Thyroglobulin: Structure, Synthesis, Function, Values ​​

The thyroglobulin is a protein of 660 kDa consisting of two identical subunits and structurally joined together by noncovalent bonds. It is synthesized by the follicular cells of the thyroid, a process that occurs in the endoplasmic reticulum, is glycosylated in the Golgi apparatus and excreted into the colloid or lumen of the follicles.

TSH or thyrotropin, secreted by the adenohypophysis, regulates the synthesis of thyroglobulin in the thyroid follicles, as well as its secretion into the follicular lumen or thyroid colloid. TSH levels are negatively feedback regulated by circulating levels of thyroid hormones and by the hypothalamic hormone TRH or thyrotropin-releasing hormone.

Thyroglobulin contains in its structure more than 100 residues of the amino acid tyrosine which, together with iodine, are the basis for the synthesis of thyroid hormones. In other words, hormone synthesis occurs within the thyroglobulin structure by iodination of tyrosine residues.

Normally, thyroxine or T4 constitutes the majority of the products of hormonal synthesis that is released into the circulation and converted, in many tissues, into 3,5,3´ triiodothyronine or T3, a much more active form of the hormone.

When the organic levels of iodine are very low, the preferential synthesis is of T3, for which directly much greater amounts of T3 are produced than of T4. This mechanism consumes less iodine and directly releases the active form of the hormone.

Under normal conditions, 93% of the thyroid hormones produced and released into the circulation are T4 and only 7% correspond to T3. Once released, they are transported for the most part bound to plasma proteins, both globulins and albumins.

Serum thyroglobulin levels are used as tumor markers for certain types of thyroid cancer such as papillary and follicular. Measuring serum thyroglobulin levels during treatment for thyroid cancer allows the effects of thyroid cancer to be evaluated.

Structure of the thyroglobulin

Thyroglobulin is a precursor molecule for T3 and T4. It is a glycoprotein, that is, a very large glycosylated protein of approximately 5,496 amino acid residues. It has a molecular weight of 660 kDa and a sedimentation coefficient of 19S.

It is a dimer composed of two identical 12S subunits, however small amounts of a 27S tetramer or a 12S monomer are sometimes found.

It contains almost 10% carbohydrates in the form of mannose, galactose, fucose, N-acetylglucosamine, chondroitin sulfate, and sialic acid. The iodine content can vary between 0.1 and 1% of the total weight of the molecule.

Each thyroglobulin monomer consists of repeats of domains that have no role in hormone synthesis. Only four tyrosine residues participate in this process: some at the N-terminal end and the other three, within a 600 amino acid sequence, linked to the C-terminal.

The human thyroglobulin gene has 8,500 nucleotides and is located on chromosome 8. It encodes a prethyroglobulin, which contains a 19 amino acid signal peptide followed by 2,750 residues that form a thyroglobulin monomer chain.

The synthesis of this protein occurs in the rough endoplasmic reticulum and glycosylation occurs during its transport through the Golgi apparatus. In this organelle, thyroglobulin dimers are incorporated into exocytic vesicles that fuse with the apical membrane of the follicular cell that produces them and release their content to the colloid or follicular lumen.

Hormone synthesis

The synthesis of thyroid hormones is produced by the iodination of some tyrosine residues of the thyroglobulin molecule. Thyroglobulin is a reserve of thyroid hormones that contains a sufficient quantity to supply the body for several weeks.

Iodination

Thyroglobulin iodination occurs at the apical border of the follicular cells of the thyroid. This entire process of synthesis and release to the follicular lumen is regulated by the thyrotropin hormone (TSH).

The first thing that occurs is the transport of iodine or iodine uptake across the basement membrane of the follicular cells of the thyroid.

In order for iodine to bind to tyrosine, it must be oxidized by means of a peroxidase that works with hydrogen peroxide (H2O2). Iodide oxidation occurs just as thyroglobulin leaves the Golgi apparatus.

This peroxidase or thyroperoxidase also catalyzes the binding of iodine to thyroglobulin and this iodination involves approximately 10% of its tyrosine residues.

The first product of hormonal synthesis is monoiodothyronine (MIT), with an iodine in position 3. Then iodination occurs in position 5 and diiodothyronine (DIT) is formed.

Coupling

Once the MIT and DIT are formed, what is called the “coupling process” occurs, for which the dimeric structure of thyroglobulin is essential. In this process, an MIT can be joined with a DIT and the T3 is formed or two DITs are coupled and the T4 is formed.

Liberation

In order to release these hormones into the circulation, the thyroglobulin must re-enter from the colloid into the follicular cell. This process occurs by pinocytosis, generating a cytoplasmic vesicle that later fuses with the lysosomes.

Lysosomal enzymes hydrolyze thyroglobulin, which results in the release of T3, T4, DIT, and MIT, plus some peptide fragments and some free amino acids. T3 and T4 are released into the circulation, MIT and DIT are deiodinated.

Function

The function of thyroglobulin is to be the precursor for the synthesis of T3 and T4, which are the main thyroid hormones. This synthesis occurs within the thyroglobulin molecule, which is concentrated and accumulated in the colloid of the thyroid follicles.

When the levels of TSH or thyrotropin are increased, both the synthesis and the release of thyroid hormones are stimulated. This release involves hydrolysis of thyroglobulin within the follicular cell. The ratio of hormones released is 7 to 1 in favor of T4 (7 (T4) / 1 (T3)).

Another function of thyroglobulin, although no less important, is to constitute a hormonal reserve within the thyroid colloid. In such a way that, when needed, it can immediately provide a rapid source of hormones to the circulation.

High, normal and low values ​​(meaning)

Normal values

Normal thyroglobulin values ​​should be less than 40 ng / ml; most healthy people without thyroid problems have thyroglobulin values ​​less than 10 ng / ml. These thyroglobulin values ​​may increase in some thyroid pathologies or may, in some cases, have undetectable values.

High values

Thyroid diseases that can be associated with high levels of serum thyroglobulin include thyroid cancer, thyroiditis, thyroid adenoma, and hyperthyroidism.

The importance of thyroglobulin measurement is its use as a tumor marker for differentiated malignant tumors of the thyroid of papillary and follicular histological types. Although these tumors have a good prognosis, their recurrence is approximately 30%.

For this reason, these patients require periodic evaluations and follow-up for long periods of time, since cases of recurrence have been reported after 30 years of follow-up.

Within the treatment used for this pathology is thyroidectomy, that is, the surgical removal of the thyroid gland and the use of radioactive iodine to remove any residual tissue. Under these conditions, and in the absence of antithyroglobulin antibodies, thyroglobulin levels are theoretically expected to be undetectable.

Low levels

If thyroglobulin levels begin to be detected during the follow-up of the patient and these levels are increasing, then there must be a tissue that is synthesizing thyroglobulin and therefore we are in the presence of a recurrence or metastasis. This is the importance of thyroglobulin measurements as a tumor marker.

References

  1. Díaz, RE, Véliz, J., & Wohllk, N. (2013). Importance of preablative serum thyroglobulin in predicting disease-free survival in differentiated thyroid cancer. Medical Journal of Chile , 141 (12), 1506-1511.
  2. Gardner, DG, Shoback, D., & Greenspan, FS (2007). Greenspan’s basic & clinical endocrinology . McGraw-Hill Medical.
  3. Murray, RK, Granner, DK, Mayes, PA, & Rodwell, VW (2014). Harper’s illustrated biochemistry . Mcgraw-hill.
  4. Schlumberger, M., Mancusi, F., Baudin, E., & Pacini, F. (1997). 131I therapy for elevated thyroglobulin levels. Thyroid , 7 (2), 273-276.
  5. Spencer, CA, & LoPresti, JS (2008). Technology Insight: measuring thyroglobulin and thyroglobulin autoantibody in patients with differentiated thyroid cancer. Nature clinical practice Endocrinology & metabolism , 4 (4), 223-233.
  6. Velasco, S., Solar, A., Cruz, F., Quintana, JC, León, A., Mosso, L., & Fardella, C. (2007). Thyroglobulin and its limitations in the follow-up of differentiated thyroid carcinoma: Report of two cases. Medical Journal of Chile , 135 (4), 506-511.

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