The thyroid gland produces thyroxine (T4), triiodothyronine (T3) and calcitonin. Thyroid hormones are responsible for maintaining adequate levels of basal metabolism and are essential to the correct functioning of several organ systems. In children, the thyroid hormones are essential for growth and development.
Thyroid hormone was crystallised in 1914 by Kendall. Thyroxine was first synthesised by Harington and Barger in 1927 and its physiological effects were first characterised that year. In 1970 triiodothyronine was found by Ingbar, Sterling, and Braverman to be the active hormone although it had been discovered by Pitt-Rivers and Gross in 1952.
Excess of thyroid hormone in tissue produces hyperthyroidism. A deficit produces hypothyroidism. Hypothyroidism is usually treated by thyroxine as it has a long half life compared to triiodothyronine. While the amount of free T3 may be lower in the serum than normal in those treated with thyroxine the benefit of supplying both hormones in the usual management of hypothyroid patients is distinctly unproven, with the trials done to date that maintained TSH unsuppressed showing no benefit1. One trial did show benefit to well being by inducing biochemical hyperthyroidism !. The serum levels of free T3 do correlate with tissue levels in critical illness (where serum free T3 is classically depressed 2.
Synthesis of T3 and T4 takes place in one of the many follicles that makes up the thyroid gland. Microscopically, each follicle consist of a ring of thyroid epithelial cells surrounding an area of 'colloid'. The colloid acts both as the site of synthesis as well as a store. Synthesis requires:
Uptake of iodine by follicular cells is active process mediated by ATP-driven cell pumps that transports iodine from the serum into the follicular cells and then, in turn, into the colloid. Pendrin is the protein transporter of chloride and iodide, although the predominant mechanism is via the sodium-iodide symporter (NIS). Thyroglobulin and thyroid perioxidase are both proteins that are synthesised in the thyroid.
Defects in thyroid hormone biosynthesis have been described with mutant genes encoding
Thyroxine itself has limited biological effects and can be regarded as precursor to the biologically active triiodothyronine (T3). T3 is produced by de-iodination of T4 in the peripheral tissue cytoplasm and cell nucleus by a deiodinase. Three deiodinases have been characterised in man. Monodeiodinisation also produces a biologically inactive reverse-T3(rT3). The conversion balance is changed by certain drugs and diseases. Indeed it has recently been shown that the physiologic inactivator of thyroid hormones Type 3 iodothyronine deiodinase (D3), an enzyme not normally expressed in the human adult, is increased in critical illness and with some malignacies. This enzyme catalyzes the inner ring deiodination of T4 to rT3 and T3 to 3, 3'-diiodothyronine (T2), both of which are biologically inactive. D3 activity in the uteroplacental unit controls the transfer of maternal thyroid hormone to the fetus. D3 is expressed in the fetus, but the uterine endometrium and the placenta are the only normal tissues known to express high levels of D3 activity in the mature human.3. Further deiodinisation produces 3-iodothyronamine(T1AM) and thyronamine (T0) both of which seem to have actions on the heart. The later was reported to have a positive inotrophic action in the 1970s but does not seem to have been investigated recently.
There exist alternate pathways for the breakdown of the thyroid hormones. These include sulfation and glucuronidation of the phenolic hydroxyl group of the iodothyronines, the oxidative deamination and decarboxylation of the alanine side chain to form iodothyroacetic acids, and ether link cleavage. Sulphonation may play a general role in regulation of iodothyronine metabolism, since sulphonation of both thyroid hormones increases deiodination to rT3 and T2. One of the natural acetic acid derivatives of thyroxine, found in very low concentrations in the thyroid, called triac, can be used to treat the syndrome of resistance to thyroid hormone action as it has higher biological affinity to the TRβ receptor than the heart predominant TRα receptor
In neonates and young children haemangiomas can have such high type III deiodinase activity that thyroxine metabolism can exceed the thyroid gland's secretory capacity producing hypothyroidism.
Mechanism of Action
Many thyroid hormone actions appear to follow the binding of T3 to the nuclear tri-iodothyronine receptor. Three isoforms exist:
These isoforms typically couple with another nuclear receptor protein, either themselves or another nuclear receptor to form a dimer. They have areas that bind to T3 and DNA at specific sequences such as AGGTCA often found in the 5′ regulatory regions of thyroid hormone-responsive genes. This then usually causes the binding of protein cofactors that either activate or repress a specific gene's transcription. This is the mechanism by which T3 feeds back on thyroid releasing hormone and the thyroids own thyrotrophe thyrotropin β subunit genes. Such regulation of gene expression takes place over days.
T3 increases calcium-ATPase activity in cardiac muscle cells, and increases mitochondrial ATP-generation.
The cellular uptake of aminoacids and glucose is increased by T3. It activates the mitogen-activated protein kinase (MAPK) pathway by generating changes in some G protein-coupled membrane receptors. Recently it has been demonstrated that T1AM, a naturally occurring metabolite of T3 is an in vitro agonist of the G protein-coupled trace amine receptor TAR1.4 T1AM induces profound hypothermia and bradycardia within minutes. It may decrease cardiac output so could form part of a cell level feedback mechanism.
Underlying the rare condition of thyroid hormone resistance, mutations exist usually in the T3-binding domain of the β-nuclear receptor. This can result in differing resistance to the actions of thyroid hormone as the different receptors are expressed in different proportions in various cell nuclei. When the pituitary is affected more than the periphery frank hyperthyroidism with classic high plasma free thyroid hormone levels but no suppression of TSH.
- Cooper CS. Hyperthyroidism. Lancet 2003; 362:459-468
- Roberts CGP, Ladenson PW. Hypothyroidism. The Lancet 2004; 363:793-803