THYROID Dr Ayisha Qureshi Assistant Professor MBBS Mphil

THYROID Dr. Ayisha Qureshi Assistant Professor MBBS, Mphil

Case History A fit 32 -year-old man presents with a lump low in the left side of his neck. He first noticed it four weeks ago. He has no other relevant personal or family history. Examination shows a 3 cm hard, mobile swelling on the front of the neck. The swelling moves when he swallows.

THYROID: a historical perspective • Goitre & mountains: Goitre was first seen in inhabitants of Alps. Initially they did not know that goitre is enlargement of thyroid gland. It was then documented that consuming sea weeds caused remarkable reduction of the swelling in these patients. It was later discovered that sea weeds contain large amounts of iodine. • 1619: Thyroid enlargement was first described as a cause of swelling on the front of the neck. It was also clearly noted that this swelling moved up and down when the patient attempts to swallow.

The Thyroid Gland is UNIQUE among other endocrine glands in 3 ways 1. PHYSICAL Only gland which can be seen & palpated. 2. BIOCHEMICAL Only hormone that needs a trace element Iodine for its production 3. PHYSIOLOGY Hormone is stored in an extracellular site in the Thyroid Colloid.

THE THYROID GLAND - The thyroid gland is the largest, butterfly-shaped endocrine glands & is located at the base of the neck immediately below the Larynx, on each side of & anterior to the trachea. - The thyroid gland consists of two lobes of endocrine tissue (lying on either side of trachea) joined in the middle by a narrow portion of the gland called as the Isthmus. - The thyroid has one of the highest rates of blood flow per gram of tissue. - In a normal adult male, it weighs 15 -20 g but is capable of enormous growth, sometimes achieving a weight of several hundred grams.

LOCATION OF THE THYROID GLAND

THYROID GLAND The thyroid gland consists of 2 types of cells: 1. Follicular cells: These are more abundant, and the major secretory cells. They secrete Thyroid hormone. 2. Parafollicular cells or C-cells: These are fewer in number & interspersed. They secrete Calcitonin.

THYROID GLAND AS A FUNCTIONAL UNIT - The functional unit of the Thyroid Gland is a Follicle (acinus) which is composed of cuboidal epithelial (follicular) cells arranged around hollow vesicles of various shapes (size: 0. 020. 3 mm in diameter). - Arrangement is such that each follicular epithelial cell lies adjacent to a capillary! - Each follicle is a closed structure filled with a glycoprotein colloid called Thyroglobulin. It is a proteinaceous material. - There about 3 million follicles in an adult human thyroid gland.

THYROID HORMONE

THYROID HORMONES • 1. 2. 3. 4. The Thyroid gland secretes 3 major hormones: Thyroxine or T 4 : having 4 atoms of Iodine. (secreted in largest amount) Triiodothyronine or T 3 : having 3 atoms of Iodine (secreted in lesser amount) Reverse T 3 also called RT 3. (secreted in the least amount) Calcitonin: which is an important hormone of calcium metabolism.

THYROID HORMONES • About 93% of secreted hormone is T 4, while 7% is T 3. However, almost all T 4 is ultimately converted into T 3. • The functions of the 2 hormones are the SAME but they differ in rapidity & intensity of action. • T 3 is about 4 times as potent as T 4, and has a much greater biological activity but is present in blood in much smaller quantities & for a much shorter time! • RT 3 is NOT biologically active.

BIOSYNTHESIS OF THYROID HORMONE

POINTS TO REMEMBER: 1. 2. 3. 4. 5. Iodine in large amounts is required for thyroid hormone synthesis. This is acquired through diet & THERE IS NO OTHER USE OF THIS ELEMENT IN THE BODY! The hormones are synthesized in the lumen of the follicular epithelial cells & then stored in the colloid of the follicle. The hormone is thus doubly secreted: once from the follicular cell into the follicular lumen where it is stored and then reuptaken by the follicular cells where thyroglobulin is degraded & the released T 3 & T 4 are again secreted into the blood. The Follicular cell has 2 surfaces: a basolateral surface facing the blood capillaries & the ECF, & an apical surface facing the follicular lumen containing the colloid. Thyroxine, the major secretory product, is not the biologically active form but must be converted into T 3 at extrathyroidal sites to exert potent effects.

Differentiate between Basolateral & Apical surface of the Follicular cells….

INGESTION OF IODINE • 50 mg of Iodine is required each year OR 1 mg/week OR 150 µg/ day. • To prevent deficiency, common table salt is iodized with about 1 part sodium iodide to every 100, 000 parts sodium chloride. • Ingested iodide is absorbed from the intestines and enters the circulation.

IODIDE TRAPPING Under normal circumstances, iodine is 25 -50 times more concentrated in the cytosol of Thyroid follicular cells than in the blood plasma. ↓ Thus, iodine moves into the thyroid cells against a steep concentration gradient! ↓ This is done with the help of an elctrogenic “Iodide pump” also called the “NIS or Sodium Iodide Symporter” located in the thyroid cell membrane. The process involved is Secondary Active Transport and the energy is provided by the concentration gradient maintained by the Sodium Potassium Pump.

NA/I SYMPORTER This pump, thus, transfers 2 Na ions for each Iodide ion. ↓ The role of the SODIUM POTASSIUM PUMP is very important as it then extrudes 3 Na ions in exchange for 2 K ions to maintain the electrochemical gradient for Na.

Is it the Iodine or the Iodide that is absorbed from the intestines? • Dietary iodine is reduced to iodide before absorption by the small intestine. • It is the IODIDE form of Iodine that takes part in the various steps of thyroid hormone biosynthesis. • In addition to Iodine, Tyrosine is essential for TH synthesis. Tyrosine is found as part of the Thyroglobulin.

THYROGLOBULIN SYNTHESIS • It is the matrix for thyroid hormone synthesis & is the form in which the hormone is stored in the gland. • It is a large glycoprotein with about 140 molecules of tyrosine and a m. w of 660, 000 Da. Synthesized on ribosomes ↓ Glycosylated in the ER ↓ Packaged in the secretory vesicles ↓ Secreted by exocytosis into the colloid of the thyroid follicle

THYROGLOBULIN SYNTHESIS The amino acid Tyrosine becomes incorporated into the much larger Thyroglobulin while it is being produced ↓ Iodination to form the mature hormone will take place once thyroglobulin is secreted into the colloid.

Transport of Iodine into the follicular lumen! • For hormone synthesis to take place, Iodide must be delivered to the follicular lumen. • The Iodide that has entered into the follicular cell from the blood stream must exit the follicular cell across the apical membrane to access the colloid, where the initial steps of hormone synthesis occur. • This is done with the help of a Chloride- Iodide exchanger known as PENDRIN. • PENDRIN is protein which is an anion exchanger.

POINTS TO REMEMBER: • Tyrosine-containing Thyroglobulin is transported from the follicular cells into the colloid by exocytosis. • Iodine is transferred into the Colloid!

OXIDATION OF THE IODIDE ION • Iodide ion is oxidized to form either nascent iodine (I°) or I 3−. • This oxidation is catalyzed by the enzyme thyroperoxidase/ peroxidase and its accompanying hydrogen peroxidase. • These enzymes are located in the apical membrane of the cell.

ORGANIFICATION • Addition of iodide molecules to tyrosine residues in the thyroglobulin is called Organification of thyroglobulin. • This reaction is catalyzed by the enzyme Iodinase. • Tyrosine + 1 Iodine = Monoiodotyrosine (MIT) • Tyrosine + 2 Iodines = Di-iodotyrosine (DIT)

COUPLING • It is the combination or coupling of 2 molecules of iodinated tyrosine molecules to form thyroid hormone: - DIT + DIT = Thyroxine (T 4) - DIT + MIT = Tri-iodothyronine (T 3) COUPLING DOES NOT OCCUR B/W 2 MIT MOLECULES! This mature hormone is formed while a part of Thyroglobulin molecule, & remains a part of this large storage molecule till the stimulus for secretion arrives.

STORAGE In normal individuals, approximately 30% of the mass of thyroid gland is thyroglobulin, which is about 2 -3 months supply of hormone.

SECRETION • For secretion to occur, thyroglobulin must be brought back into follicular cells by a process of endocytosis. • Pseudopodia reach out from the follicular cells to engulf chunks of thyroglobulin, which are taken up in endocytic vesicles- this is also called “BITING OFF”. ↓ On appropriate stimulation for thyroid secretion, the follicular cells internalize a portion of thyroglobulin- hormone complex by phagocytozing a piece of colloid

SECRETION The endocytic vesicles fuse with the lysosomes ↓ Lysosomes release enzymes that split off the biologically active hormones: T 3 & T 4, as well as the inactive iodotyrosine, MIT & DIT. ↓ The thyroid hormones being very lipophilic, pass freely through the outer membrane of the follicular cells & into the blood!

FATE OF MIT & DIT The MIT & DIT are of no endocrine value. ↓ The follicular cells contain an enzyme (deiodinase) that will swiftly remove the Iodide from MIT & DIT, allowing the freed Iodide to be recycled for synthesis of more hormone. What is the significance of the enzyme DEIODINASE?

PASSAGE THROUGH BLOOD This highly lipophilic thyroid hormone molecule binds with several plasma proteins. • The binding proteins are: 1. Thyroxine binding globulin (TBG) (binds 70% of the hormone) 2. Transthyretin (TTR)(binds 15% of the hormone) 3. Albumin (binds 15% of the hormone) The majority bind to TBG, a plasma protein that selectively binds only Thyroid hormone. Why is the TH transported in the bound form?

Significance of the Bound hormone: • Normally 99. 98% of the T 4 in plasma is bound. • Less than 0. 1% of T 4 and less than 1% of T 3 is in the unbound (free) form. • T 3 has less affinity for the plasma proteins and binds loosely with them, so that it releases quickly. T 4 has more affinity and binds strongly with them so that it is released slowly. Therefore, T 3 acts on the target cells immediately and T 4 acts slowly. • These binding proteins are synthesized by the liver. Any disease of the liver will thus have an indirect effect on the amount of Total free hormone levels. • When a sudden, sustained increase in the thyroid binding proteins in the plasma takes place, the concentration of free hormone falls. This is, however, corrected over time. • TBG levels are increased by estrogen therapy and in pregnancy while it is depressed by glucocorticoids, androgens and several chemotherapeutic drugs.

Rate of Secretion & Plasma Levels Rate of Secretion: Total T 4 : 80 -90 µg/ day Total T 3 : 4 -5 µg/ day Reverse T 3 : 1 -2 µg/ day Plasma Levels: Total T 3 : 0. 12 µg/ dl Total T 4 : 8µg/ day

METABOLISM • The thyroid hormones are deiodinated in the liver, the kidneys and many other tissues. The T 4 is converted into T 3 by being stripped of one of its Iodides. • T 4 has a long half-life of: 7 days • T 3 has a half-life of: upto 1 day • Prolonged latent period for T 4: action starts to show almost 2 -3 days after release & may persist for as long as 6 weeks to 12 months. • Shorter latent period for T 3: starts showing its effects within 6 - 12 hours & maximal cellular activity occurs within 2 -3 days.

MECHANISM OF ACTION

M. O. A • Thyroid hormone receptors are members of a large family of nuclear hormone receptors Location: Thyroid hormone receptors are either attached to the DNA genetic strands or located in close proximity to them.

M. O. A The thyroid receptor binds to hormone receptor element on the DNA either as a heterodimer with retinoid X receptor (RXR) or a homodimer. (The TR/ RXR is the most transcriptionally active form of the receptor. ) ↓ In the absence of the hormone, the thyroid hormone receptor binds to their response elements. ↓ When the thyroid hormone becomes available, the receptor becomes activated & initiates the transcription process. ↓ Large number of m. RNA are formed ↓ Within minutes or hours: RNA translation on the cytoplasmic ribosomes ↓ Hundreds of new intracellular proteins are formed ↓ Most of the actions are exerted through these proteins