L4: Thyroid Gland Physiology

Question 1

Follicles of the Thyroid gland contain _______: an extracellular storage form of thyroid hormone

Answer 1

Follicles contain Colloid: an extracellular storage form of thyroid hormone (T3/T4 bound to Thyroglobulin)

Question 2

__________ cells synthesize and secrete T3/T4 in response to ___________

Answer 2

Follicular cells synthesize and secrete thyroid hormones (T3/T4) in response to anterior pituitary TSH

Question 3

Role of Parafollicular cells of the thyroid?

Answer 3

Secrete peptide hormone calcitonin (not considered thyroid hormone)- Calcitonin plays role in calcium homeostasis

Question 4

What is required for Thyroid Hormone (T3/T4) synthesis?

Answer 4

Iodine

Inland areas w/ poor consumption of seafood=> thyroid gland deficiency due to lack of iodine

Question 5

Steps of Thyroid Hormone Synthesis/Secretion

Answer 5

1. Make Thyroglobulin
2. Iodine Trapping: transporter on the basolateral membrane, concentrates iodide in the cell
3. T3/T4 Synthesis:
   T4 (90% of output)
   T3 (10% of output) - more via peripheral deiodination of T4 in liver/kidneys
4. Secretion:
   T3/T4 attached to thyroglobulin => colloid endocytosed back into follicular cell => T3/T4 released and thyroglobulin broken down

Question 6

What regulates Thyroid Gland Function?

Answer 6

TSH (Anterior Pituitary)

Question 7

Plasma transport protein with highest affinity for Thyroid Hormones (T3/T4)?

Answer 7

Thyroxine Binding globulin (TBG) -Higher affinity for T4 than T3

Question 8

Plasma transport protein with intermediate affinity for Thyroid Hormones (T3/T4)?

Answer 8

TBPAA (Transthyretin)

Question 9

Plasma transport protein with lowest affinity for Thyroid Hormones (T3/T4)?

Answer 9

Albumin
lowest affinity but highest abundance-readily dissociable

Question 10

Which thyroid hormone do you measure to assess thyroid function?

Answer 10

T4

Question 11

Which Thyroid Hormone is more potent?

Answer 11

T3 10X more potent than T4

Question 12

Which thyroid hormone has a higher plasma half life?

Answer 12

T4&raquo_space;> T3

Question 13

Enzymes responsible for Activation/Deactivation of T3/T4? What are they dependent on?

Answer 13

Deiodinases are selenium dependent enzymes

• 5’ monodeiodinase converts T4 to T3 in target cells ( Removes C5 outer ring)
• 5 monodeiodinase inactivates T4 and T3 (removes C5 inner ring)

Question 14

What enzyme converts T4 to T3 in target cells

MOA?

When is it less active?

Answer 14

5’ Monodeiodinase

Removes C5 outer ring

Enzymes less active during fasting / starvation and cortisol excess

Question 15

What enzyme inactivates T4 and T3

MOA?

Consequences of Malfunction?

Answer 15

5 Monodeiodinase inactivates T4 and T3 (Selenium Dependent)

Removes C5 inner ring

Malfunction forms Reverse T3 (Competitive inhibitor of T3) => features of hypothyroidism

Question 16

________________ hormones play a key role in regulating Basal Metabolic Rate (BMR)

Answer 16

Thyroid hormones play a key role in regulating Basal Metabolic Rate (BMR)

• Hyperthyroidism: HIGH BMR
• Hypothyroidism: LOW BMR

Question 17

Metabolic Effects of T3

Stimulates _______ and release of ______________and ___________

Stimulates metabolism of __________ to bile acids

Facilitates removal of ________ from plasma

Generally stimulates all aspects of _________ metabolism and increases ______ turnover

Answer 17

Stimulates lipolysis and release of free fatty acids and glycerol

Stimulates metabolism of cholesterol to bile acids

Facilitates removal of LDL from plasma

Generally stimulates all aspects of carbohydrate metabolism and increases protein turnover

Question 18

Role of Thyroid Hormones in Growth/Development?

Answer 18

Essential for normal growth

• increases protein synthesis, energy production and substrate availability
• Enables anabolic actions of growth hormone

Essential for CNS development: promotes nerve cell growth and myelin formation

Question 19

Delayed CNS development and intellectual disability as a result of Thyroid hormone Deficiency?

Answer 19

Cretinism

Maternal and/or fetal hypothyroidism causes delayed CNS development and intellectual disability

Question 20

Role of Thyroid Hormones on Cardiovascular Hemodynamics?

Answer 20

T3 Upregulates Beta Adrenergic Receptors (Enhanced sensitivity to epinephrine leading to increased: heart rate, stroke volume, cardiac output and force of cardiac contractions

Question 21

Regulation of Thyroid Function?

Answer 21

Anterior pituitary (Thyroid Stimulating Hormone (TSH) )
Increased Thyroid Hormone synthesis
Stimulates follicular cell growth, follicle formation
Maintenance of function and growth of gland

Hypothalamus
TRH secretion from hypothalamus regulates secretion of pituitary TSH
Hypothermia is major stimulus to TRH secretion

Question 22

What regulates the secretion of TSH?

Major Stimulus?

Answer 22

TRH secreted from hypothalamus regulates secretion of pituitary TSH

Hypothermia is major stimulus to TRH secretion

Question 23

Causes of Primary Hypothyroidism?

Answer 23

• Iodine deficicncy
• Genetic (Receptor/enzyme mutation)
• Toxicity
• Cancer
• Hashimoto’s Thyroiditis (Autoimmune)

Question 24

MOST COMMON clinical presentation of hypothyroidism resulting from autoantibodies to TSH receptor which act as TSH antagonists

Answer 24

Hashimoto’s Thyroiditis

Question 25

Cause of Secondary Hypothyroidism?

Answer 25

Abnormality of Hypothalamus (TRH) or Anterior Pituitary (TSH)

Question 26

Symptoms of Hypothryroidism?

Answer 26

* Goitre (neck swelling) * Decreased heart rate and cardiac output * Decreased appetite * Lethargy/somnolence * Decreased basal metabolism =>Cold intolerance * Psychological disorders (depression, anxiety) Children: Intellectual disability, dwarfism (cretinism)

Question 27

Diagnosis of Hypothyroidism?

Answer 27

**Primary Hypothyroidism** (Decreased T3/T4 production) * INCREASED TSH * presence of anti-thyroid antibody (Hashimoto's Thyroiditis) **Secondary Hypothyroidism**: (Decreased T3/T4 production) * DECREASED TSH

Question 27

Treatment of Hypothyroidism

Answer 27

**Levothyroxine**: T3/T4 replacement therapy Also Dietary iodine supplementation

Question 28

What demographic does Hyperthyroidism most commonly affect?

Answer 28

Hyperthyroidism is 10x more common in women

Question 29

Symptoms of Hyperthyroidism?

Answer 29

* Increased basal metabolic rate * Heat intolerance * Increased body temperature * Increased heart rate / arrhythmias * Nervousness, anxiety * Goiter (Neck bulging) * Exophthalmos (‘bulging eyes’)

Question 30

Causes of Primary Hyperthyroidism?

Answer 30

_Abnormality of thyroid itself_: * **Graves Disease**: autoantibodies to TSH receptors which act as TSH agonists leading to: T3/T4 hypersecretion that cannot be overridden by feedback regulation * **Thyroid adenoma**

Question 31

Causes of Secondary Hyperthyroidism?

Answer 31

_Abnormality of Hypothalamus or Pituitary_: * Excess TSH (pituitary) * Excess TRH (hypothalamus)

Question 32

Disease in which autoantibodies to TSH receptor act as **TSH agonists** leading to T3/T4 hypersecretion stimulus that cannot be overridden by feedback regulation?

Answer 32

Graves Disease (Cause of Primary Hyperthyroidism)

Question 33

Difference between the two autoimmune disorders affecting the Thyroid?

Answer 33

**Hashimoto's Thyroiditis:** autoantibodies to TSH receptor which act as TSH ANTAGONIST => HYPOTHYROIDISM **Graves Disease:** Autoantibodies to TSH receptor which act as TSH AGONIST => HYPERTHYROIDISM

Question 34

Goiter in Hypothyroid vs. Hyperthyroid states?

Answer 34

**Hypothyroid State**: * Low levels of T3/T4 production due to iodine deficiency leads to reduced negative feedback => Increased TSH production from anterior pituitary => hypertrophy of thyroid gland w/o increased TH production (due to lack of iodine) * NO Feedback inhibition as no increase in T3/T4 **Hyperthyroid State**: * In Graves Disease autoantibodies to TSH receptor which act as TSH AGONISTS=>T3/T4 hypersecretion => Hypertrophy of Thyroid (GOITER) as stimulus cannot be overridden by feedback regulation * Feedback inhibition is ineffective bc TSH is not cause of thyroid stimulation

Question 35

Treatment of a Thyrotoxic Crisis (Thyroid Storm)

Answer 35

**Beta-blockers** (reduce sympathetic activation and T4 to T3 conversion) **Glucocorticoids** (reduce T4 to T3 conversion) **Thionamides** (inhibit new hormone synthesis)

Question 36

Plasma Transport of T3/T4? ______% bound to carrier proteins *__________________________* -Higher affinity for T4 than T3 **_________________________**- Intermediate binding affinity **_________________________**- Lowest binding affinity, Highest abundance

Answer 36

**99%** bound to carrier proteins **Thyroxine Binding globulin (TBG)** -Higher affinity for T4 than T3 **TBPAA (Transthyretin)**- Intermediate binding affinity **Albumin**- Lowest binding affinity, Highest abundance