Chapter 33: The thyroid gland

From Iusmphysiology

Contents

[edit] The thyroid gland

[edit] 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.

[edit] 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.

[edit] 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?).

[edit] 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.

[edit] =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.

[edit] 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.

[edit] Follicular cells synthesize iodinated thyroglobulin

[edit] 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.
[edit] 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.
[edit] 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.

[edit] 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.
[edit] 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.
[edit] 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?

[edit] 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.
[edit] 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).
[edit] 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.
[edit] 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.
[edit] Minor degradative pathways
  • T4 and some T3 are also degraded and excreted via conjugation with glucaronic acid in the liver and bile / feces.
  • Many tissues deaminate and decarboxylate T4 to form tetraiodoacetic acid (tetrac) and other waste products for excretion.

[edit] TSH regulates thyroid hormone synthesis

  • The anterior pituitary detects T4 and T3 levels in the blood and releases TSH when they follow below a threshold.
  • TSH acts on receptors found on follicular cells of the thyroid.
[edit] TSH receptors and second messengers
  • TSH acts on transmembrane, glycoprotein receptors on the basal side of follicular cells (nearest the blood supply).
  • The TSH receptor is coupled with a Gs protein that (mostly) activates the adenylyl-cyclase-cAMP-PKA pathway.
    • It can also activate the PLC-IP3-DAG-Ca++ pathway, but it is unclear what phsyiological importance this has as TSH levels must be very high for this pathway to be activated.
[edit] TSH and thyroid hormone formation and secretion
  • TSH has several affects on the follicular cell, all of which are thought to be caused by increased cAMP levels:
    • First decreased, then increased levels of iodine uptake from blood
    • Increased iodination of tyrosine residues on thyroglobulin
    • Increased coupling of iodinated tyrosine residues on thyroglobulin
    • Increased pinocytosis of colloid by pseudopods from follicular cells
  • Overall this causes an increase in T4 and T3 release.
  • TSH also significantly increases the energy metabolism of the thyroid follicular cell, which makes sense as it has to get all these ATP-dependent processes done.
[edit] TSH and thyroid size
  • Too much or too little TSH can lead to hypertrophy or atrophy of the thyroid.
  • Too much TSH:
    • Leads to a goiter
    • Causes increase in the number and in the height of the follicular cells.
  • Too little TSH
    • Leads to a small, atrophied thyroid
    • Causes follicular cells to decrease in height

[edit] Dietary iodide is essential for the synthesis of thyroid hormones

  • Note to self: iodide is just the I (-1) form of I (iodine, an element).
  • When iodide levels are limited by insufficient intake in the diet, T4 and T3 levels will be low, so TSH will be high, so follicular cells hypertrophy.
  • Hypertrophy of the follicular cells helps them take in more and more iodide from the blood.
  • This generates a goiter.

[edit] The mechanism of thyroid hormone action

  • Most cells of the body are sensitivie to T4 / T3 signaling, especially the CNS and especially the CNS in early life.
  • Thyroid hormones are particularly important for CNS development.
    • However, in adults, brain cells show little response to the signaling of T4 / T3; this discrepancy is unexplained.
  • Thyroid hormone receptors (TR) are found in the nucleus; they interact with thyroid response elements.
    • Some bind the TRE when T4 / T3 are not present and are thus considered repressors.
    • Some TRs bind TREs only in the presence of T4 / T3 and are usually activators.
  • TRs show homology to steroid and vitamin D receptors (which are generally in the cytoplasm until they bind their signal and then dimerize and head to the nucleus to become transcription factors).
  • T3 and T4 are taken into target cells by active, ATP-dependent transport from the blood.
  • Once in the cytoplasm, T4 is often activated to T3.
  • T3 enters the nucleus where it binds to the TR.
  • Once T3 and TR complex, they can homo or heterodimerize with other proteins.
  • Dimerization can cause increased or decreased mRNA expression, depending on how the complex interacts with the DNA.
  • Changes in T3 and T4 will take several hours to take effect because of the time it takes to generate new transcripts and proteins (or let old transcripts and proteins be degraded).
    • T4 changes take longer because it must be deiodinated in the cytoplasm.
  • Thyroxines also have non-transcription regulated affects, too:
    • We don't know the physiological importance of these changes.
    • Include changes in signaling, morphology, vascular tone, cellular respiration, and ion homeostasis.

[edit] Role of the thyroid hormones in development, growth, and metabolism

  • Thyroxines are critical for CNS development.
  • Thyroxines are essential for normal body growth during childhood.
  • Thyroxines are important for basal energy metabolism.

[edit] Thyroid hormones are essential for development of the CNS

  • The human brain's greatest growth is in the last 6 months of fetal growth and the first 6 months of post-natal growth.
  • Neuroblasts are multiplying at the fastest rate during the second trimester of pregnancy.
  • After the second trimester, neuroblasts differentiate into neurons and form synapses.
  • Thyroxines are critical for tell the brain when to stop multiplying neuroblasts and to start differentiating and maturing.
    • Thyroid hormone receptors (TRs) begin to be expressed in the second trimester, just as T3 and T4 levels begin to rise signficantly.
    • T3 / T4 levels rise throughout the rest of fetal life.
  • Mental retardation and growth deficits occur when T3 and T4 are not present during these important differentiation and maturation events.
    • Adding thyroxine therapy after deficits are observed will not remedy the situation.
    • Mental retardation is thought to be a function of poor circuitry formation.
    • We screen newborns for low T3 / T4 levels and provide replacement therapy when it is determined that levels are not sufficient.
  • While the details are unclear, we believe that thyroxines promote differentiation and maturation (and mental cognition) by:
    • Inhibiting proliferation
    • Stimulating nerve cell growth (inlcuding cell bodies, branches of dendrites, etc.)
    • Stimulating myelination
  • We believe these effects are exacted through gene regulation via TRs, but the exact details have not be demonstrated.

[edit] Thyroid hormones are essential for normal body growth

  • Without normal levels of thyroid hormones, patients do not grow to normal adult heights.
[edit] Thyroid hormones and the gene for GH (growth hormone)
  • Thyroxines act on the somatotrophes of the anterior pituitary to increase expression of the gene for Growth Hormone (GH).
  • Therefore, a patient who is thyroid hormone deficient will also be growth hormone deficient.
  • If these deficiencies occur in a child, the result is growth retardation, largely because of the lack of GH.
[edit] Other effects of thyroid hormones on growth
  • The thyroid hormones also affect:
    • calcification of growth plates (mechanism not well understood)
    • synthesis of structural and enzymatic proteins (like mt proteins, etc.)
      • especially in skeletal muscle, heart, and liver.

[edit] Thyroid hormones regulate the basal energy economy of the body

  • At rest:
    • 50% of the ATP is being used to maintain gradients over the cell membranes
    • The rest of the ATP is used for:
      • involuntary muscle contractions: peristalsis, heart, respiration
      • metabolic reactions including production of proteins.
  • Eventually, all the ATP burning generates some heat.
[edit] Basal oxygen consumption and body heat production
  • Recall that the rate of oxidative phosphorylation and ETC-based ATP production is based on the availability of ADP.
    • That is, as ATP burning rate goes up, ADP levels rise and the rate of oxidative phosphorylation will also rise.
    • This will cause oxygen consumption to go up.
    • This will cause heat generation to go up.
    • This is a nice feedback mechanism to make sure there is energy at the ready.
    • This is all occurring in the mt.
  • Then, we see that non-rest activities like voluntary movement, cause additional ATP to be burned, increasing the ATP burning rate.
    • This will also increase the amount of oxygen needed and the amount of heat generated.
[edit] Thermogenic action of the thyroid hormones
  • The thyroid hormones set the basal rate at which the ETC runs and thus the rate at which oxygen is consumed and heat is generated.
  • This is called the termogenic action of thyroid hormones: controlling how much oxygen is consumed and how much heat is generated.
  • Because thyroid hormones control the rate of oxygen consumption, we can use clinical measurements of oxygen consumption to determine if the thyroid hormone axis is functioning correctly.
    • We measure the basal metabolic rate via an oxygen consumption test.
[edit] Tissues affected by the thermogenic action of thyroid hormones
  • Not all tissues of the body respond to the thermogenic action of thyroid hormones.
  • In general, those with many receptors (skeletal muscle, heart, liver, and kidneys) do respond in a thermogenic way and those with few receptors (brain, skin, lymphoids, and gonads) do not respond in a thermogenic way.
  • The exception is the brain which has many receptors for thyroxines but does not respond in a thermogenic way.
[edit] Molecular and cellular mechanisms
  • The thermogenic response is, of course, not completely understood.
    • See UCPs, below.
  • However, we know that T3 increases expression of cytochromes, cytochrome oxidases, and Na/K ATPases.
    • This suggests that the cell may be increasing it's oxidative phosphorylation throughput.
  • Uncoupling protein 1, (UCP1) is a protein that allows electrons sequestered to the inner mt matrix to flow down their concentration gradient to the intermembrane space and thus generate lots of heat.
    • It is expressed only in the mt of brown fat.
    • Brown fat is found mostly in babies with very little expression in adults.
  • We have recently found UCP2 and UCP3 and determined that they are expressed in some adult tissues, however.
    • Their expression is regulated by thyroid hormones.
    • They may at least partially explain how the thermogenic response is generated.

[edit] Thyroid hormones stimulate intermediary metabolism

  • Thyroid hormones can amplify the activity of many metabolic pathways.
    • They do this by have TREs on important enzymes in the pathways.
  • This means that when thyroid hormones are low, the metabolic pathways move slowly because they have low amounts of enzymes.
  • When thyroids are increased, the throughput of these metabolic pathways are increased.
  • Examples of metabolic pathways include metabolism of carbs, lipids, and proteins.

[edit] Thyroid hormones regulate their own secretion

  • T3 affects its own regulation by affecting the thyrotrophs in the anterior pituitary.
    • (Recall that the hypothalamus releases thyrotropin-releasing hormone (TRH) to act on the thyrotrophs of the anterior pituitary.)
    • High T3 levels (probably have a gene expression affect and thus) cause thyrotrophs to decrease their sensitivity to TRH.
    • Lower sensitivity to TRH leads to lower TSH release by the thyrotrophs of the anterior pituiatary.
    • Lower release of TSH causes less release of T3 / T4 by the thyroid bringing T3 levels back to the norm.
    • Low T3 levels mean the thyrotrophs of the anterior pituitary are highly sensitive to TRH, they release lots of TSH, and the thyroid releases lots of T3 / T4 to bring levels back to the norm. 
Do TRH levels change?  If so, why?

[edit] Thyroid hormone deficiency and excess in adults

  • Deficiency or excess of thyroxines in adults lead to changes in the CNS and the overall metabolism.

[edit] Thyroid hormone deficiency causes nervous and metabolic disorders

  • There are many causes of thyroid hormone deficiency (hypothyroidism):
    • dietary iodide deficiency
    • Hashimoto's disease: "Physiologically, antibodies against thyroid peroxidase and/or thyroglobulin cause gradual destruction of follicles in the thyroid gland" per wikipedia
      • The thyroid is infiltrated with lymphocytes.
      • There is an humoral and cellular response.
    • Genetic diseases affecting enzymes in the biosynthetic pathway of thyroxines
    • Genetic diseases affecting enzymes in the biosynthetic pathway of TRH
    • Genetic diseases affecting enzymes in the biosynthetic pathway of TSH
    • Radioiodine ablation or surgical removal of the thyroid
  • The symptoms of hypothyroidism:
    • In early life, mental retardation
    • In later life, all cognitive functions slow including speech, memory, and body movements.
    • Metabolism is also reduced:
      • Reduced body heat production
      • vasoconstriction in the skin (to conserve body heat)
      • reduced heart rate and cardiac output
      • reduced food intake
      • slowed degradative and intermediary metabolism
      • myxedema occurs (hyaluronic acid complexed with protein deposited in the skin causing water retention and puffiness in face and hands).
  • In adults, hypothyroidism can be completely reversed with thyroid hormone replacement therapy.

[edit] An excess of thyroid hormone produces nervous and other disorders

  • There are several causes of hyperthyroidism (thyrotoxicosis):
    • The major cause is Graves disease
      • Here the patient has antibodies against the TSH receptor on the follicular cells of the thyroid.
      • The ab stimulates the receptor causing hypertrophy into a diffuse toxic goiter and also causing high levels of T3 / T4.
      • There is also very little feedback of the high T3 / T4 levels on the thyrotrophs of the anterior pit (which should be desensitized to TRH and thus release let TSH).
    • Other causes of hypothyroidism:
      • Adenomas of the thyroid
      • Malfunctions of the hypothal-ant-pit axis that generate high levels of TRH and / or TSH.
  • Symptoms of hyperthyroidism:
    • increased nervousness and emotional irritability,
    • compulsion to be constantly moving around.
    • physical weakness and fatigue,
    • body heat production is increased
    • vasodilation in the skin and sweating (to dissipate excessive heat)
    • elevated heart rate and cardiac output
    • elevated energy metabolism and appetite
  • Again, all these changes can be reversed with removal of the thyroid gland or source of excessive thyroxines.

[edit] Autoimmune thyroid disease: postpartum thyroiditis

  • After pregnancy, the immune system is ramped back up and can have an affect on thryoxine hormones.
    • This is especially true in women who were known to have Graves disease or Hashimoto's disease pre-conception.
  • These affects generate a cycle of hypo and hyperthyroidism (thyrotoxicosis) beginning 3 to 12 months after birth.
  • 5-10% of all women show signs and symptoms of dysregulation of thyroid hormones post-partum.
  • It is recommended that women have thyroid function tests at 2, 4, 6, and 12 months post-partum.
  • Tx includes thyroid hormone replacement or thionamides (a class of drug that inhibits oxidation and binding of iodine and thus reduce the level of thyroxine production; they can also inhibit T4 to T3 transformation).
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