1. Ms Veena Shriram

2. Introduction  Described first by Thomas Wharton (1616-1673)  Largest Endocrine Gland  Weighing 15 – 20 g  Highly Vascular ( 5 ml / g / min ). Veena

3. Functional Anatomy Thyroid : shield Two lobes are connected by isthmus infront of the larynx Receives highest rate of blood flow per gram of tissue Histologicaly made up of multiple of closed follicles (acini): 100 – 300 µm. Contd... Veena

4. http://arbl.cvmbs.colostate.edu/hbooks/pathphys/endocrine/thyroid/anatomy.html THYROID GLAND HISTOLOGY Veena

5. Follicles are lined with single layer of cuboidal epithelial cells, which secrete into interior. Filled with proteinaceous matter: colloid, made up of large glycoprotein thyroglobulin containing thyroid hormones within it. Inactive gland: Follicles - large Colloid – abundant Cells lining are flat Active gland: Follicles - small Cells lining are cuboid Reabsorption lacunae seen Veena

6. Fetal Thyroid  From 12 th week of gestation fetal thyroid begins to secrete hormones.  Th. Hormones (T. H.) are essential for normal growth & development of fetal CNS, skeletal systems.  Maternal TSH & thyroxine cannot cross placental barrier, however iodine can cross the barrier.  Fetal T. H. production depends on ant. pituitary & fetal hypothalamus. Veena

7. O OH I I I I O NH 2 Thyroxine (T 4 ) O OH I I I O NH 2 3,5,3’-Triiodothyronine (T 3 ) THYROID HORMONES Veena

8. Synthesis & secretion of T. H. 1.Iodide Trapping 2.Formation & secretion of thyroglobulin 3.Oxidation of iodide ions 4. a)Iodination of tyrosine b) Organification of TG 5.Storage of TG 6.Release of T.H. : T 4 & T 3 Veena

9. 93 % hormone secreted by T. gland is Thyroxine (T 4 ). 7 % is triiodothyronine (T 3 ). T 3 is: 4 times more potent than T 4 present in smaller quantities Persists for shorter time than T 4 Veena

10. Iodine Metabolism  Iodine is a raw material for T. H. synthesis.  Ingested iodine is converted into iodide  Daily avg. intake of iodine is 500 µg/ day.  Min. daily intake to maintain normal T. function 150 µg/ d  Normal plasma iodine level is about 0.3 µg/ dL.  To prevent iodine deficiency common table salt is iodized with 1 part Na iodide to every 1,00,000 parts of NaCl.  Fate of Ingested iodides: absorbed from GIT into blood. 1/5 th is taken up by T. gland and rest is excreted by kidneys. Veena

11. 1.Iodide Pump (Iodide Trapping)  Food iodide from blood is, taken up by the follicular cells of thyroid – a process called iodide trapping.  Thyroid cells RMP is -50 mV compared to interstitial fluid & luminal colloid.  The T. cell membrane facing capillaries contain a symporter or iodide pump : Na + / I - symporter (NIS)  It works against electrochemical gradient & traps iodide by secondary active transport mechanism.  It concentrates the iodide 30 – 250 times than in the blood. Veena

12. 2.Formation & secretion of thyroglobulin  T. cells are typical protein secreting glandular cells.  ER & GA synthesize & secrete into the follicles, a large glycoprotein molecule : thyroglobulin (TG - with MW 3,35,o00)  TG contains about 70 tyrosine amino acids.  Tyrosine combines with iodide to form T. H. ( within TG molecule). Veena

13. 3. Oxidation of Iodide ions  Conversion of the iodide ions to an oxidized form of iodine (either nascent iodine, I 0 or I - 3 ) by the enzyme peroxidase in presence of H 2 O 2. Peroxidase is attached to apical membrane of the cell.  This oxidized form of iodine can combine with the a. a. tyrosine. Veena

14. 4. a) Organification of thyroglobulin 1. Organification of thyroglobulin (TG): The binding of iodine with TG molecule is called organification. 2. Oxidized iodine in presence of enzyme iodinase binds very rapidly with thyroglobulin. Veena

15. ION TRANSPORT BY THE THYROID FOLLICULAR CELL I-I- I-I- organification Propylthiouracil (PTU) blocks iodination of thyroglobulin COLLOID BLOOD NaI symporter (NIS) Thyroid peroxidase (TPO) ClO 4 -, SCN - Perchlorate, thiocynate depress I transport by competitive inhibition Veena

16. 4. b) Iodination of Tyrosine Tyrosine + oxidized iodine monoiodotyrosine (MIT) I 0 or I - 3 diiodotyrosin (DIT)  Coupling :- MIT + DIT Triiodotyrosine (T 3 ) DIT + MIT RT 3 Veena

17. Biosynthesis of TH trap Peroxidase Organification Apical membrane E.R. Golgi Basal membrane I-I- I-I- I-I- I-I- qq. I-I-. Veena

18. Storage & Release of TG 5.STORAGE  After synthesis of TH, TG molecules contain up to 30 molecules of T 4 & few molecules of T 3  2-3 months requirement is stored. 6.RELEASE  The follicle cells engulf a little TG (containing T 4 & T 3 ) by endocytosis (by formation of reabsorption lacunae).  TG is digested by proteinase and T 4 & T 3 are set free  After cleaving of T 4 & T 3 from TG, free H is released into capillaries. Veena

19. Synthesis & Release Veena

20.  3/4 th of iodinated tyrosine in the TG never becomes TH, but remains MIT, DIT.  During digestion of TG for release of T 4 & T 3, iodinated tyrosins are also freed from TG, but not released into blood  Instead I is cleaved by deiodinase enzyme. Thus recycling I.  Congenital absence of this enzyme lead to I deficiency. Veena

21. Daily Rate of Secretion  93 % T 4  7 % T 3 is released.  Later half of the T 4 is slowly deiodinated to T 3  Finally T 3 is mainly delivered to & used by tissues, a total about 35 µg / d. Veena

22. Transport of TH In The Blood  Approximately 99 % of T 4 is bound to 3 plasma proteins: Thyroxine binding globulin (TBG) ~75%; Thyroid binding prealbumin (TBPA or transthyretin) 15- 20 %; albumin ~5-10 %  Only ~0.02% of the total T 4 in blood is unbound or free.  Only ~0.4% of total T 3 in blood is free. Veena

23. Slow release of T 4 & T 3 to the tissues  T 4 & T 3 are released slowly to the tissues because of high affinity with TBG of T 4  Half quantity of T 4 is released in 6 days and that of T 3 in 1 day  After entering tissues again it binds with protein & used slowly. Veena

24. Slow onset & long duration of action  This is due to binding with proteins both in plasma & tissue cells, and due to the way they act.  T 3 is 4 times rapid than T 4. Veena

25. Mechanism of Action transcription of large no. of genes, therefore large no. of proteins, enzymes, & other substances are synthesized. generalized in functional activity High affinity of intracellular TH receptor for T 3 TH activate nuclear receptors (TRα on gene 17 & TRβ R on gene 3 ) & initiate the transcription process. mRNA formation, then RNA translation Veena

26. Mechanism of Action Veena