Last Update: 2 November P-I

2017 Thyroid M -27

Q: Describe the histological structure of mammalian thyroid with diagram. What are the major hormones secreted by this gland?
Add a note a functions of these hormones. What do you mean by Thyroid storm?. Give a short account of extrathyroidal
biosynthesis of thyroid hormones. Comment on thyroid hormone receptors. Write briefly on the transport of thyroid hormones.
Comment on the role of thyroid hormones on growth and differentiation.

Microscopic structure
On microscopic examination, the thyroid gland is found to consist of a series of follicles of varying
sizes. The follicles contain a colloid and are surrounded by a single layer of thyroid epithelium. Tissue
culture suggest that each follicle derived from single clone of cells. These cells contain microvilli, projected
towards the lumen. It becomes columns as when stimulated by TSH and flattened when resting. The
individual epithelium cells rest on a basal lamina that separates them from the surrounding capillaries..

Histological structure
The thyroid gland is
surrounded by a thin connective
tissue capsule from which the
septa extend in to gland,
dividing in to irregular lobes
and lobules. Each lobule is
composed of spherical or short
lined ending cylindrical masses
called follicles. These follicles
vary in size from 0.02 0.9 mm
in diameter. The follicular
epithelial cells make a single
layer on the extremely thin
basal lamina vary in height
from cubical to squamous.
Depending on the activity of the
gland the shape of the gland
changes. The height of the epithelium is indicative of the functional activity. The squamous follicular cells
are referred to as resting. Colloid which is found in the lumen consists of proteolytic enzyme,
mucoproteins and a glycoprotein called thyroglobulin, which is the storage form of the thyroid hormone.
The activities of the principal cells include the synthesis of thyroglobulin, iodination and storage of
thyroglobulin within the follicular lumen, reabsorption and hydrolysis of thyroglobulin, and release of the
thyroid hormones into the blood and lymphatic capillaries. This rather complex secretary pathway is
reflected in the morphological characteristics of the peripheral cells whose complement of organelles
includes structures normally identified with secretary as well as reabsorptive cells.
Most of the follicular epithelial cells are principal cells resting on the basal lamina with their epics
directed towards the follicular cavity. The principal cells vary in height from columnar to squamous. Their
nuclei are spherical and contain one or more prominent nucleoi

The diameter of the epithelial shows their is several microvilli projecting towards the lumen . The
nucleus of the cells is spherical, centrally situated poor in coronal in and contains are or more nuclei.

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 The cytoplasm is basophilic and the mitochondria are rod shaped. The Glgi apparatus is usually
supra nuclear and lipid droplets common.

Just below the epithelial cell a nice capillary of blood vessel is present known as fenestrated blood
vessel , which takes the secretion of thyroid.

There is special type of cells known as para-folicular cells which are situated just the periphery of the
cuboidal epithelial cell. These cells secretes a hormone known as calcitonin.

Colloid cell Two types of colloid cells one present in thyroid.

a. Basophilic In hyper active stage the number mitochondria increases , the enlargement of Golgi
complex occurs. The nucleus appear vascular and colloidal material become basophilic.
b. Acidophilic In hypoactive stage the cubical epithelial cell become thin, less proliferated Golgi,
mitochondria , vascular nucleus the colloid become acidophilic.

SECRETION OF THYROID
1) Principle cells produce -
i) T4 or thyroxin or Tetra-iodo-thyronine.
ii) T3 or tri-iodo-thyronine.
2) Para-follicular cell produce calcitonin which is a peptide hormone .
Among these three the actual hormone is T3, T4 is the prohormone, it is readily converted in to T3 by
a process known as deiodination. When level of T3 is low T4 is converted in to T3.
How T3 & T4 are produced in the thyroid ?
They are the derivative of common amino acid known as tyrosine.

T3 & T4 are actually iodinated from tyrosine.

Source of tyrosine
Thyroglobulin is the actual source of tyrosine, it is a glycoprotein M/W 660,000 da, it contains, 4
peptide chains and each peptide chain contain 120 tyrosine residues. It is the main source of tyrosine.

Synthesis of thyroid hormones

Thyroid hormones are
complexed through covalent bonds
to iodine. Availability of iodine to
terrestrial species is limited so
cellular mechanisms have evolved
to for utilization and conservation
of I2. Thyroid follicular cells are
able to trap I2 at the base of the cell
and transport it against an
electrical gradient across the cell.
Accumulation of I2 by the thyroid
requires energy. Na+ and I- co-
transport is inserted into the
basolateral membrane of the
thyrocyte. Its activity is dependent
upon the Na+ gradient across the
membrane and therefore on the
Na+/K+-ATPase. This is an
example of a secondary active
transport system.I2 is then converted by a peroxidase at the luminal surface of the cell to an oxidized species
of iodine that is incorporated into tyrosyl groups of thyroglobulin (TG) as monoiodotyrosine, (MIT) and

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diiodotyrosine (DIT) residues. Within the TG, iodinated tyrosines undergo oxidative coupling that results
mainly in the formation of T4 and smaller amounts of T3. This oxidative coupling may be catalyzed by the
same peroxidase responsible for conversion of I2 to iodine. Iodination of TG tyrosyl residues and
subsequent oxidative coupling to form iodothyronines may be facilitated by intraluminal ciliary action and
movement of TG to reactive sites at the apical surface of the follicular cells.
Through the process of micropinocytosis and macropinocytosis, the colloid is engulfed by follicular
cell pseudopods and transported to cells as colloid droplets. These colloid containing vesicles fuse with
lysosomes and are referred to as secondary lysosomes. Much of the TG is degraded by the lysosomal
proteolytic enzymes. The thyroid hormones are released into the cytoplasm and enter the extracellular space
by diffusion through the basal or lateral follicular membranes. Exocytosis of vesicular products including T 3
and T4, is not excluded as TG is also secreted into the circulation. The iodinated tyrosines that are released
into the cytosol through lysosomal proteolysis are then deiodinated by a deiodinase and recycled for use
within the cell.

Function of thyroid hormone

1) Thyroid hormone regulates different body mechanisms
a) Effect on BMR : By increasing the rate of metabolism in almost all cells of body it can increase
the BMR when present in excess amount on the other hand no thyroid hormone is produced
BMR falls almost to half normal.
b) Effect on body weight : Increased thyroid hormone production decrease the body wt. And
decreased production increase the body weight.
c) Effect on cardiovascular system : Blood flow and cardial output
Output : By increasing the vasodilation inmost of the body tissue it increase the blood the flow.
Heart rate : Increase considerably under the influence of thyroid hormone. It has probably an
direct effect on the excitability of the heart. Which in turns increase heart rate.
Blood volume : Thyroid hormone increase the blood volume slightly. It is due to partly from
vasodilation which allows increased quantities of blood to circulatory system.
Arterial pressure : By increasing the stock volume thyroxin increase the systolic pressure and
decreases the diastolic pressure. The mean arterial pressure remain unchanged.
d) Effect on Respiration : The increased rate of metabolism increase the utilization of O2 and
formulation of CO2. These increase the rate and depth of respiration.
e) Effect on Gastrointestinal tract : It increase the rate secretion of digestive enzyme and motility
of gastrointestinal tract.
f) Effect on contact nervous system: In general , thyroid hormone increase the rapidity of
cerebration .On the other hand lack of thyroid hormone decreases this function.
g) Effect on the function of muscle : Slight increase in thyroid hormone makes the muscle to react
with high but when the level of hormone become excessive the muscle become weak and
because of excess protein catabolism .
h) Effect on sleep: As it has effect on the musculature and central nervous system, the hyperthyroid
has a feeding of constant tiredness but because of the unexcitable effect, of thyroid hormone on
the synapse, it is difficult to sleep

2) On metabolism of dietary substance

a) Effect on carbohydrate metabolism: Thyroid hormones stimulates the carbohydrate
metabolism by enhancing the uptake of glucose by the cells glycolysis, gluconeogenesis, rate of
absorption from GI-Tract. It also regulates the blood sugar level by stimulating the secretion of
insulin.
b) Effect on fat metabolism: It also enhance the fat metabolism. It helps in mobilization of lipids
from the fat tissue, increases the free fatty acid concentration in plasma & accelerates the
oxidation of free fatty acid by the cell.
c) Effect on vitamin metabolism: It increase the quantities of many different enzymes, because
vitamins are essential parts of some of the enzyme or co-enzyme it cause the increased used for
vitamins.

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 3) On growth
The thyroid hormone regulates the growth of individual. In its absence the rate of growth is greatly
retarded. However, when it is present in excessive amount causes the excessive skeletal growth. The
bones also matured rapidly epiphyses close at an early age.
4) Effect on the level of tissue
a) On protein synthesis:
Before acting on the genes to increase the genetic transcription, the thyroxin is deiodiated by one
iodination (T4 T3). It has a high binding affinity to the circular thyroid hormone receptor. The
thyroid hormone receptor is either attach to the DNA genetic strands or in closed proximity to them.
Then they become activated initiates the transcription process. Then large number of deferent types of
messenger RNA. Followed with in another few minutes and hours by RNA translation on cytoplasmic
ribosomes to form hundred of new types of protein.
b) Effect on Mitochondria:
Thyroxin increases the number, size and total membrane surface are of mitochondria in most cells of
the body. It is directly proportional to increased metabolic rate of the whole animal. On the other hand
we can said it increase the rate of formation of ATP. But in extremely high concentration, the
mitochondria swell inordinately and uncoupling of oxidative phosphorylation process with production of
large amount of heat but little ATP.
c) Increase active transport of ions through cell membrane:
It has been shown that thyroid hormones stimulates Na+ K+-ATPase of plasma membrane and thus
enhance the activity of tissue. This increases the rate of transport of both Na and K through the cell
membrane of some tissue. This process utilizes energy, increase the amount of heat production in the
body and increase the metabolic rate. It also caused the membrane of most cell to become leaky to Na
ions, therefore further activating the sodium, pump and further increasing heat production.

Toxicity of thyroxin (Thyroid storm)

The animal which produces large amount of T3 or posses a defective metabolic pathway, their blood
contain less amount of T3 which increase the toxicity of blood as a result various symptoms can be found is
known as thyroid storm. The patient suffering thyrotoxicosin & inhibit the following symptom.
1) Deletrium
2) Quicker biting of heart.
3) Vomiting.
4) Sweating .
5) Rest less ness.
6) Dehydration
After operation of thyroid gland the patent maydic because the hormone is directly mixed with the blood.

Extra thyroidal iodine metabolism

Aquatic forms of life abstract iodine directly from sea water, the thyroid gland of terrestrial-
vertebrates abstracts iodine from the extracellular fluid. The normal iodine concentration of extracellular
fluid in humans living in an iodine-sufficient environment is approximately 0.2 g %. However in many
parts of the world with an environmental iodine deficiency, it may be 0.05 g% or less, while in countries
like Japan where iodine intake is high, it may be 2.0 g%.
The iodide in the extracellular fluid is primarily cleared by the thyroid gland and the kidneys. Only a
small proportion of iodide in the extracellular compartment is cleared by sweat, saliva, and gastric glands.
The renal clearance of iodide in humans is relatively constant and is estimated to be about 30 per min.
However, the thyroidal clearance of iodide varies from environment to environment depending upon iodine
availability, and the stage of iodine repletion of the gland.
The thyroid abstracts iodide from the extracellular fluid against a gradient by an energy-dependent
concentrating mechanism. Under normal conditions of iodine availability, a thyroid serum (T:S)
concentration ratio of 20:40 is reached in humans by virtue of this 'active transport'. However, in iodine
deficient environments, under the influence of TSH, this ratio may increase over a hundredfold.
The main source of iodide in the extracellular fluid is dietary iodine absorbed from the gut. There are
wide variations in the daily iodine intake among humans from one geographic area to the other. The iodine
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contained in the diet is rapidly and efficiently absorbed from the gut, and normally there is no significant
loss of dietary iodine in the stool. The daily recommended iodine intake is approximately I 00 g.
The thyroid gland itself
is the second major source of
iodide to reach the extracellular
fluid. The estimated daily
discharge of iodide by the
thyroid is approximately 60 g
in iodine-rich environments,
Iodide released by the non-
thyroidal tissues of the body as
a result of deiodination of the
metabolising thyroid hormones,
constitutes the third largest
contribution to the iodide in the
extracellular compartment.
In iodine-sufficient
environments, the estimated
total iodide content of the
extracellular compartment is
200- 300 g, while the intra-
thyroidal iodine stores can be as
high as 8-10 mg. The iodine
equivalent of thyronines secreted by the gland daily is estimated to be around 60 g. The major bulk of this
iodine is released by deiodination in the peripheral tissues, and either recycled back to the thyroid or
excreted through the kidneys. Figures depicts the quantitative relationship between the different iodide
compartments of the body.

The thyroid hormone receptor

Thyroid hormones, T3 and T4, circulate in plasma largely bound to protein but in equilibrium with
the free hormone. It is the free hormone that is transported either by passive diffusion or by specific carriers
through the cell membrane, through the cell cytoplasm, to bind to a specific receptor in the cell nucleus.
Within the cell, T4 is converted to T3 by 5' deiodinase, suggesting that T4 is a prohormone and T3 the active
form of the hormone.
The nuclear receptor for T3 has been cloned. It is one of a "family" of receptors, all similar to the
receptor for the retrovirus that causes erythroblastosis in chickens, v-erb A, and to the nuclear receptors for
glucocorticoids, mineralocorticoids, estrogens, progestins, vitamin D3, and retinoic acid (Figure). Human
thyroid hormone receptor (hTR) exists in at least three forms: hTR- 1 and 2 and hTR-l. hTR- contains
410 amino acids, has a molecular weight of about 47,000, and its gene is located on chromosome 17. hTR-
contains 456 amino acids, with a molecular weight of about 52,000, and its gene is on chromosome 3.
Each receptor molecule contains three specific domains: an amino terminal domain that enhances
receptor activity; a central DNA-binding domain with two cysteine-zinc "fingers"; and a carboxyl terminal
hormone-binding domain. It is likely that hTR-l and hTR-l are the biologically active forms of the
receptor; hTR-2 lacks hormone binding capacity, but it does bind to the thyroid hormone response element
(TRE) on DNA and thus may act in some instances to inhibit the activity of T3. The binding affinity of T3
analogues to the T3 receptors is directly proportionate to the biologic activity of the analogue. Point
mutations in the hTR- gene, resulting in abnormal T3 receptors, are responsible for the syndrome of
generalized resistance to thyroid hormone (Refetoff's syndrome).
The thyroid hormone receptors bind to the specific TRE sites on DNA in the absence of T3 -unlike
the case with the steroid hormone receptors. The TREs are located near, generally upstream with respect to
the start of transcription, to the promoters where transcription of specific thyroid hormone responsive genes
is initiated. T3 binding to the receptors results in stimulation, or in some cases inhibition, of the transcription
of these genes with consequent changes in the levels of the mRNAs transcribed from them. The changes in
mRNA levels alter the levels of the protein product of these genes. These proteins then mediate the thyroid
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hormone response. These receptors often function as heterodimers with other transcription factors such as
the retinoic X receptor and the retinoic acid receptor.

Release of tyrosine from thyroglobulin or Transport of thyroid hormone

By the process of endocytosis the binding tyrosine molecule is transferred into epithelial cell.
Lysosome which is present in follicle
bound with thyroglobulin and form
phagolysosome. Now lysosomal proteases
break down the structure of thyroglobulin.
As a result DIT, MIT, T3 & T4 are released
in free from this process is known as
proteolysis.
Due to various secretion properties
of cell microtubule microfilaments, free
DIT, MIT, T3 & T4 secreted through the
follicle and is readily taken up by the
fenestrated blood vessels which lies closely
to the follicle.
Then T3 & T4 binds with protein
which is present inside the blood T4 always
binds with protein and carried in bound
from when T4 is needed it increase from the
bound form.

Hormone Receptor binding

Thyroid hormones (T3 & T4) in plasma are largely bounded up with protein and only 0.04% of the T3
circulate free in unbound state. Generally hormones bind with receptors but T4 binds with specific protein
molecule, which is present in blood vessels. These proteins are known as binding protein. These are three
major thyroid binding proteins in plasma are as follows.
1) Thyroid hormone binding (TBG): It is a monomeric glycoprotein with M/W of 60,000
concentrations in plasma is 1-2 mg/dl, half-life 5 days. The affinity of TBG for T4 is 2 6 times
grater then its affinity for T3 .
2) Thyroxin binding prealbumin (TBPA) :- It has molecular weight of 50,000 and the concentration
in plasma is 25 mg/ dl& half life about 2 days . It has much lower affinity for T4 .
3) Albumin :- Concentration in plasma is about 3500 mg/dl . It has lower affinity for T3 & T4 .

Significance of binding
1) It is the protein hormone binding by which free thyroxin level is uniquely maintained.
2) It prevent hormone less through urine. As soon as the tyrosine bind with protein, the thyroxin
molecule becomes much more vigour, so it cannot pass out through urine.
3) Binding reduces the level of free hormone inside blood.
Rate of production of T3 & T4
T4 60mg / day
T3 30mg / day
Half life for T3 & T4 T4 6 7 days
T3 not specific

Level of T3 & T4
Plasma level of total (bound + free) T4 800 mg / 100 ml of plasma . Plasma level of T3 is 3 mg / 100
ml of plasma.

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Rate of binding
T4 bind with binding proteins in following rate-
1) TBG 60%
2) TBPA30%
3) Albumin10%
Inhibitors
There are some chemicals are which act as inhibitor compound during TBG -T3 binding inhibitor-
a) Salicylate
b) Phenetion
c) Tetrachloro-thyroxine

TBG - T4 binding inhibitor

a) Barbitol
b) Penicilin
c) Salicilate.

How TSH control the secretion of T3 & T4 ?

TRH form hypothalamus TSH anterior pituitary act on thyroid gland by following way.
1) Synthesis of thyroglobulin.
2) Uptake of iodide (which comes from plasma).
3) Coupling.
4) Release of DIT , MIT , T3 & T4 etc. from follicular cells.

Monoiodinase action which occurs during conversion of T4 from T3 follow some cofactors.
1) Reduced glutathione : Original enzyme of this cofactor is present in liver microsome, called
hepatic microsmal enzymes. It is a group of enzymes ultimately give rise the reduced glutathion.
2) In vivo study it is seen that a starvation which impaired (decrease) in T3 in liver but normal in kidney.
3) Hythroidism retards and hyperthyroidism accelerate the T3 biogenesis in liver and kidney.
But in case of anterior pituitary result is just kidney.

Comment on the role of thyroid hormones on growth and differentiation.

Thyroid Hormone (TH) influence most bodily functions and directly affects a number of
physiological processes and are often permissive for the actions of other hormones. These hormones
are obligatory with Growth Hormone (GH) for early growth and development.
TH are unique in that they exert effects within almost every tissue of the body throughout life.
Absence of thyroid hormones results in severe growth retardation associated with arrest of bone
elongation and retarded bone maturation.
GH secretion is reduced without TH and is renewed when TH are given. Giving GH to hypothyroid
patients is without effect unless TH are also given.
TH are required both for production of GH and for its systemic actions.
Levels of hyaluronic acid are high in proliferating tissue and decrease as division decreases and cells
become differentiated.
Hyaluronidase splits hyaluronic acid into smaller oligosaccharides and is induced when tissues
mature and may serve as a signal for differentiation.
TH stimulates tadpole tissue differentiation and increases hyaluronidase, thus TH may stimulate
differentiation through stimulation of hyaluronidase.
Decreased serum levels of TH results in retarded growth of the mammary ducts and little alveolar
development.
TH are required for normal development of the brain and without these there is decreased proteins
synthesis, myelinogenesis and retarded axonal ramifications.
These developmental processes are irreversible and lead to mental deficiency.
NGF induces dendroitogenesis and regeneration of sympathetic neurons and TH increase NGF in the
brain.

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