17. thyroid gland

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17. thyroid gland

  1. 1. Thyroid gland The name "thyroid" comes from the Greek word which means "shield"
  2. 2. <ul><li>Thyroid gland , the largest single endocrine gland (20-25 g), is </li></ul><ul><li>located just below the level of the larynx </li></ul><ul><li>It has two lobes joined by a central isthmus at tracheal rings 2, 3, 4 </li></ul><ul><li>Blood flow is ~ 5mL/min from superior and inferior thyroid arteries </li></ul>
  3. 3. <ul><li>Composed of numerous spherical follicles with outer layer of cuboidal </li></ul><ul><li>epithelium and filled with proteinous colloid ( proteinaceous depot of thyroid </li></ul><ul><li>hormone precursor ) </li></ul><ul><li>A few C cells ( parafollicular cells ) are seen in the walls of the </li></ul><ul><li>follicles that produce calcitonin , a hypocalcemic hormone </li></ul>Ca ++
  4. 4. <ul><li>About 80 μg/day of iodine is utilized for thyroid hormone synthesis </li></ul><ul><li>Activity of the gland is regulated by TRH-TSH axis </li></ul><ul><li>TRH ( a tripeptide ) thyrotrops </li></ul><ul><li>TSH T 4 , T 3 </li></ul><ul><li>T 4 , T 3 TSH receptors on thyroid gland </li></ul><ul><li>T 4 , T 3 </li></ul>
  5. 5. <ul><li>TSH stimulates all steps of thyroid hormones synthesis </li></ul><ul><li>TSH binds with membrane receptors adenylate cyclase </li></ul><ul><li>c-AMP protein kinases effects </li></ul><ul><li>T 4 , T 3 TSH secretion </li></ul><ul><li>Circulating T 4 & T 3 act directly on the anterior pituitary (negative </li></ul><ul><li>feedback loop) </li></ul>
  6. 6. <ul><li>Hypothalamus receives input and sends a </li></ul><ul><li>signal to the Anterior Pituitary via TRH </li></ul><ul><li>Thyrotrophin Releasing Hormone . </li></ul><ul><li>TRH stimulates the Anterior Pituitary to </li></ul><ul><li>release TSH . </li></ul><ul><li>Thyrotrophin which travels in the blood to </li></ul><ul><li>the Thyroid Gland. </li></ul><ul><li>Thyrotrophin increases I- uptake and </li></ul><ul><li>stimulates production of M.I.T., D.I.T. And </li></ul><ul><li>hence production of T 3 and T 4 . </li></ul><ul><li>Somatostatin released by the Hypothalamus </li></ul><ul><li>inhibits TRH release . </li></ul><ul><li>Protirelin is a synthetic compound that mimics TRH. </li></ul>
  7. 7. Thyrotrophin There is negative feedback between Thyrotrophin and T 4 secreted by the Thyroid gland. Thyrotrophin stimulates follicle cell receptors, which leads to: <ul><li>increased uptake of I- (main mechanism of action) </li></ul><ul><li>stimulates cAMP production inside the follicle cells </li></ul><ul><li>increases synthesis of thyroglobulin </li></ul><ul><li>leads to generation of H 2 O 2 for the iodination of iodine </li></ul>Plasma Iodide Concentration <ul><li>This has a pronounced effect on Thyroid function. </li></ul><ul><li>Daily intake of Iodide (70mg) is required to maintain T 4 production. </li></ul><ul><li>Decreased Iodide in the diet causes decreased hormone production and stimulates </li></ul><ul><li>TSH release. </li></ul><ul><li>Very slow response (weeks) to changed Iodide levels in the blood. </li></ul><ul><li>C an take a long time for imbalances to manifest in symptoms . </li></ul>
  8. 8. Hormone synthesis <ul><li>Iodine trapping and organification: </li></ul><ul><li>extracellular iodide is trapped into follicular cells oxidesed (peroxidase in </li></ul><ul><li>presence of H 2 O 2 ) iodine + tyrosine molecule in thyroglobulin </li></ul><ul><li>MIT & DIT </li></ul><ul><li>Coupling (peroxidase enzyme): </li></ul><ul><li>MIT + DIT T 3 ( triiodothyronine ) </li></ul><ul><li>2 DIT T 4 ( thyroxine ) </li></ul><ul><li>T 3 & T 4 remain stored in the colloid </li></ul>
  9. 9. <ul><li>Release: </li></ul><ul><li>T4, T3, MIT, DIT on thyroglobulin endocytosis lysosomes </li></ul><ul><li>(stimulated by TSH) proteolysis of the thyroglobulin molecule T 4 , T 3 </li></ul><ul><li>secreted </li></ul><ul><li>- MIT & DIT are deiodinized iodine is reused for thyroid hormone synthesis </li></ul>
  10. 10. Steps of thyroid hormone synthesis Iodine trapping (using iodide pump); thyroglobulin synthesis; oxidation of iodide to iodine; iodination of tyrosine molecules within the thyroglobulin molecule to give MIT and DIT at the apical border of the cell; coupling of MIT and DIT to give T3 and T4 still within the thyroglobulin molecule in the colloid; pinocytosis of thyroglobulin and proteolysis of thyroglobulin and release of T3 and T4
  11. 11. Transport of Thyroid Hormones Once T 3 and T 4 are released into the blood they are bound to a serum protein, thyroxine-binding globulin (TBG) , albumin and prealbumin Only free (unbound) hormone is metabolically active Total hormone level increases when TBG increases (in pregnancy or with oral contraceptive treatment) Concentrations of T 3 and T 4 are quite different in blood and inside cells: T 3 <ul><li>Small pool in the body </li></ul><ul><li>Mostly found inside tissue cells </li></ul><ul><li>Fast turnover rate in the body </li></ul>T 4 <ul><li>Large pool in the body </li></ul><ul><li>Mostly found in the blood </li></ul><ul><li>Slow turnover rate in the body </li></ul><ul><li>T 4 is often regarded as a prohormone as it is converted to T 3 once inside cells. </li></ul>
  12. 12. Effects of thyroid hormones <ul><li>T 3 /T 4 enter the target cell cytoplasm T 3 binds to nuclear receptors </li></ul><ul><li>messenger RNA protein synthesis effects on cellular function </li></ul><ul><li>Calorigenic effects: </li></ul><ul><li>oxygen consumption (exception – brain, testes, pituitary) & heat production </li></ul><ul><li>basal metabolic rate (BMR) </li></ul><ul><li>Metabolic effects: </li></ul><ul><li>cellular & gastrointestinal absorption of glucose, glycolisis & gluconeogenesis </li></ul><ul><li>catabolism of free fatty acids + depletion of fat stores & blood lipids (cholesterol) </li></ul><ul><li>protein synthesis & breakdown </li></ul><ul><li>conversion of ß-carotene to vitamin A </li></ul><ul><li>CNS: </li></ul><ul><li>CNS activity and alertness </li></ul><ul><li>CVS: </li></ul><ul><li>enhanced effects of catecholamines cardiac output & heart rate systolic blood </li></ul><ul><li>pressure, peripheral resistance, diastolic blood pressure mean pressure is little </li></ul><ul><li>affected </li></ul><ul><li>- ß-adrenergic receptors number & affinity </li></ul>
  13. 13. <ul><li>Genitourinary: </li></ul><ul><li>deficiency / excess menstrual disturbances </li></ul><ul><li>Growth: </li></ul><ul><li>essential for growth and development </li></ul><ul><li>congenital deficiency thyroid dwarf/ cretinism </li></ul><ul><li>skeletal growth in childhood </li></ul><ul><li>promotion of normal brain development in early postnatal period, deficiency mental </li></ul><ul><li>retardation in cretins </li></ul><ul><li>Alimentary tract: </li></ul><ul><li>excess diarrhea </li></ul><ul><li>deficiency constipation </li></ul><ul><li>Muscle: </li></ul><ul><li>excess muscle weakness (thyrotoxic myopathy) </li></ul><ul><li>Mammary gland: </li></ul><ul><li>milk production </li></ul><ul><li>Bone marrow: </li></ul><ul><li>- deficiency anemia </li></ul>
  14. 14. Effects of Thyroid Hormone on Basal Metabolic rate T 3 GI activity Fat and carbohydrate mobilization Heart rate BMR Metabolic waste products Oxygen consumption Metabolic fuels Cardiac output Respiration Active hyperemia
  15. 15. Abnormalities of Thyroid Function <ul><li>Essentially there are 2 main cases: </li></ul><ul><li>Hyperthyroidism ( elevation of Thyroid </li></ul><ul><li>Hormones ) </li></ul><ul><li>2. Hypothyroidism ( suppression of Thyroid </li></ul><ul><li>Hormones ) </li></ul><ul><li>The reasons may be varied and the symptoms </li></ul><ul><li>can include any organ system . </li></ul>
  16. 16. Hyperthyroidism (Thyrotoxicosis) <ul><li>Excess activity of the Thyroid Gland leads to elevations of T 3 and T 4 . </li></ul><ul><li>The effects are often metabolic, but they can affect growth and </li></ul><ul><li>development if elevated in children. </li></ul><ul><li>Increased BMR and hence O 2 c onsumption </li></ul><ul><li>Hot flushes, or difficulty thermoregulating, sweating, heat sensitive </li></ul><ul><li>Agitated, tremor, weight loss, increased appetite </li></ul><ul><li>Fatigue, tachycardia, hypertension etc. </li></ul><ul><li>There are 2 common conditions associated with elevations in </li></ul><ul><li>Thyroid hormones: </li></ul><ul><li>1. Diffuse Toxic Goitre (or Grave's Disease) </li></ul><ul><li>2. Toxic Nodular Goitre </li></ul>
  17. 17. <ul><li>Diffuse Toxic Goitre (or Grave's Disease) </li></ul><ul><li>Organ specific autoimmune disease </li></ul><ul><li>Thyroid-stimulating immunoglobulins (IgG) targeting the </li></ul><ul><li>receptor </li></ul><ul><li>May also involve mutations in the TRH receptor </li></ul><ul><li>Often see protruding eyes (exophthalmos) </li></ul><ul><li>Often patients are sensitive to catecholamines </li></ul><ul><li>Classic increases in metabolic processes </li></ul><ul><li>Toxic Nodular Goitre </li></ul><ul><li>Usually associated with benign neoplasm, adenoma of thyroid </li></ul><ul><li>May occur in patients with chronic simple goitre </li></ul><ul><li>There is no exophthalmos seen in this condition </li></ul>
  18. 18. <ul><li>There are at least 2 conditions commonly associated with reduced </li></ul><ul><li>thyroid hormone production: </li></ul><ul><li>1. Simple Goitre (or Non-Toxic Goitre) </li></ul><ul><li>2. Myxoedema </li></ul><ul><li>3. Hashimoto's Thyroiditis Simple Goitre (or Non-Toxic Goitre) </li></ul><ul><li>Simple Goitre (or Non-Toxic Goitre) </li></ul><ul><li>Most often associated with reduced dietary iodine intake </li></ul><ul><li>This stimulates Thyrotrophic Hormone release and the </li></ul><ul><li>thyroid gland follicles make more thyroglobulin and the gland </li></ul><ul><li>hypertrophies. </li></ul><ul><li>May manifest as Cretinism if iodine deficiency occurs in children. </li></ul>
  19. 19. <ul><li>Myxoedema </li></ul><ul><li>Immunological in origin </li></ul><ul><li>Symptoms include : </li></ul><ul><li>- Low metabolic rate </li></ul><ul><li>- Slow speech </li></ul><ul><li>- Deep hoarse voice </li></ul><ul><li>- Lethargy </li></ul><ul><li>- Bradycardia </li></ul><ul><li>- Sensitivity to cold </li></ul><ul><li>- Mental impairment </li></ul><ul><li>- Thickening of the skin </li></ul>Hashimoto's Thyroiditis Simple Goitre (or Non-Toxic Goitre) <ul><li>This is a chronic autoimmune disease where thyroglobulin is attacked or another </li></ul><ul><li>part of thyroid tissue </li></ul><ul><li>Often leads to hypothyroidism and myxoedema Simple Non-Toxic Goitre </li></ul><ul><li>Most often associated with reduced iodine </li></ul><ul><li>Leads to accumulation of thyroglobulin in the gland an it hypertrophies </li></ul>
  20. 20. The Parathyroid Gland and Calcium Homeostasis <ul><li>In humans, Calcium balance is maintained by three major hormones </li></ul><ul><li>parathyroid hormone </li></ul><ul><li>calcitonin </li></ul><ul><li>calcitriol </li></ul><ul><li>These hormones regulate Calcium levels by controlling the rate of </li></ul><ul><li>absorption and excretion of Calcium from the body. </li></ul><ul><li>Calcium enters the body by absorption of dietary Calcium from the </li></ul><ul><li>gut and is lost mainly through urinary excretion. </li></ul>
  21. 21. Physiological functions of Calcium in the body include: <ul><li>Maintenance of membrane permeability </li></ul><ul><li>Maintenance of excitability of nerve & muscle </li></ul><ul><li>Release of neurotransmitters, many hormones & exocrine secretions </li></ul><ul><li>Muscle contraction </li></ul><ul><li>Formation of bone and teeth </li></ul><ul><li>Coagulation of blood </li></ul><ul><li>Activity of many enzymes </li></ul>
  22. 22. The total body calcium in adult male amounts to ~ 1200 g (30,000 mmol) <ul><li>~ 99% of body calcium & 80% of phosphorus is found in bone </li></ul><ul><li>Only 1% is found in soft tissues & body fluids </li></ul><ul><li>The exchangeable calcium pool in bone amounts to ~4000 mg (100 mmol) </li></ul><ul><li>The plasma calcium level ranges between 9.00 and 10.5 mg/dL </li></ul><ul><li>(2.1 and 2.6 mmol/L) </li></ul><ul><li>~50% is mainly bound to plasma albumin </li></ul><ul><li>The rest (1.0 – 1.3 mmol/L) is found in ionized form </li></ul><ul><li>This range is kept almost constant by a delicate regulatory mechanism, </li></ul><ul><li>involving parathyroid hormone (PTH), calcitonin and calcitriol </li></ul><ul><li>For Calcium balance to maintained, an intake of 12.5-20 mmol/day </li></ul><ul><li>is recommended for infants/adults </li></ul><ul><li>Higher daily intake (25 – 37.5 mmol) is recommended for adolescents and for </li></ul><ul><li>women during pregnancy, lactation and after menopause </li></ul>
  23. 23. <ul><li>Intestinal absorption of calcium occurs mainly in the duodenum </li></ul><ul><li>Both intestinal absorption and urinary excretion of calcium are under </li></ul><ul><li>hormonal control. </li></ul>
  24. 24. Parathyroid hormone <ul><li>Parathyroid hormone (PTH) is a polypeptide, secreted by chief cells </li></ul><ul><li>of four parathyroid glands located posterior to the lobes of the </li></ul><ul><li>thyroid gland </li></ul><ul><li>PTH is responsible for the tight control of free Calcium in ECF – </li></ul><ul><li>is essential for life </li></ul><ul><li>plasma Calcium levels PTH secretion </li></ul><ul><li>plasma Calcium levels PTH secretion ( negative feedback ) </li></ul><ul><li>levels of calcitriol PTH secretion ( negative feedback ) </li></ul>
  25. 25. Actions of parathyroid hormone (PTH) <ul><li>PTH plasma Calcium </li></ul><ul><li>PTH plasma Phosphate </li></ul><ul><li>In the bone PTH activates osteoclasts mobilezes Ca&PO4 </li></ul><ul><li>In the kidney PTH </li></ul><ul><li>- PO 4 excretion </li></ul><ul><li>- tubular reabsorption of Calcium </li></ul><ul><li>- converts 25-hydroxycholecalciferol active 1,25-dehydroxycholecalciferol </li></ul><ul><li>(calcitriol) promotes intestinal calcium absorption, also mobilizes Calcium </li></ul><ul><li>from the bone </li></ul>
  26. 26. Calcitonin <ul><li>Calcitonin , a poly- </li></ul><ul><li>peptide hormone, </li></ul><ul><li>is secreted by the </li></ul><ul><li>“ C cells” of thyroid </li></ul><ul><li>gland </li></ul><ul><li>Calcitonin secretion </li></ul><ul><li>is stimulated by: </li></ul><ul><li>- hypercalcemia </li></ul><ul><li>( plasma Calcium- </li></ul><ul><li>major) </li></ul><ul><li>- gastrin </li></ul><ul><li>- cholecysokinin (CCK) </li></ul><ul><li>- glucagon </li></ul>Actions of calcitonin <ul><li>Produces rapid in plasma Calcium by: </li></ul><ul><li>suppressing bone osteoclasts mobilization of bone Calcium </li></ul><ul><li>the activity of osteoblasts meneralization of bone ECF Calcium </li></ul><ul><li>in the long term, number of osteoclasts in bones </li></ul><ul><li>has inhibitory effects on the transport of Calcium from the intracellular fluid to the </li></ul><ul><li>extracellular fluid </li></ul>
  27. 27. Vitamin D <ul><li>Vitamin D is a fat soluble vitamin which comes from the diet (main </li></ul><ul><li>source) and the skin (vitamin D 3 /cholecalciferol) </li></ul><ul><li>UV radiation from sunlight 7-dehydrocholesterol </li></ul><ul><li>vitamin D 3 (in skin ) 25-hydroxycholecalciferol (25-(OH)-D ) </li></ul><ul><li>in the liver 1,25-hydroxychlecalciferol (calcitriol) in the kidney </li></ul><ul><li>Formation of calcitriol is stimulated by: </li></ul><ul><li>- PTH </li></ul><ul><li>- plasma Calcium </li></ul><ul><li>- plasma PO 4 </li></ul>
  28. 28. Vitamin D metabolism Actions of calcitriol <ul><li>the rate of calcium uptake </li></ul><ul><li>from the gut </li></ul><ul><li>Stimulate PO 4 reabsorption </li></ul><ul><li>from the gut </li></ul><ul><li>Stimulates Calcium and PO 4 </li></ul><ul><li>reabsorption from the kidney </li></ul><ul><li>High doses osteoclastic </li></ul><ul><li>bone resorption </li></ul>
  29. 29. Clinical Primary hyperparathyroidism ( PTH) <ul><li>Results from failure of the negative feedback of plasma Calcium on </li></ul><ul><li>parathyroid secretion </li></ul><ul><li>Often caused by PTH-secreting tumor </li></ul><ul><li>Plasma Calcium is elevated ( hypercalcemia ) </li></ul><ul><li>PO 4 is reduced </li></ul><ul><li>Bone erosions & cyst formation </li></ul><ul><li>Renal calcium formation </li></ul>Hypoparathyroidism ( PTH) <ul><li>May be caused by: </li></ul><ul><li>- parathyroid autoantibodies or </li></ul><ul><li>- accidental damage during thyroid surgery </li></ul><ul><li>Hypocalcemia </li></ul><ul><li>Elevated plasma PO 4 levels </li></ul><ul><li>Neuromuscular excitability muscle tetany, laryngeal spasm & </li></ul><ul><li>convulsions </li></ul>
  30. 30. Vitamin D deficiency <ul><li>May be due to: </li></ul><ul><li>- inadequate intake </li></ul><ul><li>- lipid malabsorption (vitamin D is a fat-soluble vitamin) </li></ul><ul><li>- patients with chronic renal failure </li></ul><ul><li>Demineralization of bone osteomalacia with bone pain in adults </li></ul><ul><li>Skeletal deformations (rickets) in children </li></ul>
  31. 31. Calcium pool

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