Thyroid Hormone Synthesis Flashcards

1
Q

location of thyroid gland

A

below larynx

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2
Q

thyroid structure

A

2 lobes in each side of trachea. A narrow band (isthmus) connects the 2 lobes

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3
Q

blood supply to thyroid

A

superior thyroid artery (from external carotid)and inferior thyroid artery (from thyrocervical trunk of subclavian)

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4
Q

T/F thyroid receives highest blood flow of all endocrine organs

A

True

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5
Q

functional unit of thyroid

A

follicle

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6
Q

follicle structure

A

layer of cells surrounding lumen filled with colloid. Colloid mostly made of thyroglobulin

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7
Q

types of cells in thyroid

A

follicular (surround colloid) and parafollicular cells (C cells)

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8
Q

role of parafollicular cells

A

parafollicular cells found between follicles and secrete calcitonin

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9
Q

ingredients for thyroid hormone synthesis

A

Iodide and tyrosine; Thyronine is the backbone of the THs, and the 3, 5, 3’, 5’ positions can be iodinated

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10
Q

thyroid hormones

A

Thyroxine (4 iodides) and triiodothyronine (3 iodides attached)

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11
Q

Iodide transport

A

ingest iodine from food– iodide absorbed from gut to enter blood/extracellular iodide pool– exits pool into follicular cells, difuses from basolateral to apical side and exits

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12
Q

where does organification of iodide occur

A

this occurs at follicular cell-colloid interface (must be oxidized before it can participate in tyrosyl iodination)

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13
Q

enzyme catalyzing iodination of thyroglobulin

A

thyroperoxidase; membrane bound glycoprotein in microvilli of apical membrane

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14
Q

Thyroglobulin

A

glycoprotein made on RER within follicular cells and transported to golgi for glycosylation and packaging. Secretory vesicles released from apical side to lumen where TG enters colloid

  • all iodination and coupling reactions of TH synthesis occur on tyrosyl residues of TG
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15
Q

Thyroid hormone synthesis

A

thyroperoxidase catalyzes iodination of tyros)l moieties on TG to form monoiodotyrosine and diiodotyrosine (MIT and DIT) on TG. 2 DITs or 1 DIT and 1 MIT couple to form iodothyronines, thought to be catalyzed by thyroperoxidase

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16
Q

iodination inhibitors

A

inhibit iodination, causing decreased TH synthesis and secretion, which causes elevated TSH and gland hypertrophy (GOITER)

  • thiourea drugs (propylhiouracil-PTU) and methimazole
  • aka goiterogens
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17
Q

thyroid hormone secretion

A

Drops of colloid move into follicular cells via endocytosis and coalesce with lysosomes. Lysosomal enzymes cleave T4 and T3. Much more T4 than T4 (about 20x)

  • DIT and MIT can also be cleaved, but these will be deiodinated and tyrosine/iodine reincorporated into TG
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18
Q

thyroid hormone transport

A

most protein bound (99.9%) and some in free form (.03% T4 and 0.3% T2)
- Free form is active

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19
Q

what proteins bind TH in blood

A

thyroid binding globulin (TBG), thyroid-binding pre-albumin (TBPA) and albumin
- about 30% of sites occupied by TH

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20
Q

role of protein bound TH

A

acts to delay, buffer, and prolong TH action; more pronounced for T4 than T3, partly since proportionally more T4 is bound due to higher affinity of TBG for T4

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21
Q

which thyroid hormone has faster onset of action

A

T3

22
Q

which thyroid hormone has shorter half life

A

T3 (7 days vs 1 day)

23
Q

which TH more active

A

T3 considered active form due to increased affinity of TH receptor for T3

24
Q

how do TH act

A

T3/T4 enter cells via active transport. T4 converted to T3 via 5’deiodinase. T3 enters nucleus and interacts with nuclear receptors. T3-receptor complex acts on DNA to direct transcription of mRNAs. (eg. NA-K ATPaseaka the Na-K pump, and respiratory enzymes stimulated)

25
Q

actions of TH

A
  1. regulate metabolic rate- most of calorigenic effect due to Na pumping. Evident in most tissues except spleen, brain, testis. More hormone = more basal heat production/O2 consumption
  2. Fetal and neonatal brain development (proliferation, differentiation, myelinogenesis, neurite outgrowth, synapse formation)
  3. normal growth
  4. enhance response to catecholamines== mimic effects of sympathetic nervous system activation
  5. Affect metabolism- time and dose-dependent. Low to mod dose tend to be anabolic, while high doses catabolic – increased fuel consumption, protein breakdown, muscle wasting, lipolysis. Low-mod doses promote conversion of glucose to glycogen; high doses enhance glycogenolysis
26
Q

TH synthesis/secretion control

A

TRH form hypothyroid acts on membrane receptor in pituitary thyrotrophs, causing increased cAMP and hydrolysis of phosphatidyl inositol. stimulates thyrotrophs in pituitary to release TSH, which is carried by blood to thyroid

  • TSH acts on membrane receptor to stimulate thyroid hormone synthesis (stimulates iodide pump (with latency), thyroperoxidase and endocytosis of colloid)
  • TSH increases iodide organification, coupling of iodotyrosines, TG synthesis, and TG proteolysis following endocytosis from colloid. Causes increased release of TH secretion– thought to me mediated by cAMP
  • Also affects gland morphology – follicular cells proliferate, enlarge, elongate and compensatory changes in colloid amount

Free T3/T4 influence response of anterior pituitary to TRH (high levels reduce response, while low sensitizes the response)

27
Q

How does TSH interact with tyroid receptors

A

Thought to be mediated by cAMP. TSH activates adenylate cyclase by binding to receptor on follicular cell membrane

  • increasing evidence of other second messengers participating in TSH stimulation
28
Q

mechanism for iodide transport into gland

A

“iodide trap” mechanism
- trap refers to fact that membrane pump on basal side promotes accumulation of concentration of iodide in thyroid about 30-40x serum. Iodide concentrated in gland against electrical and chemical gradient

  • certain anions (ClO4) transported same mechanism and act as competitive inhibitors of iodide uptake
29
Q

is iodide moving with/against gradient when exiting follicular cell on apical side

A

with chemical and electrical gradient

30
Q

what needs to happen to iodide before iodinating tyrosyl

A

have to oxidize

31
Q

enzyme catalysing iodination of thyroglobulin

A

thyroperoxidase

32
Q

what enzyme converts T4 to T3

A

5’-deiodinase

33
Q

what happens in iodine deficient diets

A

eventually get decreased TH synthesis/secretion

34
Q

what happens with high iodine doses

A

short term– elevated iodide leads to decrease TH release – called Wolff-Chaikoff effect

35
Q

Wolff-Chaikoff effect

A

when you have high doses of iodine, short term the elevated iodide will also cause decreased TH synthesis

  • underlying mechanism involves decreased incorporation of iodide into TG and consequent TH synthesis
  • high iodide diminishes response to TSH
  • high iodide diminishes response to TSH
36
Q

when is high iodine intake used

A

can be used for preparing patients for thyroid surgery

37
Q

consequence of excessive iodine intake

A

hypothyroid; iodine will inhibit TH release (Wolff-Chaikoff effect)

38
Q

consequence of too little iodine intake

A

hypothyroid

39
Q

do you use iodine for chronic hyperthyroid management

A

no; effects are transient

40
Q

three main control mechanisms for TH synthesis/secretion

A

TSH levels, Iodide, “others” (ions that inhibit uptake from blood)

41
Q

what molecules/drugs inhibit thyroid hormone synthesis and secretion

A

perchlorate and thiocyanate (found in cabbages and cassava
- Drugs: propylthiouracil and methimazole can block TPO activity and thus incorporation of iodide to form TH; also block T4 to T3 conversion in target cells of the thyroid

42
Q

what are some stimuli that alter TRH release

A

cold, fasting, stress

43
Q

control of TSH secretion

A

negative feedback. increasd levels of T3 adn T4 feed back to inhibit release of TSH. Unsure if they also inhibit secretion of TRH

44
Q

what molecule used as index of thyroid function

A

TSH since it is difficult to accurately assess free TH levels

45
Q

excess TH

A

hyperthyroidism

46
Q

conditions of excess TH

A

Graves disease (autoimmune), tumors of pituitary or thyroid, excess TH administration

47
Q

Conditions of deficiency of TH

A

Hashimoto’s thyroiditis, iodine deficient diet (in child = cretinism)

48
Q

cretinism

A

deficiency of iodine in diet

- severe mental and growth retardation

49
Q

signs and sxs of excess TH

A

BMR, nervous, pretibial myxedema (Graves), heat intolerance, muscle weakness, Goiter, palpitations, exopthalmos (Graves), lid retraction (Graves), Tachycardia

50
Q

signs and sxs of TH deficiency

A

BMR lower, lethargy, weak, myxedema, cold intolerance, slow speech, goiter, hoarseness, mental slowness, psychosis, bradycardia

51
Q

most common cause of hypothyroidism in US

A

Hashimoto’s thyroiditis

52
Q

most common cause of hypothyroidism worldwide

A

iodine deficient diet