TL;DR: This review considers recent developments in the understanding of the properties of TRAb, particularly measurement of the antibodies and their sites of action and synthesis and indicates that TSH receptor antibodies nearly always act as TSH agonists in patients with a history of Graves' hyperthyroidism.
Abstract: This review considers recent developments in our understanding of the properties of TRAb, particularly measurement of the antibodies and their sites of action and synthesis. Two new assay methods have allowed considerable improvements in the sensitivity, specificity, precision, and ease of measuring TRAb. In particular: 1) receptor assays based on inhibition of receptor-purified labeled TSH binding to detergent-solubilized TSH receptors and 2) bioassays based on stimulation of cAMP release from monolayer cultures of isolated thyroid cells. Detailed studies with the two assays indicate that TSH receptor antibodies nearly always act as TSH agonists in patients with a history of Graves' hyperthyroidism. Studies in areas of dietary iodine sufficiency suggest that measurement of the antibodies at various stages in the course of treating Graves' disease can be of value in predicting the outcome of therapy. However, in areas of iodine deficiency, difficulties in the ability of patients' thyroid tissue to recover from the effects of antithyroid drugs may prevent the receptor antibodies from causing a relapse of thyrotoxicosis. Consequently, the predictive value of receptor antibody measurements would be expected to be lower in these geographical areas. Although patients with a history of Graves' hyperthyroidism nearly always have TRAb which act as TSH agonists, about 20% of patients with frank hypothyroidism due to autoimmune destruction of the thyroid have TRAb which act as TSH antagonists (blocking antibodies). There is some evidence that these blocking antibodies can cause hypothyroidism particularly in the neonate. With regard to the site of synthesis of TRAb, there is now direct evidence that they are synthesized by thyroid lymphocytes, particularly the lymphocytes in close proximity to thyroid follicular cells. This is consistent with the well established effects of antithyroid treatment (drugs, radioiodine, or surgery) on TRAb levels in addition to their effects on thyroid hormone synthesis. Recent studies using affinity labeling with 125I-labeled TSH have enabled elucidation of the structure of the TSH receptor. TSH receptors in human, porcine, and guinea pig thyroid tissue have a two-chain structure in which the TSH binding site is formed on the outside surface of the cell membrane by a water-soluble A subunit (Mr approximately 50 K). The A subunit is linked by a disulfide bridge and weak noncovalent bonds to the amphiphilic B subunit (Mr approximately 30 K). This subunit, which penetrates the lipid bilayer, probably forms the site for interaction of the receptor with the regulatory subunits of adenylate cyclase.(ABSTRACT TRUNCATED AT 400 WORDS)
TL;DR: The majority of patients with Graves' disease gradually enter remission of TSH-receptor autoimmunity during medical or after surgical therapy, with no difference between the types of therapy.
Abstract: Introduction: Autoimmunity against the TSH receptor is a key pathogenic element in Graves’ disease. The autoimmune aberration may be modified by therapy of the hyperthyroidism. Objective: To compare the effects of the common types of therapy for Graves’ hyperthyroidism on TSHreceptor autoimmunity. Methods: Patients with newly diagnosed Graves’ hyperthyroidism aged 20–55 years were randomized to medical therapy, thyroid surgery, or radioiodine therapy (radioiodine was only given to patients R35 years of age). L-thyroxine (L-T4) was added to therapy as appropriate to keep patients euthyroid. Anti-thyroid drugs were withdrawn after 18 months of therapy. TSH-receptor antibodies (TRAb) in serum were measured before and for 5 years after the initiation of therapy. Results: Medical therapy (nZ48) and surgery (nZ47) were followed by a gradual decrease in TRAb in serum, with the disappearance of TRAb in 70–80% of the patients after 18 months. Radioiodine therapy (nZ36) led to a 1-year long worsening of autoimmunity against the TSH receptor, and the number of patients entering remission of TSH-receptor autoimmunity with the disappearance of TRAb from serum during the following years was considerably lower than with the other types of therapy. Conclusion: The majority of patients with Graves’ disease gradually enter remission of TSH-receptor autoimmunity during medical or after surgical therapy, with no difference between the types of therapy. Remission of TSH-receptor autoimmunity after radioiodine therapy is less common.
TL;DR: Age at onset of hyperthyroidism, goiter size and TRAb level are particularly helpful in identifying those patients who are more prone to undergo a remission of hyper thyroidroidism after medical treatment and may be useful to select the minority of Graves' patients who will benefit from antithyroid drug treatment as a first choice.
Abstract: The clinical course of 306 Graves' patients treated with methimazole (MMI) was reviewed with the aim of establishing criteria able to predict remission of hyperthyroidism after medical treatment. One hundred and ninety-four (149 females, 45 males) of 306 (63.4%) patients had relapse of hyperthyroidism after antithyroid drug (ATD) withdrawal. Relapse was more frequent during the first months of the follow-up, but still it was observed 3 years after MMI withdrawal. The relapse rate was dependent on the age of the patient, the size of goiter, and the level of TSH-receptor antibody (TRAb) at diagnosis, being observed in 40 of 47 (85%) patients with high (> 30 U/L) TRAb level and in 54 of 101 (53%) patients with low TRAb level ( 40 mL and high TRAb levels (9%). In the subgroup of patients with the combination: goiter 40 years, the remission rate was 80%, and all relapses occurred within the first 9 months after MMI withdrawal. In conclusion, our study confirms that hyperthyroidism relapses in the majority of patients with Graves' disease treated with ATD. Among different clinical and laboratory features, age at onset of hyperthyroidism, goiter size and TRAb level are particularly helpful in identifying those patients who are more prone to undergo a remission of hyperthyroidism after medical treatment and may be useful to select the minority of Graves' patients who will benefit from antithyroid drug treatment as a first choice.
TL;DR: Measurements of serum levels of TRAb and thyroid ultrasonography represent the most important diagnostic tests for Graves disease, and novel agents that might act on the disease process are currently under evaluation in preclinical or clinical studies, but evidence of their efficacy and safety is lacking.
Abstract: Graves disease is an autoimmune disorder characterized by goitre, hyperthyroidism and, in 25% of patients, Graves ophthalmopathy. The hyperthyroidism is caused by thyroid hypertrophy and stimulation of function, resulting from interaction of anti-TSH-receptor antibodies (TRAb) with the TSH receptor on thyroid follicular cells. Measurements of serum levels of TRAb and thyroid ultrasonography represent the most important diagnostic tests for Graves disease. Management of the condition currently relies on antithyroid drugs, which mainly inhibit thyroid hormone synthesis, or ablative treatments ((131)I-radiotherapy or thyroidectomy) that remove or decrease thyroid tissue. None of these treatments targets the disease process, and patients with treated Graves disease consequently experience either a high rate of recurrence, if receiving antithyroid drugs, or lifelong hypothyroidism, after ablative therapy. Geographical differences in the use of these therapies exist, partially owing to the availability of skilled thyroid surgeons and suitable nuclear medicine units. Novel agents that might act on the disease process are currently under evaluation in preclinical or clinical studies, but evidence of their efficacy and safety is lacking.
TL;DR: There is evidence that in some patients the lack of goiter is associated with the presence in the blood of an antibody that inhibits the binding of TSH to its receptor, which prevents TSH from stimulating the thyroid and constitutes an acceptable explanation for an agoitrous state.
Abstract: Autoimmune thyroid disease is a generic term that includes Graves' disease and Hashimoto's thyroiditis. In the former, there is overactivity of the thyroid due to the action of a thyroid-stimulating antibody (TSAb). Pathogenesis of Hashimoto's thyroiditis is largely cell-mediated immune destruction of the thyroid. Nonetheless, there may be either a goiter or an atrophic gland. There is evidence that in some patients the lack of goiter is associated with the presence in the blood of an antibody that inhibits the binding of TSH to its receptor. This TSH-binding inhibiting antibody (TBIAb), therefore, prevents TSH from stimulating the thyroid and constitutes an acceptable explanation for an agoitrous state. Collectively, TSAb and TBIAb, both of which are IgG, are known as TSH receptor antibodies (TRAb).