Serum Thyroglobulin and Thyroid Cancer

Abstract

Thyroglobulin is a large glycosylated protein (MW 660000 daltons) which is synthesised and secreted by the thyroid cell into the follicular lumen. In the thyroglobulin molecule the iodotyrosines undergo oxidative coupling to form the iodothyronines thyroxine (T4) and triiodothyronine (T3). Production of thyroid hormones results from micropinocytosis of iodinated thyroglobulin from the colloid into the thyroid cell and its hydrolysis by lysosymal enzymes. The resulting T4 and T3 diffuse across the basal membrane into the blood stream whilst iodotyrosines are de-iodinated and the iodine recycled. Thyroglobulin thus acts as the template for thyroid hormone synthesis and a storage form of inactive thyroid hormones and iodine. Thyroid function and activity are under the positive control of thyrotrophin (TSH) which stimulates many steps of thyroid cell metabolism including protein synthesis, iodothyronine synthesis, thyroglobulin secretion into the follicular lumen, and replacement of micropinocytosis of thyroglobulin by massive colloid macropinocytosis [1]. The action of TSH on the thyroid cell is mediated via adenylate cyclase activation and recent work has shown that transcription of the thyroglobulin gene is regulated by cyclic AMP [2]. For many years thyroglobulin was thought to be confined to the thyroid gland but the sensitive radioimmunoassays now available have demonstrated that the protein is unequivocally present in the peripheral circulation of man. It is assumed that some of the protein escapes the potent lysosymal mechanism of the thyroid gland and crosses the basal membrane with the thyroid hormones to appear intact in the circulation. The first radioimmunoassays for thyroglobulin in human, monkey and rat serum were reported in 1967 [3]. A wide variation in the normal range of human serum thyroglobulin levels has been reported but a recent international co-operative study evaluating serum thyroglobulin standards has shown this to be due to remarkable interlaboratory variations [4]. No age-related variation of thyroglobulin levels has been reported (except in children) although several studies have reported higher values in women than men, higher values in pregnant women at delivery than non-pregnant controls, and elevated thyroglobulin levels in cord blood from newborn infants. Serum concentrations in man appear to be closely regulated within a narrow range suggesting a mechanism for controlling thyroglobulin release. Thyroid hormone administration suppresses thyroglobulin levels and after injection of thyrotrophin releasing hormone, TSH or thyroid stimulating immunoglobulins, the levels of serum thyroglobulin rise. The data support the concept that thyroglobulin is a normal secretory product of the thyroid gland under the control of TSH, but the mechanism of this 'secretion1, rather than simple diffusion, remains unknown [3].