L3 Thyroid Hormone Flashcards Preview

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Flashcards in L3 Thyroid Hormone Deck (10):

Synthesis of T3 and T4 (basics)

Synthesized from tyrosine residues on thyroglobulin (TG)
- Requires dietary iodide
- Synthesis controlled by TSH
T3 = triiodothyronine (biologically active)
T4 = thyroxine (preferential synthesis, prohormone)
Reverse T3 also produced, biologically inactive


Iodide transport and storage

- Most is stored in the thyroid gland
- Concentrated in gland by a 2Na+/I- symporter (no ATP)
- Gland can autoregulate iodide transport according to needs
- Chronic iodide deficiency can lead to hypothyroidism (problem in landlocked areas) - can be corrected with dietary supplements
- Most is associated with colloidal TG
- Ultimately TH is metabolized and iodide is excreted


Steps of TH synthesis and storage

1. Thyroglobulin (TG) are produced in ER, packaged into vesicles, exocytosed into follicle
2. I- enters thyrocyte and rapidly associates with apical membrane
3. In follicular lumen, I- is oxidized to iodine by thyroid peroxidase and is put on tyrosine residue on TG (replaces H+)
4. MIT: binding of one Iodine, DIT: binding of two iodine (called organification). Tyrosine perioxidase also combines DIT+DIT to make T4. Also some T3 is made (DIT+MIT)
5. Endocytosed back into cell and stored as colloid
6. Colloid proteolysis is stimulated by TSH. DIT and MIT reenter pool for more synthesis, T3 and T4 released into blood


Thyrocyte response to TSH

- Secretes T4 (93%) and T3 (7%)
- Most circulating TH is bound to TBG (70%), other binding proteins are transthyretin and albumin
- Free TH is what circulates (~0.03 T4 and 0.3% T3) and enters tissues --> binds to receptor on the thyroid response element (TRE) of gene --> T3/T4 binding regulates transcription of these genes


How is T3 generated from T4?

- T4 is metabolized by peripheral deiodinases
- Antithyroid agents (used to tx hyperthyroidism) inhibit the conversion of T4 to T3
- T4 is used to treat hypothyroidism because of its longer half-life and greater stability
- THs have slow onsets and long duration of action


Effects of thyroid hormone

- Increase metabolic rate of O2 consumption
- Important for BMR (increases in hyper and decreases in hypothyroidism)
- Acts with GH and somatomedins to promote bone formation
- Promote ossification and fusion of bone plates/maturation
- Essential for CNS development in perinatal period - TH deficiency in infants results in mental and growth retardation
- Treat with thyroxine/T4


Physiological effects of low levels of thyroid hormone

- Decreased BMR
- Carbohydrate metabolism: decreased gluconeogenesis and glycogenolysis, normal serum [glucose]
- Protein metabolism: decreased synthesis and proteolysis
- Lipid metabolism: decreased lipogenesis, lipolysis, increased serum [cholesterol] - increased risk for arteriosclerosis
- Decreased thermogenesis
- Normal levels of serum catecholamines


Physiological effects of high levels of thyroid hormone

- Increased BMR
- Carbohydrate metabolism: increased gluconeogenesis and glycogenolysis, normal serum [glucose]
- Protein metabolism: increased synthesis and proteolysis, muscle wasting (proteolysis outweighs synthesis)
- Lipid metabolism: increased lipogenesis, lipolysis, decreased serum [cholesterol]
- Increased thermogenesis
- Increased expression of beta adrenoreceptors (increased sensitivity to catecholamines, which remain at normal levels). Beta adrenergic antagonists can treat hyperthyroidism symptoms


What is thyroid function regulated by?

- Hypothalamic TRH (+): stim TSH release through GPCR linked to PLC/IP3/intracellular Ca
- Anterior pituitary TSH (+): stim TH release through GPCR linked to adenylate cyclase and cAMP
- Circulating T3 and T4 (-): negative feedback
- Dopamine and somatostatin inhibit TSH release


How is primary thyroid disease diagnosed?

- Determination of serum TSH
- Elevated in primary hypothyroidism due to lack of negative feedback by low circulating T3 and T4
- Reduced in hyperthyroidism due to excessive negative feedback by high circulating T3 and T4