Endo 1.08 The thyroid gland Gross anatomy and histology of the thyroid gland Thyroid hormone synthesis Thyroid hormone secretion, peripheral conversion and metabolism Measurement of free T 4 and TSH Actions of thyroid hormones, hyper- and hypothyroidism

Blood supply Superior and inferior thyroid arteries from external carotids and subclavian arteries respectively Superior, middle and inferior thyroid veins More blood per unit weight than kidney - goitre bruit 20 grams 4 cm

Histology of the thyroid gland

Thyroid hormones derived from two iodinated tyrosine molecules

Synthesis of thyroid hormones Active uptake of iodide into follicular cell Iodide iodine - H 2 O 2 (catalysed by TPO) Active uptake of iodine at follicular/ colloid interface Incorporation of iodine onto tyrosine residues of thyroglobulin Coupling of iodinated tyrosines Storeage of T 3 and T 4

Active transport of iodine (ATP ase dependent) against electrical and chemical gradient - concentration of iodine times that of the circulation

Active uptake of iodine by a sodium iodide symporter Oxidation of iodide to iodine Iodination of tyrosine residues at apical/colloid interface to form MIT and DIT Uptake of thyroglobulin into the lumen of the follicle

Incorporation of iodine onto tyrosine residues on the thyroglobulin molecule

4) Release of T 4 and T 3 into circulation  g T 4 & 10  g T 3 /day 3) ~ 10% T 4 undergoes mono- deiodination to T 3 before secretion 2) Fusion of colloid droplets with lysosomes --> hydrolysis and release of thyroid hormones 1) Stimulated by TSH colloid droplets with the bound thyroid hormones are taken back into follicular cells by pinocytosis

Daily production of thyroid hormone secretion and serum concentrations

5’5 3’ 3 5’ 5 Thyroid hormone metabolism

Metabolism of thyroid hormones Series of deiodinations by deiodinases Type 1 - liver, kidney, thyroid, pituitary gland, CNS: 5’ and 5 positions Type 2 - brain, brown fat, placenta, pituitary gland: 5’ position only: T 4 T 3 only: intracellular concentrations of T 3 Type 3 - brain, placenta: 5 position only T 4 T 3 Other metabolic pathways: sulphation, decarboxylation, conjugated with glucuronide

Thyroxine (T 4 ) T 3 rT 3 T 3 S TRIAC T2T2 T2T2 other pathways T1 T1 T1T1 thyronine 1 & 21 & 3 3,5,3’3,5’,3’ Type 1 - 5’ and 5 Type 2 - 5’ only Type only

Control of thyroid hormone synthesis and release and feedback control

TSH Receptors TSH G protein linked receptor cAMP IP 3 + DAG Protein Ca 2+ Protein Kinase A CM Kinase C (high concentrations)

Actions of TSH Active uptake of iodine* Stimulates other reactions involved in thyroid hormone synthesis Stimulates the uptake of colloid Induces growth of the thyroid gland

Thyroid hormone receptors

Type 2 receptors in nucleus - high affinity for T 3 Dimerize with another T 3 receptor (homodimer) or retinoic acid receptor (heterodimer) Dimerized receptor + other transcription factors gene transcription Membrane receptors? Ion movements

Isoforms of the thyroid hormone receptor DBD

T3T3 Dimerization of thyroid hormone receptors and gene activation/inactivation

Functions of thyroid hormones  Stimulate metabolic rate: increasing number and size of mitochondria, increasing enzymes in the metabolic chain, increasing Na + /K + ATPase activity. Resting metabolic rate may increase 100% with excess thyroid hormones or decrease by 50% with a deficiency  Positive inotropic and chronotropic effects on the heart  Important in growth and development - particularly skeleton and nervous system

Feedback control of thyroid hormone synthesis and secretion

Radioisotopic (technetium) scanning of the thyroid gland - regional function of the gland No left lobe hyperthyroidism hypothyroidism Hot nodule Cold nodule

Measuring ‘free’ T 4 1) Add serum sample or standard (T 4 ) to latex beads coated with Abs 2) Add T 4 labelled with alkaline phosphatase. This will bind to any unoccupied Ab binding sites 3) Add a substrate that will fluoresce when the alkaline phosphatase removes a phosphate group 4) Fluorescent intensity will be inversely proportional to the concentration of T 4 Phosphate

Assay of antibodies to the human TSH receptors Patients serum Add Precipitate Count + TSH 125 I-TSH receptors (bovine) (porcine)

Circulating concentrations of TSH and pituitary function test in normal and primary hyperthyroidism

Saggital MR scans of a) normal and b) a patient with a craniopharyngioma causing bitemporal hemianopia and hypopituitarism

Primary hyperthyroidism Hypothyroidism

Grave’s disease (1 0 ) Autoimmune - activating AB’s to TSH receptor High concentrations of circulating thyroid hormones, low TSH Weight loss, tachycardia, tiredness Diffuse goitre - TSH stimulating growth Opthalmompathy and dermopathy

Symptoms and signs of hyperthyroidism

Hashimoto’s (1 o ) Autoimmune - AB’s destruction of thyroid gland Low concentrations of thyroid hormones, high TSH Lethargy, intolerance to cold Lack of growth and development Diffuse goitre - lymphocytic infiltration of gland + TSH stimulated growth

Symptoms and signs of hypothyroidism