This study related to thyroid related eye diseases.
- Registration Number
- CTRI/2018/03/012749
- Lead Sponsor
- Giridhar Eye Institute
- Brief Summary
**INTRODUCTION**
Thyroid associated orbitopathy (TAO),which is also known as Graves ophthalmopathy, thyroid eye disease, thyroidorbitopathy, thyrotoxic exophthalmos and von basedow ophthalopathy1is an autoimune inflammatory disorder that is strongly associated withdysthyroidism. Graves’ disease is the most common thyroid disorder associatedwith TAO, but other disorders of the thyroid can have similar ophthalmicmanifestations. These are Hashimoto’s thyroiditis, thyroid carcinoma, primaryhyperthyroidism, and primary hypothyroidism2,3,4. Approximately 25%to 50% of patients with Graves’ disease have or will develop clinically evidentTAO5,6 although less than 5% of patients with Graves’ disease havesevere ophthalmopathy7.
The underlyingpathophysiology is presumed to be an antibody- mediated reaction against theTSH receptor with orbital fibroblast modulation of T- cell lymphocytes. TheT-cell lymphocytes react against thyroid follicular cells with shared antigenic epitopes within the retrobulbar space8. The lymphocyticinfiltration leads to the activation of cytokine networks which lead toinflammation and interstitial edema of the extraocular muscles9. Excess secretion of glycosaminoglycans by orbital fibroblasts is believed to be an importantcontributor. The end result is the expansionof the volume of extraocular muscles, retrobulbarfat and surrounding connective tissue. Similar changes can affect the eyelids andanterior periorbital tissues10. The hydrophilicglycosaminoglycan macromolecules result in an osmotic accumulation of waterwithin the perimysial and retro-ocular connective tissues. Impaired venousdrainage from the orbit may also contribute to the increased orbital volume.
The clinical manifestations ofthyroid orbitopathy occur due to inflammation, edema, and fibrotic changes inthe soft tissues of the orbit, resulting in enlargement of retrobulbar tissuesand restriction of extraocular muscle motility11. Although asymmetriceye involvement is quite common, unilateral eye disease occurs in only 5% to14% of patients with TO12,13.
Theclinical signs are characteristic and they include a combination of eye lidretraction, lid lag, globe lag, proptosis, restrictive extraocular myopathy andoptic neuropathy13,14.
1. Lidsigns include:
· Dalrymplesign-lid retraction in straight gaze
· VonGraeefe Sign- lid lag in down gaze
· Kochersign- staring look on fixation
· Meanssign- superior scleral show on upgaze
· Griffithsign- lower lid lag in upgaze
· Vigourouxsign-eyelid fullness
· Stellwagsign-incomplete and infrequent blinking
· Grovesign- resistance to pulling down the retracted upper lid
2. Proptosis: occurs due to increase in theintra orbital volume as a result of swelling of the extraocular muscle belliesand soft tissues1,14.
3. Resrtictive myopathy signs : Balletsign- Restriction of one or more extraocular muscles, Bralleys sign-increase inintraocular pressure more than 4-6 mm Hg on upgaze
Mobiussign- poor convergence. A mechanism for restrictive myopathy is due to softtissue involvement1,14,15.
4. Conjuctival involvement occurs in the formof superior limbic keratoconjctivitis, conjuctival injection which usually seenover the recti muscle insertions, conjuctival chemosis14.
5. Corneal signs which include superficialpunctatae keratitis, corneal exposure and corneal ulceration14,15.
6. Strabismus- the extra ocular muscles areaffected in the following order IR>MR>SR>OBLIQUES>LR and confirmedwith FDT or differential tonometry14,15,16.
7. Dysthyroid optic neuropathy affects 5% ofTED patients who may present with blurry vision, visual loss, dyschromatopsia,or field loss1,14,15.Optic disc odema/optic atrophy occurs due todirect compression of nerve or its vascular supply. Glaucoma can occur due toincreased blood flow, restrictive myopathy and deposition of MPS in aqueousoutflow channels.
**CLASSIFICATIONSYSTEMS IN TAO**
There are various classificationsystems for thyroid ophthalmopathy.
VAN DYK’S CLASSIFICATION or theRELIEF CLASSIFICATION: Resistance to retropulsion, Edema of conjuctiva, Lacrimalgland enlargement, Injection of conjuntiva, Edema of lids, Fullness of lids.
Thenatural course of disease can be divided into Active phase, regressing andinactive phase. The pattern of disease was first described by Rundle and theplot of the orbital disease severity against time is graphically depicted asRUNDLE’S CURVE. The NOSPECS and EUGOGO classification assess the clinicalseverity. The VISA and CAS classification were intended to evaluate theclinical activity.
**DIFFERENTIALDIAGNOSIS**
• Allergicconjunctivitis
• Myasthenia gravis
• Orbital myositis
• Chronic progressiveexternal ophthalmoplegia
• Orbital tumors(primary or secondary).
• Carotid cavernousfistula• Any inflammatory orbitopathy
• Sarcoidosis
• Preseptalcellulitis
• Orbital cellulitis
**NEEDFOR THIS RESEARCH**
The various risk factorsmentioned in the literature are age, sex, presence of smoking, diabetes,stress, radioactive iodine treatment, thyroid surgery, statin use, recentchange in thyroid profile and the type of dysthyroid status with variedresults. All the previous studies available in literature assessed the presenceof risk factors and development ofTAO. None of these studies assessed thepresence of risk factors and the severity of TAO. Our study may help us toprognosticate the disease and determine follow up of such patients .Control ofmodifiable risk factors may help in reducing the severity of disease also.
**REVIEW OFLITERATURE**
Age and sex: Theincidence of TAO is found to be 16/ 100,000 females and 2.9/ 1 lac males withan approximate prevalence of 0.25% with no significant ethnic predisposition17.TAOis seen more common in females, with female to male ratio as 4:114. Butthe severity of disease seems to be more in males18. It is usuallyseen in the age group of 20-50 years, but severe cases are seen in agegroup>50 years19.
Bimodal peak incidence rates forwomen seen from ages 40 to 44 years and 60 to 64 years; for men for ages 45 to49 years and 65 to 69 years20.
Smoking**:** Cigarette Smoking is the strongest modifiable riskfactor of development of TAO. Itincreases the risk of TAO by 7-8 times21,22,23. In one study, smokersof European ethnicity had a 2.4 times increased risk for this conditionassociated than their Asian counterparts, the more severe the disease thestronger the association and presence of smoking reduced the effectiveness oftreatment also24. A systematic review of fourteen papers describing15 studies was done in UK by Thornton etal25showed the results asfollows; there was a positive correlation between smoking and TAO in 4 casecontrol studies with control patients with graves’ disease, but noophthalmopathy (odd’s ratio 1.94-10.1) and in seven case control studies inwhich 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 therelative risk of developing TAO is twice as high as it is for nonsmokers21. Orbitalfibroblasts when exposed to cigarette extract have a dose – dependentstatistically significant increase in GAGS production and adipogenesis26.
**Family history and genetics**:- .There have been reportssuggesting that polymorphism in genes such as HLA, cytotoxic T Lymphocyteantigen, inter leukin 23 receptor, CD 40, CD 86, thyroglobulin and thyroidstimulating hormone receptor increases the risk of TAO27,28. However, reportedassociations vary considerably between different populations and the majorityof studies do not have adequate sample size and power to detect associationswith occurrence and severity of TAO. A large recent study by yin et al concluded that patients withTAO may not have genetic susceptibility to their eye disease and suggested thattheir environmental influences are at pay1. Some studies say that thereis some genetic predisposition; the concordance level is 50% in identical twinsand 30% in non identical twins. Also, there is an increased prevalence of HLA-B8and HLA-DR3 in Caucasians29, HLA-DRW6 in African Americans30and HLA-B35 in Japanese patients with Graves’ disease31. These HLAassociations found, however, are of no predictive value for the development oforbitopathy in patients with Graves’ disease. In keeping with its probableunderlying autoimmune nature, patients with TO may have other organ-specific orgeneralized autoimmune disorders, such as diabetes mellitus, Addison’s disease,vitiligo, pernicious anemia, or myasthenia gravis32.
**Radioactive iodinetreatment**:-Radioactive iodine (I-131) is widely used to treat the thyrotoxicosis ofgraves’ disease, but, despite its demonstrable efficacy and safety profile,there have long been concerns about its possible adverse effect on thyroid eyedisease. Definitive evidence for this link has been presented in a large, welldesigned study by Bartalena et al33 treated 443 patients with Graves’ disease and mild or noophthalmopathy with methimazole until euthyroid, then randomly allocated themto continued methimazole, radioiodine, or radioiodine with adjuvantcorticosteroid therapy. The results of the study were clear cut. Afterradioiodine treatment 15% of patients developed new or worsened ophthalmopathy.It confirms the results of a previously done randomized trial, which was criticizedon methodological ground34. Two plausible theories have been elucidated1.The first is that radiation induced thyroid damage releases some kind of antigens resulting in immunemediated ophthalmopathy, second is that rapid hypothyroid state due to radio iodine stimulates the release ofTSH causing retro orbital adipocyteproliferation.
Type of thyroid disease -TED isassociated with 90 % patients withhyperthyroidism,7% with euthyroid, 3% with hashimotos thyroiditis and 1% withprimary hypothyroidism1,20. Even if the patient is euthyroid,thyroid associated orbitopathy may progress. Other related autoimmune disorderslike myasthenia gravis, which is about 50 times more common in patients withTAO in comparison to normal population, signify worsen the prognosis 35,36.Similarly, patients having TAO and diabetes mellitus seem to have a higherincidence of dysthyroid optic neuropathy (DON)37,38.
Studies for the assessment ofvarious risk factors of TAO found in literature are summarized here. In alongitudinal cohort study done by Stein JD et al39, all patients 18years of age or older with newly diagnosed Grave’s disease who were continuously enrolled in a largenationwide US managed care network and who visited an ophthalmologist 1 or moretimes from 2001 to 2009 were identified. Multivariable Cox regression was used todetermine 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. Infollow up of 8404 patients with GD who met the inclusion criteria, 740 (8.8%)developed TAO. Surgical thyroidectomy, alone or in combination with medicaltherapy, 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 beassociated with a 40% decreased hazard.
In a cross sectional study on prevalence andrisk factors for thyroid eye disease among korean dysthyroid patients by KyungIn woo et al40,all dysthyroid patients who visited endocrinology clinics in 24 generalhospitals in Korea in a chosen one-week period were studied. Data werecollected during an interviewer-administered questionnaire and, Demographicdata, lifestyle risk factors, and status of thyroid disease variables wereanalyzed as risk factors using multivariable regression models to identifyassociations with thyroid eye disease. Two hundred eighty-three of thesepatients (17.3%) had thyroid eye disease. Multiple logistic regression analysesrevealed that female gender, young age, Graves’ disease, dermopathy, andradioiodine treatment were independent risk factors for thyroid eye disease.
**AIMS AND OBJECTIVE**
**AIM** - To assess various risk factorsresulting in the development of thyroid ophthalmopathy.
**OBJECTIVE** - To determine the association ofThyroid 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
**MATERIALAND METHODS**
STUDY SITE- Giridhar eyeinstitute, Kochi
STUDY POPULATION- Patients withthyroid ophthalmopathy attending outpatient clinic at Giridhar Eye Hospital,Kochi
STUDY DESIGN-Cross-sectionalstudy.
SAMPLE SIZE CALCULATION - The sample size was calculated using the below formula
N1= [Zα + exp {(-θ2)/4}Zβ]2 (1+ 2Pδ)/Pθ2)
where,
δ = [1 + (1+θ2) exp (5θ2/ 4)] [1+exp {(-θ2) /4}]-1
θ = Loge Odds Ratio
P = OverallProportion (Proportion of Disease)
α = Significance level
1 –β = Power
Zα =1.96,Zβ=0.84
The sample size was calculated using nMaster 2.0 software. The minimum requiredsample size calculated is 81.
TIME FRAME TO ADDRESS THE STUDY-One year, from November 2016 to October 2017.
INCLUSION CRITERIA- Patientspresenting with clinical evidences of thyroid ophthalmopathy and derangedthyroid hormone status presently or in past.
EXCLUSION CRITERIA- Patients inwhom, diagnosis of thyroid ophthalmopathy was doubtful and required furtherfollow up.
METHODOLOGY- All the participantsin this study will be given patient information sheet. After reading thepatient information sheet, an informed consent will be obtained from them. Theinvestigator will meet the participant and detailed history taking andophthalmological examination will be done. In history, we will specificallyenquire the presence of smoking, nature of smoking as current or ex-smoker, consumptionin pack years, type of thyroid status at the time of diagnosis, history ofdiabetes, statin use, stress, family history of thyroid disease and TAO. Thetreatment history including details of medication, any thyroid surgery, andradio-iodine treatment also will be enquired. Specific ocular symptoms willalso be noted. The patient will be undergoing routine ophthalmologicalexamination including vision, refraction, slit lamp evaluation, soft tissuechange assessment, pupilary reactions, colour vision assessment,exophthalmometry, intra ocular pressure measurement and dilated fundusevaluation. Based on the clinical findings, patients will be divided into twogroups depending on the severity according to EUGOGO classification. The firstgroup will include those with mild TAO, second group with moderate to severeand sight threatening nature. This division is based on the fact that patientswith mild TAO require only topical medications where as patients with moderateto severe and sight threatening TAO may require systemic medications and closefollow up as they can develop vision threatening disease. These two groups willbe compared and analyzed for any association of each groups with the riskfactors.
STATISTICALMETHODS- Qualitative variables will be expressed in terms of proportions.Univariateanalysis using Chi square test will be done to find out the association betweenthe various determinants of Thyroid Ophthalmopathy.Odds ratio and 95% C.I will be measured. Logistic regression analysis to bedone to find out the independentdeterminants of Thyroid Ophthalmopathy. Resultsrelating to continuous variables to be expressed as mean and standarddeviation. The differences between quantitative variables will be analyzed usingMann-Whitney U test. Thedifferences between categorical variables will be analyzed using Fisher’s exactTest. P<0.05 isto be considered statistically significant. All the analyses will be carriedout using SPSS version 16.0.
**REFERENCES**
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4. Bartley GB, FatourechiV, Kadrmas EF, Jacobsen SJ, Ilstrup DM, Garrity JA, Gorman CA. The incidence ofGraves’ ophthalmopathy in Olmsted County, Minnesota. American journal ofophthalmology. 1995 Oct 1;120(4):511-7.
5. Bahn RS.Pathophysiology of Graves’ ophthalmopathy: the cycle of disease. The Journal ofClinical Endocrinology & Metabolism. 2003 May 1;88(5):1939-46
6. Burch HB, Wartofsky L.Graves’ ophthalmopathy: current concepts regarding pathogenesis and management.Endocrine Reviews. 1993 Dec;14(6):747-93.
7. Kriss JP, Konishi J,Herman M. Studies on the pathogenesis of Graves’ ophthalmopathy (with somerelated observations regarding therapy). Recent progress in hormone research.1975;31:533.
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9. Boboridis K, Perros P.General management plan. In: Weirsinga WM, Kahaly GJ, eds. Graves’Ophthalmopathy: A multidisciplinary approach. Basel: Karger 2008:88-95.
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19. BartleyGB, Fatourechi V, Kadrmas EF, Jacobsen SJ, Ilstrup DM, Garrity JA, Gorman CA.The incidence of Graves’ ophthalmopathy in Olmsted County, Minnesota. Americanjournal of ophthalmology. 1995 Oct 1;120(4):511-7.
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- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Completed
- Sex
- All
- Target Recruitment
- 100
Patients presenting with clinical evidence of thyroid ophthalmopathy and deranged thyroid hormone status presently or in past.
Patients in whom, diagnois of thyroid ophthalmology was doubtful and required further follow-up.
Study & Design
- Study Type
- Observational
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method To assess various risk factors and development of thyroid ophthalmopathy. 12 months
- Secondary Outcome Measures
Name Time Method To determine the association of thyroid ophthalmopathy with demographic factors; biological factors, lifestyle variable and treatment received. 12 months from date of enrolment
Trial Locations
- Locations (1)
Giridhar Eye Institute
🇮🇳Ernakulam, KERALA, India
Giridhar Eye Institute🇮🇳Ernakulam, KERALA, IndiaDr Surekha C SPrincipal investigator9446755383drsurekhacs@gmail.com