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1

Thyroid hormone

-iodide and amino acid tyrosine are the ingredients for thyroid hormone (TH) synthesis
-two tyrosine residues with ether linkage with 4 Iodines attached:
3,5,3',5' tetraiodothyronine (T4) (aka thyroxine)
or 3,5,3' triiodothyronine (T3) (3 iodides)
or reverse T3 (different position of iodides)

2

Which cell makes thyroid hormone?

Follicular cell:
Na+ enters follicular cell with iodide, Na pumped out in exchanged for K (Na/K/ATPase): Net consequence of getting I- in is an active process.
-follicular cell is an "iodide trap"
-Iodide travels to other side of follicular cell and encounters thyroperoxidase (TPO), now active iodide that is transported to tyr residues
-layer of cells surround lumen filled with colloid.
-Thyroglobulin is the primary constituent of colloid
-blood vessels b/t follicles
-parafollicular cells (C cells) b/t follicles too: secrete calcitonin.
-Nerves terminate on bv and follicular cells (direct neural control of gland)

3

Thyroglobulin

produced by follicular cell
-prod on RER, transp to Golgi, packaged into secretory vesicles
-acts as source of tyrosine
-Made by follicular cell and secreted into lumen of gland.
-concentration of thyroglobulin is high in lumen
-lumenal "colloid"
-TPO acts to transfer iodide onto tyrosine residues
-Makes MIT or DIT (reactive iodide onto tyr residues)
-Final step is to form ether link between iodinated tyr residues
-TPO again does this
-Thyroglobulin is endocytosed into follicular cell where it is degraded by the lysosomes.
-degrade to indiv components: T3, T4, reverse T3 which are transported out into blood stream

4

T3 and T4 in bloodstream bound to:

Thyroid binding globulin (TBG)
-greater than 99% of thyroid hormone exists bound to TBG

5

What happens inside target cell?

T4 can be converted to T3
-T3 enters nucleus, binds to receptors on DNA. De-represses gene expression

6

Basal metabolic rate regulated by...

thyroid hormone
-if you lower thyroid levels (T3), move towards anabolic processes
-If you increase thyroid hormone, move towards catabolic processes (lose weight, produce more heat/heat intolerant)

7

Thyroid hormone is essential for development. 3 examples

-permissive for actions of other hormones.
Ex: growth hormone (Cretinism: stunted physical and mental growth due to thyroid hormone deficiency; can overcome if caught early and given thyroid supp)

Cardiovascular:
-increases number and efficacy of Beta adrenergic system

Brain

8

Regulation of thyroid hormone

-Hypothalamic-pituitary axis
-hypothal produces TRH, acts on ant pit (inc cAMP and hydrolysis of membrane phosphatidyl inositol) to produce TSH, TSH acts on thyroid to produce thyroid hormone which has strong negative feedback regulation on hypothalamus

TSH regulates:
-follicular cell number, iodide uptake/organification, coupling of iodotyrosines, TPO/enzymes, thyroglobulin synthesis and proteolysis

-iodine deficient diets lead to decreased TH synthesis and secretion
-high doses of iodine in short term also lead to decrease in TH release (Wolff-Chaikoff effect)

9

Dysregulation of thyroid: hypofunction

Hypothyroidism:
1. endemic (prevalent in areas where water supply doesn't have enough iodide): low T3, increased TSH
2. hypofunction of gland itself: Hashimoto thyroiditis (autoimm. destruction of gland, can't produce thyroid hormone): low T3, high TSH
3. Pituitary problems: low T3, low TSH

10

Hyperfunction of thyroid

Hyperthyroidism
1. Thyroid: high t3, low TSH
2. Pituitary: high T3, high TSH
3. Grave's Disease (immunoglobulins that mimic action of TSH, produce more and more thyroid hormone). High levels of T3, low levels of TSH.

11

Intake of iodine and incorporation in thyroglobulin

-ingested iodine taken up from gut in form of iodide to enter extracellular iodide pool
-iodide exits this pool from the blood in to follicular cells of thyroid gland
-"iodide trap", accum of iodide in thyroid typically 30-40 times conc of that in serum
-moves from basolateral to apical side.
-organification of iodide (incorp into tyrosyl residues on thyroglobulin) occurs at follicular cell-colloid interface
-thyroperoxidase catalyzes iodination of thyroglobulin

12

TH synthesis

-thyroperoxidase catalyzes iodination of tyrosyl moieties on TG
-so: monoidodotyrosine (MIT) and DIT are formed on TG
-Then 2 DITs or 1 DIT and 1 MIT couple to form iodothyronines (catalyzed by thyroperoxidase)

13

TH synthesis inhibitors

-inhibit iodination
-thiourea drugs (PTU, methimazole), called "goitrogens" leading to enlarged thyroid glands

14

TH secretion

-endocytosis of TG from lumen into follicular cells
-lysosomal enzymes act on TG to cleave T4 and T3 from it (amount of T4 is 20x greater than amnt of T3 release)
-DIT and MIT are cleaved from TG too. De-iodinated and tyrosine and iodide are reincorporated into TG

15

TH transport

-in blood: protein bound or free form (0.03% T4 and 0.4% T3)
-free form is active
-binding prot: TBG, TBPA, and albumin

16

Half life of T4 and T3

T4: 7 days
T3: 1 day (higher affinity of TBG for T4)

17

Is T4 or T3 considered the active form of TH?

T3 (affinity at receptor is 10 fold greater for T3 than T4)

T3 enters nucleus and interacts w/ nuclear receptors, then T3 receptor complexes act on DNA to direct trancription of specific mRNAs. Ex: NaK ATPase, and transcription of respiratory enzymes of mitochondria

18

conversion of T4 to T3

5' deiodinase

19

Actions of Thyroid hormone

1. reg of BMR (basal heat production); F 36, M 40; not used much now, but in absence of THs it decreases dramatically; calorigenic effect (due to Na pumping and increased oxygen consump)
2. fetal/neonatal brain devel (congenital hypothyroidism can lead to severe/irrev MR)
3. TH and GH needed for nomal growth
4. TH enhances response to catecholamines, mimics sympathetic NS activation.
5. Metabolism: low TH is anabolic, high doses catabolic

20

Control of TSH Secretion/Negative feedback

-TH: neg feedback by inhibiting secretion of TSH by AP (and likely TRH by Hypothal)

21

cretinism

-severe mental and growth retardation in child with hypothyroidism