Thyroid hormones Flashcards
Hypothalamus-pituitary-thyroid axis
TRH is produced in the hypothalamusand is secreted into the portal circulation of the hypothalamus.
TRH acts on the anterior lobe of the hypophysis through a GCPR (Gq: PLC), activating intracellular pathways releasing TSH in specific cells of the adenohypophysis. TSH in turn acts on its receptor (Gs) present on thyroid cells stimulating the production of thyroid hormones.
TSH
Tyroid stimulating hormone
Glycoprotein dimer, made by alpha and beta subunits. Alpha subunit is in common with other important hormones (FSH, LH, hCG). The alpha subunit interacts with the receptor (which is a Gs: adenylate cyclase), while beta gives the specificity. When TSH binds, the receptor stabilizes in the active conformation.
It induces a signaling cascade that activates crucial steps leading to an increase in T3 and T4 synthesis.
Brief thyroid histology
Follicular epithelium line up to form a follicle that contain the colloid, a liquid full of thyroid hormones secreted by follicular cells.
Daily iodine intake
150 micrograms/day in normal people
250 micrograms/day in pregnant and lactating women
Iodine metabolism
Small reservoir of iodine in plasma, partially free and partially bound to plasma proteins.
Largest iodide reservoir is in the thyroid, thanks to Na/I symporter that allows iodide ions concentration.
Free thyroid hormones are metabolized in the liver, part of iodide ions are reintroduced into the blood, a smal portion is secreted into the GI tract
Thyroid hormone synthesis
- Iodide trapping: iodide is uptake by cells thanks to the sodium-iodide symporter, which co-transports one iodide ion along with two sodium ions. The energy for transporting iodide against a concentration gradient comes from the Na/K pump, which pumps sodium out of the cell.
- Iodide is transported out of the thyroid cells across the apical membrane into the follicle by a chloride-iodide ion counter-transporter molecule called pendrin. The thyroid epithelial cells also secrete into the follicle thyroglobulin.
- Oxidation: conversion of iodide ions to an oxidized form of iodine performed by TPO.
- Iodination/organification: iodines added on tyrosine residues on thyroglobulin molecules
Tyrosine is first iodized to monoiodotyrosine and then to diiodotyrosine. - Conjugation of MIT and DIT -> formation of T3, T4 and a small portion of reverse T3 on tyroglobulin surface
- Some of the thyroglobulin in the colloid enters the thyroid cell by endocytosis after binding to megalin, a protein located on the lumen membrane of the cells.
Digestion in lysosomes of the thyroglobulin molecule to cause release of thyroxine and triiodothyronine - Released into the blood by monocarboxylate transporters.
Wolff-Chaikoff effect
Autoregulatory phenomenon, whereby a large amount of ingested iodine acutely inhibits thyroid hormone synthesis within the follicular cells, irrespective of the serum level of thyroid-stimulating hormone (TSH)
Thought to be transient, with the thyroid gland returning to its near-normal hormone synthesis in 26-50 hours in normal subjects. It provides temporary protection against the thyroid gland synthesizing an excessive quantity of thyroid hormones in states of excess iodine.
Thyroid hormones in blood
They are lipophilic because of their phenol ring.
The majority of T4 is carried by tyroxin-binding protein.
But they can also be boun to other proteins such as albumin.
Iodothyronine deiodinases
Enzymes that transform the T4 into T3. They are selenoproteins, thus containing selenocysteine. They need selenium to be present.
- D1 is expressed at high levels in liver, kidney and thyroid. It can deiodinate both rings of thyroxine. It can produce both the active T3 and the inactive reverse T3 (rT3). Its role is not crystal clear.
- D2 is found in brain, pituitary, thyroid, skeletal muscle, heart and brown adipose tissue. It is the activating enzyme, as it can only deiodinate the outer ring of thyroxine, forming active T3. This conversion takes place at the target tissues. The presence of D2 in the pituitary is very important for the negative feedback, as T4 needs to be converted to T3 in order to inhibit TSH secretion in the pituitary. The thyroid gland also relies on thyroid hormones for its correct function.
- D3 is expressed in placenta. It can only deiodinate the inner ring and is the major inactivating enzyme. It protects the developing fetus from excess thyrodism.
Thyroid hormone receptor functioning
Found in the nucleus.
It has a ligand-binding domain (LBD) and a DNA-binding domain (DBD). Normally, it is blocked by the binding of the corepressor. When the thyroid hormone binds to its receptor on the LBD, the receptor undergoes a conformational change, the corepressor detaches, and the coactivator attaches to the receptor. The retinoid X receptor (RXR) increases the function of TR, as they dimerize. The dimer starts the transcription. TR can bind DNA as a monomer, as a heterodimer with RXT or as a homodimer. The most transcriptionally active form is the TR/RXR heterodimer.
Thyroid hormone receptor isoforms
The transcription is different from one tissue to another. It depends on which sequences are next to the thyroid hormone response elements (TREs).
- TR-α1 (widely expressed and especially high expression in cardiac and skeletal muscles). Symptoms are due to the alpha receptors.
- TR-α2 (homologous with viral oncogene c-erb-A, also widely expressed but unable to bind hormone)
- TR-β1 (predominately expressed in brain, liver and kidney). Decreases LDL in the plasma
- TR-β2 (expression primarily limited to the hypothalamus and pituitary)
Thyroid hormone functions
- regulation of metabolism (anabolic hormone): increases intestinal glucose absorption, gluconeogenesis and glycogenolysis. It also increases lipolysis.
- Acts synergistically with growth hormone, in that it regulates long bone growth.
- During foetal neural development, synthesis of myosin. deficiency will cause growth and mental retardation.
- Increases oxygen consumption and heat production which is reflected in the increased basal metabolic rate (BMR).
- Chronotropic and ionotropic effects on the heart
- Increased numbers of β-adrenergic receptor, which has both local (e.g. cardiac) and systemic implications i.e. there is increased sensitivity to catecholamines.
- In the gastrointestinal tract, it causes increased gut motility, which could predispose a patient to diarrhoea.
- It increases bone turnover which leads to excess bone resorption and thus osteopenia.
- In the neuromuscular system, it stimulates increased synthesis of many structural proteins.
- In the liver is the reduction of apolipoprotein B100 levels, which leads to decreased production of VLDL and LDL.
Thyroid hormones exert their effects by gene transcription -> take some time.
Thyroid hormone receptors defects
If you don’t have the β2 receptors you don’t have the feedback mechanism: elevated T4 with inappropriate secretion of T4 -> hyperthyroidism.
Levothyroxine
Eutirox
- Chemically identical to T4
- Gold standard therapy for iodine deficient individuals
- Oral administration, 80% is absorbed in the GI tract -> for an optimal absortion not eating at the administration and till 2 hours following it.
Thioamides
Group of antithyroid drugs, including propylthiouracil and methimazole. They interfere with tyrosine residues of tyroglobulin, those attached to TPO -> blocking the action of TPO.
Their action can be seen after 10/15 days, since thyroid hormones already present are released.
