EpidemiologyA pilot study to evaluate the levels of aqueous humor trace elements in open-angle glaucoma
Introduction
Glaucoma is a group of chronic, progressive optic neuropathies characterized by slow degeneration of the retinal ganglion cells (RGC) and their axons, resulting in cupping, a characteristic appearance of the optic disc, and visual field loss, for which elevated intraocular pressure (IOP) is one of the primary risk factors [1]. Primary open angle glaucoma (POAG) is the most common form of the disease accounting for ca. 75 % of all glaucoma cases [2]. Risk factors for POAG include, in addition to IOP, increased age, European and African ethnicity, family history, myopia and decreased corneal thickness. Another important risk factor is the oxidative stress that can cause RGC death [3,4].
The study of Tham et al. [5] reported in 2013 a worldwide prevalence of POAG of 3.05 % with 44.1 million of subjects aged 40–80 years. They also estimated that the number of subjects with the POAG will increase to 52.6 million of cases in 2020 and 79.7 in 2040. In addition, POAG can significantly affect quality of life; in the elderly, visual impairment, associated with limitation of daily functions and loss of autonomy, may lead to or exacerbate depression, loneliness and anxiety [6].
In this context, studies indicated that levels of trace elements are significantly related to several ocular pathologies, including POAG [7,8], age-related macular degeneration (AMD) [9], cataracts [10,11], and pseudoexfoliation syndrome (PEX) [12], also because they may influence the balance between oxidants and antioxidants.
With the reference to Al, intraperitoneal application of aluminum chloride to rats causes retinal toxicity, with consequent retinal pigment epithelium (RPE) thinning and loss of photoreceptor outer segments (POS) [13]. In addition, Al due to its pro-oxidant activity is able to accelerate Fe-driven peroxidation of lipids and aggravates oxidative damage by enhancing reactive oxygen species (ROS) formation [14].
Cadmium is a well-known element for its toxicity for human health. With reference to the ocular vision, the development of normal tension glaucoma (NTG) might be negatively influenced by the vascular toxicity of Cd [8] as well as the direct toxicity of this element to the RGC could contribute to the development of the glaucoma [15]. Moreover, alteration of the cellular morphology, decreased cell survival, increased levels of ROS and disruption of the integrity of the membrane depending by the concentration were observed following the exposure of cultured RPE cells to Cd [16]. Copper is found in different retinal regions and the concentrations of this element are linked to retinal physiology and functions in which Cu is involved. It has also been suggested that Cu has specialized functions in the retina as well as it is able to modify the activity of rhodopsin in retina. On the other hand, intraocular foreign bodies containing Cu may cause inflammation and injury on cell membranes and mitochondria in retina. Finally, the interaction among NMDA and AMPA receptors, nitric oxide synthase and Cu can cause retinal neuron death [17].
In the retina, Fe is particularly important for the visual phototransduction cascade, but Fe excess can be harmful [18]. Iron can cause considerable oxidative stress, lipid peroxidation, DNA damages and degradation of biomolecules with the consequent degradation of RGC and increase of IOP creating the risk to develop POAG [3,19].
About Hg, studies have revealed toxic effects on eye and visual function. In particular, in vivo studies showed toxicity of Hg on the photoreceptor layer [20,21], whereas clinical studies reported visual dysfunction caused by Hg intoxication [22,23].
Meanwhile, Mn is an essential trace element that maintains proper cell function. It is also necessary for many enzymes, including Mn-superoxide dismutase, which inhibits the death of nerve cells [24]. Dietary Mn deficiency is associated with cone function abnormalities on an electroretinogram, which correspond with impaired renewal of POS discs [25,26].
Nickel exposure results in the development of free radicals in tissues, leading to various modifications in DNA, increased lipid peroxidation and altered homeostasis [27]. Animal studies have shown cellular anomalies in the retina of fish eye exposed to Ni, affecting the primary function of retina and leading to visual loss or poor vision [28]. In human cadaver donor eyeballs, Ni levels as well as Pb and Cd contents, were significantly increased in late AMD compared to controls [29].
Concerning Pb, chronic occupational exposure to this element might lead to decreased retinal nerve fiber layer thickness [30]. Shen et al. [31] suggested that environmental and occupational Pb exposures are risk factors for increased blood retinal barrier (BRB) permeability in diseases such as AMD, diabetes and stroke. High Pb levels were observed in hair of women with low-tension glaucoma and evidence of a significant association between bone Pb and incident of POAG in men has been reported [32,33]. In rabbits, Pb toxicity leads to swelling of the RPE resulting in photoreceptors degeneration [34,35].
Zinc play vital roles in retinal cell survival; it is crucial for the normal functioning of antioxidant enzymes and protect eye structures from harmful effects of light and oxidative stress. Depletion of intracellular Zn can increase the vulnerability of cultured RPE cells to UV irradiation and may induce RPE cell apoptosis [36].
In Italy, 2% of the population above the age of 40 years is affected by POAG. The prevalence is highest in the North (ca. 50 %), followed by Centre and South Italy, with similar percentages of ca. 25 %. It has been estimated that there will be an increment of 20–30 % of POAG cases in Central and Southern Italy and of 40–50 % in North Italy [3]. A study conducted in 2014 on ca. 15,000 subjects with glaucoma living in various Italian regions indicated Sardinia as the place with the lowest prevalence of glaucoma (2.24 %) [37].
The aim of this study was to determine the concentrations of Al, Cd, Cu, Fe, Hg, Mn, Ni, Pb and Zn in aqueous humor samples of POAG patients and control subjects in Sardinia. Possible relationships between element content and variables, such as sex, age and IOP were explored. Interactions as synergisms or competitions between trace elements in POAG patients were also evaluated. In this context, the outcomes of this study may improve the knowledge on the possible role of trace elements in POAG.
Section snippets
Subjects
Twenty-five patients with POAG and 20 control patients without POAG were recruited from the Department of Medical, Surgical, and Experimental Sciences, Ophthalmology Unit, University of Sassari, Sassari, Italy. In all 25 POAG patients, except for the presence of glaucoma and cataract, no other injuries were observed in the eye structure and in the macula. Regarding other systemic diseases, 10 patients out of 25 POAG patients suffered of other illnesses (i.e., benign prostatic hyperplasia, types
Results
Table 1 describes the aqueous humor levels (μg/L) of trace elements in four different groups: all POAG patients; patients with POAG only; patients with POAG and other illnesses; and controls. The comparison between all the subjects with POAG and controls indicated significant differences for Fe (p = 0.027), Hg (p < 0.001) and Zn (p = 0.024). The differences for Fe (p = 0.044), Hg (p < 0.001) and Zn (p = 0.030) were confirmed also when the subjects with POAG only and controls were compared. In
Discussion
POAG is the most common form of glaucoma in adulthood, which can lead to loss of vision and, potentially, to blindness. Retinal deficiency or excess of trace elements may result from systemic depletion and/or overload or from mutations in genes involved in maintaining retinal element homeostasis [17]. It is known that the oxidative status is increased in the aqueous humor of POAG patients, and antioxidants are significantly reduced [40]. Thus, the determination of essential elements, such as
Conclusions
Essential and toxic trace elements may play important roles both in retinal physiology and POAG disease. In this study, significantly higher concentrations of Fe, Hg and Zn in aqueous humor of glaucoma cases respect to controls were found. Other findings were that more Cu and Fe accumulates in glaucoma patients with age less than 70 years. Nickel accumulates more in POAG females than in control females. In addition, higher concentration of Hg was observed in POAG females, in patients over 70
Author statement
The Authors (Beatrice Bocca, Giovanni Forte, Andrea Pisano, Cristiano Farace, Ermete Giancipoli, Antonio Pinna, Stefano Dore, Roberto Madeddu) declare that all subjects gave informed consent prior to procedures. The study protocol was approved by the Institutional Ethical Committee of the University of Sassari and conducted according to the declaration of Helsinki.
Ethical approval
The study was approved by the Institutional Ethical Committee of the University of Sassari and conducted in accordance with the declaration of Helsinki.
Informed consent
Informed consent was obtained from all individual participants included in the study.
Declaration of Competing Interest
The authors declare that they have no conflict of interest.
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