Autoimmune Mechanisms and Treatment Approaches in Graves' Disease-Induced Hyperthyroidism: A Comprehensive Review

Document Type : Review Article

Authors

1 Department of Biochemistry, Faculty of Basic Medical Sciences, University of Lagos, Idi-Araba, Nigeria

2 Department of Biochemistry, Faculty of Biosciences, Federal University Wukari, Taraba State, Nigeria

3 Departments of Medicine, College of Medicine, University of Gullas, Cebu, Philippines

4 Department of Medicine and Surgery, Faculty of Clinical sciences, University of Ibadan, Ibadan, Nigeria

5 Department of Medicine and Surgery, College of Medicine, Kursk State Medical University, Kursk City, Russia

6 Department of Internal Medicine, Internal Medicine and Public Health, Federal Medical Center, Ebute Metta, Lagos, Nigeria

7 Department of Pharmacognosy, Faculty of Pharmacy, University of Lagos. Idia-Araba, Nigeria

8 Department of Internal Medicine and Surgery, Faculty of Clinical Sciences, College of Medicine, University of Lagos, Idi-Araba, Lagos, Nigeria

9 Department of Computer Science, Faculty of Science and Technology, Babcock University, Ilisan-Remo Ogun State, Nigeria

10 Department of Microbiology, Faculty of Biological Sciences, University of Nigeria Nsukka, Nsukka, Nigeria

Abstract
Graves' disease represents the predominant etiology of hyperthyroidism globally, affecting 60-80% of hyperthyroid cases worldwide. This autoimmune disorder results from thyroid-stimulating immunoglobulins (TSI) inappropriately activating thyroid-stimulating hormone receptors (TSHR), leading to excessive thyroid hormone production and subsequent metabolic dysfunction. The disease predominantly affects women of reproductive age, with a female-to-male ratio of 5-10:1, and exhibits significant geographical variation in prevalence and clinical presentation. This comprehensive review aims to provide an in-depth analysis of the complex autoimmune mechanisms underlying Graves' disease pathogenesis and critically evaluate current therapeutic modalities alongside emerging treatment strategies that target specific immunological pathways. A systematic literature review was conducted using PubMed, Scopus, and Web of Science databases, focusing on peer-reviewed articles published between 2010 and 2024. Search terms included "Graves' disease," "hyperthyroidism," "autoimmune thyroid," "TSH receptor antibodies," "immunomodulatory therapy," and "thyroid autoimmunity." Articles were screened for relevance and methodological quality. The pathophysiology involves complex molecular interactions between genetic predisposition (HLA-DR3, CTLA-4 polymorphisms), environmental triggers including iodine excess and stress, and immune system dysregulation. CD11c+ B cells have emerged as novel therapeutic targets, demonstrating strong correlation with serum TRAb levels and disease activity markers. Current treatment modalities include antithyroid drugs (methimazole, propylthiouracil), radioiodine therapy, and surgical thyroidectomy. Emerging therapeutic approaches focus on TRAb-targeting strategies, including novel TSHR antagonists (K1-70) and precision medicine strategies that incorporate detailed immunophenotyping profiles. Recent advances in understanding immune mechanisms have opened promising new therapeutic avenues. TRAb-targeted biologics and personalized precision medicine approaches show significant potential for individualized treatment strategies, potentially improving long-term remission rates and substantially reducing disease recurrence in comprehensive Graves' disease management.

Graphical Abstract

Autoimmune Mechanisms and Treatment Approaches in Graves Disease-Induced Hyperthyroidism: A Comprehensive Review

Keywords

Subjects


OPEN ACCESS

©2026 The author(s). This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit: http://creativecommons.org/licenses/by/4.0/

PUBLISHER NOTE

Sami Publishing Company remains neutral concerning jurisdictional claims in published maps and institutional affiliations.

CURRENT PUBLISHER

Sami Publishing Company

[1]. Hussain, Y.S., Hookham, J.C., Allahabadia, A., Balasubramanian, S.P., Epidemiology, management and outcomes of graves’ disease—real life data. Endocrine, 2017, 56(3), 568-578.
[2]. Majid, S., Graves' disease: Pathophysiology, genetics and management. Graves' Disease, 2021, 67.
[3]. Pokhrel B, Bhusal K. Graves disease. In: StatPearls. Treasure Island (FL): StatPearls Publishing; 2023.
[4]. Stasiak, M., Stasiak, B., Zawadzka-Starczewska, K., Lewiński, A., Significance of hla in graves’ disease and graves’ orbitopathy in asian and caucasian populations–a systematic review. Frontiers in Immunology, 2023, 14, 1256922.
[5]. Bartalena, L., Tanda, M.L., Current concepts regarding graves’ orbitopathy. Journal of Internal Medicine, 2022, 292(5), 692-716.
[6]. Cao, Y., Zhao, X., You, R., Zhang, Y., Qu, C., Huang, Y., Yu, Y., Gong, Y., Cong, T., Zhao, E., Cd11c+ b cells participate in the pathogenesis of graves’ disease by secreting thyroid autoantibodies and cytokines. Frontiers in Immunology, 2022, 13, 836347.
[7]. Diana, T., Olivo, P.D., Kahaly, G.J., Thyrotropin receptor blocking antibodies. Hormone and Metabolic Research, 2018, 50(12), 853-862.
[8]. Kahaly, G.J., Diana, T., Tsh receptor antibody functionality and nomenclature. Frontiers in Endocrinology, 2017, 8, 28.
[9]. Pirahanchi Y, Toro F, Jialal I. Physiology, thyroid stimulating hormone. StatPearls. Treasure Island (FL) 2023.
-Starczewska, K., Tymoniuk, B., Stasiak, B., Lewiński, A., Stasiak, M., Actual associations between hla haplotype and graves’ disease development. Journal of Clinical Medicine, 2022, 11(9), 2492.
[11]. Li, Y., Yao, Y., Yang, M., Shi, L., Li, X., Yang, Y., Zhang, Y., Xiao, C., Association between hla-b* 46 allele and graves disease in asian populations: A meta-analysis. International Journal of Medical Sciences, 2013, 10(2), 164.
[12]. Huang, X., Liu, G., Mei, S., Cai, J., Rao, J., Tang, M., Zhu, T., Chen, W., Peng, S., Wang, Y., Human leucocyte antigen alleles confer susceptibility and progression to graves’ ophthalmopathy in a southern chinese population. British Journal of Ophthalmology, 2021, 105(10), 1462-1468.
[13]. Cheung, Y.K., Cheng, S.H., Chan, E.J., Lo, S.V., Ng, M.H., Kwan, P., Hla‐b alleles associated with severe cutaneous reactions to antiepileptic drugs in h an c hinese. Epilepsia, 2013, 54(7), 1307-1314.
[14]. Hansen, M., Cheever, A., Weber, K.S., O’Neill, K.L., Characterizing the interplay of lymphocytes in graves’ disease. International Journal of Molecular Sciences, 2023, 24(7), 6835.
[15]. Hammad, H., Lambrecht, B.N., The basic immunology of asthma. Cell, 2021, 184(6), 1469-1485.
[16]. Qin, Y., Gao, C., Luo, J., Metabolism characteristics of th17 and regulatory t cells in autoimmune diseases. Frontiers in Immunology, 2022, 13, 828191.
[17]. Bogović Crnčić, T., Girotto, N., Ilić Tomaš, M., Krištofić, I., Klobučar, S., Batičić, L., Ćurko-Cofek, B., Sotošek, V., Innate immunity in autoimmune thyroid disease during pregnancy. International Journal of Molecular Sciences, 2023, 24(20), 15442.
[18]. Yamakawa, H., Kato, T.S., Noh, J.Y., Yuasa, S., Kawamura, A., Fukuda, K., Aizawa, Y., Thyroid hormone plays an important role in cardiac function: From bench to bedside. Frontiers in physiology, 2021, 12, 606931.
[19]. Aoun, T., Danielova Gueorguieva, D., Wu, K.Y., Orbital inflammation in thyroid eye disease: Stress responses and their implications. Stresses, 2024, 4(1), 54-78.
[20]. Van Le, C., Linh, P.N.T., Thi, X.N., Vo, T.T., Pretibial myxedema in grave's disease: A case report and treatment review of the literature. Clinical Case Reports, 2024, 12(2), e8478.
[21]. Abdi, H., Amouzegar, A., Azizi, F., Antithyroid drugs. Iranian Journal of Pharmaceutical Research: IJPR, 2019, 18(Suppl1), 1.
[22]. Awosika AO, Singh G, Correa R. Methimazole. InStatPearls, 2023.
[23]. Kim, H.J., Long-term management of graves disease: A narrative review. Journal of Yeungnam Medical Science, 2023, 40(1), 12-22.
[24]. DeGroot LJ. Diagnosis and treatment of Graves' disease. Endotext. South Dartmouth (MA), 2016.
[25]. Padda IS, Nguyen M. Radioactive iodine therapy. Treasure Island (FL): 2023.
[26]. Ponto, K.A., Zang, S., Kahaly, G.J., The tale of radioiodine and graves' orbitopathy. Thyroid, 2010, 20(7), 785-793.
[27]. Jung, C.-H., Treatment of graves’ disease: Faster remission or longer but safe, that is the question. Endocrinology and Metabolism, 2025, 40(1), 70.
[28]. Biello A, Kinberg EC, Menon G, Wirtz ED. Thyroidectomy. StatPearls. Treasure Island (FL), 2024.
[29]. Lanzolla, G., Sabini, E. News in graves’ orbitopathy: Patients management and treatments. 2023, 14, 1270467.
[30]. Ugradar, S., Malkhasyan, E., Douglas, R.S., Teprotumumab for the treatment of thyroid eye disease. Endocrine Reviews, 2024, 45(6), 843-857.
[31]. Salvi, M., Vannucchi, G., Currò, N., Campi, I., Covelli, D., Dazzi, D., Simonetta, S., Guastella, C., Pignataro, L., Avignone, S., Efficacy of b-cell targeted therapy with rituximab in patients with active moderate to severe graves' orbitopathy: A randomized controlled study. The Journal of Clinical Endocrinology & Metabolism, 2015, 100(2), 422-431.
[32]. Lane, L.C., Cheetham, T.D., Perros, P., Pearce, S.H., New therapeutic horizons for graves’ hyperthyroidism. Endocrine Reviews, 2020, 41(6), 873-884.
[34]. Mozzi, A., Pontremoli, C., Sironi, M., Genetic susceptibility to infectious diseases: Current status and future perspectives from genome-wide approaches. Infection, genetics and evolution, 2018, 66, 286-307.
[35]. Moledina, M., Damato, E.M., Lee, V., The changing landscape of thyroid eye disease: Current clinical advances and future outlook. Eye, 2024, 38(8), 1425-1437.
[36]. Smith, T.J., Hegedüs, L., Graves’ disease. New England Journal of Medicine, 2016, 375(16), 1552-1565.
[37]. Rincon-Arevalo, H., Wiedemann, A., Stefanski, A.-L., Lettau, M., Szelinski, F., Fuchs, S., Frei, A.P., Steinberg, M., Kam-Thong, T., Hatje, K., Deep phenotyping of cd11c+ b cells in systemic autoimmunity and controls. Frontiers in Immunology, 2021, 12, 635615.
[38]. Huber, A., Menconi, F., Corathers, S., Jacobson, E.M., Tomer, Y., Joint genetic susceptibility to type 1 diabetes and autoimmune thyroiditis: From epidemiology to mechanisms. Endocrine Reviews, 2008, 29(6), 697-725.
[39]. Kahaly, G.J., Immunotherapies for thyroid eye disease. Current Opinion in Endocrinology, Diabetes and Obesity, 2019, 26(5), 250-255.
[40]. Ross, D.S., Burch, H.B., Cooper, D.S., Greenlee, M.C., Laurberg, P., Maia, A.L., Rivkees, S.A., Samuels, M., Sosa, J.A., Stan, M.N., 2016 american thyroid association guidelines for diagnosis and management of hyperthyroidism and other causes of thyrotoxicosis. Thyroid, 2016, 26(10), 1343-1421.
[41]. Abraham, P., Avenell, A., McGeoch, S.C., Clark, L.F., Bevan, J.S., Antithyroid drug regimen for treating graves' hyperthyroidism. Cochrane Database of Systematic Reviews, 2010, (1).
[42]. Cooper, D.S., Antithyroid drugs. New England Journal of Medicine, 2005, 352(9), 905-917.
[43]. Association, A.T., Hyperthyroidism, A.A.o.C.E.T.o., Thyrotoxicosis, O.C.o., Bahn, R.S., Burch, H.B., Cooper, D.S., Garber, J.R., Greenlee, M.C., Klein, I., Laurberg, P., McDougall, I.R., Montori, V.M., Hyperthyroidism and other causes of thyrotoxicosis: Management guidelines of the american thyroid association and american association of clinical endocrinologists. Thyroid, 2011, 21(6), 593-646.
[44]. Kim MY, Kim JH, Cho MH, Choi YH, Kim SH, Im YJ, Park K, Kang HG, Chae JH, Cheong HI. Urological problems in patients with Menkes disease. J. Korean Med. Sci. 2019 ;34:e4.
[45]. Razavi CR, Tufano RP, Russell JO. Completion thyroidectomy: what are the risks of waiting? Gland Surg. 2019; 8(Suppl 2): S112-S120.
Volume 14, Issue 1
January and February 2026
Pages 72-89

  • Receive Date 29 May 2025
  • Revise Date 07 August 2025
  • Accept Date 01 September 2025

Article View 35,762
PDF Download 31,050