Graves disease

The diffusely enlarged thyroid gland detected clinically or by radioisotope scan in conjunction with the presence of ophthalmopathy, and less commonly changes in the skin on the front of the legs (predbial myxedema) and in the nails (thyroid acropachy), allows the diagnosis of Graves' disease to be made confidently in a patient presenting with hyperthyroidism. It is the commonest cause of hyperthyroidism in the UK accounting for 75% of the cases seen.

The disease is due to autoantibodies to the TSH receptor. Historically these antibodies have proved a source of great confusion since a wide variety of assay systems for their detection have been developed and have resulted in a wide variety of terms being used to describe the activity detected. The antibodies are unique in that not only do they bind to the TSH receptor but they are also able to stimulate thyroid function and thus themselves induce hyperthyroidism, acting through the adenylate cyclase second messenger system. Assays to detect these activities are therefore able to detect binding of these autoantibodies to the TSH receptor (radioreceptor assay) or measure the ability of the antibodies to stimulate thyroid cell function (bioassay). In the radioreceptor assay measurement is made of the ability of antibodies to inhibit the binding of radiolabeled TSH to a thyroid membrane preparation. Bioassays, using predominantly human thyroid cells in primary culture or the rat FRTL5 thyroid cell line, measure end-points of cell activation which are mediated via the TSH receptor. With the increased sensitivity of the assay systems TSH receptor antibody activity is detectable in the vast majority of patients with Graves' disease when they first present with hyperthyroidism. In responses to treatment the antibody activity falls and failure of the antibody to disappear in response to treatment makes disease recurrence almost certain. The antibody does therefore seem to correlate fairly closely with disease activity.

The best evidence, however, that the antibody is indeed pathogenetic comes from studies in the offspring of mothers with Graves' disease. TSH receptor antibodies are of the immunoglobulin G1 (IgGl) class and therefore cross the placenta. When the level of antibody is high enough in the mother it will, by crossing the placenta, induce hyperthyroidism in the fetus and newborn which lasts as long as the antibody is present at sufficient concentration in the neonate (6-8 weeks).

In addition to autoantibodies which stimulate thyroid cell function, it is now also clear that autoanti bodies exist which, by binding to the TSH receptor, inhibit thyroid cell function. These TSH receptor blocking antibodies (TSHRBAb) can also be detected by the radioreceptor assay, but this assay does not itself distinguish between stimulating and blocking TSH receptor antibodies. However, a modification of the bioassay can be used to examine the ability of these antibodies to inhibit TSH-induced cyclic AMP production by thyroid cells.

Yet another group of antibodies have been described which rather than acting to stimulate or block thyroid function, are involved in inducing or inhibiting thyroid growth. Considerable controversy surrounds these antibody activities: Are the assay systems measuring parameters of growth reliable? Are the effects mediated via the TSH receptor? Is there any difference between TSH receptor-stimulating antibodies and thyroid growth stimulating antibodies? The answers are not yet available.

What is not in doubt is the fact that the spectrum of clinical presentations of AITDs with changes in both thyroid gland function and size occurring not only in different individuals but also in the same individual points to the presence of a spectrum of autoantibodies acting as agonists and antagonists and able to influence both thyroid cell function and growth. With the cloning of the TSH receptor clear characterization of the antibodies binding to it and the different epitopes of the receptor recognized by these antibodies will very soon confirm or refute the presence of antibodies which stimulate and block both thyroid function and growth.

The cloning in 1989 of the TSH receptor by the groups of Vassart and Rapoport has provided a major impetus to the work on Graves' disease. The receptor consists of a single polypeptide of 764 residues which, in keeping with other G protein-coupled receptors traverses the cell surface membrane seven times. The extracellular part of the receptor comprises 395 residues and that this is the region involved in the interaction with the glycoprotein hormone TSH and with TSH receptor antibodies has been confirmed with expression of the recombinant protein in eukaryotic cells. The field is moving rapidly; B cell epitopes are being defined and T cell epitopes will follow. Elucidation of the interaction of the spectrum of autoantibodies to the TSH receptor with the receptor is at hand.

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