Regulation of Thyroid Hormone Synthesis

Question 1

Uptake of iodide from plasma by thyroid gland

Answer 1

• Ingested iodine mostly absorbed from gut as iodide to enter extracellular iodide pool
• Iodide exits pool from blood into follicular cells of thyroid gland
• Mechanism for iodide transport into gland = “iodide trap” mechanism
  
  • Trap = membrane pump on basal side of follicular accumulation of concentration of iodide in thyroid 30-40x that in serum
• Iodide concentrated in gland against electrical gradient and chemical gradient
• Certain anions (perchlorate) transported by same mechanism
  
  • Act as competitive inhibitors of iodide uptake

Question 2

Synthesis of thyroglobulin

Answer 2

• Thyroglobulin (TG) –> 660kD glycoprotein composed of two identical polypeptides
• Synthesized on RER within follicular cell –> glycosylated and packaged into secretory vesicles in Golgi apparatus –> vesicle release from apical side of follicular cell into lumen –> into colloid

Question 3

Steps in thyroglobulin production

Answer 3

• After entering follicular cell: iodide follows electrical gradient from basolateral to apical surface
• Colloid found at apical side of follicular cell
• Iodide must be oxidized before it can participate in tyrosyl iodination
• Thyroperoxidase: enzyme that catalyzes iodization of thyroglobulin
  
  • Membrane bound glycoprotein
  • Present at microvilli on apical membrane
  • Converts I2 –> I- (active iodide)
• Iodide is organified (incorporated) into tyrosyl residue on thyroglobulin at cell-colloid surface

Question 4

Steps in thyroid hormone synthesis

Answer 4

• Thyroperoxidase catalyzes two steps of TH synthesis
  
  • Initial iodination of thyroglobulin –> MIT and DIT (intermediates to T3 and T4)
  • Thyroperoxidase catalyzes coupling of 2 DITs or 1 MIT and 1 DIT to form iodothyronines (T3 and T4) in colloid
• Then coupled TG endocytosed, heads to lysozome where T4s and T3s are cleaved off

Question 5

Steps in thyroid hormone release

Answer 5

• Thyroglobulin must first be endocytosed from lumen (colloid) back into follicular cells
• Endocytosed drops of colloid then migrate to lysosomes
• Lysozomal enzymes cleave thyroglobulin into T4 and T3
• T4 production + release exceeds T3 production + release 20x under normal conditions
• Mechanism of hormone release not well understood, may be by facilitated diffusion
• Proteolytic action of lysosomal enzymes will cleave iodotyrosines (MIT and DIT) from thyroglobulin as well
  
  • De-iodinated - tyrosine and iodide both reincorporated into TG

Question 6

Transport of thyroid hormones in plasma

Answer 6

• TH enters blood and residues as protein-bound form (99.97%) or free form (0.03% T4 and 0.4% T3)
• TH binding proteins include thyroid binding globulin (TBG), thyroid binding pre-albumin (TBPA), and albumin
• Because so much TH is bound to proteins, TSH is good way to measure thyroid function

Other relevant notes:

• Free form = active, most important form to measure when evaluating thyroid function
  
  • Both bound forms and unbound forms should be measured
  • In pregnancy, levels of TBG and TBPA are elevated
• Tyroglobulin in colloid serves as reservoir of TH
• Protein bound TH buffers TH and is more important for T4 (there is 10x more T4 protein bound)
  
  • T4 half-life = 7 days; T3 half-life = 1 day
  • T3 considered active form (form that acts on cell at transcriptional level)
  • Both T4 and T3 enter target cells via active transport –> T3 has higher affinity for TH’s cell receptor
  • T4 must be converted to T3 by 5’-deiodinase

Question 7

Actions of thyroid hormone

Answer 7

• T4 reaches target cell –> deiodinated –> T3 binds to receptors (alpha and beta) –> dimerization occurs –> binding to receptors alters gene expression
• Major regulators of basal metabolic rate (BMR)
• Necessary for normal fetal and neonatal brain development
• Both TH and GH essential for normal growth
• Enhance response to catecholamines - mimic effects of SNS
• Effects on metabolism - calorigenic actions and independent effects

Question 8

TH as regulator of BMR

Answer 8

• No THs present –> decreased BMR
• TH effect on BMR = thermogenic/calorigenic effect
  
  • Mostly due to levels of Na+/K+ ATPase pumping and O2 consumption
    
    • Decreased T3 –> low heat production –> cold intolerance
    • Increased T3 –> excess heat production –> heat intolerance
• TH stimulation of calorigenic effect is delayed - can be inhibited by blocking protein synthesis

Question 9

Role of TH in fetal/neonatal brain development

Answer 9

• TH screen in newborns very important
• Congenital hypothyroidism can lead to severe and irreversible intellectual disability
• Can lead to Cretinism (short stature, intellectual disability)
• Decreased TH in adults can also have behavioral effects

Question 10

Role of TH in growth

Answer 10

• TH permissive of GH
  
  • GH works better in presence of TH
• Decreased TH –> decreased GH

Question 11

Role of TH in response to catecholamines

Answer 11

• TH enhances response to catecholamines, mimics effects of SNS
• TH permissive of adrenergic system
  
  • Seems to be specific to beta receptors
    
    • Increased beta-adrenergic receptors with hyperthyroid status –> tachycardia, etc.
    • Often treated with beta blockers

Question 12

Role of TH in metabolism

Answer 12

• Some effects are consequences of calorigenic actions, others are independent effects
• THs low to moderate doses –> anabolic, glucose –> glycogen
• THs in high doses –> catabolic, increase fuel consumption, protein breakdown and muscle wasting, enhanced glycogenolysis
• Lipolysis is net result of actions of TH on lipid metabolism

Question 13

Normal regulation of TH levels by HPA

Answer 13

• TSH controls many things:
  
  • Follicular cell number
  • Thyroperoxidase
  • Iodide uptake
  • Organification of iodide
• High T3 downregulates TRH receptors in AP –> inhibits TSH secretion
• Low T3 levels sensitize AP to TRH stimulation
• T4 and T3 both feed back at level of AP and hypothalamus