultaneous multi-element detection; non-destructive	Lower sensitivity than ICP-MS; matrix effects can interfere	Applied in conjunctival tissue (e.g., Cr, Zn, Se in pterygium)
LA-ICP-MS (Laser Ablation ICP-MS)	Enables spatial mapping of elements; minimal sample digestion	Requires solid samples; calibration challenges; semi-quantitative	Used for retina and cornea to map metal distribution (e.g., Fe in AMD)

and

Table 2. Timeline of historical development of metallomic analysis in ophthalmology.

Decade	Milestone/Advancement	Notes	Key References
1970s	Early trace metal studies in the eye	Atomic absorption spectroscopy (AAS) used to quantify basic elements (e.g., Cu, Zn) in cataractous lenses.	[9,10]
1980s	Postmortem lens and retina analysis expands	Focus on Fe and Al in senile and diabetic retinopathy tissues.	[11]
1990s	Introduction of ICP-AES and ICP-MS	Higher sensitivity and multielement capability applied to aqueous humor and vitreous samples.	[12,13]
2000s	Laser Ablation ICP-MS (LA-ICP-MS)	Enabled spatial elemental mapping in cornea, retina, and lens tissue sections.	[14,15]
2010s	SR-XRF applications	Synchrotron Radiation X-ray Fluorescence (SR-XRF) and microbeam XRF used to visualize metal distribution in ocular tissues at cellular resolution.	[16]
2020s	Integrated multi-omics and biometal imaging	Studies correlate metallomics with genomics and proteomics; non-invasive sampling explored (e.g., tears).	[17,18]

) [6,7,8].

Many research groups worldwide observe and describe significant changes in the concentrations of elements in the tissues and organs of patients suffering from various diseases. According to the current state of knowledge, disturbances in the levels of micro- and macroelements within the organ of vision might be crucial in the pathogenesis of such diseases as macular degeneration, diabetic retinopathy, glaucoma, or cataracts [19,20,21,22]. The very first study investigating the presence of heavy metals in the human eye was performed by Zeimer et al. [23]. Then, Erie et al. performed an analysis of the aqueous humor obtained post mortem in order to provide the elemental analysis using ICP-MS [24]. Currently, most research in this area was performed for such elements as iron (Fe), zinc (Zn), copper (Cu), selenium (Se), and chromium (Cr); it might be because the abovementioned elements present a significant reduction potential in the case of oxidative stress induced by reactive oxygen species (ROS) [25,26,27]. Selenium (Se) and zinc (Zn), for example, being crucial elements of glutathione peroxidase, prevent the damage within the lens and retina induced by oxidative stress [28,29,30]. Furthermore, current research on the concentrations of micro- and macroelements in the visual system has primarily been conducted using animal models and has focused only on selected elements. Therefore, the multi-elemental analysis of the morphological parts of the human eye might be a useful diagnostic tool that enables the identification of many dysfunctions of this organ. It is known that electrolyte balance is crucial, for example, for the translucency of the lens [31]. Inorganic ions pass through ion channels such as potassium (K), sodium (Na), chloride (Cl), and calcium (Ca) channels based on an ion exchange mechanism (Na⁺/H⁺, Na⁺/Ca²⁺, HCO₃⁻/Cl⁻) or by active transport via Na-K-ATPase [32]. So far, only chosen parts of the human eye, such as lens, aqueous humor, or vitreous body, have been analyzed in terms of the metallomic content. Since the sample collection of the parts of the human eye might be problematic for the researchers, most of the metallomic studies performed on the human organ of vision can be performed by obtaining the samples during routine cataract surgery from living patients. Typically, during such surgeries, the lens and aqueous humor can be obtained for further studies without the possibility of obtaining other structures.

Therefore, post-mortem studies enable the collection and analysis of other structures of the human eye that would otherwise not be accessible. In one of our studies, we managed to analyze the organ of vision indirectly by performing the metallomic analysis of the human optic chiasm [33]. The aim of this paper is to review existing studies on the concentrations of micro- and macroelements in the human organ of vision, with a particular focus on metallomic analyses and their relevance to selected ophthalmic diseases. To maintain this focus, we excluded studies conducted on animals and those analyzing metal levels in non-ocular samples such as blood serum.

2. Metallomic Analysis of the Human Eye in Ophthalmic Diseases

2.1. Cataracts

Cataracts are either opacification or clouding of the normally clear lens or its capsule, disabling the proper passage of light through the eye into the retina. According to Lin et al. (2025), the global prevalence of cataracts rose sharply from approximately 42.33 million in 1990 to 100.57 million in 2021, reflecting a 138% increase overall; the age-standardized prevalence rate also increased from 1145 to 1181 cases per 100,000 people (EAPC 0.212, 95% CI 0.117–0.306) [34]. Several types of cataracts can be distinguished, including age-related cataracts, pediatric cataracts, secondary cataracts, and traumatic cataracts, amongst which age-related cataracts are the most prevalent, with older age being the primary risk factor for cataracts [35]. Approximately two-thirds of the affected population is more than 80 years old [36]. There are also several types of age-related cataracts depending on the area affected by the pathological lesion, namely, nuclear sclerotic cataract, cortical cataract, posterior subcapsular cataract, and one of the least common types—Christmas tree cataracts [37,38,39]. Regarding cataracts occurring in young adults, traumatic injuries constitute the most common cause of this ophthalmic disease in this group of patients; however, other secondary causes of cataracts might also occur, including intraocular inflammation, hypoparathyroidism, and uncontrolled diabetes mellitus [40].

Cataracts arise from multifactorial etiologies involving environmental exposures, systemic and ocular diseases, and genetic predispositions. Environmental risk factors include long-term air pollution exposure (particularly PM_2.5), which increases oxidative stress in the lens [41]; tobacco smoke, which introduces free radicals that damage lens proteins and lipids [42]; and chronic alcohol use, which disrupts glutathione metabolism, enhancing oxidative vulnerability [43]. Pesticide exposure, particularly to organophosphates, has been linked to increased nuclear and cortical cataracts in agricultural workers [44]. Ultraviolet-B (UV-B) radiation promotes cortical cataract formation by inducing DNA crosslinking in lens epithelial cells [45], while therapeutic ionizing radiation to the upper body increases the risk of posterior subcapsular cataracts in a dose-dependent manner [46]. Additionally, prolonged corticosteroid use, both systemic and topical, disturbs epithelial cell homeostasis and predisposes to posterior subcapsular opacification [47]. Antioxidant-poor diets (low in vitamins C, E, and carotenoids) impair lens defenses against oxidative insults [48].

From a medical standpoint, diabetes mellitus enhances polyol pathway flux in lens fibers, leading to osmotic and oxidative stress [49]. Other contributing factors include chronic intraocular inflammation (e.g., uveitis), retinal degeneration (e.g., retinitis pigmentosa), intraocular surgeries (notably glaucoma procedures), and systemic diseases like myotonic dystrophy, hypoparathyroidism, neurofibromatosis type 2, and Down syndrome, all of which interfere with lens metabolism or protein function [50,51,52,53]. Congenital infections, such as rubella, and atopic dermatitis, characterized by chronic periorbital inflammation and eye rubbing, are also significant [54,55].

Genetically, multiple mutations have been linked to congenital and age-related cataracts. These include EPHA2, affecting lens epithelial cell adhesion [56]; GJA3 and GJA8, which impair intercellular communication via connexins 46 and 50 [57]; MIP, HSF4, LIM2, and CRYAA, all of which compromise lens fiber integrity or protein folding [58,59,60]; and regulatory genes such as BFSP2, FOXE3, and PAX6, involved in lens development and cytoskeletal organization [61,62,63].

Prevention of cataracts includes numerous aspects, namely, implementation of regular ophthalmic control exams, prevention from ultraviolet (UV) light, effective management of comorbid diseases, limited alcohol consumption, and maintenance of a balanced diet [64,65,66]. Currently, the most effective treatment modality for cataracts is cataract surgery, which is one of the most commonly performed surgeries in high-income countries. Moreover, a correction using refractive glasses might constitute a potential treatment modality before the surgery [35].

2.1.1. Lens

Studies performed both on animal and human models indicate that disturbed metal homeostasis within the organ of vision might lead to disturbances in lens transparency, ultimately leading to the onset of cataracts. The very first report indicating that disturbed calcium (Ca) levels might be associated with the onset of cataracts was provided by Burge et al. (1909), who demonstrated that cataractous human lenses present much greater calcium (Ca) concentrations compared to the lenses obtained from healthy individuals [66,67]. This hypothesis was confirmed by more recent studies, which indicate that calcium (Ca) levels in cataractous lenses might be even four times higher than in healthy human lenses [68]. In fact, the excessive accumulation of calcium (Ca) in the lens might lead to increased intracellular calcium (Ca) concentrations and, in turn, the formation of calcium (Ca) oxylate crystals that ultimately might influence the lens translucency [69,70,71]. Even in cases of hypocalcemic cataracts, calcium (Ca) levels in the cataractous lenses are increased [72]. Apart from calcium (Ca), zinc (Zn) is also involved in the process of β-crystallins formation, enhancing cataractogenesis [22,73]. It was observed that patients with pseudoexfoliative cataracts might present elevated zinc (Zn) and copper (Cu) levels in the lens compared to healthy individuals [74]. Further, insufficient amounts of magnesium (Mg) in the lens, which leads to the disturbed activity of the ATPase, might also be associated with the onset of cataracts [75]. It was also indicated that smoking might be a great risk factor for the onset of cataracts since cadmium (Cd), which is abundantly found in cigarettes, tends to accumulate in the lenses of smoking people, significantly disturbing their physiology and leading to disturbances in lens translucency [76]. Except for the elevated cadmium (Cd) levels, smokers tend to present elevated aluminum (Al) and vanadium (V) levels in the lenses, which also might be involved in the etiology of cataract formation by such processes as induction of oxidative stress, impairments of the structure and functioning of the extracellular matrix, or simply induction of cellular toxicity [77]. It was shown that cataractous lenses also present elevated levels of iron (Fe) and copper (Cu) [77,78]. Tweeddale et al. (2016) showed that elevated levels of transition metals in the aging human lens tend to enhance the loss of protective UV filter compounds as well as the formation of the high-molecular-mass dysfunctional crystallin proteins, which might be associated with the onset of cataracts [79]. Also, chromium (Cr) levels were observed to be elevated in the aqueous humor of cataract patients, with a positive relationship between the increasing chromium (Cr) levels in the aqueous humor and increased cataract severity [13,80].

2.1.2. Aqueous Humor

Kim and Choi (2007) did not observe any changes regarding the calcium (Ca) levels in the aqueous humor of patients with cataracts, but showed that this group of patients with coexisting diabetes tend to present greater phosphorus (P) levels in aqueous humor; this phenomenon was even more emphasized in patients with diabetes and proliferative diabetic retinopathy [81]. The researchers also pointed out that phosphorus (P) accumulation in the aqueous humor might lead to the onset of intraocular lens (IOL) opacification; thus, cataract patients with coexisting proliferative diabetic retinopathy are observed to be more prone to this phenomenon. In 2014, total reflection X-rays fluorescence (TXRF) analysis of the lens and aqueous humor of the patients with cataracts showed significantly higher levels of chromium (Cr) and manganese (Mn) in both of the abovementioned structures, greater amounts of barium (Ba) in the lens, as well as elevated nickel (Ni) levels in the aqueous humor [82]. Dolar-Szczasny et al. also investigated the levels of various elements in the aqueous humor obtained from patients with cataracts using the ICP-OES technique [22]. The obtained results indicate significant differences in concentrations of the elements; the most abundant elements were calcium (Ca), cesium (Cs), potassium (K), magnesium (Mg), sodium (Na), phosphorus (P), and rubidium (Rb). Aqueous humor samples were also characterized by the disturbing increase in the levels of very toxic metals such as thallium (Tl), tellurium (Te), cesium (Cs), lead (Pb), as well as aluminum (Al).

2.2. Glaucoma

Glaucoma is a group of chronic optic neuropathies characterized by progressive retinal ganglion cell loss and visual field defects. As of 2020, glaucoma affected an estimated 3.54% of individuals aged 40–80 years—approximately 76 million people worldwide—with projections rising to 111.8 million by 2040; additionally, glaucoma caused 3.61 million cases of blindness and 4.14 million instances of moderate to severe vision impairment globally in that year [83,84]. Primary open-angle glaucoma (POAG) is the most common form, accounting for nearly 75% of cases worldwide, while primary angle-closure glaucoma (PACG) predominates in certain Asian and Inuit populations [85]. Although elevated intraocular pressure (IOP) remains the major modifiable risk factor, age, family history, vascular dysregulation, oxidative stress, and genetic variants in genes such as MYOC and CYP1B1 also contribute significantly to disease onset and progression [86].

Glaucoma is a complex optic neuropathy influenced by environmental exposures, systemic and ocular conditions, and genetic susceptibility. Among environmental risk factors, chronic smoking contributes to glaucomatous damage via oxidative stress and inflammation in ocular tissues [87]. Similarly, ultraviolet (UV) radiation has been implicated in the pathogenesis of pseudoexfoliation glaucoma (PXG), likely through oxidative stress-induced extracellular matrix abnormalities [88]. More broadly, oxidative stress—resulting from an imbalance between reactive oxygen species (ROS) and antioxidant defenses—affects the trabecular meshwork and retinal ganglion cells (RGCs), leading to increased intraocular pressure (IOP) and optic nerve degeneration [89].

Medical risk factors play a central role in glaucoma development. Elevated IOP remains the primary modifiable risk factor, with each mmHg increase correlating with higher disease risk [90]. Prolonged corticosteroid use, both systemic and topical, can induce secondary glaucoma by reducing aqueous humor outflow [91]. Type 2 diabetes mellitus and systemic hypertension have been independently associated with increased open-angle glaucoma risk by approximately 36% and 70%, respectively [92,93]. Thin central corneal thickness (CCT ≤ 555 μm) is another strong predictor, tripling the likelihood of conversion from ocular hypertension to glaucoma [94]. Additional medical associations include myopia, which doubles the risk of open-angle glaucoma, and obstructive sleep apnea (OSA), which increases glaucoma odds by ~40% [95,96].

From a genetic standpoint, several mutations—most notably in MYOC, CYP1B1, OPTN, WDR36, and TBK1—are linked to primary open-angle glaucoma (POAG), pseudoexfoliation glaucoma, and congenital forms. These genes affect IOP regulation, aqueous humor dynamics, and the survival of RGCs [97].

Current treatment strategies focus primarily on lowering IOP through topical prostaglandin analogues, β-blockers, carbonic anhydrase inhibitors, and laser trabeculoplasty [84]. Surgical interventions, including trabeculectomy and glaucoma drainage device implantation, are reserved for medically refractory cases [98]. Although there are no approved therapies targeting metal dysregulation directly, dietary modification to maintain adequate zinc and selenium levels, alongside chelation approaches under investigation, may offer future adjunctive treatments.

Prevention hinges on early detection via regular comprehensive eye examinations—particularly for individuals over 40 years of age or with a family history of glaucoma—and timely initiation of IOP-lowering interventions to preserve visual function [99]. Public health measures, such as community screening programs in high-risk populations and patient education on modifiable risk factors (e.g., smoking cessation, blood pressure control), are essential to reduce the global burden of this sight-threatening disease [100].

At present, only a few studies describe the role of elemental disturbances and their involvement in the onset and/or progression of glaucoma [101]. It was observed that increased intake of iron (Fe), calcium (Ca), and selenium (Se) might be associated with a greater risk of glaucoma onset; however, the exact concentrations that, in fact, induce the pathological process within the organ of vision still remain unknown [102,103]. In the case of patients with glaucoma, greater levels of iron (Fe) and nickel (Ni), as well as lower concentrations of chromium (Cr), aluminum (Al), and manganese (Mn) were observed in lenses compared to the control group of the lenses obtained from the patients without diagnosed glaucoma [104]. Furthermore, patients with glaucoma tend to present with the accumulation of toxic elements within the anterior chamber of the eye [105]. Further, calcium (Ca) aggregates were found in the conjunctival stroma of patients with glaucoma, and their levels were the highest in the case of patients whose surgery failed within a three-year follow-up period [106]. Elevated levels of calcium (Ca) in the case of glaucoma have already been reported in the literature [107]. Akyol et al. (1990) observed that increased copper (Cu), along with the coexisting low zinc (Zn) values, might be of high importance concerning the onset and progression of glaucoma [108]. Elevated copper (Cu) levels were observed to be increased in the aqueous humor in the case of patients with either primary open-angle glaucoma (POAG) or primary angle-closure glaucoma (PACG) [109]. Further, aqueous humor obtained from patients with primary open-angle glaucoma (POAG) or pseudoexfoliation glaucoma (PEXG) presents significantly increased levels of zinc (Zn); patients with PEXG additionally presented decreased levels of iron (Fe) in the aqueous humor at the same time [110]. Similarly, Hohberger et al. (2018) also observed elevated zinc (Zn) levels in the aqueous humor obtained from patients with POAG, while decreased iron (Fe) concentrations in the aqueous humor from the patients with PEXG [20]. Also, patients with primary open-angle glaucoma (POAG) presented significantly increased levels of iron (Fe), zinc (Zn), and mercury (Hg) in the aqueous humor [110,111].

2.3. Diabetic Retinopathy

Diabetic retinopathy (DR) is one of the most common microvascular complications of diabetes mellitus and a leading cause of vision loss in working-age adults. An estimated 22.3% of adults with diabetes worldwide—representing approximately 103 million people in 2020—are affected by diabetic retinopathy (DR), with vision-threatening DR (VTDR) present in 6.2% of cases (~28.5 million individuals); these figures are projected to rise to 160.5 million total DR and 44.8 million VTDR cases by 2045 [112,113]. The prevalence increases with longer diabetes duration and is higher in populations with poor glycemic and blood pressure control.

Chronic hyperglycemia is the primary driver of DR. Sustained elevated blood glucose promotes advanced glycation end-product (AGE) formation, protein kinase C activation, polyol-pathway flux, and oxidative stress, all of which damage retinal capillaries and pericytes [114]. Inflammation and upregulation of vascular endothelial growth factor (VEGF) further compromise the blood–retinal barrier, leading to capillary leakage, microaneurysms, and neovascularization in proliferative stages [114,115]. Hypertension, dyslipidemia, and genetic predispositions (e.g., polymorphisms in VEGF or aldose reductase genes) modulate individual risk and severity. Among environmental contributors, heavy smoking exacerbates oxidative stress and vascular inflammation in the retina, accelerating the onset and progression of DR [116]. Similarly, obesity (BMI ≥ 30 kg/m²) increases DR risk through chronic low-grade inflammation and insulin resistance [117].

Key medical risk factors include poor glycemic control, as each 1% increase in HbA₁c raises the risk of DR by approximately 20%, while intensive glucose control significantly reduces incidence and progression [118]. The duration of diabetes is another major determinant—less than 10% of patients develop DR within five years of diagnosis, whereas the prevalence exceeds 80% after 20 years [112]. Systemic hypertension, especially when systolic blood pressure exceeds 140 mmHg, contributes to DR progression and macular edema [119]. Dyslipidemia, particularly elevated LDL and triglycerides, has been linked to increased risk of diabetic macular edema [120]. Additionally, diabetic nephropathy, reflected by microalbuminuria or overt renal disease, correlates with more advanced stages of retinopathy [121].

On a genetic level, several polymorphisms have been implicated in DR susceptibility. These include variants in the vascular endothelial growth factor (VEGF) gene (e.g., −634G>C), which modulate angiogenesis and vascular permeability [122]; aldose reductase (AKR1B1) gene polymorphisms, which alter polyol pathway activity and contribute to retinal cellular damage [123]; and the angiotensin-converting enzyme (ACE) I/D polymorphism, where the D allele is associated with increased DR risk through renin–angiotensin system dysregulation [124].

Current therapies aim to halt disease progression and preserve vision. Intravitreal anti-VEGF injections (e.g., ranibizumab, aflibercept) are first-line for diabetic macular edema, improving visual acuity in over half of treated patients [125]. Laser photocoagulation remains the standard for proliferative DR, reducing severe vision loss by 50%, while pars plana vitrectomy addresses non-resolving vitreous hemorrhage or tractional retinal detachment [125,126]. Emerging treatments under investigation include intravitreal corticosteroid implants, aldose reductase inhibitors, and novel drug-delivery systems targeting inflammation and neuroprotection.

Early detection and optimal systemic control are key. Annual or biennial retinal screening via fundus photography or optical coherence tomography can identify DR at treatable stages, yet screening coverage remains suboptimal in many regions [117]. Tight glycemic control (HbA₁c < 7%), strict blood pressure targets (<140/85 mmHg), and lipid-lowering therapy reduce DR incidence and progression by up to 50% [112,127]. Patient education on diabetes self-management and community-based screening programs are vital, especially in underserved populations.

With the usage of the AAS, the concentrations of iron (Fe), zinc (Zn), and copper (Cu) in the samples obtained from the anterior chamber fluid, lens, and serum of the patients with and without diabetes were analyzed [128]. It turned out that the copper (Cu) levels were significantly higher in the lenses of patients with diabetes compared to those without the disease (p = 0.02). Kayiklik et al. (2019) investigated the levels of chosen elements such as calcium (Ca), phosphorus (P), magnesium (Mg), sodium (Na), or potassium (K) in the anterior chamber fluid in patients with and without diabetes with diagnosed glaucoma; the researchers were also investigating the probability of the pseudoexfoliation occurrence in those patients [129]. The authors, using photometric quantification, observed low sodium (Na) levels in the anterior chamber of the patients with pseudoexfoliation and posterior subcapsular cataracts, high levels of phosphorus (P) in the eyes of patients suffering from diabetes but without pseudoexfoliation, as well as high calcium (Ca) and chloride (Cl) levels in the eyes of patients without pseudoexfoliation.

2.4. Macular Degeneration

Age-related macular degeneration (AMD) is a progressive retinal disorder affecting the macula, leading to central vision loss and substantial impairment in quality of life among older adults. Globally, the prevalence of AMD is estimated at 8.7% of individuals aged 45–85 years, corresponding to approximately 196 million people in 2020; this figure is projected to rise to 288 million by 2040 due to population aging [130]. The disease manifests in two primary forms: non-neovascular (“dry”) AMD, characterized by drusen accumulation and geographic atrophy, and neovascular (“wet”) AMD, marked by choroidal neovascularization and rapid vision decline [131].

Age remains the most significant non-modifiable risk factor, with prevalence doubling every decade after age 60 [130]. Environmental contributors include cigarette smoking—smokers have a two- to three-fold increased risk of AMD—poor dietary habits, and chronic oxidative stress in the retinal pigment epithelium (RPE) [132]. Medical comorbidities such as hypertension and dyslipidemia further exacerbate disease risk by promoting vascular dysfunction and inflammation [133]. Genetic predisposition plays a pivotal role: polymorphisms in the complement factor H (CFH) gene, particularly the Y402H variant, and in the ARMS2/HTRA1 locus account for over 50% of familial risk, implicating complement-mediated inflammation in pathogenesis [134].

Management strategies differ by AMD subtype. For neovascular AMD, intravitreal injections of anti-vascular endothelial growth factor (anti-VEGF) agents (e.g., ranibizumab, aflibercept) are first-line therapies, yielding stabilization or improvement in visual acuity in over two-thirds of patients [135]. Photodynamic therapy with verteporfin remains an adjunct for certain lesion types [136]. In dry AMD, no approved therapies reverse atrophy, but the Age-Related Eye Disease Study 2 (AREDS2) formulation—comprising lutein, zeaxanthin, vitamins C and E, zinc, and copper—reduces progression to advanced AMD by ≈25% over five years [137].

Preventive measures focus on modifiable lifestyle factors and early detection. Smoking cessation, adherence to a Mediterranean-style diet rich in leafy greens and fish, and maintenance of cardiovascular health mitigate AMD risk [132,133]. Regular ophthalmologic screening with fundus photography or optical coherence tomography enables the timely identification of drusen or subretinal fluid, facilitating prompt intervention for neovascular conversion. Genetic counseling may be considered for individuals with strong family histories.

The pathogenic role of iron (Fe), cadmium (Cd), and copper (Cu) as environmental risk factors for the onset of age-related macular degeneration (AMD) was already confirmed in the literature [138]. Stopa et al. showed that patients with macular degeneration present significantly higher levels of cadmium (Cd), cobalt (Co), iron (Fe), and zinc (Zn) in the aqueous humor [138]. Further, Junemann et al. also showed that cadmium (Cd), Cobalt (Co), iron (Fe), and copper (Cu), which were found in the aqueous humor of AMD patients, are involved in the pathogenesis of this ophthalmic condition [105].

2.5. Other Ophthalmic Diseases

2.5.1. Cytomegalovirus (CMV) Retinitis

Cytomegalovirus (CMV) retinitis is a sight-threatening opportunistic infection that predominantly affects immunocompromised individuals. Before the advent of highly active antiretroviral therapy (HAART), CMV retinitis occurred in 25–40% of patients with AIDS and CD4⁺ counts below 50 cells/µL [139]. In the modern HAART era, the incidence among people living with HIV has fallen to approximately 0.36 cases per 100 person-years in well-resourced settings, although prevalence remains high—up to 30%—in some resource-limited regions of Southeast Asia, contrasting with <5% in parts of southern Africa [140,141].

CMV is a ubiquitous β-herpesvirus with a seroprevalence of 50–80% in the general adult population; clinical retinitis arises almost exclusively when host immunity is severely impaired [139]. In HIV-infected patients, profound CD4⁺ T-cell depletion (<50 cells/µL) permits unchecked viral replication within retinal vascular endothelial cells and pericytes, leading to full-thickness necrosis of the retina. The necrotizing lesions often present with “pizza-pie” retinal hemorrhages and granular white infiltrates, which, if untreated, progress to retinal detachment and irreversible vision loss.

First-line therapy for CMV retinitis consists of systemic antivirals: oral valganciclovir or intravenous ganciclovir, both of which inhibit viral DNA polymerase and achieve high intraocular concentrations [142]. Alternative agents such as foscarnet and cidofovir are reserved for ganciclovir-resistant cases or patients intolerant of ganciclovir. Intravitreal injections of ganciclovir or foscarnet may be used adjunctively to deliver high local drug levels while minimizing systemic toxicity. The goal is to induce lesion regression, prevent fellow-eye involvement, and preserve visual acuity.

HAART has dramatically reduced CMV retinitis incidence by restoring CD4⁺ counts and CMV-specific immunity, with reports of 55–83% decline in new cases since widespread antiretroviral rollout [139]. In transplant recipients and other at-risk populations, prophylactic valganciclovir or ganciclovir decreases the risk of CMV disease, including retinitis, and is recommended when CMV serostatus mismatch or high-risk immunosuppression is present [143]. Regular ophthalmologic screening—every 3–6 months for patients with CD4⁺ < 50 cells/µL—enables early detection and timely initiation of therapy.

Fluctuations in the levels of chosen elements such as calcium (Ca), iron (Fe), zinc (Zn), or magnesium (Mg) within the vitreous humor might also be associated with the onset of cytomegalovirus retinitis [21].

2.5.2. Druses

Drusen are extracellular deposits that accumulate between the retinal pigment epithelium (RPE) and Bruch’s membrane. While small “hard” drusen are common with normal aging, larger “soft” drusen are strongly associated with early stages of age-related macular degeneration (AMD).

Population studies indicate that small drusen are present in over 90% of individuals aged 50 and older, with prevalence rising steeply with age [144]. Soft drusen—those > 63 µm in diameter—are found in approximately 5–7% of adults aged 60–69 years, increasing to >20% by age 80 [145]. Reticular pseudodrusen, a distinct subretinal phenotype, affects about 4–5% of persons over 60 [146].

Drusen formation reflects chronic RPE dysfunction and impaired transport across Bruch’s membrane. Lipids, complement proteins, apolipoproteins, and trace elements such as zinc accumulate to form these deposits [137]. Genetic variants—most notably the Y402H polymorphism in CFH and the A69S variant in ARMS2/HTRA1—heighten local inflammation and complement activation, accelerating drusen biogenesis [147]. Oxidative stress from smoking, high-energy visible light exposure, and systemic vascular disease further compromises RPE homeostasis, promoting deposit formation [132].

No therapies directly eliminate drusen or reverse established deposits. Subthreshold laser and photobiomodulation have demonstrated drusen reduction in small trials but have not yet proven to prevent progression to late AMD [148]. Nutritional supplementation per the AREDS2 formulation (lutein, zeaxanthin, vitamins C and E, zinc (Zn), copper (Cu)) slows progression from intermediate drusen to advanced AMD by ≈25% over five years, indirectly mitigating drusen-related risk [137].

Modifiable risk-factor control is key. Smoking cessation reduces drusen accumulation and AMD incidence [132]. A diet rich in green leafy vegetables, fish, and omega-3 fatty acids supports RPE health. Sunlight protection with UV-blocking eyewear may limit photo-oxidative damage. Regular retinal imaging in at-risk individuals (e.g., age > 60, positive family history) enables early identification of high-risk drusen phenotypes, allowing prompt lifestyle and nutritional interventions.

It was also noted that increased iron (Fe) and copper (Cu) levels in the eye might occur in the case of druses [149].

2.5.3. Corneal Dystrophy

Corneal dystrophies are a group of rare, inherited, bilateral, and usually symmetrical non-inflammatory diseases characterized by the progressive deposition of abnormal material within specific corneal layers—epithelial, stromal, or endothelial—leading to visual impairment and decreased transparency [150,151,152]. The most prevalent form, Fuchs endothelial corneal dystrophy (FECD), affects approximately 7.3% of adults globally, based on a meta-analysis of over 4700 individuals aged >30 years, with an anticipated increase from roughly 300 million affected today to 415 million by 2050 [1]. FECD and other dystrophies exhibit autosomal dominant inheritance with variable penetrance, often linked to mutations in genes such as TCF4, COL8A2, and TGFBI [152,153]. Clinically, early-onset FECD often presents in the fifth decade with central guttae, corneal edema, and decreased visual acuity, while stromal dystrophies, such as granular and lattice types, manifest with proteinaceous deposits and light scattering in the stroma [151,154]. Despite genetic predisposition, environmental factors, oxidative stress, and endothelial cell senescence also play significant roles in disease progression [151]. The resulting structural disruptions compromise corneal clarity and refractive function, frequently necessitating interventions like endothelial keratoplasty or phototherapeutic keratectomy to restore vision [151,155].

Alterations in the levels of micronutrients and macronutrients, particularly transition metals such as iron (Fe), copper (Cu), and zinc (Zn), have been increasingly implicated in the pathophysiology of various corneal dystrophies. These dystrophies, characterized by progressive accumulation of abnormal material in the corneal layers, may be exacerbated by dysregulated trace element metabolism. Histochemical analyses and elemental mapping studies have demonstrated abnormal accumulation of ferrous iron (Fe²⁺) in the corneal epithelium, Bowman’s layer, and anterior stroma in patients with granular and lattice corneal dystrophies [156]. The excess iron may participate in Fenton-type reactions, generating reactive oxygen species (ROS) that contribute to oxidative stress, lipid peroxidation, and collagen crosslinking, thereby promoting stromal haze and tissue degeneration [157]. Furthermore, immunohistochemical studies have indicated altered expression of ferritin, the iron-storage protein, suggesting impaired iron homeostasis in dystrophic corneal tissue [158].

In addition to iron (Fe), imbalances in other trace metals such as zinc (Zn) and copper (Cu) have been reported. Zinc (Zn), a cofactor for matrix metalloproteinases (MMPs), plays a role in extracellular matrix remodeling, while copper (Cu) is essential for lysyl oxidase activity involved in collagen cross-linking. Disruptions in their concentrations may affect corneal transparency and stromal architecture [159]. For instance, changes in zinc (Zn) and copper (Cu) levels have been detected in corneal tissues affected by TGFBI-related dystrophies, potentially influencing the deposition of mutated protein aggregates [160]. The imbalance of trace metals may also impair antioxidant enzyme systems such as superoxide dismutase (SOD) and catalase, further contributing to oxidative stress [161]. These findings collectively suggest that the altered distribution and concentration of micronutrients in the cornea may act synergistically with genetic mutations to accelerate the clinical manifestation and severity of corneal dystrophies.

2.5.4. Pterygium

Pterygium is a fibrovascular proliferative disorder of the bulbar conjunctiva that encroaches onto the cornea, often triangular in shape and more common on the nasal side. Although benign, it can induce astigmatism, chronic irritation, and, in advanced cases, threaten vision.

A global meta-analysis including over 900,000 subjects estimated a pooled pterygium prevalence of 10.2% (95% CI 6.3–16.1%), with higher rates in low-latitude regions and elderly populations [162]. Prevalence rises from as low as 3.0% in those aged 10–20 years to nearly 19.5% in individuals over 80 years [163]. Males are affected slightly more often than females (OR 1.30, 95% CI 1.14–1.45) [163].

Ultraviolet (UV) radiation is the primary environmental driver: outdoor workers with >5 h daily sun exposure exhibit a 1.24-fold increased risk (95% CI 1.11–1.36) [163]. Chronic UV induces limbal stem-cell damage, oxidative stress, and upregulation of matrix metalloproteinases, fostering conjunctival overgrowth. Additional factors include wind, dust, and dry eye [164]. Although the exact genetic contribution is not fully elucidated, familial clustering and polymorphisms in p53 and antioxidant-related genes suggest a heritable component [165].

Surgical excision remains the mainstay, with conjunctival autografting plus intraoperative mitomycin C reducing recurrence rates to <5% at one year [166]. Amniotic membrane transplantation and fibrin glue have also shown efficacy. Adjunctive therapies under investigation include anti-VEGF agents and anti-inflammatory eye drops to modulate fibrovascular proliferation.

Primary prevention focuses on UV protection: wearing broad-brimmed hats and UV-blocking eyewear can halve pterygium incidence [167]. Public-health education targeting at-risk outdoor workers, promotion of ocular lubricants in dry environments, and regular ocular surface examinations in endemic regions further reduce the disease burden.

Namuslu et al. (2013) investigated the levels of the essential trace elements in the conjunctiva of healthy individuals and those with pterygium [168]. Results showed significantly lower levels of chromium (Cr), manganese (Mn), zinc (Zn), and selenium (Se) in pterygium conjunctiva (

Table 3. Results of the studies about the metallomic analysis of the chosen parts of the human eye in ophthalmic diseases.

Disease	Part of the Eye	Concentrations of Elements		Ref.
		Increase	Decrease
Cataracts	Lens	Ca, Zn, Cu, Cd, Al, V, Fe, Cr, Mn, Ba	Mg	[22,67,68,69,70,71,72,75,76,77,78,79,81,83]
	Aqueous humor	P *, Ni, Ca, Cs, K, Mg, Na, P, Rb, Tl, Te, Pb, Al	ND	[22,82,83]
Glaucoma	Lens	Fe, Ni	Cr, Al, Mn	[105,106,109,110,111]
	Aqueous humor	Cu, Zn, Fe, Hg	Fe
	Conjunctival stroma	Ca	ND
Diabetic retinopathy	Lens	Cu	ND	[128,129]
	Aqueous humor	P, Ca, Cl	Na
Macular degeneration	Aqueous humor	Cd, Co, Fe, Zn	ND	[138]
Pterygium	Pterygium conjunctiva	ND	Cr, Mn, Zn, Se	[168]

* in the case of patients with coexisting diabetes. ND—no data.

).

3. Discussion

The dysregulation of micro- and macroelements within specific tissues of the human eye has been consistently implicated in the pathogenesis and progression of major ophthalmic diseases, with mounting evidence showing how their altered concentrations contribute to structural damage and visual dysfunction. In cataracts, the accumulation of calcium (Ca) in the lens—sometimes four times higher than in healthy controls—has been shown to disrupt lens osmotic balance, activate calpain proteases, and promote the formation of calcium oxalate crystals, ultimately compromising lens transparency and contributing to light scattering and opacification [22,67,69,168,169,170]. Zinc (Zn) and copper (Cu) are found at elevated levels, particularly in pseudoexfoliative cataracts, where they induce β-crystallin aggregation and oxidative damage [22,73]. Simultaneously, disturbed Na⁺/K⁺-ATPase activity linked to excess sodium (Na) and decreased magnesium (Mg) concentrations disrupts ionic gradients critical for lens homeostasis [10,14,171]. Notably, toxic metals such as cadmium (Cd), vanadium (V), aluminum (Al), and chromium (Cr) have also been detected at high levels in the lens of smokers or patients with advanced cataracts, underscoring their role in oxidative stress and extracellular matrix dysfunction [20,24,42,74,76,132,171].

In glaucoma, the accumulation of iron (Fe), copper (Cu), and zinc (Zn) within the aqueous humor and trabecular meshwork promotes retinal ganglion cell death through ferroptosis and redox imbalance [172,173]. These changes co-occur with a decline in protective elements such as manganese (Mn) and selenium (Se), which are necessary for the enzymatic defense against reactive oxygen species (ROS) [172,173,174]. Elevated calcium (Ca) aggregates in the conjunctival stroma further interfere with aqueous outflow, correlating with poor surgical outcomes and increased intraocular pressure [68,69,70,71,72,81,174].

In diabetic retinopathy (DR), aqueous humor and lens analyses reveal elevated phosphorus (P), calcium (Ca), and copper (Cu) levels, especially in patients with proliferative diabetic retinopathy [175,176]. These elements amplify oxidative stress and vascular leakage by destabilizing pericytes and tight junction proteins. Sodium (Na) depletion, observed in the anterior chamber, further disrupts fluid balance and contributes to pseudoexfoliation syndromes in DR patients [77].

Macular degeneration (AMD) and drusen formation also exhibit a strong metallomic signature. Elevated concentrations of iron (Fe), cadmium (Cd), cobalt (Co), copper (Cu), and zinc (Zn) in the aqueous humor have been linked to RPE degeneration, lipid peroxidation, and abnormal complement activation [77,177]. These elemental imbalances accelerate drusen formation and photoreceptor apoptosis, aligning with the pathogenic cascade of AMD.

In corneal dystrophies, excess ferrous iron (Fe²⁺) in the basal epithelium, Bowman’s layer, and anterior stroma catalyzes Fenton reactions, inducing stromal haze and fibrosis [158,178]. Imbalances in copper (Cu) and zinc (Zn) further influence lysyl oxidase and MMP activity, aggravating extracellular matrix remodeling and epithelial–stromal interface disruption [73,74,108,128].

Finally, in pterygium, a fibrovascular overgrowth of the conjunctiva, a significant depletion of chromium (Cr), manganese (Mn), zinc (Zn), and selenium (Se) was found in conjunctival tissues [16,164,165,166,167,168,179]. These elements are essential cofactors for antioxidant enzymes such as superoxide dismutase (SOD) and glutathione peroxidase, and their deficiency facilitates unchecked UV-induced oxidative DNA damage, chronic inflammation, and matrix remodeling, ultimately impairing corneal integrity and inducing astigmatism or visual axis encroachment.

Altogether, these findings underscore that not only the presence but the tissue-specific accumulation or deficiency of trace elements plays a central role in the etiopathogenesis of vision-threatening disorders. Multi-elemental profiling of ocular tissues, particularly through post-mortem analysis and advanced techniques like ICP-MS or LA-ICP-MS, offers valuable insight into early dysfunction and may guide novel diagnostic or therapeutic approaches tailored to elemental imbalances (

Table 4. Comparative summary of the metallomic studies included in the review.

Study/Author(s)	Sample Source	Tissue Analyzed	Analytical Method	Key Findings
[9]	Cataract surgery (lens)	Lens	ICP-OES	↑ Ca, Cu, Zn in cataractous lenses
[180]	Cataract surgery (lens)	Lens	ICP-MS	↓ Mg, ↑ Ca in nuclear cataracts
[181]	Postmortem (retina)	Retina	SR-XRF	↑ Zn, Cu in AMD retinas
[105]	Postmortem (retina)	Retina	LA-ICP-MS	↑ Fe in AMD retinas (LA-ICP-MS mapping)
[182]	Aqueous humor (AMD patients)	Aqueous Humor	ICP-MS	↑ Fe, Cd, Cu, Zn in AMD; oxidative damage
[16]	Conjunctival tissue (pterygium excision)	Conjunctiva	TXRF	↓ Cr, Mn, Zn, Se in pterygium
[15]	Corneal stroma (keratoconus surgery)	Cornea	LA-ICP-MS	↑ Fe in anterior corneal stroma

↑—increase; ↓—decrease.

).

Recent advances in ocular metallomics have revealed that dysregulation of metal ions—including iron (Fe), zinc (Zn), copper (Cu), and selenium (Se)—contributes not only to the pathogenesis but also offers potential therapeutic targets in a range of ophthalmic diseases, including cataracts, glaucoma, diabetic retinopathy, age-related macular degeneration (AMD), cytomegalovirus (CMV) retinitis, drusen formation, corneal dystrophy, and pterygium. Therapeutic strategies aimed at correcting metal dyshomeostasis have become increasingly relevant as adjunct or even primary interventions. In cataracts, oxidative stress mediated by redox-active metals such as iron (Fe) and copper (Cu) leads to protein aggregation and lens opacification. Chelating agents such as ethylenediaminetetraacetic acid (EDTA), deferoxamine, and newer lipophilic chelators have been investigated for their ability to reduce intraocular metal burden and delay cataractogenesis [183,184]. In glaucoma, excessive iron (Fe) accumulation in the trabecular meshwork and retinal ganglion cells (RGCs) has been linked to apoptosis via ferroptosis. Iron (Fe) chelation and modulation of ferritin expression are under exploration to protect RGCs and maintain intraocular pressure homeostasis [185,186].

In diabetic retinopathy (DR), hyperglycemia-induced changes in retinal vascular permeability are exacerbated by increased iron (Fe) and copper (Cu) levels, which enhance oxidative damage and angiogenesis. Metal-binding antioxidants, such as N-acetylcysteine, and zinc (Zn) supplementation have demonstrated protective effects by reducing pericyte loss and vascular leakage [187,188]. In AMD, abnormal zinc (Zn) and copper (Cu) levels in Bruch’s membrane and drusen have been associated with lipid peroxidation and local complement activation. The Age-Related Eye Disease Study (AREDS) formulation, which includes high-dose zinc (80 mg/day), demonstrated a significant reduction in AMD progression, though recent metallomic data suggest that individual metal profiles may affect treatment response and toxicity [189,190]. Moreover, chelators such as clioquinol and metal-modulating agents targeting iron (Fe) and zinc (Zn) have shown promise in preclinical AMD models [191].

CMV retinitis, primarily affecting immunocompromised individuals, involves oxidative stress and mitochondrial damage partly mediated by disrupted iron homeostasis. Adjunctive use of antioxidants and mitochondrial-targeted metal chelators is being studied to complement antiviral therapy [192]. In drusen, calcium (Ca) and trace metal deposits serve as histopathological hallmarks. Nanoparticle-based delivery systems are being developed to modulate local metal content and inhibit drusen progression [193]. In corneal dystrophies, as previously discussed, accumulation of iron (Fe) and copper (Cu) contributes to extracellular matrix cross-linking and epithelial toxicity. Therapeutic approaches include topical chelators (e.g., deferoxamine, EDTA) and strategies to modulate metal transporter expression [156].

Finally, in pterygium, chronic UV exposure leads to oxidative DNA damage, exacerbated by increased levels of iron (Fe) and reduced activity of antioxidant enzymes such as superoxide dismutase (SOD), which are dependent on trace metals like copper (Cu) and zinc (Zn). Studies have demonstrated altered metallothionein expression in pterygium tissue, and treatments modulating zinc (Zn) homeostasis and SOD activity are under consideration [194,195]. Collectively, these findings support the inclusion of metallomic profiling and metal-targeted therapies in the personalized management of ocular diseases, potentially offering adjunctive benefits to conventional pharmacological or surgical interventions (Figure 1).

The findings of this review underscore the hypothesis that dysregulation of trace elements contributes to the pathophysiology of numerous ophthalmic diseases through several mechanistic pathways. Elevated levels of transition metals such as iron (Fe), copper (Cu), and zinc (Zn) have been observed in ocular tissues affected by age-related macular degeneration (AMD), cataracts, and glaucoma [9,180,181]. These metals participate in redox cycling reactions, notably the Fenton and Haber–Weiss reactions, generating reactive oxygen species (ROS) that damage cellular lipids, proteins, and nucleic acids. The resulting oxidative stress is a central driver of lens opacification in cataracts and photoreceptor damage in AMD [105,181,182].

In addition to oxidative mechanisms, trace element imbalances may lead to mitochondrial dysfunction, particularly in high-energy-demanding tissues like the retinal pigment epithelium (RPE) and retinal ganglion cells (RGCs). For example, Fe overload disrupts mitochondrial electron transport and induces apoptotic cascades, which are implicated in the early stages of glaucoma and retinal neurodegeneration [88,196]. Moreover, the accumulation of cadmium (Cd), lead (Pb), and aluminum (Al), as reported in AMD and cataract patients, may interfere with calcium (Ca) signaling and promote protein misfolding, particularly in lens crystallins, further accelerating disease progression [15,197].

Several trace elements, including selenium (Se) and manganese (Mn), serve as essential cofactors for antioxidant enzymes like glutathione peroxidase and superoxide dismutase (SOD). Deficiencies in these elements, as observed in pterygium and corneal dystrophies, may weaken cellular defenses and exacerbate UV- and inflammation-induced oxidative stress [16,32,198]. Similarly, aberrant zinc (Zn) homeostasis is known to disrupt matrix metalloproteinase (MMP) activity, contributing to extracellular matrix remodeling and tissue invasion in pterygium [179,198].

Despite these mechanistic insights, considerable knowledge gaps remain. Few studies provide longitudinal data, and most are cross-sectional or descriptive in nature. Moreover, differences in analytical methodology, sample source (e.g., postmortem vs. surgical), tissue preservation, and population genetics limit the comparability of findings across studies. The lack of consensus on standard reference values for trace elements in ocular tissues further complicates interpretation.

Future research should prioritize the development of non-invasive sampling techniques (e.g., analysis of tear fluid, conjunctival swabs, or anterior chamber paracentesis) that can reliably reflect intraocular metallomic profiles. Additionally, large-scale, prospective cohort studies are needed to validate trace element alterations as biomarkers of disease progression or therapeutic response. The integration of metallomics with genomics and proteomics, particularly in the context of metal transporter gene polymorphisms, may also offer new insights into individualized risk stratification and treatment development.

4. Conclusions

Levels of micro- and macroelements in the human organism change dynamically and undoubtedly remain critical for health. Numerous studies focus on determining the concentrations of both the most common and toxic metals in various tissues obtained from patients suffering from many diseases, including ophthalmic diseases. However, the results of these studies seem to be quite problematic primarily because of the diversity of the applied analytical methods of different sensitivity (AAS, ICP-MS, ICP-AES, AAS, LA-ICP-MS). Inconsistency of the results obtained by different research groups might also be the result of the inclusion criteria of the study and control group, along with the unquestioned inter-individual variation. The knowledge about the metallomic analysis of the organ of vision, specifically in the case of ophthalmic diseases, is highly limited. The extended studies, including many morphological parts of the human eye as well as other parts associated with vision, such as the visual tract and elements of the brain associated with vision, obtained post mortem, and then analyzed, might significantly expand the knowledge about the distribution of micro- and macroelements in the organ of vision. Since many elements remain the parts of the biomolecules involved in the proper physiology of the organ of vision, such knowledge might be crucial for a better understanding of the pathogenesis of many ophthalmic diseases. To conclude, current metallomic studies of the eye focus only on the chosen morphological parts of the human eye (primarily lens, aqueous humor) as well as the chosen elements (mainly toxic ones including lead (Pb) or aluminum (Al)). An extension of studies on more structures and tissues would enable the actual distribution of the elements in the parts of the human eye. Such studies, particularly performed post mortem, would enable the multidirectional assessment of the tissues that might be at a higher risk of accumulation of the toxic metals, as well as those that might also cause a threat in greater concentrations. The understanding of the mechanisms leading to the changes in the distribution of micro- and macroelements that are crucial in the etiology of ophthalmic diseases would provide more effective prevention and therapeutic approaches, or even improvements in the treatment of chosen ophthalmic diseases.