Exam 1 thyroid Flashcards
1
Q
Thyroid (what it do)
A
- largest organ for endocrine hormone production
- secrete T4 and T3
- promote normal fetal/childhood growth and devel
- regulate hr and myocardial contractility
- affect GI motility and renal water clearance
- modulate body’s energy expenditure, heat generation, and weight
2
Q
Thyroid gland gross anatomy
A
- richly vascularized
- 15-20g in N American adults
- can weigh many hundreds of grams in a goiter
- 2 lobes connected by band of tissue (isthmus)
- attached to trachea
3
Q
Thyroid Gland Structure
A
- composed of follicles
- follicular epithelium makes up outside of follicle
- follicle center is filled with colloid
- 20-40 follicles in a lobule
- connective tissue separates lobules
4
Q
Follicular Epithelium function
A
- produce and secrete T4 and T3
5
Q
Colloid function
A
- produces and stores thyroglobulin (prohormone)
6
Q
Cell types in Thyroid gland (2)
A
- Follicular epithelium (colloid, T3, T4)
- cells have extensive ER, many lysosomes and mitochondria
- Parafollicular cells (calcitonin): calcitonin controls Calcium levels in body
7
Q
Overall function of thyroid follicular epithellium
A
- generate the amt of thyroid hormone necessary for homeostasis or fetal devel
- 80ug T4/T3 per day
- 3 major roles:
- capture and transport sufficient iodide
- synthesize sufficient thryoglobulin
- recapture of the thyroglobulin and removal and secretion of thyroid hormones
8
Q
3 thyroid hormones
A
- T4: most abundant
- T3: most potent activator of the thyroid hormone receptor
- rT3: isomer of T3 that binds the thyroid hormone receptor but does not activate it
9
Q
Iodine Requirements
A
- need iodine from diet
- converted to iodide
- absorbed in GI
- most iodide excreted by kidneys
- dietary iodine deficiency affects ~100 million people in world
10
Q
Iodine dietary deficiency
A
- less than 50ug/day
- thyroid cannot sustain adequate hormone production
- results in gland enlargement (goiter) and HYPOthyroidism
- results in neurological and growth deficits in children
11
Q
Transport and concentration of iodide
A
- Sodium-Iodide symporter (NIS)
- energy from Na-K ATPase
- maintains a [ ] for free iodide in the thyroid gland 30-40x higher than in plasma (8-10mg) (buffers variation in dietary intake)
12
Q
Sodium Iodide Symporter (NIS)
A
- iodide atom moved AGAINST electrochem gradient
- also transports TcO4, ClO4, and SCN
- controlled by TSH (increased transcription of NIS gene, target NIS to cell membrane, prolongs NIS half life)
13
Q
radioactive TcO4 used for
A
- imaging thyroid
14
Q
KClO4 does what?
A
- block iodide uptake by NIS
15
Q
Which disease pathologically stimulates NIS?
A
- Graves’ Disease (autoimmune hyperthyroidism)
16
Q
Wolff-Chaikoff Effect
A
- large amts of iodine in system (15-20 fold above normal) suppresses both NIS transporter activity AND NIS gene expression
- this causes temporary hypothyroidism
- effect lasts few days and is followed by the “escape phenomenon”: recover ability to produce and secrete hormone
17
Q
Iodotyrosine dehalogenase (Dhal) enzymes
A
- Dhal1 transcription is stimulated by cAMP (induced by TSH)
- membrane protein concentrated at the apical cell surface which faces the colloid
- catalyzes NADPH-dependent deiodination of monoiodotyrosine (MIT) and diiodotyrosine (DIT)
- iodide released is reconjugated to newly synthed thryoglobulin
18
Q
Pendrin
A
- located on apical membrane
- transports iodide to membrane-colloid interface
- key in binding iodide to thyroglobulin
19
Q
Thyroglobulin Synth
A
- three to four T4 molecs in each molec of human Tg dimer under normal conditions
- one in five molecs of human Tg contains a T3 residue
20
Q
Organification of Iodide
A
- oxidation of iodide
- incorporation of oxidated iodide into MIT and DIT (MIT and DIT are hormonally inactive)
- ? of page 8
- mediated by TPO (thyroid peroxidase)
21
Q
TPO
A
- located in apical membrane of thyroid cell
- requires H2O2 generated by calcium dependent Duox1 and 2 enzymes (AKA THOX1 and THOX2)
22
Q
Thiourea Drugs
A
- inhibit TPO
- can cause intrathyroidal deficiency in patients receiving these agents
- Methimazole (MMI)
- Carbimazole (CBZ)
- Propylthiouracil (PTU)
23
Q
Rate of organic iodinations is dependent on _____
A
- the degree of thyroid stim by TSH
24
Q
Iodide excess does what in iodide oxidation and organification?
A
- inhibits DUOX2 glycosylation
- may be additional mech for Wolff-Chaikoff effect
25
Iodothyronine Synth: what are they and how made?
- MIT and DIT precursors of active iodothyronines T4 and T3
- to make T4 you need 2 DIT molecs
- to make T3 you need 1 DIT and 1 MIT
26
What drugs inhibit binding and coupling of DITs and MITs for iodothyronine synth?
- Thiourea drugs
27
T4 has highest concentration where?
- the colloid
28
Thyroglobulin is stored where and contains what?
- stored in the colloid
| - contains MIT, DIT, T3, and T4
29
How much T4 in a 20g thyroid gland? and how long can that much maintain normal thyroid funct?
- 5000 ug of T4
- enough to maintain a euthyroid state (normal) for at least 50 days
- low rate of hormone turnover (1% per day)
30
Thyroid hormone release steps
- ENDOcytosis of colloid from follicular lumen
- does this by macropinocytosis (non-selective uptake) by small coated vesicles that form at the apical surface (dominant process)
- or by macropinocytosis by pseudopods formed at the apical membrane
- both processes stimed by TSH
- then the vesicles fuse with lysosomes which cleave off T3s and T4s from thryoglobulin and MCT8 moves them to the cytosol, and then is transported out by transporters
31
T4 is accessible to thyroidal type 1 and 2 _______ which does what?
- deiodonases
- this does basal and TSH stimulated conversion of T4 to T3
- most T3 produced by peripheral 5' deiodination of T4
32
Conversion of T4 to T3 is inhibited by ____
propylthiouracil (PTU)
33
What can inhibit thyroid hormone release from a transporter?
- iodide by inhibiting stim of thyroid adenylate cyclase by TSH and by stim immunoglobulins of Graves' Disease
- why you see rapid improvement that iodine causes in hyperthyroid patients
- lithum also inhibits thyroid hormone release (less commonly used)
34
Circulation of Thyroid hormone (makeup)
- T4= 90%
- T3 = 9%
- rT3 = 1%
- most bound to plasma proteins
- very very little T4 and T3 are unbound or free (0.04% and 0.4%
35
Three major thyroid hormone transport proteins
- Thyroxine-binding globulin (TBG)
- Transthyretin
- Albumin
36
How long is half life of thyroid hormone in the plasma/
- stable 7 day half life
37
Thyroxine-binding globulin (TBG): drugs that decrease plasma TBG (4)
- Androgenic steroids
- glucocorticoids
- danazol
- L-asparaginase
38
Thyroxine-binding globulin (TBG): drugs that can increase plasma TBG (2)
- estrogens
| - 5-fluorouracil
39
Thyroxine-binding globulin (TBG): drugs that can displace T4 and T3 binding to TBG (4)
- salicylates
- high-dose phenytoin
- phenylbutazone
- IV furosemide
40
Thyroxine-binding globulin (TBG): heparin stimulation of lipoprotein lipase
- release FFA that displace thyroid hormones from TBG
41
What happens when TBG levels are altered/ there is displacement of thyroid hormones from TBG?
- initiates feedback loops due to high free hormone levels
- hypothalamic-pituitary-thyroid axis preserves normal free hormone concentrations by lowering serum total thyroid hormone levels
42
Type 1 5'-deiodinase
- activity increased in hyperthyroidism (greater conversion of T4 to T3)
- activity decreased in hypothyroidism
- inhibited by propylthiouracil and amiodarone
- also inhibited by iodinated radiocontrast dyes
- dietary selenium deficiency can also impair T4-T3 converison
43
Type 2 5'- deiodinase
- predominantly expressed in brain and pituitary
- maintains a constant level of intracellular T3 in the CNS
- very sensitive to circulating T4
- lower circulating T4 rapidly increases [enzyme] to maintain level of intracellular T3
44
Type 3 5'-deiodinase
- found in placental chorionic membranes and glial cells in CNS
- inactivated T4 by converting to rT3
- inactivates T3 by converting it ot 3,3-diiodothyronine (3,3-T2)
- may protect fetus and brain from excess T4 or deficiency
45
Type 3 5-deiodinase is what in hyperthyroidism and what in hypo?
- hyper: elevated
| - hypo: decreased
46
Other forms of T4 metabolism
- ~80% of T4 is metabolized by deiodination
- remainder is inactivated by glucuronidation in the liver and billiary secretion!!
- lesser extent sulfination, deamination or decarboxylation
47
Plasma half lives of T4, T3, and rT3
- T4: 7 days (10% of extrathyroidal T4 cleared/day)
- T3: 1 day (lower binding affinity for plasma proteins)
- rT3: 0.2 days
48
Thyroid hormone receptors overview
- present in most cells of the body
- contrain thyroid hormone-binding, DNA-binding, and dimerization domains
- Two classes of thyroid hormone receptors (TRalpha and TRbeta)
49
TRalpha and beta
- can be expressed as multiple isoforms
- TR monomers can interact in a dimerization rxn to form homodimers
- TR monomers can interact with RXR to form heterodimers
- TR dimers bind to gene promoter regions!
- activated by binding of thyroid hormone
- mulitiple different combos of TRs and tissue distribution create tissue specificity
50
affect of the absence of thyroid hormone on receptors
- alters their conformation
- associate with compressor molecs
- bind to and inactivate thyroid hormone stimulated genes
51
What is the effect of thyroid hormone binding to TR:RXR or TR:TR dimers
- promotes dissociation of the corepressors
| - recruits coactivators to the DNA and activates gene transcription
52
Effects of hormone at target tissues
- is able to down-regulate TSH gene expression
- causes neg feedback of thyroid hormone on hypothalamic-pituitary-thyroid axis
- also nongenomic effects on mitochondrial metabolism
- plasma membrane receptors that stim intracellular signal transduction
- thyroid hormone present, T3 interacts with coactivator and corepressor dissociates
53
General Phys effects of the thyroid hormones: infancy
important for growth and devel of the nervous system
| - congentical deficiency in thyroid hormone rsults in cretinsim (severly stunted physical and mental growth)
54
General Phys effects of the thyroid hormones: adulthood
- regulate general body metabolism and energy expenditure
| - regulates Na+/K+ ATPase and many enzymes of intermediary metabolism
55
High levels of thyroid hormone: Adults
- can result in futile cycling and an increase in body temp
- many effects resemble sympathetic neural stim
- increase contractility and hr
- excitability, nervousness, and sweating
56
Low levels of thyroid hormone: Adults
- mxyedema (swelling of skin, waxy appearance)
- lethargy
- dry skin
- coarse voice
- cold intolerance
57
Calorgenic actions of thyroid hormone
- T4 and T3 increase the O2 consumption of almost all metabolically active tissues
- some exceptions, T4 of the anterior pituitary INHIBITS TSH secretion
- single does of T4 has measurable effects after several hours and lasts 6+ days
- some calorgenic action due to metabolism of FA
- increases activity of Na/K ATPase in many tissues
58
Effects secondary to calorigenesis
- nitrogen excretion increased
| - if food intake is not increased, endogenous protein and fat stores are catabolized - weight loss
59
Calorigenesis: hypothyroid children
- small does of thyroid hormone causes positive nitrogen balance due to growth
- large doses cause protein catabolism similar to that in adults
- potassium liberated during protein catabolism excreted in urine
- increase in urinary hexosamine and uric acid excretion
60
hypothyroidism and vitamins
- vitamin deficiency syndromes may be precipitated
- need for all vitamins is increased
- thyroid hormones are necessary for hepatic conversion of carotene to Vit A
- carotene accumulation in blood gives yellow tint to skin
61
hypothyroidism and skin
- ECM complex parts (proteins w/ polysaccharides, hyaluronic acid, and chondriotin sulfate) accumulate
- promote water retention
- get myxedema
62
hypothyroidism and women repro
- milk secretion decreased in hyop
| - thyroid hormone essential for normal menstrual cycles and fertility
63
hyper and CV system
- raise body temp
- vasodilation
- renal Na increased and water absorption increases which expands blood volume
- so cardiac output is increased
- pulse pressure and hr increased, increased contractility too
64
hyper and hypo effects on nervous system
- hypo: mentation slow, cerebrospinal fluid protein level elevated
- hyper: rapid mentation, irritability, and restlessness
- thyroid hormones enter brain as adults
- astrocytes in brain convert T4 to T3
- hyper: some effects probably secondary to increased responsiveness to catecholamines
65
brain devel and thyroid hormone
- deficiency during devel: cause mental retardation, motor rigidity, and def-mutism
- effects on brain devel, esp cerebral cortex, basal ganglia, and cochlea
- rxn time of stretch reflexes prolonged in hypo, shortened in hyper
66
Thyroid hormones and rxn to catecholamines
- increased metabolic rates, stim nervous sys, produce CV effects
- tremlousness, sweating
- can be reduced by b-blockers such as propanolol
67
b-blockers used extensively in what? (& ex of b-blocker)
- propanolol
- treatment of thyrotoxicosis, thyroid storms
- little effect on other actions of thyroid hormones
68
thyroid effects on skeletal muscle
- muscle weakness in HYPERthyroidism (may b/c increased protein catabolism
- HYPO also associated w/ muscle weakness, cramps, and stiffness (less clear)
69
thyroid effects on carb metabolism
- thyroid hormone increases rate of absorption from GI
- independent of calorigenic action
- plasma glc levels rise rapidly after a meal
- lowers circulating cholesterol levels
- action independent of stim of O2 consumption
- due to increased formation of LDL receptors in liver which takes up cholesterol
70
Thyroid effects on growth
- essential for normal growth and skeletal maturation
- hypothyroid children:
* bone growth slowed and epiphysial closure delayed
* growth hormone secretion depressed
* thyroid hormones potentiate effect of growth hormone on tissue
71
Hypothalamic- Pituitary- Thyroid Axis
- Hypo: secrets TRH (thyrotropin releasing hormone)
- Pituitary: secretes TSH in response to TRH
- Thyroid Gland: TSH stims every aspect of thyroid hormone production, also promotes increased vascularization and growth of thyroid gland
72
Pathology in HPT axis-
- TSH or TSH mimic secreted at high levels: thyroid gland enlarged to several times its size (goiter)
- neg feedback to hypothalamus/pituitary inhibits TRH and TSH gene transcription (thyroid hormone effects both the hyp and pituitary
73
Graves disease
- IgG for TSH receptor that activates it
- stimulates synthesis and release thyroid hormone
- does not respond to neg feedback, get hyperthyroidsim
- high plasma thyroid hormone levels, low or undetectable TSH, High Tslg
74
Hashimoto's
- antibodies specific for many thyroid gland proteins found in patients
- selectively destroy thyroid function, gradual, inflammatory (analogous to type I diabetes)
- results in hypothyroidism, early may be transient increase in thyroid hormone levels, eventually gland is almost completely destroyed
- clinical symptoms lethargy and decreased metabolic rate
- need pharmacological replacement with oral synthetic thyroid hormone
75
Thyroid function can alter which categories of drugs? (4)
- anticoagulation
- glc control
- cardiac
- sedatives, analgesics
76
Treatment of hypo
- replace with regular administered exogenous thyroid hormone
- generally T4, can make a reservoir of prodrug to be an effective buffer
- also normalizes metabolic rates
- longer half life, only need 1 pill/day
77
Synthetic T4 used to treat hypo? (and adverse)
- Levothryoxine
- adverse: hyperthyroidism, osteopenia (bone loss), pseudotumor cerebri (increased intracranial pressure), seizure, myocardial infarction
78
What to take when in myxedema coma?
- Liothyronine
- synthetic T3
- faster onset, enhances recovery from life-threatening hypo
79
Thyroid Storm overview
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