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Intro to Endocrinology BSC 345, Lecture 07, Dr. David Rubin


                          Thyroid Hormones and Metabolism: C...
Intro to Endocrinology BSC 345, Lecture 07, Dr. David Rubin


             6. Drugs affecting iodide [I-] uptake:
        ...
Intro to Endocrinology BSC 345, Lecture 07, Dr. David Rubin


III. Physiological Effects of Thyroid Hormones (Table 6-4)
 ...
Intro to Endocrinology BSC 345, Lecture 07, Dr. David Rubin


       3. Thyroiditis (inflammation of Thyroid follicles)
  ...
Intro to Endocrinology BSC 345, Lecture 07, Dr. David Rubin


              e. Exophthalmus caused by immune-related enlar...
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Thyroid Hormones and Metabolism: Chapter 6 I. Metabolic and ...

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Transcript of "Thyroid Hormones and Metabolism: Chapter 6 I. Metabolic and ..."

  1. 1. Intro to Endocrinology BSC 345, Lecture 07, Dr. David Rubin Thyroid Hormones and Metabolism: Chapter 6 I. Metabolic and Endocrine Physiology of Thyroid Glands A. Anatomy (Fig. 6-1, 2, 3, 9, and Table 6-1) 1. Butterfly-like shaped gland that lies across the trachea 2. Tyrosine is the precursor for Thyroid hormones a. T3 [3,5,3'-Triiodo-L-thyronine] and T4 [L-Thyroxine (3,5,3',5'-tetraiodo-L- thyronine)] are iodinated in three or four positions from free inorganic iodide [I-], respectively. b. T3 is 5-8 fold more active T4. c. rT3 (reverse T3) is present in low concentrations in the thyroid and blood, and is produced by Peripheral Monodeiodination of thyroxine; very low activity compared to T3 & T4. 3. One of the largest endocrine glands composed of Two distinct cell types: a. Follicle cells secrete Thyroid hormones (T3 & T4 Thyroxine = major form) in response to TSH stimulation b. Parafollicular cells "C" (clear) cells secrete Calcitonin (calcium-lowering hormone) and are found in the interfollicular spaces. 4. The Follicle cells consist of a single layer of epithelial cells enclosing the follicle lumen. The lumen is filled with the viscous proteinaceous solution, Colloid. The colloid is composed of granules that are the secretory products of the follicle cell, Thyroglobulin (Tg). Colloid is where the thyroid hormones are stored. 5. Iodide is converted into thyroid hormones in seven steps (Fig. 6-7, KNOW**) a. Active transport of iodide into the thyroid follicular cells across the basal lateral membrane of the thyroid follicle. b. Thyroid Peroxidase (TPO)-catalyzed oxidation1 of iodide into iodine, AND the subsequent Iodination2 of tyrosyl residues with Tg to form mono-iodotyrosyl (T1, MIT) or di-iodotyrosyl (T2, DIT). c. Transfer and Coupling3 of T1 and T2. These then couple via TPO to form T3 (T2 and T1) or T4 (T2 and T2), while still attached to Tg. d. Storage of Tg in the lumen of the thyroid follicle as colloid. e. Under TSH stimulation: Endocytosis of colloid droplets back into the follicle by Pinocytosis where they fuse with Lysosomes and are Proteolysed to release the residues from the glycoprotein (T4, T3, T2, and T1, as well as free iodotyrosines). T1 and T2 are rapidly de-iodinated and the liberated iodine is recycled/scavenged in the follicle cell. Tg is reabsorbed along with Tyrosine in the follicle and sequestered into the colloid to go through another round of Iodide Organification. f. T4 and T3 are released into the circulation, where they are bound to plasma proteins Thyroid-Binding Globulins (TBG). g. Most is bound and physiologically inactive, only the free fraction is active. 1
  2. 2. Intro to Endocrinology BSC 345, Lecture 07, Dr. David Rubin 6. Drugs affecting iodide [I-] uptake: a. Enhancers: TSH, iodine deficiency (⇑ MIT:DIT ratios), TSH receptor antibodies, autoregulation b. Inhibitors: I- excess (down-regulation of uptake, Wolff-Chaikoff effect), cardiac glycosides (digoxin), Oubain (effects Na+-K+ ATPase), and perchlorate (PClO4-, competes with I- transport proteins). B. General Physiology of Thyroid hormones 1. Principal targets are: skeletal & cardiac muscle, liver, GI, and kidney 2. ⇑ O2 consumption and the Basal Metabolic Rate (BMR) a. Euthyroid (normal) is about 30-40 kcal/m2 body surface area/hr b. Hyperthyroid = 60-65 kcal/m2 body surface area/hr along with ⇑ cardiac output, ⇑ body temp., warm skin, ⇑ food intake but weight loss, sweating, hyperactive, exagerated reflexes, insomnia and irritability, goiter, Exopthalmus (bulging eyes), and short attention span c. Hypothyroid = 20-25 kcal/m2 body surface area/hr Inverse symptoms compared to hyperthyroid, and a Myexdemic "Puffy" appearance: accumulation of mucoproteins and fluid under the skin due to altered electrolytes. 3. T3 and T4 are lipophilic 4. Nuclear Hormone Receptors ⇒ affect gene transcription 5. Long-term physiological homeostasis maintenance II. Secretion Mechanisms of Thyroid Hormones A. Metabolism (Fig. 6-12) 1. Although T4 is the major product released from the thyroid, T3 is the active form The ratio of T4:T3 is about 20:1. 2. Although both T4 & T3 circulate, the tissues obtain 80% of their T3 by de-iodinating T4 to convert it to T3 (deiodinase removes an iodide from T4 to convert it to T3). 3. 95% of the rT3 is produced by de-iodinating T4 to convert it to rT3. B. Stimulators of T4 and T3 release: 1. TSH is the main stimulator 2. VIP (vasoactive intestinal peptide) and β-adrenergic agonists both acting through adenylcyclase-cAMP pathway. 3. Long-Acting Thyroid Stimulators (LATS) are Antibodies (Ab) which mimic the actions of TSH. (also called Thyroid Stimulating Immunoglobulins (TSI)). Because LATS are not down-regulated by high blood levels of thyroid hormones, their expression levels represent a pathological state. 4. Low temperature will stimulate TRH release. C. Catabolism of thyroid hormones (Fig. 6-13) 1. One third of T4 leaving the plasma is conjugated with glucuronide or sulphate in the liver and excreted in the bile. 2
  3. 3. Intro to Endocrinology BSC 345, Lecture 07, Dr. David Rubin III. Physiological Effects of Thyroid Hormones (Table 6-4) A. Two main categories of biological responses: 1. Effects on cellular differentiation and development 2. effects on metabolic pathways Response Observation(s) Fetal Development a. Fetal Thyroid-Pit axis functions @ week 11 in mammals. b. Also acts as a developmental hormone in synergism with GH to affect development in mammals, and metamorphosis in non- mammalian vertebrates. Ex. frog tadpoles. O2 consumption/heat production T3 ⇑ O2 consumption & heat production by stimulation of Na+, K+ ATPase (Fig. 6-16) (except in brain, spleen, testis, & ovary) C.V. effects T3 ⇑ gene transcription of myosin & Ca2+ ATPase, and ⇑ C.O. an H.R. in hyperthyroidism. Sympathetic effects T3 ⇑ the number of β-adrenergic receptors in the heart & skeletal muscles, adipose tissue, and lymphocytes. Skeletal Actions Stimulation of osteoclasts & osteoblasts for bone turnover (resorption > formation) CHO and lipid metabolism ⇑ hepatic gluconeogenesis and glycogenolysis G.I. effects T3 stimulates gut motility Hyperthyroidism ⇑ Protein catabolism III. Pathophysiology A. Hypothyroidism 1. Insufficient synthesis of thyroid hormones due to lack of iodine in diet (destruction of thyroid tissue) Fetal. Hypothyroidism due to lack of dietary iodine during early stages of development results in Cretinism in humans (decreased mental capacity). Adult. Hypothyroidism due to lack of dietary iodine in adults causes Goiter, an enlargement of the thyriod due to hypertrophy due to excess TSH stimulation. 2. Hypothyroidism pituitary lesions on thyrotropes, or ⇓ TRH, or ⇓ TSH 3
  4. 4. Intro to Endocrinology BSC 345, Lecture 07, Dr. David Rubin 3. Thyroiditis (inflammation of Thyroid follicles) a. Primary Hypothyroidism Plasma TSH is ⇑, and T4 is low b. Hashimoto's Disease i. Thyroid follicles are attacked by the immune system (⇑ IgG-type) ii. Plasma TSH is ⇑, and T4 is low iii. Goiter is also present B. Hyperthyroidism, 1a. Antibodies called Thyroid Stimulating Immunoglobulins (TSI) can attack the TSH receptors on the thyroid gland causing it to be stimulated (Autoimmune Disease) which also may result in Goiter. 1b. Thyrotoxicosis is the clinical term for hyperthyroidism, Grave's Disease is the most frequent form of thyrotoxicosis. i. ⇑ T3 & T4 ii. Goiter iii. Exopthalmus (can see "top" white of the eyes) iv. Due to the presence of an IgG globulin of the LATS type which stimulates the TSH receptor on the thyroid follicle. 2. Negative Feedback shuts down TRH and TSH but still ⇑ [thyroxine] 3. If a sudden episode occurs, it's sometimes referred to as a Thyroid Storm 4. Some types of Diabetes are also caused by autoimmune reactions C. Pathophysiological Symptoms of Thyroid Disease 1. Hypothyroidism Symptoms (⇓ Thyroxine) due to a. ⇓ Thyroxine slows the metabolic rate and oxygen consumption cold-intolerant, Lethargy, Obesity b. ⇓ Thyroxine ⇒ ⇓ protein synthesis Results in brittle nails, thinning hair and dry skin slow bone and tissue growth of children, shorter stature c. ⇓ Thyroxine ⇒ ⇓ Nervous System actions Slowed reflexes, slowed speech and thought process d. ⇓ Thyroxine ⇒ ⇓ Cardiac output slower heart rate = Bradycardia 2. Hyperthyroidism Symptoms (⇑ Thyroxine) a. ⇑ Oxygen consumption and metabolic rate ⇒ warm and sweaty skin warm-intolerant b. ⇑ Protein catabolism and muscle weakness ⇒ weight loss c. ⇑ Thyroxine induces nervousness and excitability, sleeplessness (insomnia), irritability, and psychosis. d. ⇑ Thyroxine influences the heart β-adrenergic receptors ⇒ rapid heart beat and force of contraction due to up-regulation of β1-cardiac receptors  Up-regulation of receptors is analagous to the PRL-LH receptors in the gonads 4
  5. 5. Intro to Endocrinology BSC 345, Lecture 07, Dr. David Rubin e. Exophthalmus caused by immune-related enlargement of muscles and tissues in the eye sockets. f. Diffuse Goiter (swollen neck) D. Treatmant for Thyroid Disease 1. Hypothyroid a. Administer synthetic T4; Synthroid. 2. Hypterthyroid (Thyrotoxicosis) a. Reduce the T3:T4 levels to acheive a euthyroid state b. Administering antithyroid drugs such as Thiouracil (which block the peroxidase system) c. Ingesting radioactive iodine to cause destruction of the tissue d. Surgical Ablation of the thyroid gland. 5

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