Week 4 Thyroid (lectures 1 & 2) Flashcards
Weight of thyroid gland:
15-20 grams
Functional histological unit of thyroid, and its diameter
follicle, 200-300 micrometers
What is the name of the homogenous material inside thyroid follicles? What secretes this? What is its major component?
Colloid, secreted by epithelial cells. Major component is thyroglobulin (TG)
What are the 2 main thyroid hormones?
T3 (triiodothyronine) and T4 (thyroxine)
What is the difference between T3 and T4?
T4 has 4 iodine, while T3 has only 3. The missing one is from the 5’ position on the benzyl ring
What is the difference between regular T3 and reverse T3?
Reverse T3 is missing an iodine on its 5 position, while T3 is missing it on the 5’ position. Reverse T3 has no hormonal activity because of this
Where does the benzyl ring come from in thyroid hormone synthesis? What is the effect of having these benzyl rings?
Comes from Tyrosine molecules, and the benzyl rings make the molecule hydrophobic so it can diffuse through membranes easier
Inside of what protein is thyroid hormone synthesized?
Thryoglobulin (TG)
What are the 2 steps for thyroid hormone synthesis?
- Iodination: adding one or two iodines to the benzyl ring of tyrosine residues within TG, forming either monoiodotyrosine (MIT) or diiodotyrosine (DIT); 2. Coupling, where two benzyl rings of either MIT or DIT are coupled together
Thyroid epithelial (follicular) cells are able to take in iodide via what mechanism? How does it work?
The Na-Iodide symporter (NIS), takes 2 Na and 1 iodide through from the basolateral side as secondary active transport (Be able to draw the one from lecture!)
How much more iodide accumulates in the thyroid than in the plasma due to the sodium-iodide symporter (NIS?)
30 x more
What mechanism is responsible for secreting iodide from the thyroid epithelial cell into the luminal side?
Pendrin (also known as the sodium-independent chloride/iodide transporter) - exchanges 1 iodide for 1 chloride, thus it’s an anion antiporter
How is iodide (I-) made into its covalent iodine form (I2) on the luminal side of the thyroid epithelial cells? Why must this occur?
Iodide is oxidized by Thyroperoxidase (TPO), using hydrogen peroxide. Iodine then is added to the Tyrosine residues of TG, forming MIT and DIT
What makes the H2O2 to be used by thyroperoxidase (TPO) in the synthesis of iodine from iodide?
Duox2 enzyme, using NADPH
What happens after MIT and DIT are formed in the thyroglobulin (TG) molecule?
Coupling reactions occur between either two DIT or one DIT and one MIT, which -> bound T4 or T3. These are also facilitated by thyroperoxidase (TPO), according to Costanzo. However, a portion of MIT and DIT does not couple.
When the thyroid gland is stimulated, what happens to the thyroglobulin (TG) molecule containing T3, T4, and uncoupled MIT and DIT that is inside the colloid near epithelial cells
TG is endocytosed into thyroid epithelial cells, and it begins moving towards the basal surface
How are the T4, T3, MIT, and DIT bound to thyroglobulin ever released? What happens after this?
Lyosozomal enzymes hydrolyze TG, freeing them. T3 and T4 are hydrophobic and easily diffuse out of the cell membrane, while MIT and DIT are deiodinated inside the cell by thyroid deiodinase, then they are recycled.
What is the minimal requirement for iodine consumption? What is the average daily intake?
Minimal = 50-100 micrograms / day. Avg diet = 400 micrograms / day
What happens if someone consumes an excessive amount of iodine (>2 mg/ day)?
Inhibits thyroid hormone synthesis by inhibiting several of its enzymes, such as TPO and Duox2, as well as proteolysis of T3/T4 from thyroglobulin
What is thiocyanate? What is its importance?
Thiocyanate, like iodide, can be transported by the NIS transporter, essentially amounting to inhibition. This compound exists in foods called glucosides
What is pertechnetate? What is its significance?
TcO4-, it’s similar to iodide in size and charge, and can also be transported by the NIS transporter. Used for radioactive labeling of the thyroid gland
What is propylthiouracil? What is its significance?
An inhibitor of TPO, used sometimes for hyperthyroidism
What percentage of T4 is free and unbound in the bloodstream? What percentage of T3? What is the significance of the unbound thyroid hormone?
T4: 0.02%, T3: 0.5% (much larger proportionally). This is the only active form of the hormone
What percentage of thyroid hormones bind to TBG: Thyroxine-Binding Globulin?
80%
What percentage of thyroid hormones bind to TBPA: thyroid-binding pre-albumin
15%
What percentage of thyroid hormones bind to albumin?
5%
If there is a sudden increase in thyroid-binding globulin (TBG), what happens to the free T4 concentration?
In the short term it decreases as more T4 becomes bound to TBG, however the regulation of synthesis will quickly be increased to compensate and bring free T4 back to normal levels. Total T4 (including bound) will then be elevated, but free T4 is the same
What is the advantage of having thyroid hormone-binding proteins in regards to kidney filtration?
They mean that more thyroid hormone is reabsorbed in the kidney / less is excreted, providing a larger hormone reservoir for when it is needed
What is the most common cause of hypothyroidism?
Insufficient iodine intake
How do thyroid hormones cross the membrane into target cells?
Because they are hydrophobic, they can freely cross, but they also use transporter molecules
What happens to T4 after it crosses the membrane into a target cell?
T4 is rapidly converted into T3, which is the more important effector form of thyroid hormone. (However, T4 is the major secretory product of the thyroid gland). Enzyme for T4 conversion = 5’ deiodinase
What is the effect of T3 once it is inside a target cell?
It goes inside the nucleus and binds to the thyroid hormone receptor (TR) part of a homodimer complex between both TR and RXR (Retinoic Acid Receptor). The T3-receptor complex then goes off to bind to the thyroid-responsive element (TRE) and stimulates DNA transcription -> mRNA translation -> protein synthesis
What does the type I deiodinase do?
It’s a 5’ deiodinase that converts T4 into T3 (an activatory step), and exists in the liver, kidney, and skeletal muscle - which then release T3 back into the hormone for other tissues to use
What does the type II deiodinase do?
Also a 5’ deiodinase, converting T4 to T3 (activatory), but the cells with this enzyme don’t release T3 back into the bloodstream. Exists in CNS and pituitary cells
What does the type III deiodinase do?
a 5 deiodinase, converts T4 into reverse T3. This makes it an inactivatory enzyme, since rT3 doesn’t have an effect
What is the effect on thyroid hormone of being cold? What is the effect of fasting?
Cold -> increased thyroid hormone synthesis, because its metabolic effects cause the body to generate heat. Fasting -> inhibition, helps to slow metabolism down.
What are the permissive effects of thyroid hormones? Give an example
Permissive effect = when thyroid hormone assists in making the effects of a different hormone more powerful. e.g. thyroid hormones increase beta 1 receptors in the heart, making the effects of catecholamines more powerful when they stimulate those beta 1 receptors
What does it mean by the “calorigenic” effect of thyroid hormone? What are 2 large-scale effects of this?
Stimulates basal metabolic rate (BMR). Leads to increased body temperature and oxygen consumption.
What are two mechanisms by which thyroid hormone increases body temperature / basal metabolic rate?
1: Stimulates activity & expression of the sodium-potassium pump, which leads to more ATP consumption and mitochondrial respiration. 2: Stimulates expression of uncoupling protein (UCP), which damages the proton gradient in mitochondria, and increases heat
What are 3 organs where thyroid hormone does not stimulate an increase of basal metabolic rate?
Brain, testis, spleen
What is the effect of thyroid hormone on carbohydrate metabolism?
Increase intestinal glucose absorption, gluconeogenesis is stimulated, and glycogenolysis is also stimulated (via permissive effects of epinephrine receptors)
What is the effect of thyroid hormone on lipid metabolism?
TH stimulates lipolysis (also permissive effect with epinephrine) and decrease in plasma cholesterol level
What is the effect of thyroid hormone on protein metabolism?
Stimulates both protein synthesis and proteolysis (but usually with net effect of proteolysis)
What are the (broad) effects of thyroid hormone on the heart?
Increase in Cardiac Output via increase in HR and Stroke Volume (via permissive effects creating more beta 1 receptors). Increased CO helps match the increased demands of higher metabolism.
What are 3 specific things in the heart that are stimulated by thyroid hormone?
- Expression of adenylate cyclase, 2. increase expression of calcium pumps, 3. increase expression of myosin heavy chain (heart-specific isoform)
What are the effects of thyroid hormone on systolic and diastolic blood pressure?
Systolic blood pressure increases (increased cardiac output), however diastolic pressure is the same or slightly decreased due to increase in basal metabolic rate -> increased metabolites -> peripheral vasodilation -> decrease in TPR. Overall, the pulse pressure is wider!
What are the effects of thyroid hormone on ventilation / oxygen transport?
Rate and minute volume are increased, EPO is expression is stimulated -> increased RBC’s and transport capacity
What are the effects of thyroid hormone on the CNS?
Essential for development: stimulates myelination, increase in # of synapses, dendrite arborization, and cell migration. Essential for normal reaction time, cognitive and motor functions
What are 4 ways the thyroid hormone stimulates the growth of bones?
Stimulates chondrocyte differentiation, linear bone growth, bone remodeling, and growth hormone is stimulated. (Although GH stimulus is only shown in rats so far)
What is the effect of thyroid hormone on connective tissue?
Thyroid hormone stimulates the degradation of glycoproteins and proteoglycans. This decreases water retention / edema that can occur in hypothyroidism
Thyroid Stimulating Hormone is what type of molecule? What is important to know about its subunits?
It’s a glycoprotein, with alpha and beta subunits. The alpha subunits are the same for LH and FSH, but the beta subunit is specific for thyroid hormone.
What stimulates the anterior pituitary gland to release TSH?
TRH (thyotropin-releasing hormone), coming from the hypothalamus
What are two things that can influence the hypothalamus to secrete TRH?
food, temperature
What type of signaling mechanisms does TSH use to stimulate thyroid hormone synthesis?
Uses both cAMP and calcium signal
What are 4 immediate effects of TSH binding to its receptor?
Iodide uptake accelerated, iodination increased, endocytosis of thyroglobulin (TG) increased, and proteolysis of TG increased
What is the intermediate effect of TSH binding to its receptor?
mRNA synthesis is increased for the enzymes and transporters that help produce thyroid hormone (NIS, TPO, Duox2, etc.)
What are the long-term effects of TSH binding to its receptor?
An increase in number and size of thyroid follicular cells, resulting in larger size of the gland. (If big enough, will cause goiter)
Which form of thyroid hormone performs negative feedback on its own production, and where does it inhibit?
T3 inhibits the anterior pituitary gland and hypothalamus. T4 doesn’t do this only because it is rapidly converted to T3 by the cells in these areas
What is measuring TSH level good for, as a diagnostic test?
If TSH level is normal, then thyroid hormone level is probably normal due to negative feedback. However, any abnormality in TSH level needs further investigation to find out the cause, because negative feedback on TSH synthesis can influence the results in many possible ways.
Why is it difficult to measure thyroid hormone levels directly?
It is not difficult to measure total thyroid hormone, but chemically it is difficult to measure the difference between free and bound thyroid hormone (which is also more important). It is possible, but frequently not done due to difficulty/cost
What type of assessment does a thyroid scan with pertechnetate provide?
A functional/morphological assessment
What condition results from hypothyroidism during infancy?
cretinism: severe mental retardation, short stature, facial abnormalities, abnormally large tongue
What is myxedema?
A result of hypothyroidism where, due to build-up of connective tissue proteins that are normally degraded by thyroid hormone, severe edema develops
What happens to a person’s speech when they have hypothyroidism?
“Diagnosis can be made over the phone” - due to hoarse voice and slow speech (slower mental functions)
What are some effects of hypothyroidism that result from decreased BMR?
Weight gain, inability to stay warm, fatigue, dry/cool skin
What are two causes of hyperthyroidism?
- TSH is increased, 2. antibodies develop that have TSH-like function and stimulate TSH receptors without any regulation (aka Grave’s disease)
Why can muscle weakness occur during hyperthyroidism?
Because TH stimulates proteolysis, which in hyperthyroidism can be a strong enough effect to degrade muscles
