|Year : 2021 | Volume
| Issue : 1 | Page : 45-51
Clinical Features and Associated Risk Factors for Thyroid Eye Disease Among Goiter Patients Who Attended Jimma University Medical Center Surgical Referral Clinic, Jimma Town, Ethiopia
Dagmawit Kifle1, Aemero Abateneh1, Sisay Bekele1, Tsedeke Asaminewu1, Melese Sinaga2
1 Department of Ophthalmology, Jimma University, Jimma, Ethiopia
2 Department of Nutrition and Dietetics, Jimma University, Jimma, Ethiopia
|Date of Submission||20-May-2020|
|Date of Decision||30-Aug-2020|
|Date of Acceptance||06-Dec-2020|
|Date of Web Publication||16-Jul-2021|
Dr. Dagmawit Kifle
Department of Ophthalmology, Jimma University, P. O. Box 378, Jimma
Source of Support: None, Conflict of Interest: None
Introduction Eye involvement is the most common extrathyroidal manifestation of Graves disease. Regarding our study area, there is no previous study done on the prevalence of thyroid eye disease among goiter patients. Methods: Institution-based cross-sectional study was carried out among 211 patients seen in Jimma University Medical Center surgical referral clinic from April to July 2018. The collected data were coded and entered into Epi data version 3.1 and analyzed using SPSS version 20. Variables having a P-value of less than 0.25 in the bivariate analyses were entered into a multivariable regression analysis to control the confounding variables. Results: Two hundred eleven goiter patients presented for care at JUMC surgical referral clinic over the 3 months study period; 57 (27%) of them were found to have thyroid eye disease. Lid retraction (40; 19%) was the most frequently observed sign of thyroid eye disease, whereas proptosis was found only in one case and no exposure to keratopathy or dysthyroid optic neuropathy was found. The factors that had statistically significant association with the prevalence of thyroid eye disease were thyroid dysfunction [adjusted odds ratio (AOR) = 2.781, (95% CI, 1.362–5.678) P = 0.005], smoking [AOR = 6.391, (95% CI, 1.868–21.860) P = 0.003], high blood pressure [AOR = 2.062, (95% CI, 1.001–4.251] P = 0.050] and high pulse rate [AOR=2.277 (95% CI, 1.003–5.167) P = 0.049]. Conclusion: Thyroid eye disease among goiter patients is common and many patients are followed up for goiter.
Keywords: Graves disease, proptosis, thyroid eye disease
|How to cite this article:|
Kifle D, Abateneh A, Bekele S, Asaminewu T, Sinaga M. Clinical Features and Associated Risk Factors for Thyroid Eye Disease Among Goiter Patients Who Attended Jimma University Medical Center Surgical Referral Clinic, Jimma Town, Ethiopia. Niger J Ophthalmol 2021;29:45-51
|How to cite this URL:|
Kifle D, Abateneh A, Bekele S, Asaminewu T, Sinaga M. Clinical Features and Associated Risk Factors for Thyroid Eye Disease Among Goiter Patients Who Attended Jimma University Medical Center Surgical Referral Clinic, Jimma Town, Ethiopia. Niger J Ophthalmol [serial online] 2021 [cited 2021 Nov 30];29:45-51. Available from: http://www.nigerianjournalofophthalmology.com/text.asp?2021/29/1/45/321639
| Introduction|| |
Thyroid eye disease (TED) is an auto-immune disorder triggered by infiltration of the orbit by autoreactive T-lymphocytes resulting in the proliferation of orbital fibroblasts and increased orbital fat. The relationship between exophthalmos and thyroid disease was first recognized by the Iranian scientist Sayyid Ismail Al-Jurjani in the 12th century. Graves disease (GD) is a disease of autoimmunity, which is characterized by the presence of antibodies directed against thyroid tissue antigens. It involves not only the thyroid gland but also has systemic manifestations such as thyrotoxicosis, goiter, exophthalmos, and pretibial myxedema. Eye involvement is the most common extrathyroidal manifestation of GD.
Eyelid retraction is the most frequent sign in TED. It affects 90% to 98% of patients and frequently varies with attentive gaze. The other signs such as proptosis, eyelid edema, and erythema result due to inflammation and secondary glycosaminoglycan (GAG) deposition. In the muscles, this leads to dysfunction due to failure of relaxation, limiting movement and causing diplopia. Orbital swelling at the apex can cause pressure on the optic nerve leading to dysthyroid optic neuropathy (DON).
The onset of TED may not coincide with the onset of the hyperthyroid state but about 80% of cases occur in association with hyperthyroidism. A study done in Europe on the temporal relationship between the onset of Graves hyperthyroidism and the onset of Graves ophthalmopathy has showed 80% of cases of TED occurred in association with hyperthyroidism, although not all coincide with the onset of hyperthyroid symptoms. Similar data have also been found by the Pisa group in a pooled analysis and over 40% of Graves disease patients developed orbitopathy after the onset of hyperthyroidism, whereas 5% to 10% of patients developed TED in the absence of hyperthyroidism.
Ethnicity is likely to play an important role in the development of TED. In a study of 155 patients with GD (116 European, 39 Indian), patients of European descent had a 6.4 times higher risk of TED compared to Indians.
The incidence of TED is 16 per 100,000 females and 2.9 per 100,000 males. However, for severe TED, the ratio of females to males reverses to approximately 1:4.
In Europe, Graves ophthalmopathy, like Graves hyperthyroidism, is more common in women than in men. The female to male ratio was 9.3:1 in patients with mild ophthalmopathy, 3.2:1 in those with moderate ophthalmopathy, and 1.4:1 with severe ophthalmopathy. A sex-related difference in the severity of TED has also been noted, with men comprising a relatively greater proportion of cases of severe ophthalmopathy. The reason for this effect of gender is not clear but the higher prevalence of smoking among men likely plays a role.
Regarding the association between smoking and TED, a retrospective study was conducted in China to identify predictive factors that can be used in screening the healthy subjects who are at high risk of developing Graves’ orbitopathy. Among the factors, the incidence of Graves orbitopathy was significantly higher in patients who were smokers than nonsmoker. Clinically recognizable TED occurs in about 25–50 smoking cases of GD in Caucasians and may be sight-threatening in 3% to 55%. A higher number of patients with Graves orbitopathy also had a positive family history of thyroid disease when compared to patients without Graves orbitopathy.
The presentation of TED also varies in different ethnic groups. Upper eyelid retraction and soft tissue involvement are reported as the commonest manifestations in Caucasians and a high likelihood of exophthalmos and lower lid retraction in Asians.
According to a study done in India, upper eyelid retraction was the most common manifestation 54 (83%), followed by exophthalmos 49 (75%) and soft tissue involvement 26 (40%). Extra-ocular muscle involvement (3; 5%) and optic nerve dysfunction (1; 2%) were uncommon.
In Southwestern Nigeria, 66.7% of patients reported painless eye swelling and 58% complained of ocular irritation.
In Ethiopia, there was a prospective study done and evaluated the clinical manifestations in 37 patients with Graves thyroid ophthalmopathy (GTO). Upper lid retraction was the most common clinical finding, being detected in 31 (83.8%) of the patients. One (2.7%) patient had marked extraocular muscle involvement, involving the inferior rectus muscle of one eye. None of the patients had sight loss from the complications of GTO.
In Europe, the prevalence of TED seems to have declined in recent years, as well as that of the more severe expression of eye disease. This might be related to both an earlier diagnosis and treatment by the endocrinologists as well as enhanced attention of the ophthalmologists to the link between the initial ocular manifestations and thyroid dysfunction.
General health-related quality of life is markedly impaired in patients with TED and could be even worse than in patients with other chronic conditions such as diabetes, emphysema, or heart failure.
Despite these facts, the information regarding the prevalence, risk factors, and severity of GO in Africa and also in Ethiopia is deficient.
Regarding our study area and to the best of our knowledge, there are no previous studies done on the prevalence of thyroid eye disease among goiter patients. This study therefore aims at providing baseline data on the clinical pictures and associated risk factors among thyroid eye disease patients with goiter as well as provide knowledge on better counseling, management, and improvement in the quality of life of these patients.
| Methods|| |
Study setting and sampling
An institutional-based cross-sectional study was conducted from April to July 2018 on patients who presented at Jimma University Medical Center surgical referral clinic for goiter. Jimma is located in the southwest of Ethiopia and Western Oromia region, 352 km from the capital city, Addis Ababa. According to the Central Statistical Agency 2007 report, Jimma town has a total population of 120,960. Jimma University Medical Center is the only referral hospital in Southwest Ethiopia providing service for approximately 15,000 inpatients and 160,000 outpatients in a year coming from a catchment population of about 15 million people. It has a total of 1448 staff from which 816 are medical and the remaining 587 are supportive staff.
The sample size was determined using a single population proportion formula by taking the prevalence of thyroid eye disease as 50% with 95% confidence interval and 10% nonresponse rate. Because the source population was less than 10,000, a correction formula was used and the final study population was 211.
- n = (Z 1-α/2) 2 p (1–p)
- n = minimum sample size,
- Z1-α/2 = significance level at α = 0.05 (1.96)
- d = margin of error (5%)
- p = prevalence of refractive error = 50%n = 384
- Since source population was less than 10,000, using correction formula
- n = no/(1 + no/N), where N = population size (352).
- n = 192 and taking 10% nonresponse rate, n = 211
- K = N/n = 1.67 = 2.
The sampling procedure was as follows: the previous year record was evaluated and the number of new goiter patients seen at surgical referral clinic over three consecutive periods of time (from April to July 2017) was 352. The sample size was calculated using this number as N making K value 1.67 and every two patients were selected randomly until the sample size was attained. Precaution was taken not to examine one patient twice by putting a sign on the patient’s card.
The inclusion criteria were that all goiter patients attended at surgical referral clinic, whereas the exclusion criteria were that patients with another known eye disease who had similar presentation with TED-like pseudo orbital tumor and patients with similar presentation as goiter but had other diagnosis, like cyst.
Patients with another known eye disease that had a similar presentation with TED-like pseudo-orbital tumor, optic nerve tumor, and patients with similar presentation as goiter but had other diagnoses, such as cyst, thyroid gland malignancy were excluded.
Data collection procedure
Patients were informed about the research and the socio-demographic data were collected by a trained ophthalmic nurse using a well-constructed questioner.
Factors that contribute to the development or severity of TED-like geographical location, positive family history of TED, goiter, smoking, and pregnancy, any use of medication, history of thyroid surgery, and thyroid hormone level were assessed.
Systemic manifestations of hyperthyroidism such as heat intolerance, palpitation, tachycardia, and pretibial myxedema were checked. Patients were asked if they had experienced double vision, pain in the eye, redness, tearing, and foreign body sensation. Thyroid function test (TFT) was done for all candidates to classify them as hyperthyroid, euthyroid, or hypothyroid.
Based on the T3, T4, and thyroid-stimulating hormone (TSH) patients were diagnosed as euthyroid if they have a normal range of T3, T4, and TSH. Patients with low TSH plus and high T3 and T4 were diagnosed as hyperthyroid. Patients with high TSH plus and low T3 and T4 were diagnosed as hypothyroid.
Visual acuity was measured in well-lighted rooms using the Snellen E chart and other detailed eye examinations such as evaluation for lid retraction, lid lag, eyelid, and conjunctival edema, proptosis measurement by using Hertel’s exophthalmometry, motility examination, corneal evaluation IOP measurement, and fundoscopy were done. TED was diagnosed if a patient has one or more eye symptom or sign that is associated with goiter. Those patients with visual acuity <6/9 without TED manifestations were referred to Jimma University Department of Ophthalmology (JUDO) outpatient department for further evaluation and management.
Data processing and analyses
The data collected were exported to SPSS (Statistical Package for Social Sciences IBM, Inc.) after being entered into Epi data (version 3.1 Jens M. Lauritsen and Michael Bruus). Data were cleaned and coded using SPSS version 20.0 for analysis. Descriptive statistics (frequencies and percentages) were computed. Binary logistic regression was used to identify the association between each independent variable and the outcome variables. Variables having P-value ≤ 0.25 in the bivariate analyses were entered into a multivariable regression analysis to control for confounding variables. Multivariable logistic regression models were used to determine independent predictors of the development of TED.
Ethics approval and consent to participate
Before starting the research, the ethical review committee of Jimma University Institute of Health (IRB) approved this research project. A support letter was obtained from the ethical board of Jimma University Institute of Health and given to the head of Jimma University Medical Center. Informed written consent was also obtained from the study participants. Each study participant was informed about the research and reassured that confidentiality of information will be maintained during data collection, analysis, interpretation, and publication of results. Patients found to have TED were referred to JUDO for further management and follow up.
| Results|| |
Two hundred eleven participants were included in the study with the age range of 15 to 78 years. One hundred ninety-six (92.9%) were females and 15 (7.1%) were males with M:F ratio of 1:13. Almost half of the study participants were in the age range of 15 to 30 years (100; 47.4%) followed by the age category of 31 to 45 years (77; 36.5%). One hundred eleven (52.6%) of the participants were urban dwellers and the rest were from rural communities. One hundred fifty-four (73%) were goiter patients, whereas 57 (27%) were TED patients. Majority of the patients were farmers (102; 48.3%) followed by merchants (44; 20.9%) and government workers (35; 16.6%) [Table 1]. Regarding the occupation of TED patients, 25 (43.9%) of them were farmers, whereas 16 (28%) of them were merchants and nine (15.8%) of them were government employees. Out of TED patients, 33 (57.9%) of them were urban dwellers, whereas 26 (45.6%) were from rural communities. Thirteen (6.16%) participants had a history of cigarette smoking. Two (0.94%) were males and the rest 11 (5.2%) were female passive smokers.
|Table 1 Socio-demographic characteristics of goiter patients seen from April to July 2018.|
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Ocular clinical presentations
Among the 211 goiter patients studied, thyroid eye disease was present in 57 (27%) goiter patients. The most frequently occurring clinical signs of thyroid eye disease were lid retraction in 40 (19%), conjunctival redness 24 (11.4%), eyelid swelling 13 (6.2 %). Less commonly were lid lag 5 (2.4%) and eyelid erythema in three (1.4%) patients. There was only one (0.5%) patient with unilateral proptosis and none with dysthyroid optic nerve dysfunction.
Systemic clinical presentation
Shortness of breath was the commonest, presenting in 182 (86.3%) of goiter patients. Blood pressure level ≥140/90 mm Hg in six (2.8%) patients and pulse rate above 100 beats/min in 37 (17.5%) patients. Finger tremor was observed in 30 (14.2%) patients and pretibial edema was present in only two (0.95%) patients [Table 2].
|Table 2 Systemic symptoms and signs seen among goiter patients from April to July 2018.|
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Based on the TFT reports, the majority of the patients were euthyroid 104 (49.3%), followed by hyperthyroidism 60 (28.4%) and hypothyroidism 17 (7.6%).
Out of the 211 patients, 134 (63.5%) were on medication, whereas the rest 77 (36.5%) were not. Among the euthyroid patients, 73 (54.5%) were on antithyroid medications, whereas 61 (45.5%) were not. The majority of the drug used was propylthiouracil (58.3%) followed by thyroxin (3.3%), propranolol (1.4%), and calcium (0.5%). Fifteen (7.1%) of the goiter patients had neck surgery.
As this study tried to show, the prevalence of TED is higher in patients that had thyroid dysfunction than in those without thyroid dysfunction. Out of the patients with TED, 28 (49.1%) were hyperthyroid, whereas 24 (42.1%) were euthyroid and five (8.8%) were hypothyroid.
Associated risk factors
Bivariate analysis has shown that cigarette smoking, thyroid dysfunction, and blood pressure were significantly associated (P-value < 0.05) with the prevalence of TED [Table 3].
|Table 3 Bivariate analysis for factors associated with TED among goiter patients seen from April to July 2018.|
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On multivariate analysis, participants of the study with thyroid hormone dysfunction were three times more likely to develop TED than euthyroid patients, with a P-value of 0.005 [adjusted odds ratio (AOR) = 2.78; 95% CI, 1.362–5.678]. Patients with a history of cigarette smoking had six times higher risk of developing TED than nonsmokers with P-value of 0.003 (AOR= 6.391; 95% CI, 1.868–21.860). Participants of the study with high blood pressure had two times higher chance to have TED with a P-value of 0.050 (AOR = 2.062; 95% CI, 1.001–4.251). Patients with a high pulse rate were two times more likely to have TED with a P-value of 0.049 (AOR=2.277; 95% CI, 1.003–5.167) [Table 4].
|Table 4 Multivariable logistic regression model predicting the likelihood of thyroid eye diseases among patients with Goiter, Jimma University Medical Center, 2018|
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| Discussion|| |
This study has found the prevalence of TED among goiter patients seen at JUSH surgical referral clinic over 3-month period to be 27%. According to the study done in Ghana, prevalence of TED among patients with thyroid disorder was higher than our finding (60.30%). The prevalence of TED in our study was lower compared to the prevalence in Europe (37.5%) and in Malaysia that was 34.7%. This was similar to the prevalence of thyroid eye disease in India that was 28% and in Korea (21.3%). But there was a difference in the severity of cases. It is possible that the difference in epidemiology and clinical pictures of TED could be related to the low prevalence of smoking in our population or differences in environmental or genetic factors. There are genes involved in regulating T-cell, which is necessary in autoimmune thyroid disease. These, include the genes for the α-chain of the interleukin-2 receptor as well as thyroid-specific genes including thyroglobulin (Tg) and the thyroid-stimulating hormone receptor (TSHR). The similarity of prevalence could be due to similarity in selection of the study population or use of the same criteria to define TED.
This study also demonstrated a significant association between the development of TED and thyroid dysfunction. Among patients with TED, 49% of them were hyperthyroid, 42% euthyroid and 8.8% of them were hypothyroid based on TSH, T3, and T4 results. This was a similar result to a study done in Addis Ababa that showed TED to be diagnosed in 83.8% of dysthyroid patients and 13.5% euthyroid patients. Also, a study done in Nigeria found 78% of patients with TED to be hyperthyroid, 11.8% euthyroid, and only 9.8% of patients hypothyroid. Although the result has similarity to our study findings, their study population with hyperthyroidism was much higher. This could be due to differences in patient selection in which our study included all goiter patients, whereas the other study involved patients with Grave’s disease only. The participant’s age at the time of diagnosis, their social habit, and their medication use will be the reason for the difference in the thyroid function test results. Also, the interpretation for the tests of T3, T4, and TSH vary greatly according to the laboratory’s reference range in different countries and regions.
TED in the presence of hyperthyroidism could be due to autoimmunity in which T-lymphocyte suppressor cell function and the cell number will be reduced. The clinical manifestations of TED result are due to infiltration of the orbit by auto-reactive T-lymphocytes resulting in the proliferation of orbital fibroblasts and increased orbital fat.
In our study, patients with a smoking history had six times higher risk for the development of TED compared to those with no smoking history. Similarly, a study conducted in China reported that 38% of patients with a smoking history had a prevalence of TED. European patients who smoke were found to have a five times higher risk of developing TED than those who do not. A study done in India also found that the risk of having Graves eye disease was two times higher in smokers, as compared with nonsmokers. Pryor and Stone proposed that the formation of superoxide radicals and tissue hypoxia may be the underlying pathogenesis. Superoxide radicals can induce orbital fibroblasts in patients with TAO to proliferate and cigarette smoke either contains or can generate a variety of oxidants and free radicals. In vitro and in vivo studies revealed that antithyroid drugs and antioxidants influence parameters of oxidative stress both in retro-orbital tissue and in the whole organism.
Concerning sex as a risk factor, our present study showed that prevalence of TED varies by sex with higher proportion of females compared to males with a ratio of 13:1, although statistically, it was not significant. The clinical severity did not show a difference among them. In a study that was conducted in Korea, the prevalence of TED was higher in females with female-to-male ratio of 3.9:1. Also, in a study done in Nigeria reported, the prevalence of TED in females to male ratio was 5:1, whereas in Ghana, the male:female ratio was 1:4. The number of males in our study was minimal and a history of smoking was not prominent in comparison to other study reports., This may account for the difference in clinical severity and the criteria for classifying TED into different severity grades could be different.
According to our study, there was a statistically significant association between the development of TED and high blood pressure. Kotsis et al. reported the association between hyperthyroidism, high systolic blood pressure, and high pulse pressure over a 24-hour period compared with euthyroid.
High pulse rate (≥100 beats/min) had a statistically significant relation with the development of TED with a P-value of 0.049. The majority of patients having TED were hyperthyroid. With high amounts of T3 and T4 secretion into the body, this can spike the metabolism rate. In this process, a patient may notice the heart rate increasing rapidly, blood pressure elevation, and tremors in the hands and feet.
| Conclusion|| |
The prevalence of thyroid eye disease among goiter patients seen in JUMC surgical referral clinic was 27%.
The ocular symptoms identified in goiter patients were tearing, gritting sensation, double vision, and eye pain. The ocular signs of thyroid eye disease observed were lid retraction, conjunctival injection, eyelid swelling, and lid lag.
The factors that had a statistically significant association with the prevalence of thyroid eye disease were thyroid dysfunction, smoking, high blood pressure, and pulse rate.
To consider thyroid eye disease in patients with goiter and link them to ophthalmology for a detailed eye evaluation. Researchers may use this data for conducting further study.
Shortage of laboratory investigation facility in the hospital.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3], [Table 4]