TSH Receptor

Thyroid autonomy appears as a solitary toxic nodule or toxic multinodular goitre. In toxic thyroid, the nodule s synthesis and secretion of thyroid hormones is autonomous from the thyroid-stimulating hormone (TSH), which is produced in the pituitary gland. Accordingly TSH is suppressed and the extranodular thyroid tissue is functionally downregulated. Thyroid autonomy occurs frequently in iodine-deficient countries, whereas it is much less common in iodine-sufficient areas. Constitu-tively activating mutations in the TSH receptor and in the Gs a protein are the major molecular aetiology of toxic thyroid nodules. 

Thyrotropin (TSH) regulates the production and secretion of thyroid hormones as well as thyroid epithelial cell growth via the TSH receptor. The TSH receptor belongs to the family of G protein-coupled receptors. It is composed of 764 amino acids. The receptor contains a long hydrophilic region orientated towards the exterior of the cell (ectodomain), 7 hydrophobic transmembrane domains and a short cytoplasmic region. 

Patients receiving amiodarone must receive monitoring for thyroid abnormalities. Baseline measurements of serum TSH, FT4, FT3, antithyroid peroxidase antibody (anti-TPOAb) and TSH receptor-stimulating antibodies (TSHR-SAb) should be performed. TSH, FT4, and FT3 should be checked 3 months after initiation of amiodarone and then every 3 to 6 months. 

Mutations that shift the equilibrium toward the constitutively active form will often cause disease. For example, activating mutations in the TSH or LH receptors are responsible for the development of thyroid adenomas and the development of puberty in small children, respectively. In the case of the thyroid adenomas, a normal TSH receptor is expressed in the surrounding normal thyroid tissue. 

Cho, B. 2002. Clinical applications of TSH receptor antibodies in thyroid diseases. Journal of Korean Medical Science 17(3), 293-301. 

Artuii, F., Capula, C., Chiefari, E., Filetti, S., and Russo, D. (1998) Thyroid hyperfunctioning adenomas with and without Gsp/TSH receptor mutations show similar clinical features. Exp. Clin. Endocrinol. Diabetes. 106, 234-236. 

Biebermann, H., Schoneberg, T., Hess, C., Germak, J., Gudermann, T., and Graters, A. (2001) The first activating TSH receptor mutation in transmembrane domain 1 identified in a family with nonautoimmune hyperthyroidism. J. Clin. Endocrinol. Metab. 86, 4429 433. 

Karges, B., Krause, G., Homoki, J., Debatin, K. M., de, R. N., and Karges, W. (2005) TSH receptor mutation V509A causes familial hyperthyroidism by release of interhelical constraints between transmembrane helices TMH3 and TMH5. J. Endocrinol. 186, 311-3S5. 

Opitz R, Maquet E, Zoenen M, Dadhich R, Costagliola S (2011) TSH receptor function is required for normal thyroid differentiation in zebrafish. Mol Endocrinol 25 1579-1599... 

Because lithium affects second-messenger systems involving both activation of adenylyl cyclase and phosphoinositol turnover, it is not surprising that G proteins are also found to be affected. Several studies suggest that lithium may uncouple receptors from their G proteins indeed, two of lithium s most common side effects, polyuria and subclinical hypothyroidism, may be due to uncoupling of the vasopressin and thyroid-stimulating hormone (TSH) receptors from their G proteins. 

TSH receptor-stimulating antibody or thyroid-stimulating immunoglobulin (TSI) < 125% Test not indicated Elevated in Graves disease... 

In Graves disease (see below), lymphocytes secrete a TSH receptor-stimulating antibody (TSH-R Ab [stim]), also known as... 

Congenital (cretinism) Athyreosis or ectopic thyroid, iodine deficiency TSH receptor-blocking antibodies Absent or present Severe... 

Graves disease is considered to be an autoimmune disorder in which helper T lymphocytes stimulate lymphocytes to synthesize antibodies to thyroidal antigens. The antibody described previously (TSH-R Ab [stim]) is directed against the TSH receptor site in the thyroid cell membrane and has the capacity to stimulate growth and biosynthetic activity of the thyroid cell. Spontaneous remission occurs but some patients require years of antithyroid therapy. 

While this pattern of biochemistry does not exclude transient relapse of Graves hyperthyroidism (despite the finding of negative TSH receptor antibodies), or a transient thyroiditis, the authors speculated that indinavir (prescribed in this patient together with stavudine and lamivudine) had inhibited the glucuronidation of thyroxine and hence caused a rise in serum thyroid hormone concentrations. 

In five patients who presented in Tasmania during 1 year, all of whom were taking amiodarone 200 mg/day, serum TSH was undetectable and the free thyroxine and triiodothyronine concentrations were raised (46). In one case there was a low titer of TSH receptor antibodies and in another a high titer of antithyroid peroxidase antibodies. In all cases the hyperthyroidism was severe and occurred after at least 2 years of treatment with amiodarone. In one of two patients in whom it was measured the serum concentration of interleukin-6 was raised, as has been previously shown (SEDA-19, 193). In two cases the hyperthyroidism was refractory to treatment with propylthiouracil, lithium, and dexamethasone in these cases thyroidectomy was required. Two patients responded to propylthiouracil, lithium, and dexamethasone, and one responded to carbimazole. 

Thyrotropin alpha has the biologic properties of pituitary TSH. It binds to TSH receptors on both normal thyroid and differentiated thyroid cancer cells. The TSH-activated receptor stimulates intracellular adenylyl cyclase activity. Increased cAMP production causes increased iodine uptake and increased production of thyroid hormones and thyroglobulin. 

Hypothyroidism, known as myxedema in adults, when severe, is the most common disorder of the thyroid gland. Worldwide, hypothyroidism is most often the result of endemic iodine deficiency. In nonendemic areas, where iodine is sufficient in the diet, chronic autoimmune thyroiditis (Hashimoto s thyroiditis) accounts for the majority of cases. This disorder is primarily characterized by high levels of circulating antibodies against a key enzyme (thyroid peroxidase) in the processing of iodine in the thyroid gland. Blocking antibodies directed at the TSH receptor may also be present. Thyroid destruction may also occur via apoptotic cell death. 

The leading cause of Graves disease occurs when there is a defect in the immune system that causes the production of autoantibodies to TSH receptors located on the surface of thyroid cells. These antibodies act as agonists to stimulate the thyroid, causing it to enlarge (goiter formation), with the overproduction of thyroid hormones... 

Recombinant human thyroid stimulating hormone TSH receptors... 

---