What is Thyroxine

Thyroid Hormone Properties

Thyroxine is tetraiodothyronine. There are DL, L, and D types. L type is white crystal and decomposes at 235~236℃; D type is crystal and decomposes at 237℃; DL type is needle crystal and decomposes at 231~233℃. Thyroxine is soluble in alkaline solution and insoluble in water, ethanol and ether. It has not been confirmed to exist in natural free form, but it may be a product of thyroglobulin splitting, which can be extracted from animal thyroid glands. L-type is highly active, and D-type is less active. It has the function of promoting cell metabolism, increasing oxygen consumption, and stimulating tissue growth, maturation and differentiation. Therefore, quantitative measurement of human serum FT4 is of great significance for the diagnosis of thyroid diseases and the study of thyroid pathology and physiology. Using a solid-phase substance coupled to T4 antibodies, the radioimmunoassay method using 25I-FT4 and antiserum can simply and quickly determine the FT4 content in plasma.

Thyroxine Production and Metabolism

Figure 1. TH biosynthesis. (Noel P S., et al.; 2020)

1. Thyroid hormones are synthesized, stored and released by the thyroid gland. The raw materials for the synthesis of thyroid hormone are iodine and tyrosine in the body. Under normal dietary conditions, the human body consumes 100 to 200 micrograms of iodine every day. Intestinal absorption of iodine is complete. Iodine in the diet is first converted into iodide on the intestinal mucosa and then absorbed; the skin, mucosa and lungs can also absorb iodine, but it is much worse than intestinal absorption. The iodine absorbed by the intestine is mainly distributed in the extracellular fluid. The thyroid gland has the ability to concentrate iodine. The iodine concentration in the thyroid gland is 20 to 40 times higher than the iodine concentration in the blood. The concentration ability of patients with hyperthyroidism can be increased by 100 to 200 times. The salivary glands and the thyroid gland are also derived from the foregut, so the salivary glands also have the function of concentrating iodine. The normal salivary iodine/serum iodine ratio is 20. Clinically, the ability of the thyroid gland to concentrate iodine can be easily judged by measuring the iodide content of the salivary glands. In addition to the salivary glands, other glands in the body also have a similar ability to concentrate iodine than the thyroid gland. Under normal circumstances, iodine in saliva and gastric juice is reabsorbed through the digestive tract and returned to the extracellular fluid.
2. The thyroid gland concentrates iodine from low concentration to high concentration, which requires energy consumption. The thyroid's ability to concentrate iodine is mainly stimulated by pituitary thyroid-stimulating hormone (TSH) and is also inhibited by high concentrations of iodide in the body. The higher the thyroid-stimulating hormone, the stronger the thyroid's ability to concentrate iodine; the higher the iodine concentration in the blood, the lower the thyroid's ability to concentrate iodine.
   Iodine enters the thyroid follicular epithelial cells and is converted into active iodine under the action of peroxidase, and rapidly synthesizes monoiodotyrosine (T1) and diiodotyrosine with tyrosine on thyroglobulin(T2). Two diiodotyrosines are coupled to form thyroxine (T4), and one diiodotyrosine and one monoiodotyrosine are coupled to form one triiodotyrosine (Acid-T3). The main component of the thyroid follicle cavity is thyroglobulin, and the synthesis of thyroid hormones occurs on the surface of the globulin. The synthesized thyroid hormone is stored in the thyroid follicular cavity and can be used by the body for 2 to 3 months.
   When the body needs it, the thyroid follicle absorbs the colloid in the follicle cavity into the follicle through pinocytosis to form colloid droplets, and combines with lysosomes to form phagolysosomes. Lysosomes contain proteolytic enzymes and peptidases. T4 and T3 are hydrolyzed from thyroglobulin and released into the blood, where they are transported throughout the body to play their role. When lysosomal enzymes hydrolyze T4 and T3 on thyroglobulin, they also hydrolyze monoiodotyrosine and diiodotyrosine, and further release free inorganic iodine under the action of deiodinase. Most of the latter is reused by follicular cells to synthesize thyroid hormone. This is very important for the thyroid gland to economically utilize the limited iodine in the body.

   Figure 2. Regulation of TH.(Noel P S., et al.; 2020)

3. Most of the thyroid hormones in the blood are bound to proteins in the plasma, mainly to thyroid-binding globulin (TBG), but also to plasma proteins (ALB) and thyroid-binding prealbumin (TBPA). T4 (75%) is mainly combined with TBG, and T3 (90%) is mainly combined with thyroid binding globulin and plasma albumin; 99.97% of T4 in the blood circulation is in a bound state, and 99.7% of T3 is in a bound state. Although conjugated thyroid hormone accounts for the vast majority in the blood, it is still free thyroid hormone that truly exerts physiological effects. Thyroid-binding globulin is a single-chain glycoprotein produced by the liver with a half-life of 5 to 6 days. It carries 70% of T4 and T3; thyroid-binding prealbumin is produced by the liver and has a half-life of 1 to 2 days. Its affinity for T4 is lower than that of thyroid-binding globulin for T4. It carries 10% to 20% The T4 carries almost no T3. Plasma albumin concentration is high, reaching 3000~4500 ml/dl, but it has the lowest affinity for thyroid hormones, and can only carry 5%~15% of T4 and 30%~50% of T3.
   Some factors that affect thyroid binding protein can affect thyroid hormone levels, but free thyroid hormone levels are normal and thyroid function is normal. In order to better understand the relationship between different states of thyroid hormone in the blood, we can analogize serum total thyroid hormone and free thyroid hormone to commodities. Thyroid binding protein is like a "warehouse". There are countless "warehouses" in our body. Most of the items produced by the "factory" are first stored in the "warehouse", and a few are placed in the "store". These items can be purchased in the "store", but most of the items placed in the "warehouse" cannot be purchased. Thanks to the powerful "warehouse" items as a backing, the items in the "store" are always maintained at a very stable level. Although there are many items in the "warehouse", none of them circulate and cannot function. The items that are truly valuable and can exert physiological effects are those items placed in the "store". The size of the "warehouse" can affect the number of our items, but it does not affect the items in the "store". A large amount of conjugated thyroid hormone exists in the blood, which prevents a large amount of thyroid hormone from being lost in the urine when the blood is filtered through the kidneys, ensuring a more economical use of iodine after human evolution from the iodine-rich ocean to the relatively iodine-deficient land. Secondly, a large amount of conjugated thyroid hormone exists in the body, maintaining the stability of thyroid hormone day and night and ensuring the continued need for thyroid hormone by metabolism in the body.
   T4 binds tightly to proteins and is cleared slowly, with a half-life of 7 days in the plasma; T3 is relatively loosely bound to proteins and is cleared quickly from the plasma, with a half-life of 1 day. 100% of T4 in plasma comes from the thyroid, 20% of T3 in plasma comes from direct secretion by the thyroid, 80% comes from the peripheral conversion of plasma T4, and more than 95% of rT3 (reverse T3) comes from the peripheral deiodination of T4. Therefore, what truly represents thyroid function should be serum T4 concentration, not T3 concentration.
4. When thyroid hormone is metabolized in the body, part of it is directly filtered out from the kidneys, and part of it is excreted after being degraded in the body. Its degradation pathway in the body: a. Excreted after deiodination; b. Excreted after side chain degradation. The degradation of thyroid hormone mainly occurs in the liver, and is also degraded and metabolized in surrounding muscle tissue to generate inactive iodide.
   The metabolites of thyroid hormone are mainly excreted through the kidneys, and a small amount is excreted into the intestines through bile, and then enters the blood through liver-intestinal circulation and is reused. Urinary iodine content accounts for about 90% of our iodine intake, so we can estimate daily iodine intake by measuring urine iodine content.
5. In addition to deiodination metabolism, thyroid hormones also have other metabolic pathways. For example, T4 and T3 can be oxidatively deiodinated to generate tetraiodothyronacetic acid and triiodothyronacetic acid; T4 is combined with glucuronic acid, and T3 is combined with sulfate and excreted from the body.