Thyroid Levels That Deviate From Normal Yield Sizable Risk For Macular Degeneration
Overview
The relationship between thyroid dysfunction and exudative age-related macular degeneration (AMD) remains unclear. This Danish longitudinal cohort study utilized nationwide registry data to investigate this potential association. The study included all Danish residents aged 50 to 100 years between 2008 and 2018. Thyroid dysfunction was identified through the use of the Danish national registries, where hypothyroidism was defined by two consecutive filled prescriptions for thyroid hormones, and hyperthyroidism by two consecutive filled prescriptions for anti-thyroid medications. Exudative AMD was identified using ICD codes for AMD diagnosis combined with records of anti-VEGF treatment. Since all patients with exudative AMD in Denmark receive treatment in hospitals, the study ensured comprehensive registration of this patient group.
Introduction
Exudative age-related macular degeneration (AMD) is a leading cause of severe visual impairment and blindness in Western countries. It is initially characterized by the accumulation of metabolic waste in Bruch’s membrane, the basement membrane of the retinal pigment epithelium (RPE). This accumulation impedes nutrient diffusion from the choroid, leading to the atrophy of the outer retinal layers. In advanced stages, choroidal neovascularization can breach the diseased Bruch’s membrane, resulting in hemorrhages and edema, defining exudative AMD.
The exact pathophysiology of AMD is not fully understood, but animal studies indicate that thyroid hormone receptors are present in the RPE. Inhibition of thyroid hormone signaling in this layer may protect photoreceptor cells from oxidative damage. This potential link necessitates an investigation into the relationship between thyroid dysfunction and AMD.
Previous epidemiological studies on this association have yielded inconsistent results, likely due to variations in study design, thyroid disease definitions, and AMD classifications. Many prior studies focused on early AMD stages using retinal photographs and had relatively small sample sizes (28–805 participants). However, none specifically examined the association between thyroid dysfunction and exudative AMD.
To address this gap, we conducted the first comprehensive, nationwide, longitudinal registry-based study in Denmark, encompassing 2,087,305 individuals aged 50 and older. This study included all patients treated for hypothyroidism, hyperthyroidism, and exudative AMD in Denmark from 2008 to 2018.
Methods
This longitudinal, nationwide, retrospective cohort study included all Danish residents aged 50 to 100 years from January 1, 2008, to December 31, 2018. The study period began with the systematic administration of anti-vascular endothelial growth factor (VEGF) treatments in Denmark, adhering to uniform national coding standards. Healthcare in Denmark is publicly funded, with all relevant data centrally stored for statistical and research purposes. The Danish Data Protection Agency approved the study (reference number p-2019-381), and due to the registry-based design, ethics committee approval was not required. The study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines.
Data sources included the Danish National Patient Registry, which has recorded all hospital discharge diagnoses since 1977 (using ICD-8 until 1994 and ICD-10 thereafter), and the National Register of Medicinal Product Statistics, which documents all dispensed prescriptions. The Danish Civil Registry provided demographic data, including birth dates, vital status, and sex. All these registries are linked via a unique civil registration number (CPR). The study included all residents with a CPR number who were between 50 and 100 years old as of January 1, 2008. Exclusion criteria included a history of thyroid cancer, thyroidectomy, prior age-related macular degeneration (AMD), or use of lithium or amiodarone. Participants meeting exclusion criteria during the follow-up were censored at that point.
Thyroid dysfunction was classified based on the redemption of two consecutive prescriptions for thyroid hormones (hypothyroidism) or anti-thyroid medication (hyperthyroidism). Individuals prescribed both types of medication were classified as hyperthyroid.
Cataract surgery was considered a potential confounder, as both cataracts and AMD share common risk factors like smoking. Cataract surgery was defined as having both an ICD code for cataract and a procedure code for surgery, excluding cases due to trauma, diabetes, or congenital conditions.
Exudative AMD was defined as having an ICD-10 code for AMD and a subsequent treatment code for anti-VEGF injection, with ranibizumab approved for use starting January 22, 2007. The study start date of January 1, 2008, reflects the nationwide implementation of treatment guidelines with ranibizumab. Before this, exudative AMD diagnoses were underreported, as most patients were managed in primary care without centralized registration. Since 2008, all patients diagnosed with exudative AMD in Denmark have been referred to hospitals for treatment and registered accordingly. The study end date corresponds to the most recent available registry data.
Covariates and confounders included sex, age, educational level, chronic obstructive pulmonary disease (COPD), hypertension, and cataract surgery. COPD served as a proxy for smoking history, while hypertension was defined as two concurrent prescriptions for different antihypertensive medications. These definitions have been previously validated in Danish nationwide studies.
Analysis
The study monitored Danish residents from January 1, 2008, until the occurrence of one of the following: a first diagnosis of exudative age-related macular degeneration (AMD), death, emigration, a competing event (such as thyroid cancer, thyroidectomy, or the prescription of lithium or amiodarone), or until December 31, 2018, whichever occurred first. Individuals diagnosed with AMD or who experienced a competing event prior to the inclusion date were excluded. Patients who developed cataracts during the study period were censored and re-enrolled, and their other covariates were updated only if they developed cataracts, allowing for time-updated analysis. This method primarily relies on baseline characteristics for 10-year predictions, except for cataracts, as more individuals developed this condition after inclusion. This approach simulates clinical practice, where a 10-year risk assessment is made during a patient visit and updated if the patient later attends the ophthalmology department for cataracts.
A Cox regression model was utilized to evaluate the relationship between thyroid dysfunction and the onset of exudative AMD. The model was adjusted for known AMD risk factors, including sex, age, cataract surgery, educational level, hypertension, and chronic obstructive pulmonary disease (COPD), which was used as a proxy for smoking. The data analysis was conducted using R software (version 4.2.1), and statistical significance was determined by a two-sided p-value of less than 0.05.
Results
The study included 2,087,305 individuals, monitored over a period of up to 11 years. During this time, 1.3% (26,998 individuals) developed exudative age-related macular degeneration (AMD), 24% (504,944) died without AMD, 1.9% (38,984) experienced competing events such as thyroid cancer, thyroidectomy, or the prescription of lithium or amiodarone, and 72.6% (1,516,379) were followed for the entire study period.
At the beginning of the study in 2008, 51.4% (1,072,567) of participants were women, the median age was 63.4 years, 2.8% (59,318) had hypothyroidism, 1.6% (33,922) had hyperthyroidism, and 6.6% (137,622) had undergone cataract surgery. During the follow-up, 254,639 individuals (12.2%) had cataract surgery and were subsequently re-enrolled in the study.
Upon diagnosis of exudative AMD, the median age of patients was 79.4 years, with 63.6% being women. Additionally, 37% had a history of cataract surgery, 46% had hypertension, and 11% had chronic obstructive pulmonary disease (COPD).
Both hypothyroidism (hazard ratio [HR] 1.15; 95% confidence interval [CI] 1.09–1.21, p < 0.001) and hyperthyroidism (HR 1.18; 95% CI 1.10–1.27, p < 0.001) were linked to a higher risk of developing exudative AMD. Prior cataract surgery also increased the risk (HR 2.03; 95% CI 1.97–2.08, p < 0.001), with no significant interaction observed between thyroid dysfunction and cataract presence (p = 0.13).
Other notable risk factors included age, with older age being the predominant factor, COPD (as a proxy for smoking) associated with an HR of 1.30 (95% CI 1.24–1.37, p < 0.001), and hypertension associated with an HR of 1.17 (95% CI 1.14–1.20, p < 0.001).
The unadjusted 10-year cumulative incidence of exudative AMD was 0.9% for both hypothyroid and hyperthyroid individuals aged 50–70, and 0.5% for the euthyroid group. The risk exceeded 3% for individuals over 70 years of age in both hypothyroid and hyperthyroid groups. The adjusted 10-year absolute risk, considering factors such as sex, age, cataract surgery, hypertension, and COPD, indicated the highest risk of exudative AMD in hypothyroid and hyperthyroid women aged over 70, regardless of other risk factors.
Conclusion
In this pioneering nationwide cohort study of Danish residents with free access to healthcare, both hyperthyroidism and hypothyroidism were associated with an increased risk of developing exudative age-related macular degeneration (AMD) compared to euthyroid individuals. This study is the first to longitudinally examine the impact of thyroid dysfunction specifically on exudative AMD, distinguishing it from previous studies that focused on a composite outcome of “any AMD” without specifying AMD types. Prior research, including a meta-analysis that found an association between hyperthyroidism and “any AMD,” varied widely in their geographical scope, study design, definitions of thyroid disease, and AMD classification. These studies often combined early and late forms of AMD without isolating cases of exudative AMD and did not utilize anti-VEGF treatment codes, as they predated the treatment’s introduction.
The study demonstrated that although thyroid dysfunction contributes to the risk of exudative AMD, the overall clinical impact is modest. However, due to the high prevalence of exudative AMD and the associated treatment costs, these findings could have public health implications. The study also identified a significant association between prior cataract surgery and an increased risk of exudative AMD, corroborating recent findings that suggest a link between cataract surgery and the progression of late AMD.
The study’s strengths include its nationwide, register-based design and the comprehensive data capture, which ensured that all patients with exudative AMD receiving anti-VEGF treatment in Denmark were included. The use of the Danish National Patient Registry provided complete data on thyroid disease treatment and ensured a uniform diagnostic process for exudative AMD across the country. However, the study’s limitations include the lack of data on potential AMD risk factors such as genetic information, smoking habits, diet, and physical activity, which could not be accounted for as confounders. COPD was used as a proxy for smoking, but this likely underestimated the prevalence of smoking in the cohort.
The findings, derived from a large and well-defined cohort, indicate an association between thyroid dysfunction and exudative AMD, necessitating further research to explore the mechanisms underlying this relationship. Given the predominantly Caucasian population in Denmark, these results may be most applicable to similar populations. Future studies should aim to include more diverse populations and consider additional data sources, such as retinal images and laboratory results, to further elucidate the nature of this association.
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