Lecture 4: Endocrinology of the Thyroid Gland Flashcards
1
Q
What are the 2 iodotyrosils?
A
MIT and DIT
2
Q
What is MIT?
A
Monoiodotyrosine
3
Q
What is DIT?
A
Diiodotyrosine
4
Q
Where is the 1st iodide added onto to Tyr?
A
3’
5
Q
Where is the 2nd iodide
added onto to Tyr?
A
5’
6
Q
What is T3?
A
MIT + DIT
7
Q
What is T4?
A
DIT + DIT
8
Q
How many iodides does T3 have on the outer ring?
A
1
9
Q
How many iodides does T4 have on the outer ring?
A
2
10
Q
Which thyroid hormone is the active one in the body?
A
T3
11
Q
What are T3 and T4 bound to? Which one is more bound that the other?
A
Thyroid hormone binding globulin (TBG) (~70% of it)
Higher percentage of T4 is bound (99.97% T4 bound vs. 99.7% T3 bound)
12
Q
What is reverse T3? When is it created? What is it a sign of?
A
It has 2 iodides on the outer ring and 1 on the inner ring
Created by improper conversion of T4 to T3 in the periphery
Usually a sign of illness, carb starvation, and in the fetus
13
Q
Where are the thyroid hormones produced? Describe their structure.
A
In the follicles of the thyroid gland in the neck made of single layer of follicular cells surrounding the follicular space containing colloid (made by follicular cells)
14
Q
What are the 3 roles of the follicular cells of the thyroid gland?
A
- Bring in iodide
- Transport iodide to the follicular space
- Makes enzymes for thyroid hormone production
15
Q
What are the 3 effects of TSH on the thyroid gland?
A
- Stimulation of hormone production/secretion
- Increase in size
- Stimulation of iodide uptake
16
Q
What type of receptor is the TSH receptor on the thyroid gland? How many membrane spanning regions does it have?
A
G-protein coupled receptor
7 membrane-spanning regions
17
Q
Where is the TSH receptor located in the thyroid gland?
A
Basolateral surface of the follicular cells
18
Q
How does the TSH receptor in the thyroid gland work to increase thyroid hormone production?
A
Activates adenylyl cyclase which increases cAMP in the cells, which accelerates ALL hormone producing processes
19
Q
What is the major inhibitor of thyroid hormone production?
A
Propylthiouracil (PTU)
20
Q
What is the precursor of thyroid hormones?
A
Tyr
21
Q
How is iodide pumped into the follicular cells of the thyroid gland?
A
I-/Na+ symporter on basolateral membrane through secondary active transport as the Na+/K+ ATPase provides the concentration gradient of sodium
22
Q
What are the 4 competitive inhibitors of the I-/Na+ symporter of the follicular cells of the thyroid gland? What do these inhibit exactly? How?
A
- Thyocyanate: SCN-
- Perchlorate: ClO4-
- Perrhenate: ReO4-
- Pertechnetate: TcO4-
Inhibit the UPTAKE of iodine, not the pump itself because they are transported instead (indirect inhibition)
23
Q
How does iodide leave the follicular cells of the thyroid gland?
A
Simple diffusion
24
Q
What is the ratio of iodide inside a thyroid follicular cell to that of serum in humans?
A
25:1
25
How do we treat thyroid tumors? What can this damage as collateral?
Radioactive iodide therapy to ablate the tumor
| Salivary glands can be damaged also
26
What happens to the iodide once it has entered the follicular cells of the thyroid gland? How? To what end? What does this require?
It is transported through the apical membrane in the follicular space (on the luminal surface) through which it travels due to the electrochemical gradient (the follicular space has similar ectrochemical characteristics to the exterior of the cell) to be oxidized by thyroperoxidase (TPO), which requires NADPH
27
How is TPO activated to oxidize iodide once it has entered the follicular cells of the thyroid gland? What inhibits it?
Stimulated/Activated by TSH
| Inhibited by PTU
28
Is the thyroid the only place where iodide can be oxidized?
Yes
29
How is thyroid storm treated during pregnancy? Why?
With PTU only during the first trimester (because it also causes liver damage) and then methimazole
30
In what food is thyocyanate found in?
Cassava (from Zaire, central Africa)
31
What does eating cassava cause in people from Zaire?
They already are not ingesting enough iodide and by eating cassava they cannot pump iodide into the follicular cells of the thyroid gland, so this causes:
1. Low iodide
2. High amounts of TSH: thyroid gland growth = goiter
32
What is cretinism due to? Symptoms?
Insufficient amounts of thyroid hormones during development causing short stature and stunted brain development
33
How are thyroid hormones produced at the laminal surface?
TPO adds iodide to the tyrosine portions of thyroglobulin (TGB) to form MIT and DIT and then TPO fuses them to form T3 or T4
34
What protein can inhibit the fusion of MIT and DIT?
PTU
35
What causes the release of thyroglobulin complex from the colloid surrounding the follicular cells of the thyroid gland? How?
TSH
| Invagination of follicular membrane into vesicles
36
What happens to the thyroglubulin complex containing vesicles inside the follicular cells of the thyroid gland?
They fuse with lysosomes to give rise to secondary lysosomes: phagolysosomes where the complex is completely hydrolyzed by proteases into AAs, DIT, MIT, T3/T4
37
What happens to the non-T3/T4 products in the lysosomes inside the follicular cells of the thyroid gland? Why?
Recycled because there is no tRNA to incorporate them into new proteins
38
What happens to the iodide in the lysosomes inside the follicular cells of the thyroid gland?
Has to go through the whole oxidation process all over again
39
What is the predominant form of the thyroid hormone produced in the thyroid gland?
T4: inactive
40
Which has more affinity for thyroid hormone receptors on target cells: T3 or T4? By how much?
T3
| x10
41
What happens to T4 once it binds to thyroid hormone receptors on target cells?
Converted to T3 by 5' thyroxine deiodinase
42
Can T4 be converted to T3 in the plasma?
Yes, a small amount is
43
What 2 enzymes block the conversion of T4 to T3? How?
1. Methimazole
2. PTU
Inhibit the deiodinase
44
What feedback do thyroid hormones have on the hypo and pit? Do both T3 and T4 have these effects?
Hypo: -TRH
Pit: -TSH
YUP
45
How will an increase in GH affect thyroid hormone production?
Inhibit it because IGF-1 will +SS, which inhibits TSH production by pit
46
What is newborn hypothyroidism caused by? How is it treated? Symptoms if not treated?
Inability to make thyroid hormones at birth
Treatment: administer thyroid hormones to prevent cretinism and growth defects (downturned mouth and dead eyes) FOR THE REST OF THEIR LIVES
47
What is endemic goiter caused by? 3 symptoms?
Not enough iodide in diet
1. Increased TRH
2. Increased TSH
3. Thyroid growth
48
What is Grave's disease caused by? More prevalent in what patients? Symptoms? Treatment? Side effects?
Autoimmune disease where antibodies (TSI: Thyroid Stimulating Igs) attack the TSH receptor of the thyroid gland stimulating it and causing high thyroid hormone production = hyperthyroidism and sometimes diffuse goiter
More common in women
10% of patients also have
Symptom: big eyes (proptosis), heat intolerance, tremor, weight loss, perspiration, diarrhea, oilier skin
Treatment: thiourea drugs (methimazole, not PTU), surgery, and/or radioactive iodine (I131)
Side effects: weight gain
49
What is Hashimoto's thyroiditis caused by? Symptoms?
Autoimmune disease where antibodies attack thyroglobulin and break down the thyroid gland = hypothyroidism
Symptoms: cold intolerance, weight gain, cold clammy skin, slow reflexes and reactions, constipation
50
What causes inhibition of thyroid hormone release in the blood?
Lithium
51
What is the Wolff-Chiakoff effect? How long does it last? Why? What is it often used to manage/prevent (2 things)? In what form?
Short-term effect of excess levels of iodide exerting negative feedback on the production/release of thyroid hormones at the point of thyroglobulin release of T3/T4 (vesicle formation). Relieved after 48 hrs due to increased export of iodide.
Solution of K+I- can be used to:
1. Manage or prevent thyroid storm
2. Decrease size (therefore vasculature) of thyroid and amount of THs
52
How does ouabain affect thyroid hormone production?
It inhibits the Na+/K+ ATP-ase, therefore inhibiting iodide transport into the follicular cells of the thyroid gland, thereby inhibiting TH production
53
What is used for radiographic imaging of the thyroid?
Radioactive derivatives of the competitive inhibitors of the iodide pump
54
What is the ratio of iodide inside a thyroid follicular cell to that of serum in animals that have been chronically stimulated with TSH?
500:1
55
What is the ratio of iodide inside a thyroid follicular cell to that of serum in hypophysectomized animals?
5:1
56
Other than through cAMP levels, how can the TSH receptor on the thyroid increase TH levels?
Phospholipase A activation
57
What other 4 organs can take up iodide? +?
1. Salivary glands
2. Mammary glands
3. Chorion
4. Stomach
58
Describe the composition of thyroperoxidase.
Heme containing and glycosylated
59
What does TPO require to function? Where does it come from?
Hydrogen peroxide H2O2 produced by NADPH-dependent enzyme resembling cytochrome C reductase
60
What is the class of drugs that PTU is part of?
Thiourea drugs
61
What is the organification of tyrosine?
The ionidation of Tyr
62
What is the full name of T3?
Triiodothyronine
63
What is the full name of T4? 2 names
Tetraiodothyronine = thyroxine
64
What are the 4 thiourea class antithyroid drugs?
1. Thiourea
2. Thiouracil
3. Propyllthiouracil (PTU)
4. Methimazole
65
Does the coupling of MIT and DIT/DIT and DIT cleave the peptide bond? What does it leave behind?
NOPE
| Leaves dehydroalanine behind
66
Describe the structure of thyroglobulin.
Homodimer with 8-10% carbs, 0.2-1% iodide, 5 MIT, 4.5 DIT, 2.5 T4, 0.7 T3 and close to 5500 AAs
67
How many Tyr does thyroglobulin contain?
134
68
How many ATPs are required to produce 1 T3 or T4?
~3,400
69
How much TH supply does the extracellular colloid contain?
Months supply
70
Once thyroglobulin is hydrolyzed, how are MIT and DIT deiodinated to be recycled? What does this require?
By deiodinase requiring NADPH
71
What % of dietery iodide is absorbed?
30%
72
What are the medium-term effects of excess iodide levels? Why? How long does it take cells to recover?
Increased organification leading to increased MIT and DIT but decreased T3/T4 possibly because of decreased T3/T4 content of TGB
Takes cells 7-10 days to recover
73
What are the long-term effects of excess iodide levels? Why?
Permanent iodide block and a goiter and hypothyroidism develop probably due to some underlying defect in thyroid
74
What is the role of arachidonic acid in the effects of excess levels of iodide?
Might be involved in recovery mechanism after iodide inhibition
75
What is the T3/T4 that is not bound to TBG bound to? 2 molecules? What %?
1. Thyroxine-binding pre-albumin (TBPA): 10-15%
| 2. Albumin: 15-20%
76
What is the plasma half life of T3?
1.5 days
77
What is the plasma half life of T4?
6.5 days
78
Why is it important to measure free and total thyroid hormone levels?
Because many agents alter TBG levels (total hormone) without altering free hormone levels and those are the only ones that are biologically active ie hyper/hypothyroidism can only be determined by free hormone levels
79
What organ synthesizes TBG? What stimulates its production? What inhibit its production?
Liver
+ estrogen
- glucocorticoids
80
What 2 molecules compete with THs for TBG binding?
1. Phenytoin
| 2. Salicylates
81
Where is the thyroid hormone receptor located?
Nuclear receptor on thyroid response elements (TRE) of the DNA
82
How does the thyroid hormone receptor bind to DNA? 2 ways. Which form is the most active?
Either as a homodimer or as heterodimer with RXR (most active)
83
What stimulates TRH release by hypo?
Low T3 levels
84
What are the 2 genes that encore thyroid hormone receptors?
TRalpha and TRbeta
85
What do TREs consist of?
Inverted (palindromic) or direct repeats of: AGGTCA
86
Are direct repeats of TREs one after another?
NOPE, separated by 4 base pairs
87
Where are TREs found in DNA?
1. Growth hormone gene
2. Cardiac sarcoplasmic reticulum Ca2+-ATP gene (SERCA2)
3. Isoform of myosin genes
4. Beta-adrenergic receptors of cardiac muscle and arterioles
(2 and 3 increase heart rate)
88
What mediates transcriptional repression of TREs? How?
nTREs: TR binds to them to repress transcription
89
Where are nTREs found?
TSH subunits genes
90
What is the effect of TH on oxygen consumption? Why?
Increases O2 consumption by increasing number of Na+K+ ATP-ases
91
What is the effect of TH on protein synthesis? What does this cause?
Increase in protein synthesis --> positive nitrogen balance = intake of nitrogen into the body is greater than the loss of nitrogen from the body, so there is an increase in the total body pool of protein
92
What metamorphosis is TH necessary for?
Amphibian metamorphosis: tadpole to frog
93
How does gene activation happen when TH binds to the TH receptor on DNA?
TH recruits coactivators to the receptor that interact with the initiation complex
94
What is the most common form of hyperthyroidism?
Grave's disease
95
To what family does the TH receptor belong to?
Steroid/Thyroid/Retinoic acid superfamily of nuclear receptors
96
What is proptosis due to in Grave's disease? 3 aspects.
1. TSIs are attacking receptors on fibroblasts in the eye causing them to proliferate leading to inflammation behind the eye.
2. TSIs also cause the accumulation of mycopolysaccharides in the interstitial space leading to an increase in osmotic pressure in IS
3. Muscle damage and inability to close eye lids and sometimes eye has to be enucleated because it is so dry.
97
Does reverse T3 have a function?
No known one
98
Which membrane is considered the outside membrane of the follicles of the thyroid?
The apical membrane toward the follicular space
99
What are the 3 types of patients to whom we recommend PTU instead of methimazole?
1. First trimester pregnant women
2. Thyroid storm
3. Allergic to methimazole
100
What is a thyroid storm? What can it be caused by? What is the main risk? Treatment?
Huge amount of TH entering your system at once.
Can be caused during neck surgery (may or may not involve thyroid), by surgeon causing a huge release by touching the colloid space that has months worth of hormones
Risk: ventricular fibrillation and heart attack. Very dangerous.
Treatment: PTU, lithium, and methimazole
101
What is a goitrogen?
Food containing TH production/release inhibiting agent
102
What does the response of cell to T3 vs T4 depend on?
The amount of tyrosine deiodinase
103
How long does it take for newborn hypothyroidism to be noticed? How come?
Few days because of T4 half life in newborn blood from mother
104
Are autoimmune disorders more common in females or males? Why?
Females because of birth process where antibodies are produced by the mother
105
What other condition is often seen alongside Grave's disease? Why?
70% of patients also have Hashimoto's thyroiditis because different kinds of antibodies are being produced: some will activate some will destroy
106
Can iodide be used to treat hyperthyroidism? When?
Yes, in the short-term
107
Why does hyperthyroidism cause weight loss and hyperphagia?
Because excess TH causes an increase in the basal metabolic rate causing an increased caloric intake which is then burned fast:
1. Na+ is more permeable so the Na+/K+ ATPase channels are doing more work
2. Gut motility is increased
108
Why does hyperthyroidism cause heat intolerance? 2 reasons
1. Excess TH increases the basal metabolic rate
2. Excess TH causes an increase in uncoupling proteins: mitochondrial inner membrane proteins channels/transporters that are capable of dissipating the proton gradient and use that energy to generate heat
109
What is the effect of VERY high TH levels? Eg?
Catabolic effect which increases blood glucose levels and breaks down macromolecules
Eg: collagen and finger nails fall off
110
What does a diffuse goieter mean?
Means the size increase is consistent all around the gland
111
What is NADPH used for during TH synthesis? 2 things
1. Oxidizing iodine
| 2. MIT and DIT deiodination when recycled
112
What does constitutive production of a hormone mean? Eg?
Production without negative feedback.
| Eg: endemic goitier
113
What does a bounding pulse mean?
Noticeable/Pulsating
114
What is the thyroid isthmus?
The tissue connecting the four poles across the trachea
115
What does exophtalmos mean?
Bulging of the eyes = proptosis
116
What is cold iodine?
Iodine ingested to inhibit TH
117
Are THs anabolic or catabolic?
Both depending on amount:
Normal amount: anabolic effect (eg: increase in beta adrenergic receptors)
Excess: catabolic effect (eg: collagen breakdown)
