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Thyroid Hormones

  I.    Functional anatomy
        a. In mammals, thyroid hormones are essential for normal growth and
 ...
to as much as 250x that of the plasma. The pump can be blocked by
           anions like percholate and thiocynate, which ...
1. Attachment of one iodine to a tyrosine produces
            monoiodotyrosine (MIT or T1)
         2. Attachment of two ...
ix. PTU can also block the condensation of thyroglobulins as well as
                  the deiodinase enzyme that converts...
2. Increased TSH (primary), decreased total T4, decreased free
            T4 and Decreased T3 uptake
         3. Total T4...
iii. Phenobarbital
b. Hyperthyroidism
       i. Also known as Graves’ disease, toxic adenoma and goiter
      ii. Symptoms...
1. In the short term it may focus on making the body less
   responsive to the stimulus given by the thyroid hormone
   (b...
6. The conversion of T4 to T3 by 5’-deiodinase in the peripheral
   tissues is inhibited by ipodate, propanolol and a high...
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Thyroid Hormones.doc

  1. 1. Thyroid Hormones I. Functional anatomy a. In mammals, thyroid hormones are essential for normal growth and maturation. Therefore, thyroid hormones are major anabolic hormones. b. Iodine is gathered by dietary intake in the form of iodide. The ion form is absorbed from the small intestine c. Thyroid consists for two lobes attached to either side of the trachea i. Butterfly d. They are connected to each other by the isthmus (a band of thyroid tissue) e. It consists of an aggregate of follicles, which contain a thick, gel-like substance called colloid. Colloid is a solution of one large protein, thyroglobulin, which is the storage form of the thyroid hormones f. In between follicles are the parafollicular cells (C cells) which are the source of calcitonin. II. Thyroid Hormones a. Secreted by the thyroid gland b. Required for growth and maturation c. T4 (thyroxine), T3 (triiodothyronine--most active) and Calcitonin (decreases serum calcium) d. Inadequate hormones leads to hypothyroidism i. Signs and symptoms 1. bradycardia 2. poor resistance to cold 3. mental and physical retardation e. Excess hormones leads to hyperthyroidism i. Signs and symptoms 1. tachycardia 2. cardiac arrhythmia 3. body wasting 4. nervousness 5. tremor 6. excess heat production f. These hormones have an effect on every cell in the body except for the adult brain, spleen, testes, uterus and the thyroid gland itself g. To form normal quantities of thyroid hormone, about 50mg of iodine is required each year or about 1mg/wk. Iodine is absorbed from the GI and excreted by the kidney, but some is absorbed by the thyroid. h. Iodide transports actively transport iodide from the basal membrane of follicular cells (called an iodide trap) to the apical membrane where they are used for iodination of thyroglobulin in the thyroid i. An active transport mechanism (pump) on the basal surface of the thyroid follicle can raise the concentration of iodine within the cell
  2. 2. to as much as 250x that of the plasma. The pump can be blocked by anions like percholate and thiocynate, which compete with iodine. Large amounts of iodide with also inhibit the pump and thyroid hormone synthesis (Wolff-Chaikoff effect). i. Iodine ions are oxidized to iodine by peroxidase located on the apical membrane. Iodine is capable of combining with the amino acid tyrosine. This peroxidase also catalyzes iodination and coupling of tyrosine residues within thyroglobulin. j. Binding Mechanism i. Binds to a receptor located in the nucleus or cytoplasm ii. Causes transformation of the receptor to an exposed DNA binding domain iii. Binds to an enhancer like element in DNA and causes the transcription of genes for a new protein leading to a physiologic response 1. the need for gene transcription and protein synthesis delays the onset of action of these hormones k. Synthesis and Secretion i. It involves six interrelated processes that begin when TSH binds to follicular cell receptors ii. Formation and storage of thyroglobulin 1. Thyroglobulin is synthesized on the ribosomes then sugar residues are attached (glycosylated) in the ER, and molecules are packed into vesicles and then transport to the Golgi. These transport vesicles move to the apex of the follicle cell where their contents are discharged into the lumen and become part of the stored colloid. iii. Iodide trapping and oxidation to iodine 1. To produce the functional iodinated hormones the follicle cells must accumulate iodide (anions of iodide) from the blood. Since their intracellular concentration of iodides is over 30x higher than that in blood, iodide trapping depends on active transport. Upon entry, iodides are oxidized by removal of electrons and converted to iodine. The enzyme peroxidase, which is located at the apical border of the follicle cell, catalyzes oxidation and coupling iv. Ionidation 1. blocked by propylthiouracil (PTU) and methmazole 2. Once formed, iodine is attached to the tyrosine amino acids forming part of the thyroglobulin colloid. This iodination reaction occurs at the apical follicle cell colloid junction and is mediated by peroxidase enzymes v. Coupling of T2 and T1
  3. 3. 1. Attachment of one iodine to a tyrosine produces monoiodotyrosine (MIT or T1) 2. Attachment of two iodines produces diiodotyrosine (DIT or T2) 3. Then enzymes within the colloid link T1 and T2 together a. Tow linked DITs result in T4 and a coupling of MIT and DIT produces T3. 4. At this point, however, the hormones are still part of the thyroglobulin colloid. When iodine is abundant mainly T4 is formed but when iodine becomes scarce, the production of T3 increases. vi. Colloid endocytosis 1. Hormone secretion requires that the follicle cells reclaim iodinated thyroglobulin by endocytosis and combine the vesicles with lysosomes vii. Cleavage of the hormones for release 1. With in the lysosomes, the hormones are cleaved out of the colloid by lysosomal enzymes. The hormones then diffuse from the follicle cells into the bloodstream. The main hormonal product secreted is T4 (20 T4 to 1 T3). Some T4 is converted to T3 before secretion (blocked by PTU), but most T3 is generated in the peripheral tissues. When iodide availability is restricted, the formation of T3 is favored. Because T3 is 3x as potent as T4, this response provides more active hormone per molecule of organified iodide. The proportion of T3 is also increased when the gland is hyperstimulated by TSH or other activators. viii. Peripheral conversion of Thyroid hormones 1. More than 99% of the T4 and T3 molecules in the blood are bound to serum proteins. About 80% bind to thyroxine binding globulin (TBG) and most of the rest is bound either to albumin or thyroxine binding prealbumin (TBPA). Less than 1% of the T4 and T3 is in a free and active form. 2. The protein bound fraction serves as a reservoir of preformed hormone. T4 binds more tightly to serum binding proteins than T3 resulting in a lower clearance rate and longer half life. (6-7 days for T4 vs. 1 day for T3). 3. T4 is the major hormone. About 40% of the T4 is converted to T3 by a 5’-deiodinase present in many tissues of the body, especially liver, kidney and the anterior pituitary. T3 is more potent. This deiodination reaction is the major pathway for metabolic inactivation or disposal of T4.
  4. 4. ix. PTU can also block the condensation of thyroglobulins as well as the deiodinase enzyme that converts T4 to T3 x. Elevated iodide levels can competitively inhibit the iodination of tyrosine residues l. Function and Regulation i. Bone growth (synergizes with GH) 1. it is required for normal synthesis and secretion of GH ii. CNS maturation (during fetal life and for the first few years of postnatal life) 1. includes neuronal proliferation, differentiation, myelinogenesis, neuronal outgrowth and synapse formation iii. Beta adrenergic effects 1. increase the number and affinity of beta adrenergic receptors (heart) iv. Increases basal metabolic rate via sodium-potasium ATPase activity 1. increases oxygen consumption and body temperature 2. calorigenic action v. Increased glycogenolysis, gluconeogenesis and lipolysis 1. accelerates cholesterol clearance from the plasma vi. Increases cardiac output, heart rate, stroke volume, contractility and respiratory rate vii. T4 functions: 4 Bs 1. brain maturation 2. bone growth 3. beta adrenergic effects 4. BMR increase viii. Regulation 1. TRH (thyroid regulatory hormone) form the hypothalamus stimulates TSH from the pituitary which stimulates follicular cells 2. Negative feedback by T3 to the anterior pituitary decreases sensitivity to TRH. 3. TSI, like TSH, stimulates follicular cells (seen is Graves’ disease) III. Thyroid Disorders a. Hypothyroidism i. Signs and Symptoms: 1. Cold intolerance, hypoactivity, weight gain, fatigue, lethargy, decreased appetite, constipation, weakness, decreased reflexes, myxedema (facial or periorbital) dry cool skin and coarse brittle hair
  5. 5. 2. Increased TSH (primary), decreased total T4, decreased free T4 and Decreased T3 uptake 3. Total T4 will increase in pregnancy and with the use of oral contraceptives. It will will decrease in such disorders as nephritic syndrom and with the use of androgens. Therefore, total T4 is often a poor index of thyroid function 4. Decreased mental capacity: thought and speed are slow and memory is poor 5. Lack of thyroid hormone is likely to cause loss of libido, while great excesses can cause impotence. In women, lack of thyroid hormone often causes excessive a frequent bleedings in some women. 6. A complex of protein, hyaluronic acid and chondroitin sulfate (mucopolysaccharide) accumulates in the extracellular space of the skin. Its oncotic action holds water giving rise to a nonpitting edema (myxedema). 7. Cretinism a. Endemic cretinism occurs where ever endemic goiter is prevalent (lack of dietary iodine) b. Sporadic cretinism is caused by a defect in T4 formation or developmental failure in thyroid formation c. Symptoms: pot-bellied, pale, puffy faced child with protruding umbilicus and protuberant tongue ii. The most common cause of low thyroid production is an autoimmune disease called Hashimoto’s thyroiditis in which your lymphocytes make antibodies, which slowly and gradually disable the hormone producing cells in your thyroid gland. iii. In severe cases, hyaluronic acid and chondroitin sulfate complexes with protein and is deposited in the extracellular spaces of the skin causing water to accumulate osmotically (myxedema) iv. Drug: Levothyroxine (T4) 1. adverse effects: a. nervousness b. heart palpitations c. tachycardia d. intolerance to heat e. unexplained weight loss 2. Metabolized by the P 450 enzyme system a. Drug interaction with anything that induces the p450 enzyme i. Phenytoin ii. Rifampin
  6. 6. iii. Phenobarbital b. Hyperthyroidism i. Also known as Graves’ disease, toxic adenoma and goiter ii. Symptoms: 1. Heat intolerance, hyperactivity, weight loss, chest pain and palpitations, arrhythmias, diarrhea and increased reflexes iii. Signs: 1. Decrease TSH (if primary) increased total T4, increased free T4 and increased T3 uptake, tremor and difficulty sleeping 2. Hyperthyroid women often exhibit greatly reduced bleeding or none at all 3. Increased metabolic rate and oxygen consumption 4. In spite of increased appetite, there is generally weight loss, protein wasting and muscle weakness (thyrotoxic myopathy) 5. Excitability, irritability and restlessness 6. Tachycardia and increased cardiac output (increased beta adrenergic stimulation) 7. Exophthalmos (Graves’ disease) iv. Graves’ Disease 1. thyrotoxicosis 2. ophthalmopathy (proptosis, EOM swelling), pretibial myxedema, diffuse goiter 3. And autoimmune hyperthyroidism with thyroid stimulating TSH receptor antibodies over stimulate the whole gland to make too much hormone. 4. About 5% of patients with Graves’ disease also have some involvement with their eyes in which the eyes may become inflamed and appear enlarged. 5. Autoantibodies called LATS long acting thyroid stimulator) interact with the TSH receptor on the follicular cell and mimic the stimulator actions of TSH. 6. The thyroid gland enlarges and forms a diffuse toxic goiter with synthesizes thyroid hormones at an accelerated rate v. This most commonly (70-80% of US cases) results from a generalized over activity of the entire thyroid gland, a condition also know as diffuse toxic goiter or Graves’ disease. 10% of hyper thyroid patients have one or more small benign tumors in their gland (hot nodules), which make hormone at too high a rate. This is called toxic nodular goiter or plummer’s disease. vi. Treatment:
  7. 7. 1. In the short term it may focus on making the body less responsive to the stimulus given by the thyroid hormone (beta blockers). 2. removal of part or all of the thyroid glad by surgery or radioactive iodide (beta particle radiation with I131) a. the active accumulation of iodide into the thyroid gland is the basis for selective cell destruction by radioactive iodide b. avoid radiation therapy during pregnancy and in children and in Graves’ disease if characterized by prominent exopthalmia c. useful in patients in which antithyroid drugs are not effective or not tolerated 3. inhibition of thyroid hormone synthesis by PTU and methimazole (short half life) a. used in uncomplicated hyperthyroid conditions b. inhibits the iodination of tyrosyl residues on the thyrogobulin c. inhibits the coupling reactions to form DIT, T3 and T4 d. slow onset e. not effective in the case of thyroid storm f. adverse effects are rare and include agranulocytosis, rash and edema, maculopapular rash, hypersensitivity and immune based arthralagia, jaundice, lupis and vasculitis g. both drugs cross the placental barrier but PTU is safer in pregnancy because it is extensively protein bound 4. blockade of proteolytic hormone release from thyroglobulin a. also done by ipodate b. iodide inhibits iodination of tyrosine and the release of the hormone by an unknown mechanism i. inhibits coupling to form DIT, T3 and T4 c. good for short term therapy d. reduces thyroid vascularity e. given PO f. adverse effects i. sore throat ii. rashes iii. ulceration of mucous membrane iv. metallic taste 5. use of beta blockers such as propanolol to block the sympathetic stimulation
  8. 8. 6. The conversion of T4 to T3 by 5’-deiodinase in the peripheral tissues is inhibited by ipodate, propanolol and a high dose of PTU 7. Iodide a. Usually given as KI (lugol’s solution) b. Possible use in thyrotoxicosis and preoperatively c. Decreases gland size and fragility and vascularity d. Not good for long term use as the thyroid gland escapes from its effects after 10-14 days 8. Block-replace regimen means that a thioamide plus L- thyroxine is given

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