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 – background cont. It is the largest endocrine gland and highly vascular Its size/ 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 cells Thyroid gland is composed of closed follicles and are lined with follicular/Principal (cuboidal) cells The follicular cavity is filled with a colloid material - the Thyroglobulin - THG Thyroglobulin is synthesized and secreted by the : Follicular cells into the cavity

Histology cont. 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 B/W the follicles They secrete 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 Ca++ 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 - 90-93% Triiodo Thyronine, T3 2 - 7-10% Calcitonin / Thyrocalcitonin 3 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 Albumin and Globulins T4 have more affinity for binding with plasma proteins and have delayed action >2 weeks thanT3 T3 acts more rapidly than T4 and is 10 times more active T4 is converted first to T3 in target tissue – Deiodination

Biosynthesis 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 TH – 5 Stages Thyroglobulin (THG) synthesis Iodide trapping or iodide pump Oxidation of Iodide (for elemental iodine) Iodination of tyrosine Coupling Reactions

Thyroglobulin synthesis (THG) influenced by TSH THG Is a large Glycoprotein, have115 -140 moles of Tyrosine depending upon the type of THG It is synthesized in the RER 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 trapping Iodide pump Iodides; ingested orally, are absorbed from GIT into blood in the same manner as chlorides 1/5th of blood Iodides is actively removed by the follicular cells This is achieved against a concentration gradient and is called Iodide trapping - Sodium Iodide symporter - NIS 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 the blood TSH level 1 Iodine trapping is ↑ with the ↑ in the serum TSH level I2 is also recycled through the de iodination of the 2 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/ stops the hormone synthesis

Iodination of Tyrosine Iodination of Tyrosine takes place in Follicular cavity and TH remain part of the Thymoglobulin (THG) THG and TH remain stored in the Follicular cavity and are sufficient for months (4 months) Iodine is present in the Fol. cells for iodination in the cavity

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 ( Iodine) 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 (F.Cavity) to: Form Mono to Tetra iodo thyronine (T4) Pendrin is the integral membranous protein (I2 Cl 2symporter) that regulates the Exocytosis of iodine 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