Ms Veena Shriram

Introduction

Described first by Thomas Wharton (1616-1673)

Largest Endocrine Gland

Weighing 15 – 20 g

Highly Vascular ( 5 ml / g / min ).

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Functional Anatomy

•Thyroid : shield

• Two lobes are connected by isthmus infront of the larynx

•Receives highest rate of blood flow per gram of tissue

•Histologicaly made up of multiple of closed follicles (acini): 100 – 300 µm.

Contd. ..Veena

http://arbl.cvmbs.colostate.edu/hbooks/pathphys/endocrine/thyroid/anatomy.html

THYROID GLAND HISTOLOGY

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• Follicles are lined with single layer of cuboidal epithelial cells, which secrete into interior .

• Filled with proteinaceous matter: colloid, made up

of large glycoprotein thyroglobulin containing thyroid

hormones within it.Inactive gland:Follicles - largeColloid – abundantCells lining are flat

Active gland:Follicles - smallCells lining are cuboidReabsorption lacunae seenVeena

Fetal Thyroid From 12th week of gestation fetal thyroid begins

to secrete hormones.

Th. Hormones (T. H.) are essential for normal

growth & development of fetal CNS , skeletal

systems.

Maternal TSH & thyroxine cannot cross placental

barrier, however iodine can cross the barrier.

Fetal T. H. production depends on ant. pituitary &

fetal hypothalamus.Veena

O OH

I

I

II

OH

O

NH2

Thyroxine (T4)

O OH

I

I

IOH

O

NH2

3,5,3’-Triiodothyronine (T3)

THYROID HORMONES

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Synthesis & secretion of T. H.

1. Iodide Trapping

2.Formation & secretion of thyroglobulin

3.Oxidation of iodide ions 4.

a) Iodination of tyrosine

b) Organification of TG5.Storage of TG

6.Release of T.H. : T4 & T3

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93 % hormone secreted by T. gland is Thyroxine

(T4).

7 % is triiodothyronine (T3).T3 is:

4 times more

potent than T4

present in smaller

quantities

Persists for shorter

time than T4Veena

Iodine Metabolism Iodine is a raw material for T. H. synthesis. Ingested iodine is converted into iodide Daily avg. intake of iodine is 500 µg/ day . Min. daily intake to maintain normal T. function 150 µg/ d Normal plasma iodine level is about 0.3 µg/ dL .

To prevent iodine deficiency common table salt is iodized with 1 part

Na iodide to every 1,00,000 parts of NaCl.

Fate of Ingested iodides: absorbed from GIT into blood.

1/5th is taken up by T. gland and rest is excreted by

kidneys.

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1. Iodide Pump (Iodide Trapping)

Food iodide from blood is , taken up by the follicular

cells of thyroid – a process called iodide trapping.

Thyroid cells RMP is -50 mV compared to interstitial

fluid & luminal colloid.

The T. cell membrane facing capillaries contain a

symporter or iodide pump : Na+/ I

- symporter (NIS)

It works against electrochemical gradient & traps

iodide by secondary active transport mechanism.

It concentrates the iodide 30 – 250 times than in the

blood.Veena

2. Formation & secretion of thyroglobulin

T. cells are typical protein secreting glandular cells.

ER & GA synthesize & secrete into the follicles, a

large glycoprotein molecule : thyroglobulin (TG - with

MW 3,35,o00)

TG contains about 70 tyrosine amino acids.

Tyrosine combines with iodide to form T. H. ( within

TG molecule).

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3. Oxidation of Iodide ions

Conversion of the iodide ions to an oxidized

form of iodine (either nascent iodine, I0 or I-3) by

the enzyme peroxidase in presence of H2O2.

Peroxidase is attached to apical membrane of the cell.

This oxidized form of iodine can combine with

the a. a. tyrosine.

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4. a) Organification of thyroglobulin

1. Organification of thyroglobulin (TG): The

binding of iodine with TG molecule is called

organification.

2. Oxidized iodine in presence of enzyme

iodinase binds very rapidly with

thyroglobulin.Veena

ION TRANSPORT BY THETHYROID FOLLICULAR CELL

I- I- organification

Propylthiouracil (PTU) blocks iodination of thyroglobulin

COLLOID

BLOOD

NaI symporter (NIS)

Thyroid peroxidase (TPO)

ClO4-, SCN-

Perchlorate, thiocynate depress I transport by competitive inhibition

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4. b) Iodination of Tyrosine

Tyrosine + oxidized iodine monoiodotyrosine(MIT)

I0 or I-3

diiodotyrosin (DIT)

Coupling :-

MIT + DIT Triiodotyrosine (T3)

DIT + MIT RT3

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Biosynthesis of TH

trap

Peroxidase

Organification

Apical membrane

E.R.

Golgi

Basal membrane

I-

I-

I-

I-

qqqq

.

I-

.

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Storage & Release of TG5. STORAGE After synthesis of TH , TG molecules contain

up to 30 molecules of T4 & few molecules of T3

2-3 months requirement is stored.

6. RELEASE The follicle cells engulf a little TG (containing T4 &

T3) by endocytosis (by formation of reabsorption lacunae).

TG is digested by proteinase and T4 & T3 are set free

After cleaving of T4 & T3 from TG, free H is released into capillaries.

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Synthesis & Release

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3/4th of iodinated tyrosine in the TG never

becomes TH, but remains MIT, DIT.

During digestion of TG for release of T4 &

T3 , iodinated tyrosins are also freed from

TG, but not released into blood

Instead I is cleaved by deiodinase enzyme.

Thus recycling I.

Congenital absence of this enzyme lead to I

deficiency.

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Daily Rate of Secretion

93 % T4

7 % T3 is released.

Later half of the T4 is slowly deiodinated

to T3

Finally T3 is mainly delivered to & used

by tissues, a total about 35 µg / d.

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Transport of TH In The Blood

Approximately 99 % of T4 is bound to 3 plasma proteins: Thyroxine binding globulin (TBG) ~75%; Thyroid binding prealbumin (TBPA or transthyretin) 15-20 %; albumin ~5-10 %

Only ~0.02% of the total T4 in blood is unbound or free.

Only ~0.4% of total T3 in blood is free.

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Slow release of T4 & T3 to the tissues

T4 & T3 are released slowly to the tissues

because of high affinity with TBG of T4

Half quantity of T4 is released in 6 days

and that of T3 in 1 day

After entering tissues again it binds with

protein & used slowly.

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Slow onset & long duration of action

This is due to binding with proteins both in

plasma & tissue cells, and due to the way they

act.

T3 is 4 times rapid than T4 .

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Mechanism of Action transcription of large no. of genes, therefore

large no. of proteins, enzymes, & other substances

are synthesized.

generalized in functional activity

High affinity of intracellular TH receptor for T3

TH activate nuclear receptors (TRα on gene 17 &

TRβ R on gene 3 ) & initiate the transcription process.

mRNA formation, then RNA translation

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Mechanism of Action

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