A sight into the pathogenesis and treatment of thyroid-associated ophthalmopathy
DOI:
https://doi.org/10.15584/ejcem.2024.2.28Keywords:
Graves’ disease, TAO, thyroid-associated ophthalmopathy, thyroid eye diseaseAbstract
Introduction and aim. Thyroid-associated ophthalmopathy (TAO), often referred to as thyroid eye disease or Graves’ ophthalmopathy, is a syndrome characterized by autoimmune inflammation affecting the eye muscles, connective tissue, and orbital fat. The aim of this literature review is to present TAO and integrate the available data in the literature regarding the pathogenesis and treatment methods. Based on these, the authors aim to examine whether, despite the extensive knowledge already available on TAO, there are still issues to be investigated.
Material and methods. In this literature review, books and scientific publications in both Polish and English languages have been assessed. The search criteria included keywords such as TAO, Graves’ disease, thyroid-associated ophthalmopathy. The evaluation covered the following databases: PubMed, Scopus, Google Scholar.
Analysis of the literature. Typically, the eyeball is not involved, but in exceptional cases, corneal ulceration may occur, or inflammation of the optic nerve may ensue. TAO most commonly occurs in the course of hyperthyroidism in Graves’ disease, involving up to 25–50% of cases. The coexistence of autoantigens shared between the thyroid and orbital tissues is considered the primary cause of TAO when it occurs concurrently with hyperthyroidism, later in its course, or even preceding the manifestation of hyperthyroidism, with or without concurrent thyroid dysfunction. TAO is generally bilateral, although dominance on one side is often observed. Common symptoms include eye pain, photophobia, diplopia, varying degrees of proptosis, and impaired vision. The cornerstone of treatment lies in managing hyperthyroidism, as TAO cannot be cured without it.
Conclusion. First-line treatment involves glucocorticoids, with radiation therapy as a supplementary option, and in cases unresponsive to pharmacological treatment, surgical intervention may be necessary.
Downloads
References
Şahlı E, Gündüz K. Thyroid-associated Ophthalmopathy. Turk J Ophthalmol. 2017;47(2):94-105. doi: 10.4274/tjo.80688
Moledina M, Damato EM, Lee V. The changing landscape of thyroid eye disease: current clinical advances and future outlook. Eye. 2024. doi:10.1038/s41433-024-02967-9
Zhang P, Zhu H. Cytokines in Thyroid-Associated Ophthalmopathy. J Immunol Res. 2022;2022:2528046. doi: 10.1155/2022/2528046
Feldon SE, Weiner JM. Clinical significance of extraocular muscle volumes in Graves' ophthalmopathy: a quantitative computed tomography study. Arch Ophthalmol. 1982;100(8):1266-1269. doi: 10.1001/archopht.1982.01030040244006
Nunery WR, Nunery CW, Martin RT, Truong TV, Osborn DR. The risk of diplopia following orbital floor and medial wall decompression in subtypes of ophthalmic Graves’ disease. Ophthal Plast Reconstr Surg. 1997;13:153-60. doi: 10.1097/00002341-199709000-00001
Smith TJ, Hoa N. Immunoglobulins from patients with Graves’ disease induce hyaluronan synthesis in their orbital fibroblasts through the self-antigen, insulin-like growth factor-I receptor. J Clin Endocrinol Metab. 2004;89:5076-5080. doi: 10.1210/jc.2004-0716
Maheshwari R, Weis E. Thyroid associated orbitopathy. Indian J Ophthalmol. 2012;60(2):87-93. doi: 10.4103/0301-4738.94048
Panagiotou G, Perros P. Asymmetric Graves’ Orbitopathy. Front Endocrinol (Lausanne). 2020;11:611845. doi: 10.3389/fendo.2020.611845.
Bartalena L, Tanda M. Current concepts regarding Graves’ orbitopathy. J Intern Med. 2022; 292(5):692-716. doi: 10.1111/joim.13524
Taylor P, Zhang L, Lee R, et al. New insights into the pathogenesis and nonsurgical management of Graves orbitopathy. Nat Rev Endocrinol. 2020;16(2):104-116. doi: 10.1038/s41574-019-0305-4.
Neag E, Smith T. 2021 Update on Thyroid-Associated Ophthalmopathy. J Endocrinol Invest. 2022;45(2):235-259. doi: 10.1007/s40618-021-01663-9
Turck N, Eperon S, De Los Angeles Gracia M. Thyroid-Associated Orbitopathy and Biomarkers. Where We Are and What We Can Hope for the Future. Dis Markers. 2018;2018:7010196. doi: 10.1155/2018/7010196
Weiler D. Thyroid eye disease: a review. Clin Exp Optom. 2017;100(1):20-25. doi: 10.1111/cxo.12472
Hennein L, Robbins S. Thyroid-Associated Orbitopathy. Management and Treatment. J Binocul Vis Ocul Motil. 2022;72(1):32-46.
Lazarus J. H. Epidemiology of Graves' orbitopathy (GO) and relationship with thyroid disease. Best Pract Res Clin Endocrinol Metab. 2012;26(3):273-279. doi: 10.1016/j.beem.2011.10.005
Perros P, Hegedüs L, Bartalena L, et al. Graves' orbitopathy as a rare disease in Europe. a European group on Graves' orbitopathy (EUGOGO) position statement. Orphanet Journal of Rare Diseases. 2017;12(1):72. doi: 10.1186/s13023-017-0625-1
Chin YH, Ng CH, Lee MH et al. Prevalence of thyroid eye disease in Graves’ disease. a meta‐analysis and systematic review. Clin Endocrinol. 2020;93:363-374. doi: 10.1111/cen.14296
Ippolito S, Cusini C, Lasalvia P, et al. Change in newly diagnosed Graves’ disease phenotype between the twentieth and the twenty‐first centuries. meta‐analysis and meta‐regression. J Endocrinol Invest. 2021;44:1707-1718. doi: 10.1007/s40618-020-01479-z
Barbesino G, Salvi M, Freitag S. Future Projections in Thyroid Eye Disease. J Clin Endocrinol Metab. 2022;107(1):47-56. doi: 10.1210/clinem/dgac252
Bahn R. Graves’ Ophthalmopathy. N Engl J Med. 2010;362(8):726-738. doi: 10.1056/NEJMra0905750
Burch HB, Wartofsky L. Graves’ ophthalmopathy: current concepts regarding pathogenesis and management. Endocr Rev. 1993;14:747-793. doi: 10.1210/edrv-14-6-747
Boschi A, Daumerie C, Spiritus M, et al. Quantification of cells expressing the thyrotropin receptor in extraocular muscles in thyroid associated orbitopathy. Br J Ophthalmol. 2005;89:724-729. doi: 10.1136/bjo.2004.050807
Hai YP, Lee ACH, Frommer L, Diana T, Kahaly GJ. Immunohistochemical analysis of human orbital tissue in Graves’ orbitopathy. J Endocrinol Invest. 2020;43:123-137. doi: 10.1007/s40618-019-01116-4
Wakelkamp IM, Bakker O, Baldeschi L, Wiersinga WM, Prummel MF. TSH‐receptor expression and cytokine profile in orbital tissue of active vs. inactive Graves’ ophthalmopathy patients. Clin Endocrinol. 2003;58:280-287. doi: 10.1046/j.1365-2265.2003.01708.x
Ahn E, Subramanian P. Treatment modalities of thyroid related orbitopathy. Indian J Ophthalmol. 2014;62(10):999-1002. doi: 10.4103/0301-4738.145994
Tsui S, Naik V, Hoa N, et al. Evidence for an association between thyroid‐stimulating hormone and insulin‐like growth factor‐1 receptors. a tale of two antigens implicated in Graves’ disease. J Immunol. 2008;181:4397-4405. doi: 10.4049/jimmunol.181.6.4397
Krieger CC, Sui X, Kahaly GJ, Neumann S, Gershengorn MC. Inhibition of TSH/IGF‐1 receptor crosstalk by teprotumumab as a treatment modality of thyroid eye disease. J Clin Endocrinol Metab. 2021;107(4):1653-1660. doi: 10.1210/clinem/dgab824
Akaishi P, Cruz A, Silva F. The role of major histocompatibility complex alleles in the susceptibility of Brazilian patients to develop the myogenic type of Graves' orbitopathy. Thyroid. 2008;18(4):443-447. doi: 10.1089/thy.2007.0194
Wiersinga WM, Kahaly GJ. Graves orbitopathy. A multidisciplinary approach. J Clin Endocrinol Metab. 2001;86(2):501-503. doi: 10.1210/jcem.86.2.7338
Gilbard JP, Farris RL. Ocular surface drying and tear film osmolarity in thyroid eye disease. Acta Ophthalmol (Copenh). 1983;61:108-116. doi: 10.1111/j.1755-3768.1983.tb01401.x
Dickinson AJ, Perros P. Controversies in the clinical evaluation of active thyroid-associated orbitopathy. Use of a detailed protocol with comparative photographs for objective assessment. Clin Endocrinol (Oxf). 2001;55:283-303. doi: 10.1046/j.1365-2265.2001.01349.x
Frueh BR, Musch DC, Garber FW. Lid retraction and levator aponeurosis defects in Graves’ eye disease. Ophthalmic Surg. 1986;17:216-220.
Cawood TJ, Moriarty P, O’Farrelly C, O’Shea D. Smoking and thyroid-associated ophthalmopathy. A novel explanation of the biological link. J Clin Endocrinol Metab. 2007;92:59-64. doi: 10.1210/jc.2006-1824
Krassas GE, Wiersinga W. Smoking and autoimmune thyroid disease. The plot thickens. Eur J Endocrinol. 2006;154:777-780. doi: 10.1530/eje.1.02157
Marino M, Morabito E, Brunetto R. Acute and severe liver damage associated with intravenous glucocorticoid pulse therapy in patients with Graves' ophthalmopathy. Thyroid. 2004;14(5):403-406. doi: 10.1089/105072504774193276
Nagayama Y, Izumi M, Kiriyama T, et al. Treatment of Graves’ ophthalmopathy with high-dose intravenous methylprednisolone pulse therapy. Acta Endocrinol (Copenh).1987;116(4):513-518. doi: 10.1530/acta.0.1160513
Dandona P, Havard CW, Mier A. Methylprednisolone and Graves’ ophthalmopathy. BMJ. 1989;298(6676):830-830. doi: 10.1136/bmj.298.6676.830
González-García A, Sales-Sanz M: Treatment of Graves' ophthalmopathy. Med Clin (Barc). 2021;156(4):180-186. doi: 10.1016/j.medcli.2020.07.031
Ye X, Bo X, Hu X, et al. Efficacy and safety of mycophenolate mofetil in patients with active moderate-to-severe Graves’ orbitopathy. Clin Endocrinol (Oxf). 2017;86(2):247-255. doi: 10.1111/cen.13170
Kahaly GJ, Riedl M, Konig J, et al. European Group on Graves’ Orbitopathy (EUGOGO). Mycophenolate plus methylprednisolone versus methylprednisolone alone in active, moderate-to-severe Graves’ orbitopathy (MINGO): a randomised, observer-masked, multicentre trial. Lancet Diabetes Endocrinol. 2018;6(4):287-298. doi: 10.1016/S2213-8587(18)30020-2
Bartalena L, Kahaly GJ, Baldeschi L, et al. The 2021 European Group on Graves’ orbitopathy (EUGOGO) clinical practice guidelines for the medical management of Graves’ orbitopathy. Eur J Endocrinol. 2021;185(4):43-67. doi: 10.1530/EJE-21-0479
Kahaly G, Riedl M, König J. Mycophenolate plus methylprednisolone versus methylprednisolone alone in active, moderate-to-severe Graves' orbitopathy (MINGO): a randomised, observer-masked, multicentre trial. Lancet Diabetes Endocrinol. 2018;6(4):287-298. doi: 10.1016/S2213-8587(18)30020-2
Kelley W, Rosenbloom F, Seegmiller J. The effects of azathioprine (imuran) on purine synthesis in clinical disorders of purine metabolism: J Clin Invest. 1967;46(9):1518-1529. doi: 10.1172/JCI105643.
Salvi M, Vannucchi G, Beck-Peccoz P. Potential utility of rituximab for Graves’ orbitopathy. J Clin Endocrinol Metab. 2013;98(11):4291-4299. doi: 10.1210/jc.2013-1804
Silkiss RZ, Reier A, Coleman M, Lauer SA: Rituximab for thyroid eye disease. Ophthalmic Plast Reconstr Surg. 2010;26(5):310-314. doi: 10.1097/IOP.0b013e3181c4dfde
Chen J, Chen G, Sun H. Intravenous rituximab therapy for active Graves' ophthalmopathy: a meta-analysis. Hormones (Athens). 2021;20(2):279-286. doi: 10.1007/s42000-021-00282-6
Moreiras J, Gomez-Reino J, Perez-Pampis. Efficacy of Tocilizumab in Patients with Moderate-to-Severe Corticosteroid-Resistant Graves Orbitopathy. A Randomized Clinical Trial. Am J Ophthalmol. 2018;195:181-190. doi: 10.1016/j.ajo.2018.07.038
Bartley G, Gorman C. Perspective--Part I: the Mayo Orbital Radiotherapy for Graves Ophthalmopathy (ORGO) study lessons learned. Ophthalmic Plast Reconstr Surg. 2002;18(3):170-172. doi: 10.1097/00002341-200205000-00002
Grassi P, Strianese D, Piscopo R, Pacelli R, Bonavolonta G. Radiotherapy for the treatment of thyroid eye disease-a prospective comparison is orbital radiotherapy a suitable alternative to steroids. Ir J Med Sci. 2017;186(3):647-652. doi: 10.1007/s11845-016-1542-3
Finn AP, Bleier B, Cestari DM, et al. A retrospective review of orbital decompression for thyroid orbitopathy with endoscopic preservation of the inferomedial orbital bone strut. Ophthalmic Plast Reconstr Surg. 2017;33(5):334-339. doi: 10.1097/IOP.0000000000000782
Rootman DB, Golan S, Pavlovich P, Rootman J. Postoperative changes in strabismus, ductions, exophthalmometry, and eyelid retraction after orbital decompression for thyroid orbitopathy. Ophthalmic Plast Reconstr Surg. 2017;33(4):289-293. doi: 10.1097/IOP.0000000000000758
Kahaly GJ, Hardt J, Petrak F, Engle UT. Psychosocial Factors in Subjects with Thyroid-Associated Ophthalmopathy. Thyroid. 2002;12(3):237-239. doi: 10.1089/105072502753600205
Abraham-Nordling M, Wallin G, Traisk F, et al. Thyroid-associated ophthalmopathy; quality of life follow-up of patients randomized to treatment with antithyroid drugs or radioiodine. Eur J Endocrinol. 2010;163(4):651-657. doi: 10.1530/EJE-10-0475
Downloads
Published
How to Cite
Issue
Section
License
Copyright (c) 2024 European Journal of Clinical and Experimental Medicine

This work is licensed under a Creative Commons Attribution 4.0 International License.
Our open access policy is in accordance with the Budapest Open Access Initiative (BOAI) definition: this means that articles have free availability on the public Internet, permitting any users to read, download, copy, distribute, print, search, or link to the full texts of these articles, crawl them for indexing, pass them as data to software, or use them for any other lawful purpose, without financial, legal, or technical barriers other than those inseparable from having access to the Internet itself.
All articles are published with free open access under the CC-BY Creative Commons attribution license (the current version is CC-BY, version 4.0). If you submit your paper for publication by the Eur J Clin Exp Med, you agree to have the CC-BY license applied to your work. Under this Open Access license, you, as the author, agree that anyone may download and read the paper for free. In addition, the article may be reused and quoted provided that the original published version is cited. This facilitates freedom in re-use and also ensures that Eur J Clin Exp Med content can be mined without barriers for the research needs.




