Thyroid Gland

Question 1

Describe development of thyroid.

Answer 1

• Thyroid tissue arises in the midline at a point on the tongue later known as the foramen caecum
• Epithelial cells sink downwards anterior to the hyoid and larynx (week 7)
• Thyroglossal duct connects the developing thyroid to the tongue (“normally atrophies and closes off as the foramen cecum before birth”)

Question 2

Describe histology of the thyroid gland.

Answer 2

• Heavily vascularised
• Capillaries surround thyroid follicles which are sacs of cells, on surface of which are epithelial cells
• These epithelial cells are called follicular cells, and synthesize and secrete thyroglobulin (precursor for thyroid hormone) protein into center of sac, along with other proteins and enzymes
• Follicles are “filled with a fluid known as colloid (highly proteinaceous material) that contains thyroglobulin”
• In between follicles, parafollicular C cells which synthesize and store Calcitonin

Question 3

Describe the Hypothalamo- pituitary control
of Thyroid Hormone
release.

Answer 3

• TRH neurohormones are synthesised in arcuate nucleus and released into this capillary network (within the median eminence of the hypotT). They are then collected by a venous drainage known as the hypothalamo-hypophyseal portal system (via long portal veins) that directs the blood flow to a second capillary network within the anterior lobe.
• There, binds to receptors on thyrotrophs and stimulate TSH secretion. In order to do this:
• TRH binds to G-protein coupled receptor, which activates it. The receptor interacts with a G protein.
• Alpha subunit of G-protein interacts with and stimulates PLPC, which hydrolyses PIP2 membrane phospholipid, yielding IP3 (Inositol Triphosphate, liberated from membrane into cytosol) and DAG (Diacyl Glycerol).
• Both IP3 and DAG act as secondary messengers:
  1) DAG activates PKC, which subsequently phosphorylated number of enzymes inside the cell which help stimulate secretions from the cell
  2) IP3 binds to IP3 receptors on ER which contains Calcium stores. Upon binding, Calcium channel receptors are opened and Calcium moved from high (in stores) to low concentration
• Combination of 1) and 2) results in exocytosis of secretory vesicles insides these cells that contain TSH

• TSH released into systemic circulation, then binds to TSH receptor on follicular cells, which activates G protein, which subsequently activates Adenylate Cyclase. AC then converts ATP into cAMP.
1) cAMP activates PKA which will phosphorylate proteins involved in function of follicular cells. One such protein is CREB, which subsequently migrates into the nucleus where it binds as a transcription factor to the cAMP response element. This results in increased synthesis of a range of proteins, especially thyroglobulin.

• Release of T3 and T4 from follicular cells into the systemic circulation, may be through simple diffusion (partially soluble in membrane) but may also use thyroid hormone transporters (down concentration gradient)

Question 4

Identify hormones which stimulate, and inhibit TSH secretion.

Answer 4

STIMULATE
TRH

INHIBIT
Somatostatin
Dopamine
TSH itself (autocrine actions on TSH receptors on thyrotrophs, suppressing further release)

Question 5

Describe the feedback resulting from increased Thyroid levels in the blood.

Answer 5

• As Thyroid hormone levels in blood increase, dual feedback:
1) Feeds back to thyrotrophs, reducing number of receptors for TRH on their surface.

2) Acts on higher centers in the brain, suppressing the phasic depolarisation of small bodied cell nuclei (suppresses TRH release)

Question 6

Describe structure of thyroid hormones.

Answer 6

All result from peptide backbone of thryoglobulin molecule (tyrosine is part of this backbone). Each monomer (thryoglobulin is a dimer) contains about 110 tyrosines, of which about 20 are iodinated to form iodotryosine. These are then modified to produce 10 thyroxine molecules.

• Thyroxine (T4)
• Triiodothyronine (T3): iodine removed from outer B ring.
• Reverse T3: iodine removed from inner A ring

Question 7

Rank the main thyroid hormones by level of activity. Explain how this may be used to regulate thyroid hormone activity in the body.

Answer 7

• T3 most active (5x more than T4, more affinity for its receptor)
• T4
• Reverse T3 completely inactive

Can increase effectiveness/impact of thyroid hormones in circulation by increasing presence of enzyme which removes iodine from B ring (thereby producing T3, most active thyroid hormone).
Likewise, can suppress effects of thyroid hormones by removing iodine from inner A ring (thereby producing reverse T3)

Question 8

Draw T3 and T4.

Answer 8

Refer to slide 5.

Question 9

Describe the synthesis and secretion of T3 and T4 (especially effects on TSH on this).

Answer 9

1) Trapping: TSH increases activity of Na/I cotransporter on the basolateral membrane of the thyroid follicular cell. The result is increased iodine trapping (ratio of follicular cell iodine to plasma iodine increases under conditions of high TSH.
2) Iodide leaves the cell, via pendrin, and enters lumen. The follicular cell also secretes thyroglobulin. Thyroif peroxidase, on the luminal surface of secretory vesicle, oxidises 1^- to 1^0.
3) Iodination: TSH also stimulates iodination of thyroglobuin in follicular lumen
4) Conjugation: TSH stimulates conjugation of iodinated thyrosines to form T4 and T3 linked to thyroglobulin
5) Endocytosis: TSH stimulates endocytosis of iodinated thryoglobulin into follicular cells from the thyroid colloid
6) Proteolysis: TSH stimulates proteolysis of iodinated thyroglobulin, forming T4 and T3 in the lumen of the lysoendosome
7) Secretion: TSH stimulates secretion of T4 and T3 into the circulation

TSH also exerts growth-factor effect, stimulating hyperplasia within the thyroid gland.

Question 10

State any other names of ratio of follicular cell iodine to plasma iodine.

Answer 10

Thyroid/serum or T/S ratio

Question 11

Describe peripheral metabolism of T4.

Answer 11

• In circulation, two classes of monodeiodinases:

• 5-/3- monodeiodinase
• 5/3 monodeiodinase

• 5-/3- monodeiodinases remove iodine atoms from outer ring (first time, get T3)
5/3 monodeiodinases remove iodine from inner ring (first time, get rT3)

• Depending which path, get all different types of metabolites of thyroid hormone. If remove all 4 iodines, get thyronine

Question 12

Identify a way to increase removal of thyroid hormone metabolites from circulation.

Answer 12

• T4 metabolites with only one and no iodines are susceptible to sulphation by other enzymes (sulphates added to ring structures), as a result of which they become more aqueous soluble, not bound to binding protein in circulation, and excreted better in
kidney (hence when take urine sample, find sulphate derivates, of those groups of T4 metabolites)

HENCE sulphated derivates are a way of removing thyroid hormone metabolites from circulation.

Question 13

Identify mechanisms of action of Thyroid Hormones.

Answer 13

• Thyroid hormones are carried in bloodstream. Because of limited solubility, bound by Thyroxin Binding Globulin.

• Can subsequently diffuse across lipid bilayer and enters any cell in the body (all cells in the body contain thyroid hormone receptors). HOWEVER, some cells are more sensitive to thyroid hormones than others because they contain transporters which help thyroid hormones enter the cell.
Cells that respond very well to thyroid hormones may also have a cytosolic 5-/3- monodeiodinase which can convert T4 into T3 (much more active, so bigger response inside that cell). Some cells turn it into reverse t3 (via 5/3 mono…) so less sensitive.

• Once in the cell, T3 or T4 enter the nucleus and bind to transcription factors (e.g. THR, Retinoid X receptor). The thyroid response element (DNA sequence) also binds to those transcription factors.
• Effect is increase in transcription, mRNA moves to cytosol, translated into various proteins. Hence, many different proteins are up-regulated, depending on the type of cell.

Question 14

Why are Thyroid hormones bound to TBG in the circulation ?

Answer 14

1) Protect thyroid hormones from being deiodinated by
peripheral deiodinases
2) Prevents excretion in the kidney (thyroid hormones are small), by acting as a store of T3/4

Question 15

Identify examples of proteins which are upregulated by Thyroid hormone.

Answer 15

Sodium Potassium ATPase

Many gluconogenic enzymes in liver (increase ability of liver cells to make glucose)

Respiratory enzymes in mitochondria (increase ability to make ATP and increase oxygen consumption and respiratory rate)

Myosin heavy chain (in muscle)

Beta Adrenergic Receptors

Question 16

Identify physiolgoical actions of the Thyroid Hormone.

Answer 16

Activation of nuclear receptors induce new protein synthesis which produce physiological effects:

• Increase Basal Metabolic rate ➡ Increased O2 consumption ➡ Heat Production
• Increased mobilisation of carbs, fats, and protein stores (both directly i.e. by binding to cell and inducing transcription response that increases enzymes involved in metabolism, and indirectly i.e. increasing number of receptors for another hormones which stimulates metabolism)
• Growth: ⬆Soft tissue growth and ⬆bone maturation
• CNS: ⬆Maturation of the CNS
• CVS: ⬆Ionotropic, ⬆Chronotropic, ⬆CO

Question 17

State the effect of hyperThyroidism and hypoThyroidism on BMR.

Answer 17

Hyper = Increased BMR (increases by up to 100%)

Hypo = Decreased BMR (decreases to 50-60%)

Question 18

Give specific examples of how thyroid hormone increases mobilisation of carbs, fats, and protein stores.

Answer 18

• ⬆Glucose uptake from GI Tract
• ⬆Glucose utilisation (esp. muscle and adipose tissue)
• ⬆Liver glycogenolysis and gluconeogenesis (releases glucose)
• ⬆Lipolysis in adipose tissue (⬆plasma FFA)
• ⬆Tissue oxidation of FFA
• General increase in protein turnover with net increase in anabolism
• Increase in specific enzymes / membrane proteins / hormone receptors (e.g. beta adrenergic receptor, so increases sensitivity to catecholamines)
• Permissive actions for other hormones (GH, prolactin, gonadal and adrenal steroids) (e.g. provides receptors for other hormones)
• Essential for normal development and function of central and peripheral nervous systems

Question 19

Identify the main clinical features of hypoThyroidism.

Answer 19

• Poor mental ability

- Lack of memory and initiative

Question 20

Identify the main anatomical and clinical features of fetal hypoThyroidism.

Answer 20

Fetal hypothyroidism (AKA Cretinism) leads to:

• Neuronal hypoplasia
• Delayed myelination in specific neurones
• Mental retardation

Question 21

Identify examples of Thyroid Disorders.

Answer 21

Goitrogens
Pituitary Tumors
Graves Disease
Hashimoto’s Disease

Question 22

What is goitre ? Is goitre associated with hypo or hyperthyroidism ?

Answer 22

Goitre is essentially hypertrophy of thyroid (occurs in many thyroid disorders)
Can occur with EITHER

Question 23

What are the main causes of Goitre ?

Answer 23

• Excess iodide- iodine required for functioning of thyroid follicular cells and sythesis of mature thyroglobulins. If excess, inhibition of peroxidase enzymes and process of iodination, so iodine does not get incorporated into tyrosines.
• Excess thiocyanate or perchlorate- Inhibit iodine trapping mechanism so no iodine taken up.

These both result in decreased thyroid hormone production, decreased levels in the blood, feedback to the hypoT-pituitary is lost, so increased levels of TRH and TSH, and high levels of TSH binds to receptor on thyroid gland and increase protein synthesis in follicular cells, resulting in hypertrophy of the thyroid. Cells can make more thyroglobulin, but cannot iodinate it.
End result is large amount of thyroglobulin produced, hypertrophy of follicular cells, increase in colloid, and goitre.

All cause excess TSH secretion and hypertrophy of thyroid, and hypothyroidism.

Question 24

What are the main results of pituitary tumours on thyroid hormones ?

Answer 24

Excess TSH: hypertrophy of thyroid and hyperthyroidism (uncontrolled stimulation of thyroid, large amounts of T3/4 produced, no negative feedback back to hypoT-pituitary to suppress further release if tumor is insensitive to thyroid hormones)

Lack of TSH- (if tumor affects other cell type in pituitary, pituitary may swell up and cause compression and atrophy of some cells including thyrotrophs) hence, atrophy of thyroid and hypothyroidism

Question 25

Describe the mechanism behind Grave’s disease.

Answer 25

Long-acting Thyroid Stimulator (LATS) AI stimulation of thyroid)

Antibodies act on TSH receptor and stimulate it, so hypertrophy of thyroid and hyperthyroidism

Question 26

Identify a clinical feature of Grave’s disease.

Answer 26

Exophthlamos

Question 27

Describe the mechanism behind Hashimoto’s disease.

Answer 27

AI destruction of thyroid, causing lesions in follicular cells and release of colloid- atrophy of thyroid and hypoT

Question 28

Describe anatomical location of the thyroid gland.

Answer 28

The thyroid gland is located in the anterior neck, lying like a small bow tie across the front of the trachea. In adults, the normal thyroid weighs approximately 20 g. It is composed of left and right lobes and a small connecting branch, or isthmus.

Question 29

Graph the effect of fetal hypoT on bone age, height age, and mental age. To what extent can tyroxine therapy correct this ?

Answer 29

Refer to slide 13

Bone and height age can both recover if given tyroxine, but mental age cannot recover because myelination that did not occur in the brain during development prevented normal development.