Thyroid Hormones [I]

 Thyroid Hormones: Analogues & Their Inhibitors

  Thyroid gland: 

  - Location: front of Neck, below the Adam's Apple (larynx).

  - butterfly-shaped gland.

  - it is composed of Million clusters of follicles.

  - a follicle is a structure having epithelial cells surrounding a central mass (colloid).

  - Epithelial cells: 

        (i) follicular cells[T3 & T4]

        (ii) parafollicular cells [calcitonin]

  - having two lobes; either on the windpipe (trachea).

 Thyroid Hormone Actions: 

  i.Growth & Development

  ii.Intermediary metabolism (lipid,carbohydrate & protein metabolism)

  iii.Caloriegenesis-production of heat via digestion of food or action of several hormones thus BMR increases

  iv.Haemopoiesis

  v.Modulate gene transcription

 Synthesis, Storage & Release of Thyroid Hormones: 

  1.Iodine uptake/Trapping:

   -total iodine content in body is 30-50 mg out of which ⅕th is present in thyroid

   -blood iodine concentration is low i.e. 0.2-0.4 μg/dl

   -thyroid cells have active transport process Na+:I2 symporter (NIS) to concentrate sodium ion which is get stimulated by TSH

   -there are many locations where this type of transport happens but it is not stimulated by TSH 

  2.Oxidation & Iodination:

   -iodide trapped by follicular cells via NIS is carried across the apical membrane of another transporter termed as Pendrin & then that iodide is oxidised by membrane-bound thyroid peroxidase enzyme to iodinium ions or hypoiodous acid (HOI) or enzyme-linked hypo iodate(E-OI) with the help of hydrogen peroxide

   -these all forms of iodine combine with tyrosine residue of thyroglobulin(TG) apparently without any enzyme intervention to form mono-iodotyrosine(MIT) & di-iodotyrosine(DIT)

   -these residues are still attached to TG chains

  3.Coupling:

   -pairs of tyrosine residues couple together to form T3 and T4 (formation of T4 >>> T3)

   -but during iodine deficiency relatively more MIT is available and hence more T3 is formed thus, more active hormone(T3) is generated with a lesser amount of iodine

   -coupling is an oxidative reaction and is catalyzed by the same enzyme i.e. thyroid peroxidases

   -oxidation of iodide and coupling both are stimulated by TSH

   - MIT + DIT = T3

   - DIT + DIT = T4

  4.Storage & Release:

   -MIT, DIT, T3, T4 all are attached to TG & stored as colloid till it is taken back into the cells by endocytosis and broken down by lysosomal proteases(as shown in diagram)

   -T3 & T4 are released to be secreted, while MIT & DIT residues are deiodinated & thus iodine release is finally reutilized.

   -uptake of colloid and proteolysis are stimulated by TSH.

   - normal human thyroid secrets 60-90 μg of T4 & 10-30 μg of T3.

  5.Peripheral conversion of T4 to T3: (in liver and kidneys)

   -about ⅓rd part of total T4 secreted goes in in this process and hence most of the plasma T3 is derived from liver

   -target tissues take up T3 except brain and pituitary gland which converts T4 to T3 by their own cell components

   -there is always equal amount of active(T3) & inactive(rT3) thyronine in the periphery

   -this process is carried out by iodothyronine deiodinase which exist in three forms:(D1, D2, D3)

 D1  = produces T3 & rT3

 D2 = produces T3

 D3 = produces rT3

          

  Transport,Metabolism & Excretion:

  -thyroid hormones are mostly bound to plasma proteins

  -0.03-0.08% of T4 & 0.2-0.5% of T3 are present in free form

  -almost all Protein-Bound Iodine(PBI) in plasma is Thyroid hormone.

  -plasma protein binding affinity for T4 (decreasing order) viz:

   1) Thyroxine Binding Globulin (TBG)

   2) Thyroxine Binding Prealbumin (Transthyretin)

   3) Albumin

  -Normal concentration of PBI is 4-10 μg/dl where 0.1-0.2 μg/dl is of T3 and rest is T4.

  -Only free hormone is available for metabolism, excretion as well as various actions as mentioned before.

  -Metabolic inactivation of T3 & T4 occurs by deiodination & glucuronide/sulfate conjugation.

  -liver is the primary site for metabolism & excretion processes along with salivary glands(Very rare) and kidneys.

  -conjugates excreted as bile of which significant fraction get deconjugated in intestines & reabsorbed in enterohepatic circulation then finally excreted through urine.

  -plasma t½ of T4 is 6-7 days & of T3 is 1-2 days.

  -half-lives are shortened in hyperthyroidism due to faster metabolism & they get lengthened in hypothyroidism due to relatively slower metabolism. 

In next post:Thyroid Hormones [II], the following topics will be covered:

       1.Regulation of secretion

       2.Relationship between T3 & T4

       3.Pharmacokinetics & Interactions

       4.Uses

       5. Thyroid Inhibitors

So, be in touch folks..!