77 - Thyroid Flashcards
What is the thyroid gland anterior to?
Cricoid cartilage
What aa. supply the thyroid gland?
- Superior thyroid a. (from external carotid)
- Inferior thyroid a. (from thyrocervical trunk)
Thyroid gland is 2 symmetrical lobes fused by an ___________.
Isthmus
What veins drain the thyroid gland?
Plexus drains into superior, middle, and inferior thyroid veins (to IJV)
What innervates the thyroid gland?
Symp or parasymp?
Middle and inferior cervical ganglion
- Sympathetic NS
What’s the major functional unit of the thyroid gland?
Follicle
What is the name of the internal component of the thyroid gland follicle?
What’s in this compartment, generally?
Colloid
- TH precursor
What cells line the periphery of the thyroid gland’s colloid?
What occurs here?
Thyroid epithelial cells- where synthesis of TH occurs
In addition to thyroid epithelial cells, the thyroid gland houses one other important endocrine cell. Nestled in spaces between thyroid follicles are ____________ (2 names), which secrete _____________.
- Parafollicular or C cells
- Calcitonin (hormone)
(Do not touch colloid; have many small granules on histology)
What are the major components of the colloid?
- Large stores of thyroglobulin
- T3/T4
What’s the difference in the epithelial architecture of inactive follicles vs active follicles stimulated by TSH?
- Inactive: squamous epithelium
- Active: cuboidal epithelium
Describe some of the properties of follicular cells in the thyroid gland. (not parafollicular)
(shape, surface features, spatial arrangement)
- Cuboidal shape
- Microvilli extend into colloid
- Basement membrane – delineates follicle
- Close to fenestrated capillaries
Thyroid hormones are iodothyryonines that require 2 precursors:
- Thyroglobulin (TG)
2. Iodide
Less than ____ of iodine daily results in a TH deficiency.
20 micrograms
How is most of the excessive iodide processed?
Secreted into the urine as iodine.
What is the Wolf-Chaikoff effect?
Autoregulation of iodide uptake:
- An intrathyroid response that assures constancy of iodide storage in the face of changes in dietary iodide
- Increases in iodide intake decrease gland xport (and vice versa)
How is the Wolf-Chaikoff effect taken advantage of clinically?
Very high iodide doses are used to rapidly shut down TH production in hyperthyroid pts
What’s another name for T4?
Thyroxine
What’s another name for T3?
Triiodothyronine
What’s the 1/2-life of T4?
T3?
T4: ~ a week
T3: ~ a day
How is T4 found in the blood?
Tightly bound to xport proteins (that’s why it has long 1/2-life)
Which binds to receptors w/high affinity, T4 or T3?
T3 much higher (T4 basically inactive form)
Thyroid hormones are more similar in characteristics to what hormone class?
Steroid hormones
What’s rT3?
Reverse triiodothyronine (biologically inactive)
Thyrotropin-releasing hormone (TRH) is released from what hypothalamic nucleus?
PVN
What provide tonic inhibition to thyrotropes (that release TSH) in the anterior pituitary?
*Dopamine and somatostatin
What types of receptors do TSH bind in the anterior pituitary?
GPCRs
T3/T4 provide negative feedback to the PVN in the hypo. What provides negative feedback to the thyroid hormone “sensor” in the anterior pituitary to stop release of TSH?
T3 (formed locally from T4 via type II deiodinase)
- Recall: also tonic inhibition by dopamine, somatostatin.
What’s the 2nd messenger cascade for TRH receptor stimulation in the ant pit?
GPCR -> PLC/DAG -> IP3/PKC -> ^ Ca2+ -> TSH release
What’s the 2nd messenger cascade for TSH receptor stimulation in the thyroid gland?
GPCR -> AC -> cAMP -> T4/T3 release
What is the first precursor for TH’s?
Tyrosine (on thyroglobulin)
What key enzyme is necessary in TH synthesis?
What 2 products are formed?
- Thyroid peroxidase (TPO)
- Makes MIT, or adding another I- makes DIT
What 2 compounds combine in the thyroid follicle to make T4?
2x DIT
What 2 compounds combine to make T3?
Describe where the I’s are (outer and inner ring)
1x DIT + 1x MIT
Outer ring has 1 I-, inner ring has 2x I-
What’s the difference b/w reverse T3 (rT3) and T3?
T3’s outer ring has only 1 I-, rT3’s inner ring has only 1 I-
What drug inhibits thyroid peroxidase (TPO)?
What is it used to treat?
- Carbimazole
- Tx for hyperthyroidism
Name the 7 steps of TH synthesis.
- Iodide trapping
- Transport
- Iodination (AKA organification)
- Conjugation
- Endocytosis
- Proteolysis
- Secretion
What’s the common factor of all 7 steps of TH synthesis?
What cell does it occur in, mostly?
All steps are stimulated by TSH
thyroid epithelial cell, though some middle steps occur in the colloid
Thyroid follicle is functionally polarized. What is the basolateral surface exposed to?
What occurs on the basolateral side?
- Blood
- Iodine uptake “trap”; TH release
Thyroid follicle is functionally polarized. What is the apical surface exposed to?
What occurs on the apical side?
- Colloid
- Organification, TH synthesis, etc.
What occurs during step 1 of TH synthesis (iodide trapping)? (name the protein that’s involved)
- TSH stimulates iodide (I-) trapping by increasing the activity of the NIS co-transporter in the basal membrane of the follicular epithelial cell.
(NIS = sodium iodide symporter)
What drug inhibits the NIS cotransporter in step 1 of TH synthesis?
Lithium
What occurs during step 2 of TH synthesis (transport)?
name the protein that’s involved and the product
I- transported to follicular lumen and oxidized by thyroid peroxidase (TPO) to form iodine (I).
- TG xported to follicle lumen as well.
What occurs during step 3 of TH synthesis (iodination/organification)?
Iodination of tyrosyl residues on thyroglobulin (via TPO)
What occurs during step 4 of TH synthesis (conjugation)?
what is formed?
Conjugation of iodinated tyrosines to form T4 and T3-linked thyroglobulin (via TPO)
What occurs during step 5 of TH synthesis (endocytosis)?
What ptn is involved?
Conjugated thyroglobulin with T4/T3 enters follicular epithelial cell. (has 4 attachment sites, can have MIT, DIT, T4 or T3.
- Packaged in endosomes (via megalin)
What occurs during step 6 of TH synthesis (proteolysis)?
TG, MIT, DIT, T4, T3 released from vesicle (in thyroid epithelial cell)
What occurs during step 7 of TH synthesis (secretion)?
T4/T3 secreted into circulation
How does the radioactive iodide uptake scan work?
- Used to determine function of thyroid gland
- Iodide uptake in thyroid epithelial cell
- Iodide is transported by the sodium iodide symporter (NIS)
- Image = autoradiograph
What are egs of some substances that can be xported by the NIS besides I-?
- Radioactive iodide (131I, 123I) and anions like pertechnetate (TcO4)
On a radioactive iodide uptake scan, what is a “hot nodule”?
What’s its clinical importance?
Area of increased follicular iodide uptake and TH synthesis.
- Usually benign
On a radioactive iodide uptake scan, what is a “cold nodule”?
What’s its clinical importance?
Inactive/dysfunctional thyroid follicle.
- Can be benign or malignant
In a radioactive iodide uptake scan, normal uptake is __% s/p 24 hrs.
25%
In a radioactive iodide uptake scan, normal uptake is 25% s/p 24 hrs. What is the clinical threshold for hyper and hypothyroidism?
- Hyper: greater than 60%
- Hypo: less than 5%
In a radioactive iodide uptake scan, extreme stimulation of thyroid gland (high turnover) is seen in what condition?
Grave’s disease
What is an organification defect? How could you test for it?
Iodide cannot be incorporate into tyrosine
- Test by blocking NIS w/inhibitor (i.e. perchlorate)
What is a Type I deiodinase?
Where is it found?
What does it make? (activates or inactivates?)
Outer and inner ring deiodinase
- Found in liver, kidney, thyroid, SkM
- Makes T3 (activates) or rT3 (inactivates)
What is a Type II deiodinase?
Where is it found?
What does it make? (activates or inactivates?)
Outer ring deiodinase
- Found in brain, pituitary, placenta, cardiac m.
- Always T3 (activates)
What is a Type III deiodinase?
Where is it found?
What does it make? (activates or inactivates?)
Inner ring deiodinase
- Found in brain, placenta, skin
- Makes rT3 (inactivates)
Which of the deiodinases forms most of the T3 in circulation?
Type I deiodinase
What form of TH is produced and stored in the thyroid the most?
T4
Wyhat serves as the TH “sensor” in the anterior pituitary?
Type II Deiodinase
How much TH is bound in circulation?
99%+
Name the proteins and the % of TH bound for each of the proteins that bind TH.
- Thyroxine-binding globulin (TBG) (70%)
- Albumin (15 – 25%)
- Transthyretin (TTR) (10%)
Which of the binding proteins for TH has the highest affinity?
TBG (but lowest concentration in the blood)
How many AA’s is TBG?
394 AAs
unique: TBG can reversibly release T4 to target tissues
Name a hormone and a disease the increase TBG.
- Estrogen
- Hepatitis (it’s made in the liver)
Name a hormone class and a disease the decrease TBG.
- Steroids
- Nephrotic syndrome
If a pt has a deficiency or excess of TBG, how is the total “free” concentration of TH altered?
This effect is different than what major binding protein?
No net change
- CBG (because 75% of cortisol is free)
(changes in TBG don’t usually effet bioavailable T3, but do affect total T4/T3 levels)
Describe the structure of the THR (TH receptor). What hormone class is it similar to?
Nuclear receptor family
- Same as steroid hormones
- Forms heterodimers with
retinoic acid receptor (RXR) -> TS activation
What cells types generally express THR?
All
THRs have a (high/low) affinity, (high/low) capacity for T3.
They have a (high/low) affinity for T4.
T3: High affinity, low capacity
T4: Low affinity
In general, what are the overall effects of TH?
(effect of metabolism, brain, receptors)
(read for now, leads into future questions)
- Increases Basal Metabolic Rate (BMR)
- Stimulates hepatic gluconeogenesis
- Stimulates proteolysis
- Stimulates lipolysis
- *Overall increased energy/oxygen consumption, increased thermogenesis
- Promotes Brain (CNS) Maturation
- Increases β-adrenergic receptors: heart (B1), skeletal muscle, adipose tissue
How is BMR affected by hyper and hypothyroidism?
Hyper: increased
Hypo: decreased
How is carb metabolism and serum [glucose] affected by hyper and hypothyroidism?
Hyper: ^ GNG, ^ glycogenolysis, nl serum glc
Hypo: v GNG, v glycogenolysis, nl serum glc
How is protein metabolism affected by hyper and hypothyroidism?
Hyper: ^ Synthesis, ^ proteolysis (m. wasting)
Hypo: v Synthesis, v proteolysis (no change)
How is lipid metabolism and total serum [chol] affected by hyper and hypothyroidism?
Hyper: ^ lipogenesis, ^ lipolysis, v serum chol.
Hypo: v lipogenesis, v lipolysis, ^ serum chol.
How is thermogenesis affected by hyper and hypothyroidism?
Hyper: increased (heat intolerant)
Hypo: decreased (cold intolerant)
Some of the effects of T3 are futile cycles. What does this mean?
Occurs when two metabolic pathways run simultaneously in opposite directions and have no overall effect other than to dissipate energy in the form of heat
- E.g. increasing GNG and increasing glycogenolysis simultaneously
Why is lack of iodine salt the leading cause of mental retardation worldwide?
Because TH is critical for brain development
What what causes cretinism? Provide the clinical presentation.
Iodine deficiency during development
- Short stature/impaired bone formation
- Mental retardation
- Delayed motor development
What are TH’s effects on the heart?
- Increases CO
- Resting HR and SV increase
- Increases B1 adrenergic receptors
(also decreases PVR)
Hyperthyroidism can cause arrhythmias. What is the primary reason?
Due to increased beta-adrenergic receptors
What is a goiter?
Is it more common in men or women?
Enlarged thyroid
- 3:1 women to men
What pathology occurs w/Grave’s disease?
Autoimmune: antibodies created that stimulate the thyroid’s TSH receptors (LATS- long-acting thyroid stimulator), leading to elevated T3/T4
What are the sx of Grave’s dz? (think)
Diffuse symmetrical goiters with hyperthyroid sx: tachycardia, exopthalmopathy, irritability, hyperactivity, heat intolerance, weight loss, nervousness, muscle wasting
What pathology occurs w/Hashimoto’s thyroiditis?
Autoimmune destruction of thyroid follicular cells. AB’s made against TPO, TG (T3/T4 can’t be formed).
What are the sx of Hashimoto’s thyroiditis? (think)
Diffuse goiter with hypothyroid sx: lethargy, fatigue, hair loss, cold intolerance, brittle nails decreased appetite, weight gain
What is thyroid storm?
Hyperthyroid coupled with severe acute illness (emergency, life threatening situation)
What are the sx of thyroid storm?
High fever, tachycardia, AMS, severe N/V/D, severe circulatory collapse resulting in death.
How do you treat thyroid storm?
- Propylthiouracil (PTU – only acute treatment, decreases TH produced by gland)
- Carbimazole (methimazole)- inhibits TPO, used to treat hyperthyroism
- Beta blockers to restore normal heart function
What catalyzes all of the steps of TH synthesis that lead to thyroglobulin w/bound T3/T4/MIT/DIT (in some combination)?
*Thyroid peroxidase
What two classes of protein are responsible for recycling I- and TG in the epithelial cell?
Proteases and deiodinases
