Thyroid hormones

Question 1

Iodine transport: pump (5)

Answer 1

1. Basolateral membrane: Iodine / Na symport pump, secondary active transport coupled with Na/K pump
2. Iodine has a high concentration inside
3. Iodine exits into follicular space down concentration gradient
4. Inhibition:

• thiocyanate: competes with iodide; blocks pump
• perchlorate, perrhenate, petechneate; competitively inhibit by using pump (enter)

5. TSH increases activity by increasing cAMP levels or PLA2 activation

Question 2

Oxidation & Organification

Answer 2

1. Thyroperoxidase on follicular space side of apical membrane oxidizes I^- –> I⁺

• Requires NADPH and peroxide
• inhibited by PTU: propylthiouracil (anti-thyroid drug)

2. Thyroperoxidase iodinates Tyrosine residues on Thyroglobulin
   * MIT, DIT, T4, T3
3. Coupling of MIT and/or DIT –> T3 and T4

• cleaves to leave behind dehydroalanine
• Inhibited by PTU

*All steps activated by TSH

Question 3

Release of Thyroid hormones (3)

Answer 3

1. Phagocytosis of thyroglobulin
2. Fusion with lysosome –> cleave off MIT, DIT< T3 and T4
   * Hydrolysis stimulated by TSH; inhibited by Iodine (Wolff-Chiakoff effect)
3. T4 and T3 released

• MIT and DIT –> deiodinase (uses NADPH)–> free Tyrosines & Iodine
• Iodide recycled back

Question 4

TH production regulation

Answer 4

1. Activation: increased TSH
2. Inhibition: increased Iodide
3. Wolfe-Chaikoff effect (short term): transient block in organification
4. Medium term: increased organification leading to increased MIT and DIT but decreased T4 and T3 –> decreased T3 and T4 released (cells recover after a week)
5. Long term: iodide block becomes permanent –> goiter and hypothyroidism
   * often due to underlying defect in thyroid

Question 5

Half-life & Conversion in periphery (5)

Answer 5

1. T4: 99.97 % bound; 6.5 days
2. T3: 99.7% bound; 1.5 days
3. Both bind to thyroxine-binding globulin (TBG) and a smaller percentage to TBPA (pre-albumin)
4. T3 has stronger affinity (10x) to receptors than T$
5. Thyroxine deiodinase converts T4 –> T3 and rT3 ( little activity, but increase in number during disease)
   * Inhibited by PTU
6. Taking birth control pills can increase TBG, will increase T4 and T3 in whole blood, but ratios remain the same; euthyroid
   * important reason to measure free hormone levels, not just total

Question 6

Feedback regulation & Mechanism of Action

Answer 6

1. T3 inhibits TRH and TSH secretin
2. Somatostatin inhibits TSH release (and GH)

• GH –> IGF1 –> somatostatin –x TSH
• Those who take GH are at risk for hypothyroidism

3. Thyroid receptor binds to DNA in presence and absence of hormone –> T3 binding causes activation of txn by recruiting coactivators

• RXR-TR heterodimer is most active form
• TRE: inverted pallindrome or direct repeats (4) DNA sequence recognized by TR
• nTREs mediate txn repression; TR binds as monomer

Question 7

Thyroid hormone: biological effects

Answer 7

1. Increases energy consumption; increase # of Na/K ATPase molecules (TREs on SER Ca ATPase gene, SERCA2)
2. Enhances protein synthesis = positive nitrogen balance
3. amphibia metamorphis is dependent on TH
4. Required for normal growth and development (TREs found in GH gene)
5. Increases heart rate (TREs on myosin isoforms)

Question 8

Endemic goiter (3)

Answer 8

1. Insufficieny dietary intake of iodine
2. Low TH production
3. Constant stimulation/release of TSH

TSH –> thyroid growth

HYPOTHYROIDISM

Question 9

Graves’ disease (4)

Answer 9

1. Autoimmune attack on TSH Receptor by TSI (thyroid stimulating immunoglobulins)
2. Continually stimulates TR –> increased TH production

HYPERTHYROIDISM (bulging eyes, eye muscle damage, diffuse goiter)

3. 70% patients have Hashimoto’s also (mixture of Ab)
4. Treatment: radioactive I, PTU, surgery

Question 10

Hashimoto’s thyroiditis (3)

Answer 10

1. autoimmune; production of antibodies against **thyroglobulin **
2. deterioration of thyroid
3. HYPOTHYROIDISM

dull eyes, turned down mouth, mental retardation

*can be treated at birth w/ TH

Question 11

Iodine administration (3)

Moderate levels

& high levels

Answer 11

1. Moderate levels increase TH production
2. High levels: transient block in organification: Wolff-Chiakoff effect
3. inhibits TH production and I uptake in thyroid

*Used to prevent radioactive uptake after radioactive exposure b/c it can lead to tumors

*Used during surgeries near thyroid –> to prevent thyroid storm (surge of TH released leading to increase in HR)

*constant high levels can lead to long-term effects –> goiter & asphyxiation

Question 12

Lithium drug interaction (2)

Answer 12

1. Inhibits TH release
2. 25% have a goiter; HYPOTHYROIDISM

Question 13

Cretinism & congenital hypothyroidism

Answer 13

1. Low TH production from birth
2. Short stature, mental retardation
3. Mix with low iodine in diet or high thiocyanate (casava) in diet –> goiter

*can be treated at birth

1. Defect in thyroid gland leading to Low TH production

untreated congenital hypothyroidism can lead to cretinism

Question 14

Antithyroid drugs (4)

Answer 14

1. Propylthiouracil (PTU): blocks every step except pump

• 1st trimester of pregnancy (no birth defects)
• thyroid storm: more effective
• patient is allergic to methimazole

2. Methimazole: more commonly used b/c doesn’t lead to liver damage (PTU effect). Doesn’t block T4–> T3 conversion so not effective in thyroid storm
3. Thiouracil & Thiourea

Question 15

Hyperthyroidism

vs.

Hypothyroidism

Symptoms

Answer 15

1. Hyper: proptosis, heat intolerance, termor, weight loss
   * Low TSH levels due to high TH levels
2. Hypo: cold intolerance, weight gain, cold clammy skin
   * High TSH levels due to low TH levels