Lecture Objectives- thyroid

Question 1

follicles

Answer 1

consists of the colloid surrounded by thyrocytes; functional units that make up the thyroid gland

Question 2

thyrocyte

Answer 2

follicular epithelial cells around the colloid

Question 3

thyroblobulin (Tg)

Answer 3

synthesized on ribosomes of thyroid follicular cells, its packaged in a secondary secretory vesicles on the golgi and extruded into the follicular lumen; once inside the colloid, it binds with iodine to make MIT and DIT, and it broken down again in the cell to be recycled.

Question 4

TSH receptors

Answer 4

TSH receptors are on the thyroid gland and some other places, binding of TSH receptors has trophic and tropic effect. IgGs fragments of plasma proteins can act as an antibody to the TSH receptors (Grave’s disease

Question 5

thyroid hormone receptor beta2

Answer 5

receptors are found in the hypothalamus and pituitary and participates in the negative feedback loop, it can be bound by T3 and T4

Question 6

thyroid hormone receptor TRalpha1 and TRbeta1

Answer 6

receptors are found in target tissues

Question 7

thyroid peroxidase (TPO)

Answer 7

organifies iodine into tyrosine residues within thyroglobulin, forming T4/T3 in the colloid

Question 8

thyrotrope cells

Answer 8

• are cells in the anterior pituitary; they receive signals from the hypothalamus (TRH) and secrete TSH into circulation.

Question 9

tri-iodothyronine (T3)

Answer 9

most bio active form in tissue because it has a greater receptor affinity. Converted from T4 via 5’monodieiodinase in tissues, or made from MIT + DIT. Its 10% of the secretion from the thyroid cells. Provides feedback to the hypothalamus and the pituitary.

Question 10

thyroxine (T4)

Answer 10

this is homeostatically regulated in the blood, makes up 90% of the secretion from thyroid cells. Its very hydrophobic and is a prohormone bound to plasma proteins, thyroid binding globulin (TBG). Made from DIT + DIT

Question 11

Na/K pumps

Answer 11

on the basolateral side of the thyroid follicular cells, creates a sodium gradient. Creates sodium vacuum.

Question 12

Na/iodide co-transporter

Answer 12

on basolateral side of the cell, bring sodium down its concentration gradient and at the same time drawing in iodine

Question 13

Iodide/Cl- co-transporter

Answer 13

Iodine gets carried out into the colloid via I-/Cl- co transporter

Question 14

thyroid binding globulin

Answer 14

99% of the T4 and T3s totally are bound, 70% bound to TBG; TBG maintains a large reservoir of circulating T4 and buffers against large acute changes in the circulating levels. (15% to TTR (transthyretine) and other 14% bound to albumin and lipoproteins.)

Question 15

TRH receptors

Answer 15

are on the anterior pituitary thyrotrophes and causes release of TSH

Question 16

TRH

Answer 16

is released by the hypothalamus and stimulates the anterior pituitary thyrotrophes to release TSH.

Question 17

TSH

Answer 17

has both TROPHIC (stimulating gland growth) and TROPIC (stimulating T3/T4 production), it stimulates all steps of T3/T4 production/release

Question 18

5’ monodeiodinase

Answer 18

converts T4 to T3 in tissues

Question 19

goiter

Answer 19

hyperstimulation of the TSH receptors, chronic elevation of TSH causes hypertrophy of thyroid gland

Question 20

colloid

Answer 20

lumen of the thyroid gland follicles, storage location of thyroid hormones

Question 21

Describe the hypothalamic-pituitary feedback regulation of thyroid hormone function

Answer 21

1) . Hypothalamus releases TRH into the portal veins where it binds to receptors in the anterior pituitary. T4/T3 provides negative feedback. Successive TRH injections show diminishing TSH responses due to more T4 in blood and its long 1/2 life (7 days).
2) . Thyrotropes in the anterior pituitary release TSH into the systemic circulation. TSh stimulates steps in synthesis/release of T3/T4. T3/T4 provides negative feedback as well.
3) . T3 - the bioactive form of thyroid hormone released by the thyroid gland. 10% of thyroid hormone.
4) . T4 - homeostatically regulated. tissues contain 5’- monodeiodinase that converts it to T3. 90% of thyroid hormone in the systemic circulation.
5) . T3/T4 bind TRalpha1 & TRbeta1 receptors in target tissues
6) . thyroid hormone receptor beta 2– In Anterior pituitary and hypothalamus, binding of T3/T4 provides negative feedback.

Question 22

What is the iodide trap, and what factors can stimulate and inhibit it?

Answer 22

● The trap is a basal Na+/K+ ATPase that pumps out Na+. Na+/I- are cotransported inside, down Na+ gradient
●Stimulators: TSH
●Inhibitors: Dietary iodide intake > 2 mg/day - Wolff-Chaikoff effect

Question 23

What factors account for the incredibly long half-life of thyroid hormones, as compared to other hormones?

Answer 23

99.95% of it is bound to plasma proteins.

half life T4 = 7 days; T3=1 day

Question 24

Compare/contrast T3 and T4 with regard to prevalence, transport, half-life and potency. Which form is best-suited for pharmacological supplementation, and why?

Answer 24

T3:
Prevalence: 10%
Transport: 70% is bound to thyroxine binding globulin, 15% to TTR, 14% to albumin.
1/2 life: 1 day
Potency: Higher potency - greater receptor affinity

T4:
Prevalence: 90%
Transport: same as T3
1/2 life: 7 days
Potency: Prohormone: 99.95% bound to plasma proteins

Question 25

Describe the involvement of T3 action with regard to: BMR, brain development, adrenergic signaling, CVS, bone

Answer 25

-Increases BMR: Increases Na/K channels + ATPase --> hyperpolarization --> increased O2 and energy use --increases mitochondrial uncoupling proteins --> thermogenesis -Brain maturation: neural cell migration, differentiation and signaling. T4 - activated to T3 in glial cells, astrocytes and tanycytes T3 - controls expression of genes involved in myelination, cell diff. migration and signaling. -Increased adrenergic signaling: more receptors, amplification of receptor signaling but NOT more catecholamines -CVS effects: increases HR, SV, CO, and vasodilation; B-adrenergic effects -Increases bone remodeling

Question 26

What is cretinism?

Answer 26

Hypothyroidism leading to mental retardation.

Question 27

Graves' Disease

Answer 27

-Hyperthyroidism -Autoantibodies that mimic TSH ● Presents with bilateral thyroid enlargement, ○ mild weight loss ○ increased restlessness ○ tachycardia ○ excessive sweating ○ wide-eyed stare ● T4 and Free T4 are elevated ● TSH is low ● Thyroid stimulating immunoglobulin (TSI) is elevated ~1 in 50 women, lower incidence in men, autoimmune

Question 28

Hashimoto's Thyroiditis

Answer 28

-Hypothyroidism -Autoantibodies that attack thyroid gland, specifically Thyroid peroxidase (TPO) ● Presents with bilateral thyroid enlargement ○ mild weight gain ○ fatigue ○ slow pulse ○ dry skin ○ difficulty concentrating ● T4 and Free T4 are low ● TSH and TRH are high ● TPO blood test positive ~1 in 200, autoimmune

Question 29

pheochromocytoma

Answer 29

- Pheochromocytoma can result from a neuroendocrine tumor of the medulla of the adrenal glands (originating in the chromaffin cells) that secretes excessive amounts of catecholamines, adrenaline and noradrenaline - Presents: Classic Triad of episodic headache, sweating, and tachycardia, hypertension

Question 30

What effect should hyperthyroidism have on a person’s diastolic blood pressure?

Answer 30

Cardiovascular effects are increased CO = SV * HR. It also has beta 2 adrenergic effects so while systolic BP increases, diastolic remains relatively unchanged. While thyroid hormone causes heart rate and stroke volume to increase, these effects are matched in diastole by thyroid hormone’s stimulation of vasodilation (beta adrenergic effects are responsible for vasodilation in the periphery).

Question 31

What is the Wolff-Chaikoff effect?

Answer 31

● Very high iodide intake (>2mg/day) transiently suppresses the thyroid gland’s production of mRNA for the Na+/I- cotransporter and TPO for ~ 2 days. ● Plasma [I-] has a biphasic effect on T3/T4 secretions (both low levels and high levels of iodide limit T4/T3 production). The acute increase in [I-] in thyrocytes inhibits TPO and Na+/I- cotransporter. The inhibition of Na+/I- cotransporter results in the reduction of intracellular [I-], which releases inhibition of TPO and Na+/I- cotransporter, so that I- uptake and T3/T4 production resumes after about 2 days (even with persistently high plasma [I-]). ● Hence, the Wolff-Chaikoff effect can be used transiently to treat acute effects of life-threatening hyperthyroid states (eg “thyroid storm” - Sx include: agitation, confusion, tachycardia, restlessness, shaking, and hypertension).

Question 32

Describe the conditions under which a goiter can form and the patient is in a: euthyroid, hypothyroidism, hyperthyroidism.

Answer 32

- euthyroid: iodine deficiency - hypothyroidism: Hashimoto’s thyroiditis - hyperthyroidism: Grave’s disease

Question 33

How produce thyroid hormone?

Answer 33

1) thyrocytes trap I- with Na+/I- cotransporter: Na+/K+ ATPase pumps Na+ out, so then Na+/I- cotransporter moves Na+ back in, and I- against conc. gradient. 2) I- released into colloid via I-/Cl- cotransporter on apical membrane. 3) ER makes thyroglobulin, exocytosed into colloid. 4) Thyroid peroxidase organifies I- into thyroglobulin, forming T3/T4 on tyrosine residues. Stored in colloid. 5) Endocytosis of T3/T4 from colloid. 6) Lysosomal hydrolysis: thyroglobulin --> T3/T4 + iodinated tyrosine residues (MIT, DIT) 7) T3/T4 into blood via thyroid hormone transporter (little thyroglobulin released unless thyroid is inflamed) 8) I- from MIT/DIT is recycled in thyrocyte.

Question 34

Characteristics of hyperthyroidism vs hypothyroidism

Answer 34

Hyper: excitable, sweating, restless, insomnia, fast reflexes, weight loss/catabolism Hypo: dull, lethargic, slow reflexes, psychotic (myxedema madness), weight gain.

Question 35

Hyperthyroidism treatment

Answer 35

Propylthiouracil (PTU) or methimazole: inhibit thyroid peroxidase *PTU also decreases T4 to T3 conversion in tissues.

Question 36

Hypothyroidism treatment

Answer 36

T4 pill (levothyroxine)