Thyroid
What is thyroid stimulating hormone
Activation of the TSH receptor results in stimulation of all steps involved in TH synthesis
TSH from the ant pit binds to the TSH receptor on the basolateral membrane of the follicular epithelial cells - stimulates 2nd messenger pathways
What converts T4 to T3? What ring has to be worked on to be active? Inactive?
Enzymes - Deiodinases
Active = outer ring
Inactive = inner ring
What are the two main categories of biological responses to TH
Effects on metabolic pathways
Effects on cellular differentiation and development
What are the iodine states in the thyroid
Normal
Inactive thyroid - englarged celloid, thinner follicle lining
Hyperactive thyroid - no colloid fluid, enlarged epithelial follicular cells
What are the hyperthyroidism symptoms and diagnosis
Increased metabolic rate, increased protein catabolism, increased nervousness and excitability, increased beta-adrenergic receptors
Diagnosis - symptoms based, Low TSH and Norm/high free T4, anti TSH antibodies
Why do we need iodide
Its required for TH synthesis and is readily absorbed from dietary sources - major source is iodized salt
Iodide deficiency is still a problem in many parts of the world, particularly areas with iodine- deficient soils
What is TH action in target tissues
TH action is mediated by T3 at the nuclear thyroid hormone receptor
Transcription of Many genes -> multiple proteins -> various effects
also non-genomic effects via 2nd messenger activation
What are the metabolism functions of TH
A increase in basal metabolic rate in many tissues
- lipid metabolism = stimulate fat mobilization which means more FA in plasma
- Carbohydrate metabolism = enhancement of insulin-dependent entry of glucose into cells
What is hypothyroidism? its signs
Insufficient synthesis of TH due to lack of iodine - fetal and adult versions = Cretinism - retarded development + stunted growth, mental retardation (signs = Lack of appetite, slow HR, reduced fertility)
Pituitary lesions on thyrotropes in AP -> secondary hypothyroidism = decreased TSH release from Ant pit
Hypothalamic failure - tertiary hypothyroidism
All result in decreased T4 release from thyroid gland
What is the treatment for hyperthyroidism
Removing all or part of the thyroid gland (surgery, radiation)
Inhibiting the synthesis (drugs)
Blocking the release of THs (dose of iodide prevent iodination and release of THs)
What is goiter
An enlarged thyroid gland usually associated with hypothyroidism - happens when iodide deficient
What are thyroid receptors encoded by
Two genes - designated alpha and beta = there is alpha 1, alpha 2, beta 1 and beta 2
What are the growth and development functions of TH
Growth - necessary for normal growth in children and young animals
Development - Fetal Hyp-Pit-Thyroid axis functions at week 11 gestation in mammals, TH essential for brain development
What is autoimmune thyroiditis
Very common cause of hypothyroidism
Autoimmune condition - immune system attacks normal follicles
most common form in dogs
Hashimotos disease in humans
results in Antibodies to TPO, TGB
What is the role of TH in hatching
the Thyroid gland develops early in life in precocial birds
in altricial thyroidal T4 content is very low throughout embryonic life, increases slightly during about the 1st week post hatch
Perihatch thyroid hormones - hatching muscle development, lung maturation, yolk sac retraction, digestive tract maturation, activation of lipogenesis, brain development and imprinting, thermogenesis
What are the key steps in TH synthesis
Uptake or trapping by thyroid follcile
Iodide efflux into colloid via pendrin and oxidation to iodine by TP and H2O2
TGB synthesis with tyrosine residues and exocytosis
Iodination of tyrosine residues via TPO
Coupling of MIT and DIT on TGB
Endocytosis of TBG into follicular epithelial cell
Fusion of vesicles with lysozomes -> proteolysis
Release of T4 and T3 to bloodstream by simple diffusion across the basolateral membrane
Deiodination of MIT and DIT by deiodinase
Recycling of Iodide
Where are different TRs found
TR alpha 1 is the first isoform expressed in the fetus -> there is a profound increase in expression of TR beta receptors in brain shortly after birth
Alpha 1 = heart, alpha 2 = ubiqutous, beta 1 = liver, beta 2 = pituitary
What are other functions of TH
Cardiovascular system - increase heart rate, cardiac contractility and cardiac output
CNS - decrease TH and the individual tends to feel mentally sluggish, which increases induces anxiety and nervousness
Reproductive system - reproductive behaviour and physiology is dependent on having essentially normal levels of TH
What are the symptoms of hypothyroidism? Diagnosis and treatment
Lower metabolic rate, lower protein synthesis, lower nervous systems actions, lower cardiac output
Diagnose - low T4, high TSH = primary which means check for antibodies hypothyroidism, or Low T4, Low TSH = secondary or tertiary which means TRH stimulation test
What is the importance of calcium
Structural component of bones and teeth
blood clotting
maintain transmembrane potential of cells
muscle contraction
second messenger in hormonal and neurocrine signal transduction
How are thyroid hormones transported
THs are poorly soluble in water
thyroxine-binding globulin (TBG) is the principle carrier
transthyretin and albumin also carrier proteins
How do TRs interact with DNA
TH receptors bind to short, repeated sequences of DNA called thyroid/T3 response elements - composed of two AGGTCA half sites separated by four nucleotides
TRs can bind to a TRE as monomers, as homodimers or as heterodimes with the retinoid X receptor, another member of the nuclear receptor superfamily that binds to retinoic acid
TRs bind to TRE on DNA regardless of whether they are occupied by T3
What are the 3 mechanisms dysfunction can result through
Alterations in the circulating levels of TH - primary
Impaired metabolism of TH in the periphery
Resistance to TH actions at the tissue level
What is hyperthyroidism
TSH receptors in thyroid gland attacked by thyroid stimulating immunoglobulins - autoantibodies = causes the TSH receptors in the gland to be stimulated, autoimmune disease, increased TH production and disease
Where in the body is calcium distributed
Bone - 99% of it is tied up in the mineral phase
Blood and extracellular fluid
Intracellular calcium