Triiodothyronine (T3) is a hormone produced in part by the follicular cells of the thyroid gland, and in part synthesized in the peripheral body tissues starting from the other thyroid hormone, thyroxine (T4). Triiodothyronine, a molecule characterized by 3 iodine units, circulates in the blood bound to specific plasma proteins, and only a small part is free from this bond (free triiodothyronine or fT3). Given that the most active fraction of the hormone at the metabolic level is precisely the free one, it is preferable to measure fT3 in blood tests, rather than T3. Triiodothyronine free o fT3, together with free thyroxine or fT4, is a useful test for monitoring the endocrine activity of the thyroid. In the presence of high free triiodothyronine (high fT3) you will have a hyperthyroid condition.
Normal values of FT3 and T3 - Free and total triiodothyronine
The following reference values are considered normal values of free (fT3) and total (T3) Triiodothyronine:
T3 or triiodothyronine: 100–200 ng / dL (1.54–3.08 nmol / L according to the SI unit of measurement, the International System Units).
FT3 or free triiodothyronine: 2.6–4.8 pg / ml (4.0–7.4 pmol / L according to the SI unit of measurement, the International System Units).
Mechanism of action of triiodothyronine - FT3 and T3
There triiodothyronine, commonly defined T3, and thyroxine (T4) represent the hormones produced by the thyroid, a gland found on the neck on either side of the trachea.
The main regulator of the thyroid and the TSH (Thyroid-stimulating hormone), also called thyrotropin, a hormone produced in the pituitary gland, which in turn is stimulated by a hormone produced in the thalamic level, the TRH (thyrotropin-releasing hormone). Low levels of thyroid hormones stimulate greater production of TRH and increase TRH receptors in the pituitary cells: consequently, the pituitary gland produces greater quantities of TSH, which acts directly on the thyroid cells and on various thyroid enzymes, resulting in greater hormone production. The reverse happens when there is too much thyroid hormone in the bloodstream.
There triiodothyronine has a molecular structure based on 3 iodine molecules, and is produced from thyroglobulin, a precursor located in the colloid of the thyroid follicles. However, the blood levels of T3 do not depend only on thyroid production: in fact, a large part of T3 (more than 80%) is produced at the peripheral level, starting from the other thyroid hormone, thyroxine or T4, thanks to the activity of a group of specific enzymes, the deiodases. This class of enzymes works by subtracting an iodine molecule from thyroxine, thereby converting it to T3.
There triiodothyronine it is present in less quantity than T4 in the blood, but has a higher metabolic activity. This hormone is highly lipophilic, i.e. it is soluble in fatty substances but does not dissolve in water and water-based substances such as blood. In order to travel in the bloodstream, triiodothyronine must move bound to specific proteins, the main of which is (Thyroid Binding Globlulin, TBG.
Two other plasma proteins important for the transport of T3 in the blood are albumin and transthyretin. To express its real biological and metabolic activity, triiodothyronine must necessarily detach itself from the transport proteins; there free fraction from proteins or "free"Of T3 is called fT3, and it is the substance that is commonly measured in blood tests, as it better expresses the activity of the thyroid.
In hyperthyroidism, the total amount of T3 will be increased compared to normal values, but a total T3 / free T3 ratio will be observed shifted in favor of the protein-bound fraction, due to a compensation mechanism that tries to "buffer" the excess of thyroid hormones by sequestering as much as possible in plasma proteins.
In hyperthyroidism, the total amount of T3 will be reduced compared to normal values, but it will be possible to observe a total T3 / free T3 ratio shifted in favor of the protein-free fraction, due to a compensation mechanism that tries to "buffer" the lack of hormones thyroid glands by releasing as much as possible of circulating plasma proteins.
FT3, or free triodothyronine, should be measured to evaluate thyroid function and identify any alterations both in the sense of thyroid hyperactivity (hyperthyroidism), with high fT3, and in the case of hypofunction (hypothyroidism), with reduced levels of fT3; this test must be associated with the dosage ofthyrotropic hormone, or TSH, and of fT4, or free thyroxine, essential to understand the real activity of the thyroid and the possible causes of its malfunction.
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Total triiodothyronine (T3) is high when it exceeds 200 ng / dL (or 3.08 nmol / L according to the SI unit of measurement, the International System of Units)
Free or free triiodothyronine (fT3) is high when it exceeds 4.8 pg / ml (or 7.4 pmol / L according to the SI unit of measurement, the International System of Units)
The values of T3 and fT3 they are regulated by a sophisticated mechanism called hypothalamus pituitary thyroid axis, which allows the body to optimize the production of thyroid hormones. Thanks to this system, the hormones fT3 and fT4 are kept in the normal range from TSH (thyroid stimulating hormone or thyrotropin), produced at the level of the pituitary gland, which in turn is regulated by the production of TRH (Thyrotropin releasing hormone or thyrotropin releasing hormone) produced at the thalamic level.
When, for various reasons, there is an excessive production of thyroid hormones, the pituitary intervenes by decreasing the production of TSH, so as to decrease the productive thrust towards the thyroid and to restore thyroxine and triiodothyronine to normal values. As soon as the fT3 and fT4 values return to normal, the TSH also quickly returns to normal.
Sometimes, however, this regulation mechanism does not work, or it works but it is not sufficient to balance an excessive increase in thyroxine and triiodothyronine. In this case, we will have a hyperthyroidism with low TSH values.
Other times, there is an excessive production of TSH, independent of the thyroid function, which exaggerates the production of T3. In this case we will have a situation of hyperthyroidism with high levels of TSH.
The other mechanism that our body uses to limit the effects of thyroid hormones, and in particular of triiodothyronine, is to act on the activity ofenzyme that largely produces it, that is the deiodase and in particular of the 5-deiodase, thus limiting the conversion from T4 and T3.
The main causes of high T3 and high fT3 are:
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Basedow-Graves disease: or diffuse toxic goiter, is an autoimmune disease characterized by the presence of antibodies directed against the TSH hormone receptor. The reaction of the antibodies causes the thyroid to produce thyroxine and triiodothyronine in an abnormal and disproportionate way. In addition, this abnormal stress can cause the formation of an enlargement of the thyroid gland, defined as thyroid goiter. Graves' disease is often characterized by hyperthyroidism, and in laboratory tests by high fT4 and fT3, low TSH and anti-TSH receptor antibody positivity.
Thyroiditis: are diseases of an inflammatory nature of the thyroid, and can have an infectious cause (as in the case of acute or sub-acute thyroiditis) or more frequently autoimmune (as in the case of chronic thyroiditis), which leads in the initial stages to the release of large quantities of T3 and T4. These diseases then evolve into a secondary phase of hypothyroidism, as the inflammation in the long run "destroys" the tissue of the thyroid gland which is unable to produce sufficient quantities of hormones.
In autoimmune thyroiditis there is a frequent finding of anti-thyroid antibodies, in particular of antibodies to thyroperoxidase (anti TPO) is antibodies to thyroglobulin anti TGB), usually associated with Low TSH and high values of fT3 and fT4. The most common forms of thyroiditis are Hashimoto's thyroiditis (which in its early stage of hyperthyroidism is called Hashitoxicosis), postpartum thyroiditis and silent lymphocytic thyroiditis.
In non-autoimmune thyroiditis (e.g. De Quervain's subacute thyroiditis or in acute bacterial thyroiditis), anti-thyroid antibodies are found less frequently than in autoimmune thyroiditis.
Toxic adenoma, toxic nodular goiter: it is also said Plummer's disease, is a benign neoplasm of the thyroid gland, characterized by a single nodule (uninodular goiter) or multiple nodules (multinodular goiter) which may behave as a cold, and therefore non-secretory (i.e. non-producing) nodule, or may produce large amounts of T3 and T4 completely unregulated by the hormonal compensation mechanism. At the level of the blood tests they will be evident High T3 / T4 and fT3 / fT4, and reduced TSH levels.
Incorrect dose of HRT, other drugs: in patients who are taking thyroid replacement therapy, i.e. in therapy with thyroxine (e.g. Eutirox), the response to blood tests of high fT3 and fT4 and low TSH it may be the consequence of too high a dose of the drug.
Familial non-autoimmune hyperthyroidism: it is a hereditary disorder, linked to the mutation of a gene encoding the TSH receptor. The thyroid no longer responds to the classical TSH-mediated hormonal control mechanism produced by the pituitary, and begins to produce thyroid hormones in an exaggerated and uncontrolled way. The pituitary will decrease TSH production to try to limit the elevated levels of fT3 and fT4. The blood tests are therefore found high thyroxine and triodothyronine and low TSH.
Ovarian teratoma: it is a neoplasm of the ovaries, in which there is growth of embryonic tissues (in our case of thyroid tissue). This tumor is not always malignant, and causes a state of hyperthyroidism for production not thyroid of triodothyronine and thyroxine resulting drop in TSH is increase in T3 / T4 and fT3 / fT4.
Pituitary adenoma: also called pituitary adenoma: sometimes the cells of the anterior lobe of the pituitary become autonomous and are subject to uncontrolled growth. An adenoma is therefore formed in the adenohypophysis, that is, a benign nodule that can produce large quantities of TSH. The blood tests are therefore found High TSH and high fT4 and high fT3, and typical signs and symptoms of hyperthyroidism may arise.
Hyperpituitarism:in case of pituitary hyperfunction, a large quantity of high pituitary hormones will be released into the bloodstream. As already seen for TSH-secreting pituitary adenoma, the affected person will suffer from defined secondary hyperthyroidism, characterized by high values of TSH and fT4 and high fT3.
TSH-secreting tumors: some neoplasms, such as cancer al lung, to prostate or al otherwise, they can produce TSH hormone within them, which, once it enters the blood, will stimulate the thyroid to produce thyroxine and triiodothyronine. This mechanism is called paraneoplastic syndrome, which is a set of signs and symptoms caused by a neoplasm in an organ far from the site of tumor development.
Symptoms of free and high total triiodothyronine - FT3 and high T3
The finding of high values of thyroid hormones, and in particular of free and total triiodothyronine (fT3 and T3) allows to identify a state of hyperthyroidism. The main symptoms in the presence of high fT3 and high fT4 are:
- excitement and increased reactivity
- intense sweating
- weight loss
- difficulty falling asleep and / or frequent nocturnal awakenings
- vision disturbances (photophobia)
- alteration of the menstrual cycle
- widespread itching
- hot flashes
- exophthalmos and eyelid swelling
Free and low total triiodothyronine - FT3 and low T3
Total triiodothyronine (T3) is low when it falls below 100 ng / dL (or the 1.54 nmol / L according to the SI unit of measurement, the International System of Units)
Free or free triiodothyronine (fT3) is low when it falls below 2.6 pg / dL (or 4.0 pmol / L according to the SI unit of measurement, the International System of Units)
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Causes of free and low total triiodothyronine - FT3 and low T3
The values of T3 and fT3 are regulated by a sophisticated mechanism called hypothalamus pituitary thyroid axis, which allows the body to optimize the production of thyroid hormones. Thanks to this system, the hormones fT3 and fT4 are kept in the normal range from TSH(thyroid stimulating hormone or thyrotropin), produced at the level of the pituitary gland, which in turn is regulated by the production of TRH (Thyrotropin releasing hormone or thyrotropin releasing hormone) produced at the thalamic level.
When, for various reasons, the thyroid gland produces thyroid hormones in reduced quantities, the pituitary gland increases the production of TSH, so as to increase the productive impulse of the thyroid gland and to restore the values of thyroxine and triiodothyronine to normal. As soon as the T3 / fT3 and T4 / fT4 values return to normal, the TSH also returns to normal values. Sometimes, however, this self-regulation system is defective, or it is not sufficient to remedy the deficiency of thyroxine and triiodothyronine. In this case, we will have a hypothyroidism with high TSH values. Less frequently, there is a drop in TSH production not related to thyroid function, but to a defect in pituitary production. As a result, adequate production of T3 and T4 will be lacking, and we will have a situation of hypothyroidism with Low TSH.
Unlike thyroxine or T4, whose production is solely linked to TSH, the levels of T3 (and secondarily of fT3) also depend largely on the activity ofdeiodinase enzyme and in particular of 5-deiodinase, primarily responsible for the conversion from T4 to T3.
The main causes of low T3 and low fT3 I'm:
Autoimmune thyroiditis: these inflammatory thyroid diseases are the most common cause of hypothyroidism: They are characterized by an inflammatory process that affects the thyroid gland, secondary to an abnormal immune response caused by our own organism, which does not recognize the thyroid cells and attacks them by damaging them. Hypothyroidism from thyroiditis is characterized by High TSH, low fT3 and fT4 and presence of anti-thyroid antibodies , that is the antibodies to thyroperoxidase (anti TPO), antibodies to TSH receptor (anti TSH) and antibodies to thyroglobulin anti TGB). Hasimoto's thyroiditis is the most frequent autoimmune thyroiditis.
Poor iodine intake: a raw material, iodine, is essential for the production of thyroxine and triiodothyronine: if it is not introduced into the body in adequate quantities with food, the thyroid will not be able to produce normal quantities of T3 and T4. In some parts of Italy, foods are less rich in iodine than indicated by the FDA, which is why table salt is added with small amounts of iodine.
Viral thyroiditis: are inflammatory processes affecting the thyroid gland, linked to a viral infection that causes sub-acute thyroiditis. A classic example is De Quervain's thyroiditis, which occurs in two distinct phases: at first the thyroid is stimulated by the inflammatory process and produces thyroid hormones even in excess, resulting in low TSH in the blood. Later, the thyroid enters a phase of less activity, and is often no longer able to maintain adequate levels of thyroid hormones. In this more prolonged phase, it is therefore common to find High TSH and decreased triiodothyronine and thyroxine.
Thyroidectomy or chemical destruction of the thyroid: in case of neoplasms or diseases that require partial or total removal of the thyroid, there will be a block in the production of thyroid hormones (low or no fT3 and fT4). This, if not corrected by adequate drug replacement therapy, will result an increased production of TSH on the part of the pituitary. In addition to surgical removal, this can also occur in the case of thyroid destruction by drugs such as radioactive iodine, or following its damage after radiation therapy (for example following radiotherapy sessions aimed at neoplasms located in the vicinity of the neck ).
Congenital hypothyroidism: in some individuals the thyroid gland presents a malformation from birth which results in reduced activity and a situation of hypothyroidism, which must be corrected immediately to allow psychophysical development.
Peripheral conversion deficiency of triiodothyronine T3:in situations of stress, in prolonged fasting, in infections, and above all in chronic diseases, it frequently happens that peripheral conversion from T4 to T3 is deficient.
The reasons for this deficit defined as low T3 syndrome or low T3 syndrome, must be sought among the following hypothetical causes:
- alterations of the hypothalamus-pituitary axis (due to the action of proinflammatory cytokines that act at the hypothalamic level, reducing the production of TRH),
- reduction of transport proteins of thyroid hormones,
- inhibition of binding to transport proteins and hormone uptake by cells,
- inhibition of membrane transport of thyroid hormones,
- reduction of the levels and effects of thyroid hormones in many target organs due to decreased cell uptake and to the
- reduced expression of cell receptors for thyroid hormones,
- reduction of the deiodinase activity of the three deiodinases (D1, D2, D3) due to acute phase proinflammatory cytokines, and finally
- decrease in the nocturnal peak of TSH due to a decrease in TRH and a simultaneous increase in cortisolemia.
The desiodinase furthermore, the enzymes responsible for the peripheral transformation of thyroxine into triiodothyronine function if there is an appropriate amount of selenium: in patients with chronic diseases this trace element is often missing, compromising the normal function of these enzymes. Even some drugs, such as amiodarone, inhibit the action of 5-deiodinoase: here is that in patients treated with amiodarone with appropriate thyroid function and normal TSH and T4 / fT4 values, an isolated T3 deficiency may be found. / fT3.
Medicines: there are some drug therapies that can impair the production of thyroid hormones, with low total and free thyroxine blood levels, and inducing a secondary increase in blood levels of thyrotropin (TSH). Among these the most frequent is amiodarone, an iodine-rich antiarrhythmic drug that can cause both hypothyroidism and hyperthyroidism. As already mentioned, amiodarone has an inhibiting action on the deiodinase enzyme which converts thyroxine into triiodothyronine. Other drugs that can generate this side effect are interferon (mainly used in antiviral therapy and in immunohematological therapy), and the lithium, a psychiatric drug used in the treatment of psychiatric conditions such as bipolar disorder or in some types of headache.
Inadequate thyroid replacement hormone therapy: patients with recognized hypothyroidism, who are on replacement therapy with thyroid hormones (for example with Eutirox, the most used drug in Italy), must carry out periodic blood checks, to regulate the therapy. Often the dose of thyroid hormones taken is insufficient, this will be reflected in the finding of low fT3 (low free triiodothyronine) and low fT4 (low free thyroxine) in the blood.
Storage diseases: these are quite rare pathologies, in which substances that damage the tissues and make it malfunctioning accumulate in the thyroid. As a consequence of the biohumoral tests we will have low fT4 and fT3, and, due to the secondary pituitary response, High TSH. Among the diseases that deposit at the thyroid level we remember amyloidosis, which causes the deposit of low molecular weight proteins produced by the organism in an anomalous way that accumulate between the intracellular spaces of the gland and damage it, and hemochromatosis, characterized from iron storage.
Pregnancy: during pregnancy there is an increase in circulating estrogen, which stimulates the production of proteins that carry the hormones T3 and T4 in the circulation. Consequently on the one hand increases the fraction of "bound" thyroid hormones to these transporter proteins, on the other decreases the fraction of "free" thyroid hormones in the blood, and therefore there is a decrease in fT3 and fT4 in the bloodstream.
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Symptoms of free and low total triiodothyronine - FT3 and low T3
The finding of low values of free and total triiodothyronine (fT3 and T3), if also associated with reduced values of free and total thyroxine (fT4 and T4) allows us to diagnose the presence of hypothyroidism. The main symptoms in the presence of low fT4 and low fT3 are:
- Low cold tolerance
- Instability of mood
- Tendency to depressed mood
- Easy fatigue
- Increased body weight
- Dry and fragile skin
- Loss of eyebrows (especially the outer part)
- Thin and brittle nails
- Irregularity of the menstrual cycle
- Increased fat (especially the cholesterol)
- Memory loss
If, on the other hand, there is an isolated decrease in fT3 and T3, with fT4 / T4 and / or TSH in the normal range, probably there is no picture of hypothyroidism as described above, but only a transformation deficit from T4 to T3. This, as already explained in the previous paragraphs, often happens in case of chronic diseases, in states of malnutrition, or during therapy (the most frequent is with amiodarone), which inhibit the action of deiodases, enzymes that convert thyroxine (T4) in triiodothyronine (T3).
The analysis is carried out starting from a blood sample through a venous blood sample. You don't need to fast before the exam. Since some medications can alter free and total triiodothyronine values, you should warn your doctor about all medications you are taking at the time of the exam.
Numerous drugs can decrease or increase T3 and fT3 levels. Of the drugs that can decrease the values of free and total triiodothyronine in the blood we point out anabolic steroids, androgenic hormones, anti-thyroid drugs (propylthiouracil and methimazole, which obviously will inhibit the production of thyroid hormones), interferon alpha, interleukin 2, lithium, some beta-blocking drugs (for example propanolol) and phenytoin.
Among the drugs that can increase the real values of FT3 and T3 we remember estrogen (and therefore drugs like the contraceptive pill), drugs that lower triglycerides such as chlorofibrate, and methadone, used in therapy for opiate addiction. It is also good to remember that a pregnant woman can have values of T3 and fT3 slightly increased, since it tends to increase the synthesis of the precursor molecule thyroglobulin.
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