9 Thyroid Physiology

• Thyroid


  Master gland of the body

  
• Thyroid hormone synthesis


  1. Iodine actively transported into gland against gradient by NIS

  2. Iodide oxidized and incorporated into thyroglobulin

  3. Coupling of iodinated tyrosines to form T3 and T4

  4. Thyroglobulin stored as colloid

  5. Release of T4 and T3 into bloodstream

  
• NIS


  • 2Na+-1I- symporter that transports iodide into thyroid epithelial cells
  • Expression inhibited by iodide and stimulated by TSH

  
• Thyroid peroxidase (TPO)


  • Enzyme complex that catalyzes iodination of thyroglobulin
  • Uses H2O2 as oxidant

  
• NADPH oxidase


  • Generates H2O2 in thyroid gland

  
• When iodide availability is restricted, formation of T3 is favored
• Megalin


  Receptor required for release of T4 and T3 from thyroglobulin
• Organs that sequester iodine


  • Thyroid gland
  • Salivary glands
  • Gastric glands
  • Lacrimal glands
  • Mammary glands
  • Choroid plexus

  
• The iodine intake is 400 μg, of which 80 μg goes to the thyroid gland
• The good thing with iodine is it can be stored within 6 months in the thyroid gland
• Daily iodine requirement


  • Adults: 150 μg
  • Pregnant: 200 μg
  • Children: 90-120 μg
• The loss of iodine is 400 μg which is equal to the intake
• Deiodinase Type 1


  Seen in vascular structures, physiologically converts T4 to T3, low affinity for T4, more abundant

  
• Deiodinase Type 2


  Acts as 'thyroid axis sensor' in anterior pituitary, senses T4 levels, high affinity for T4, more active than T4, less abundant

  
• Deiodinase Type 3


  Also known as 'inactivating deiodinase', high during hyperthyroidism, renders thyroid hormones inactive

  
• Both Type 1 and 2 Deiodinases form active T3, Type 3 forms inactive/reverse T3
• Histologic differences


  • Normal: Simple cuboidal epithelium, round colloid
  • Hyperthyroidism: Simple columnar epithelium, less colloid
  • Hypothyroidism: Simple squamous epithelium, more colloid
• Parafollicular cells/C cells/Clear cells secrete Calcitonin
• The thyroid gland secretes two hormones: Thyroid hormones (T3 & T4) and Calcitonin

  
• Thyroglobulin binds the thyroid hormones (MIT, DIT, T3, T4) and keeps them inside the colloid

  
• Once needed, the thyroid gland will release T3 and T4 while recycling MIT and DIT

  
• The old classification of endocrine disease is primary, secondary, and tertiary, but the new classification is anything not primary is secondary
• TSH or Thyrotropin is tropic (causes release of hormones) and trophic (causes enlargement/hypertrophy of the organ)

  
• The thyroid gland is medially located just underneath the thyroid cartilage and is normally not palpable

  
• The thyroid gland has a superior and inferior thyroid artery blood supply and superior, middle, and inferior thyroid vein drainage

  
• A 'hot nodule' on thyroid scan indicates a hyperfunctioning nodule, while a 'cold nodule' indicates a more severe concern, commonly cancer

  
• Thyroid hormone synthesis


  1. Iodide trapping

  2. Oxidation of iodide ions

  3. Iodination of tyrosine molecules

  4. Coupling of iodinated tyrosine molecules

  
• Monoiodotyrosine (MIT)


  One iodine atom bound to a tyrosine molecule
• Diiodotyrosine (DIT)


  Two iodine atoms bound to a tyrosine molecule
• Coupling reaction


  1. Two DIT molecules coupled to form T4

  2. One MIT molecule and one DIT molecule coupled to form T3
• Thyroid peroxidase (TPO)


  • Enzyme complex that catalyzes the entire sequence of thyroid hormone synthesis reactions
  • Spans the apical membrane

  
• Hydrogen peroxide (H2O2)


  Immediate oxidant (electron acceptor) for the thyroid hormone synthesis reactions

  
• NADPH oxidase


  Enzyme that generates H2O2 in the thyroid gland, localized to the apical membrane

  
• When iodide availability is restricted


  Formation of T3 is favored
• Release of T4 and T3 into the bloodstream


  1. Binding of thyroglobulin to the receptor megalin

  2. Receptor-mediated endocytosis

  3. Lysosomal degradation of thyroglobulin
• Recycling of iodide


  1. MIT and DIT molecules released during proteolysis of thyroglobulin are rapidly deiodinated within the follicular cell by the enzyme intrathyroidal deiodinase

  2. Iodide is then recycled into synthesis of T4 and T3
• Amino acids from the digestion of thyroglobulin re-enter the intrathyroidal amino acid pool and can be reused for protein synthesis
• T3 and T4


  • Lipid soluble because they have intracellular (nuclear) receptors
  • Under the Amines category
  • No transporter needed
• Classification of ligands based on composition


  • Water-soluble (membrane receptors): Ionotropic, Metabotropic (G-protein coupled), Enzyme-linked (Kinases)
  • Lipid-soluble (intracellular receptors): Nuclear receptor, Cytosolic receptor
• Steps in thyroid hormone synthesis


  • Iodide trapping
  • Oxidation of iodide ions
  • Iodination of tyrosine molecules
  • Coupling reaction