THYROID HORMONE

biochemistry

THYROID GLANDTwo lobes connected by isthamus

On ventral aspect of trachea just below larynx

Vascularised by sup- & inf- thyroid artey

The thyroid gland consists of 2 types of cells:

1. Follicular cells: are the major secretory cells releasing thyroid hormones &

2. Parafollicular cells or C-cells: are fewer in number, interspersed & secrete calcitonin

FUNCTIONAL UNIT

The functional unit of the Thyroid Gland is a Follicle which is composed of cuboidal epithelial (follicular) cells arranged around hollow vesicles of various shapes (size: 0.02-0.3 mm in diameter). Arrangement is such that each follicular epithelial cell lies adjacent to a capillary!

Each follicle is a closed structure filled with a glycoprotein colloid called as Thyroglobulin.

There are about 3 million follicles in an adult human thyroid gland.

• Normally, the thyroid gland secretes 80–100 g T4 and approximately 5g T3 per day. The additional 22–25g T3 “produced” daily is the result of the deiodination of the 5-carbon of T4 in peripheral tissues.

• T3 is believed to be the predominant biologically active form of thyroid hormone in the body.

TRH (hypothalamus)

a tripeptide, all components are essential.Regulates TSH secretion from thyrotrophs.also regulates sec- of other Ant- pit hormones.Play an imp- role in post translational pro- cessing of oligo-sec moiety of TSH.It is resistant to intestinal peptidase action.Its effects are mediated by membrane receptor coupled to phospholipase C as a second messenger.

TSH(thyrotropin) a glycoprotein, sec- by Ant- pit. (thyrotroph)

• Its secretion is regulated by a balance b/w TRH & -ve feedback of T3 & T4.

• It stimulates all phases of thyroid hormone synthesis.

• Also increases the blood flow of the gland, hypertrophy & hyperplasia.

• It binds to its specific receptor on acinar cells → ↑cAMP and Ca level

Normal = 1ng/ml • the TSH receptor which is

located on the basal surface of the thyroid follicular cell

THYROID HORMONES

• The Thyroid gland secretes 2 major hormones:

1. Thyroxine or T4 having 4 atoms of Iodine &

2. Triiodothyronine or T3 having 3 atoms of Iodine

It also secretes:3. Calcitonin which is an important

hormone for calcium metabolism

THYROID HORMONES

• About 93% of secreted hormone is T4,

while 7% is T3. However, almost all T4 is ultimately converted in to T3.

• The functions of the 2 hormones are the SAME but they differ in rapidity & intensity of action.

• T3 is about 4 times as potent as T4, but is present in blood in much smaller quantities & for a much shorter time!

Synthesis of the thyroid hormones (T3 and T4)

BIOSYNTHESIS OF THYROID HORMONE

POINTS TO REMEMBER:1. Iodine in large amounts is required for thyroid hormone

synthesis. This is acquired through diet & THERE IS NO OTHER USE OF THIS ELEMENT IN THE BODY!

2. The hormones are synthesized in the follicular epithelial lumen & then stored in the follicular cell!

3. The hormone is thus doubly secreted: once from the follicular cell as thyroglobulin into the follicular lumen, then reuptaken by the follicular cells where thyroglobulin is degraded & the released T3 & T4 are then secreted into the blood.

4. Thyroxine, the major secretory product, is not the biologically active form but must be transformed to T3 at extrathyroidal sites.

INGESTION OF IODINE

• 50 mg of Iodine is required each year OR 1 mg/week.

• To prevent deficiency, common table salt is iodized with about 1 part sodium iodide to every 100,000 parts sodium chloride.

• Ingested iodide is absorbed from the GIT.

IODINE TRAPPING

Under normal circumstances, iodine is 25-50 times more concentrated in the cytosol of Thyroid

follicular cells than in the blood plasma

↓

Thus, iodine moves into the thyroid cells against a steep concentration gradient!

↓

This is done with the help of an elctrogenic “Iodide pump” located in the thyroid cell membrane.

IODIDE PUMP

The Iodide pump is a Sodium Iodide Symporter.

↓

This pump, thus, transfers 2 Na ions with each Iodide ion.

↓

Na pump then extrudes 3 Na ions in exchange for 2 K ions to maintain the electrochemical gradient

for Na.

THYROGLOBULIN SYNTHESIS

• It is the other substance needed for thyroid hormone synthesis.

• It is the matrix for thyroid hormone synthesis & is the form in which the hormone is stored in the gland.

• It is a large glycoprotein with a m.w of 660,000 Da.Synthesized on ribosomes

↓Glycosylated in the ER

↓Packaged in the secretory vesicles

THYROGLOBULIN SYNTHESIS

Tyrosine becomes incorporated into Thyroglobulin while it is being formed

↓

Iodination to form the mature hormone will not take place until the thyroglobulin is not

secreted into the lumen of the follicle.

Transport of Iodine into the follicular lumen!

• For hormone synthesis to take place, Iodine must be delivered to the follicular lumen.

• The Iodine that has entered into the follicular lumen from the blood stream diffuses across the follicular cuboidal cell & exits it to enter the colloid of the Follicle!

POINTS TO REMEMBER:

• Tyrosine-containing Thyroglobulin is exported from the follicular cells into the

colloid by exocytosis.

• Iodine is transferred into the Colloid!

OXIDATION OF THE IODIDE ION

• Iodide ion is oxidized to form either nascent iodine (I°) or I3− .

• This oxidation is then promoted by the enzyme thyroperoxidase/ peroxidase and its accompanying hydrogen peroxidase.

• These enzymes are located in the apical membrane of the cell or attached to it.

ORGANIFICATION

• Addition of iodine molecules to tyrosine residues in the thyroglobulin is called Organification of thyroglobulin. This reaction is catalyzed by the enzyme Iodinase.

1. Attachment of 1 Iodine to tyrosine yields MONOIODOTYROSINE (MIT)

2. Attachment of 2 Iodines to tyrosine yield DI-IODOTYROSINE (DIT)

ORGANIFICATION

• Tyrosine + 1 Iodine = Monoiodotyrosine

(MIT)

• Tyrosine + 2 Iodines = Di-iodotyrosine

(DIT)

COUPLING

• It is the combination or coupling of 2 molecules of iodinated tyrosine molecules to form thyroid hormone:

- DIT + DIT = Thyroxine (T4)- DIT + MIT = Tri-iodothyronine (T3)

COUPLING DOES NOT OCCUR B/W 2 MIT MOLECULES!

COUPLING

This mature hormone is formed while a part of Thyroglobulin molecule, & remains a

part of this large storage molecule till the stimulus for secretion arrives.

STORAGE

In normal individuals, approximately 30% of the mass of thyroid gland is thyroglobulin,

which is about 2-3 months supply of hormone.

SECRETION

• For secretion to occur, thyroglobulin must be brought back into follicular cells by a process of endocytosis.

• Pseudopodia reach out form the follicular cells to engulf chunks of thyroglobulin, which are taken up in endocytic vesicles- this is also called “BITING OFF”.

↓On appropriate stimulation for thyroid secretion,

the follicular cells internalize a portion of thyroglobulin- hormone complex by

phagocytozing a piece of colloid

SECRETION

The endocytic vesicles fuse with the lysosomes

↓

Lysosomes release enzymes that split off the biologically active hormones: T3 & T4, as well as

the inactive iodotyrosine, MIT & DIT.

↓

The thyroid hormones being very lipophilic, pass freely through the outer membrane of the

follicular cells & into the blood!

FATE OF MIT & DIT

The MIT & DIT are of no endocrine value.

↓

The follicular cells contain an enzyme

(deiodinase) that will swiftly remove the Iodine from MIT & DIT, allowing the freed

Iodine to be recycled for synthesis of more hormone

PASSAGE THROUGH BLOOD

This highly lipophilic thyroid hormone molecule binds with several plasma proteins.

• The binding proteins are:1.Thyroxine binding globulin (TBG)2.Transthyretin (TTR)3.Albumin The majority (70%) bind to TBG, a plasma protein

that selectively binds only Thyroid hormone.Less than 0.1% of T4 and less than 1% of T3 is in

the unbound (free) form.

POINT TO REMEMBER:

• T3 is about 4 times more potent than T4 in its biological activity.

• Most of the hormone released by the thyroid gland is T4.

• Most of the T4 is converted to T3, or activated, by being stripped of one of its iodines outside of thyroid gland, primarily in the liver & kidneys.

• T3 is the major biologically active form of thyroid hormone at the cellular level, even though the thyroid gland secretes mostly T4.

METABOLISM

• Thyroxine half-life: 6.2 days

• Tri-iodothyronine: 1 day

• Prolonged latent period for Thyroxine: action starts to show almost 2-3 days after release & may persist for as long as 6 weeks to 12 months.

• Tri-iodothyronine: 6- 12 hours & maximal cellular activity occurs within 2-3 days.

Effects of Thyroid Hormone on The Liver• affect carbohydrate and lipid metabolism• increases glycolysis and cholesterol synthesis• increases the conversion of cholesterol to bile salts.

Through its action of increasing the sensitivity of the hepatocyte to the gluconeogenic and glycogenolytic actions of epinephrine,

• T3 indirectly increases hepatic glucose production (permissive or facilitatory action). Because of its ability to sensitize the adipocyte to the lipolytic action of epinephrine,

• T3 increases the flow of fatty acids to the liver and thereby indirectly increases hepatic triacylglycerol synthesis. The concurrent increase in the flow of glycerol to the liver (as a result of increased lipolysis) further enhances hepatic gluconeogenesis.

Effects of Thyroid Hormone on The Adipocyte

• T3 has an amplifying or facilitatory effect on the lipolytic action of epinephrine on the fat cell.

• Yet thyroid hormone has a bipolar effect on lipid storage, because it increases the availability of glucose to the fat cell, which serves as a precursor for fatty acid and glycerol 3-phosphate synthesis.

• The major determinant of the rate of lipogenesis, however, is not T3, but rather the amount of glucose and insulin available to the adipocyte for triacylglycerol synthesis

Effects of Thyroid Hormone on Muscle

• In physiologic concentrations, T3 increases glucose uptake by muscle cells. It also stimulates protein synthesis, and, therefore, growth of muscle, through its stimulatory actions on gene expression.

• In physiologic concentrations, thyroid hormone sensitizes the muscle cell to the glycogenolytic actions of epinephrine.

• Glycolysis in muscle is increased by this action of T3.

Effects of Thyroid Hormone on The Pancreas

• Thyroid hormone increases the sensitivity of the cells of the pancreas to those stimuli that normally promote insulin release and is required for optimal insulin secretion.

Calorigenic action

• Thyroid hormone participates in this acute response by sensitizing the sympathetic nervous system to the stimulatory effect of cold exposure. The ability of T3 to increase heat production is related to its effects on the pathways of fuel oxidation, which both generate ATP and release energy as heat.

• The effects of T3 on the sympathetic nervous system increase the release of norepinephrine. Norepinephrine stimulates the uncoupling protein thermogenin in brown adipose tissue (BAT), resulting in increased heat production from the uncoupling of oxidative phosphorylation

Goiter

• swelling in neck due to thyroid hypertrophy• both hypo- and hyperthyroidism

Thyroid Dysfunctions

• cretinism

- congential absence of T3 and T4 or chronic iodine deficiency during childhood

- retarded growth

- sluggish movements

- mental deficiencies

• adult hypothyroidism

- low rate of metabolism and lethargy

- decreased body temp

- decreased heart rate

- outer skin becomes scaley

- myxodema – swelling of sub-cu connective tissues

• adult hyperthyroidism

- Grave’s Disease

- tall stature, hyperactivity

- high rate of metabolism

- high body temp

- high heart rate

Exophthalmus

- edematous swelling at the rear of eye socket