Thyroid dysfunction as a modiable risk factor for age-related macular degeneration: A case-control investigation

Background: Age-related macular degeneration (AMD) is regarded amongst as a common conditions resulting in visual impairment in elderly. Age and gender are unmodiable risk factors for AMD, obesity, smoking, and hyperlipidemia are known to be modiable culprits. This has remained controversial for hypertension and thyroid dysfunction. The present study attempted to investigate possible links between thyroid dysfunction and incidence of wet AMD. Methods: The present case-control study enrolled a total number of 90 patients with wet AMD and 90sex-, age-matched control subjects through a convenient sequential sampling method. Thyroid hormones were proled in serum assay. Statistical measures were done to compare means between groups. Results: Our ndings showed a signicant difference in free T4 levels between the between wet AMD and control groups (p = 0.002), though this has not been the case for T3 and TSH l. In addition, there were no differences in serum lipid prole between groups. Although there found to be no signicant difference in the past history of hypertension and hyperlipidemia between wet AMD and control groups, history of smoking was higher in controls) (p = 0.039). Conclusion: Based on our ndings retinal examination and proper screening need to perhaps be a part of the overall health examination especially in elderly subjects with thyroid dysfunction. The clinical signicance and related recommendations on the above need ti substantiated in future community-based research. gathering


Introduction
Age-related macular degeneration (AMD) is considered amongst the main causes of irreversible vision loss constituting the underlying cause of 8.7% of blindness at global scale [1]. While the de nite etiopathophysiological underpinnings of AMD are yet to be clear, factors such as genetics, diet, in ammation and oxidative stress seem to be of etiological signi cance in AMD [2]. Clinically, AMD is classi ed into two types including the geographic atrophy (dry AMD) and neovascular or exudative AMD (wet AMD) [3]. It has been estimated that 10-15% of all AMD cases t into the wet classi cation [4]. Where Drusen accumulation around the retinal pigmented epithelium (RPE) and retrogressive changes in the RPE are the main characteristics of dry AMD, wet AMD is characterized by choroidal neovascularization (CNV) leading to severe vision loss [5]. The diagnosis of AMD largely depends upon fundus examination with dilated pupils as well as con rmatory optical coherence topography (OCT) and uorescein angiography where applicable. As such and in clinical practice, individuals with visual problems including decreased vision, central visual eld defect or metamorphopsia would need to be referred to an ophthalmologist to have ruled-out AMD [6]. While aging, white race, having fair colored irises, and obesity are among well-described risk factors for AMD, the contributing role of factors such as gender and hypertension in the prevalence of AMD has remained controversial across studies [7]. Among all risk factors of AMD, some including obesity, smoking, and hyperlipidemia are generally considered as modi able risk factors [8]. Some recent studies have proposed that thyroid dysfunction may also be considered as a modi able risk factor for AMD. In fact, thyroid dysfunction predisposes the individual to other risk factors including dyslipidemia, atherosclerosis, and hypertension. Moreover, recent investigations have revealed that the suppression of thyroid hormone signaling is associated with cone photoreceptors preservation in mouse models [9]. Considering hyperthyroidism as an independent yet controversial risk factor for AMD, the present study was designed as an attempt to distinguish any association between thyroid dysfunction and AMD in clinical setting. To do so, serum thyroid hormone levels in AMD patients who referred to a referral ophthalmology center in Fars province, Southern Iran, were measured in relation with the severity of their macular degenerative disease.

Methods
Setting: This study was conducted as a case-control study in …. ophthalmology clinics from January 2014 till December 2014. The Study population was selected from wet AMD patients and cataract surgery candidates referring to these two university a liated ophthalmology clinics.
Ethical issues: Study protocol was approved by ethics committee … and each participant signed a written informed consent after briefed about the purpose and method of the study.
Study population: A total number of 90 patients with wet AMD were recruited in the case group through a sequential sampling method. The diagnosis of wet AMD was based on clinical ndings, optical coherence tomography (OCT), uorescein angiography, and presence of choroidal neovascularization.
Control group (n=90) was recruited from sex-, age-matched cataract surgery candidate patients likewise through a convenient sequential sampling method. The exclusion criteria for both groups comprised the presence of any other retinal or choroidal vascular problems, diabetic retinopathy, retinal and choroidal dystrophy, hypertensive retinopathy or choroidopathy, autoimmune diseases, diabetes mellitus, renal disease, liver disease, cancer, rheumatoid diseases, and also the current use of thyroidal or glucocorticoid hormones.

Variables and measurements
All individuals' demographic data as well as past history of hypertension, hyperlipidemia and smoking were recorded in data gathering forms with their blood samples referred to Motahhari clinic's laboratory.
Blood sampling ( 5 ml clot) was done for the fasting patients at 9:00 AM and T3, free T4, TSH, and lipid pro le were measured. Thyroid function test was done through ELISA (enzyme-linked immunosorbent assay) technique. Moreover, for wet AMD patients, the number of intravitreal Bevacizumab injections were asked and recorded in their data gathering forms.

Statistical analysis
Quantitative and qualitative data were described by mean ± standard deviation and frequency (percent), respectively. To compare means in quantitative data (thyroid hormones blood levels and lipid pro le) between case and control groups, independent t-test was employed. All statistical analysis was done using the SPSS statistical software (version 18) and p value less than 0.05 was considered as statistically signi cant.

Results
A total number of 90 patients with wet AMD, and 90 controls who were candidate for cataract surgery were enrolled in this study. Both groups were sex-matched (45.6% of wet AMD subjects and 51.1% of controls were male). The mean age in wet AMD and control group were 76.04 and 62.45 years, respectively.
Results of our statistical analysis revealed that freeT4 level was signi cantly different between wet AMD and control groups (p = 0.002). Meanwhile, there were no statistically signi cant difference in T3 and TSH levels between wet AMD and control groups ( Table 1).The comparison of lipid pro le between the wet AMD and control groups showed no statistically signi cant difference( Table 2).Comparison of the past medical history of wet AMD patients and control subjects revealed no statistically signi cant differences for hypertension and hyperlipidemia. However, there was a signi cant difference between the wet AMD patients and control subjects with regards to their past history of smoking (higher in controls) (p = 0.039) (   We also evaluated the relationship between the total number of Bevacizumab intravitreal injections and the serum level of thyroid hormones. Results of the statistical analysis showed no relationship between such parameters (Table 4).

Discussion
The current study has been an attempt to nd any association between the prevalence of wet AMD and thyroid dysfunction as a modi able risk factor. Our ndings revealed that free T4 serum level has direct relationship with wet AMD, while there was no relationship between TSH serum level and wet AMD. These ndings were concordant with earlier reports. In a population based study by Völzke et al, no signi cant association was detected between serum TSH levels and macular degeneration [10]. Moreover, LayalChacker et al, reported similar ndings about free T4 and TSH serum level in patients with dry AMD.
In addition, the above study highlighted an adverse relationship between high free T4 serum level and pigmented retinal epithelium [9].
Gopinath and his colleagues demonstrated that overt hyperthyroidism (low TSH and high FT4 levels) in older cases is independently associated with 3 times increased risk for developing any AMD, but they did not verify the signi cant positive association between serum FT4 levels and the incident AMD observed in their study.
Other than the above, several studies have shown appositive association between the usage of both synthetic and desiccated thyroid hormones and the risk of AMD [11,12]. Indeed, elevated serum thyroid hormones can augment the basic metabolic rate and oxidative metabolism potentially inducing mitochondrial activities, which result in a hypermetabolic state an increased reactive oxygen species. This condition is shown to occur in patients with Graves' disease [13].
The TSH serum level is shown to be decreased in healthy elderly subjects potentially due to a its diminished level of secretion from the pituitary gland [14]. Although the decreased TSH level results in diminished T4 secretion, total T4 and free T4 level would not be altered [15]. Nevertheless, T4 level would be decrease with aging, freeT4 de-iodination and its conversion to T3 would subsequently diminish. As such, free T4 level would not be changed by aging [16]. The above insights are in agreement with our results denoting that although AMD risk would be increased by aging; there are no relationship between aging and an increased free T4 level.
In another investigation, SeeJoon Woo et al., showed that age, smoking, hyperlipidemia, spherical equivalent, and education are important environmental factors for AMD [17]. Smoking is known to be a risk factor strongly linked with AMD [18]. Despite that, we reported that smoking rate was higher in the control group than AMD cases. This disparity in results might have been due to recruiting the control subjects from cataract surgery candidates. Indeed, smoking has been documented among the most considerable risk factors for cataract development by exposing the lens to oxidation [19].
On the other hand, hyperlipidemia and hypertension are controversially regarded as risk factors for AMD. Some studies have proposed that high dietary intake of docosahexaenoic fatty acid reduces the risk of neovascular AMD by increasing mitochondrial activity through anti-oxidative, anti-in ammatory, antiapoptotic, and anti-angiogenic effects [20]. While there has been studies claiming that there is no de nite relationship between hypertension and AMD, others consider hypertension as a risk factor due to its effect on the choroidal circulation [21]. The present study revealed that although thyroid function has a close relationship with cardiovascular diseases such as vascular disorders, hyperlipidemia, and hypertension, there fund to be no associative links between hyperlipidemia or hypertension and wet AMD [22].

Conclusion
The effect of thyroid hormone derangements on retina should not be neglected. In other words, retinal examination and proper screening need to perhaps be a part of the overall health examination especially in elderly subjects with thyroid dysfunction. However, further studies on this topic should be conducted to substantiate the above and describe underlying structural and ultra-structural mechanisms of thyroid dysfunction with regards to the pathogenesis of AMD.

Declarations
Certify any disclosure of funding received for this work from any of the following organizations: National Institutes of Health (NIH); Wellcome Trust; Howard Hughes Medical Institute (HHMI); and others Availability of data and materials All data are included in this published article.

Ethics approval and consent to participate
The study was approved by shiraz University of medical sciences.
Consent for publication each participant signed a written informed consent after briefed about the purpose and method of the study