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Thyroid-1- TH synthesis lecture NO : 2nd MBBS Dr Muhammad Ramzan Thyroid Gland – the background • Thyroid gland is an endocrine gland, situated at the root of the neck on either side of the trachea • It has got 2 lobes, connected in the middle by an isthmus • Thyroid derives its name from Greek word for Shield for its resemblance with Thyroid cartilage • It is also called Adams˝ Apple for laryngeal prominence Thyroid gland – the background cont. • It is the largest endocrine gland and highly vascular • Its size and weight is variable in normal physiological conditions • Thyroid gland commonly weighs 20-40G Thyroid gland – Sex differences • Thyroid is larger in females than males • Structure and function of thyroid gland is variable in sexual cycle, pregnancy and lactation • Diseases of thyroid gland are more common in females Thyroid Gland Thyroid Gland – the secretions • Thyroid functions in fetus (>11wks) and achieves its maximum activity at puberty • Thyroid gland secrets 3 hormones (TH) : • T3 and T4 from Follicular • and Calcitonin from Para follicular cells Thyroid Gland – Histology Follicular/Principal • Thyroid gland is composed of closed follicles and are lined with cuboidal epithelium/follicular/Principal cells • The follicular cavity is filled with a colloid material - the Thymoglobulin - THG • Thymoglobulin is synthesized and secreted by the : • Follicular cells into the cavity TH are synthesized within THG • Thyroid hormones (TH) are synthesized within THG • Each THG mole have 5-6 mol of TH - T4 • Para follicular cells are present in between the follicles • Secreting Calcitonin, hormone Thyroid gland Histology Thyroid Gland- Histology Parathyroid Glands the chief cells • 2 pairs of parathyroid glands are present on the posterior surface of thyroid gland • They secrete a hormone from their component cells the Chief cells, Parathormone (PTH) • PTH regulates the Calcium and Po4 ions in the serum/ECF and activates the vitamin D Parathyroid Glands TH – their proportion and potency • Thyroid gland secrets 3 hormones • Tetra iodo thyronine, T4 or Thyroxin 1 • Triiodo Thyronine, 2 T3 • Calcitonin / Thyrocalcitonin 3 • T4 constitutes the 90-93% of the total secretion • T3 about 7-10 % • Potency of T3 is 10 times more than T4 TH – the properties free and bound forms • TH are hydrophilic and occur in free and bound form • Free TH are – FT4 and FT3 • Bound forms are transported with plasma proteins like Albumin and Globulin • T4 have more affinity for binding with proteins and have delayed action >2 weeks thanT3 • T3 acts more rapidly than T4 and is active biologically • T4 is converted first to T3 – Deiodination Synthesis of TH – the essentials • Amino acid Tyrosine and Iodine are the 2 essentials for the synthesis of TH • Both are available in diet and are absorbed from GIT • 1mg of iodide/week is required for normal synthesis of thyroid hormones (50mg/year) Synthesis of thyroid hormones – 5 Stages • Thyroglobulin (THG) synthesis • Iodide trapping or iodide pump • Oxidation of Iodide • Iodination of tyrosine • Coupling Reactions Thyroglobulin synthesis (THG) • THG Is a large Glycoprotein, have115 -140 moles of AA.Tyrosine depending upon the type of THG • It is synthesized by the endoplasmic reticulum (ER) of the Follicular cells under the influence of TSH • THG synthesis is continuous and is stored as colloid in the cavity of Follicles Thyroglobulin synthesis Iodide pump (Iodide Trapping) • Iodides ingested orally, are absorbed from GIT into blood in the same manner as chlorides • About 1/5th of the Iodides in the blood is actively removed by the follicular cells • This is achieved against a concentration gradient and is called Iodide trapping • The Iodine pump concentrates the iodide to about 30 – 250 times its concentration In blood when gland is active Factors affecting Iodine trapping • Iodine trapping is influenced by many factors • Most important is TSH level in the blood • Iodine trapping is ↑ with the ↑ in the serum TSH level • I2 is also recycled through the de iodination of the TH(10%) in liver and kidneys Oxidation of the Iodide ion to elemental I2 • Iodide must be converted to elemental iodine for its binding with Tyrosine to form TH • Oxidation occurs inside follicular cells by an enzyme called the Thyroperoxidase (TPO) • Iodine is also present in the Follicular cells • Deficiency or absence of TPO reduces or stops the hormone synthesis Iodination of Tyrosine • Iodination of Tyrosine takes place in Follicular cavity • and TH remain part of the Thyroglobulin • THG and TH remain stored in the Follicular cavity and are sufficient for months (4 months) • TH are released through an enzymatic process whenever needed Iodination of Tyrosine – Organization occurs in follicular cavity • Iodination is the binding of Tyrosine with I2 (organization) • It takes place in the follicular cavity where THG is present and : • amounts to 1/6th of the AA Tyrosine in THG Iodination of Tyrosine – Organization cont. the mechanism • I2 is released from follicular cells (Exocytosis) and binds with Tyrosine with in the THG to: • Form Mono to Tetra iodo thyronine (T4) • This binding is catalyzed by the enzyme Thyroperoxidase (TPO) present in the follicular cells Iodination/organization of Tyrosine Coupling Reactions • The Iodo tyrosine residues get coupled with one another through the coupling reactions • Coupling reactions give rise to different hormones • 1mol of DIT+1mol of MIT=Tri iodo thyronine T3 • 2 moles of DIT = Thyroxin T4 Coupling Reactions cont. • 1 mol of MIT+1 mol of DIT = Reverse ,rT • rT3 is 1% and is biologically inactive • MIT and DIT are not released into the blood Coupling reactions Storage of Thyroid Hormones • TH remain as vesicles in the THG present in colloid • One mol of THG have 5- 6 moles of Thyroxin • I mol of T3 for every 10 moles of T4 in THG • Stores of TH in THG are sufficient for 4 months • As such, symptoms of TH deficiency occurs after this period- 4 months Release of TH • TH are first cleaved from THG and then released in circulation • Under the influence of TSH, THG droplets are taken up by follicular cells by a process of Pinocytosis • Fusion of the droplets with Lysosomes results in the hydrolysis of THG and release of T3 and T4 in blood