Thyroid

Front 1

What is the result of a lack of thyroid hormone early in development? What is the result late in development?

Back 1

Early → Disorder of growth and neurological development known as CRETINISM

Late → hypothyroidism

Front 2

Discuss the role of iodine and thyroid hormone. Where does iodine come from in our diet?

Back 2

Thyroid hormone is essentially an iodated tyrosine molecule → really the only known role for iodine in the body is in thyroid hormone production. Iodine deficiency is one of the most common nutritional deficiencies in the world (1.5 billion people worldwide).

Iodine is naturally abundant in seawater and seaweed (kerogenin, a common food filler, comes from seaweed and thus is high in iodine). Fruits and vegetables are iodine poor. Most of the iodine in our diet comes from iodized salt or pharmaceuticals.

Front 3

Where is iodine absorbed, is it efficiently absorbed, and what can hinder its absorption? What proportion of absorbed iodine is taken up by the thyroid?

Back 3

Iodine is efficiently absorbed by the stomach, though soy products can hinder its absorption. 20% of daily iodine intake is delivered to the thyroid gland (the rest is secreted in urine)

Front 4

What are goitrogens? What are examplesof goitrogens in the diet?

Back 4

Goitrogens are substances that cause goiters by blocking thyroid hormone production by interfering with the incorporation of iodine into thyroglobulin. (Thus, TSH levels are raised, causing goiter.)

Nutritional goitrogens: Cabbage, cauliflower, broccoli → potentiate iodine deficiency in societies without supplementation, leads to goiter.

Front 5

Normal daily intake of iodine is about _____ μg/day. The normal thyroid contains ____ mg of iodine, mostly bound to ______ as thyroid hormone (and its metabolic precursors). ____ μg of this iodine is released daily as thyroid hormone SO → there’s lots of storage space in the thyroid (in contrast to the adrenal and pituitary gland) and there is a slow, leisurely release of intrathyroidal iodine at about ____% per day

Back 5

250
6
tyrosine
60
1

Front 6

What is deiodination and where does it occur?

Back 6

Removal of iodine from thyroid hormone, occurs in kidney and liver. Of the 60 μg in circulation, 10 μg are recycled for reuptake to the thyroid, 15 μg are lost in the feces, and 35 μg are filtered out by the kidneys and excreted in the urine (so urinary iodine tests can tell if you have an iodine deficiency → < 50 μg/liter = iodine insufficiency).

Front 7

Describe the thyroid gland histologically.

Back 7

“Big, juicy” follicles filled with eosinophilic COLLOID (the storage form of thyroid hormone).

Front 8

What are the precursors to thyroid hormone?

Back 8

Tyrosine is the amino acid building block. This is iodinated into the intermediate compounds monoiodotyrosine and diiodotyrosine. These two intermediates are coupled to form either triiodothyronine (T3) and tetraiodothyronine (a.k.a. thyroxine = T4).

monoiodotyrosine + diiodotyrosine = T3

diiodotyrosine + diiodotyrosine = T4

Front 9

What are the three steps in the synthesis of thyroid hormone?

Back 9

1.) Iodide transport
2.) Oxidation, organic binding & coupling
3.) Proteolysis, release & dehalogenation

Front 10

What is the rate-limiting step in thyroid hormone biosynthesis?

Back 10

Iodide transport via the I-/Na+ Symporter. APT is required to get iodine into thyrocytes against a 30-fold concentration gradient.

Front 11

Where else in the body, besides the thyroid gland, are I-/Na+ Symporters located? What are the clinical implications of this?

Back 11

Salivary glands, gastric mucosa and lactating breast.

So administering radioactive iodine to treat thyroid cancer or hyperthyroidism will lead to dry mouth, upset stomach, and will irradiate the baby (so you never give it to a breastfeeding female).

Front 12

What are two substances that block iodine transport in the thyroid (first step)?

Back 12

Thiocyanate (SCN–) → naturally-occurring, endogenous, potentiates environmental iodine insufficiency
Perchlorate (ClO4–) → can be used as an anti-thyroid agent

Front 13

During the second step in thyroid hormone synthesis, I- is ________ and then bound to tyrosine molecules, which are themselves attached to a larger molecule called ________. The enzyme _______ controls this whole process.

Back 13

Oxidized
Thyroglobulin
Thyroperoxidase

Front 14

What is the T4:T3 ratio by weight? Where is the newly-synthesized T3/T4 stored?

Back 14

10:1.

They are stored on the thyroglobulins within the follicle as colloid.

Front 15

What are thioureas and how do they work?

Back 15

Thiorureas are the major anti-thyroid medication used to treat hyperthyroidism. They act as a competitive inhibitor of the thyroperoxidases, thus blocking their action in the second step of thyroid hormone synthesis.

Front 16

Describe the acute Wolff-Chaikoff Effect? What step(s) in thyroid hormone synthesis does it interfere with?

Back 16

“prevents you from getting thyrotoxic every time you go to the sushi bar.”

A high intake of iodine can inhibit thyroid hormone synthesis. It is an internal regulatory process that prevents the thyroid from overproducing thyroid hormone when exposed to too much iodine. With increased iodine dosage, thyroxine synthesis increases until a breakpoint is reached at 2 mg of iodine (100x normal dietary intake), at which point inhibition thyroid hormone biosynthesis begins.

Both the coupling and deiodination steps are blocked by excess iodine. This is a short-term response. After a few days, thyroid hormone synthesis will start up again.

Front 17

Describe the final step of thyroid hormone synthesis.

Back 17

Proteolysis, Release, and Dehalogenation …

Thyroglobulin is internalized from the colloid in the follicular lumen into the thyrocytes. There the droplets are attacked by lysosomes, which cleave all the various components of the colloid. T3 and T4 are cleaved and secreted into circulation. Monoiodothyronine and diiodothyroine are also cleaved, but they are retained and broken down by deiodinases to release the I– (dehalogenated) for recycling or excretion.

Front 18

How much T4 is secreted in relation to T3 per day?

Back 18

The thyroid secretes about 90 μg/day of T4 and 9 μg/day of T3 (10:1, same as storage ratio).

Front 19

Why can iodide be used as an anti-thyroid agent?

Back 19

Excessive intake of dietary iodide actually causes hypothyroidism (see Wolff-Chaikoff Effect). Excess iodide blocks both the coupling and proteolysis steps of thyroid hormone synthesis. This technique is used preoperatively for people who are getting their thyroid surgically removed to decrease thyroid hormone synthesis and vascularity of the gland.

Front 20

Besides iodine, what is another inhibitor of the third step of thyroid hormone synthesis?

Back 20

Lithium – side effect of treating personality disorders is mild hypothyroidism.

Front 21

What is monodeiodination? Where does it take place?

Back 21

Only 20% of circulating T3 comes directly from the thyroid gland, while 80% is derived from T4 upon release from the gland. Monodeiodination is the process by which T4 is converted to T3 via enzyme deiodinases. This occurs at the target tissues, mainly in the kidney, liver, and skeletal muscle.

Front 22

Which form of thyroid hormone is the active form (T3 or T4)?

Back 22

T3 is the active form. T4 is considered a “prohormone” that must be converted to T3 to become activated.

Front 23

How does thyroid hormone travel in the blood?

Back 23

T3 and T4 are very hydrophobic, so they must travel via carrier proteins: thyroid hormone binding globulin (TBG), transthyretin (TTR, which binds only T4), and albumin (ALB).

**Note: overall, 99.97% of T4 and 99.7% of T3 in the blood is bound to carrier proteins, but only the free thyroid hormone can cross cell membranes and have physiological effects.

Front 24

Remember this!!! → Thyroid status depends on ____ levels of thyroid hormone, not _____ levels.

Back 24

Free T3 and T4
Total Serum

Remember: ONLY FREE THYROID HORMONE CAN CROSS CELL MEMBRANES!

Front 25

What are the proportions of carrier proteins (TBG, TTR, ALB) bound to T4 and T3?

Back 25

For T4: TBG = 75%; TTR = 15%; ALB = 10%
For T3: TBG = 80%; TTR = 0%’ ALB = 20%

Front 26

What is reverse T3? How can the thyroid hormonal system be amplified/diminished at a tissue-specific level?

Back 26

The principal pathway of thyroid hormone metabolism is by deiodination from T4 to T3 by removal of an iodide from the 5’ position, catalyzed by 5’-iodinase. This deiodination can also remove an iodide from an alternate position (the 5 position), forming reverse T3, which is inactive. Selective deiodination allows the body to increase or decrease thyroid hormone activity as needed, by converting T4 to either T3 (highly active) or reverse T3 (inactive).

Front 27

Distinguish the three kinds of deiodinase enzymes. What is the required cofactor for all three?

Back 27

*type I deiodinases are found in the thyroid, liver, kidney, and skeletal muscle, and can remove either the 5 or the 5’ iodide from T4 (both outer and inner rings), acting as a source of PLASMA CIRCULATING T3 for SYSTEM-WIDE USE.
*type II deiodinases are found in the CNS, pituitary, and brown adipose tissue and can remove only the 5’ iodide, producing T3 for LOCAL (INTRACELLULAR) USE.
*type III deiodinases are found throughout the body, especially in the liver, and can remove only the 5 iodide, INACTIVATING T4 to REVERSE T3

Selenium is required as a cofactor.

Front 28

Give examples of times when you’ll see a reduction in peripheral conversion of T4 to T3. Why does this occur?

Back 28

*The bookends of life: (fetus/neonate, elderly)
*Pathologic: Starvation, Major systemic illness, Post-op (75-80% of hospital patients have a low T3)
*Pharmacologic (Don’t memorize this …): Propylthiouracil (anti-thyroid), Glococorticoids, Propranolol (beta-blocker), Contrast agents, Amiodarone (anti-arrhythmia)

It’s a protective mechanism to protect the “sick tissues” from the metabolically-active hormone. This is a reversible adaptation to metabolic stress.

Front 29

As T3 concentrations fall, what happens to reverse T3 levels?

Back 29

Reverse T3 levels rise – an inverse relationship. So you’ll see high reverse T3 levels in sick/weak patients.

Front 30

What is the main way in which the body responds to thyroid hormone? What sites in the body DO NOT respond in this way?

Back 30

Increased thyroid hormone results in increased oxygen consumption. BUT – the spleen, testes, and brain are NOT responsive to thyroid hormone (they don’t have the receptors).

Front 31

Compare the action of T3 to T4 administration.

Back 31

T3 is more potent and more fast-acting (quick on and off). T4 administration leads to slower, more maintained changes.

Front 32

How does T3 get into the target cell and what does it do once inside? Where are the T3 receptors located? Where does the main action of T3 take place?

Back 32

Unclear. It binds to a receptor and is brought in via some energy-requiring mechanism (probably similar to other amino acid transport mechanisms). From there, it binds to a cytosolic binding protein.

In addition to the cell membrane, there are T3 receptors located on inner mitochondrial membranes → the presence of these receptors is indicative of the higher metabolic activity of those cells that respond to T3 compared to those that do not. There are also T3 receptors in the nucleus. The MAIN action takes place in the nucleus (just like most hormones).

Front 33

Contrast the cytosolic binding proteins in T3 activity with those in steroid hormones.

Back 33

Unlike with steroid hormones, the T3 CBPs do not activate T3 and transport it to the nucleus – they are, in fact, RESTRICTIVE of T3 activity. (The CBPs buffer excess T3 and prevent its translocation to mitochondria.)

Front 34

What accounts for the greater metabolic activity of T3 vs. T4?

Back 34

This is due to the 10x higher affinity of nuclear thyroid hormone receptors to bind T3 compared to T4.

Front 35

Describe the nuclear thyroid hormone receptor and the effect of binding of T3.

Back 35

The nuclear thyroid receptor (c-erbA) is structurally very similar to other hydrophobic hormone receptors (i.e. glucocorticoid, estrogen, etc). The receptor binds to T3 response elements (TREs), which are located on the DNA near the start site of the genes that are regulated by thyroid hormone. The receptor also forms a complex with T3 Receptor Auxiliary Proteins (TRAPs) in hetero or homodimers to induce gene transcription. When T3 binds, there is a positive (ex: GH) or negative (ex: TSH) modulation depending on what is being transcribed at the target tissue.

Front 36

How does T3 lead to increased oxygen consumption? What is the physiologic result?

Back 36

T3 stimulates the Na+/K+ ATPase by increasing the synthesis of new pump units.

This drives mitochondrial activity, which increases O2 consumption, increases cell energy and metabolic rate and PRODUCES HEAT.

The end result is increased ATP production, which is used for the other cellular processes stimulated by thyroid hormone (ex: muscle contraction, protein/lipid synthesis, etc.)

Front 37

Hyperthyroidism leads to _____ intolerance, while hypothoroidism causes _______ intolerance.

Back 37

Heat
Cold

Front 38

Describe the negative feedback control of thyroid function.

Back 38

TRH (thyrotropin releasing hormone), a tripeptide, is secreted by the hypothalamus into the hypothalamic-pituitary portal system. This stimulates the production of TSH by the thyrotrophs of the anterior pituitary. TSH binds to specific receptors on thyroid follicular cells and controls all the steps in the synthesis and release of thyroid hormone. In peripheral circulation, T3 (mostly converted from T4) is mainly what feeds back on the thyrotrophs – just like with metabolic effects, T3 is 10x more effective than T4 in shutting down production.

Front 39

Where is TRH found?

Back 39

Mainly in the hypothalamus, but it is also scattered throughout the CNS and spinal cord. There is growing evidenc that TRH acts as a neurotransmitter.

Front 40

TSH is much ___(larger/smaller)____ in size than TRH. It is very homologous with ______. What are the physiologic consequences of this homology?

Back 40

Larger
The gonadotropins

Consequences: high levels of hCH (human chorionic gonadotropin) during pregnancy can stimulate T3/T4 production rate because TSH receptors on follicular cells accepts hCH. This increase in thyroid hormone is NECESSARY for a normal pregnancy.

Front 41

________ levels are the major factor in TSH serum levels (an inverse parabolic function). How can this be used clinically?

Back 41

Free thyroxine

So → low thyroxine = high TSH

So clinically, elevated TSH levels can be indicative of primary hypothyroidism. A TSH level of zero is indicative of hyperthyroidism. TSH is the most sensitive test for thyroid function.

Front 42

What is secondary hypothyroidism? How can this be clinically differentiated from primary hypothyroidism?

Back 42

Low thyroid function due to a pituitary problem. (Insufficient TSH production) → Hypothyroidism where TSH levels are paradoxically normal.

Primary vs. secondary can be detected by measuring TSH levels after TRH administration. In the case of secondary hypothyroidism, TSH levels will remain flatlined. In primary hypothyroidism, TRH administration will result in prolonged and elevated levels of TSH (due to absence of T3 negative feedback).