Thyroglobulin (Tg) is a 660 kDa, dimericglycoprotein produced by the follicular cells of the thyroid and used entirely within the thyroid gland. Tg is secreted and accumulated at hundreds of grams per litre in the extracellular compartment of the thyroid follicles, accounting for approximately half of the protein content of the thyroid gland.[5] Human TG (hTG) is a homodimer of subunits each containing 2768 amino acids as synthesized (a short signal peptide of 19 amino acids may be removed from the N-terminus in the mature protein).[6]
Thyroglobulin is in all vertebrates the main precursor to thyroid hormones, which are produced when thyroglobulin's tyrosine residues are combined with iodine and the protein is subsequently cleaved. Each thyroglobulin molecule contains approximately 16 tyrosine residues, but only a small number 10 of these are subject to iodination by thyroperoxidase in the follicular colloid. Therefore, each Tg molecule forms approximately 10 thyroid hormone molecules.[5]
Thyroglobulin (Tg) acts as a substrate for the synthesis of the thyroid hormonesthyroxine (T4) and triiodothyronine (T3), as well as the storage of the inactive forms of thyroid hormone and iodine within the follicular lumen of a thyroid follicle.[7]
Newly synthesized thyroid hormones (T3 and T4) are attached to thyroglobulin and comprise the colloid within the follicle. When stimulated by thyroid stimulating hormone (TSH), the colloid is endocytosed from the follicular lumen into the surrounding thyroid follicular epithelial cells. The colloid is subsequently cleaved by proteases to release thyroglobulin from its T3 and T4 attachments.[8]
The active forms of thyroid hormone: T3 and T4, are then released into circulation where they are either unbound or attached to plasma proteins, and thyroglobulin is recycled back into the follicular lumen where it can continue to serve as a substrate for thyroid hormone synthesis.[8]
Clinical significance
Half-life and clinical elevation
Metabolism of thyroglobulin occurs in the liver via thyroid gland recycling of the protein. Circulating thyroglobulin has a half-life of 65 hours. Following thyroidectomy, it may take many weeks before thyroglobulin levels become undetectable. Thyroglobulin levels may be tested regularly for a few weeks or months following the removal of the thyroid.[9] After thyroglobulin levels become undetectable (following thyroidectomy), levels can be serially monitored in follow-up of patients with papillary or follicular thyroid carcinoma.[clarification needed]
A subsequent elevation of the thyroglobulin level is an indication of recurrence of papillary or follicular thyroid carcinoma. In other words, a rise in thyroglobulin levels in the blood may be a sign that thyroid cancer cells are growing and/or the cancer is spreading.[9] Hence, thyroglobulin levels in the blood are mainly used as a tumor marker[10][9] for certain kinds of thyroid cancer (particularly papillary or follicular thyroid cancer). Thyroglobulin is not produced by medullary or anaplastic thyroid carcinoma.
Thyroglobulin levels are tested via a simple blood test. Tests are often ordered after thyroid cancer treatment.[9]
Thyroglobulin antibodies
In the clinical laboratory, thyroglobulin testing can be complicated by the presence of anti-thyroglobulin antibodies (ATAs, alternatively referred to as TgAb). Anti-thyroglobulin antibodies are present in 1 in 10 normal individuals, and a greater percentage of patients with thyroid carcinoma. The presence of these antibodies can result in falsely low (or rarely falsely high) levels of reported thyroglobulin, a problem that can be somewhat circumvented by concomitant testing for the presence of ATAs. The ideal strategy for a clinician's interpretation and management of patient care in the event of confounding detection of ATAs is testing to follow serial quantitative measurements (rather than a single laboratory measurement).
ATAs are often found in patients with Hashimoto's thyroiditis or Graves' disease. Their presence is of limited use in the diagnosis of these diseases, since they may also be present in healthy euthyroid individuals. ATAs are also found in patients with Hashimoto's encephalopathy, a neuroendocrine disorder related to—but not caused by—Hashimoto's thyroiditis.[11]
^Ferracci F, Moretto G, Candeago RM, Cimini N, Conte F, Gentile M, et al. (February 2003). "Antithyroid antibodies in the CSF: their role in the pathogenesis of Hashimoto's encephalopathy". Neurology. 60 (4): 712–714. doi:10.1212/01.wnl.0000048660.71390.c6. PMID12601119. S2CID21610036.
^Delom F, Lejeune PJ, Vinet L, Carayon P, Mallet B (February 1999). "Involvement of oxidative reactions and extracellular protein chaperones in the rescue of misassembled thyroglobulin in the follicular lumen". Biochemical and Biophysical Research Communications. 255 (2): 438–443. doi:10.1006/bbrc.1999.0229. PMID10049727.
Henry M, Zanelli E, Piechaczyk M, Pau B, Malthièry Y (February 1992). "A major human thyroglobulin epitope defined with monoclonal antibodies is mainly recognized by human autoantibodies". European Journal of Immunology. 22 (2): 315–319. doi:10.1002/eji.1830220205. PMID1371467. S2CID38620713.
Targovnik HM, Cochaux P, Corach D, Vassart G (March 1992). "Identification of a minor Tg mRNA transcript in RNA from normal and goitrous thyroids". Molecular and Cellular Endocrinology. 84 (1–2): R23–R26. doi:10.1016/0303-7207(92)90087-M. PMID1639210. S2CID35326294.
Kubak BM, Potempa LA, Anderson B, Mahklouf S, Venegas M, Gewurz H, Gewurz AT (September 1988). "Evidence that serum amyloid P component binds to mannose-terminated sequences of polysaccharides and glycoproteins". Molecular Immunology. 25 (9): 851–858. doi:10.1016/0161-5890(88)90121-6. PMID3211159.
Malthiéry Y, Lissitzky S (June 1987). "Primary structure of human thyroglobulin deduced from the sequence of its 8448-base complementary DNA". European Journal of Biochemistry. 165 (3): 491–498. doi:10.1111/j.1432-1033.1987.tb11466.x. PMID3595599. S2CID24724872.
Parma J, Christophe D, Pohl V, Vassart G (August 1987). "Structural organization of the 5' region of the thyroglobulin gene. Evidence for intron loss and "exonization" during evolution". Journal of Molecular Biology. 196 (4): 769–779. doi:10.1016/0022-2836(87)90403-7. PMID3681978.
Bergé-Lefranc JL, Cartouzou G, Mattéi MG, Passage E, Malezet-Desmoulins C, Lissitzky S (1985). "Localization of the thyroglobulin gene by in situ hybridization to human chromosomes". Human Genetics. 69 (1): 28–31. doi:10.1007/BF00295525. PMID3967888. S2CID9234835.
Avvedimento VE, Di Lauro R, Monticelli A, Bernardi F, Patracchini P, Calzolari E, et al. (1985). "Mapping of human thyroglobulin gene on the long arm of chromosome 8 by in situ hybridization". Human Genetics. 71 (2): 163–166. doi:10.1007/BF00283375. PMID4043966. S2CID28315029.
Xiao S, Pollock HG, Taurog A, Rawitch AB (June 1995). "Characterization of hormonogenic sites in an N-terminal, cyanogen bromide fragment of human thyroglobulin". Archives of Biochemistry and Biophysics. 320 (1): 96–105. doi:10.1006/abbi.1995.1346. PMID7793989.
Corral J, Martín C, Pérez R, Sánchez I, Mories MT, San Millan JL, et al. (February 1993). "Thyroglobulin gene point mutation associated with non-endemic simple goitre". Lancet. 341 (8843): 462–464. doi:10.1016/0140-6736(93)90209-Y. PMID8094490. S2CID34165624.
Yang SX, Pollock HG, Rawitch AB (March 1996). "Glycosylation in human thyroglobulin: location of the N-linked oligosaccharide units and comparison with bovine thyroglobulin". Archives of Biochemistry and Biophysics. 327 (1): 61–70. doi:10.1006/abbi.1996.0093. PMID8615697.
