#13345 - Endocrine Thryoid - Organisation of the Body

THE THYROID GLAND...

Foetal growth

-Thyroid divertiulum-forms from an epithelial downgrowth in the midline of the floor of the mouth between the 1^st and 3^rd branchial arch components of the developing tongue. It grows uadally over the developing larynx to the anterior aspect of the trachea

-As it descends it associates with the superior/inferior parathyroids which develop from the 3^rd/4^th pharyngeal pouches and with neural crest cells which forms parafolliular C cells (calcitonin cells)

-Two lateral lobes and a central isthmus form-tissue along the line of descen usually disappears. Ectopic thyroid tissue can be found in the tongue along the line of descent and in the thorax.

Anatomy of the thyroid gland

-The isthmus lies anterior to the 2^nd-4^th collagenous costal rings

-lateral lobes are found on either side of the trachea and larynx

-thyroid gland is enveloped by a fibrous capsule- fine collagenous septa extend into the gland dividing it into lobules

-pretrachial fascia anchors it to the airway- moves on swallowing- this makes it easy to examine

-rich blood supply- superior thyroid artery-branch of the external carotid artery and the inferior thyroid artery branch of the thyrocervical trunk, subclavian artery. It also a rich venous drainage- superior thyroid vein-internal jugular vein, inferior thyroid veins-brachiocephalic veins Rich blood supply ensures an efficient transport of hormones stimulating it and transport of hormones secreted by the thyroid gland

-functional units of the thyroid gland are the thyroid follicles (secrete thyroid hormones)-spheroid structures made of a single layer of cuboidal epithelial cells bounded by a basement membrane

-follicle lumen contain colloid material- stained pink in preparation using H&E stain- colloid consists of iodinated thryoglobulin- large extracellular storage protects against nutrient deficiency

-C cells (parafollicular cells) release peptide hormone calcitonin- located at the base of the follicle epithelium.

Synthesis of T3 and T4

-Follicular cells make T3 and T4 in response to TSH thyroid stimulating hormone from the anterior pituitary. TSH binds to GPCR on the basolateral surface of the follicular cells. This results in an increased cyclic AMP concentration which stimulates the Na/K ATPase pump which maintains a high extracellular sodium concentration

-This allows follicular cells concentrate iodide from the blood by a sodium/iodide symporter in the basal plasma membrane- the symporter traps and pumps iodide from the plasma.

-Within the cell iodide is oxidised to iodine via a thyroperoxidase enzyme on the apical plasmalemma and transported to the follicular plasma membrane where it is released into the follicular lumen via the transporter Pendrin

-glycoprotein thryoglobulin is synthesised in the RER, glycosylated and packaged by the golgi apparatus-then released across the apical surface into the lumen by excocytosis

-thyroid follicles store thryoglobulin within the colloid (store more than 100x than daily requirement: within the follicular lumen, iodine combines with tyrosine residues of thryoglobulin to form T3, T4 : iodinated glycoprotein- storage form of T4, T3.

-When active thyroid hormone is required- TSH stimulates endocytosis of the colloid- the epithelial cells remove segment of colloid and detach T3 (tri-iodothryonine) + T4 *tetraiodothryonine. – Pinocytosis of the thyroglobulin-hormone complex to form cytoplasmic vacuoles- the vacuoles fuse with the lysosomes of the follicular cell cytoplasm and hydrolytic enzymes cleave the hormone from thryoglobulin-These pass through the cell into the capillary

Structure of Follicular cells related to function

EM

-The follicular cells have large amounts of RER which is required for synthesis of thryoglobulin

-There are also large, dark prominent lysosomes

-the nuclei consist of dilated chromatin- active synthesis is occurring.

-There are large number of synthetic vesciles which are important in trafficking hormones.

-active thyroids- epithelial cells are tall and colloid is reduced in size. In inactive glands the cells are low cuboidal and the follicles are filled with colloid

-stores large amounts of hormone in an inactive form within extracellular compartments in the centre of follicles- other endocrine glands only store small amounts of hormones

Hormones of the thyroid gland

-the main hormone secreted by the thyroid gland is T4-Thryoxine (tetra-iodothryonine) and a small amount of T3 is released Tri-iodothryonine

-Thryoid hormones have 2 tyrosine residues (hydrophobic amino acids) which are also attached to iodine.

Plasma transport: T3 and T4 circulate bound to plasma protein and so have a long half life. Binding proteins include thyronine-binding globulin (glycoprotein with higher affinity for T4 than T3 and is produced by the liver) Albumin-low affinity but high capacity

-The thyroid hormones binding to proteins is essential- ensures active concentrations of hormone in the circulation change very little- prolongs the half life

-thyroxine is not metabolically active so is converted into metabolically active tri-iodothryonine through removal of one iodothyronine unit which is catalysed by Type 1 deiodinase in the liver and kidney

Types of deiodinases

Type 1: (located in the liver, kidney) provides T3 to the plasma , can also form Rt3

Type 2: provides intracellular T3 (brain, pituitary, adipose), active T3 in the pituitary is important for negative feedback – The importance of Type 2 deiodinases is shown in knockout mice which is unable to maintain core body temperature. These mice had normal plasma T3 concentrations which shows that it is also important to check concentration of the enzyes.

-the importance of peripheral deiodination is seen from observation that persons whose thyroids have been removed have normal circulating concenctrations of T3 when they receive oral T4 supplementation

Type 3: inactivates T3 and T4

Deiodination to active T3 or inactive T3 is controlled by the need for metabolism- it is reduced in starvation due to raised cortisol, in severe illness and by propranol

-deiodination can also form deiodinothryonine, and monoiodothryonine- biologically inactive

Effect of thyroid hormones

-T3/T4 enter cells via specific transporters-monocarboxylate transporter 8-mutations in these transporters leads to effects of hypothyroidism even through levels of T3/T4 are normal- absence in speech-never walked, muscle hypoplasia

-Once in the cytoplasm T4 is converted into metabolically active form T3- which then bind to nuclear receptors- these act on response elements in gene promoters TRE

-this interaction results in stimulation or inhibition of production of many different mRNAs and proteins

-sensitivity is regulated via a number of nuclear receptors

Actions

-thyroid hormones increase basal metabolic rate by stimulating futile cycles of catabolism/ anabolism

-excess thyroid hormones increases the basal metabolic rate- seen by measuring heat production / consumption

Carbohydrate metabolism: thyroid hormones riase the rate of hepatic glucose production- increase in gluconeogenic activity- increased expression of the gluconeogenic enzymes (phosphoenolpyruvate, carboxykinase, pyruvate carboxylase, glucose 6-phosphatase)

-This doesn’t raise blood glucose concentrations- pancreas responds by increasing insulin secretion- increased glucose uptake and glycogenesis

Protein metaboslim: thyroid hormones stimulate increased proteolysis mainly in muscle for hepatic gluconeogenesis

-thyroid hormones also increase protein synthesis, stimulates RNA polymerase I and II activity so increase production of proteins

-break down of protein outweighs the synthesis of proteins- net loss of proteins

-when T3 is in excess- there is excess muscle wasting, weakness- increased nitrogen loss in the urine as urea

Lipid Metaboslim: glycerol required for increased hepatic gluconeogenesis- increased degradation of stored triglycerides- fatty acids provide fuel to the liver, glycerol gluconeogeneis

-thyroid hormones also increase lipogenesis

-very high levels of T3 lead to excess lypolysis- excess mobilisation of fat

Na/K pump: in muscle/ liver / kidney, thyroid hormone induced activity increases oxygen consumption

-Thyroid hormone also increases the synthesis of Na-K pump (uses 20-45% of all ATP)- increase in activity leads to more ATP useage, more O2 consumption, more heat

Thermogenesis: Thyroid hormone sensitises tissues to adrenergic hormones. In the heart skeletal muscle and adipose tissue- increased expression of B adrenergic receptors

Heart: increased expression of myosin heavy chain, increase rate and force of contraction- bounding pulse in hyperthyroidism

Other: stimulates gut motility- stimulates bone turnover, affects speed of muscle contraction- if in excess muscle breakdown causes muscle weakness

Developmental effects of T3

Essential for postnatal growth of CNS, stimulates production of myelin, neurotransmitters, axonal growth

• bone: stimulates linear growth by effects on chondrocytes.

• stimulates normal development, maturation and eruption of teeth, hair, epidermis.

These effects were seen in tadpoles- when the thyroid gland was removed the tadpole continue to grow but failed to metamorphise into frogs but when it was fed thyroid it metamorphosed automatically.

Prenatal thyroid deficiency:...