Unit 6 - Thyroid Physiology

Question 1

thyroid gland structure and function

-what makes it unqiue as an endocrine gland?

Answer 1

regulates vertebrate growth, development, and metabolism

• bilobulated, large (10-25 g), and stores large amounts of hormones
• only endocrine gland that is easily palpated during routine exam
• tremendous potential for growth (goiters weigh 100s g)
• highly vascularized (blood flow 4-6 mL/min/g)
• attached to trachea by loose CT
• made of numerous follicles (100-300 micrometers)

Question 2

what are thyrocytes? what do they contain?

Answer 2

follicular epithelial cells (AKA thyrocytes) that are sites of thyroid hormone synthesis and release

• TH is stored with thyroglobulin (TG) in colloid (gelatinous inner area of follicles)
• has scattered parafollicular C-cells (sites of calcitonin synthesis/release)
• has fibroblasts, lymphocytes, adipocytes, and endothelial cells lining

Question 3

how are T3 and T4 made?

Answer 3

made from tyrosine on thyroglobulin, and need iodide (I-) from diet

• preferential synthesis of T4 (prohormone), but T3 is biologically active
• rT3 is also made, and biologically inactive

Question 4

what makes thyroid hormones unique?

Answer 4

they are the only hormones that need iodine

• most iodide is stored in thyroid gland while associated with thyroglobulin
• the rest is in target tissues or in circulation as organic/inorganic

Question 5

what does TH bind to in bloodstream?

Answer 5

TBG; thyroid binding globulin

-not as commonly transthyretin and albumin

Question 6

what is needed to stay in thyroid balance?

Answer 6

need to ingest adequate amounts of dietary iodide (70-300 ug/day)

• I- is concentrated in thyroid gland by specific transport PRO (2 Na+/I- symport) that uses inwardly-directed electrochemical Na+ gradient as driving force
• -not a “pump” and doesn’t use ATP directly

Question 7

how does thyroid gland “autoregulate”?

Answer 7

autoregulates iodide transport according to needs

• if dietary iodide is low, it concentrates more
• if I- is high, it concentrates less

Question 8

what does chronic iodide deficiency lead to? where is this true/

Answer 8

a form of hypothyroidism that is corrected by providing adequate dietary iodide
-found in “land-locked” mountainous areas outside USA

Question 9

what is the “end” of TH?

Answer 9

metabolized

-iodide is excreted in urine and feces

Question 10

6 steps of synthesis and storage of thyroid hormones

Answer 10

1. in ER, thyroglobulin (TG) molecules are produced and packaged in vesicles by golgi, and exocytosed into lumen of follicle
2. I- enters thyrocyte via basolateral Na+/I- cotransporters (iodide trap), and exits apical side via I-/Cl- antiporters
3. in follicular lumen, I- is oxidized to iodine by thyroid peroxidase, and substituted for H+ on benzene ring of tyrosine residues of TG
4. binding 1 iodine = MIT, while 2 = DIT (organification)
   - thyroid peroxidase catalyzes coupling of DIT to DIT (T4) or MIT (T3) that remain attached to TG
5. mature TG (with MIT > DIT > T4 > T3) are endocytosed back to follicular cell, and stored as colloid until secreted
6. colloid proteolysis is stimulated by TSH, and constituent molecules released
   - DIT/MIT reenter synthetic pool
   - T3/4 exit basolateral membrane to blood

Question 11

what is diodinase?

Answer 11

in follicular cell of thyroid

• breaks MIT and DIT into I- to be recycled
• rarely deficient, and can be found in different cell types with different jobs

Question 12

what is the main TH secreted?

Answer 12

93% T4
7% T3 and rT3
-most of these are derived from T4

Question 13

how much of TH is “free”?

Answer 13

T4 is 0.03%, T3 is 0.3%

-it needs to be in this form to enter target tissues and bind to TH receptors in nucleus

Question 14

how are THs metabolized in tissues (like liver/kidney?)

Answer 14

via 5’ peripheral deiodinases

• convert T4 to T3 or rT3
• if further deiodinate T3, will make inactive organic compounds

Question 15

what toes propyltiouracil (PTU) do?

Answer 15

inhibits deiodinases that convert T4 to T3

• given to inhibit follicular cells in hyperthyroidism
• will take a while to get relief, so give beta-blockers for tachycardia as well

Question 16

why is T4 given instead of T3 for treatment of hypothyroidism?

Answer 16

has longer half-life and greater stability

• slower onsets and longer duration of action
• T4 will convert to T3, which acts 4x as rapidly

Question 17

how do TH enter cell and exert effect?

Answer 17

unknown method of entry

• T4 usually converted to T3 by cytoplasmic 5’/3’-monodeiodinase, so cytoplasmic levels of T3 = T4
• these bind to thyroid hormone receptor (THR) bound to retinoid X receptor (RXR), which are bound to nuclear DNA at thyroid response elements in promoter regions of genes regulated by TH for transcription

Question 18

where are TH receptors expressed? what are their effects?

Answer 18

expressed in virtually all tissues of the body

• regulate metabolism of CHO, PRO, and lipids by way of:
• -Na/K pump
• -gluconeogenic and respiratory enzymes
• -myosin heavy chain
• -beta-adrenergic receptors
• overall increase metabolic rate and O2 consumption

Question 19

what are TH effects on

• bone
• CNS
• lungs
• heart
• kidney

Answer 19

1. act synergistically with GH to promote bone formation, ossification, fusion of bone plates, and maturation
2. essential for development in perinatal period
3. increased CO2 output
4. increased CO
5. increased urea excretion and renal function

Question 20

what happens to bone in hypothyroidism?

Answer 20

bone age is less than chronological age

-excessive replacement therapy with thyroxine can lead to bone loss and osteoporosis

Question 21

what does TH deficiency do in infants? how is this treated?

Answer 21

mental retardation (cretinism) and growth retardation

• growth fixed with treatment of T4 (thyroxine)
• mental only fixed if initiated shortly after birth

Question 22

effects of TH on BMR, metabolism, and cardiovascular

Answer 22

BMR increased

• more Na/K ATPase, O2 consumption, heat production
• more glucose absorption, glycogenolysis, gluconeogenesis, lipolysis, and net PRO catabolism
• increased CO

Question 23

what does complete lack of TH secretion VS extreme excess secretion do to BMR?

Answer 23

lack: BMR falls to 40-50% below normal
excess: BMR rises 60-100% above normal

Question 24

what does hypothyroidism do to serum cholesterol?

Answer 24

increased serum cholesterol will increase risk for atherosclerosis (LDL receptor expression and cholesterol excretion in bile are decreased)
-women who take T4 must be careful during menopause b/c of osteoporosis

Question 25

what does hperthyroidism do to sympathetic system?

Answer 25

increased expression of beta-adrenergic receptors leads to enhanced sensitivity to circulating E and NE -TH interact with SNS in unknown ways, so antagonists are effective in treating it

Question 26

how is thyroid function regulated?

Answer 26

1. thyrotropin-releasing hormone (TRH) is tripeptide hypothlamic releasing factor that stimulates TSH release by activating GPCR linked to PLC, to generate IP3 and mobilize intracellular Ca++ 2. TSH stimulates TH synthesis via GPCR to AC that increases cAMP 3. T3 (especially) and T4 act on target tissues for negative feedback on anterior pituitary and hypothalamus 4. dopamine and somatostatin exert inhibitory effects on TSH release

Question 27

where is the defect in primary hyperthyroidism?

Answer 27

antibodies VS TSH receptors make it constantly on to make high T4 and T3 -strong negative feedback to hypothalamus (low TRH) and anterior pituitary (low TSH)

Question 28

where is the defect in secondary hyperthyroidism?

Answer 28

tumor in AP constantly makes TSH - high TSH makes high T4 and T3 - strong negative feedback to hypothalamus (low TRH) and AP (but can't do anything b/c tumor)

Question 29

symptoms of hyperthyroidism

Answer 29

increased BMR (30-60%), tachycardia, sweating, heat intolerance, nervousness, muscle wasting, weakness, tremor, difficulty sleeping, changes in hair growth and skin texture

Question 30

toxic VS nontoxic goiter

Answer 30

toxic: hyperthyroidism (enlarged thyroid containing increased amounts of TH on TG) nontoxic: hypothyroidism (enlarged thyroid due to fibrosis and lymphocytic infiltration)

Question 31

Grave's disease

Answer 31

most common hyperthyroidism (2% females) - thyroid-stimulating IgGs cause hypertrophy of thyrocytes to cause goiter by acting directly on TSH receptors in follicle cells - increased circulating TH causes decreased TSH release from AP by negative feedback

Question 32

thyroid storm

Answer 32

exacerbation of hyperthyroidism, and medical emergency

Question 33

when is exopthalmos experienced?

Answer 33

in Grave's disease (Ab VS TSH receptors in follicle cells) | -NOT from pituitary tumor that increases TSH production

Question 34

where is the defect in primary hypothyroidism?

Answer 34

in thyroid itself (makes low amounts of T4 and T3) | -weak negative feedback to hypothalamus and anterior pituitary makes high amounts of TRH and TSH

Question 35

where is the defect in secondary hypothyroidism?

Answer 35

in anterior pituitary (makes low amounts of TSH, so low amounts of T4/3) - weak negative feedback to hypothalamus and anterior pituitary - hypothalamus makes high TRH

Question 36

what are symptoms of hypothyroidism?

Answer 36

low BMR, cold intolerance, lethargy, increased fat deposition, hypotension, non-pitting edma (myxedema), headache, skin changes, and constipation

Question 37

Hashimoto's thyroiditis

Answer 37

most common form of hypothyroidism (1% females) - insiduous, slow-developing process - antithyroid Abs that gradually destroy gland and cause fibrosis and lymphocytic infiltration - elevated TSH and reduced TH

Question 38

what does dietary iodine deficiency lead to?

Answer 38

hypothyroidism and goiter | -have high TSH levels

Question 39

what is myxedema coma?

Answer 39

end stage of untreated hypothyroidism - medical emergency in hypothyroid patients - edema from depoxition of mucoPRO in subcutaneous and EC spaces throughout body (nonpitting)

Question 40

what happens to TH in pregnancy?

Answer 40

estrogen levels are high, and liver makes increased TBG (to bind circulating TH) so increased TSH but normal TH