Embryological development and functions of thyroid

Question 1

Briefly describe the features of the thyroid gland

Answer 1

• Only gland to store hormones extracellularly
• Divided into 2 lobes → lobules → follicles (20-40 follicles per lobule)
• Height of follicular cuboidal epithelium and size of follicular lumen depends on metabolic activity of follicular
  cells
• Epithelium produces thyroglobulin, which is stored in colloid

Question 2

Describe the phylogeny and ontogeny of the thyroid gland

Answer 2

• Primary event in thyroid phylogeny is development of capability to collect iodide
  ion and bind it to protein → capable of producing iodotyrosines and
  iodothyronines
• First endocrine gland to develop by day 24
• Homeobox genes HOXB3 and HOXA3 activate essential transcription factors
  (TTF1/2) for development of thyroid peroxidase, thyroglobulin and TSH receptor
• Determine location of thyroid
• Development
• Thickening of endodermal cells lying in midline of floor of pharynx between
  first and second pharyngeal pouches
• Thickening grows for form a median diverticulum and tubular duct
• Median diverticulum connected to pharynx by thyroglossal duct and foramen caecum
• Cells of lower portion of duct differentiate into thyroid tissue
• Thyroid still connected to tongue via thyroglossal duct
• Weeks 7-10: tubular duct solidifies and subsequently obliterates entirely
• As thyroid gland descends, it forms its mature shape with a median isthmus connecting 2 lateral lobes
• 7 weeks: thyroid completes descent, resting in final location immediately anterior to trachea
• 13-14 weeks: complex, interconnecting, cord-like arrangements of cells interspersed with vascular connective tissue replace the solid epithelial mass
  and become tubule-like structures - developing foetus is entirely dependent on maternal T4 until this point

Question 3

Describe congenital primary hypothyroidism

Answer 3

• 1:2000 to 1:4000 live births
• 2:1 female to male
• 85% sporadic - thyroid dysgenesis
  (ectopy, aplasia, hemiagenesis,
  hypoplasia), 15% hereditary
• 95% asymptomatic at birth
• Untreated associated with a loss of 5-7
  IQ points monthly during early postnatal
  life - over 6-8 months = 30-40 point IQ
  deficit
• Universal screening programs for thyroid
  function in early post-natal period

Question 4

Descrube thyroid hormones synthesis and secretion

Answer 4

• Thyroid hormones (T4 and T3) are essential for the regulation of
  metabolic processes
• Most important factors controlling TH synthesis are iodine
  availability and TSH
• TSH secretion from anterior pituitary stimulated by thyrotropin
  releasing hormone (TRH) from hypothalamus
• 1. Iodine transport: TSH binds to receptors on follicular cells,
     resulting in active transport of dietary iodide I– via Na+/I–
     symporter into thyroid
• Diffuses into colloid via anion exchange protein (Pendrin)
• 2. Thyroglobulin synthesis: protein with many tyrosine AAs
     that eventually become individual thyroid hormones
• 3. Thyroid peroxidase: catalyses oxidation 2I– → I2 + 2 e– in
     follicular lumen
• I2 covalently linked to thyroglobulin, forming MIT (single-
  iodinated) or DIT (double-iodinated)
• MIT and DIT are coupled to generate T3/T4
• 4. Endocytosis: peroxidase-processed thyroglobulin is
     endocytose into the epithelial cell and combines with lysosomes
• 5. Release: thyroglobulin is broken down by lysosomes, releasing T4 and T3 which are transported out
     of follicular epithelial cells into circulation
• Log linear relationship between circulating T4 and pituitary TSH - as T4 levels fall, feedback inhibition is
  reduced and TSH levels rise

Question 5

Describe the non-genomic actions of the thyroid

Answer 5

• Alterations in solute transport e.g.
  calcium, sodium, glucose
• Changes in activity of several kinases,
  including protein kinase C
• Modulation of mitochondrial respiration
• Regulation of actin polymerisation
• Regulation of contractile elements in
  vascular smooth muscle
• Cardiac contractility and cardiac output

Question 6

Describe teh effects of thyroid on target tissue

Answer 6

Question 7

Describe the interaction between thyroid hormone and receptor

Answer 7

Thyroid hormone/receptor interaction
* Interact with nuclear receptors - thyroid response elements (TRE)
* T4 (thyroxine) is predominant pro-hormone produced by thyroid gland
but is de-iodinated to active T3 (tri-iodothyronine)
* Formed by deiodinase enzymes (selenoproteins)
* 100% of T4 is produced in the thyroid, but 80% of T3 is derived from
5’-monodeiodination of T4 in peripheral tissues (e.g. liver, kidney)
through action of D1 and D2
* D1: liver, kidneys and thyroid - responsible for peripheral formation
of T3
* D2: brain, pituitary, brown fat (intracellular)
* D3: brain and reproductive tissues - only inner ring activity, mediates degradation of thyroid hormone
* Forms reverse T3
* Thyroid peroxidase is fundamental to generation of thyroid hormone and coupling of iodine to tyrosine residues of thyroglobulin

Question 8

Describe transport of thyroid hormone

Answer 8

• TH effects are dependent on quantity of hormone that reaches tissues, hormone activation and availability of TH receptors
• > 99% of circulating TH is bound to serum proteins, including thyroxine-binding globulin, transthyretin and albumin
• Total T4 ~100nmol/L
• Free T4 ~15 mmol/L
• Total T3 ~2.3mmol/L
• Free T2 ~5pmol/L
• Total TH concentration in serum normally kept at level proportional to concentration of carrier proteins and appropriate to maintain
  constant free hormone level
• Gives large pool of TH and ensures even delivery to all tissues of body
• Thyroxine-binding globuline (TBG): high affinity but low capacity for both T4 and T3
• Under normal circumstances, most T4 is bound to TBG
• Transthyretin (TBPA): intermediate affinity and capacity for T4, but low capacity for T4
• Albumin: high capacity, low affinity

Question 9

Describe metabolism of thyroid hormone

Answer 9

• Metabolism of thyroid hormones occurs primarily through sequential monodeiodination in numerous tissues including liver, kidney, thyroid,
  skin and placenta
• Normally, ⅓ of T4 is converted to T3 and ⅓ to reverse T3 - remainder undergoes hepatic conjugation with sulphates and glucuronides and
  billiary excretion

Question 10

Discuss iodine and iodide

Answer 10

• Thyroid hormone physiology depends on iodide
• Dietary iodine converted to iodide (I–) in the gut and absorbed (small intestine)
• Iodide (I–) excreted by kidney or taken up against a concentration gradient into tissues
• Tissues which can concentrate iodide include thyroid, placenta, salivary glands, choroid plexus and breast
• Concentration gradient thyroid:circulation can be 40-100
• Process is energy-dependent, requires O2 and is stimulated by TSH
• Iodide taken to ER and incorporated into Tg in colloid lumen
• High urine iodine indicates adequate iodine stores, low urine iodine indicates low iodine stores
• TSH levels rise with low iodine diet as thyroid hormones fall and bc of feedback regulation, TSH is stimulated
• In the developing world, iodine deficiency is the most common cause of hypothyroidism
• Iodine intake calculated by dietary assessment or urinary iodine excretion as a proxy measurement of intake (90% of intake is
  excreted in urine within 24-48 hours)
• Insufficient if <150ug/L in pregnant women
• Insufficient if <100ug/L in adults and children
• Low iodine diet has immediate effect on circulating thyroid hormone levels and rise in TSH levels (feedback stimulation)
• Can cause goitre and cretinism in newborns
• Can be ameliorated by supplementation with potassium iodide

Question 11

Discuss thyroid physiology in pregnancy

Answer 11

• Pregnancy makes thyroid physiologically stressed
• Homology between HCG and TSH stimulates thyroid hormone activity
• Significance iodide load because of oestrogen production of thyroid binding globulin (TBG)
• T4 transferred to foetus for development and maturation
• Increased maternal dietary iodine required in pregnancy
• Increased demand for thyroid hormones (↑ 50%) rehires additional 50-100ug iodine
• Increased thyroid stimulation by hCG
• Oestrogen-mediated TBG increase
• Iodide transferred to foetus (50-75μg/day)
• Increased renal iodine clearance (↑ 30-50%)

Question 12

Describe the concept of thyroid biography

Answer 12

• Thyroid physiological changes occur
  with ageing and illness
• Increasingly understood that production
  of thyroid hormone and metabolism
  change with ageing
• There should be differences in reference
  ranges with age

Question 13

Describe blood supply of thyroid gland

Answer 13

• First branch of external carotid → superior thyroid artery
• Subclavian artery → thyrocervical trunk → inferior thyroid artery
• Brachiocephalic trunk → thyroid ima artery
• Only in a small amount of people to supply anterior surface and isthmus