The Thyroid Gland

Question 1

Describe the anatomy of the thyroid gland?

Answer 1

• Lies across the trachea at the base of the larynx
• Butterfly shaped, not visible nor palpable in health though
• 15-20g weight

Question 2

What are the physiologically active forms of the thyroid hormones?

Answer 2

• T3: triiodothyronine

- T4: thyroxine

Question 3

What are the 2 cell types in the thyroid gland? And brief description of each function

Answer 3

• C (clear) cells: secrete calcitonin

- Follicular Cells: Facilitate thyroid hormone synthesis and surround hollow follicles

Question 4

What are thyroid follicles? Which hormone do they act as a reservoir of?

Answer 4

• Spherical structures with walls composed of follicular cells
• Centre of follicles filled with colloid (glycoprotein matrix)
• Contain about 2-3 months worth of thyroid hormones

Question 5

Brief description of how thyroid hormones are synthesized

Answer 5

• Follicular cells synthesize enzymes (thyroperoxidase) and thyroglobulin and export into the colloid
• Follicular cells import iodide from the plasma and export it into the colloid
• In the colloid thyroperoxidase combines iodine with tyrosine residues to form MIT & DIT
• MIT & DIT undergo conjugation reactions to form thyroid hormones

Question 6

Where do the tyrosine residues involved in thyroid hormone synthesis in the colloid come from? (what form are they in..?)

Answer 6

• Thyroglobulin, a protein rich in tyrosine residues
• Thyroglobulin is synthesized by follicular cells and exported into the colloid in vesicles alongside enzymes responsible for TH synthesis

Question 7

Where does the tyrosine and iodide in the body come from?

Answer 7

• All derived from diet

Question 8

How does iodide get from the plasma to the colloid?

Answer 8

• Na / iodide symporter on the membrane of follicular cells imports iodide from the plasma, symport means this can even occur against concentration gradient
• Iodide is then transported into the colloid via the pendrin transporter on the other side of follicular cells

Question 9

Once iodide and thyroglobulin are into the colloid along with enzymes, what is the first step in TH synthesis?

Answer 9

• Iodide is oxidized to iodine and then iodine is added to tyrosine residues from thyroglobulin

Two different intermediates are formed:

• MIT (monoiodotyrosine)
• DIT (diiodotyrosine)

Question 10

What are MIT and DIT? What are the constituents of each?

Answer 10

• Intermediates in TH synthesis
• MIT: Iodine + tyrosine residue
• DIT: Iodine + Iodine + tyrosine residue

Question 11

How do MIT and DIT go on to form thyroid hormones?

Answer 11

• They undergo conjugation reactions
• MIT + DIT = triiodothyronine aka T3
• DIT + DIT = tetraiodothyronine aka Thyroxine T4
  (still attached to thyroglobulin)

Question 12

How many tyrosine and iodine molecules are in T3 and T4 respectively?

Answer 12

• T3: 2 Tyrosine + 3 iodine

- T4: 2 Tyrosine + 4 iodine

Question 13

How are the thyroid hormones mobilized from the colloid to the plasma?

Answer 13

• TSH stimulates portions of the colloid to be taken up into follicular cells via endocytosis
• Within the cells vesicles form that contain the thyroglobulin bound THs and proteolytic enzymes
• Proteolytic enzymes cut thyroglobulin and release THs
• T3 and T4 freely diffuse across follicular membrane into plasma

Question 14

Why do T3 and T4 freely diffuse across follicular membrane? What does this mean for them once they are in the plasma?

Answer 14

• because they are lipid soluble hormones

- Means they need to bind carrier proteins in the plasma, mainly thyroxine-binding globulin

Question 15

Where is the TSH (thyroid stimulating hormone) that mobilizes TH secreted from?

Answer 15

• TSH secreted by pituitary gland

Question 16

How is most of T3 and T4 found in the plasma? Compare half lives of T3 and T4? Why is there a difference?

Answer 16

• Bound to plasma proteins
• T3: half life of about 1 day, T4: 6 days
• Thyroxine Binding Globulin (TBG) has a higher affinity for T4 than T3, accounting for longer half life

Question 17

Is there more T4 or T3 in plasma? Which one is more physiologically active?

Answer 17

• Much more T4 (50x more) than T3 in the plasma

- 90% of TH binding to cell receptors is T3 though, T3 is 3-5x more physiologically active than T4

Question 18

How is the large reservoir of T4 in the plasma made physiologically active? Where does this process occur?

Answer 18

• It is deiodinated to make T3 from the T4
• Around half of the T4 is deiodinated in plasma, the remaining fraction inside target cells.
• The level of deiodination can be adjusted to meet TH demand

Question 19

Describe the hormone cascade responsible for the release of T4 & T3, including the endocrine glands involved

Answer 19

• TRH released from hypothalamus
• Stimulates TSH release from anterior pituitary
• Stimulates TH release from thyroid

Question 20

List stimuli increasing TH release

Answer 20

• Cold, exercise, pregnancy

Act via stimulating TRH release

Question 21

List hormones / stimuli that are inhibitory towards TH release

Answer 21

• Glucocorticoids: Inhibit TSH and conversion of T4 to T3
• Somatostatin: Inhibits TSH (bc TSH needed for GH action)
• Presence of T3 and T4 in plasma negatively feedbacks on TSH and TRH release. (only free hormone, not protein bound form)

Question 22

List the actions of Thyroid Hormone

Answer 22

• Boost metabolic rate
• Stimulates GH receptor expression
• Promote thermogenesis (via stimulation of futile cycles of catabolism and anabolism)
• Permissive effect on catecholamines
• Net increase in proteolysis (in supraphysiological doses*?) and lipolysis
• Increase hepatic gluconeogenesis (no effect on BG as long as pancreas is secreting sufficient insulin - therefore not a counter-regulatory hormone)

Question 23

Mechanism via which TH acts within cells?

Answer 23

• Bind to nuclear receptors WITHIN target cells to alter gene expression

Question 24

What effect does a maternal iodine deficiency have on offspring?

Answer 24

• Congenital hypothyroidism
• Possibly other issues?

(TH is essential for brain development in utero)

Question 25

Pathologies that can cause hyperthyroidism?

Answer 25

• Grave’s Disease (common)
• Thyroid Adenoma (rare)
• Pituitary adenoma

Question 26

Describe the pathophysiology of Grave’s Disease?

Answer 26

• Antibodies produced mimic TSH and increase TH release
• Increased TH negatively feedbacks and inhibits TSH release so plasma [TSH] is very low
• Thyroid gland hyperplasia due to overstimulation, gland can grow to 2-3x size

Question 27

Symptoms of hyperthyroidism?

Answer 27

• Increased metabolic rate & heat production: weight loss and heat intolerance
• Increased protein catabolism: muscle weakness / weight loss
• Altered Nervous function: hyper-excitable reflexes and psychological disturbances
• Elevated heart function: TH is permissive to epinephrine, B receptors (elevated HR, CO, contractile force - can lead to heart failure)

Question 28

Causes of hypothyroidism?

Answer 28

• Hashimoto’s disease: autoimmune attack of thyroid gland
• Dietary iodine deficiency
• Idiopathic (thyroiditis?)

Question 29

Symptoms of hypothyroidism?

Answer 29

• Decreased metabolic rate & heat production: weight gain and cold intolerance
• Disrupted protein synthesis: brittle nails / thin skin
• Altered Nervous function: slow speech / reflexes, fatigue
• Depressed heart function: lower HR, weak pulse

Question 30

Does a goitre form due to hyperthyroidism or hypothyroidism? Why?

Answer 30

• Both
• Hypo: Increased TSH action on follicular cells causes thyroid enlargement
• Hyper: Over-activity as a result of autoimmune (Grave’s) disease causes thyroid growth

Question 31

What is a goitre? How does it appear?

Answer 31

• Enlarged thyroid gland

- Appears as a large bulge in the neck of the patient

Question 32

What types of endocrine disorder are Grave’s and Hashimoto’s disease?

Answer 32

• Primary: direct effect is on gland producing the end hormone
• Secondary and tertiary disorders also possible from pituitary and hypothalamic defects