Thyroid Hormones

Thyroid

Lower part of neck- 2 lobes

Complications of thyroidectomy in a bad surgeon:

• Hypothyroidism

• Hypoparathyroidism

• Hoarseness

What is the thyroid made of ?

Masses of colloid units in which TH is stored. Colloid is surrounded by single layer of epithelial cells in which the action takes place. Thyroid is lumpy in a healthy individual in 40% of population in colloid is where hormone is stored. Parafollicular cell secretes calcitonin.

What are the thyroid hormones?

Tyrosine-alanine c chain and phenyl ring

Thyroid hormone is iodinated tyrosine

Tyrosine goes to monoiodotyrosine (MIT) goes to diiodotyrosine (DIT) goes to 3,5,3’, 5’ tetraiodothyronine or thyroxine or T₄.

In T₄, 4I molecules- inner ring with Iodine 3 and 5, outer ring with iodine at 3’and 5’.

Or DIT and MIT form 3,5,3’ triiodothyronine (T₃)

Or 3,3’,5’ triidothyronine = reverse T₃

We started with the anatomy of the thyroid – lower part of the neck, two lobes one on each side then it migrates to where it is located in the adult. Some children have a lingual thyroid a condition in which the thyroid does not migrate. The thyroid can be identified during swallowing.

When performing surgery there is risk involved with the thyroid, parathyroid gland and the recurrent laryngeal, their destruction can lead to hypothyroidism, hypoparathyroidism, and hoarseness. The patient should be informed prior to surgery (sign a consent form).

At the end of the chapter in Bern and Levy there are 13 summary points (know them)

The thyroid is made of colloid units where the hormone is stored surrounded by epithelium. The epithelium is where the action takes place. During fine needle aspiration you realize that the thyroid is not a smooth surface in about 40% of the population. Follicular cell of the thyroid is where calcitionin is stored. Two distinct forms of carcinoma exist follicular cells or parafollicular cells (different pathology) .

What are the thyroid hormones? Tyrosine – alanin chain attached to a phenol ring. The hormone is this basic unit after it is iodinated (mono (position 3), di (position 5), tri, tetra-iodinated). After the phenol is diiodinated the two rings are brought together creating the tetra-iodinated form.

T4 thyroxin has 4 iodine molecules positioned on two rings and loss of one of the alanin chains. The inner ring iodine is 3 and 5 position; the outer ring is 3' and 5' position. Combining a diiodinated and monoiodinated rings forms T3 is the iodine molecules are in position 3,5,3’ known as the most active hormone triiodotyrosine. Reverse T3 is 3,5’,3’ it way to neutralize T3. The outer ring activates and the inner ring has the activity.

Both T4 and T3 are available on the market when the 5’ is removed from T4 it is converted to T3 (most active hormone).

Intrathyroid to extrathyroid concentration is 30:1. Thyroid pool vs. plasma pool is much higher this is a benefit because some areas do not have iodine in the environment such as Nepal. Each day 75ug of thyroid hormone is secreted it is regulated by TSH and TRH, in the plasma there is another pool of hormone due to binding protein of T4. The 75ug that is secreted is picked-up by the tissue it is essential to increased oxygen consumption and increased basal metabolic rate. Thyroid hormones help maintain body temperature and are important in the development of fetal brain (will not be completed without thyroid hormone).

Small amount is extreted to bile and secreted iodine is picked up by thyroid, salivary glands and intestinal mucosal. When giving radioactive iodine a piece of gum should be chewed at the same time so that the iodine would not be picked up by the salivary gland. Majority of the iodine will be secreted into urine, has been reported to cause temporary amenorea due to proximity.

Iodine is picked up by the symporter (active transport) against a gradient of 30:1 for every iodine transported two sodium will leave the cell. Perchlorate (ClO4-) blocks the symporter coming in at base toward apex where all action takes place, stored at caloids. The enzyme thyroid peroxidase (TPO) performs the active transport of inorganic iodine to organic and iodination of tyrosine.

Block of transporter TPO (organification) will cause iodine to leave the thyroid and into the plasma in accordance with gradient.

Major steps in thyroid hormone synthesis: hyperthyroidism or goiter can occur at any step. No trapping of iodine stops synthesis of hormone but the thyroid grows because TSH levels are high. Iodination is done on tyrosine molecule which is found in the TG (also referred to as the pre-hormone). TG is like the mother ship where all the little spaceships come out off.

1. Active transport of I- across basement membrane into thyroid cell (trapping)

2. Oxidation of iodide and iodination of tyrosyl molecules within thyroglobulin (TG)

3. Coupling of iodotyrosine molecules within TG

4. Proteolysis of TG and release of free iodothyronines and iodotyrosines

5. Deiodination of iodotyrosines within thyroid cell with conservation and reuse of the liberated iodine.

Formation and maturation of Thyroid hormone: TG has 140 tyrosyl residues a lot of places where iodine can be attached. Distribution is mostly in mono and di forms which are inactive.

TG: Prehormone!

Glycoprotein molecule, 5496 AA and 140 tyrosyl residues

Iodine content varies from 0.1 – 1%

Usual distribution of iodoaminoacids per molecule of TG are MIT 7, DIT 6, T4 2 and T3 0.2

More T3 produced if iodine deficient or hyperstimulated by TSH or TSH like activators

MAJORITY OF T3 IS NOT PRODUCED IN THE TYROID BUT IN THE PERIPHERY. T3 is produced under TSH stimulation or shortage of iodine in the thyroid.

Inorganic iodine becomes organified by TPO and H2O2 which then hooks on to a tyrosine molecule on TG. TG breaks down due to TSH into free T4, T3, and tyrosine are released into the blood. Diiodotyrosine and monoiodotyrosine can be broken up within the thyroid by DI enzyme into tyrosine and inorganic iodine.

Amount of iodine taken-up (use iodine tracer)? TSH is responsible for the uptake of iodine in normal individuals. Hypothyroid is a condition of increased uptake and hyperthyroid is a condition of decreased uptake. Some thyroids have an iodine leak and have a high uptake but normal action. Unless THS is compensatory you have hypothyroidism.

Normally iodine is trapped and organified a defect causing XS of iodine in follicular cells of the thyroid. Administration of percholrate will cause a discharge of iodine due to organification defect. Agents to treat hyperthyroidism such as propylthiouracil and methimazole blocks the organification these drugs have sever side effects in 1% of population.

Feedback mechanism to prevent over/under production of thyroid hormones:

1. TSH

2. inerthyroid iodine releasing control – if too much iodine is taken up the gland shuts off the pickup and blocks organification. This stops the production of the hormone.

Gland output is exact (75ug/day) thus when you give iodine some patient become hypothyroid and some hyperthyroid. If the block remains the production decrease and result in hypothyroidism, in other patient the block doesn’t take effect resulting in hyperthyroidism. Amnioderon is a drug that contains iodine certain percent of the patient will develop hyperthyroid and certain percent hypothyroidism. This will be a condition known as the Wolf-Chalkoff block found form giving iodine to rats. When doing a CT the contrast media contains iodine cause the same effects.

This was repeated a few time as you can well read might be important.

Thyroid hormone has binding protein, T4 bound cannot act. Free hormone acts on tissue and responsible for feedback control. Protein bound hormone is the plasma pool. FREE HORMONE DOES WORK. Protein electrophoresis, with which fraction does the radioactive hormone go? 75% of T3 and T4 is bound to globulin TBG (thyroxin binding globulin), has serine protease inhibitor action (read about this protein in Berne and Levy), about 25% is bound to pre-albumin and 5-10% bound to albumin.

67% of T4 bound to TBG, 20% bound to transthyretin (pre-albumin). More T4 is bound than T3, majority is on TBG for both hormones. Increased TBG cause decrease in fT4 (free T4), leads to increased TSH production. Increased TBG can be caused by pregnancy and estrogen. In the states you measure both total T4 and fT4. Decreased TBG is caused by androgens, T4 levels are measured in the Olympics to determine steroid usage.

Drugs that decrease the binding of T4 and TBG disease called thyroid toxic storm, symptoms include high pulse and temperature. Aspirin decreases the binding of the hormone thus should not be used because makes condition worse. Salcylates decrease binding – don’t give aspirin increase pulse and temp. by increasing metabolic rate.

Relationship of TSH and FT4 –

High TSH, Low Ft4 Primary hypothyroid, normal FT4 is 10-20, subclinical hypothyroid elevated TSH and FT4 is normal.

High TSH, High FT4 Pituitary tumor or Receptor unresponsiveness to thyroid hormone, give somatostatin will shut off TSH and the tumor shrinks.

Low TSH and Low FT4 central hypothyroid, either pituitary or hypothalamus.

Low TSH and High FT4 = primary hyperthyroidism

Discrepancy between free and bound hormone indicates binding protein problem.

The four D’s of thyroidism:

1. Dysphagia – thyroid enlarged posterior hits esophagus

2. Dysphonia – recurrent laryngeal is hit

3. Dyspnea – difficult breathing

4. Dysfunction – of thyroid

If the fetus doesn’t receive enough thyroid hormone it results in impaired growth and mental development. Pregnant women taking thyroid hormone needs to increase does to prevent relative lack of hormone from 1^st knowledge of pregnancy.

Chart: the thyroid puts out 100mn of T4 and only 5nm of T3 and less than 5nm of reverse T3 (rT3). In the periphery there is synthesis of T3 and rT3. the diagram shows deiodination of T4 outer ring to get T3 and deiodination of inner ring to get rT3. 5’ deiodinase produces T3 form T4 and degrade rT3.

Deiodinases in different part of the body:

Type 1 (5’ deiodinase) produce T3 has highest affinity to rT3 followed by T4 and least to T3, basic element is selenium otherwise inactive. Deiodinase found in liver, kidney and thyroid major enzyme to produce T3 for plasma.

Type 2 provides intracellular T3 for brain and pituitary, increase metabolism in brown fat, also selenium dependent. High TSH and high T4 but defect in Type 2 deiodinase (known in one family) will cause no negative feedback. Feedback carrier in pituitary converts T4 to T3. Thyroid Toxic Strom can be treated organification block but also the stop conversion of T4 to T3 by giving propylthiouracil and don’t give aspirin, instead give iodine to cause Wolf-Chalkoff block.

Type 3 has 5’ and 5 deiodinase primary in placenta stops both T3 and T4 to prevent too much hormone reaching the fetus also found in CNS, selenium dependent.

Extra Thyroidal factors effecting conversions of T4 to T3:

1. restricted calorie uptake decreases 5’ deiodinase – leads to less formation of T3 and rT3 – in starvation T3 goes down and rT3 increases to prevent weight loss.

2. Drugs such as propylthiouracil

3. selenium deficiency

Category: Physiology Notes