Transcript THYROID HORMONE

THYROID
Dr. Ayisha Qureshi
Assistant Professor
MBBS, Mphil
Case History
A fit 32-year-old man presents with a lump
low in the left side of his neck. He first
noticed it four weeks ago. He has no other
relevant personal or family history.
Examination shows a 3 cm hard, mobile
swelling on the front of the neck. The
swelling moves when he swallows.
THYROID:
a historical
perspective
• Goitre & mountains:
Goitre was first seen in inhabitants
of Alps. Initially they did not know
that goitre is enlargement of
thyroid gland. It was then
documented that consuming sea
weeds
caused
remarkable
reduction of the swelling in these
patients. It was later discovered
that sea weeds contain large
amounts of iodine.
• 1619:
Thyroid enlargement was first
described as a cause of swelling
on the front of the neck. It was also
clearly noted that this swelling
moved up and down when the
patient attempts to swallow.
The Thyroid
Thyroid Gland
is UNIQUE among other endocrine
glands in 3 ways
1. PHYSICAL
Only gland which
can be seen &
palpated.
2. BIOCHEMICAL
Only hormone that
needs a trace
element Iodine for
its production
3. PHYSIOLOGY
Hormone is stored
in an extracellular
site in the Thyroid
Colloid.
THE THYROID
GLAND
- The thyroid gland is the
largest, butterfly-shaped
endocrine glands & is
located at the base of the
neck immediately below the
Larynx, on each side of &
anterior to the trachea.
- The thyroid gland
consists of two lobes of
endocrine tissue (lying on
either side of trachea) joined
in the middle by a narrow
portion of the gland called as
the Isthmus.
- The thyroid has one of
the highest rates of blood
flow per gram of tissue.
- In a normal adult male, it
weighs 15-20 g but is
capable of enormous growth,
sometimes achieving a
weight of several hundred
grams.
LOCATION OF THE THYROID GLAND
THYROID
GLAND
The thyroid gland
consists of 2 types of
cells:
1.
Follicular cells:
These are more
abundant, and the
major secretory
cells. They secrete
Thyroid hormone.
2.
Parafollicular
cells or C-cells:
These are fewer in
number &
interspersed. They
secrete Calcitonin.
THYROID GLAND AS A
FUNCTIONAL UNIT
- The functional unit of the
Thyroid Gland is a Follicle
(acinus) which is composed
of cuboidal epithelial
(follicular) cells arranged
around hollow vesicles of
various shapes (size: 0.020.3 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
Thyroglobulin. It is a
proteinaceous material.
- There are about 3 million
follicles in an adult human
thyroid gland.
THYROID HORMONE
THYROID HORMONES
•
1.
2.
3.
4.
The Thyroid gland secretes 3 major
hormones:
Thyroxine or T4 : having 4 atoms of
Iodine. (secreted in largest amount)
Triiodothyronine or T3 : having 3 atoms
of Iodine (secreted in lesser amount)
Reverse T3 also called RT3. (secreted in
the least amount)
Calcitonin: which is an important
hormone of calcium metabolism.
THYROID HORMONES
• About 93% of secreted hormone is T4,
while 7% is T3. However, almost all T4 is
ultimately converted into 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, and
has a much greater biological activity but
is present in blood in much smaller
quantities & for a much shorter time!
• RT3 is NOT biologically active.
BIOSYNTHESIS OF THYROID
HORMONE
POINTS TO REMEMBER:
1.
2.
3.
4.
5.
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!
The hormones are synthesized in the lumen of the follicular
epithelial cells & then stored in the colloid of the follicle.
The hormone is thus doubly secreted: once from the
follicular cell into the follicular lumen where it is stored and
then reuptaken by the follicular cells where thyroglobulin is
degraded & the released T3 & T4 are again secreted into the
blood.
The Follicular cell has 2 surfaces: a basolateral surface
facing the blood capillaries & the ECF, & an apical surface
facing the follicular lumen containing the colloid.
Thyroxine, the major secretory product, is not the
biologically active form but must be converted into T3 at
extrathyroidal sites to exert potent effects.
Differentiate between Basolateral & Apical surface
of the Follicular cells….
INGESTION OF IODINE
• 50 mg of Iodine is required each year OR
1 mg/week OR 150 µg/ day.
• 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
intestines and enters the circulation.
IODIDE 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”
also called the “NIS or Sodium Iodide Symporter”
located in the thyroid cell membrane.
The process involved is Secondary Active Transport and
the energy is provided by the concentration gradient
maintained by the Sodium Potassium Pump.
NA/I SYMPORTER
This pump, thus, transfers 2 Na ions for each Iodide ion.
↓
The role of the SODIUM POTASSIUM PUMP is very important as it then extrudes 3 Na ions in
exchange for 2 K ions to maintain the electrochemical gradient for Na.
Is it the Iodine or the Iodide that
is absorbed from the intestines?
• Dietary iodine is reduced to iodide before
absorption by the small intestine.
• It is the IODIDE form of Iodine that takes
part in the various steps of thyroid
hormone biosynthesis.
• In addition to Iodine, Tyrosine is essential
for TH synthesis. Tyrosine is found as part
of the Thyroglobulin.
THYROGLOBULIN 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 about 140 molecules of
tyrosine and a m.w of 660,000 Da.
Synthesized on ribosomes
↓
Glycosylated in the ER
↓
Packaged in the secretory vesicles
↓
Secreted by exocytosis into the colloid of the thyroid
follicle
THYROGLOBULIN
SYNTHESIS
The amino acid Tyrosine
becomes incorporated
into the much larger
Thyroglobulin while it is
being produced
↓
Iodination to form the
mature hormone will
take place once the
thyroglobulin is secreted
into the colloid.
Transport of Iodine into the
follicular lumen!
• For hormone synthesis to take place, Iodide must
be delivered to the follicular lumen.
• The Iodide that has entered into the follicular cell
from the blood stream must exit the follicular cell
across the apical membrane to access the colloid,
where the initial steps of hormone synthesis occur.
• This is done with the help of a Chloride- Iodide
exchanger known as PENDRIN.
• PENDRIN is protein which is an anion exchanger.
POINTS TO REMEMBER:
• Tyrosine-containing Thyroglobulin is
transported 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 catalyzed by the enzyme
thyroperoxidase/ peroxidase and its
accompanying hydrogen peroxidase.
• These enzymes are located in the apical
membrane of the cell.
ORGANIFICATION
•
Addition of iodide molecules to tyrosine
residues in the thyroglobulin is called
Organification of thyroglobulin.
• This reaction is catalyzed by the enzyme
Iodinase.
• 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!
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 from 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
Iodide from MIT & DIT, allowing the freed
Iodide to be recycled for synthesis of more
hormone.
What is the significance of the enzyme
DEIODINASE?
PASSAGE THROUGH BLOOD
This highly lipophilic thyroid hormone molecule
binds with several plasma proteins.
• The binding proteins are:
1. Thyroxine binding globulin (TBG) (binds 70% of
the hormone)
2. Transthyretin (TTR)(binds 15% of the hormone)
3. Albumin (binds 15% of the hormone)
The majority bind to TBG, a plasma protein that
selectively binds only Thyroid hormone.
Why is the TH transported in the bound form?
Significance of the Bound hormone:
• Normally 99.98% of the T4 in plasma is bound.
• Less than 0.1% of T4 and less than 1% of T3 is in the unbound (free)
form.
• T3 has less affinity for the plasma proteins and binds loosely with
them, so that it releases quickly. T4 has more affinity and binds
strongly with them so that it is released slowly. Therefore, T3 acts on
the target cells immediately and T4 acts slowly.
• These binding proteins are synthesized by the liver. Any disease of
the liver will thus have an indirect effect on the amount of Total free
hormone levels.
• When a sudden, sustained increase in the thyroid binding proteins in
the plasma takes place, the concentration of free hormone falls. This
is, however, corrected over time.
• TBG levels are increased by estrogen therapy and in pregnancy
while it is depressed by glucocorticoids, androgens and several
chemotherapeutic drugs.
Rate of Secretion & Plasma Levels
Rate of Secretion:
Total T4 : 80-90 µg/ day
Total T3 : 4-5 µg/ day
Reverse T3 : 1-2 µg/ day
Plasma Levels:
Total T3 : 0.12 µg/ dl
Total T4 : 8µg/ day
METABOLISM
• The thyroid hormones are deiodinated in the
liver, the kidneys and many other tissues.
The T4 is converted into T3 by being stripped
of one of its Iodides.
• T4 has a long half-life of: 7 days
• T3 has a half-life of: upto 1 day
• Prolonged latent period for T4: action starts to
show almost 2-3 days after release & may
persist for as long as 6 weeks to 12 months.
• Shorter latent period for T3: starts showing its
effects within 6- 12 hours & maximal cellular
activity occurs within 2-3 days.
MECHANISM OF ACTION
M.O.A
• Thyroid hormone receptors are members
of a large family of nuclear hormone
receptors
Location: Thyroid hormone receptors are
either attached to the DNA genetic strands
or located in close proximity to them.
M.O.A
The thyroid receptor binds to hormone receptor element on the DNA either as a
heterodimer with retinoid X receptor (RXR) or a homodimer.
(The TR/ RXR is the most transcriptionally active form of the receptor.)
↓
In the absence of the hormone, the thyroid hormone receptor binds to their
response elements.
↓
When the thyroid hormone becomes available, the receptor becomes activated
& initiates the transcription process.
↓
Large number of mRNA are formed
↓
Within minutes or hours: RNA translation on the cytoplasmic ribosomes
↓
Hundreds of new intracellular proteins are formed
↓
Most of the actions are exerted through these proteins