There thyroglobulin (Tgb or Tg) is a glycoprotein that is produced by thyroid cells, and is a precursor substance for the synthesis of hormones triiodothyronine (T3) is thyroxine (T4). It is used, like calcitonin, as a tumor marker for thyroid cancer.
Before starting, some technical data that are of particular interest to professionals, but which are important to be given in order to understand the functions and clinical usefulness of the thyroglobulin.
There thyroglobulin (also defined human thyroglobulin or hTg) is an iodinated glycoprotein weighing 660 KDa made up of two units or dimers of 115 tyrosine residues each, and is produced in the basal portion of the thyroid follicular cells (thyrocytes), the epithelial cells that line the thyroid follicles.
There molecule of thyroglobulin it contains in total about 5000 amino acids; approximately 8% -10% of the total mass of thyroglobulin is given by carbohydrates, while 0.2% -1% is linked to the iodine content (varies according to the amount of iodine introduced with the diet).
Once produced, it is stored in the thyroid follicles, the "cisterns" of glycoprotein material called colloid, the walls of which consist of a single layer of thyrocytes.
Thyroglobulin: normal values
THE normal thyroglobulin values differ according to the country or geographical area of belonging: in fact, the values are affected by the daily intake of iodine taken with food,
Using the Certified Reference Material-457 (CRM-457) standards, in subjects with normal thyroid function (euthyroid) without antibodies to thyroglobulin (AbTg) living in countries with adequate iodine intake, normal thyroglobulin values They are included between 3 ng / mL and 40 ng / mL (µg / L). To be more precise, given that an amount of thyroglobulin equal to 1 ng / ml per gram of thyroid is estimated, and considering that the thyroid usually lost 20-25 grams, the reference range should generally be included between 20-25 ng / ml.
Low thyroglobulin values (less than 10 ng / mL) are found in approximately 8% of the general population. In neonates, the thyroglobulin level can be physiologically high (values between 36 ng / mL and 48 ng / mL) for up to 48 hours after birth (Medscape).
As already mentioned, the production of thyroglobulin occurs by the follicular cells of the thyroid, under the stimulus of the hormone thyroid stimulant or thyrotropin (TSH).
In the thyroid follicles the tyrosine residues are iodinated (i.e. they are added with iodine atoms) to form 3-monoiodotyrosine (MIT) and 3,5-diiodotyrosine (DIT).
A molecule of monoiodiotyrosine and one of diiodiotyrosine joining together inside the follicular lumen will then compose the 3,5,3′-triiodothyronine (simply defined triiodothyronine or T3) while if instead two residues of DIT join together it will give rise to a molecule of tetraiodothyronine (called thyroxine or T4).
T3 and T4 constitute the thyroid hormones, and their free fractions, i.e. free triiodothyronine (fT3) and free thyroxine (fT4) constitute the part with greater biological activity of the same. About 70% of the iodine contained in thyroglobulin is within the precursors MIT and DIT, while the remaining 30% is contained in the molecules of thyroxine and triiodothyronine.
Thyroglobulin can remain stored at the level colloidal even for weeks, and then re-enter the thyrocytes when the body needs to produce new thyroid hormones. In this case, in fact, under the action of TSH, thyroid follicular cells “recover” thyroglobulin from the follicles through endocytosis, and hydrolyze it with enzymes such as proteases and peptidases to form single molecules of thyroxine and triiodothyronine, ready for release into the bloodstream.
What is thyroglobulin and why is it tested
There thyroglobulin (TBG) it is produced exclusively by the follicular cells of the thyroid. Thyroglobulin it is therefore a marker of the presence of thyroid follicular cells, and NOT of thyroid cancer. Its use for screening for differentiated thyroid cancer (i.e. to try to identify the presence of cancer) it is therefore not useful, while it is very useful for post-operative follow-up in the operated patient for differentiated neoplasia of the thyroid.
There thyroglobulin therefore it is mainly used as a tumor marker, to evaluate the efficacy of therapies in people affected by differentiated thyroid tumors, and to monitor any relapses in patients already treated. Neoplasms of the thyroid gland that produce thyroglobulin in significant quantities are the so-called thyroid carcinomas differentiated, i.e. the papillary thyroid cancer and follicular thyroid cancer: they are formations that synthesize thyroglobulin causing an increase in measurable concentrations in the blood. It should be borne in mind that not all thyroid cancers synthesize thyroglobulin, for example, medullary thyroid cancer is monitored by another substance, the calcitonin.
Measurement of thyroglobulin should be done before surgical removal of the thyroid gland in case of carcinoma. It is then requested after removal to see if there is any thyroid tissue still in place (in this case measurable levels of thyroglobulin persist, rather than being very low or absent). Thyroglobulin can then be measured at regular intervals to monitor the possible return of thyroid cancer (recurrence of thyroid cancer, in this case after having been with very low or undetectable values stably, thyroglobulin becomes detectable again).
What does it mean to have high thyroglobulin? The finding of elevated thyroglobulin values must always be carefully evaluated, since one of the causes of an increase in blood analysis values is thyroid cancer. It should also be said, however, that there are many pathologies, not necessarily cancerous, that can lead to high thyroglobulin values, such as thyroiditis or a state of hyperthyroidism.
High Thyroglobulin: Causes
Here are the most frequent causes of high thyroglobulin:
- Papillary thyroid cancer: it is the most frequent thyroid carcinoma, in fact it represents about 80% of thyroid neoplasms. It is often not enveloped in a capsule, and occurs in multiple (multifocal) nodules. Diagnosis is made throughultrasound of the thyroid gland, and often with a subsequent one fine needle aspiration thyroid on the thyroid nodule suspected. Therapy is surgical (hemithyroidectomy, i.e. removal of half of the thyroid gland, or total removal, i.e. total thyroidectomy), followed or not by metabolic radiotherapy with iodine. Papillary carcinoma of the thyroid gland leads to the release of thyroglobulin into the blood, therefore common will be the finding of high thyroglobulin
- Follicular thyroid cancer: approximately 10% of thyroid cancers are follicular carcinomas. They are neoplasms often limited to one single thyroid nodule which may have an external capsule, and are spread through the blood (to the bones and lungs mainly) rather than the lymphatic route. Also for this tumor the therapy is basically surgical and metabolic with radioiodine. As mentioned for papillary thyroid cancer, the follicular carcinoma thyroid leads to the finding in the circulation of elevated thyroglobulin.
- Metastasis of papillary carcinoma or follicular carcinoma of the thyroid gland: the metastases of thyroid tumors, being made up of tumor tissue identical to that of intra-thyroid neoplasms, cause the release of thyroglobulin into the bloodstream, with the finding of elevated thyroglobulin values in the blood.
- Thyroid cancer recurrence: thyroglobulin is especially useful for controlling thyroid tumors treated with surgery (partial or total thyroidectomy) and / or with metabolic radiotherapy (radioiodine), are not present again in the thyroid gland or in other sites (appearance of metastases). If high thyroglobulin is found, relapse (return) of the disease is suspected
- Hyperthyroidism: an increased activity of the thyroid gland, producing a high amount of thyroid hormones it also leads to a greater production of the precursor substance of T3 and T4, that is thyroglobulin. It is therefore not uncommon to find one high thyroglobulin in the course of hypertoriodism
- Subacute thyroiditis: acute stage thyroiditis often leads to a state of thyrotoxicosis with release of thyroid hormones by the thyroid tissue damaged by the inflammatory process. in this phase the thyroglobulin contained in the damaged thyroid follicles is also released, with evidence of tElevated ireoglobulin in the blood. Most thyroiditis are autoimmune, and are characterized by the presence of antibodies to thyroid peroxidase and to thyroglobulin.
- Benign adenoma: often from thyroid hormone-producing follicular thyroid adenoma, there is also release of thyroglobulin, with high thyroglobulin being found in blood tests.
- Cigarette smoking: not infrequently there may be an overactivation of the thyroid gland in smokers, leading to even minimal overproduction of thyroglobulin and thyroid hormones. In some cases you will have an elevated thyroglobulin, albeit slightly, compared to normal values.
Please note: the presence of high thyroglobulin therefore it does not automatically mean having thyroid cancerThere are many other causes that can increase thyroglobulin levels in the blood. A finding of high thyroglobulin should lead to further investigations, such as the complete picture of thyroid function, image test (thyroid ultrasound, thyroid scintigraphy in an econd step), but without forgetting that the diagnosis of thyroid neoplasia is always histological, and not through blood tests.
The above also explains why currently Thyroid cancer screening is not helpful by measuring the thyroglobulin, precisely because of its poor specificity (in other words, due to the fact that it can be high for causes very different from thyroid cancer).
What it means to have low thyroglobulin? Low values of thyroglobulin they can be normal values, for example after thyroidectomy, or in any case after a process that has damaged the thyroid. Often the dosage of thyroglobulin is required precisely to check that the values remain low, as an increase in the same could mean a relapse of neoplastic thyroid disease.
Low thyroglobulin: causes
The most frequent causes of low thyroglobulin I'm:
- Outcomes of thyroidectomy (surgical removal of the thyroid): as already mentioned, thyroglobulin is a marker of the presence of thyroid follicular cells. Thyroidectomy, which involves removing part or all of the thyroid gland, is followed by finding low or no thyroglobulin on blood tests.
- Factitic thyrotoxicosis (voluntary or involuntary intake of excessive amounts of thyroid hormones): the intake of thyroid hormones puts the thyroid gland "at rest": in this situation it is possible to find low thyroglobulin values.
- Congenital hypothyroidism with goiter: the most frequent cause of congenital hypothyroidism is endemic cretinism, a severe iodine deficiency linked to the reduced iodine content in water and food. Another, less frequent cause are genetic defects that lead to impaired synthesis of thyroid hormones and cause hypothyroidism with goiter. In all these cases, blood tests may show evidence of low thyroglobulin.
Thyroglobulin and iodine
The iodine, a fundamental molecule for the production of thyroid hormones, is a rare element, poorly represented at ground level; consequently, the normal human diet is low in iodine. The total body reserve of iodine is around 20-30 mg. In an average adult, the recommended average daily amount of iodine is about 150 mg. For pregnant or breastfeeding women, the average recommended daily intake is slightly higher. The table salt that we normally take with meals is added with iodine to help us reach the recommended daily dose.
Iodine is absorbed in the intestine and then collected in the thyroid, concentrating in the thyroid follicles. The ratio of thyroid iodine to serum iodine, which is normally 25: 1, depends on the action of this membrane carrier molecule and the action of TSH.
Thyroglobulin and recombinant TSH (rh TSH)
The dosage of the thyroglobulin must always be related to that of TSH, the level of which must be kept very low, or in any case in the low part of the normal range, through replacement therapy with thyroid hormones that the thyroidectomized patient must take due to the removal of the thyroid.
Keeping the TSH low induces a very low production of thyroglobulin in normal thyroid follicular cells but also in some thyroid tumors very dependent on the action of TSH. To prevent this reduced production masking the presence of tumor recurrence (i.e. to prevent the tests finding a false negative) we resort to the use of recombinant human TSH test.
This test involves the intramuscular administration of recombinant TSH and the subsequent measurement of serum thyroglobulin: in the case of tumor cells, stimulation with TSH will allow an increase in the production of thyroglobulin which will then be detectable in blood analyzes.
The drug usually used for the stimulation test is 0.9 mg Thyrogen (thyrotropin alfa), in two intramuscular administrations 24 hours apart, with subsequent blood sampling to measure thyroglobulin.
The measurement of TBG after recombinant TSH test, combined with ultrasound of the neck, is the optimal standard for monitoring patients who have undergone total thyroidectomy and any subsequent radiotherapy with Iodine 131.
sometimes the organism produces autoantibodies to thyroglobulin (anti-Tg), which are self-antibodies produced by the body against thyroglobulin. They are produced by our body in an unpredictable way and not linked to lifestyle, and once in the circulation they bind to the blood thyroglobulin, interfering with its measurement. It is therefore necessary to measure the antibodies to thyroglobulin because, if present, reduce the usefulness of thyroglobulin analysis as a tumor marker!
And now let's answer together some of the most frequently asked questions regarding thyroglobulin.
What is thyroglobulin used for?
Thyroglobulin serves as a precursor for the formation of the thyroid hormones T3 and T4, as well as for storing inactive forms of thyroid hormones and iodine within the colloid of the thyroid follicles.
What does it mean if my thyroglobulin is high?
Although thyroglobulin can be altered for many types of diseases, high thyroglobulin can be a wake-up call for the presence of papillary or follicular thyroid cancer.
When we can talk about indosable or negative thyroglobulin.
Undetectable serum Tgb is defined as unstimulated thyroglobulin of less than 1 ng / mL measured at least 5 weeks after total thyroidectomy and at least 3 months (3-11 months; median 6 months) after any adjuvant radiotherapy (source).