The thyroid

The thyroid

1. Thyroid hormone functions

   • Growth and cellular development
     • Rate of postanatal growth
     • Functional and biochemical maturation of foetal brain and bone
     • Gene switching during development
     • Regulation of mitochondrial metabolic enzymes and membrane synthesis
   • Metabolism
     • Regulation of basal metabolic rate (can control temperature)
     • Movement of H2O and Na(+) across cell membrane
     • Calcium and phosphorus metabolism
     • Regulation of cholesterol and lipid metabolism
     • Nitrogen (urea) metabolism
     • Control of glucose metabolism

2. Development and strcuture

   • During development the thyroid arises from a downward growth from the floor of the pharynx where it develops infront kf the trachea
   • Bilobular strucutre in the neck also feature parathyroid glands
   • Hstology
     • Thyroid follicular cells line colloid filled follicles
     • Between each follicle are cells which produce calcitonin (C cells or parafollicular cells)

3. Hormones

   • Modified dipeptitde (two tyrosines) - requires iodine
     • Source of iodine
       • Milk
       • Iodised salt
       • Fish
       • Nuclear fallout
         • Radioactive iodine concentrates in the thyroid and kills cells
     • Iodine metabolism: there are two main pools of iodine in the body (the thyroid pool and the hormone [T3 and T4] pool)
       • Most of the iodine intake Is excreted in the urine
   • Synthesis and storage
     • Thyroid hormone (T3 abd T4) is made up from two amino acids (Tyr) linked together - they are both iodinated
       • T3 has three iodines attached
       • T4 has four iodines
       • Each hormone is made and stored in a large (660,000 MW) protein molecule called thyroglobulin
         • Has many tyrosine residues
         • Stored in colloid
       • TSH stimulates thyroid hormone synthesis - which occurs on the thyroglobulins in the colloid
   • Thyroid hormone structure
     • T3H (active)
       • • • • • O
                 • • • • • CH2
                           • CH
                             • HOOC
                             • NH2
                     • I
                   • • I
           • I
         • OH
       • T4 (inactive)
         • OH
           • • I
           • • • • O
                   • • • • • • • I
                           • CH2
                             • CH
                               • HOOC
                               • NH3
                       • I
             • I
         • Thyroxine
       • If the iodinated pattern of T3 reversed (i.e. one iodine on the bottom ring and two on the top) = "reverse T3" (inactive)
       • Triiodothyronine
     • Produced on the thyroglobulin within the thyroid follicles
       • Follicular cells line the follicles and receive TSH on there basal membrane - there apical membrane faces into the follicle
         • The enzyme which catalyses the production of T3/4 is on the apical membrane and is expressed in response to TSH
   • Synthesis
     • Iodine in the blood is taken up through the basal membrane of the follicular cell
       • Via a sodium/iodine symporter protein
         • Sodium is constantly being exchanged out of the cell by a 3Na/2K ATPase protein (also basal)
           • Na(+)
             • Na cycle
         • Iodine then passes through the cell to apical membrane where it passes into the follicle via a second iodine transporter called PENDRIN
         • +
           • TSH -> receptor (G protein coupled) -> increased cAMP
     • Thyroglobulin is made in the follicular cell and packaged by the golgi
       • Thyroglobulin vesicles release thyroglobulin into the follicle lumen
         • 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
       • +
         • TSH -> receptor (G protein coupled) -> increased cAMP
     • Cell morphology
       • Thyroglobulin synthesis (in preparation for TH production)
         • Columnar cells with active organelles and many apical vesicles
       • Resting (storage)
         • Small cuboidal cells - less active ER/golgi and no vesicles
       • TSH stimulated (active)
         • Columnar cells with cytoplasmic folds collecting colloid from the follicle lumen - many vesicles throughout the cell
   • Hormone dynamics
     • Most abundant TH secreted is T4 (with comparatively little T3 and rT3)
       • T4 has t1/2 of about 7days (T3 = <1day)
         • 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
   • Regulation
     • Stimuli: cold stress, exercise and pregnancy
       • Deteced by hypothalamus
         • 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
                   • -
                   • -
   • Mechanism of TH action
     • T3 uptake into TH-sensitive cell
       • Via membrane carrier proteins (Na/taurochloratecotransporter, organic anion transporter and L-amino acid transporters)
       • Binds to TH nuclear receptor
         • Multiple TH receptors (alpha and beta)
           • Alpha-knockout = bradychadia and hypothermia (main peripheral receptor)
           • Beta-knockout = deafness (important for development)
         • 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

4. Thyroid disorders

   • TH deficiency (Hypothyroidism)
     • Causes cretinism in children
       • Short stature and slow development
     • In adults
       • Gradual onset: fatigue, lethargy, reduced mental function, cold intolerance, accumulation of mucopolysaccharides (e.g. in the face = myxoedema)
       • Fat deposition (e.g. Central, slubclavicular and 'buffalo hump')
     • Causes
       • Most common = iodine deficiency
         • Particularly in less developed countries
         • Can't synthesise THs
           • Enlargement of the thyroid to compensate (goitre)
       • Autoimmune (Hashimoto's) thyroiditis
         • Ab's against follicular cells
           • Inflammation and destruction of the thyroid (+/- goitre or nodules)
       • Secondary hypothyroidism - TSH deficiency
         • From disruption to the pituitary (tumour, trauma, radiation)
     • Low T4, normal TSH
   • TH excess (hyperthyroidism)
     • Signs and symptoms
       • Nervousness, irritability, sweating, heat intolerance, weight loss, tachycardia, tremor, exophthalmos (bulging eyes)
     • Causes
       • Grave's disease
         • IgG interacts with TSH receptor -> chronic stimulation
           • Classically presents as; high T4, low TSH and exophthalmos with goiter!
         • Treatment; with carbamizole (inhibitor of TPO)
           • Or radioactive iodine and surgery (thyroidectomy)

5. Non-TH producing cells

   • Parafollicular (C-) cells
     • Found inbetween follicles
       • Produce calcitonin
         • Lowers blood calcium (very little effect in humans)
           • Inhibits; osteoclasts, Ca(2+) absorption in the intestines and renal Ca(2+) reabsorption
   • Parathyroid gland
     • Adipocytes
     • Chief cells
       • Produce parathyroid hormone
         • Raises blood calcium
           • Promotes; bone turnover (osteoclasts), intestinal Ca(2+) absorption and renal Ca(2+) reabsorption [opposite to calcitonin]
     • Oxyphil cells
       • No endocrine activity