[Molecular endocrinology of thyroid diseases]

Over the last decade it has become possible to investigate the molecular basis of functional and neoplastic thyroid diseases, leading to the elucidation of various genetic defects at the level of the pituitary, thyroid and target organs. Mutations in either the pituitary-specific transcription factor Pit-1 or its target gene, TSH beta, lead to rare forms of hereditary congenital hypothyroidism. However, somatic mutations in thyroid epithelial cells causing an increase in hormone production and/or cellular proliferation are much more frequent. Nearly 50% of all toxic adenomas were shown to harbour activating mutations in either the TSH-receptor or certain G-proteins. In contrast, follicular and papillary thyroid malignancies are associated with mutations in the ras and ret genes respectively. Intriguingly, different mutations and rearrangements in the ret gene were shown to cause medullary thyroid cancer and MEN2 as well as to be specifically associated with papillary thyroid cancer. In contrast, mutations in thyroid-specific genes, such as thyroid peroxidase and thyroglobulin, causing congenital hypothyroidism are extremely rare. Besides the molecular abnormalities at the pituitary and thyroidal level leading to altered hormone secretion, genetic defects impairing thyroid hormone action at the target level also occur. Specifically, mutations in one of the thyroid hormone receptor genes (the proto-oncogene c-erbA beta) were shown to cause the autosomal dominant syndrome of resistance to thyroid hormone. The quest for a better understanding of the molecular defects in the pituitary-thyroid axis has led to the cloning of some of the key proteins, which can now be used for diagnostic purposes in vivo and in vitro. The use of recombinant thyroid peroxidase and TSH-receptor proteins has made possible the development of more sensitive and specific in vitro assays for autoantibodies. In addition, recombinant TSH was recently shown to be effective in stimulating radioiodine uptake in patients with residual differentiated thyroid cancer who remained on suppressive thyroid hormone therapy. Recombinant human TSH may therefore become a convenient diagnostic tool in the follow-up of patients with thyroid cancer by allowing for thyroglobulin measurements and radioiodine scanning without the need for the patient to become hypothyroid.