The thyroid

The thyroid

Thyroid hormone functions
1. Growth and cellular development
  1. Rate of postanatal growth
  2. Functional and biochemical maturation of foetal brain and bone
  3. Gene switching during development
  4. Regulation of mitochondrial metabolic enzymes and membrane synthesis
2. Metabolism
  1. Regulation of basal metabolic rate (can control temperature)
  2. Movement of H2O and Na(+) across cell membrane
  3. Calcium and phosphorus metabolism
  4. Regulation of cholesterol and lipid metabolism
  5. Nitrogen (urea) metabolism
  6. Control of glucose metabolism
Development and strcuture
1. During development the thyroid arises from a downward growth from the floor of the pharynx where it develops infront kf the trachea
2. Bilobular strucutre in the neck also feature parathyroid glands
3. Hstology
  1. Thyroid follicular cells line colloid filled follicles
  2. Between each follicle are cells which produce calcitonin (C cells or parafollicular cells)
Hormones
1. Modified dipeptitde (two tyrosines) - requires iodine
  1. Source of iodine
    1. Milk
    2. Iodised salt
    3. Fish
    4. Nuclear fallout
      1. Radioactive iodine concentrates in the thyroid and kills cells
  2. Iodine metabolism: there are two main pools of iodine in the body (the thyroid pool and the hormone [T3 and T4] pool)
    1. Most of the iodine intake Is excreted in the urine
2. Synthesis and storage
  1. Thyroid hormone (T3 abd T4) is made up from two amino acids (Tyr) linked together - they are both iodinated
    1. T3 has three iodines attached
    2. T4 has four iodines
    3. Each hormone is made and stored in a large (660,000 MW) protein molecule called thyroglobulin
      1. Has many tyrosine residues
      2. Stored in colloid
    4. TSH stimulates thyroid hormone synthesis - which occurs on the thyroglobulins in the colloid
3. Thyroid hormone structure
  1. T3H (active)
    1. 1. O
        CH2
        CH
        HOOC
        NH2
        I
        I
        I
      3. OH
    2. T4 (inactive)
      1. OH
        I
        O
        I
        CH2
        CH
        HOOC
        NH3
        I
        I
      2. Thyroxine
    3. If the iodinated pattern of T3 reversed (i.e. one iodine on the bottom ring and two on the top) = "reverse T3" (inactive)
    4. Triiodothyronine
  2. Produced on the thyroglobulin within the thyroid follicles
    1. Follicular cells line the follicles and receive TSH on there basal membrane - there apical membrane faces into the follicle
      1. The enzyme which catalyses the production of T3/4 is on the apical membrane and is expressed in response to TSH
4. Synthesis
  1. Iodine in the blood is taken up through the basal membrane of the follicular cell
    1. Via a sodium/iodine symporter protein
      1. Sodium is constantly being exchanged out of the cell by a 3Na/2K ATPase protein (also basal)
        Na(+)
        Na cycle
      2. Iodine then passes through the cell to apical membrane where it passes into the follicle via a second iodine transporter called PENDRIN
      3. +
        TSH -> receptor (G protein coupled) -> increased cAMP
  2. Thyroglobulin is made in the follicular cell and packaged by the golgi
    1. Thyroglobulin vesicles release thyroglobulin into the follicle lumen
      1. Colloid = pool of thyroglobulin
        The apical membrane enzyme THYROID PEROXIDASE (TPO) catalyses the iodination and coupling of tyrosine residues in the thyroglobulin
        Tyrosines can be mono-iodinated (MIT) or di-iodinated (DIT)
        TPO then catalyses the coupling of two tyrosine residues; (MIT + DIT = T3 and DIT + DIT = T4)
        Much more T4 is synthesised than T3
        Thyroglobulin is then endocytosed -> inside the follicular cell
        Thyroglobulin is then proteolytically degraded in lysosome
        Releasing; T3, T4, MITs and DITs
        T3 and T4 leave the lysosome (some T4 is converted to T3 by cytosolic deiodinaseY) are secreted into the highly vascular thyroid stroma
        Thyroid hormones require transport proteins to travel in the blood
        Thyroid binding globulin (TBG) ~75%
        Transthyretin and albumin (~10 -15%)
        -
        Excess iodine inhibits TH release
        MITs and DITs are recylced
        +
        TSH -> receptor (G protein coupled) -> increased cAMP
    2. +
      1. TSH -> receptor (G protein coupled) -> increased cAMP
  3. Cell morphology
    1. Thyroglobulin synthesis (in preparation for TH production)
      1. Columnar cells with active organelles and many apical vesicles
    2. Resting (storage)
      1. Small cuboidal cells - less active ER/golgi and no vesicles
    3. TSH stimulated (active)
      1. Columnar cells with cytoplasmic folds collecting colloid from the follicle lumen - many vesicles throughout the cell
5. Hormone dynamics
  1. Most abundant TH secreted is T4 (with comparatively little T3 and rT3)
    1. T4 has t1/2 of about 7days (T3 = <1day)
      1. Circulating T4 can be converted into active T3 (or rT3) by peripheral tissues (i.e. when tissues need T3)
        5'-deiodinase catalyses this conversion
        There are three types of human deiodinases
        Type 1
        Converts T4 to T3 in periphery
        Location: Thyroid hormone sensitive peripheral tissues
        Role: produce active T3 in peripheral tissues
        Type 2
        Converts T4 to T3 in brain
        Location: in the brain (mostly the pituitary)
        Role: negative feedback in the pituitary (inhibit TSH release)
        Type 3
        Converts T3 to T4 in placenta
        Location: placenta
        Role: inactivation of T3 to protect foetus from mother's T3
6. Regulation
  1. Stimuli: cold stress, exercise and pregnancy
    1. Deteced by hypothalamus
      1. Release of TRH into the portal system -> ant. pituitary
        TRH binds to its receptor (G protein coupled) on thyrotrope -> increase in Ca(2+) from IP3
        TSH release into the blood
        TSH acts on thyroid follicular cells -> T3/4 synthesis and secretion
        T3 and T4
        -
        -
7. Mechanism of TH action
  1. T3 uptake into TH-sensitive cell
    1. Via membrane carrier proteins (Na/taurochloratecotransporter, organic anion transporter and L-amino acid transporters)
    2. Binds to TH nuclear receptor
      1. Multiple TH receptors (alpha and beta)
        Alpha-knockout = bradychadia and hypothermia (main peripheral receptor)
        Beta-knockout = deafness (important for development)
      2. Bind to TH response element (TRE)
        As a heterodimer with retinoid-X receptor (RXR)
        Without ligand binding the dimer recruits a transcriptional corepressor
        HDAC complex
        Recruits transcriptional coactivator upon ligand (T3) binding
Thyroid disorders
1. TH deficiency (Hypothyroidism)
  1. Causes cretinism in children
    1. Short stature and slow development
  2. In adults
    1. Gradual onset: fatigue, lethargy, reduced mental function, cold intolerance, accumulation of mucopolysaccharides (e.g. in the face = myxoedema)
    2. Fat deposition (e.g. Central, slubclavicular and 'buffalo hump')
  3. Causes
    1. Most common = iodine deficiency
      1. Particularly in less developed countries
      2. Can't synthesise THs
        Enlargement of the thyroid to compensate (goitre)
    2. Autoimmune (Hashimoto's) thyroiditis
      1. Ab's against follicular cells
        Inflammation and destruction of the thyroid (+/- goitre or nodules)
    3. Secondary hypothyroidism - TSH deficiency
      1. From disruption to the pituitary (tumour, trauma, radiation)
  4. Low T4, normal TSH
2. TH excess (hyperthyroidism)
  1. Signs and symptoms
    1. Nervousness, irritability, sweating, heat intolerance, weight loss, tachycardia, tremor, exophthalmos (bulging eyes)
  2. Causes
    1. Grave's disease
      1. IgG interacts with TSH receptor -> chronic stimulation
        Classically presents as; high T4, low TSH and exophthalmos with goiter!
      2. Treatment; with carbamizole (inhibitor of TPO)
        Or radioactive iodine and surgery (thyroidectomy)
Non-TH producing cells
1. Parafollicular (C-) cells
  1. Found inbetween follicles
    1. Produce calcitonin
      1. Lowers blood calcium (very little effect in humans)
        Inhibits; osteoclasts, Ca(2+) absorption in the intestines and renal Ca(2+) reabsorption
2. Parathyroid gland
  1. Adipocytes
  2. Chief cells
    1. Produce parathyroid hormone
      1. Raises blood calcium
        Promotes; bone turnover (osteoclasts), intestinal Ca(2+) absorption and renal Ca(2+) reabsorption [opposite to calcitonin]
  3. Oxyphil cells
    1. No endocrine activity

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