THYROID

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THYROID

• Dr. Ayisha Qureshi
• Assistant Professor
• MBBS, Mphil

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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.

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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.
  

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The Thyroid
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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.

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LOCATION OF THE THYROID GLAND
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THYROID GLAND

• The thyroid gland
• consists of 2 types of
• cells
• Follicular cells These are more abundant, and
  the major secretory cells. They secrete Thyroid
  hormone.
• Parafollicular cells or C-cells These are fewer
  in number interspersed. They secrete Calcitonin.

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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 0.02-0.3 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 Thyroglobulin. It is a proteinaceous
  material.
• There are about 3 million
• follicles in an adult human thyroid gland.

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THYROID HORMONE
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THYROID HORMONES

• 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.

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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.

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Biosynthesis of thyroid hormone
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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 lumen of the
   follicular epithelial cells then stored in the
   colloid of the follicle.
3. 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.
4. 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.
5. Thyroxine, the major secretory product, is not
   the biologically active form but must be
   converted into T3 at extrathyroidal sites to
   exert potent effects.

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Differentiate between Basolateral Apical
surface of the Follicular cells.
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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.

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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.

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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.

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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.

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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

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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.

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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.

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POINTS TO REMEMBER

• Tyrosine-containing Thyroglobulin is transported
  from the follicular cells into the colloid by
  exocytosis.
• Iodine is transferred into the Colloid!

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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.

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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)

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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.

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STORAGE

• In normal individuals, approximately 30 of the
  mass of thyroid gland is thyroglobulin, which is
  about 2-3 months supply of hormone.

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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

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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!

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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?

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PASSAGE THROUGH BLOOD

• This highly lipophilic thyroid hormone molecule
  binds with several plasma proteins.
• The binding proteins are
• Thyroxine binding globulin (TBG) (binds 70 of
  the hormone)
• Transthyretin (TTR)(binds 15 of the hormone)
• 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?

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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.

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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

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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.

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MECHANISM OF ACTION
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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.

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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

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