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      Clinical course of thyroid function and thyroid associated-ophthalmopathy in patients with euthyroid Graves’ disease

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          Abstract

          Background

          Euthyroid Graves’ disease (EGD) is a rare condition defined as the presence of thyroid-associated ophthalmopathy (TAO) in patients with normal thyroid function. Due to the rarity of this disease, only a limited number of studies and case reports are available for further evaluation of the characteristics of the disease. The aim of this study was to examine the changes in the thyroid function, thyrotropin receptor antibodies (TRAb) and eye symptoms, and then determine whether TRAb is related to TAO in EGD patients. TRAb in this study was defined as including both thyrotropin-binding inhibitory immunoglobulin (TBII) and thyroid-stimulating immunoglobulin (TSAb).

          Patients and methods

          Medical records of patients diagnosed with EGD were reviewed. Ophthalmologists specializing in TAO examined the eyes of all subjects.

          Results

          Of the 58 patients diagnosed with EGD, 24.1% developed hyperthyroidism, while 3.4% developed hypothyroidism. A total of 72.4% of the 58 patients remained euthyroid throughout the entire follow-up period. At the initial presentation, TBII and TSAb were positive in 74.5% and 70.5%, respectively. Ophthalmic treatments were administered to 30 (51.7%) out of the 58 patients. A significant spontaneous improvement of the eye symptoms was found in 28 of the EGD patients who did not require eye treatments. EGD patients exhibited positive rates for both TBII and TSAb, with the number of the TRAb-positive patients gradually decreasing while the eye symptoms spontaneously improved over time. There were no correlations found between TRAb at initial presentation and the eye symptoms.

          Conclusion

          TBII and TSAb were positive in about 70% of EGD patients at their initial visit. Thyroid functions of EGD patients who have been euthyroid for more than 6.7 years may continue to remain euthyroid in the future.

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          Most cited references27

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          Clinical features of Graves' ophthalmopathy in an incidence cohort.

          To determine the clinical characteristics of an incidence cohort of patients with Graves' ophthalmopathy. We reviewed the community medical records of 120 patients residing in Olmsted County, Minnesota, in whom Graves' ophthalmopathy was diagnosed between 1976 and 1990. Among 120 patients with Graves' ophthalmopathy, 108 (90%) patients had Graves' hyperthyroidism, one (1%) had primary hypothyroidism, four (3%) had Hashimoto's thyroiditis, and seven (6%) were euthyroid. At some point in their clinical course, eyelid retraction was present in 108 patients, whereas the approximate frequency of exophthalmos was 62% (73 patients); restrictive extraocular myopathy, 43% (51 patients); and optic nerve dysfunction, 6% (seven patients). Only six (5%) patients had eyelid retraction, exophthalmos, optic nerve dysfunction, extraocular muscle involvement, and hyperthyroidism. At the time of diagnosis of ophthalmopathy, upper eyelid retraction and eyelid lag were documented in 85 and 52 patients, respectively, and the most frequent ocular symptom was pain (36 patients, 30%). Diplopia was noted at the initial examination by 20 patients, lacrimation was present in 25 patients, 19 patients had photophobia, and nine patients had blurred vision. Decreased vision from optic neuropathy was present in less than 2% of eyes at the time of diagnosis. Thyroid dermopathy and acropachy accompanied Graves' ophthalmopathy in five patients (4%) and one (1%) patient, respectively. Myasthenia gravis occurred in only one patient. Eyelid retraction is the most common clinical sign of Graves' ophthalmopathy. The complete constellation of typical features (hyperthyroidism, eyelid retraction, exophthalmos, restrictive extraocular myopathy, and optic nerve dysfunction) occurs relatively infrequently.
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            Graves' ophthalmopathy: current concepts regarding pathogenesis and management.

            Referring to the hyperadrenergic theory on the pathogenesis of Graves' ophthalmopathy, a 1934 JAMA editorial (513) stated "the mechanism of exophthalmos is well understood though the knowledge would seem to be poorly disseminated." Several subsequent theories on pathogenesis, stated equally emphatically, have experienced a similar fate to that prompting this remark, but not before negatively impacting upon the management of patients suffering from this disorder. Thus, it is with an element of caution that we conclude that the sequence of events contributing to the pathogenesis of Graves' ophthalmopathy has become progressively more lucid, due to the assiduous efforts of many investigators in this field. Demonstration of an inextricable link between the eye and the thyroid in Graves' ophthalmopathy seems limited only by our ability to detect subtle involvement of one or the other of these two organs in exceptional cases, although not all authors share this viewpoint (514). The factors modulating the degree of expression of the thyroid component, such as concurrent lymphocytic thyroiditis or qualitative differences in TRAb seem more tangible than those affecting the clinical expression of eye involvement. Environmental factors such as smoking are associated, to a degree that matches or surpasses that known for genetic predisposition to this disorder. Local anatomy, including such factors as vulnerability to obstruction of venous drainage, must play a role as evidenced by asymmetric eye involvement and rapid relief of inflammatory changes after orbital decompression surgery. The transition from palliative to curative measures in Graves' ophthalmopathy will require further advances in our understanding of the putative shared thyroid-eye antigens, demonstration that these antigens are etiologically important and concomitant advances in antigen-specific immune therapy.
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              Association of thyrotrophin receptor antibodies with the clinical features of Graves' ophthalmopathy.

              Graves' ophthalmopathy (GO) and Graves' hyperthyroidism are closely associated diseases and thought to be caused by the same autoimmune process. An obvious explanation for this would be the presence of autoantibodies reacting with an autoantigen present in the orbit and the thyroid gland. The TSH-Receptor (TSH-R) antibodies are a likely candidate, because they cause Graves' hyperthyroidism and the TSH-R appears to be present also in orbital tissues. If TSH-R antibodies are responsible for the ophthalmopathy one would expect their titres to correlate with clinical characteristics of the eye disease. The aim of the present study is to see whether TSH-R antibodies are related to the activity and severity of the thyroid-associated ophthalmopathy. TSH-R antibody levels were measured as TBII (TRAK assay), and TSI (cAMP response of a TSH-R transfected cell line) in serum of 63 patients with untreated moderately severe GO, accompanying Graves' thyroid disease; all patients had been euthyroid for > 2 months. TBII and TSI titres were strongly related to each other. TBII or TSI titres did not correlate with thyroidal or orbital disease duration, nor with TPO antibody levels. In contrast, we found a striking and highly significant correlation between the Clinical Activity Score (CAS) of the eye disease, and both TBII (r = 0.54; P < 0.0001) and TSI (r = 0.50; P < 0.0001). In addition, a weaker but significant relation was found between proptosis (in mm) and TBII (r = 0.36; P = 0.004) and TSI (r = 0.49; P = 0.0001). No correlation was found with eye muscle motility. TSH-R antibody levels correlate directly with clinical features of Graves' ophthalmopathy. The results support the hypothesis of a pathogenetic role of TSH-R antibodies and the TSH-R in the orbit of Graves' ophthalmopathy patients.
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                Author and article information

                Journal
                Clin Ophthalmol
                Clin Ophthalmol
                Clinical Ophthalmology
                Clinical Ophthalmology (Auckland, N.Z.)
                Dove Medical Press
                1177-5467
                1177-5483
                2018
                19 April 2018
                : 12
                : 739-746
                Affiliations
                [1 ]Department of Internal Medicine, Ito Hospital, Tokyo, Japan
                [2 ]Department of Ophthalmology, Olympia Eye Hospital, Tokyo, Japan
                Author notes
                Correspondence: Nami Suzuki, Department of Internal Medicine, Ito Hospital, 4-3-6 Jingumae, Shibuya-ku, Tokyo 150-8308, Japan, Tel +81 3 3402 7447, Fax +81 3 3402 7439, Email n-suzuki@ 123456ito-hospital.jp
                Article
                opth-12-739
                10.2147/OPTH.S158967
                5914550
                29719374
                6b3cd97f-e1a3-45c7-be01-fad3570d78c3
                © 2018 Suzuki et al. This work is published and licensed by Dove Medical Press Limited

                The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

                History
                Categories
                Original Research

                Ophthalmology & Optometry
                euthyroid graves’ orbitopathy,euthyroid graves’ ophthalmopathy,thyroid-associated ophthalmopathy,tsh receptor antibody,thyroid-stimulating immunoglobulin

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