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Pathogenesis of Graves' disease

Author
Terry F Davies, MD, FRCP, FACE
Section Editor
Douglas S Ross, MD
Deputy Editor
Jean E Mulder, MD

INTRODUCTION

Graves' disease is a syndrome that may consist of hyperthyroidism, goiter, eye disease (orbitopathy), and occasionally a dermopathy referred to as pretibial or localized myxedema. The terms Graves' disease and hyperthyroidism are not synonymous, because some patients may have orbitopathy but no hyperthyroidism, and there are many other causes of hyperthyroidism in addition to Graves' disease.

Hyperthyroidism is the most common feature of Graves' disease, affecting nearly all patients, and is caused by autoantibodies to the thyrotropin receptor (TRAb) that activate the receptor, thereby stimulating thyroid hormone synthesis and secretion as well as thyroid growth (causing a diffuse goiter). The presence of TRAb in serum and orbitopathy on clinical examination distinguishes the disorder from other causes of hyperthyroidism. Other causes of an overactive thyroid gland are discussed separately. (See "Disorders that cause hyperthyroidism".)

This topic will review the immune pathogenesis of Graves' thyroid disease, with emphasis on the role of B and T cells in the production of the TRAb that are responsible for the thyroid stimulation and growth. The pathogenesis of Graves' orbitopathy and dermopathy are reviewed separately. (See "Pathogenesis and clinical features of Graves' ophthalmopathy (orbitopathy)" and "Pretibial myxedema (thyroid dermopathy) in autoimmune thyroid disease".)

The TSH receptor — In Graves's disease, the main autoantigen is the thyroid-stimulating hormone (TSH) receptor (TSHR) which is expressed primarily in the thyroid but also in adipocytes, fibroblasts, bone cells, and a variety of additional sites [1,2]. This antigen has been reviewed extensively elsewhere (figure 1) [1,2]. The TSHR is a G-protein coupled receptor with seven transmembrane-spanning domains. TSH, acting via the TSHR, regulates thyroid growth and thyroid hormone production and secretion. The TSHR undergoes complex post-translational processing involving dimerization and intramolecular cleavage; the latter modification leaves a two-subunit structural form of the receptor. Data suggest that there is eventual shedding or degradation of the TSHR ectodomain [3], although this has not been demonstrated in vivo. Each of these post-translational events may influence the antigenicity of the receptor. However, factors that contribute to TSHR presentation as a target for the immune system in humans are not well understood, but are considered to be primarily factors that build on a state of enhanced genetic susceptibility. Such susceptibility may be translated by variable expression of the TSHR on thymic epithelial cells, which is of great importance in determining self-tolerance [4,5].

The thyroid gland in Graves' disease — The thyroid is usually, but not always, diffusely enlarged. The histology of the thyroid gland in patients with Graves' hyperthyroidism is characterized by follicular hyperplasia, intracellular colloid droplets, cell scalloping, a reduction in follicular colloid, and a patchy (multifocal) lymphocytic infiltration. Only rarely are lymphoid germinal centers seen. The histological picture may be greatly influenced by pretreatment with antithyroid drugs (picture 1). The majority of intrathyroidal lymphocytes are T cells but plenty of B cells may be present, though nothing like that seen in chronic autoimmune thyroiditis (Hashimoto's disease). In some areas, thyroid epithelial cell size correlates with the intensity of the lymphocytic infiltrate, suggesting thyroid-cell stimulation by local B cells secreting stimulating TRAb [6].

                         

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Literature review current through: Nov 2016. | This topic last updated: Thu Nov 19 00:00:00 GMT+00:00 2015.
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