LECTURE 3 (Thyroid)

Question 1

Thyroid secretion is controlled by which hormone?

Answer 1

Thyroid-stimulating hormone (TSH)

[secreted by the anterior pituitary gland]

Question 2

What is the difference between Triiodothyronine and Thyroxine?

Answer 2

• T3 is more potent than T4
• T3 is present in the blood in much smaller quantities
• T3 persists for a much shorter time

Question 3

Describe the physiologic anatomy of the Thyroid gland

Answer 3

• Large number of follicles filled with “colloid”
• Follicles lined with cuboidal epithelial cells that secrete into the interior of the follicles
• Thyroglobulin found in colloid
• Large blood supply

Question 4

Describe the process of Iodide tapping

Answer 4

Iodide is pumped actively into the cell by a SODIUM-IODIDE SYMPORTER (NIS) which co-transports one iodide ion along with 2 Na2+ ions across the plasma membrane
[energy comes from sodium-potassium ATPase pump which generates a gradient for facilitated diffusion of Na2+ into the cell]

Question 5

What is the difference between TSH and Hypophysectomy?

Answer 5

TSH = stimulates iodide pump

Hypophysectomy (surgical removal of pituitary gland) = greatly diminishes activity of iodide pump in thyroid cells

Question 6

How is iodide transported out of the thyroid cells?

Answer 6

Iodide is transported out of the thyroid cells across the apical membrane into the follicle by a chloride-iodide ion counter-transporter called PENDRIN

Question 7

What are Thyroid hormones synthesised from?

Answer 7

Tyrosine & Iodine

Question 8

What is Thyroglobulin?

Answer 8

• Large protein produced by thyroid follicular cells
• “backbone” containing numerous tyrosine molecules

Question 9

What must happen to iodide in our diet for thyroid hormone synthesis?

Answer 9

1) Taken up by follicular cells
2) Oxidised to I2 “OXIDATION”
3) Added to organic/carbon structures “ORGANIFICATION”

Question 10

Where is Thyroid peroxidase usually located?

Answer 10

In the apical membrane or attached to it

Explanation: Provides oxidised iodine the point in the cell where the thyroglobulin molecule issues forth from the Golgi apparatus and through the cell membrane into the stored thyroid gland colloid

Question 11

What happens when the peroxidase system is blocked or when it is hereditarily absent from cells?

Answer 11

The rate of formation of thyroid hormones falls to zero

Question 12

Describe Thyroid hormone synthesis

Answer 12

1) Iodide enters the follicular cell via NA-IODINE SYMPORTER with Sodium
2) “OXIDATION” Iodide is oxidised to I2 via THYROID PEROXIDASE
3) “ORGANIFICATION” Tyrosine + Iodine (I2) is converted to either MONOIODOTYROSINE (MIT) [1 iodine] or DIIODOTYROSINE (DIT) [2 iodine] via THYROID PEROXIDASE
4) “COUPLING REACTIONS” MIT + DIT = TRIIODOTHYRONING (T3) or DIT + DIT = THYROXINE (T4)

Question 13

Describe how T3 and T4 is released from Thyroglobulin

Answer 13

1) Apical surface of thyroid cells sends out PSEUDOPOD EXTENSIONS that close around small portions of the colloid to form PINOCYTIC VESICLES that enter the apex of the thyroid cell
2) Lysosomes in cell cytoplasm fuse with vesicles to form digestive vesicles containing digestive enzymes from the lysosomes mixed with the colloid
3) Multiple proteases digest thyroglobulin molecules and release thyroxine and triiodothyronine in free form
4) T3 and T4 diffuse through the base of the thyroid cell into the surrounding capillaries

Question 14

What happens to the freed T3 and T4 not secreted into the blood?

Answer 14

Iodine is cleaved from them by DEIODINASE ENZYME that makes the iodine available for recycling

ADDITIONAL INFO: In people with absence of the enzyme, they can become iodine deficient because of failure to recycle

Question 15

What is the function of Thyroid Peroxidase (TPO)?

Answer 15

It catalyses
- Oxidation of iodide
- Organification into MIT/DIT
- Coupling of MIT/DIT into T3/T4

Question 16

What is produced more, T3 or T4?

Answer 16

T4 (>90% of thyroid hormone produced is T4)

Explanation: More T4 is produced initially but more T3 is needed since it is a more POTENT hormone, thus T4 must be converted to T3 via 5’-DEIODINASE

Question 17

How are T3 and T4 transported in the blood?

Answer 17

By binding to plasma proteins

PLASMA PROTEINS:
- Thyroxine-binding globulin (main!!)
- Thyroxine-binding pre-albumin
- Albumin

Question 18

What is the general effect of thyroid hormone?

Answer 18

• Activate nuclear transcription of large number of genes
• Generalised increase in functional activity throughout the body

Question 19

How do thyroid hormones work?

Answer 19

1) Thyroid hormone receptors are either attached to the DNA genetic strands or located close to them -> thyroid hormone receptor forms a heterodimer with RETINOID X RECEPTOR (RXR) at specific THYROID HORMONE RESPONSE ELEMENTS on the DNA
2) Thyroid hormone binds, receptors become activated and initiate transcription process
3) Large number of mRNAs are formed followed by RNA translation to form new intracellular proteins

Question 20

What happens to mitochondria when the number of thyroid hormones increases?

Answer 20

• Mitochondria increase in size and number
• Total membrane surface area increases in proportion to metabolic rate
• Increase in activity -> increase in ATP for cellular function

Question 21

What is the effect of thyroid hormones on active transport?

Answer 21

Increase in thyroid hormones acts on Sodium-Potassium ATPase which increases the rate of transport of Na2+ and K+ across cell membranes. It also makes some cell membranes “leaky” to Na2+ -> further activates sodium pump -> further increase in heat production

Question 22

What is the Thyroid hormone’s effect on growth?

Answer 22

• hyperthyroid = excessive growth of children + bones mature rapidly, epiphyses close earlier -> eventual height shortened
• hypothyroid = growth and maturation of brain are greatly retarded -> no thyroid therapy -> child will remain mentally deficient throughout life

Question 23

What is the Thyroid hormone’s effect on Plasma and liver fats?

Answer 23

Increased thyroid hormone decreases the concentrations of cholesterol, phospholipids and triglycerides in the plasma even though it increases the free fatty acids

Question 24

Why do you need more vitamins when you increase thyroid hormones?

Answer 24

Thyroid hormone increases the quantities of many bodily enzymes which require vitamins -> vitamin deficiency can occur when excess thyroid hormone is secreted (unless increased quantities of vitamins are made available)

Question 25

What are the different effects of the thyroid hormone on the cardiovascular system?

Answer 25

• Increased blood flow & cardiac output (increased metabolism + oxygen utilisation -> greater release of metabolic end products -> increased vasodilation to get rid of heat)
• Increased HR (increase excitability of heart -> increased HR)
• Increased heart strength (thyroid hormone increased a lot -> heart muscle strength depresses due to long-term excessive protein catabolism -> death due to cardiac decompensation)
• Arterial pressure stays normal
• Increased respiration
• Increased GI motility
• Excitatory effects on the CNS (anxiety, worry, paranoia)
• Increased muscle strength (overtime muscles become weakened due to protein catabolism)
• Muscle tremor
• Sleep (increase = cannot sleep, decrease = sleep too much)
• Sexual function (decreased = libido and polymenorrhea (frequent menstrual bleeding in women), increased = impotence in men and amenorrhea in women)

Question 26

What is TSH?

Answer 26

Also known as “Thyroid Stimulating Hormone” or “Thyrotropin”
- an anterior pituitary gland hormone
- increases thyroid secretion

Question 27

What are the effects of TSH on the Thyroid gland?

Answer 27

• Increased proteolysis of thyroglobulin stored in follicles (increases T3 and T4 release)
• Increased activity of the iodide pump (increases “iodide tapping”)
• Increased iodination of tyrosine to form thyroid hormones
• Increased size and secretory activity of thyroid cells
• Increased number of thyroid cells (also change from cuboidal to columnar cells + infolding of thyroid epithelium into follicles)

Question 28

Describe how cAMP mediates the stimulatory effect of TSH

Answer 28

1) TSH binds with specific TSH receptors on the basal membrane surfaces of the thyroid cell which activates ADENYLYL CYCLASE, increasing formation of cAMP in the cell
2) cAMP acts on a second messenger to activate protein kinase which causes a cascade
3) Causes increased secretion of thyroid hormones and prolonged growth of thyroid glandular tissue

Question 29

Describe how TSH is released from the pituitary gland

Answer 29

1) Thyrotropin-releasing hormone (TRH) is secreted by nerve endings in the median eminence of the hypothalamus and is then transported to the ANTERIOR PITUITARY via the HYPOTHALMIC-HYPOPHYSIAL PORTAL BLOOD
2) TRH binds with TRH receptors in the pituitary membrane which activates the PHOSPHOLIPASE SECOND MESSENGER SYSTEM inside the pituitary cells to produce large amounts of PHOSPHOLIPASE C
3) A cascade of second messengers (Ca2+ and diacyl glycerol) follows which leads to TSH release

Question 30

What happens when the blood portal system from the hypothalamus to the anterior pituitary gland becomes blocked?

Answer 30

The rate of secretion of TSH by the anterior pituitary decreases greatly but is not reduced to zero

Question 31

What are the effects of cold on TRH and TSH secretion?

Answer 31

Decrease in temperature -> Excitation of hypothalamic centers for body temp control -> Increase in TRH and TSH secretion -> Increase in metabolism

Question 32

What are the effects Anxiety and Excitement on TRH and TSH secretion?

Answer 32

Excitement and anxiety greatly stimulate the sympathetic nervous system -> increase metabolic rate and body heat -> decrease in secretion of TRH and TSH to counteract effect

Question 33

What is the feedback effect of thyroid hormone?

Answer 33

Increased thyroid hormone in the body fluid decreases secretion of TSH by the anterior pituitary

Question 34

What are the different Antithyroid drugs?

Answer 34

• Thiocyanate
• Propylthiouracil
• Inorganic iodides

Question 35

What is the MOA of Thiocyanate?

Answer 35

The same active pump that transports iodide ions into the thyroid cells pump thiocyanate ions -> high concentration cause COMPETITIVE INHIBITION of iodide transport into the cell, inhibiting “iodide trapping” -> prevents thyroglobulin from being iodinated forming thyroid hormones -> increased secretion of TSH by anterior pituitary gland -> overgrowth of thyroid gland “goitre”

[DOES NOT PREVENT FORMATION OF THYROGLOBULIN]

Question 36

What is the MOA of Propylthiouracil?

Answer 36

• Inhibits TPO (Thyroid peroxidase) -> decreases T3/T4 from thyroid gland
• Inhibits 5’deiodinase -> decreased T4 into T3 conversion in peripheral tissues
• Overstimulation of TSH causes goitre

Question 37

What is the MOA of Iodides in high concentrations?

Answer 37

• It reduces the rate of Iodide trapping -> rate of iodination of tyrosine to form thyroid hormones I decreased
• Normal endocytosis of colloid from follicles by thyroid glandular cells is paralysed -> immediate shutdown of thyroid hormone secretion
• Decrease all phases of thyroid activity -> slight decrease in size of thyroid gland + blood supply

CLINICAL CORRELATION:
frequently administered to patients for 2 to 3 weeks before surgical removal of thyroid gland to decrease necessary amount of surgery and bleeding

Question 38

What happens in Hyperthyroidism?

Answer 38

The thyroid gland is increased to two to three times the normal size, with tremendous hyperplasia and infolding of the follicular cell lining into the follicles

Question 39

What is Graves’ disease?

Answer 39

An autoimmune disease in which antibodies called “Thyroid-stimulating immunoglobulins (TSIs)” form against the TSH receptor in the thyroid gland

CAUSE:
Antibodies bind with the same membrane receptors that bind TSH and induce continual activation of the cAMP system of cells, resulting in hyperthyroidism.

LAB FINDINGS:
High level of hormone secretion cause by TSI suppress anterior pituitary formation of TSH -> TSH concentrations are less than normal rather than enhanced

Antibodies were formed due to autoimmunity against Thyroid

Question 40

What is Thyroid Adenoma?

Answer 40

A localised adenoma (tumour) that develops in the thyroid tissue and secretes large quantities of thyroid hormone causing hyperthyroidism

[It depresses the production of TSH by the pituitary gland]

Question 41

What are the symptoms of Hyperthyroidism?

Answer 41

• High state of excitability
• Intolerance to heat
• Increased sweating
• Mild to extreme weight loss
• Varying degrees of diarrhoea
• Muscle weakness
• Nervousness/other psychic disorders
• Extreme fatigue/inability to sleep
• Tremor of the hands

Question 42

What is Exophthalmos?

Answer 42

Protrusion of the eyeballs that is caused by oedematous swelling of the retro-orbital tissues and degenerative changes in the extraocular muscles

COMPLICATIONS:
- Eyeball protrusion stretches the optic nerve enough to damage vision
- Eyelids do not close completely when the person blinks or is asleep -> epithelial surfaces of the eyes become dry and irritated and often infected, resulting in ulceration of the cornea

Question 43

What diagnostic tests are used for Hyperthyroidism and Hypothyroidism?

Answer 43

• Direct measurement of “free” thyroxine in the plasma using appropriate radioimmunoassay procedures
• Basal metabolic rate is increased
• Concentration of TSH in plasma is measured
• Concentration of TSI is measured (high in thyrotoxicosis but low in thyroid adenoma)

Question 44

What is the treatment for Hyperthyroidism?

Answer 44

• Surgical removal of the thyroid gland
  [administer PROPYLTHIOURACIL for several weeks for normal basal metabolic rate then HIGH CONCENTRATIONS OF IODIDES for 1-2 weeks before the operation]
• Injected iodide (if injected iodide is radioactive, it can destroy most of the secretory cells of the thyroid gland)

Question 45

What is Hypothyroidism and what causes it?

Answer 45

It is when your thyroid gland does not produce enough thyroid hormones

CAUSES:
- Autoimmunity against the thyroid gland (Hashimoto disease)
- “thyroiditis” (thyroid inflammation) which causes progressive deterioration and fibrosis of the gland

Question 46

What is Endemic colloid goitre?

Answer 46

“goitre” is a greatly enlarged thyroid gland

CAUSE:
Lack of iodine prevents production of both thyroxine and triiodothyronine -> no hormone to inhibit production of TSH by anterior pituitary which causes pituitary to secrete excessively large quantities of TSH -> TSH stimulates thyroid cells to secrete a lot of THYROGLOBULIN colloid into follicles -> gland grows larger and larger
[due to lack of iodine, T3 and T4 production doesn’t occur in thyroglobulin -> doesn’t cause normal suppression of TSH]

Question 47

What is the difference between Idiopathic nontoxic colloid goitre and Endemic colloid goitre?

Answer 47

Endemic colloid goitre = caused by iodine deficiency

Idiopathic nontoxic colloid goitre = not caused by iodine deficiency

Question 48

What is Idiopathic nontoxic colloid goitre?

Answer 48

An enlarged thyroid gland NOT caused by iodine deficiency

CAUSES:
Slight hypothyroidism -> Increased TSH secretion and progressive growth on the non-inflamed portions of the gland -> Some portions are growing whereas some are being destroyed by thyroiditis

Question 49

Which hormone systems are affected in Colloid goitre?

Answer 49

• Deficient iodide-trapping mechanism (iodine is not pumped adequately into thyroid cells)
• Deficient peroxidase system ( iodides are not oxidised to the iodine state)
• Deficient coupling of iodinated tyrosines in thyroglobulin molecules (thyroid hormones cannot be formed)
• Deficiency of deiodinase enzyme (prevents recycling of iodine -> iodine deficiency)

Question 50

What are the symptoms of Hypothyroidism?

Answer 50

• Extreme fatigue
• Extreme muscular sluggishness
• Slowed heart rate
• Decreased cardiac output
• Decreased blood volume
• Increase in body weight
• Constipation

Question 51

What is Myxedema?

Answer 51

Development of an oedematous appearance throughout the body due to hypothyroidism

CAUSE:
Greatly increased quantities of of hyaluronic acid and chondroitin sulphate bound with protein form an excessive tissue gel in the interstitial spaces -> total quantity of interstitial fluid increases -> excess fluid makes it immobile and non-pitting

Question 52

What is the treatment of Hypothyroidism?

Answer 52

Daily oral ingestion of Thyroxine

Question 53

What is Cretinism?

Answer 53

Failure of body growth and mental retardation due to extreme hypothyroidism during fatal life, infancy or childhood

CAUSES:
- Congential lack of a thyroid gland (Congenital cretinism) from failure of the thyroid gland to produce thyroid hormone because of a genetic defect of the gland
- Iodine deficiency in diet (Endemic cretinism)

EFFECTS:
After birth the baby is normal (since it got thyroid hormones from mother whilst in utero) but after a few weeks the movements become sluggish and both physical and mental growth become retarded -> Adequate iodine or thyroxine usually causes normal return of physical growth -> If given more than a few weeks, mental growth remains permanently retarded (due to retardation of growth, branching, myelination of neuronal cells of CNS) -> Skeletal growth is more inhibited than soft tissue growth so child is obese and short -> Tongue becomes so large that it obstructs swallowing and breathing causing GUTTURAL BREATHING