INTRODUCTION

Thyroid associated orbitopathy (TAO), which is also known as Graves ophthalmopathy, thyroid eye disease, thyroid orbitopathy, thyrotoxic exophthalmos and von basedow ophthalopathy¹ is an autoimune inflammatory disorder that is strongly associated with dysthyroidism. Graves’ disease is the most common thyroid disorder associated with TAO, but other disorders of the thyroid can have similar ophthalmic manifestations. These are Hashimoto’s thyroiditis, thyroid carcinoma, primary hyperthyroidism, and primary hypothyroidism^2,3,4. Approximately 25% to 50% of patients with Graves’ disease have or will develop clinically evident TAO^5,6 although less than 5% of patients with Graves’ disease have severe ophthalmopathy⁷.

The underlying pathophysiology is presumed to be an antibody- mediated reaction against the TSH receptor with orbital fibroblast modulation of T- cell lymphocytes. The T-cell lymphocytes react against thyroid follicular cells with shared antigenic epitopes within the retro bulbar space⁸. The lymphocytic infiltration leads to the activation of cytokine networks which lead to inflammation and interstitial edema of the extra ocular muscles⁹. Excess secretion of glycosaminoglycans by orbital fibroblasts is believed to be an important contributor. The end result is the expansion of the volume of extraocular muscles, retrobulbar fat and surrounding connective tissue. Similar changes can affect the eyelids and anterior periorbital tissues¹⁰. The hydrophilic glycosaminoglycan macromolecules result in an osmotic accumulation of water within the perimysial and retro-ocular connective tissues. Impaired venous drainage from the orbit may also contribute to the increased orbital volume.

The clinical manifestations of thyroid orbitopathy occur due to inflammation, edema, and fibrotic changes in the soft tissues of the orbit, resulting in enlargement of retrobulbar tissues and restriction of extraocular muscle motility¹¹. Although asymmetric eye involvement is quite common, unilateral eye disease occurs in only 5% to 14% of patients with TO^12,13.

The clinical signs are characteristic and they include a combination of eye lid retraction, lid lag, globe lag, proptosis, restrictive extraocular myopathy and optic neuropathy^13,14.

1.        Lid signs include:

·           Dalrymple sign-lid retraction in straight gaze

·           Von Graeefe Sign- lid lag in down gaze

·           Kocher sign- staring look on fixation

·           Means sign- superior scleral show on upgaze

·           Griffith sign- lower lid lag in upgaze

·           Vigouroux sign-eyelid fullness

·           Stellwag sign-incomplete and infrequent blinking

·           Grove sign- resistance to pulling down the retracted upper lid

2.    Proptosis: occurs due to increase in the intra orbital volume as a result of swelling of the extraocular muscle bellies and soft tissues^1,14.

3.    Resrtictive myopathy signs : Ballet sign- Restriction of one or more extraocular muscles, Bralleys sign-increase in intraocular pressure more than 4-6 mm Hg on upgaze

Mobius sign- poor convergence. A mechanism for restrictive myopathy is due to soft tissue involvement^1,14,15.

4.    Conjuctival involvement occurs in the form of superior limbic keratoconjctivitis, conjuctival injection which usually seen over the recti muscle insertions, conjuctival chemosis¹⁴.

5.    Corneal signs which include superficial punctatae keratitis, corneal exposure and corneal ulceration^14,15.

6.    Strabismus- the extra ocular muscles are affected in the following order IR>MR>SR>OBLIQUES>LR and confirmed with FDT or differential tonometry^14,15,16.

7.    Dysthyroid optic neuropathy affects 5% of TED patients who may present with blurry vision, visual loss, dyschromatopsia, or field loss^1,14,15.Optic disc odema/optic atrophy occurs due to direct compression of nerve or its vascular supply. Glaucoma can occur due to increased blood flow, restrictive myopathy and deposition of MPS in aqueous outflow channels.

CLASSIFICATION SYSTEMS IN TAO

There are various classification systems for thyroid ophthalmopathy.

VAN DYK’S CLASSIFICATION or the RELIEF CLASSIFICATION: Resistance to retropulsion, Edema of conjuctiva, Lacrimal gland enlargement, Injection of conjuntiva, Edema of lids, Fullness of lids.

The natural course of disease can be divided into Active phase, regressing and inactive phase. The pattern of disease was first described by Rundle and the plot of the orbital disease severity against time is graphically depicted as RUNDLE’S CURVE. The NOSPECS and EUGOGO classification assess the clinical severity. The VISA and CAS classification were intended to evaluate the clinical activity.

DIFFERENTIAL DIAGNOSIS

• Allergic conjunctivitis

• Myasthenia gravis

• Orbital myositis

• Chronic progressive external ophthalmoplegia

• Orbital tumors (primary or secondary).

• Carotid cavernous fistula• Any inflammatory orbitopathy

• Sarcoidosis

• Preseptal cellulitis

• Orbital cellulitis

NEED FOR THIS RESEARCH

The various risk factors mentioned in the literature are age, sex, presence of smoking, diabetes, stress, radioactive iodine treatment, thyroid surgery, statin use, recent change in thyroid profile and the type of dysthyroid status with varied results. All the previous studies available in literature assessed the presence of   risk factors and development of TAO.  None of these studies assessed the presence of risk factors and the severity of TAO. Our study may help us to prognosticate the disease and determine follow up of such patients .Control of modifiable risk factors may help in reducing the severity of disease also.

REVIEW OF LITERATURE

Age and sex: The incidence of TAO is found to be 16/ 100,000 females and 2.9/ 1 lac males with an approximate prevalence of 0.25% with no significant ethnic predisposition¹⁷.TAO is seen more common in females, with female to male ratio as 4:1¹⁴. But the severity of disease seems to be more in males¹⁸. It is usually seen in the age group of 20-50 years, but severe cases are seen in age group>50 years¹⁹.

Bimodal peak incidence rates for women seen from ages 40 to 44 years and 60 to 64 years; for men for ages 45 to 49 years and 65 to 69 years²⁰.

Smoking:  Cigarette  Smoking is the strongest modifiable risk factor of development of  TAO. It increases the risk of TAO by 7-8 times^21,22,23. In one study, smokers of European ethnicity had a 2.4 times increased risk for this condition associated than their Asian counterparts, the more severe the disease the stronger the association and presence of smoking reduced the effectiveness of treatment also²⁴. A systematic review of fourteen papers describing 15 studies was done in UK by Thornton etal²⁵showed the results as follows; there was a positive correlation between smoking and TAO in 4 case control studies with control patients with graves’ disease, but no ophthalmopathy (odd’s ratio 1.94-10.1) and in seven case control studies in which control subjects do not have thyroid disease.(odd’s ratio 1.22-20.2). There is increased prevalence of thyroid disease in smokers, for whom the relative risk of developing TAO is twice as high as it is for nonsmokers²¹. Orbital fibroblasts when exposed to cigarette extract have a dose – dependent statistically significant increase in GAGS production and adipogenesis²⁶.

Family history and genetics:-  .There have been reports suggesting that polymorphism in genes such as HLA, cytotoxic T Lymphocyte antigen, inter leukin 23 receptor, CD 40, CD 86, thyroglobulin and thyroid stimulating hormone receptor increases the risk of TAO^27,28. However, reported associations vary considerably between different populations and the majority of studies do not have adequate sample size and power to detect associations with occurrence and severity of TAO. A large recent study by yin et al concluded that patients with TAO may not have genetic susceptibility to their eye disease and suggested that their environmental influences are at pay¹. Some studies say that there is some genetic predisposition; the concordance level is 50% in identical twins and 30% in non identical twins. Also, there is an increased prevalence of HLA-B8 and HLA-DR3 in Caucasians²⁹, HLA-DRW6 in African Americans³⁰ and HLA-B35 in Japanese patients with Graves’ disease³¹. These HLA associations found, however, are of no predictive value for the development of orbitopathy in patients with Graves’ disease. In keeping with its probable underlying autoimmune nature, patients with TO may have other organ-specific or generalized autoimmune disorders, such as diabetes mellitus, Addison’s disease, vitiligo, pernicious anemia, or myasthenia gravis³².

Radioactive iodine treatment:- Radioactive iodine (I-131) is widely used to treat the thyrotoxicosis of graves’ disease, but, despite its demonstrable efficacy and safety profile, there have long been concerns about its possible adverse effect on thyroid eye disease. Definitive evidence for this link has been presented in a large, well designed study by Bartalena et al³³ treated 443 patients  with Graves’ disease and mild or no ophthalmopathy with methimazole until euthyroid, then randomly allocated them to continued methimazole, radioiodine, or radioiodine with adjuvant corticosteroid therapy. The results of the study were clear cut. After radioiodine treatment 15% of patients developed new or worsened ophthalmopathy. It confirms the results of a previously done randomized trial, which was criticized on methodological ground³⁴. Two plausible theories have been elucidated¹. The first is that radiation induced  thyroid damage releases some kind of antigens resulting in immune mediated ophthalmopathy, second is that  rapid hypothyroid state due to radio iodine stimulates the release of TSH causing retro orbital  adipocyte proliferation.

Type of thyroid disease -TED is associated with 90  % patients with hyperthyroidism,7% with euthyroid, 3% with hashimotos thyroiditis and 1% with primary hypothyroidism^1,20. Even if the patient is euthyroid, thyroid associated orbitopathy may progress. Other related autoimmune disorders like myasthenia gravis, which is about 50 times more common in patients with TAO in comparison to normal population, signify worsen the prognosis ^35,36. Similarly, patients having TAO and diabetes mellitus seem to have a higher incidence of dysthyroid optic neuropathy (DON)^37,38.

Studies for the assessment of various risk factors of TAO found in literature are summarized here. In a longitudinal cohort study done by Stein JD et al³⁹, all patients 18 years of age or older with newly diagnosed Grave’s disease  who were continuously enrolled in a large nationwide US managed care network and who visited an ophthalmologist 1 or more times from 2001 to 2009 were identified.  Multivariable Cox regression was used to determine the hazard of developing TAO among persons with newly diagnosed GD, with adjustment for social and demographic parameters, systemic co morbidities, , and medical and surgical interventions for management of hyperthyroidism. In follow up of 8404 patients with GD who met the inclusion criteria, 740 (8.8%) developed TAO. Surgical thyroidectomy, alone or in combination with medical therapy, was associated with a 74% decreased hazard for TAO (adjusted HR, 0.26 [95% CI, 0.12-0.51]) compared with radioactive iodine therapy alone. Statin use (for ≥60 days in the past year vs <60 days or nonuse) was found to be associated with a 40% decreased hazard.

 In a cross sectional study on prevalence and risk factors for thyroid eye disease among korean dysthyroid patients by Kyung In woo et al⁴⁰, all dysthyroid patients who visited endocrinology clinics in 24 general hospitals in Korea in a chosen one-week period were studied. Data were collected during an interviewer-administered questionnaire and, Demographic data, lifestyle risk factors, and status of thyroid disease variables were analyzed as risk factors using multivariable regression models to identify associations with thyroid eye disease. Two hundred eighty-three of these patients (17.3%) had thyroid eye disease. Multiple logistic regression analyses revealed that female gender, young age, Graves’ disease, dermopathy, and radioiodine treatment were independent risk factors for thyroid eye disease.

AIMS AND OBJECTIVE

AIM - To assess various risk factors resulting in the development of thyroid ophthalmopathy.

OBJECTIVE - To determine the association of Thyroid ophthalmopathy with various risk factors such as:

(a) Demographic factors-Age, Gender

(b ) Biological factors- Family history, Type of dysthyroid status, Diabetes

(c) Life style variable-smoking

(d) Treatment received- Radioactive iodine treatment

MATERIAL AND METHODS

STUDY SITE- Giridhar eye institute, Kochi

STUDY POPULATION- Patients with thyroid ophthalmopathy attending outpatient clinic at Giridhar Eye Hospital, Kochi

STUDY DESIGN-Cross-sectional study.

SAMPLE SIZE CALCULATION - The sample size was calculated using the below formula

N₁= [Z_α + exp {(-θ²)/4}Z_β]²  (1+ 2Pδ)/Pθ²)

where,

               δ       =  [1 + (1+θ²) exp (5θ² / 4)] [1+exp {(-θ²) /4}]^-1

                  θ       =  Log_e Odds Ratio

                P       =  Overall Proportion (Proportion of Disease)

                  α       =  Significance level

                            1 –β  =  Power

Z_{α =1.96,}  Z_β=0.84

The sample size was calculated using nMaster 2.0 software. The minimum required sample size calculated is 81.

TIME FRAME TO ADDRESS THE STUDY- One year, from November 2016 to October 2017.

INCLUSION CRITERIA- Patients presenting with clinical evidences of thyroid ophthalmopathy and deranged thyroid hormone status presently or in past.

EXCLUSION CRITERIA- Patients in whom, diagnosis of thyroid ophthalmopathy was doubtful and required further follow up.

METHODOLOGY- All the participants in this study will be given patient information sheet. After reading the patient information sheet, an informed consent will be obtained from them. The investigator will meet the participant and detailed history taking and ophthalmological examination will be done. In history, we will specifically enquire the presence of smoking, nature of smoking as current or ex-smoker, consumption in pack years, type of thyroid status at the time of diagnosis, history of diabetes, statin use, stress, family history of thyroid disease and TAO. The treatment history including details of medication, any thyroid surgery, and radio-iodine treatment also will be enquired. Specific ocular symptoms will also be noted. The patient will be undergoing routine ophthalmological examination including vision, refraction, slit lamp evaluation, soft tissue change assessment, pupilary reactions, colour vision assessment, exophthalmometry, intra ocular pressure measurement and dilated fundus evaluation. Based on the clinical findings, patients will be divided into two groups depending on the severity according to EUGOGO classification. The first group will include those with mild TAO, second group with moderate to severe and sight threatening nature. This division is based on the fact that patients with mild TAO require only topical medications where as patients with moderate to severe and sight threatening TAO may require systemic medications and close follow up as they can develop vision threatening disease. These two groups will be compared and analyzed for any association of each groups with the risk factors.

STATISTICAL METHODS- Qualitative variables will be expressed in terms of proportions.Univariate analysis using Chi square test will be done to find out the association between the various determinants of Thyroid Ophthalmopathy. Odds ratio and 95% C.I will be measured. Logistic regression analysis to be done to find out the independent determinants of Thyroid Ophthalmopathy. Results relating to continuous variables to be expressed as mean and standard deviation. The differences between quantitative variables will be analyzed using Mann-Whitney U test. The differences between categorical variables will be analyzed using Fisher’s exact Test. P<0.05 is to be considered statistically significant. All the analyses will be carried out using SPSS version 16.0.

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