Introduction
Iron-deficiency anemia (IDA) is a public health concern that affects expectant women and children and is the major cause of several health problems in developing countries.[ 1 ] IDA affects 4–5 million individuals each year.[ 2 ] IDA is a major contributing factor to anemia in developed countries. The etiological factors for the development of IDA include insufficient dietary iron intake or conditions causing hemorrhage and decreased iron absorption.[ 3 , 4 ] The iron requirement is increased during pregnancy due to excessive menstrual bleeding, particularly in women in the fertile age group. Common causes in the elderly population include chronic hemorrhage through the gastrointestinal tract, renal disease, chronic infections, and inflammations. Iron is a vital element that helps in the production of red blood cells and is also indispensable for the proper functioning of the circulatory system. Iron is abundant in hemoglobin, which carries oxygenated blood to all organs.[ 5 ] Hypoxia of the retina has been implicated in the pathogenesis of diabetic retinopathy, retinal vascular occlusions, and the development of glaucomatous optic nerve damage.
IDA affects the ocular tissues too, including the optic nerve.[ 6 ] Deficiency of iron has been shown to reduce visual evoked potential.[ 7 ] Moreover, reduced oxygen supply has been shown to cause damage to the ganglion.[ 8 ]
Spectral-domain optical coherence tomography (SD-OCT) has enabled a better understanding of the diseases affecting the retinal nerve fiber and the optic nerve. The method is also indispensable in the evaluation and monitoring of systemic diseases affecting the retinal nerve fibers.[ 9 ] The effect of IDA on the retinal nerve fibers and optic nerves may develop before IDA becomes evident.
To the best of our knowledge, literature related to the effect of IDA on the retinal nerve fiber layer (RNFL) thickness in the Central Indian population is sparse. Therefore, the present study aimed to evaluate the effect of IDA on peripapillary RNFL.
Materials and Methods
Sample size
The sample size was calculated to detect the difference in RNFL thickness (RNFLT) of 5 μm between the patients and controls with a power of 90% and an α-level of 0.05. Therefore, the sample size in each group was 58 patients.
The sample size is calculated using the formula:
Ethical committee approval
The present study adhered to the tenets of the Declaration of Helsinki and was approved by the institutional review board of the hospital (Government Medical College and Hospital, Nagpur, Maharashtra, India).
Patient selection and study design
The study period was from November 2019 to October 2021. Written informed consent was obtained from all participants of the study.
This prospective, cross-sectional, case–control, and observational study included patients diagnosed with IDA. IDA was defined as a serum hemoglobin level of <10 gm/dL, serum transferrin level of <15%, serum iron level of <50μg/dL, and serum ferritin level of <15μg/dL.
The inclusion criteria were patients of either sex attending the ophthalmology and medicine outpatient department who were diagnosed with IDA and were in the age group of 20–50 years. Patients <20 years of age and >50 years of age, having other causes of anemia, visual acuity <20/20, media opacities, ocular trauma, intraocular operations, glaucoma, uveitis, amblyopia, myopia, and hypermetropia of more than 4.0 diopters, and retinal disorders were excluded from the study.
The control group was composed of age and sex-matched healthy nonanemic patients attending the ophthalmology outpatient department.
A complete eye examination included visual acuity, autorefractometry, refractive error, slit-lamp biomicroscopy of the anterior segment, intraocular pressure using an applanation tonometer, dilated retinal examination using indirect ophthalmoscopy, and 90D examination.
Peripapillary RNFLT was measured in all patients using SD-OCT (Optovue ivue OCT system, Fremont, CA, USA). Peripapillary RNFLT assessments were obtained for the mean total, inferior, superior, nasal, and temporal quadrants using an optic disc of 200 × 200 pixels with a 6 mm × 6 mm cube scan protocol within a diameter of 3.45 mm centered on the optic nerve. All scans were performed after full dilatation of the pupil with a combination of 5% phenylephrine and 0.8% tropicamide.
Statistical analysis
The collected data were entered into an Excel sheet and analyzed using SPSS software 26.0 (IBM Corp USA). The quantitative data were expressed as mean and standard deviation (SD). Categorical variables were expressed as percentages. The quantitative data were analyzed using the t -test (laboratory parameters). Nonparametric data were assessed using the Mann–Whitney U -test (distribution of peripapillary nerve fiber thickness in groups) and the categorical data using the Chi-square test (age and sex). Pearson’s correlation coefficient analysis was done for the correlation of intragroup quantitative variables (correlation between RNFLT and hemoglobin, ferritin, and transferrin level). Statistical values of <0.05 were considered to be significant.
Results
The present study included a total of 116 eyes. There were 73 (62.9%) women and 43 (37.1%) men with female: male ratio of 1:1.6. The average age of the cases was 33.53 ± 5.2 (range 21–45) years, and that of the controls was 34.31 ± 4.6 (range 20–47) years (P = 0.43). Table 1 shows the comparison of the laboratory parameters between the cases and controls. Serum hemoglobin, serum iron, serum ferritin, total iron-binding capacity, and serum transferrin saturation were significantly lower in the cases than in the controls. The values of the mean intraocular pressure in the cases and controls were 15.2 ± 3.6 and 16.4 ± 3.4 (P = 0.43), respectively. The average C: D ratios in the cases and controls were 0.34 ± 0.11 and 0.40 ± 0.12 (P = 0.22), respectively. Rim area (cases: 1.44 ± 0.22, controls: 1.43 ± 0.24, P = 0.32) and disc area (cases: 2.22 ± 0.23, controls 2.21 ± 0.23, P = 0.34) were comparable. The average nerve fiber thickness in the cases was 97.26 ± 5.96 and that in the controls was 102.32 ± 6.26 (P = 0.005). This suggests a thin nerve fiber layer in patients with IDA. The distribution of peripapillary nerve fiber thickness in the cases and controls is depicted in Table 2 .
Table 1: Laboratory parameters of the cases and controls
Table 2: The distribution of peripapillary nerve fiber thickness in cases and controls
A positive correlation was noted between average RNFT and hemoglobin (r = 0.321), iron (r = 0.122), ferritin (r = 0.152), and transferrin (r = 0.190) levels.
No other demographic or confounding factors were found out in the present study, which will affect the results.
Discussion
The world health organization has estimated that nearly two billion people suffer from anemia globally.[ 10 ] Hence, it is a public health problem that affects people worldwide. The national family health survey has reported a high prevalence of anemia among women aged 15–49 years and 22.7% among men in the same age group in the Indian population.[ 11 ] A study by Szpakowski and Tucker. found out IDA anemia is common in women aged 20–49 years due to excessive menses and gastrointestinal cancers.[ 12 ] A high prevalence has been documented in preschool children and women in the reproductive age group in Africa and Southeast Asia.[ 13 ] The etiology of IDA is multifactorial, and the causes include nutritional deficiencies, chronic and acute infections, blood dyscrasias, obesity, and parasitic infestations.[ 14–16 ]
The ocular problems associated with IDA include corneal thinning, choroidal thinning, anemic retinopathy showing hemorrhages, Roth spots, cotton wool spots, retinal edema, hard exudates, vascular changes, and a decrease in peripapillary RNFLT.[ 17–21 ] RNFL thinning is seen in various ocular conditions, such as myopia, diabetic and hypertensive retinopathy, and uveitis.
The present study evaluated the peripapillary RNFLT in patients with IDA in Central India as there are no studies documenting RNFLT in this population.
Significant global, inferior, superior, nasal, and temporal nerve fiber losses were the hallmarks of the study. The findings from our study revealed that the mean RNFLT in the cases and controls was 97.26 ± 5.96 and 102.32 ± 6.25, respectively (P = 0.005). There were significant retinal nerve fiber losses in the temporal (66.76 ± 6.1, P = 0.02), superior (119.66 ± 10.47, P = 0.01), nasal (73.59 ± 9.52, P = 0.003), and inferior (129.05 ± 10.96, P = 0.001) quadrant RNFLs in the cases and controls.
Some studies have presented the results of RNFLT loss in patients with IDA. However, these studies were conducted in a different subset of the population.
Cikmazkara et al . recently reported the peripapillary RNFLT in 102 women with IDA. They determined that the average RNFLT as well as the temporal, nasal, and lower quadrant RNFLT were lower than those of the age and sex-matched nonanemic group. A positive correlation was noted between hemoglobin levels and various hematological parameters and mean RNFLT and nasal, temporal, and lower quadrant RNFLT.[ 22 ]
Akdogan et al . conducted a study on peripapillary RNFLT in adult women with IDA whose mean age was 38.8 ± 9.2 years (range 19–54 years) and 40 women who served as age-matched healthy controls (mean age 38.2 ± 9.6 years, range 19–52 years). Only women of childbearing age were selected. They found a decrease in the average RNFLT, but it was not statistically significant. Moreover, there was a significant thinning in the nasal and inferior quadrants but no statistically significant thinning in the superior and temporal quadrants. A significant correlation was seen between inferior quadrant RNFLT and hemoglobin level and between nasal quadrant RNFLT and serum iron and ferritin levels and total iron-binding capacity.[ 23 ]
Oncel et al. , in their study on 73 eyes with IDA and 68 healthy controls with mild to moderate anemia, found that the peripapillary RNFL thickness was significantly lower in the nasal–inferior area. In our study too, significant thinning was seen in the nasal and inferior quadrants.[ 24 ]
Kocer et al . studied radial peripapillary capillary density in patients newly diagnosed with IDA. The findings suggested that changes in the radial peripapillary capillary vessel density are more important than those in RNFLT. No significant difference in the RNFLT values between the IDA and control group was seen in their study. A significant positive correlation was observed between radial peripapillary capillary vessel density and the hematological values of hemoglobin, mean corpuscular volume, mean corpuscular hemoglobin, and ferritin.[ 25 ]
In the study conducted by Coskun and Sevencan., 105 patients were included and were categorized into three groups: 35 women with IDA with an average age of 37.85 ± 11.06 years were assigned to Group 1, 35 women with combined IDA-B12DA with an average age of 34.54 ± 7.44 years were assigned to Group 2, and 35 healthy women with an average age of 33.48 ± 9.03 years were assigned to Group 3 (control group). In this study, the retinal nerve fiber thickness of patients with IDA and vitamin B12 deficiency was compared with that of the healthy controls. In the present study, it was found that all retinal quadrants showed statistically significant thinning in patients with anemia when compared with the healthy controls, but the inferior quadrants showed less thinning than the other quadrants.[ 21 ]
Acir et al. , in their study on 73 eyes with IDA and 68 healthy controls with mild-to-moderate anemia, found that the peripapillary RNFLT was significantly lower in the nasal – inferior area. In our study too, significant thinning was seen in the nasal and inferior quadrants.[ 24 ]
In their study on RNFLT in patients with thalassemia, Datta et al . observed that patients with IDA and anemia with chronic diseases exhibited RNFL thinning in all quadrants. Maximum thinning was found in the nasal quadrant, followed by the temporal, inferior, and superior quadrants. This observation correlates with the finding of our study. We found a positive correlation between the average RNFLT and the serum hemoglobin, iron, ferritin, and transferrin level, which correlates with the findings of Datta et al .[ 26 ]
Peripapillary RNFLT profile in children with IDA is different when measured using SD-OCT.[ 27 ] Türkyilmaz et al . demonstrated a significant thinning of the average RNFL in all quadrants, and the superior and inferior quadrant RNFLs showed more thinning compared with the other quadrants in children with IDA. They found a positive correlation between the average peripapillary RNFLT and the hemoglobin level, but no significant correlations were observed with the other hematological parameters.[ 27 ] Another study on RNFLT in the pediatric population revealed lower RNFLT in the inferior quadrant. The study also identified a positive correlation between RNFLT and hemoglobin levels.[ 28 ] However, in our study, we observed maximum thinning in the inferior and nasal retinal quadrants. Furthermore, we noted a positive correlation between average RNFLT and other hematological parameters. This comparison suggests that in pediatric patients with anemia, the RNFL thinning is in different quadrants as compared with adult-onset anemia. This may be due to hypomyelination of the nerve fibers during early development because iron is required for oligodendrocyte functioning. In adult-onset anemia, chronic hypoxia can be the main pathology.
In our study, we selected individuals in the age group of 21– 45 years (33.53 ± 5.2) to avoid the bias of age. In younger individuals, the retina is healthy and may mask the changes in IDA. On the contrary, in older individuals, the retina shows age-related thinning and other comorbidities. Studies performed in the pediatric population have shown higher RNFLT.[ 29–31 ]
From the above studies, we can speculate that IDA is associated with thinning of the RNFL due to various pathological conditions, such as hypoxia, hypomyelination, and dopaminergic and serotonergic alterations. This suggests that iron plays an important role in the above pathological conditions.
The limitation of the study is that the exact duration of the anemia was not known, which is difficult to determine. The strength of the study is that it was performed after proper sample size calculation and that both men and women were included in the study.
We recommend replicating similar types of study in different populations with different geographical locations and age groups.
Conclusions
In patients with IDA, the average RNFLT was decreased in all quadrants as compared with the normal healthy controls. The inferior and nasal RNFLs showed a significant decrease in thickness as compared with the temporal and superior RNFLs. This difference can be attributed to the susceptibility of the neuronal and ganglionic layers in the nasal and inferior temporal quadrants to ischemia as compared with the macular and superior RNFLs. The presence of myopia, glaucoma, and diabetic and hypertensive retinopathy can exert an additive effect on the thinning of RNFLs and result in significant visual loss. Hence, the correction of anemia is essential.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
Acknowledgment
The authors would like to thank Dr. Avinash Turankar, Associate professor, Department of Pharmacology, Government Medical College, Nagpur, Maharashtra, and Dr. Rohit Khanna, Consultant Ophthalmologist, LVP Eye Institute, Hyderabad, India, for the statistical assistance.
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