The Thyroid Gland Flashcards
Where is the thyroid gland?
wrapped around the trachea
How is the thyroid gland structured?
follicles lined with epithelial thyrocytes which are spherically arranged
What cells are in the thyroid gland?
C -cells which are parafollicular and thyrocytes
What does the thyroid gland secrete?
T3, T4 and calcitonin
What are the proportions of thyroid hormone produced?
T3-10%, reverse T3-1% and T4-90%
T3 is more potent than T4
How is T4 converted to T3?
a deiodinase enzyme found in peripheral tissues
What is the action of T3?
binds to high affinity T3Rs (TRa and TRb) associated with DNA in cell nucleus -> activate or represses gene transcription and thus regulate mRNA synthesis and protein synthesis
What are the features of the different types of deiodinases?
Type 1 - low affininty 10microM km, occurs in tissues with high blood flow and plasma exchange…i.e. liver, kidney and skeletal muscle, supplies circulating T3 for uptake by other tissues
Type 2 - high affinity 1nanoM km, expressed by glial cells in the CNS, provides T3 even when T4 levels are low, present in the thyrotropes of the pituitary acting as a thyroid axis sensory
Where does thyroid hormone biosynthesis occur?
Within the colloidal cavity
What does TH biosynthesis require?
thyroglobulin - secreted into follicle colloid
iodine ions - transported into follicular cells by Na-I symporter and into colloid by pendrin
Tyrosine
What transports I into the colloid?
pendrin
What is iodination?
adding iodine to thyroglobulin
How is thyroglobulin made into thyroid hormone after iodination?
endocytosed into vesicles and then fuse into lysosomes which degrade the tyrosine molecules into thyroid hormones
which enzyme catalyses the synthesis of thyroid hormones?
thyroid peroxidase
What processes does thyroid peroxidase catalyse?
iodination
coupling sequential reactions
What are the carrier proteins that thyroid hormones bind to?
thyroxine-binding globulin - major TBG
transthyretin - delivering to CNS - minor
albumin
How much iodine is ingested and excreted everyday?
400micrograms ingested:
150micrograms in adults
90-120micrograms in children
200micrograms in pregnant women
how much iodine is taken up by the thyroid gland?
70-80micrograms
what is the total iodide content of the average thyroid?
7500micrograms - about 70-80 micrograms is released daily
Where is iodide actively concentrated?
thyroid gland, salivary glands, gastric glands, lacrimal glands, mammary glands and choroid plexus
What can stimulate thyroid hormone secretion?
Low BMR, cold
What can inhibit thyroid hormone secretion?
trauma, stress, T3 - ant. pit/hypothalamus, T4 - ant. pit./hypthalamus and TSH - hypothalamus
What pathways does TSH stimulate at the thyrocytes?
Gs -> Ac -> PKA
Gq -> PLC -> PKC and Ca[i]
What does the stimulation by TSH result in?
increased iodide uptake
increased synthesis of peroxidase
increased synthesis of thyroglobulin
increased colloid uptake
what is the Thyroid receptor?
a nuclear receptor that regulates transcription
How does the thyroid receptor function?
as a heterodimer with the retinoic acid X receptor, TR-RXR binds to the thyroid response element on target gene
What happens with TR-RXR in the absence of TH?
represses gene transcription through recruitment of a compressor complex containing histone deacetylase (HDAC)
What happens with TR_RXR in the presence on TH?
coactivator complexes including histone acetyl transferase, increased acetylation and promotes transcription
What binds RXR?
Retinoic acid
How do T3 and T4 promote accelerated metabolism?
increased fat, carbohydrate and protein turnover
increase O2 consumption and heat production
regulate BMR and body temperature
How do T3 and T4 act during development and growth?
promote growth of neurons and maturation of the CNS
essential between week 11 and birth
correct mental development and body growth
How do T3 and T4 act on the sympathetic system?
increase responsiveness to catecholamines by increasing the no. of receptors in tissue
How do T3 and T4 act on the respiratory and cardiovascular system?
alters expression of ryanodine Ca channels in SR and promote calcium release
enhances sensitivity and expression of adrenoceptors to stimulation by noradrenaline (esp. B1 receptors)
How do T3 and T4 act on the BMR?
adjust heat loss through sweating and ventilation
accelerates response to starvation
How do T3 and T4 act on the ANS and catecholamines??
increase the no. of b-adrenergic Rs in the heart
increase the generation of intracellular second messengers
How do T3 and T4 act on the nervous system?
development
enhances wakefullness, alertness, responsiveness to various stimuli
What are the possible causes of hyperthyroidism?
Autoimmune disease such as Graves
Benign tumour causing enlargement of gland
Excessive TSH secretion from a TSH producing tumour
What are the possible causes of hypothyroidism?
Autoimmune disease such as Hashimoto disease
Dietary Iodine Deficiency
Defective hypothalamic and pituitary function resulting in insufficient thyrotropin secretion for thyroid gland stimulation
What is Goitre?
An enlarged thyroid gland - with 90% of cases caused by iodine deficiency
Why does iodine deficiency cause Goitre?
TSH secretion increases and thryoid cells proliferate to try and make more TH
What is another cause of Goitre?
Hyperthyroidism - Graves and excess TSH from pituitary tumour
What are the symptoms of Graves disease?
weight loss, excessive sweating, HR trouble, periorbital oedema, difficulty swallowing due to Goitre
How do you distinguish between Graves and a pituitary adenoma?
Graves has increase TSI and decreased TSH
Adenoma has decrease TSI and increased TSH
What are the possible treatments for hyperthryoidism?
Surgery - partial or complete removal
Drugs - thioureylenes, iodine contatining preparations, b-adrenoceptor antagonists
What do thiourelyenes require?
Thiocarbamide - S-C-N for activity
What are the effects of thiourelyenes?
Inhibit thyroid hormone synthesis - prevent iodination of tyrosine, and prevent coupling reactions of mono-iodo and di-iodo
What are some common thioureylenes used?
Carbimazole, Methimazole and Propylthiouracil which also inhibits deiodinases in peripheral tissues converting T4 to T3
Why do hormone changes and effects take so long in treating hyperthyroidism?
hormone stores and T4 bound to binding proteins
What is the effect of iodine containing preparations?
Radioiodine given as Na I, or I-131 produces y-rays and b-particle causing localised damage to follicular cells
half life of 8 days
How does KI preparation work and what is the effect called?
suppresses NADPH oxidase activity and peroxidase genes
Wolff-Chaikoff effect
inhibitory effect for up to 2 weeks then tolerant
used frequently before surgery or treatment of thyroid storm
How do b-adrenoceptors work to reduce hyperthyroidism?
no direct on synthesis or release but blocks cardiac b-adrenoceptors normalising HR
used in patients waiting for surgery or waiting for thiouryelenes to work
How is hypothyroidism treated?
synthetic T4 and T3 as replacement
Why is T4 first choice for replacement therapy?
builds up over days to max effects as it binds to plasma proteins and binding sites need to saturate for free hormone to become available
T3 is only used in emergencies such as coma as they have rapid action
What is the issue of replacement therapy?
If it is too high may cause cardiac dysregulation
How does T3 enter the brain?
T4 enters a glial cell where it is converted to T3 by D2
T3 exits cell and transported into neuron by MCT8
Enters the nucleus, binds a TR or inactivated to T2 by D3 iodinase
What is the molecule that converts T4 to T3 in the glial cell?
D2
What is the molecule that converts T3 to T2?
D3 iodinase
Where is the MCT8 gene located?
X chromosome
What does MCT8 deletions result in males?
Allan-Herndon-Dudley syndrome - abnormal plasma TH, global developmental delay, spastic quadraplegia, impaired gaze and hearing, hypotonia
What does MCT8 deletion result in females?
have two copies of gene
heterozygous mutants have mild thyroid phenotype and no neurological defects
50% chance of passing onto son
