Thyroid Gland Endocrinology | Dr Najeeb Lecture Notes

 Basic Functions of T3,T4:

1) Increase Basal metabolic rate (BMR)
2) Mental Development
3) Physical Maturation
4) Sensitive to Adrenal glands

Synthesis & Release of T3,T4

1) First step in synthesis is uptake of iodine and tyrosine across basement membrane.
2) Then there is synthesis of thyroglobulin in follicular cells. The tyrosine reduce are present on thyroglobulin on which iodide ions are attached.
3) Release of thyroglobulin to lumen
(Thyroglobulin is an essential substrate for organification of iodine and is the major protein component of the colloid in the thyroid follicular lumen. It is an iodinated glycoprotein with a molecular weight approximating 650,000 daltons. It consists of two monomeric chains, each with 67 tyrosine residues) ( some synthetic steps are done )

5) Formation of colloids ( it contains large account of thyroglobulin)
6) the United thyroglobulin is then released into the follicle cells by endocytosis and with these vehicles lysosomes fuse and causes digestion of thyrpglobin into triiodothyrosine (T3) , T4 and di-iodo tyrosine(DIT) mono-iodo tyrosine(MIT) and other amino acids.

Thyroid peroxidase

1)Thyroid peroxidases are special enzyme present in luminal or apical membrane that causes the oxidation of iodide Ion into Iodine molecule.
2) incorporation of iodine to tyrosine residue of thyroglobulin (organification)
3) 3rd function of thyroid peroxidase is fusion of mono Iodine tyrosine residues with Di iodine tyrosine.
Tyroid De-iodinase : this is important for the recycling of iodine it causes de-iodination of MIT and DIT.

Drug inhibitions

1) anions like thiocyanate and perchlorates utilize the iodine transporters present on the basement membrane so enough iodine can't get into the cell. It causes deficiency of T3 T4 , low level of T3 T4 does not inhibit TSH by negative feedback which results in high level of TSH.

NOTE: TSH causes increase synthesis , increase follicle size and proliferation of follicle cells.

2) Propyl Thyro uracil ,carbimazol inhibitors of thyroid peroxidase.
3) wolff chaikoff effect: an autoregulatory phenomenon, whereby a large amount of ingested iodine acutely inhibits thyroid hormone synthesis within the follicular cells, irrespective of the serum level of thyroid-stimulating. (High configuration of iodine will inhibit the Iodine transporters which results in less function less vascularization and less size of thyroid)

*Transport and release of T3,T4 in blood*:

1)99% of T3 T4 is binded with plasma proteins less than 1% are in free form.
2) T3 is biologically active form it loosely attached with plasma proteins and strongly attached with target cells and are more effective in activating the response ,T4 has to be converted in to T3 for action (5 prime mono Deiodinase is used for this conversion)
3) T4 is produced in more amount than T3 , T4 has more half life than T3
4) They bind mostly with thyroxine binding globulin , some percent is bind with albumin and transthyretin.
5) total T4 is far more than total T3 so feedback is dependent mainly on T4. The circulating T4 emter into the pituitary and got converted into T3 and downregulate the TRH receptors.

Regulation hypothalamic pituitary thyroid axis

1)TSH receptors present on follicle cells are GS coupled 7 pass receptors. Activated Gs protein stimulates adenylyl cyclase which results in an increase in cyclic AMP ,it than stimulate Protein kinase A (PKA). PKA has following functions:
-PKA leads to phosphorylation of iodide transporters
-pkA stimulates thyroid peroxidase
-increase synthesis of thyroid by acting on nuclear proteins.
-the most important early effect of TSH on follicle cells is increased in endocytosis.
-long term effect are : hypertrophy ( follicular cells increase in size and become columnar from cuboidal); number of follicular cells and Follicles inreaseses.
-thyroid stimulating immunoglobulins (TSI) are autoantibodies which can pathologicaly over stimulate TSH receptors for long duration.

2) cool temperature stimulates more release of TRH from hypothalamus.

Low T3 syndrome:

Due to stressful catabolic state for example starvation ,surgery , trauma , body will inhibit 5 prime mono de-iodinase. (So there will be less active T3 but T4 and TSH levels will be normal)

*Factor which increase T3,T4 levels*
1) High TSH level
2) TSI (graves disease)
3) high TBG(thyrosine binding globulin) like in pregnancy.

*Factors which Decrease T3 T4 levels*

1) low TSH
2) low iodide
3) very high concentration of iodide wolff chaikoff effect
4) thiocyanate ,perchlorate
5) thio propyl uracil(T.P.V)
6) thyroid deiodinase absent
7) low level of TGB (e.g chirosis)

How T3,T4 works on target Cells?

Less than 1% free T3,T4 is present in circulation.
T4 is converted into T3. T3 enter the cell and act on receptors ( which are present in nucleus )

Receptors has three domains:
One bind with T3, other binds Retinoic acid X Receptor (RxR) {RxR assit the action of T3 by stimulating one of the domains }
The 3rd domain stimulate and binds with *Hormone responsive DNA-sequence* so specific genes are activated which results in formation of specific proteins.
These proteins are:
1) Functional : enzymes ( increase metabolism)
2) Structural: (Physical and mental growth)
3) Regulatory: Na+-K+ ATPase , LDL receptors.

Major effects of T3,T4:
1) increase BMR:
2) growth and maturation
3) maintain responsiveness of body to adrenergic drive.[it increases Beta receptors {B1,B2,B3(present on adipocytes)}]

BMR : it doesn't increase the BMR in CNS, gonads, retina ,spleen, lymph nodes. Doesn't effect directly on them.

*How it increases BMR??*

Number of sodium potassium ATPases , which requires energy in the form of ATM (more need of Oxygen and nutrients) --> the size and number of mitochondria will increase.

*Physiological Actions:*

1) transcription of many genes
2) Cellular Metabolic Activity
3) physical & mental growth & maturation.( Brain fails to develop properly.
4) effect on specific bodily mechanism

3) Synapses abnormal , not developing dendrites ,mylenation problem...
No normal developing of basal ganglia(due to this baby will suffer rigidity) ... If T3,T4 are low.

*Hyperthyroid babies are also dwarf. Intially they grow very fast , but closure of metaphyseal growth plate occurs earlier.*

*specific bodily mechanism*

ATP is being used and is being made so we need more neutrons and oxygen therefore different systems co-ordinate with each other, effects are as follows:
1) under the influence of thyroid hormones is observed more glucose. (Secretory Activity increase, motility increase, appetite is good)
2) There Will be more release of glucose from liver ( from glycogenolysis , gluconeogenesis)
3) capibilaty of cells to intake glucose in order to utilize it.(with help of insulin).
4) more experession of B3 receptors result in more lipolysis in adipocytes and more release of Free Fatty acids.
5) increase Receptors of LDL(low density lipoprotein) - LDL uptake will be more ( cholesterol uptake) by Liver , when there is increased uptake by liver then there is decreased de novo (by liver) synthesis of cholesterol and the extra cholesterol is going into bile and go outside the body. There will be less level of LDL in blood.
6) extra vitamins to blood.
7) hyperthyroidism cause hyper-motility of GIT which results in inadequate (less time for)digestion and absorption. Therefore instead of eating more and good appetite but the person loses his weight.
8) We need faster circulation so effect on heart is : increase expression of beta 1 Receptors,increased expression of myosin and increased expression of calcium ATPase is that results in positive inotropic effects.will be increase in heart rate and stroke volume which means there is increase in rate of cardiac output, leading to increase in systolic B.P, due to heat production and other waste the arterioles dilate and the total peripheral resistance is decrease and hence diastolic blood pressure decreases.
9) Lungs: increased respiratory rate and increased tidal volume..
10) CNS: does not act directly to increase BMR, it expresses more adrenergic receptors and neurotransmitter activity is altered.

Hyperthyroidism cause anxious and insomnia, but hypothyroidism depression,lack of consentraion, excessive sleep........(recording)

11) Gonads: loss libido, hyperthyroidism: less frequent mensural bleeding. Hypo: most frequent menustral bleeding both can make the female infertile. Males also lose the libido anf they may also become infertile and impotent. Impotence usually in hypothyroidism because of depression.

*Brief Pathology*

1)Graves' Disease:
More common in females.
it is an autoimmune disease in this disease the immune headquarters start producing antibodies which attach with the TSH receptors of follicle cells and hyperstimulate them and also increase their growth.
These antibodies are called TSI or TGI.
*There is diffuse hypothyroid goiter in Graves' disease.* Causes thyrotoxicosis ( Thyrotoxicosis is the clinical manifestation of excess thyroid hormone action at the tissue level due to inappropriately high circulating thyroid hormone concentrations.)

*also attack extra ocular retro-orbital connective tissue and extra orbital muscles* tissue become inflammed and causes protusion of eyes.
There is also Pretibial myxedema in Graves'disease.

2)Toxic Thyroid Adenoma

It is a neoplastic process. A one particular cell in Gland undergo neoplastic transformation and forms adenoma. It is atonomous adenoma which means its activity is not dependent on TSH. This adenoma produce massive amount of T3,T4.
In it TSH levels go down and normal Thyroid gland undergoes hypotrophy.

3) Multinodular toxic goiter
It is due to iodine deficiency( usually leads to hypothyroidism) Some are working well and some Follicles are not working, so intially TSH level rises, when TSH level goes up it over stimulate some of the follicular cells that end up into autonomous growth formation or hyper-functoioning Thyroid areas. Multinodular goiter may become toxic but remember iodine deficiency usually and more commonly lead to hypothyroidism.


4) Primary hyperthyroidism
_Cause of hypothyrodism is within the thyroid gland_ e.g graves disease, toxic adenoma, multinodular toxic goiter.
-T4 level is high but TSH and TRH is low.

5)Secondary hyperthyroidism
Problem is is not within the thyroid gland, it is within the pituitary or hypothalamus. Due to pituitary adenoma there is high level of TSH release and which causes hyperthyroidism.
- elevated TSH and T4 but low TRH.

Very rare, when hypothalamus release excessive TRH.
-TRH, TSH ,T4 are high.

*Treatment of primary hyperthyroidism:*

1) propanolol ( block beta adrenergic receptors, clinical features related with adrenergic Activity will subside like anxiety, trachycardia,tremors will be less)
2) Thio propyl uracil or carbimazole ( decrease T3,T4 synthesis, inhibit Thyroid peroxide enzyme)
3) surgery --> subtotal Thyroidectomy
4) radioactive iodine

6) Hypothyroidism
"is a clinicopathological syndrome which results due to chronic deficiency of action of T3 and T4 on the tissue"
 Causes;
Primary: cause within gland.
-autoimune disease that produces antibodies against the gland and destroys the follicle cells , is called hashimotos thyroditis.
-Endemic goiter which are due to the iodine deficiency in a specific geographical area.
-hormonesdysgenesis*
Due to some enyzme problem.
TSH,TRH high, T3T4 low in primary hyperthyroidism.

7)Cretenism
There may be congenital and endemic cretenism.

In congenital: 1)short stature 2)obese 3)Metal retardation (plus rigidity due to basal ganglia not developed well, cochlear system also don't develop well baby can't hear anything and that's why can't talk well-->deaf mutism).