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Thyroglobulin

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Not to be confused with thyroxine-binding globulin, or thymoglobulin.
TG
Identifiers
AliasesTG, AITD3, TGN, thyroglobulin
External IDsOMIM: 188450; MGI: 98733; HomoloGene: 2430; GeneCards: TG; OMA:TG - orthologs
Orthologs
SpeciesHumanMouse
Entrez

7038

21819

Ensembl

ENSG00000042832

ENSMUSG00000053469

UniProt

P01266

O08710

RefSeq (mRNA)

NM_003235

NM_009375

RefSeq (protein)

NP_003226

NP_033401

Location (UCSC)Chr 8: 132.87 – 133.13 MbChr 15: 66.54 – 66.72 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Thyroglobulin (Tg) is a 660 kDa, dimeric glycoprotein 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 around 10 of these are subject to iodination by thyroperoxidase in the follicular colloid. It takes two iodinated tyrosines to make a thyroid hormone molecule; therefore, each Tg molecule forms approximately 5 thyroid hormone molecules.[5]

Function

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Thyroid hormone synthesis, this image traces thyroglobulin from production within the rough endoplasmic reticulum until proteolytic release of the thyroid hormones.

Thyroglobulin (Tg) acts as a substrate for the synthesis of the thyroid hormones thyroxine (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) exist as prohormonal modified tyrosine residues of thyroglobulin, which comprise the colloid within the follicle.[8] When stimulated by thyroid stimulating hormone (TSH), the colloid of the follicular lumen is endocytosed into the surrounding thyroid follicular epithelial cells. When endosomes fuse with lysosomes in these cells, Tg is subsequently cleaved by proteases to release thyroglobulin from its T3 and T4 attachments.[9]

Because of the hydrophobic nature of T3 and T4, they are able to then diffuse across the lysosomal membrane and into the cytoplasm. The active forms of thyroid hormone (T3 and T4), are then released into circulation where they are either unbound or attached to plasma proteins.[10] Iodine is recycled back into the follicular lumen where it can continue to serve as a substrate for thyroid hormone synthesis, while the non-modified residues of Tg reenter cellular metabolic pathways.[9]

Clinical significance

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Half-life and clinical elevation

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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.[11] After thyroglobulin levels become undetectable (following thyroidectomy), levels can be serially monitored in follow-up of patients with papillary or follicular thyroid carcinoma.[12]

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.[11] Hence, thyroglobulin levels in the blood are mainly used as a tumor marker[13][11] 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 blood tests including immunoassays and highly-sensitive thyroglobulin (hsTg) assays.[14] These tests are often ordered after thyroid cancer treatment.[11]

Thyroglobulin antibodies

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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.[15]

Interactions

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Thyroglobulin has been shown to interact with Binding immunoglobulin protein.[16][17]

References

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  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000042832 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000053469 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ a b Boron WF (2003). Medical Physiology: A Cellular And Molecular Approach. Elsevier/Saunders. p. 1044. ISBN 1-4160-2328-3.
  6. ^ "Protein" thyroglobulin precursor [Homo sapiens]". National Center for Biotechnology Information, U.S. National Library of Medicine.
  7. ^ "TG thyroglobulin [Homo sapiens (human)] – Gene – NCBI". National Center for Biotechnology Information (NCBI). Retrieved 2019-09-16.
  8. ^ Tosatto L, Coscia F (2022-06-01). "A glance at post-translational modifications of human thyroglobulin: potential impact on function and pathogenesis". European Thyroid Journal. 11 (3). doi:10.1530/ETJ-22-0046. PMC 9254275. PMID 35544053.{{cite journal}}: CS1 maint: PMC format (link)
  9. ^ a b Rousset BL, Dupuy C, Miot F, Dumont J (2000). "Chapter 2 Thyroid Hormone Synthesis and Secretion". In Feingold KR, Anawalt B, Boyce A, Chrousos G (eds.). Endotext. MDText.com, Inc. PMID 25905405. Retrieved 2019-09-17.
  10. ^ Gant Kanegusuku A, Araque KA, Nguyen H, Wei B, Hosseini S, Soldin SJ (2021-01-01). "The effect of specific binding proteins on immunoassay measurements of total and free thyroid hormones and cortisol". Therapeutic Advances in Endocrinology and Metabolism. 12: 2042018821989240. doi:10.1177/2042018821989240. ISSN 2042-0188. PMC 7844449. PMID 33552466.{{cite journal}}: CS1 maint: PMC format (link)
  11. ^ a b c d "Thyroglobulin: MedlinePlus Lab Test Information". medlineplus.gov. Retrieved 2019-05-06.
  12. ^ Knappe L, Giovanella L (2021-11-02). "Life after thyroid cancer: the role of thyroglobulin and thyroglobulin antibodies for postoperative follow-up". Expert Review of Endocrinology & Metabolism. 16 (6): 273–279. doi:10.1080/17446651.2021.1993060. ISSN 1744-6651. PMID 34693849.
  13. ^ "ACS :: Tumor Markers". American Cancer Society. Archived from the original on 2010-05-13. Retrieved 2009-03-28.
  14. ^ Giovanella L, Castellana M, Trimboli P (2020-01-01). "Unstimulated high-sensitive thyroglobulin is a powerful prognostic predictor in patients with thyroid cancer". Clinical Chemistry and Laboratory Medicine (CCLM). 58 (1): 130–137. doi:10.1515/cclm-2019-0654. ISSN 1437-4331.
  15. ^ 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. PMID 12601119. S2CID 21610036.
  16. ^ Delom F, Mallet B, Carayon P, Lejeune PJ (June 2001). "Role of extracellular molecular chaperones in the folding of oxidized proteins. Refolding of colloidal thyroglobulin by protein disulfide isomerase and immunoglobulin heavy chain-binding protein". The Journal of Biological Chemistry. 276 (24): 21337–21342. doi:10.1074/jbc.M101086200. PMID 11294872.
  17. ^ 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. PMID 10049727.

Further reading

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