Thyroid Metabolic Hormones PDF

Thyroid Metabolic Hormones Lecture Outline I. Synthesis and secretion of the thyroid metabolic hormones II. Physiological functions of the thyroid hormones III. Regulation of thyroid hormone secretion IV. Diseases of the thyroid 1 Thyroid Metabolic Hormones Objectives 1. 2. 3. 4. 5. 6. 7. Describe t...

Thyroid Metabolic Hormones Lecture Outline I. Synthesis and secretion of the thyroid metabolic hormones II. Physiological functions of the thyroid hormones III. Regulation of thyroid hormone secretion IV. Diseases of the thyroid 1 Thyroid Metabolic Hormones Objectives 1. 2. 3. 4. 5. 6. 7. Describe the anatomy and histology of the thyroid gland and how these relate to its function Explain the synthesis and secretion of thyroid hormones T3 and T4 Define the role of iodine in the thyroid gland and its incorporation into tyrosine residues of thyroglobulin Identify thyroid hormone mechanism of action Describe the roles of the hypothalamus and pituitary in regulating thyroid function – including TSH Understand pathophysiology of hyperthyroidism Understand pathophysiology of hypothyroidism 2 References Assigned reading from your text: Hall Chapter 77 3 I. Synthesis And Secretion Of The Thyroid Metabolic Hormones 4 Thyroid Gland Anatomy ❑ Thyroid Gland Normal thyroid is a firm, reddish brown, smooth gland It synthesizes thyroid hormones Iodine-containing amino acids that regulate body’s BMR – Thyroxine (T4) and Triiodothyronine (T3) Normal thyroid function required for: – Normal infant development of CNS – Pediatric skeletal growth and maturation – Adult function of multiple organ systems Thyroid dysfunction is a common endocrine disorder 5 Thyroid Gland Anatomy ❑ Location and structure – Located in the neck below the larynx – Palpable in the anterior neck in front of the trachea – “H” – shaped left and right lobes interconnected by a narrow isthmus Covers rings 2-4 of the trachea ❑ Parathyroid glands embedded in the four lobes of thyroid tissue 6 Innervation ❑ Autonomic nerves innervate the thyroid gland – During thyroid surgery- anticipate intraoperative nerve monitoring of the RLN 7 Blood Supply ❑ Thyroid gland has one of the highest rates of blood flow per gram of tissue Arterial supply – – Superior thyroid artery – Supplied from the external carotid artery Inferior thyroid artery – Supplied from the thyrocervical trunk of the subclavian artery Venous drainage – – Superior and middle thyroid veins drain into the IJ vein Inferior thyroid vein drains into the brachiocephalic vein 8 Thyroglobulin ❑ Thyroid gland composed of closed follicles lined by cuboidal epithelia that secrete into the interior of the follicles Lined by cuboidal epithelia that secrete into the interior of the follicles Protein-rich colloid Composed of a large glycoprotein-thyroglobulinthat contains the thyroid hormones T4 and T3 9 Histology ❑ Histologic appearance d/t presence of sacs- thyroid follicles – Follicles have a layer of simple cuboidal epithelial cells at their surface; ❑ Between follicles in the interstitium are C cells that secrete calcitonin – Calcitonin is a minor hormone involved in Ca2+ and phosphate homeostasis – Calcitonin has no relationship to T4 nor T3 follicles 10 Thyrotropin-Releasing Hormone (TRH) ❑ TRH is produced and release by neurons in the paraventricular nucleus of the hypothalamus- a major location for mediating stress responses Its release has a diurnal rhythm Its is inhibited by stress Acts on thyrotrope cells in the anterior pituitary 11 Iodide Pump- The Sodium-Iodide Symporter ❑ Formation of thyroid hormones – requires iodine Iodide Trapping by follicular cells from ECF by Na+/I- Cotransport Iodide and chloride transported by pendrin Facilitated diffusion Thyroglobulin synthesized in follicular cells (to Golgi); secreted→ colloid by exocytosis; Oxidation of iodide - vesicle containing thyroglobulin also contains peroxidase; peroxidase oxidizes iodide 12 Outline of Thyroid Hormone Biosynthesis 13 Synthesis of Thyroid Hormone ❑ Iodination- stimulated by TSH – Oxidized iodine combines with tyrosine amino acids in the thyroglobulin molecule to form: Monoiodotyrosine (MIT) and Diiodotyrosine (DIT) – Occurs in seconds to minutes) ❑ Conjugation of two iodinated tyrosyl groups (DIT and MIT) on TG produce T4 and T3 – Stimulated T3 and T4 (+ MIT and DIT residues) remain attached to thyroglobulin in the form of colloid within thyroid follicles for months – Small droplets of follicle colloid taking up by pinocytosis at apical membrane. – Droplets contain T3, T4, RT3, MIT, and DIT ❑ Endocytosis of thyroid colloid→ follicular cells – Hydrolysis of TG when endocytic vesicles enter lysosomal pathway → produce free T4 and T3 + iodinated residue MIT & DIT returns iodide to intracellular pool within follicular cells – T4 (90%) T3 (10%) secreted by exocytosis into the ECF 14 Thyroid Hormone Function ❑ T4 acts as a prohormone Outer ring deiodonation converts to active form T3 T3 acts on TR which is linked to thyroid regulatory elements (TREs) on target genes. Major determinant of metabolic rate. – Increases heart rate, cardiac output and respiration – Increases heat production – Critical for normal growth and development. 15 Peripheral Activation of T4 ❑ T4 and T3 poorly soluble in water- so bound to plasma proteins Most secreted hormone is T4 directly released from thyroid Most activity from T3; 75% T3 from deiodination of T4 in peripheral tissues Thyroid binding globulin- Protein binding provides a large reservoir of hormones- long ½ half – T4 7 days; T3 1 day 99% both T4 and T3 are protein bound; T4 More bound During starvation, enzyme that converts T4→T3 shows a different expression – Lowers basal metabolic rate 16 Effect of Starvation on Plasma Levels of T4, T3, and RT3 17 II. Physiological Functions of Thyroid Hormones 18 Thyroid Hormones Activate Nuclear Receptors ❑ Thyroid hormones are transported across the plasma membrane by carrier-mediated processes. Intracellularly- bind with receptors on mitochondria and in nucleus Increase rate of ATP synthesis in mitochondria In nucleus, the hormone-receptor complex activates specific genes – Changes rate of transcription which affects metabolic activities by increasing/decreasing enzymes 19 Mechanism of Action ❑ General genomic mechanism of action occurring in peripheral tissues T3 and T4 are released from plasma binding proteins and enter cells by simple diffusion through the plasma membrane or by carrier – mediated transport – Exact mechanism is unknown T4 is deiodinated to T3 in the cytosol and T3 enters the nucleus T3 combines with a nuclear receptor that stimulates transcription of genes for the production of mRNAs with the subsequent translation of proteins in the cytosol; Several types of proteins are produced Nongenomic mechanisms of action occur in some tissues – Not by means of transcription and translation – But possibly by means of G-protein mediated reactions 20 23 T4 ❑ T3 (2-3%), T4 (97-98%) and RT3 (virtually nil) are released from the basolateral membrane into blood capillary plasma by an unknown mechanism Greater than 99.5% of the T3 and T4 bind to thyroid-binding globulin (TBG) or transthyretin (TTR) in the plasma very quickly So there are small amounts of free T3 and T4 also present in the plasma TBG and TTR are made in the liver – Hormones have a much higher affinity for TBG 21 22 Most Thyroxine Secreted Converted to Triiodothyronine Secretion and Interconversion of Thyroid Hormones in Adults 22 III. Regulation of Thyroid Hormone Secretion 23 Thyroid Stimulating Hormone (TSH) ❑ Effects of TSH operate through a G-protein reaction and the 2nd messenger cAMP – Increased activity of the iodide pump – Increased iodination of tyrosine residues – Increased endocytosis from thyroid follicle – Increased break down of thyroglobulin – Increased secretion of T3 and T4 into blood plasma – Increased thyroid hyperplasia (increased number of follicular cells) and alteration of histology 24 24 Control Of TSH Secretion ❑ The hypothalamus neurons secrete thyrotropin – releasing hormone (or TRH) into portal blood TRH stimulates the anterior pituitary to produce and increase the secretion of TSH TSH is released into the general circulation and exerts its effects on the thyroid gland- Thyroid hormone synthesis and secretion by thyroid follicular cells TSH has a trophic effect on the thyroid gland; sustained excess causes hyperplasia When thyroid hormone levels reach 1.75x normal, negative feedback mechanisms exerted by T4 and T3 by inhibiting TRH and TSH 25 IV. Diseases of the Thyroid 26 TSH and Goiter ❑ TSH- Thyroid Stimulating Hormone or thyrotropin- binds to TSH receptors on thyroid epithelial cells Excess TSH can produce hypertrophy of the thyroid gland called goiter 27 Pathophysiology - Hyperthyroidism ❑ Hyperthyroidism – Thyroid Gland Becomes Hyperplastic/Hypertrophied – Graves Disease (Exophthalmic Goiter) Most common Most Common Form of Hyperthyroidism Females: Males 8:1 Diagnosis- Low TSH, High T3 and T4 – Symptoms High Body Temperature and BMR with Excessive Sweating Hypertension, hypersympathetic state Increased minute ventilation Weight loss Heat intolerance, warm skin Hand Tremor (Mild as Compared to Parkinson’s) Exopthalmos Goiter ❑ Thyroid storm – An acute increase in thyroid activity – Anesthetic concern 28 Anesthetic Considerations of Hyperthyroidism Elective surgery→ euthyroid patient is optimal Emergency surgery→ beta blocker, glucocorticoid, 6-8 weeks treatment with propylthiouracil (PTU) and beta blocker – PTU decreases thyroid hormone formation Goiter may cause tracheal deviation Exopthalmos increases the risk of corneal abrasion Thyroidectomy may be done to treat hyperthyroidism. – Risks include: Hypothyroidism Hemorrhage Recurrent laryngeal nerve injury Hypocalcemia 29 Pathophysiology – Hypothyroidism ❑ Hypothyroidism –mostly opposite of hyperthyroidism (may include goiter) Hashimoto’s disease or thyroiditis – – Autoimmune antibodies are made against thyroid gland tissues. – Tissues converted to non-functional fibrotic tissues, therefore, little or no T3 nor T4 are Produced. Most common form of hypothyroidism and predominant in females Diagnosis- high TSH and low T3 and T4 – Synthetic T4; Initial response to therapy is decreased TSH Symptoms – Peripheral vasoconstriction – Decreased heart rate/contractility – Decreased minute ventilation/ reduced response to low O2/high CO2 – Effusions common – Weight gain – Cold intolerance – Dry hair, skin; – Constipation – Depression 30 Myxedema ❑ Myxedema- Total lack of thyroid function Symptoms opposite those of hyperthyroidism – Hypoventilation, hypothermia, CHF – Elevated ADH → dilutional hyponatremia → edema – Prone to drug-induced respiratory depression – Edematous skin (facial and under eyes) - caused by deposition of glycosaminoglycans in interstitium of skin Old molecules remain, attract fluid, result in non-pitting edema – Deposition attract fluid (edema) resulting in non-pitting edema) Cretinism – irreversible intellectual disability d/t hypothyroidism in childhood ❑ Myxedema coma – Impaired mentation resulting from severe hypothyroidism Has a high mortality rate – Typically occurs in elderly patients → precipitated by infection 31 Anesthesia Concerns of Hypothyroidism ❑ Hypothyroid patient typically ok for elective surgery; cancel myxedema – Airway obstruction due to swollen vocal cords, large tongue, goiter – Delayed gastric emptying – More susceptible to hypotension of anesthetic agents Decreased CO, blunted baroreceptor reflexes 32 1. Which of the following is not essential for normal biosynthesis of thyroid hormones? A. Iodine B. Ferritin C. Thyroglobulin D. Protein synthesis F. TSH 2. The metabolic rate is least affected by an increase in the plasma level of A. TSH B. TRH C. TBG D. Free T4 E. Free T3 3. In which of the following conditions is it most likely that the TSH response to TRH will be reduced? A. Hypothyroidism due to tissue resistance to thyroid hormone B. Hypothyroidism due to disease destroying the thyroid gland C. Hyperthyroidism due to circulating antithyroid antibodies with TSH activity D. Hyperthyroidism due to diffuse hyperplasia of thyrotropes of the anterior pituitary E. Iodine deficiency 4. Which of the following would be least affected by injections of TSH? A. Thyroidal uptake of iodine B. Synthesis of thyroglobulin C. Cyclic adenosine monophosphate (cAMP) in thyroid cells D. Cyclic guanosine monophosphate (cGMP) in thyroid cells E. Size of the thyroid 5.A patient has an elevated thyroxine (T4) concentration, a low plasma TSH concentration, and her thyroid gland is smaller than normal. What is the most likely explanation for these findings? A. A lesion in the anterior pituitary that prevents TSH secretion B. Patient is taking propylthiouracil C. Patient is taking thyroid extract D. Patient is consuming large amounts of iodine E. Graves’ disease 33