View source for Thyroglobulin

{{short description|Protein produced and used by the thyroid}}
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{{No footnotes|date=August 2017}}
{{distinguish|text=[[thyroxine-binding globulin]], or [[thymoglobulin]]}}
{{Infobox_gene}}

'''Thyroglobulin''' ('''Tg''') is a 660 [[kDa]], [[Dimer (chemistry)|dimeric]] [[glycoprotein]] produced by the [[Thyroid epithelial cell|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.<ref name="Boron">{{cite book | author = Boron WF | title = Medical Physiology: A Cellular And Molecular Approach | publisher = Elsevier/Saunders | year = 2003 | page = 1044 | isbn = 1-4160-2328-3 }}</ref> 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).<ref>{{cite web | title = Protein" thyroglobulin precursor [Homo sapiens] | work = National Center for Biotechnology Information, U.S. National Library of Medicine |url=https://www.ncbi.nlm.nih.gov/protein/NP_003226.4}}</ref>

Thyroglobulin is in all vertebrates the main precursor to [[thyroid hormone]]s, 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.<ref name="Boron"/>

== Function ==
[[File:Thyroid hormone synthesis.png|thumb|left|[[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 hormone]]s [[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.<ref>{{cite web|url=https://www.ncbi.nlm.nih.gov/gene/7038|title=TG thyroglobulin [Homo sapiens (human)] – Gene – NCBI|website=National Center for Biotechnology Information (NCBI)|access-date=2019-09-16}}</ref>

Newly synthesized thyroid hormones (T3 and T4) exist as prohormonal modified tyrosine residues of thyroglobulin, which comprise the colloid within the follicle.<ref>{{cite journal | vauthors = Tosatto L, Coscia F | title = A glance at post-translational modifications of human thyroglobulin: potential impact on function and pathogenesis | journal = European Thyroid Journal | volume = 11 | issue = 3 | date = June 2022 | pmid = 35544053 | pmc = 9254275 | doi = 10.1530/ETJ-22-0046 }}</ref> 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.<ref name = "Rousset_2000" />

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.<ref>{{cite journal | vauthors = Gant Kanegusuku A, Araque KA, Nguyen H, Wei B, Hosseini S, Soldin SJ | title = The effect of specific binding proteins on immunoassay measurements of total and free thyroid hormones and cortisol | journal = Therapeutic Advances in Endocrinology and Metabolism | volume = 12 | article-number = 2042018821989240 | date = 2021-01-01 | pmid = 33552466 | pmc = 7844449 | doi = 10.1177/2042018821989240 }}</ref> 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.<ref name = "Rousset_2000">{{cite book | vauthors = Rousset BL, Dupuy C, Miot F, Dumont J | chapter = Chapter 2 Thyroid Hormone Synthesis and Secretion |date=2000| chapter-url= https://www.ncbi.nlm.nih.gov/books/NBK285550/| title = Endotext | veditors = Feingold KR, Anawalt B, Boyce A, Chrousos G |publisher=MDText.com, Inc.|pmid=25905405|access-date=2019-09-17}}</ref>

== 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.<ref name=":0">{{Cite web|url=https://medlineplus.gov/lab-tests/thyroglobulin/|title=Thyroglobulin: MedlinePlus Lab Test Information|website=medlineplus.gov|language=en|access-date=2019-05-06}}</ref> After thyroglobulin levels become undetectable (following thyroidectomy), levels can be serially monitored in follow-up of patients with papillary or follicular thyroid carcinoma.<ref>{{cite journal | vauthors = Knappe L, Giovanella L | title = Life after thyroid cancer: the role of thyroglobulin and thyroglobulin antibodies for postoperative follow-up | journal = Expert Review of Endocrinology & Metabolism | volume = 16 | issue = 6 | pages = 273–279 | date = November 2021 | pmid = 34693849 | doi = 10.1080/17446651.2021.1993060 }}</ref> 

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.<ref name=":0" /> Hence, thyroglobulin levels in the blood are mainly used as a [[tumor marker]]<ref name="urlACS :: Tumor Markers">{{cite web | url = http://www.cancer.org/docroot/PED/content/PED_2_3X_Tumor_Markers.asp | publisher = American Cancer Society | title = ACS :: Tumor Markers | access-date = 2009-03-28 | archive-date = 2010-05-13 | archive-url = https://web.archive.org/web/20100513023244/http://www.cancer.org/docroot/ped/content/ped_2_3x_tumor_markers.asp }}</ref><ref name=":0" /> 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.<ref>{{cite journal | vauthors = Giovanella L, Castellana M, Trimboli P | title = Unstimulated high-sensitive thyroglobulin is a powerful prognostic predictor in patients with thyroid cancer | journal = Clinical Chemistry and Laboratory Medicine | volume = 58 | issue = 1 | pages = 130–137 | date = December 2019 | pmid = 31444962 | doi = 10.1515/cclm-2019-0654 }}</ref> These tests are often ordered after thyroid cancer treatment.<ref name=":0" />

=== 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.<ref name="pmid12601119">{{cite journal | vauthors = Ferracci F, Moretto G, Candeago RM, Cimini N, Conte F, Gentile M, Papa N, Carnevale A | title = Antithyroid antibodies in the CSF: their role in the pathogenesis of Hashimoto's encephalopathy | journal = Neurology | volume = 60 | issue = 4 | pages = 712–714 | date = February 2003 | pmid = 12601119 | doi = 10.1212/01.wnl.0000048660.71390.c6 | s2cid = 21610036 }}</ref>

== Interactions ==

Thyroglobulin has been shown to [[Protein-protein interaction|interact]] with [[Binding immunoglobulin protein]].<ref name="pmid11294872">{{cite journal | vauthors = Delom F, Mallet B, Carayon P, Lejeune PJ | title = 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 | journal = The Journal of Biological Chemistry | volume = 276 | issue = 24 | pages = 21337–21342 | date = June 2001 | pmid = 11294872 | doi = 10.1074/jbc.M101086200 | doi-access = free }}</ref><ref name="pmid10049727">{{cite journal | vauthors = Delom F, Lejeune PJ, Vinet L, Carayon P, Mallet B | title = Involvement of oxidative reactions and extracellular protein chaperones in the rescue of misassembled thyroglobulin in the follicular lumen | journal = Biochemical and Biophysical Research Communications | volume = 255 | issue = 2 | pages = 438–443 | date = February 1999 | pmid = 10049727 | doi = 10.1006/bbrc.1999.0229 }}</ref>

== References ==
{{Reflist}}

== Further reading ==
{{Refbegin | 30em}}
* {{cite journal | vauthors = Coscia F, Taler-Verčič A, Chang VT, Sinn L, O'Reilly FJ, Izoré T, Renko M, Berger I, Rappsilber J, Turk D, Löwe J | title = The structure of human thyroglobulin | journal = Nature | volume = 578 | issue = 7796 | pages = 627–630 | date = February 2020 | pmid = 32025030 | pmc = 7170718 | doi = 10.1038/s41586-020-1995-4 | bibcode = 2020Natur.578..627C }}
* {{cite journal | vauthors = Mazzaferri EL, Robbins RJ, Spencer CA, Braverman LE, Pacini F, Wartofsky L, Haugen BR, Sherman SI, Cooper DS, Braunstein GD, Lee S, Davies TF, Arafah BM, Ladenson PW, Pinchera A | title = A consensus report of the role of serum thyroglobulin as a monitoring method for low-risk patients with papillary thyroid carcinoma | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 88 | issue = 4 | pages = 1433–1441 | date = April 2003 | pmid = 12679418 | doi = 10.1210/jc.2002-021702 | doi-access = free }}
* {{cite journal | vauthors = Henry M, Zanelli E, Piechaczyk M, Pau B, Malthièry Y | title = A major human thyroglobulin epitope defined with monoclonal antibodies is mainly recognized by human autoantibodies | journal = European Journal of Immunology | volume = 22 | issue = 2 | pages = 315–319 | date = February 1992 | pmid = 1371467 | doi = 10.1002/eji.1830220205 | s2cid = 38620713 }}
* {{cite journal | vauthors = Targovnik HM, Cochaux P, Corach D, Vassart G | title = Identification of a minor Tg mRNA transcript in RNA from normal and goitrous thyroids | journal = Molecular and Cellular Endocrinology | volume = 84 | issue = 1–2 | pages = R23–R26 | date = March 1992 | pmid = 1639210 | doi = 10.1016/0303-7207(92)90087-M | s2cid = 35326294 }}
* {{cite journal | vauthors = Dunn AD, Crutchfield HE, Dunn JT | title = Thyroglobulin processing by thyroidal proteases. Major sites of cleavage by cathepsins B, D, and L | journal = The Journal of Biological Chemistry | volume = 266 | issue = 30 | pages = 20198–20204 | date = October 1991 | pmid = 1939080 | doi = 10.1016/S0021-9258(18)54909-7 | doi-access = free }}
* {{cite journal | vauthors = Lamas L, Anderson PC, Fox JW, Dunn JT | title = Consensus sequences for early iodination and hormonogenesis in human thyroglobulin | journal = The Journal of Biological Chemistry | volume = 264 | issue = 23 | pages = 13541–13545 | date = August 1989 | pmid = 2760035 | doi = 10.1016/S0021-9258(18)80031-X | doi-access = free }}
* {{cite journal | vauthors = Marriq C, Lejeune PJ, Venot N, Vinet L | title = Hormone synthesis in human thyroglobulin: possible cleavage of the polypeptide chain at the tyrosine donor site | journal = FEBS Letters | volume = 242 | issue = 2 | pages = 414–418 | date = January 1989 | pmid = 2914619 | doi = 10.1016/0014-5793(89)80513-7 | s2cid = 32367745 | doi-access = free | bibcode = 1989FEBSL.242..414M }}
* {{cite journal | vauthors = Christophe D, Cabrer B, Bacolla A, Targovnik H, Pohl V, Vassart G | title = An unusually long poly(purine)-poly(pyrimidine) sequence is located upstream from the human thyroglobulin gene | journal = Nucleic Acids Research | volume = 13 | issue = 14 | pages = 5127–5144 | date = July 1985 | pmid = 2991855 | pmc = 321854 | doi = 10.1093/nar/13.14.5127 }}
* {{cite journal | vauthors = Baas F, van Ommen GJ, Bikker H, Arnberg AC, de Vijlder JJ | title = The human thyroglobulin gene is over 300 kb long and contains introns of up to 64 kb | journal = Nucleic Acids Research | volume = 14 | issue = 13 | pages = 5171–5186 | date = July 1986 | pmid = 3016640 | pmc = 311533 | doi = 10.1093/nar/14.13.5171 }}
* {{cite journal | vauthors = Kubak BM, Potempa LA, Anderson B, Mahklouf S, Venegas M, Gewurz H, Gewurz AT | title = Evidence that serum amyloid P component binds to mannose-terminated sequences of polysaccharides and glycoproteins | journal = Molecular Immunology | volume = 25 | issue = 9 | pages = 851–858 | date = September 1988 | pmid = 3211159 | doi = 10.1016/0161-5890(88)90121-6 }}
* {{cite journal | vauthors = Malthiéry Y, Lissitzky S | title = Primary structure of human thyroglobulin deduced from the sequence of its 8448-base complementary DNA | journal = European Journal of Biochemistry | volume = 165 | issue = 3 | pages = 491–498 | date = June 1987 | pmid = 3595599 | doi = 10.1111/j.1432-1033.1987.tb11466.x | s2cid = 24724872 | doi-access =  }}
* {{cite journal | vauthors = Parma J, Christophe D, Pohl V, Vassart G | title = Structural organization of the 5' region of the thyroglobulin gene. Evidence for intron loss and "exonization" during evolution | journal = Journal of Molecular Biology | volume = 196 | issue = 4 | pages = 769–779 | date = August 1987 | pmid = 3681978 | doi = 10.1016/0022-2836(87)90403-7 }}
* {{cite journal | vauthors = Bergé-Lefranc JL, Cartouzou G, Mattéi MG, Passage E, Malezet-Desmoulins C, Lissitzky S | title = Localization of the thyroglobulin gene by in situ hybridization to human chromosomes | journal = Human Genetics | volume = 69 | issue = 1 | pages = 28–31 | year = 1985 | pmid = 3967888 | doi = 10.1007/BF00295525 | s2cid = 9234835 }}
* {{cite journal | vauthors = Malthiéry Y, Lissitzky S | title = Sequence of the 5'-end quarter of the human-thyroglobulin messenger ribonucleic acid and of its deduced amino-acid sequence | journal = European Journal of Biochemistry | volume = 147 | issue = 1 | pages = 53–58 | date = February 1985 | pmid = 3971976 | doi = 10.1111/j.1432-1033.1985.tb08717.x | doi-access = free }}
* {{cite journal | vauthors = Avvedimento VE, Di Lauro R, Monticelli A, Bernardi F, Patracchini P, Calzolari E, Martini G, Varrone S | title = Mapping of human thyroglobulin gene on the long arm of chromosome 8 by in situ hybridization | journal = Human Genetics | volume = 71 | issue = 2 | pages = 163–166 | year = 1985 | pmid = 4043966 | doi = 10.1007/BF00283375 | s2cid = 28315029 }}
* {{cite journal | vauthors = Xiao S, Pollock HG, Taurog A, Rawitch AB | title = Characterization of hormonogenic sites in an N-terminal, cyanogen bromide fragment of human thyroglobulin | journal = Archives of Biochemistry and Biophysics | volume = 320 | issue = 1 | pages = 96–105 | date = June 1995 | pmid = 7793989 | doi = 10.1006/abbi.1995.1346 }}
* {{cite journal | vauthors = Corral J, Martín C, Pérez R, Sánchez I, Mories MT, San Millan JL, Miralles JM, González-Sarmiento R | title = Thyroglobulin gene point mutation associated with non-endemic simple goitre | journal = Lancet | volume = 341 | issue = 8843 | pages = 462–464 | date = February 1993 | pmid = 8094490 | doi = 10.1016/0140-6736(93)90209-Y | s2cid = 34165624 }}
* {{cite journal | vauthors = Gentile F, Salvatore G | title = Preferential sites of proteolytic cleavage of bovine, human and rat thyroglobulin. The use of limited proteolysis to detect solvent-exposed regions of the primary structure | journal = European Journal of Biochemistry | volume = 218 | issue = 2 | pages = 603–621 | date = December 1993 | pmid = 8269951 | doi = 10.1111/j.1432-1033.1993.tb18414.x | doi-access = free }}
* {{cite journal | vauthors = Mallet B, Lejeune PJ, Baudry N, Niccoli P, Carayon P, Franc JL | title = N-glycans modulate in vivo and in vitro thyroid hormone synthesis. Study at the N-terminal domain of thyroglobulin | journal = The Journal of Biological Chemistry | volume = 270 | issue = 50 | pages = 29881–29888 | date = December 1995 | pmid = 8530385 | doi = 10.1074/jbc.270.50.29881 | doi-access = free }}
* {{cite journal | vauthors = Yang SX, Pollock HG, Rawitch AB | title = Glycosylation in human thyroglobulin: location of the N-linked oligosaccharide units and comparison with bovine thyroglobulin | journal = Archives of Biochemistry and Biophysics | volume = 327 | issue = 1 | pages = 61–70 | date = March 1996 | pmid = 8615697 | doi = 10.1006/abbi.1996.0093 }}
* {{cite journal | vauthors = Molina F, Bouanani M, Pau B, Granier C | title = Characterization of the type-1 repeat from thyroglobulin, a cysteine-rich module found in proteins from different families | journal = European Journal of Biochemistry | volume = 240 | issue = 1 | pages = 125–133 | date = August 1996 | pmid = 8797845 | doi = 10.1111/j.1432-1033.1996.0125h.x | doi-access = free }}
* {{cite journal | vauthors = Grani G, Fumarola A | title = Thyroglobulin in lymph node fine-needle aspiration washout: a systematic review and meta-analysis of diagnostic accuracy | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 99 | issue = 6 | pages = 1970–1982 | date = June 2014 | pmid = 24617715 | doi = 10.1210/jc.2014-1098 | doi-access = free }}
{{Refend}}

== External links ==
* [https://www2.mrc-lmb.cam.ac.uk/first-look-at-the-atomic-structure-of-thyroglobulin/ First look at the structure of human TG]
* [http://labtestsonline.org/understanding/analytes/thyroglobulin/tab/test/ Thyroglobulin] – Lab Tests Online
* {{KansasHistology|endo|endo11}}
* [http://www.vivo.colostate.edu/hbooks/pathphys/endocrine/thyroid/synthesis.html Overview at colostate.edu]
* {{BUHistology|14302loa}}

{{Globulins}}
{{Glycoproteins}}
{{Tumor markers}}
{{Thyroid hormone receptor modulators}}

[[Category:Diagnostic endocrinology]]
[[Category:Endocrinology]]
[[Category:Thyroid]]
[[Category:Tumor markers]]