Thyroid Hormones
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- Created by: amazingemilyjones
- Created on: 23-04-19 17:58
Thyroid Hormones
Thyroid Hormones
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Development of the Thyroid Gland
- Appears very early in life
- Develops about 4 weeks after conception as an epithelial invagination of the tongue
- Moves down the neck while forming bilobular structure, completed by third trimester
- Composed of two large lobs, 20-25g, either side of the trachea, below the larynx, joined by the isthmus
- 'Butterfly' shape
- Pyramidal lobe often present
- Rich blood supply from thyroid arteries
- Innervated by the autonomic nervous system
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Anatomy of the Thyroid Gland
Cellular Structure
- Thyroid gland has a very distinctive cellular organisation related to its function
- Its cells are arranged in follicles
- There are very a million follicles in your thyroid gland
- Follicles are spherical bodies composed of epithelial cells surrounding a colloidal storage protein, thyroglobulin
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Histology
- Epithelial cell height varies depending on the activity of the gland
- inactive, epithelial cells are flattened, with a large colloidal mass
- active, cells are columnar in shape, with a small colloidal lumen
- Epithelial cells are exocrine, absorptive and endocrine
- Larger epithelial cells lie between the follicles, parafollicular C cells, produce calcitonin
- Connective tissue, blood vessels and nerves surround groups of follicles, forming the lobule
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Synthesis of Thyroid Hormones
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Thyroid Hormones
- Dietary iodide (I-) taken up by iodide pump from the blood
- I- concentrated to 25-50 times plasma concentration, 600ug/g tissue
- Iodide uptake enhanced by thyroid stimulating hormone (TSH), iodine deficiency, TSH receptor antibodies
- Iodide pump inhibited by I-, perchlorate (ClO4-), thiocyanate (SCN-), pertechnetate (TcO4-)
- I- oxidised by H2O2 from thyroid peroxidase to I2 at apical surface
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Thyroid Hormones
- I2 immediately incorporated into tyrosyl residues covalently bound to thyroglobulin (TG) molecules at apical border to form monoiodotyrosine (MIT) and diiodotyrosine (DIT)
- MIT and DIT coupled by thyroid peroxidase to form T3 (3,5,3'-triiodothyronine, thyroxine)
- T3 is the active hormone
- Also get reverse T3, not active
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Thyroid Hormones
- TG continually produced by cells as secretory vesicles and exocytosed into colloid
- Thyroid hormones stored in colloid until secretion
- TSH causes endocytosis and proteolysis by lysosomes of TG-hormone complex
- T3 and T4 released into blood stream
- MIT and DIT de-iodinated by halogenases and free iodine and tyrosine reused by gland
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Transport
- Iodine not essential for biological activity
- T4 ~90%, T3 ~10% of thyroid hormones, 80-100ug/day
- T3 and T4 transported in plasma bound to proteins - thyroid binding globulin, transthyretin and albumin. T3 less avidly bound than T4
- Only free hormone not bound to plasma proteins is biologically active
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Metabolism
- T4 de-iodinated to T3 in the periphery (liver/kidney), most T3 is obtained via this route
- T4 plasma, half-life 6-7 days, T3 24-36 hours
- T3 ~10 times more potent than T4
- T3 and T4 conjugated to glucuronide or sulphate in the liver and excreted in the bile
- Iodide is excreted in the urine or re-circulated to the thyroid
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Regulation of Thyroid Hormone Release
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Control of Synthesis and Release
- Thyrotrophin releasing hormone (TRH)
- Tripeptide from the hypothalamus
- Stimulates release of thyrotrophin or thyroid stimulating hormone (TSH) from the anterior pituitary
- Also releases prolactin
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Control of Synthesis and Release
- Thyroid stimulating hormone (TSH)
- TSH acts on specific receptors on basal membrane
- Increases synthesis of iodide pumps
- Increases synthesis of thyroglobulin
- Increases synthesis and secretion of T3 and T4
- Increases thickness of follicular epithelium and vascularity
- Release of TSH inhibited by thyroid hormones, cortisol, growth hormone, oestrogens, dopamine and somatostatin
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Control of Synthesis and Release
Control of Synthesis and Release
- Nuclear events
- T3 and T4 enter cells by passive diffusion or by active uptake
- T4 de-iodinated to T3 or rT3
- T3 actively transported into the nucleus, also binds to cytosolic thyroid hormone binding protein (CTBP)
- T3 binds to thyroid receptors (TR) in the nucleus already bound to regulatory thyroid hormone response elements (TREs)
- Thyroid hormone receptor auxiliary protein (TRAP) necessary to stabilise TR binding to DNA
- Stimulation of target genes
- Several TR (alpha1-3, beta1-2) exist, different distributions
- Cellular events
- T3 binds to membrane-associated receptors to activate Na+/K+ ATPase pump. Increased uptake of glucose and amino acids
- T3 directly activates mitochondria to increase energy production
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Physiological Actions of Thyroid Hormones
- Thyroid hormones increase basal metabolic rate (BMR)
- Calorigenesis
- Increase O2 consumption in all tissues except brain, spleen, testes and anterior pituitary --> increased heat production
- Important for thermoregulation
- Take 4-5 days to occur, involves synthesis of new Na+/K+ ATPase pumps in cell membrane and direct activation of mitochondria
- Blockers of Na+/K+ ATPase pumps such as cardiac glycosides (digoxin) inhibit actions of thyroid hormones
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Physiological Actions of Thyroid Hormones
- Carbohydrate, protein and fat metabolism
- Direct effect on carbohydrates involving increased GI glucose absorption and synthesis of metabolic enzymes
- Indirect effect due to sensitising tissues to insulin, catecholamines and GH
- Increase in gluconeogenesis and glycogenolysis in the liver and glucose utilisation in fat, liver and muscle cells
- Synthesis and degradation of protein seen equally with low thyroid hormone levels, degradation predominates with abnormally high levels
- Synthesis and lipolysis of fat occur, but lipolysis is more important. Potentisation of catecholamine activity on adipocytes
- Increases oxidation of free fatty acids, calorigenic
- Plasma cholesterol lowered by increasing liver uptake through increased synthesis of LDL receptors and increasing bile acid formation
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Physiological Actions of Thyroid Hormones
- Maturation of the central nervous system
- Essential for normal CNS development during foetal and early neonatal life. T3 and T4 do not cross the placenta
- Growth of cortical and cerebellar neurones and myelination of nerve fibres
- Skeletal growth and maturation
- Synergistic effects with GH, essential for bone growth and development and normal stature
- Also essential for normal functioning of nervous and cardiovascular systems, GI tract, development of teeth, skin and hair
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Why do we need thyroid hormones?
- Responses to extremes of temperature
- Body maintained 37.2 degrees
- In the Arctic:
- Body detects low temperature
- Immediate release of T3 and T4 from the thyroid gland
- More O2 used by tissues and mitochondria makes heat
- Useful clinical sign
- underactive thyroid gland - people feel cold
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