Thyroid gland

From Iusmphysiology

Contents

[edit] Feedback loops

  • We call ultrashort feedback when the released hormone feedbacks directly on the organ that released it.

[edit] TSH and the rest of the family

  • TSH is closely related to FSH, LH, and hCG.
    • hCG is placental in source.
  • There is a common alpha-GSU subunit to TSH, FSH, and LH.
  • There is a unique beta subunit to each of TSH, FSH, and LH.
    • Note that assays have to recognize the beta subunit otherwise it won't be speicifc to a given hormone.
  • There are many disulfide bridges that hold these hormones together.

[edit] Regulation of TSH by TRH

  • TRH from the hypothalamus stimulates release of TSH and PRL at the pituitary.
  • TRH is made of 3, modified, amino acids.
  • TRH activates the IP3/DAG pathway in thyrotrope cells of the anterior pituitary.
  • TRH has some signaling roles in the brain and may have a role in seizures.

[edit] Thyroid development

  • Recall from anatomy that the thyroid develops partially from neural tissue (ectoderm, C cells = parafollicular cells, calcitonin) and partially from the tongue (endoderm).
  • The parathyroids are also pulled along by the developing thyroid.
  • The thyroid a composite organ.
  • The female thyroid is larger than the male thyroid.

[edit] Thyroid hormone synthesis

  • Recall that follicular cells are epithelial cells.
  • Halogenase collects the iodide removed from TG as it is broken down in the cell.

[edit] Sodium / Iodide symporter protein (NIS)

  • Note that iodide ions are transported, not iodine molecules.
  • The Na / I- symporter is a 13 transmembrane protein.
  • Generates a 30x gradient.

[edit] Pendrin iodide transporter

  • Pendrin is on the apical surface and can move iodide into the colloid via transport coupled with chloride.
  • Pendrin is found in the thyroid, the kidney, the lungs, and the ears.
    • Easy to remember the thyroid and the ears b/c mutations of pendrin cause hypothyroidism and deafness (pendrin syndrome).
    • Easy to remember the lungs because pendrin is being investigated for allergic reaction medicine.

[edit] Thyroglobulin

  • About 1/3 of the 125 tyrosines on the protein are available for iodination.
  • Thyroglobulin is a glycoprotein that homodimerizes.

[edit] Anti-thyroid compounds

  • Anti-thyroid compounds can block the action of the thyroid in the case of an overactive thyroid.
  • There are three types of compounds, each with a different mechanism: monovalent ions, thiocarbamines, and giotrogens.
    • Monovalent ions block the accumulation of iodide in the thyroid.
      • Monovalent ions include perchlorate (ClO4-) and thiocyanate (SCN-)
    • Thiocarbamides block the reactions that organify (adding iodide to the protein tyrosines) the iodide and also block the reactions that couple the iodinated tyrosine residues of the thyroglobulin.
    • Goitrogens are "any substance (such as thiouracil) that induces the formation of a goiter" per wordnetweb
      • This may be a general term.
      • These can be found naturally in foods like cabbage, cassava, cauliflower, brussel sprouts, and turnips. However, these foods would have to make up a large portion of the pt's diet to have a clinically significant effect.

[edit] Transport and metabolism of thyroxines

  • There are three major proteins that carry T3 and T4: thyroxine-binding globulin (TBG), transthyretin (thyroxine binding prealbumin = TBPA), and albumin.
  • T3 and T4 are found bound to these proteins in different distributions:
    • T4: TBG = 67%, TBPA = 20%, Albumin = 13%
    • T3: TBG = 46%, TBPA = 01%, Albumin = 53%
  • Note that while albumin is found in the greatest concentration in the blood and TBP (thyroxine binding protein) is found at the lowest concentration, their affinities affect the percentages of the thyroxines they carry.

[edit] T4 conversion

  • T4 conversion to T3 is called outer ring deiodination (ORD).
  • T4 conversion to rT3 is called inner ring deiodination (IRD).
  • Type 1 deiodinase from the liver is the primary source of serum T3.
  • Sometimes, when recovering from an illness that is not thyroid related, patients will develop "Euthyroid sick syndrome" which manifests as low T3 levels and high rT3 levels and is reversible.
    • This is also called "low T3 syndrome".
    • As the primary problem is resolved, the thyroid will fix itself.

[edit] Actions of thyroid hormones in mammals

  • The actions of thyroxines are called "permissive" because the presence of thyroid hormones is sometimes required for other hormones to have their intended effects.
  • Actions of thyroid hormones:
    • Increase BMR
    • Induce synthesis of proteins
    • Increase lipid synthesis, mobilization, and oxidation
    • Increase heart rate
    • Increase glycogen at the liver (when given at low doses)
    • Decrease glycogen at the liver (when given at high doses) 
How does this work?
    • Decrease plasma cholesterol
    • Increase heat generation (mt, O2 consumption, ATP synthesis)
    • Promote GH synthesis at the pit
    • Promote PRL synthesis at the pit
    • Nervous system dev
    • Bone growth and dev
    • Promote carotene's conversion to vitamin A at the liver
    • Decreases TSH by negative feedback on anterior pituitary

[edit] Cellular signaling of Thyroxines

  • Thyroxines bind to nuclear receptors (TRs).
    • Each of these receptors has a transactivation domain (think dimerization), a DNA binding domain (think TRE), and a hormone binding / dimerization / transactivation domain (think "multitasking")
  • TRs can homodimerize or heterodimerize.
    • Most heterodimerize with RXR proteins (alpha, beta, and gamma versions).
  • TRs are generally found in the nucleus, even when thyroxines are not present.
  • There are three major types of thyroid receptors:
    • All bind T3
    • TRalpha1: binds T3 in many tissues
    • TRbeta1: binds T3 in many tissues
    • TRbeta2: binds T3 in the pituitary
      • So TRbeta2 is the receptor type found on thyrotropes in the anterior pit and will receive the feedback signal.

[edit] Goiter

  • Note that a goiter can show up in hypo- or hyper-thyroidism!

[edit] Hypothyroidism

  • Hypothyroidism comes in three general forms: primary, secondary, and childhood.


  • Primary hypothyroidism occurs when the thyroid itself isn't functioning because of some inherent problem:
    • Thyroid dysgenesis (the thyroid simply didn't develop)
      • Transcription factor mutations
    • Genetic dysfunction of follicular cells
      • Mutations in the NIS (Na / I- transporter)
      • Mutations in the thyroid peroxidase (TPO) genes
      • Mutations in the thyroglobulin gene
      • Mutations in the dual oxidase genes
        • These help generate H2O2 (hydrogen peroxide) which is used by thyroid peroxidase to oxidize iodide and tyrosine.
      • Mutations in the thyroid receptor gene (think TRH receptor)
    • There can also be resistance to TSH in the thyroid


  • Secondary hypothyroidism occurs when there is a problem with the signaling to or from the thyroid (think pituitary or hypothalamus and TSH, TRH).
    • Pituitary: defect of the thyrotropes or TSH
    • Hypothalamic hypothyroidism: lack of TRH signaling
      • This is also called tertiary hypothyroidism
    • There can be end-organ resistance to thyroid hormones, too.
    • TBG deficiency syndrome can occur and is familial but does not usually cause hypothyroidism.


  • Childhood hypothyroidism (also called cretinism)
    • Goitrous cretinism is a lack of iodine in the diet.
    • Lacking a thyroid at all is called athyreotic cretinism.
    • Antithyroid poisons can also cause this (or really high diets in those veggies with anti-thyroid effects)

[edit] Myxedema = adult hypothyroidims

  • Myxedema manifests with a goiter for lack of iodide.
  • Primary myxedma can be idiopathic, iatrogenic (drugs, surgery), or spontanous (like an autoimmune disease like Hashimoto).
  • Treatment of myxedema (adult hypothyroidism) usually involves surgical removal of the thyroid or radioactive ablation of the thyroid.
  • Note that patients who have had the thyroid removed or ablated often require hormone replacement therapy.

[edit] Hypothyroidism S&S

  • Weight gain
  • Goiter
  • Puffy appearance
  • Loss of hair
  • Low BMR, low body temp, decreased perspiration
  • Lethargy, depression, intolerance to cold

[edit] Hyperthyroidism

  • Hyperthyroidism generates too much T3 / T4.
  • Hyperthyroidism is pretty common (2% of adult females).
  • Hyperthyroidism comes in primary and secondary forms.
  • Primary hyperthyroidism is a problem with the thyroid or a tumor of the pituitary tissue:
    • An adenoma is a tumor of the pituitary that is noncancerous.
    • A carcinoma is a tumor of the epithelial cells of the pituitary that is cancerous.
  • Secondary hyperthyroidism is a problem with the signaling to or from the thyroid.
    • Pituitary defect (generates too much TSH)
    • Hypothalamic defect (generates too much TRH)
      • Called hypothalamic hyperthyroidism or tertiary hyperthyroidism
    • Pituitary T3 receptor (TRbeta2) malfunction (no feedback via T3 such that TSH levels are not decreased)
    • Ectopic TSH secretion (by a tumor)
    • Grave's disease
      • This is the case of a long-acting thyroid stimulator (LATS)
      • Grave's disease occurs when an antibody to the TSH receptor in the thyroid are produced cause follicular cells to be constitutively activated.
      • Note that in Grave's disease, the feedback loops are functional (that is, T3 on the hypothalamus and the pit's thyrotropes is causing them to decrease their release of TRH and TSH, respectively) but the follicular cells are still highly active because of the ab affect on their TSH receptors.

[edit] Hyperthyroid S&S

  • Weight loss
  • Goiter
  • High BMR, high body temperature, intolerant to heat, excessive sweating
  • Agitated, nervous, easy to fatigue
  • Tachycardia, atrial fibrillation
  • Loss of muscle mass
  • Eyes: upper-lid retraction, exophtalmos ("bulging of the eye anteriorly out of the orbit" per wikipedia), loss of vision
  • Pretibial myxoedema (thickening of skin in tibial region)
  • Premature greying
  • Patched depigmentation of the skin
  • Clubby fingers

[edit] TRH stimulation test

  • Give lots of TRH, measure TSH.

[edit] Disease models in rats

  • The WIC-rdw rat has a missense mutation in the Tg gene (thyroglobulin).
  • Presents as dwarf and models congenital primary hypothyroidism.
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