Lecture 7 (74): Thyroid

Question 1

Where is the thyroid gland located?

What fuses the 2 symmetrical lobes?

Answer 1

Located anterior to cricoid cartilage

Two symmetrical lobes fused by the isthmus

Question 2

What is the blood supply to the thyroid?

What is the innervation?

Answer 2

Blood Supply:

1. Superior (ext. carotid) and
2. Inferior (thyrocervical trunk) thyroid arteries

Venous plexus on surface gives rise to superior, middle, and inferior thyroid veins — drain into internal jugular vein

Innervation:
Middle and inferior cervical ganglion (sympathetic NS)

Question 3

What is the thyroid derived from?

Epithelium is arranged in follicles that contain a large storage of what?

How do inactive follicles look? What type of epithelium?

Follicles become active when stimulated by what? What do they transform into?
(test)

Answer 3

1. Derived from branchial pouch endoderm.
2. large storage of thyroglobulin (colloid)
3. Inactive follicles have flattened, SQUAMOUS epithelium.
4. Stimulated by TSH, follicles become active.
   Follicular cells transform to CUBOIDAL epithelium

Question 4

What epithelial cells surround the lumen of the thyroid gland?

What is the lumen filled with?

What other cells are found? What is the main function of the 2nd most abundant cell type?

Answer 4

1. Follicle epithelial cells surrounding lumen
2. lumen filled with COLLOID (thyroglobulin (TG) is major component)
3. Parafollicular Cells (C Cells)
   - produce CALCITONIN
   - other proteins that maintain follicle

Other cells:
Epithelial cells, fibroblasts, lymphocytes, adipocytes

Question 5

Parafollicular cells do not come into contact with what cells?

Answer 5

Parafollicular cells:
Do not touch colloid
Many small granules

Question 6

Thyroid hormones are _______.

What 2 precursors are required?

What is a critical component of thyroid hormones?

What happens to most excess iodide?

Answer 6

1. Iodothyronines
2. Thyroglobulin (TG)
   & IODIDE
3. Iodide is a critical component of THYROID hormones
4. Most excess iodide is excreted in urine as iodine

Question 7

What is the Wolf-Chaikoff Effect?

As iodide intake increases, what happens to gland transport and hormone synthesis?

Clinically, what are very high iodide doses used for?

Answer 7

1. An intrathyroidal response that assures constancy of iodide storage in the face of changes in dietary iodide
   = AUTOREGULATION

• stable at about 25-100 (uptake decreases after 100)
  2. Increases in iodide intake decrease gland transport and hormone synthesis (dashed line), and vice-versa
  3. Clinically: very high iodide doses are used to rapidly SHUT DOWN THYROID PRODUCTION in hyperthyroid patients

Question 8

The following describes T4, T3, or rT3?

1. Long half-life in plasma ~ 7-8 days
2. Tightly bound to transport proteins in blood
3. Binds to receptor with low affinity

Answer 8

T4

• LONG Half life***
• tightly bound to transport proteins which is why it has such a long half life
• no biological activity on its own, but precursor to active form of T3

Question 9

The following describes T4, T3, or rT3?

1. Primary active form
2. Most is converted intracellulary from T4
3. Binds with high affinity, low capacity to receptor

Which of these is biologically inactive?

Answer 9

T3

• converted intracellularly (low extracellular)
• binds with HIGH affinity
• do not need much to saturate the receptor

RT3
- reverse triidothyronine

Question 10

T4 is peripherally deiodinated to T3 in the thyrotropes and brain by which deiodinase?

Intracellular T3 then acts by negative feedback to inhibit _____ and _______

Answer 10

Type II deiodinase

T4 = thyroid hormone sensor

2. inhibits TRH and TSH
   - dopamine and somatostatin also inhibit TSH release!

Question 11

Describe the HPT Axis for Thyroid Hormone Regulation:

1. TRH is released from neurons where? What does it bind after it is release and where does this occur?
2. What signaling pathway is activated?
3. What is synthesized after this?
4. Where does it bind next?
5. TSH stimulates what synthesis?
6. What happens to T4?
7. What does intracellular T3 then do?

Answer 11

1. TRH release from neurons in the PVN bind G protein coupled receptors on the THYROTROPE cells in the ANTERIOR pituitary
2. Activate DAG/IP3 signaling pathway
3. Stimulate the synthesis and release of TSH
4. Binds to basolateral membrane of follicular epithelial cells
5. TSH stimulates T4/T3 synthesis and release from the thyroid follicle
6. T4 is deiodinated to T3 in the thyrotropes and brain by Type II deiodinase which acts as a thyroid hormone sensor
7. Intracellular T3 then acts by negative feedback to inhibit TRH and TSH

Question 12

All steps in thyroid hormone synthesis are mediated by what?

Answer 12

TSH

Question 13

What are the 7 steps of Thyroid Hormone Synthesis?

Answer 13

1. Iodide trapping
2. Transport
3. Iodination
4. Conjugation
5. Endocytosis
6. Proteolysis
7. Secretion

Question 14

What converts Iodase to Iodine?

Answer 14

Thyroid Peroxidase

Question 15

Describe the major events in the following events of thyroid hormone synthesis:

1. Iodide Trapping
2. Transport

What inhibits the NIS symporter?

Answer 15

1. Iodide Trapping
   - TSH stimulates iodide (I-) trapping by increasing the activity of the NIS co-transporter in the basal membrane of the follicular epithelial cell.
2. Transport:
   I- transported to follicular lumen and oxidized by thyroid peroxidase (TPO) to form iodine (I).
   - Thyroglobulin is transported into the lumen

NIS symporter inhibited by LITHIUM!!

Question 16

What is the function of Carbimizole?

What is it used as a treatment for?

Answer 16

Inhibits thyroid peroxidase (TPO)

• Used as a treatment for HYPERTHYROIDISM

Question 17

1 MIT and 1 DIT is what?

2 DIT is?

Options:

1. T3
2. T4

Answer 17

1. T3

2. T4

Question 18

If iodinated residue is on the OUTER RING what is formed?

Inner ring?

Answer 18

1. REVERSE T3
   (2 I’s on the aromatic circle)
2. T3

Question 19

Describe the major events in the following events of thyroid hormone synthesis:

3. Iodination
4. Conjugation

Answer 19

3. Iodination
   - Iodination of Tyrosil residues on THYROGLOBULIN
4. Conjugation
   - Conjugation of Iodinated TYROSINES to form T4 and T3 linked thyroglobulin

Question 20

Describe the major events in the following events of thyroid hormone synthesis:

5. Endocytosis
6. Proteolysis
7. Secretion from thyroid follicular epithelial cells

Answer 20

5. Endocytosis
   - Conjugated thyroglobulin with T4/T3 enters follicular epithelial cell
   - packaged in endosomes
6. Proteolysis
   - TG, MIT, DIT, T4, T3 released from vesicle
7. Secretion from thyroid follicular epithelial cells
   - T4/T3 secreted into circulation

Question 21

What is T3 formed from?

Answer 21

Coupling of one MIT and 2 DIT residues

• reverse T3 is inactive and is distinguished from active T3 by the presence of two iodinated residues on the OUTER ring

T4 = formed from coupling of 3 DIT

Question 22

What is T3 formed from?

Reverse T3?

T4?

Answer 22

Coupling of one MIT and 2 DIT residues

• reverse T3 is inactive and is distinguished from active T3 by the presence of two iodinated residues on the OUTER ring

T4 = formed from coupling of 3 DIT

Question 23

How does the radioactive Iodide uptake scan work?

What is it used to determine?

Which one is more predictive of thyroid cancer, cold or hot nodule?

Answer 23

1. Iodide uptake in thyroid epithelial cell

Iodide is transported by the sodium iodide symporter (NIS)

Radioactive iodide (131I, 123I) and anions like pertechnetate (TcO4) can be transported by NIS

2. Used to determine function of thyroid gland
3. COLD NODULE

Question 24

What is the normal percentage of Iodide uptake after 24 hours?

What percentages qualify someone as hyperthyroid?
Hypothyroid?

Accelerated turnover of thyroid is seen in hyper stimulated thyroid gland or what disease?

Answer 24

1. Normal uptake is 25% after 24 hours
2. > 60% = hyperthyroid
3. Grave’s Disease

Question 25

What is the Organification Defect? How does the graph look?

Answer 25

Organification defect - iodine cannot be incorporated into tyrosine. Test by blocking NIS with inhibitor (i.e. perchlorate) - Add percolate, and the levels fall significantly (flat orange dashed line) **inject radioisotope & block the SYMPORTER (NIS) over time = no more uptake anything put into the cell will DIFFUSE RIGHT BACK OUT - so see nothing on the scan dashed line!!!

Question 26

State the following for Type I Thyroid conversion: 1. Outer or inner ring deiodinase or both 2. Where is it found primarily? 3. Function?

Answer 26

TYPE I: 1. OUTER AND INNER ring deiodinase 2. Liver, kidney, thyroid, skeletal muscle (3) 3. Primary source of T3 in circulation

Question 27

State the following for Type II Thyroid conversion: 1. Outer or inner ring deiodinase or both 2. Where is it found primarily? 3. Function?

Answer 27

Type II: 1. OUTER ring 2. Brain pituitary placenta cardiac muscle 3. THYROID HORMONE SENSOR

Question 28

State the following for Type III Thyroid conversion: 1. Outer or inner ring deiodinase or both 2. Where is it found primarily? 3. Function?

Answer 28

TYPE III: 1. INNER RING 2. Brain, placenta, skin

Question 29

More _____ produced and stored in thyroid T4 has ____ receptor affinity (low/high) Reverse T3 has no ______ ______ is the thyroid hormone “sensor” in the pituitary

Answer 29

1. T4 - 80% of T4 is peripherally deiodinated to T3 2. low 3. biological activity 4. Type II deiodinase

Question 30

What is the point of making reverse T3 if it is biologically inactive?

Answer 30

If making too much, use it to turn off the signal | - enzymes decide if making active or inactive hormone

Question 31

What are the 3 main transport proteins of Thyroid Hormone. More than 99% of Thyroid Hormone is BOUND or UNBOUND in circulation?

Answer 31

1. Thyroxine-binding globulin (TBG) (70%) - HIGH AFFINITY for thyroid even though less around 2. Transthyretin (TTR) (10%) 3. Albumin (15 – 25%) - T4 tightly bound = longer half-life approx. 7 days; T3 approx. 1 day

Question 32

TBG 1. 394 AA glycoprotein made in the _____ 2. What has highest affinity for it even though TBG is lowest in concentration? 3. Estrogen and hepatitis increase or decrease TBG? 4. Nephrotic syndrome, steroid increase or decrease TBG? 5. What is unique about TBG?

Answer 32

1. LIVER - if liver disease = no TBG - 99% of T4 and T3 are bound to TBG 2. T4 3. INCREASE 4. DECREASE - but no net change in "free" T4/T3 5. TBG can reversibly release T4 to target tissues

Question 33

Thyroid Hormone Receptor (THR) What type of receptor? This is the same as what? Forms HETERODIMERS with what? Expressed in what cell types? High/low affinity? High/low capacity for T3? ____ affinity for T4. Very little biological activity at physiological conditions.

Answer 33

1. Nuclear receptor family - same as steroid hormones 2. forms heterodimers with retinoic acid receptor (RXR) 3. Expressed in nearly every cell type 4. High affinity, low capacity for T3 5. Low affinity for T4 – very little biological activity at physiological concentrations

Question 34

What are the 3 major affects of Thyroid Hormone on PHYSIOLOGICAL FUNCTIONS?

Answer 34

1. Increase BMR 2. Promote Brain (CNS) Maturation 3. Increases B-Adrenergic receptors - heart, skeletal muscle, adipose tissue

Question 35

How specifically does Thyroid hormone affect BMR? (4)

Answer 35

1. Stimulates hepatic gluconeogenesis (like cortisol) 2. Stimulates proteolysis 3. Stimulates lipolysis 4. Overall increased energy/oxygen consumption, increased thermogenesis (hyperthyroid people are very HEAT INTOLERANT)

Question 36

By increasing mitochondrial activity, what 2 major things does T3 increase?

Answer 36

1. Increase cellular Oxygen consumption | 2. Increase Heat production

Question 37

T3 is critical for normal brain development, as seen in what disease that is caused by iodine deficiency? What 3 things does T3 do in the brain?

Answer 37

Cretinism Iodine deficiency during development Short stature/impaired bone formation Mental retardation Delayed motor development 1. Neuronal cell migration/differentiation 2. Myelination 3. Synaptic Transmission

Question 38

What are the main effects of T3 on the heart? How can hyperthyroidism cause arrhythmias?

Answer 38

1. Increases Cardiac Output 2. Increases Resting Heart Rate and stroke volume - Hyperthyroidism can cause arrhythmias due to increase beta-adrenergic receptors

Question 39

What is a goiter? What disease are associated with the following: 1. Hyperthyroidism 2. Hypothyroidism

Answer 39

1. Enlarged thyroid 2. Grave's disease 3. Hashimoto's thyroiditis, idoine deficiency

Question 40

Graves Disease: 1. What stimulates TSH 2. What is elevated 3. Hyperthyroid or Hypo? What are some associated symptoms? What is the histology of the thyroid gland from a patient with graves disease?

Answer 40

1. ANtibodies stimulate TSH receptor 2. ELevated T4/T3 3. HYPERTHYROID Diffuse symmetrical goiters with hyperthyroid symptoms: tachycardia, opthalmopathy, irritability, hyperactivity, heat intolerance, weight loss, nervousness, muscle wasting

Question 41

Why is there a goiter in both Hyperthyroid and Hypothyroid patients?

Answer 41

Due to NEGATIVE feebdack 1. HYPOTHYROID - not enough thyroid hormone - no negative feedback on anterior pituitary INCREASED PRODUCTION OF TSH = hyperactive follicular cells that result in goiter formation 2. Hyperthyroid: also making more thyroid hormone - not due to negative feedback though, just more production of thyroid hormone in general

Question 42

Autoimmune Hasimotos Thyroiditis: 1. Autoimmune destruction of what? 2. Antibodies against? (2) 3. Hyperthyroid or Hypothyroid?

Answer 42

1. Destruction of thyroid follicles 2. Antibodies against TPO, TG 3. Diffuse goiter with hypothyroid symptoms: lethargy, fatigue, hair loss, cold intolerance, brittle nails decreased appetite, weight gain

Question 43

What is a THYROID STORM? What is coupled? What are the symptoms? Tx?

Answer 43

Emergency life-threatening situation HYPERTHYROID coupled with severe acute illness Symptoms: 1. High fever 2. Tachycardia 3. Altered Mental Status 4. Severe Nausea, vomiting, diarrhea 5. Severe circulatory collapse (resulting in death) TX: 1. PTU (propylthiouracil) 2. Carbimazole (methimazole) 3. Beta Blockers to restore normal heart function