Thyroid and the HPT Axis Flashcards
Where is the thyroid located?
anterior to the cricoid cartilage, two symmetrical lobes fused by isthmus
What is the blood supply of the thyroid?
superior (ext. carotid) and inferior (thyrocervical trunk) thyroid arteries
venous plexus on surface gives rise to superior, middle, and inferior thyroid veins which drain into the internal jugular
What is the innervation of the thyroid?
middle and inferior cervical ganglion (sympathetic NS)
What is the thyroid derived from?
Branchial pouch endoderm
What do thyroid follicles contain?
large storage of thyroglobulin (colloids)
What is the appearance of inactivated vs activated thyroid cells, and what activates them?
inactive: flattened, squamous
active: cuboidal
stimulated by TSH
What is the functional unit of the thyroid?
the follicle
What is the follicle?
epithelial cells with microvilli extending into a lumen filled with colloid which forms 30% of the thyroid mass
What is the major component of colloid?
thyroglobulin
What are parafollicular (C) cells?
produce calcitonin
What are iodothyronines?
thyroid hormones
What are the two precursors required for iodothyronines?
thyroglobulin (TG) and iodide
What is the lower limit of iodide intake that will result in ormone deficiency?
20 ug per day
What is the wolf-chaikoff effect?
an autoregulatory intrathyroidal response that maintains iodide stores in the face of of changes in dietary iodide
How does the wolf-chaikoff effect work?
increases in dietary iodide decrease gland transport and hormone synthesis and vice versa
How can the wolf-chaikoff effect be used clinically?
give high doses of iodide to shut down thyroid hormone production in hyperthyroid pts
What is the most preventable cause of mental retardation?
TH deficiency
What is T4?
thyroxine
What are some general functions of thyroxine?
long half life in plasma (~7-8 days)
tightly bound to transport proteins
binds to receptors with low affinity
What is T3?
Triiodothyronine
What are some general functions of triiodothyronine?
primary active form
most is converted intracellulary from T4
binds with high affinity, low capacity to receptor
What is rT3?
biologically inactive T3
What are the hypothalamic features of the HPT axis?
PVN
Thyrotropin releasing hormone (TRH)
negative feedback by T3/T4 synthesis
What are the pituitary features of the HPT axis?
Thyrotropes
TSH
negative feedback by intracellulary T3 release- thyroid sensor
tonically inactivated by dopamine and somatostatin
What is the apical surface of the thyroid follicles exposed to, and what does it do?
exposed to lumen (colloid)
thyroid hormone synthesis
iodination of TG
What is the basolateral surface of the thyroid follicles exposed to, and what does it do?
exposed to blood
iodine uptake “trap”
thyroid hormone release
What are all the steps in thyroid hormone biosynthesis mediated by?
TSH
What are the steps in thyroid hormone synthesis
- iodine trapping
- transport
- iodination
- conjugation
- endocytosis
- proteolysis
- secretion
What occurs during iodine trapping?
TSH stimulates iodide trapping by increasing activity of NIS cotransporter in the basoateral membrane of the follicular epithelial cell
What occurs during transport?
Iodide transported to follicular lumen and oxidized by thyroid peroxidase (TPO) to form iodine
thyroglobulin transported to lumen
What inhibits NIS?
lithium
What occurs during iodination?
iodination of tyrosyl residues on thyroglobulin (organification)
What occurs during conjugation?
conjugation of iodinated tyrosines to form T4 and T3 linked thyroglobulin
What inhibits TPO?
carbamizole
What are MIT and DIT?
modified tyrosines
1 DIT and 1 MIT = T3
2 DIT = T4
What is the difference between T3 and reverse T3?
DIT on inner ring = T3 (active)
DIT on outer ring = rT3 (inactive)
What occurs during endocytosis?
conjugated thyroglobulin with T4/T3 enters the follicular endothelial cell and is packaged in endosomes
What occurs during proteolysis?
TG, MIT, DIT, T3, T4 released from vesicle
What occurs during secretion?
T4/T3 secreted into circulation
What is radioactive iodide uptake scan useful for?
can determine the function of the thyroid gland
What is a cold/hot nodule?
cold nodule: non-functioning follicles that aren’t taking up iodine –> more predictive of a malignancy
hot nodule: overactive follicle
What is a normal iodide uptake and what are pathological scenarios?
25% after 24 hours
> 60% hyperthyroid
When is accelerated turnover seen, and what is a disease associated with this?
hyperstimulated thyroid gland - Graves disease
What is the issue with a organification defect, and how could you test this?
iodine cannot be incorporated into tyrosine
test by blocking NIS with an inhibitor (perchlorate)
What does type I deiodinase do?
outer and inner ring deiodinase
Where is type I deiodinase found?
liver, kidney, thyroid, skeletal muscle
What is the primary source of T3 in the circulation?
Type I deiodinase
What does type II deiodinase do?
outer ring deiodinase for T4
Where is type II deiodinase found?
brain, pituitary, placenta, cardiac muscle
What does type III deiodinase do?
inner ring diodinase
Where is type III deiodinase found?
brain, placenta, skin
What is primarily synthesized and stored in the thyroid
T4
What percentage of T4 is converted to T3 peripherally?
80%
what affinity does T4 have?
low receptor affinity
What is the thyroid hormone “sensor” in the pituitary?
type II deiodinase
What percent of thyroid hormone is bound to protein in the blood?
99%
What are the transport proteins that bind thyroid hormone in the blood?
thyroxine-binding globulin (TBG) - 70%
transthyretin (TTR) - 10%
albumin - 15-25%
What are the half lives of T4 and T3?
T4 tightly bound, half life of ~7 days
T3 half life 1 day
What family are TBG and TTR in?
serpine protease inhibitors (but not a serpine inhibitor) - same as CBG
Where are TBG and TTR made?
in the liver
What does T4 have the highest affinity for?
TBG
What increases TBG?
estrogen, hepatitis
What decreases TBG?
nephrotic syndrome, steroids
What is a result of increased or decreased TBG?
No change in “free” T4/T3!!
What is unique about TBG?
TBG can reversibly release T4 to target tissues
What kind of receptor is the thyroid receptor (THR)?
nuclear receptor family
What does THR form a complex with?
forms a heterodimer with retinoic acid receptor
Where is THR expressed?
in almost every cell type
What is the affinity and capacity to T3?
High affinity, low capacity
What is the affinity for T4?
low affinity - very low biological activity at physiological concentrations
What are the main physiological functions of thyroid hormone?
increases basal metabolic rate
promotes brain (CNS) maturation
increases beta adrenergic receptors (transcription): heart, skeletal muscle, adipose tissue
How does thyroid hormone stimulate an increase in basal metabolic rate, and what is the overall effect?
stimulates hepatic gluconeogenesis
stimulates proteolysis
stimulates lipolysis
increased E/O2 consumption and an increase in thermogenesis
How does T3 stimulate an increase in O2 consumption and thermogenesis?
increasing mitochondrial activity
What would the BMR be in hypothyroidism?
decreased
What would the BMR be in hyperthyroidism?
increased
How would carbohydrate metabolism be affected in hypothyroidism?
decrease in gluconeogenesis and glycogenolysis with normal serum glucose
How would carbo metabolism change in hyperthyroidism?
increase in gluconeogenesis and glycogenolysis with normal serum glucose
How would protein metabolism change in hypothyroidism?
decreased synthesis, decreased proteolysis
How would protein metabolism change in hyperthyroidism?
increased synthesis, increased proteolysis
muscle wasting
How would lipid metabolism change in hypothyroidism?
decreased lipogenesis, decreased lipolysis, increased serum cholesterol
How would lipid metabolism change in hyperthyroidism?
increased lipogenesis, increased lipolysis, decreased serum cholesterol
How would thermogenesis change in hypothyroidism?
decreased (cold intolerant)
How would thermogenesis change in hyperthyroidism?
increased (heat intolerant)
What is T3 required for in the CNS?
normal brain development
neuronal cell migration/differentiation
myelination
synaptic transmission
What is cretinism and what is it caused by?
iodine deficiency during development
short stature/impaired bone formation
mental retardation
delayed motor development
What are the physiological effects of T3 on the heart?
increases cardiac output
resting heart rate and stroke volume increased
hyperthyroidism can cause arrhythmias due to increased beta adrenergic receptors
What is a goiter?
hyperproliferation of cells due to hyperstimulation of TSH
What can cause a goiter?
cancer - 3:1 women:men
hyperthyroid - Grave’s disease
hypothyroid - Hashimoto’s thyroiditis, iodine deficiency
What is Grave’s disease?
autoimmune - Ab stimulate TSH receptor (Long Acting-Thyroid Stimulator) (LATS)
What is elevated in Grave’s?
T3/T4
What is the presentation and symptoms of Grave’s?
diffuse, symmetrical goiter with hyperthyroid symptoms: tachycardia, opthalmopathy, irritability, hyperactivity, heat intolerance, weight loss, nervousness, muscle wasting
What is Hashimoto’s thyroiditis?
autoimmune destruction of the thyroid follicles
What are Ab directed against in Hashimoto’s?
TPO, TG
What is the presentation and symptoms of Hashimoto’s?
Diffuse goiter with hypothyroid symptoms: lethargy, fatigue, hair loss, cold intolerance, brittle nails, decreased appetite, weight gain
What is a thyroid storm?
hyperthyroid coupled with acute illness (hyperthyroid + infection or trauma)
What are the symptoms of thyroid storm?
high fever, tachycardia, altered mental status, severe nausea, vomiting, and diarrhea, severe circulatory collapse
What is the treatment of thyroid storm?
Propylthiouracil (PTU – only acute treatment) - stops TH production
Carbimazole (methimazole) - inhibit TPO
Beta blockers to restore normal heart function
What is the cause of circulatory collapse in thyroid storm?
TH + Catecholamines results in massive vasodilation and perfusion of all tissues at once
