Thyroid gland_fumction_pathology_drugs_pptx

Thyroid gland

1. THYROID GLAND Dr. E. Muralinath Associate Professor & Head Dept. of Veterinary Physiology College of Veterinary Science, Proddatur, Andhra Pradesh

2. Associate Professor & Head Dept. of Veterinary Physiology College of Veterinary Science, Proddatur Andhra

3. THYROID GLAND Butterfly shaped, red − brown, vascular gland Located on anterior mid neck line region Extends from C5 − T1 vertebrae in humans A largest endocrine glands, weighs ~15 − 25 g Major laryngeal cartilages serve as scaffold F irst endocrine gland to start developing (≈ 22 days, humans) Secretes thyroid hormone & maintains iodine balance 90% of hormone secreted is inactive (T 4 ), while 10% is active (T 3 ) Superior & Inferior thyroid arteries, both bring O 2 & nutrients to thyroid gland

4. Thyroid gland is predominantly endodermal in origin Fully formed gland has two lobes joined by an isthmus Lobes consists of two cell types Follicular cells / thyrotrophs – T 4 (L-3,5,3',5'-tetraiodothyronine) & T 3 ( 3,5,3'-Triiodothyronine, T 3 ) Parafollicular cells/ C cells – Calcitonin Differences in T 4 compared to T 3 Shortened C4'-O4' bond Contraction of C3'-C4'-C5' angle ↑ C3' and C5' angles in T 4 THYROID HORMONES

5. Thyroid glands secretions, known as colloid, are stored in their follicular lumen Thyroid follicles cluster together to form numerous lobules Each follicle consists of either a simple columnar/cuboidal epithelium surrounding a central lumen Thyrocytes (follicular cells) have rounded nucleus, and abundant numbers of mitochondria, rough endoplasmic reticulum, Golgi bodies The rough endoplasmic reticula are more abundant near the base, while Golgi bodies are more at the apex HISTOLOGY OF THYROID GLAND

6. NEGATIVE FEEDBACK CONTROL High levels of circulating T 3 & T 4 feedbacks Inhibition of TRH & TSH T 4 is converted to T 3 and reverse T 3 (rT 3 - during stress) in both circulation & in tissues Thyroid hormones transported in serum bound to TBG (75%), Transthyretin & albumin T3 & T4 secretion is mediated via negative feedback loop among hypothalamus, anterior pituitary & thyroid gland

7. THYROTROPIN RELEASING HORMONE (TRH) Thyrotropin releasing hormone TRH ( pGlu-His-Pro-NH 2 ) functions both as a tropic & non-tropic hormone Secreted by cell bodies of PVN in hypothalamus Transduced by coupled G q /11 protein & β - Arrestin receptors TRH activates anterior Pituitary cells (AP) that secrete TSH Norepinephrine & Histamine stimulate TRH release Signal Cascade Activates PLC → PIP2 hydrolysis → IP3 & 1,2-diacylglycerol (DAG) ↑intracellular ca 2+ & PKC activation → ras /cRaf1 →ERK1/2 Stimulates ca 2+ /calmodulin-dependent protein kinase & MAPK TRH Stimulates acidophilic lactotrophs’ in Anterior Pituitary to produce prolactin (non-tropic)

8. THYROID STIMULATING HORMONE (TSH) TSH is synthesized by basophilic thyrotropes of anterior pituitary gland Glycoprotein of 211 amino acids & has an α & a β chain Molecular mass is ≈ 28 kDa, plasma half life is ≈ 60 minutes TSH maintains growth, secretory activity & structure of thyroid by augmenting HMP Shunt, Glycolysis, Protein synthesis & TCA cycle Oxygen consumption & thyroidal uptake of I - TSH (& LH, FSH, HCG) share same α chain & function via. cAMP cAMP & IP3/Ca 2+ cascades lead to downstream physiological effects of TSH Somatostatin & Dopamine inhibits TSH release from AP Cortisol & Estrogen ↓ Pituitary response to TRH

9. T 3 /T 4 SYNTHESIS & SECRETION There are seven steps: Thyroglobulin (TG) synthesis & secretion into follicular lumen a. Macromolecular precursor of thyroid hormone b. Synthesized in thyrocyte endoplasmic reticulum (ER) c. Large glycoprotein, synthesized as 12S molecule (330 kDa), and forms 19S homodimer (660 kDa) Iodine uptake into thyroid follicular epithelial cells a. Na + /I - symporter (NIS), TSH sensitive, active uptake b. Intracellular I - conc. 20 − 40 times > plasma c. NIS essential for iodine uptake or trapping in thyrocytes d. Daily recommended uptake : 150 μ g/day or 1 mg/week

10. Iodine transport & efflux into follicular lumen a. Pendrin: Iodine efflux on thyrocytes’ apical surface Oxidation of iodine , iodination of TGs’ tyrosyl residues & coupling of iodotyrosines a. I - oxidation essential for iodine-tyrosine coupling b. TPO catalyses I - oxidation & iodination of Tg tyrosyl residues, & iodotyrosine coupling into T 3 & T 4 c. H 2 2 serves as an oxidant for TPO catalyzed oxidation d. 2 DIT → T 4 + Alanine; d. MIT + DIT → T 3 (rT 3 ) e. Iodotyrosines distribution: 23 % MIT, 33 % DIT, 35 % T 4 & 7 % T 3 f. Dual oxidase 2 (Duox2) & its maturation factor, Duoxa2 are responsible for H 2 O 2 generation at the apical membrane d. TG undergoes iodination mediated by thyroperoxidase (TPO) and H 2 O 2 at the apical membrane of thyrocyte e. Iodine covalently bound to tyrosine residues in molecule to form monoiodotyrosine (MIT) and diiodotyrosine (DIT)

11. Hydrolysis of TG − T 4 /T 3 complex a. Iodinated tyrosines with Tg . (colloid droplets) enters thyrocytes, reaches lysosomes forming phagolysosomes b. Proteolysis is key to releasing T 4 and T 3 Storage & Secretion of T 4 /T 3 , the thyroid hormone a. Ratio f T 4 : T 3 secretion = 5:1 (dogs) b. Ratio of circulating levels = 20 : 1 ( T 4 tight bound) c. Dogs: Half life of T 3 : 6 hrs; T 4 : 12-24 hrs d. Primates: Half life of T 3 : 24 hrs; T 4 : 7 days e. Each Tg . molecule have, around 30 T 4 & few T 3 molecules f. Thyroid gland secretes ~ 70-90 μ g of T 4 each day Endocytosis of TG − thyroid hormone complex into follicular epithelial cells a. Iodinated Tg through micro-pinocytosis or phagocytosis, enters thyrocytes again, through apical membrane

12. THYROID HORMONE SYNTHESIS 1 2 3 4 5 6 7

13. THYROID HORMONE SYNTHESIS 1 3 2 4 5 6 7

14. FUNCTIONS OF THYROID HORMONE Causes positive Chronotropic & Inotropic effects in excitable tissues ↑CO, SV, resting HR ↑Myocardial intracellular Ca2+ ↑ contraction force & speed ↑Diameter of blood vessel in skin, muscle & heart, ↓ TPR ↑Renin-angiotensin-aldosterone system activity ↑ blood volume Elevates BMR, thermogenesis & oxygen consumption Activation of UCPs ↑Glucose & fatty acid uptake ↑Glucose & fatty acid oxidation, thermogenesis (heat intolerance) and heat dissipation Augmented thermogenesis causes compensatory ↑ in blood flow, sweating & ventilation

15. Increases pulmonary & alveolar Ventilation Triiodothyronine (T3) ↑ Resting respiratory rate (RR) & Respiratory minute ventilation (RMV) to normalize arterial O 2 concentration to compensate for higher oxidation rates ↑ O 2 delivery to tissues by ↑ erythropoietin production Hemoglobin production Folate & cobalamin absorption in GIT Augments growth & maturation of bone & cartilage ↑ fetal linear bone growth, endochondral ossification, epiphyseal bone center maturation after birth Enhances adult bone remodelling, degradation of mucopolysaccharides & fibronectin in extracellular connective tissue

16. Stimulates nervous system ↑ wakefulness, alertness & responsiveness to sensory stimuli ↑ peripheral reflexes, gastrointestinal tone and motility Promotes reproductive health & other endocrine organ function Regulates both ovulatory cycle & spermatogenesis Regulates pituitary function ↑ growth hormone production & release ↓ prolactin production & release ↑ renal clearance of some medications, by enhancing renal blood flow & glomerular filtration rate

17. SUMMARY OF THYROID ACTION

18. GOITERS Any enlarged thyroid is considered as a goiter Hypothyroid Goiter Type I (Primary) Caused by Primary hypothyroidism, ↑TSH due to ↓ T 4 & T 3 feedback Excess TSH causes thyroid enlargement Hyperthyroid Goiter Type II (toxic) : Autoimmune disorder with l ow levels of TSH, Grave’s disease Type III (physiological): Seen during pregnancy, elevated TBG synthesis & renal iodide clearance Euthyroid Goiter Type IV (normothyroid): Pseudo-goiter, normal functioning gland, but enlargement due to invasion by adenomas, carcinomas, bacteria viruses or parasites

19. Thyroid disorder manifested mainly due to T 4 deficiency Depending on the position of lesion, thyroid disorders are Primary disorder: ↓ T 3 & T 4 , & compensatory ↑ in TSH levels suggest a thyroid gland lesion Causes: Bilateral thyroidectomy, 131 I mediated thyroid ablation, Hashimoto’s disease, Pregnancy during prior 6 months, Chromosomal disorder causing turner syndrome, excessive use of antithyroid drugs, lymphocytic thyroiditis, idiopathic thyroid atrophy, neoplastic invasion, antibodies against TSH etc. Secondary disorder: TRH levels may ↑, & TSH, T 3 & T 4 levels ↓, suggests an anterior pituitary lesion Causes: Pituitary neoplasms, Cystic Rathke’s pouch & hyperadrenocorticism, excessive use of antithyroid drugs & Iatrogenic reasons & Glucocorticoid excess HYPOTHYROIDISM

20. Tertiary disorder: ↓ TRH,↑TSH, secondary to administration of TRH, suggests a hypothalamic lesion Causes: Iatrogenic reasons, neoplasms in hypothalamus Other causes of hypothyroidism : Peripheral resistance to T 3 & T 4 due to receptor/post-receptor defects Comorbidities Pernicious anemia Type I & Type II diabetes Lupus erythematous (AI disorder) Sjogren’s syndrome Rheumatoid arthritis celiac disease HYPOTHYROIDISM

21. Symptoms: Loss of appetite, lethargy, obesity, fatigue, weight gain, cold intolerance, joint/muscle pains, ↓ myocardial contractility, bradycardia, depression, fertility issues, constipation, anemia (iron, folate, B 12 & T4 deficiency, defective hemoglobin biosynthesis), accumulation of β -Carotene pigments in liver, β - Carotenemia (herbivores), coarse & dull hair coat (ex: dogs/cats) dry skin, hair thinning etc. Cretinism (congenital hypothyroidism in newborns): impaired neurological functions, stunted growth & physical deformities Myxedema: Severe form of hypothyroidism, thickening of hair & skin, due t accumulation of mucopolysacchrides, hypothermic shock & coma Incidence: Hypothyroidism is more common in females as well as in individuals who are older than 60 years, common in dogs (95% acquired) Treatment: Thyroxine, Levothyroxine HYPOTHYROIDISM

22. HYPERTHYROIDISM Pathogenesis arise due excess production & secretion T 3 & T 4 Causes: Thyroid tumor involving follicular cells Symptoms: Weight loss: ↑BMR, muscle wasting, vitamin deficiency Augmented GI permeability: Diarrhea, vomition, ↑thirst, PU/PD and azotemia Respiratory depression: ↓V T , ↓pulmonary compliance, panting & hypercapnia Cardiovascular effects: ↓TPR, tachycardia, ↑VR, ↑CO, dilatation & LV hypertrophy Blood count: ↑ Erythropoietin, erythrocytosis, leukocytosis, eosinopenia, lymphopenia Serum Enzymology: ↑ALT, ↑AST, ↑AP, ↑LDH, hyperbilirubinemia, fatty liver infiltration Serum Biochemistry: ↑TSH, ↑T 3 & T 4 cells in blood (both bound & free forms) Others: Heat intolerance, hyperglycemia, hyper- cholesterolemia & hyperlipidemia

23. GOITROGENS Thiocarbamide groups in natural goitrogens show antithyroid activity Synthetic drugs carrying thiocarbamide group inhibits thyroxinogenesis Concentrate in thyroid gland, b inds thyroglobulin, gets oxidated Interfere with thyroglobulin activity Prevents coupling of iodotyrosyl groups into T 4 Inhibits activity of Type I deiodinases ( occur in thyroid, liver, kidney & pituitary tissues) Examples of Synthetic Goitrogens Thioamide drugs: Propylthiouracil, Methimazole & Carbimazole Propylthiouracil: t 1/2 = 1 h, binds plasma proteins, cross placenta, blocks peroxidase system, forms PTU-SO 2 H Methimazole: t 1/2 = 2−6 h, cross, placenta & forms, methylthiohydantoin Thiocyanate (SCN − ), pertechnetate (TCO4 − ), perchlorate (CIO4 − ) ions: inhibit NIS & iodine trapping Iodides: decreases T 4 & T 3 release

24. DRUGS TREATING HYPERTHYROIDISM Lithium: Inhibit thyroid hormone synthesis & secretion Amiodarone: Inhibits T 4 → T 3 conversion in peripheral tissue by blocking deiodinases Antiepileptics/ Rifampcin : Augment metabolism in thyroid hormones Sulphonamides: Inhibits iodination & coupling reactions in T 4 , T 3 synthesis Expectorants & topical agents: Iodine containing agents may inhibit hormone synthesis & release

25. REFERENCES Basic and Clinical Pharmacology, 13th Ed., Thyroid & Antithyroid Drugs, Betty J. Dong & Francis S. Greenspan. https://doctorlib.info/pharmacology/basic-clinical-pharmacology-13/38.html Koibuchi , N. (2018). Molecular Mechanisms of Thyroid Hormone Synthesis and Secretion. Belfiore , A., LeRoith , D. ( eds ) Principles of Endocrinology and Hormone Action. Endocrinology. Springer, Cham. https://doi.org/10.1007/978-3-319-44675-2_5 Text book of Medical Physiology, 11th Ed., Guyton & Hall Dukes’ Physiology of Domestic Animals, 12th Ed., William, O Reece Metabolic & Endocrine Physiology, 3 rd edition, Larry R Engelking