Enfermedad de draves

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The Ne w E n g l a nd Jo u r n a l o f Me d ic i ne

Review Article

Medical Progress


tration is often present, occasionally resulting in the formation of germinal centers. These intrathyroidal lymphocytes are a major source of autoantibodies, with contributions from the cervical lymph nodes and bone marrow.7 Antithyroid drugsameliorate the histologic changes.8
Autoimmunity to the Thyrotropin Receptor


OBERT Graves first identified the association of goiter, palpitations, and exophthalmos in 1835, although Caleb Parry had published details of a case 10 years earlier. The discovery of a thyroid-stimulating factor that was not thyrotropin in the serum of patients with Graves’ hyperthyroidism1 was followed by theidentification of this stimulator as an IgG antibody.2 It is now clear that Graves’ hyperthyroidism is caused by these thyroid-stimulating antibodies, which bind to and activate the thyrotropin receptor on thyroid cells.3 Graves’ disease also affects the eyes (Graves’ ophthalmopathy) and the skin (localized dermopathy or myxedema), but the causes of these less common components of the disease are notknown.

Graves’ disease shares many immunologic features with autoimmune hypothyroidism, including high serum concentrations of antibodies against thyroglobulin, thyroid peroxidase, and possibly the sodium– iodide cotransporter in thyroid tissue.4 The serum concentrations of these antibodies vary among patients, and the antibodies themselves may modify the stimulatory effects ofthyroid-stimulating antibodies. In some patients, the simultaneous production of antibodies that block the thyrotropin receptor reduces the stimulatory action of thyroid-stimulating antibodies. For these reasons there is no direct correlation between serum concentrations of thyroid-stimulating antibodies and serum thyroid hormone concentrations in patients with Graves’ hyperthyroidism.5 Thethyroid-stimulating antibodies cause not only thyroid hypersecretion but also hypertrophy and hyperplasia of the thyroid follicles, which have a columnar and folded epithelium and little colloid.6 The result is the characteristic diffuse goiter (Fig. 1A). Lymphocytic infil-

The thyrotropin receptor is a member of the family of G protein–coupled receptors.9 The mechanism by which thyroid-stimulatingantibodies bind to and activate the thyrotropin receptor is not known,10 but studies with mutated receptors and thyrotropin-receptor sequences have revealed that thyroid-stimulating antibodies bind to conformational epitopes in the extracellular domain of the thyrotropin receptor. These epitopes make up discontinuous segments that overlap the binding site for thyrotropin.11,12 The production ofthyroid-stimulating antibodies is dependent on T cells, and circulating T cells recognize multiple epitopes of the thyrotropin receptor.13 Although thyroid-stimulating antibodies cause Graves’ hyperthyroidism, the serum antibody concentrations are very low11 and are even undetectable in a few patients. The most likely reason for this finding is assay insensitivity, exclusively intrathyroidal production ofthe antibodies, or misdiagnosis (for example, when the patient actually has familial nonautoimmune hyperthyroidism). The hyperthyroidism and goiter are caused primarily by the ability of the thyroid-stimulating antibodies to increase the production of intracellular cyclic AMP. Some of these antibodies also activate phospholipase A2, and antibodies with this activity may be especiallygoitrogenic.14
The Role of Thyroid Cells

From the University of Sheffield Division of Clinical Sciences, Clinical Sciences Centre, Northern General Hospital, Sheffield S5 7AU, United Kingdom, where reprint requests should be addressed to Dr. Weetman. ©2000, Massachusetts Medical Society.

In Graves’ disease, thyroid cells not only are sources of thyroid antigens and the target of thyroid-stimulating...
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