Chapter 33: The thyroid gland

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The thyroid gland

Key concepts

  • There are two lobes, flanking the trachea. Within the lobes are spherical follicles that are surrounded by a signle layer of epithelial cells. Parafollicular cells secrete calcitonin are also found in the walls of the follicles.
  • T4 = thyroxine, T3 = iodothyronine; both contain iodine.
  • The enzyme thyroid peroxidase converts iodine and tyrosine to T3 and T4 in a process called iodination.
  • Thyroglobulin chelates T3 and T4; as thyroglobulin is degraded, T3 and T4 is released from follicular cells.
  • TSH (thyroid stimulating hormone) controls the release of thyroid hormones through a cAMP pathway.
  • TSH is released by the anterior pituitary; TSH's release is regulated by the levels of T3 and T4 in the blood.
  • T3 is the physiologically active form; T4 is deiodinated to T3 at the peripheral tissue.
  • T3 binds the thyroid hormone receptor (TR) which then dimerizes or binds a nuclear receptor.
  • TR affects transcription by binding to specific regulatory sequences called thyroid response elements.
  • Thyroid hormones are especially important in central nervous system development.
  • Thyroid hormones affect growth by regulating growth hormone release (anterior pit) and by direct effects on the metabolism of tissues like bone.
  • At the target tissue, thyroid hormones affect the basal metabolic rate by affecting ATP synthesis by mitochondria and expression of metabolic genes.
  • An excessive amount of thyroid hormone leads to weight loss and nervousness.
  • A deficient amount of thyroid hormone leads to weight gain.

Introduction

  • Development from person to person is pretty darn consistent between individuals.
  • Cells have to make enough ATP to maintain their basal rate (like maintaining homeostasis, an osmotic gradient, etc.) as well as enough excess energy to perform their special function (like conducting action potentials or contracting).
  • Thyroxine (T4) and triiodothyronine (T3) are not essential for life.
    • Without them, however, development and metabolic regulation are screwed up.

Functional anatomy of the thyroid gland

  • The thryroid gland has two lobes with an isthmus connecting them along the anterior aspect of the trachea.
  • The thyroid sits just inferior to the cricoid cartilage.
  • A healthy thyroid weighs about 20 grams.
  • The thyroid has a higher rate of blood flow per gram of tissue then even the kidney.
    • The arterial supply is made up of the superior and inferior thyroid arteries from the external carotid and subclavian arteries.
    • The venous drainage is via the external jugular and other inominate veins.
  • The thyroid also has both vagal (cholinergic) nervous supply and cervical ganglia (adrenergic) innervation.
    • The vagal supply uses Ach, is generally parasympathetic, and acts to increase blood flow to the thryoid.
      • This makes sense because if you're resting and digesting, you have lots of nutrients and want to get the TSH, iodine, and other intermediates to the thyroid so it can make and release T3 and T4 so that the rest of the body can get the message to grow and have high metabolism.
    • The cervical ganglion supply can have a direct effect on the cells of the thyroid (more later, perhaps?).

Thyroxine (T4) and Triiodothyronine (T3) are synthesized and secreted by the thyroid follicle

  • Follicles aggregate to make up the lobes of the thyroid.
  • And follicles are lined with a single layer of epithelial cells.
  • The apical surface of the follicular cells face the lumen and have microvilli to increase surface area for high movement rates.
  • The basolateral surfaces of follicular cells have tight jxns to keep everything in / out of the lumen.
  • The basal surface of the follicular cells interface with many, many capillaries for easy access to nutrients and to T3/4 release.
  • The lumen contains colloid which is gel-like (highly viscous) because of the large concentration of thyroglobulin.
    • Thyroglobulin is the protein that chelates T3/4.
  • T3 and T4 are derivatives of tyrosine.
    • They are ethers generated by iodinated two tyrosines and then linking them by their phenyl rings.
    • Recall that an ether is an R-O-R'.
    • Both T3 and T4 are considered iodothyronines.
    • The iodines are found on the 3, 5, 3', and 5' carbons (not on 5' carbon for T3).
  • A full iodine supplies is required for proper T3 / T4 production.

=Parafollicular cells are the sites of calcitonin synthesis

  • Parafollicular cells are part of the follicles.
    • They are found within the basal lamina of the the follicles.
    • Their membranes do not make up the wall of the lumen.
  • Parafollicular cells secrete calcitonin.
    • Calcitonin acts at the gut, kidney, and bone to decrease Ca++ blood levels.
    • See chapter 36.

Synthesis, secretion and metabolism of the thyroid hormones

  • T3 and T4 are actually modifications of the tyrosine amino acids that make up the thyroglobulin structure.
  • So thyroglobulin is translated, then the follicular cells modify the tyrosine residues through iodination and put the modified thyroglobulin into the lumen.
  • T3 and T4 are generated by pinocytosing some of the colloid thyroglobulin and using lysosomal enzymes to cut up the thyroglobulin, thus releasing the modified tyrosine residues as T3 and T4.

Follicular cells synthesize iodinated thyroglobulin

Synthesis and secretion of the thyroglobulin precursor
  • The first step in making T3 and T4 is to make thyroglobulin.
  • Thyroglobulin must end up in the colloid, so we know it is secreted.
    • Therefore, it makes sense that it is made on the rER and glycosylated in the golgi.
  • Thyroglobulin is a homodimer of two 330 kda proteins.
  • Iodination takes place on the apical surface of the follicular cells.
Iodine uptake
  • Iodine is taken up from the capillary blood supply on the basal surface.
  • Iodine uptake is an ATP-driven process.
  • Iodine uptake is saturate-able.
  • The same transporter that moves iodine across the basal membrane can also move other anions like bromide, thocyanate, and perchlorate.
  • The follicular cells can concentrate iodine to many times the concentrations found in the blood.
Formation of the iodothyronine residues
  • There are 134 tyrosine residues in thyroglobulin, but only a fraction of these get iodinated.
    • In a typical thyroglobulin, about 20-30 iodine atoms will have been added to the 134 tyrosines.
  • The enzyme thyroid peroxidase is bound to the apical membrane and performs the iodination of the tyrosines.
    • Thyroid peroxidase acts by binding an iodine atom and a tyrosine residue on the thyroglobulin and bringing them in close proximity.
    • Thyroid peroxidase uses peroxides generated by mitochondria of the follicular cells to oxidize the (oxidation is loss; remove an electron) iodine and also to oxidize the tyrosine residue.
    • Upon oxidation the iodine and tyrosine become free-radicals and then undergo "addition" to bind stably forming a monoiodotyrosine (MIT).
    • A second iodine atom can be added to an "MIT" to form a diiodotyrosine (DIT).
    • Note that the modified tyrosines remain in peptide linkage as part of the thryoglobulin protein during this modification.
  • Thyroid peroxidase can then cause two adjacent DITs of the same thyroglobulin protein to bind stably through the same oxidation-free-radical reaction.
    • This forms a two-ringed iodothyronine residue (which will become T4 or T3) and a dehydroalanine residue (which is a tyrsine residue that lack's its phenyl ring).
  • The thyroid secretes substantially more T4 than T3; there is 1 T3 for every thyroglobulin but 9-12 T4 for every three thyroglobulin.

Thyroid hormones are formed from the hydrolysis of thyroglobulin

  • To generate T3 and T4 from thyroglobulin, pseudopods reach into the colloid, engulf a chunck (pinocytosis) and bring it into the cell forming colloid droplets (endocytotic vesicles).
  • The vesicles migrate to the basal membrane where most of the lysosomes persist.
  • Fusing of the lysosomes with colloid droplets allows enzymes to hydrolyze the thyroglobulin, releasing constituent amino acids, including T3 and T4.
  • The amino acids and T3 / T4 are released into the cytoplasm of the follicular cell.
Secretion of free T4 and T3
  • The mechanism by which T4 and T3 are moved over the folluclar cell basal membrane into the capillaries has not been defined.
  • We do know that DIT and MIT that did not get secondarily acted on by thyroid peroxidase to form T4 or T3 and has now been released into the follicular cytoplasm is deiodinated and reused, along with the iodine.
Binding of T4 and T3 to plasma proteins
  • There are three proteins that bind over 99% of the T4 and T3 released into the blood:
    • Thyroxine binding globulin (TBG) binds 70-80% of the T4 and T3
      • 54 kDa, one binding site per protein
    • Transthyretin
    • Albumin
    • All these proteins are made by the liver.
  • The remaining 1% of the the released T4 / T3 is the form that interacts with target proteins.
  • The protein-bound thyroxine population provides a buffer against drastic changes in thyroxine release or thyroxine metabolism.
  • The half-life of T4 is about 7 days and the half-life of T3 is about 1 day. 
Why such a difference in half-life if the main protein (thyroxine binding protein) can bind either of them?

Thyroid hormones are metabolized by peripheral tissues

  • Thyroxines can be activated or deactivated by deiodination reactions in the peripheral tissues.
    • T4 deiodinated to T3 is activation; T3 deiodinated to T2 is deactivation.
  • The enzymes that catalyze such deiodination are differentially regulated between tissues such that the thyroid hormone concentrations will vary by tissue and by physiological state.
Conversion of T4 to T3
  • There are two types of 5'-deiodinase which serve to remove one iodine from T4, generating T3.
    • Both types of deiodinases contain selenocysteine which make them ideal for oxidoreductive reactions.
    • Note that this is 5' deiodination; simply 5 deiodination generates reverse T3 (rT3) which is biologically inactive.
  • Type 1 5'-deiodinase is located in the liver, kidneys, and thyroid and acts to affect the circulating levels of T3.
    • About 40% of the T4 secreted by the thyroid gland is converted to T3 by type 1 5'-deiodinase.
  • Type 2 5'-deiodinase is located in the muscle, CNS, pituitary, and the placenta.
    • It is thought that type 2 deiodinase may play a small role in regulating circulating levels but is primarily used for maintaining intracellular T3 levels in these tissues (muscle, CNS, pituitary, and placenta).
Deiodinations that inactivate T4 and T3
  • While T4 -> 5'-deiodinated T3 is an activating process, T4 -> 5-deiodinated generates reverse T3 (rT3) and is an inactivationg process because rT3 has little to no affect on thyroxine receptors.
    • 40% of the T4 released by the thyroid is deiodinated into rT3.
  • T3 and rT3 can slobe deiodinated to yield 3,3'-diiodothyronine (T2).
    • This metabolite may be further deiodinated before being excreted.
Regulation of 5'-deiodination
  • Physiological states like pregnancy, trauma, and fasting can affect the rate of 5'deiodination (that is, conversion of T4 to active T3).
  • Note that this regulation affects the formation of both T3 and rT3; changes in regulation are seen in comparing the relative amounts.
  • 5' deiodination is reduced in the fetus and in fasting states; that is, the enzyme that perfoms 5'deiodination is less active (perhaps less transcription or some phosphorylation change).
    • This leads to less T3.
    • This also leads to higher levels of rT3 because rT3's metabolic pathway is T4 -> 5-deiodination -> rT3 -> 5'-deiodination -> 3,3' diiodination -> deiodination -> excretion.
      • So when 5' deiodination is inhibited there is a backup of rT3.
  • Moral of the story is that when the body or tissue is trying to decrease activation of T4 to T3, it decreases activity of 5'-deiodination enzymes causing a decrease in T3 and an increase in rT3.
  • Note that in these states (fetus, trauma, fasting) the T4 levels are not elevated which indicates that low levels of circulating T3 does not cause the hypo-pit-thyroid axis to be activated.
Minor degradative pathways
  • page 600.


The mechanism of thyroid hormone action

Role of the thyroid hormones in development, growth, and metabolism

Thyroid hormone deficiency and excess in adults

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