W2 L4: The Thyroid Gland

Anatomy/Function of the Thyroid Gland:

• Adheres to the trachea, just below the larynx

  • Tissue mass: 10-20g
  • 2 flat lobes connected by an isthmus

• right lobe > left

• well supported by blood vessels so hormones can be easily transported around the body, iodine is supplied by the blood stream

• Secretes thyroxine (T4), tri-iodothyronine (T3) and calcitonin

  • T3, T4→ iodine containing hormones acting throughout the body
  • Calcitonin→ regulates plasma calcium

  

Morphology of the Thyroid Gland

• Functional unit → follicle

• Basement membrane anchors follicle to connective tissue

• Epithelial outer layer (“follicular cells”)→ secrete T3 and T4

  • generating lots of T3 & T4 - colloid starts to shrink
  • generating plentiful iodine - colloid swells

• Central colloid-filled cavity

• Changes morphology between active and inactive states (↑ activity → ↓ colloid storage)

• Colloid: mainly consists of glycoprotein (thyroglobulin)

• C-cells present in basement membrane and between follicles – Secrete calcitonin

• Secretion regulated by ANS

• Rich blood supply

  • Approx twice kidney blood flow
  • Regulated by ANS

  

Thyroid Feedback Pathways

• Thyrotrophin-releasing hormone (TRH) stimulates Thyroid stimulating hormone (TSH) release from anterior pituitary - TRH released from hypothalamus

• Thyroid-stimulating hormone (TSH) controls the thyroid gland

• Thyroid hormones promote oxidative metabolism, influence metabolism, necessary for full expression of growth hormone in children

• T3 used to stimulate growth, metabolism and temp

• Loads of T3 → turn on -ve feedback → bind to receptors in anterior pituitary and reduce TSH release

• T4 slightly less active than T3- T4 more bioactive

  

Synthesis of Thyroid Hormones (T3 /T4 ): Thyroglobulin & Iodination

• 2 components are necessary: thyroglobulin and iodine
• Thyroglobulin = 670kDa glycoprotein
  • Comprises 2 peptides of 330kDa and carbohydrate moieties
  • Synthesised in follicular cell rough endoplasmic reticulum
  • Packaged into vesicles and released into lumen by exocytosis
  • Stored as colloid (known as organification) up to 3 months
• Iodination
  • T3 and T4 require dietary iodine (≈ 75mg/day; 140µg/day recommended in UK)
  • “Iodide trapping”: trapping iodine in the cell - ↑ conc
  • Inorganic iodide enters follicular cells via Na/I symporter (NIS)
  • Iodine transported → incorporated into tyrosine molecules to form follicle lumen
  • Iodination of free tyrosine residues of thyroglobulin
  • Hydrolysis of iodinated thyroglobulin → T3 /T4
• Some T3 synthesised, but approximately 20-fold more T4
• Thyroid stores several weeks supply of T3 /T4

Secretion of Thyroid Hormones

• Colloid droplets taken up by follicle cells by endocytosis
• endosomes fuse with lysosome
• Lysosomes fuse with colloid droplets
  • Thyroglobulin degrades
  • Degradation products recycled
• Released T3 and T4 hormones keep in vesicles until they diffuse into fenestrated capillaries surrounding the follicles
• In blood, hormones bind to plasma proteins
  • Mostly thyronine-binding protein (TBP) (specific to T3 & T4)
  • can bind to prealbumin (TBPA) & albumin
  • T4 binds with ↑ affinity → ↑ half life (t½)

Summary of Synthesis and Secretion

• Primary function is to produce the hormones calcitonin, thyroxine (T4) and tri-iodothyronine (T3)
• Main steps in the synthesis, storage & secretion of thyroid hormone are:
  • Iodide trapping → Iodine only moves in when the NIS is present
  • Organification
  • Secretion of T3 and T4

Roles of TSH in Thyroid Function

• TSH receptors on follicular cell surface
• G- protein coupled receptors (GPCR) coupled to adenylate cyclase (adenylate cyclase makes cAMP)
• Stimulation of hormone synthesis
  • Iodide trapping via Na/I co-transporter
  • ↑ Thyroglobulin synthesis
  • ↑ Iodination of thyroglobulin
• Stimulation of hormone secretion
  • ↑ Uptake of colloid by follicular cells
• Necessary for thyroid gland maintenance
  • Gland rapidly atrophies in absence of TSH

Action of Thyroid Hormones

• T3 has far greater activity than T4

  • Intracellular conversion of T4 to T3 by deiodinase 2
  • Deiodinase 2 provides a mechanism by which cells control sensitivity to thyroid hormones -

• Act as “growth factors” in multiple tissues

• Regulate gene transcription

  • Cytoplasmic (intracellular) receptors → nucleus to turn on specific genes (when bond to T3)
  • Effects take hours/days

• Induce specific tissue effects; also ↑ O2 consumption and heat production of whole body

  • Able to manipulate body temp
  • Altered protein metabolism
  • ↑ Basal Metabolic Rate (>100 enzyme systems sensitive to T3)
  • ↑ activity of Na+ /K+ -ATPase
  • ↑ glucose uptake & lipolysis by regulating glucose transporters

  

Abnormal Thyroid Function

Diagnoses confirmed by assay of plasma T3 and T4

• Hyperthyroidism (thyrotoxicosis)
  • e.g. Grave’s disease (autoimmune – antibodies block TSH receptor- ↑ thyroid cells to try to ↑ NIS)
  • Symptoms include goitre (enlarged thyroid), exophthalmos (protrusion of eyeballs). ↑ Basal Metabolic Rate (BMR) & heart rate, weight loss (due to ↑ BMR)
  • Treatment→ surgical removal or 131I ingestion
• Hypothyroidism
  • Causes:
  • Iodine deficiency → ↓ T3 feedback → ↑ TSH → goitre (haven’t got enough NIS, so generates more cells to produce more NIS)
  • Hashimoto’s thyroiditis (autoimmune) → thyroid destruction
  • Myxedema→ adults
  • Symptoms include facial swelling, ↓ mental function, lethargy, ↓ BMR (↑ weight) & heart rate
  • Cretinism→ congenital, children
  • Symptoms inc. mental retardation (cretinism), ↓ body growth
  • Treatment→ regular medication of hormone replacement (T4) or iodine supplements (in deficiency states)

Quiz

1. • What would be the likely effect of 5 days without dietary iodine on,
   • TRH
   • TSH
   • T3
   • T4
2. • What would be the likely effect of 5 weeks without dietary iodine on,
   • TRH
   • TSH
   • T3
   • T4
3. How might a loss of deiodinase 2 activity affect physiology?
4. What would be the effect of iodine supplementation in
   Hashimoto’s disease?