Anatomy of the thyroid??
Thyroid structure ??
(a) Thyroid follicles = balls of epithelial cells surrounding proteinaceous (non-cellular) colloid - where thyroid hormones are stored.
(b) Inactive thyroid
(c) Active thyroid
Thyroxine (T4) and Tri-iodothyronine (T3)
- iodinated derivatives of tyrosine.
Synthesis and secretion of thyroid hormones
1. is totally dependent on iodide obtained from the diet
active transport by an iodide pump linked to the activity of Na+/K+-ATPase.
Hormone synthesis takes place outside the thyroid cells in the colloid on a protein template (THYROGLOBULIN)
peroxidase enzyme activates iodide (drugs act here)
tyrosine residues on thyroglobulin are iodinated forming di-iodotyrosine (DIT)
DIT couple together to form T4
The hormones are stored in the colloid (attached to the thyroglobulin)
thyroid hormone mode of action?
T4 and T3 are strongly bound to serum proteins (Thyroid Binding Globulin - TBG) in the circulation, less than 0.5% of each is present in the free form which is biologically active.
T4 may be a "pro-hormone". T3 is the most potent form (up to 10x as active as T4 ).
T3 is mainly produced by de-iodination of T4 within target cells outside the thyroid gland.
The receptors for thyroid hormones are found in the cell nucleus and are part of the super-family of nuclear receptors.
They interact with DNA (as transcription factors) and produce changes in gene transcription and protein synthesis
Thyroid Hormone Receptors
located in nucleus (unlike steroid R)
hormone binding allows receptor to bind to specific DNA sequence(s)
requires heterodimer with RXR to enhance transcription (unlike steroid R) of specific genes
enhanced synthesis of specific proteins
Control of thyroid function
TRH from hypothalamus stimulates TSH release from pituitary
TSH stimulates production and release of T4 and T3 from thyroid. T4 de- iodinated to T3 at target tissues
TSH also stimulates growth of thyroid
~99% of T4 in plasma is bound to Thyroid Binding Globulin (TBG)
'free' (unbound) fraction is biologically active
‘free’ hormone ( mainly T3) feeds back to inhibit TSH secretion at the level of the pituitary and hypothalamus
Actions of thyroid hormones
increased O2 consumption in most body tissues resulting in increased basal metabolic rate and heat production
increased responsiveness to catecholamines, particularly in the cardiovascular system, leading to increased heart activity
increased nervous system excitability
permissive effects on growth and development.
Thyroid defects: hypothyroidism
(a) Congenital (from birth) produces severe developmental abnormalities if untreated
To prevent mental impairment babies must be treated with replacement thyroid hormone as soon as possible after birth. In developed countries neonatal screening is carried out routinely.
Thyriod insufficency in infancy: cretinism
Thyroid hormones play an essential role in the proper development and functioning of nervous system – neonatal thyroid deficiency can lead to permanent mental deficiency - "cretinism".
Thyroid defects: hypothyroidism
(b) Acquired in later life
(i) Autoimmune destruction of the thyroid- Hashimoto's thyroditis
- about 1 in 1000 occurences, 8 - 15 times moe common ini women, most often middle aged (40 - 60)
- circulating antibodies against thyroid peroxidase, thyroglobulin and/or TSH receptors
- TSH is increased as the pituitary tries to compensate for decreased T4
- treated with T3/T4 replacement (oral)
(ii) Lack of iodide in the diet, very common in certain areas of the world
- Easily treated with dietary supplement (in salt)
Symptoms of hypothyroidism in adults ?
low metabolic rate
slow mental processes
decreased cardiac activity
lack of T3/T4 means no inhibition of TSH release so elevated levels
TSH stimulates thyroid growth
thyroid goitres form
Thyroid defects: hyperthyroidism
most common form of hyperthyroidism
autoimmune disease with antibodies that stimulate the thyroid to secrete T3 and T4 (agonist antibody)
high metabolic rate, weight loss, heat sensitivity
increased cardiac activity
hyperactive nervous system, tremor, anxiety
thyroid growth (toxic goitre) and exopthalamus
Pharmacological blocking of peroxidase blocks
T4 and T3 synthesis