Download NME2.30 - Thyroid

NME2.30: THYROID
06/03/08
OVERVIEW
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The bow-tie-shaped thyroid gland is situated in the anterior neck across the front of the trachea
o It consists of left and right lobes and an isthmus (‘connecting branch’)
o It normally weighs 10-20g
The thyroid produces thyroid hormones that are:
o The only hormones that require an essential trace element – iodine (150μg/day)
o Stored in an extracellular site – thyroid colloid
o Essentially peptide hormones but act like steroid hormones by binding to nuclear receptors
The primary histological unit of the thyroid gland is the follicle
Each follicle comprises a central mass of colloid surrounded by cuboidal follicular cells
o Capillaries and parafollicular cells are interspersed around the follicular cells
Development of the thyroid gland is dependent on TTF1/2 and PAX8 genes
o Initially attached to the base of the tongue by the thyroglossal duct which later degenerates
o The gland then grows down from the floor of mouth into the neck
o Failure of descent results in lingual thyroid
The foetal thyroid starts producing hormones around 10 weeks gestation
o Prior to this the maternal thyroid supplies hormones across the placenta
BLOOD SUPPLY
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The thyroid is supplied by two arteries:
o Superior thyroid – branch of external carotid artery
o Inferior thyroid – branch of subclavian artery via thyrocervical trunk
 At the inferior border of the thyroid gland, this artery crosses the recurrent
laryngeal nerve which may be damaged during thyroidectomy
There are three veins – superior, middle and inferior
THYROID HORMONE SYNTHESIS
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There are two active thyroid hormones:
o Thyroxine (T4) – comprising four iodine atoms
o Tri-iodothyronine (T3) – comprising three iodine atoms
Each are derived from thyroglobulin, a large protein containing linked tyrosyl residues
o Essentially a large tyrosine polymer (roughly 100 residues per molecule)
o Synthesised in follicular cells
Iodine is rapidly absorbed as iodide (I-) in the GI tract and actively taken up by the thyroid
o Na/I-cotransporters (NIS) on the basolateral membrane of follicular cells import iodide
o Anion transporters (Pendrin) on the apical membrane release iodide into the colloid
Follicular cells release thyroglobulin into the colloid
o The secretory vesicles contain thyroid peroxidase which oxidises iodide to iodine
Iodine attaches selectively to tyrosyl residues and thyroid peroxidase conjugates iodinated residues
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o At this point nascent T3 and T4 structures are held on the thyroglobulin backbone
The iodinated thyroglobulin molecule is taken up by follicular cells and hydrolysed in lysosomes
o T3 and T4 are released from the thyroglobulin chain and secreted into the circulation
LEARNING OUTCOMES
Describe the control, mechanism of action and function of thyroxine
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Thyroxine (T4) accounts for 90% thyroid hormone secretions
o It is significantly less active than T3
o It has a half-life of 8 days
o There is a large reservoir of circulating T4 in the body – more than 50-fold that of T3
Both active thyroid hormones are highly plasma protein bound (above 99%)
o Albumin and particularly thyroid-binding globulin (TBG) account for most of this binding
DEIODINATION OF THYROXINE
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Thyroxine is deiodinated in peripheral tissues to produce T3
o If the outer aromatic ring is deiodinated then it forms T3 – the active hormone
o If the inner aromatic ring is deiodinated then it forms rT3 – biologically inactive
T3 is responsible for the majority of actions of thyroid hormone and has a half-life of only 24 hours
Formation of the active T3 is catalysed by mostly locally-acting deiodinase enzymes:
o Type 1 deiodinase is found principally in the liver and kidneys
o Type 2 deiodinase is found in the pituitary and central nervous system
CONTROL OF THYROID HORMONES
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The hypothalamic-pituitary-thyroid axis regulates and controls thyroid hormone synthesis
o The hypothalamus releases thyrotropin releasing hormone (TRH)
o The pituitary releases thyrotropin (TSH)
o The thyroid releases T3 and T4
TRH is secreted from the supraoptic and paraventricular nuclei of the hypothalamus
o Half-life of 3 minutes
o Binds to receptors in the anterior pituitary triggering the PLC pathway
o Stimulates synthesis and secretion of TSH in the pituitary
o T3, T4 and dopamine inhibit its secretion
TSH is secreted from thyrotrophs in the anterior pituitary
o Half-life of 1 hour
o Binds to receptors on follicular cells of the thyroid triggering the cAMP pathway
o Stimulates iodide uptake, iodination, conjugation etc. and hyperplasia of the thyroid
o T3, T4, dopamine and somatostatin inhibit its secretion
ACTION OF THYROID HORMONES
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Both T3 and T4 can enter target cells and bind to thyroid hormone receptors (THR) in the nucleus
o In conjunction with the retinoid X receptor (RXR) gene transcription is altered
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Effects of thyroid hormones include:
o Synthesis of membrane proteins including Na/K-ATPase
o Synthesis of gluconeogenic enzymes
o Synthesis of β-adrenergic receptors in the heart and skeletal muscle
o Stimulation of carbohydrate, protein and lipid metabolism
Thyroid hormone levels have a powerful effect on BMR
o Hypothyroid conditions can reduce BMR by up to 50%
o Hyperthyroid conditions increase BMR
Overall, high levels of thyroid hormones:
o Stimulate futile cycles (synthesis and degradation) that expend energy and generate heat
o Promote a hypersympathetic state through increased expression of adrenergic receptors
THYROID HORMONES IN DEVELOPMENT
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Thyroid hormones are essential for normal growth and development affecting:
o Motor function
o Speech and language
o Hearing
o Intelligence
Cretinism is a hypothyroid condition resulting from endemic iodine deficiency or congenital defects
o Profound mental retardation
o Short stature
o Impaired motor development
o Protuberant abdomen
Hypothyroidism is one of the most common endocrine illnesses
o Affects 1-2% of adults, more often women
o Common causes include iodine deficiency and autoimmune disorders
o Characterised by goitre, dry skin, facial oedema, fatigue, anovulation
Hyperthyroidism is less common
o Characterised by weight loss, sweating, rapid heartbeat, muscle weakness, anxiety