Journal of Clinical Ophthalmology and Research

: 2021  |  Volume : 9  |  Issue : 3  |  Page : 108--111

Risk factors for thyroid-associated orbitopathy due to Graves' disease

Tauseef Nabi1, Nadeema Rafiq2, Imtiyaz Ahmad Dar3,  
1 Department of Endocrinology, MMIMSR, Ambala, Haryana, India
2 Department of Physiology, Government Medical College, Baramulla, India
3 Department of Ophthalmology, Government Medical College, Srinagar, Jammu and Kashmir, India

Correspondence Address:
Tauseef Nabi
E 32, MMIMSR, Mullana, Ambala, Haryana


Background: Thyroid-associated orbitopathy (TAO) is the principal extrathyroidal manifestation of Graves' disease (GD). TAO is described as chronic inflammation of orbital and periorbital tissue. Environmental risk factors variably influence the development of TAO and risk factors vary with ethnicity and geographical region. Aims: To evaluate the clinical factors for TAO in patients with GD. Setting and Design: This was a hospital-based cross-sectional study done on consecutive 76 newly diagnosed patients of GD documented by thyroid 99mtechnetium-pertechnetate scan. Materials and Methods: Patients were subjected to a complete clinical workup and thyroid profile. The diagnosis of TAO was based on the criteria of Bartley and Gorman. Fifty-two TAO patients were compared with 24 non-TAO patients (controls) for risk. Statistical Analysis Used: All analyses were performed using SPSS software (version 21.0). Results: TAO was present in 52 (68%) of patients with GD. TAO was bilateral in 50 (96%) patients. Majority of the patients had mild orbitopathy (34, 65.4%) and none of the patients showed any signs of sight-threatening disease. Clinical activity score was active in 13.5% of the study group. There was significant female preponderance in TAO. Current smoking increased the risk of TAO (P = 0.023). Total triiodothyronine (T3) and mean intraocular pressure (IOP) in primary and upward gaze were significantly elevated at baseline in TAO patients. Braley's sign was seen in 30.7% of patients with TAO and in 8.3% of patients in the control group (P = 0.033). Current smoking, total T3 >4 ng/dl, and differential IOP >6 mmHg were found to be associated with the risk of TAO. Conclusion: TAO was clinically inactive and of mild severity in most cases. This study identified current smoking, total T3 >4 ng/dl, and differential IOP > 6mmHg as risk factors for TAO.

How to cite this article:
Nabi T, Rafiq N, Dar IA. Risk factors for thyroid-associated orbitopathy due to Graves' disease.J Clin Ophthalmol Res 2021;9:108-111

How to cite this URL:
Nabi T, Rafiq N, Dar IA. Risk factors for thyroid-associated orbitopathy due to Graves' disease. J Clin Ophthalmol Res [serial online] 2021 [cited 2021 Nov 30 ];9:108-111
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Full Text

Thyroid-associated orbitopathy (TAO) is the principal extrathyroidal manifestation of Graves' disease (GD), a systemic autoimmune disorder. It usually involves an antibody reaction against the thyroid-stimulating hormone (TSH) receptor, which results in the activation of T-cells against the retro-orbital space tissues, which share antigenic epitopes with thyroid follicular cells.[1] TAO is a common orbital disease due to autoimmune pathogenesis with important genetic, epigenetic, and environmental influences, particularly smoking.[2] Among the risk factors predisposing to TAO, smoking, older age, radioactive iodine, and thyroid dysfunction appear to correlate with the onset of TAO.[3],[4],[5],[6] TAO is clinically evident in about a third of patients with GD, although it can be demonstrated by orbital imaging in nearly all.[2],[7],[8] Most patients have a mild eye disease, while approximately 5% have severe, potentially sight-threatening orbitopathy.[2] TAO is usually bilateral (90%), asymmetrical in 10%–15%, and unilateral in 2% of cases.[9],[10] A more detailed protocol with a soft-tissue atlas was published[11] and adopted by the European Group on Graves' Orbitopathy (EUGOGO);[12] however, a further less detailed protocol has also been published from North America,[13] and worldwide, consensus remains elusive. Given the variable presentation of TAO, so each feature should be assessed individually.

Patients most commonly present in the third to fifth decade of life, with women more often affected, with a female-to-male ratio of 5:1.[14] Ethnicity is likely to play an essential role in the development of TAO.[6],[15],[16] A study in patients with GD revealed that Europeans have a higher risk of TAO compared to Indians.[15] Risk factors for TAO vary with ethnicity and geographical region, with smoking being the consistent risk factor from various studies across the globe including India. Therefore with this study, we looked at the factors predisposing to orbitopathy in patients with GD from Kashmir, a mountainous northern part of India, which is ethnically different from India.

 Materials and Methods

It was a hospital-based cross-sectional study of adult patients with GD. This study was carried out in the department of endocrinology and ophthalmology of a tertiary care hospital in Jammu and Kashmir. The study was approved by the institutional ethical committee. Informed consent was obtained from all the recruited subjects.

Patients with diagnoses of GD with and without orbitopathy who fulfilled eligibility criteria were recruited in the study. This study was conducted over a period of 3 years from May 2016 to May 2019. Information regarding various demographic characteristics was taken through well-structured questionnaires from all subjects. Besides a detailed history, physical examination and biochemical workup were carried out. Inclusion criteria include patients having age >18 years with GD. Diagnosis of GD was made based on clinical features of thyrotoxicosis, suppressed TSH, elevated thyroid hormones, and thyroid 99mtechnetium-pertechnetate scan evidence of diffuse homogeneous increased uptake in both lobes of the thyroid. The diagnosis of TAO was based on the criteria given by Bartley and Gorman. Exclusion criteria include (i) orbitopathy other than GD.

In each patient, the initial screening for TAO was performed by an endocrinologist. The patients were referred to the department of ophthalmology where a comprehensive clinical examination as per the protocol for determining the clinical activity and severity was done. The findings were classified as per the EUGOGO[17] recommendations – preliminary case record form. The diagnosis of TAO was based on the criteria of Bartley and Gorman.[18] Clinical activity of TAO was classified as per the clinical activity score (CAS) recommended by EUGOGO. A CAS of <3 is considered inactive and ≥3 active TAO. The severity of TAO was classified into mild, moderate–severe, and sight-threatening based on the EUGOGO classification. The degree of proptosis was measured using a Hertel's exophthalmometer. All patients who had clinical evidence of orbitopathy underwent CT scan of orbits. Serum total triiodothyronine (T3), total thyroxine (T4), and TSH were estimated by chemiluminescence immunoassay. Serum thyroid peroxidase antibodies (TPOAb) were measured using radioimmunoassay. A cutoff value of TPOAb ≥20 IU/ml was considered positive, with an analytical sensitivity of 2 IU/ml. Normal absolute neutrophil count (ANC) ranges from 1.5 to 8.0/mm3. Neutropenia was defined as ANC <1500/microliter.

The sample size of this cross-sectional study was calculated using Epi Info software. Results of sample size were taken using the method of Fleiss with continuity correction. The calculation was made for two-sided confidence level of 97% and power of 95%. The prevalence of GD was taken as 4.6%. The sample size came out to be 70. Further, a nonresponse rate of 10% was added and the final sample size was taken as 78. Frequency distribution was assessed in terms of means ± standard deviation for quantitative variables and number (percentages) for categorical variables. The Student's t-test or Mann–Whitney U-test was used for comparison of continuous variables as appropriate. The Chi-square test was used to compare categorical variables. Multivariate binary logistic regression analysis was performed to study the presence or absence of TAO (dependent variable) with various risk factors including age at onset of GD, gender, current smoking (in males only), serum total T3, TPOAb titer, and differential intraocular pressure (IOP) >6 mmHg. P < 0.05 was considered statistically significant. All the analyses were performed by the Statistical Package for the Social Sciences (SPSS, Chicago, IL, USA, version 21.0).


A total of 76 patients who met the inclusion criteria were included in the study. All the patients were of Kashmiri ethnicity. Age of the study subjects ranged from 18 to 68 years, with a mean age of 42.1 ± 11.49 years. TAO was present in 52 patients (prevalence 68%). TAO was bilateral in 50 (96%) of patients. The disease was of mild in severity in majority number of patients (65.4%) and moderate to severe in 34.6%. None of the patients had any evidence of sight-threatening disease. CAS was active in 13.5% of the study group.

[Table 1] shows the baseline characteristics of GD divided on the base of orbitopathy (TAO group and control group). Demographic, clinical, and biochemical parameters were compared between patients with and without TAO. The mean age of patients with TAO was 44.9 ± 12.2 years as compared to 36.5 ± 16.4 years and the difference was statistically significant (P = 0.014). There was significant female preponderance in the TAO group. Current smoking increased the risk of TAO (P = 0.043). Total T3 was significantly elevated at baseline in TAO patients. Mean IOP in primary and upward gaze was significantly increased in TAO patients. Braley's sign, i.e., the differential IOP of >6 mmHg, between the primary gaze and upgaze was seen in 30.7% of patients with TAO and 8.3% of patients in the control group and the difference was statistically significant. There was no statistically significant difference between the two groups with regard to dermopathy, mean goiter grade, TSH, total T4, TPOAb, ANC, neutropenia, and erythrocyte sedimentation rate.{Table 1}

Factors predicting the risk of TAO are shown in [Table 2]. On multiple logistic regression analysis, which included all patients with GD; current smoking, total T3 >4 ng/dl, and differential IOP >6 mmHg were found to be associated with TAO.{Table 2}


GD is often associated with orbitopathy and the natural course of TAO is benign in most patients and improvement is often seen with conservative treatment. Clinical decisions would be simpler if the course of TAO could be predicted. Multiple varying risk factors have been identified in several reports as possible predisposing factors for TAO, with smoking being the consistent factor.

In our study of 76 patients with GD at a tertiary care center, TAO was present in 68% of patients and was bilateral in 96%. Majority of patients had mild orbitopathy (65.4%) and none of the patients showed any signs of sight-threatening disease. CAS was active in 13.5% of the study group.

Among patients with GD, the prevalence of TAO varies widely with geographic location and within ethnic groups. Unlike our study, previous studies in India[19] and other studies reported the prevalence of TAO between 25% and 50%.[15],[20] The prevalence of TAO was 58% in the Australian Thyroid-Associated Orbitopathy Research study.[21] In a retrospective study on surgically treated Indian patients with GD, TAO was noted in 58%.[22] The higher prevalence of TAO in our study could be because of proper protocol of ophthalmic examination and diagnosis of TAO as per Bartley and Gorman criteria, in addition to geographic and ethnic variation. In the study by Marcocci et al.,[23] and Wiersinga et al.,[14] age distribution revealed a peak prevalence TAO in the fifth decade of life, which is comparable to our study. The Indian study reported TAO was mild in 83%, moderate to severe in 15%, and sight-threatening in 2%.[19] Savku and Gündüz[24] in a study found that TAO disease was an active phase in 32.6% and inactive phase in 67.4%. However in an Indian study by Reddy et al.,[19] TAO was clinically active in only 3% of cases, while Khong et al.[21] in their study reported that CAS was active in 16.5%.

In our study, current smoking, total T3 >4 ng/dl, and differential IOP >6 mmHg significantly increased the risk of TAO. Female gender increased the risk of TAO on univariate analysis but not on multivariate analysis. Female gender as a risk factor is in part due to the modulation of the autoimmune response by estrogen.[25] Tallstedt et al.[26] in their study suggested that high pretreatment T3 was a risk factor, in contrast to another study[27] where no association was found between pretreatment TSH and free T4 levels or levels at the time of ocular examination, with the risk of TAO.

Among various environmental factors associated with increased risk of TAO, smoking has been consistently noted as risk,[5],[6],[15],[28] perhaps by causing tissue hypoxia or simply direct inflammation.[29],[30] This risk was similar to that reported in previous studies in India.[19] The increase in IOP may be due to tethering by a fibrotic rectus muscle or to orbital congestion and venous stasis-limiting aqueous outflow. The clinical sensitivity and specificity of this increase in IOP, especially in upgaze, have been debated, although its existence has not.[31] In our previous study, we also noted differential IOP >6 mmHg to be associated with severe Graves' orbitopathy.[28]

The prospective nature and modest sample size were some of the strengths of the study. The study is also the first of its find from Kashmir, a mountainous northern part of India. The present study had several limitations. First, it was a single-center study; second, association with thyrotropin receptor antibody was not assessed, as it was done in few patients. Furthermore, various genetic factors which affect TAO were not studied, as Kashmir is ethnically different from India.


The current study concludes that like rest of studies, TAO was significantly associated with current smoking in addition to total T3 >4 ng/dl and differential IOP >6 mmHg. Therefore, it is important for patients with TAO to refrain from smoking. The disease was clinically inactive and of mild severity in most cases. These TAO patients need regular follow-up to manage any deterioration at earliest.

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Conflicts of interest

There are no conflicts of interest.


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