Thyroid gland Flashcards
Where is thyroid gland found and is its blood supply
located below larynx
Large blood supple and innervated with sympathetic nerves
What is the functional unit of thyroid gland
Thyroid follicles
what is found in thyroid follicle
a single layer of epithelial cells surrounding a lumen that contains colloid ( few 100 follicles per gland)
and parafollicular cells
What is colloid made from
thyroglobullin in the collide
What is present on the apical surface of the thyroid follicle
Cilia
The other name for parafollicular cells and what they are source of
C-cells
Calcitonin
Function of thyroid gland
Function: to secrete
the quantity of
thyroid hormone to
meet the demand of
peripheral tissues
How the secretion of thyroid hormone is regulated
- The blood flow regulates the thyroid hormones release by affecting the the delivery of TSH, iodine and nutrients
- Postganglionic sympathetic nerves control the blood flow through the gland
How c-cell can be found within thyroid gland
Associated with thyroid cell or outside the follicle
What is the structure of the cell when it is inactive and when overreactive
inactive-cuboidal
very active- columnar
T4 and T3 are made of (AA)
Iodinated tyrosine
Mono or diiodotyrosine
Tyrosine can take up up to 2 I per ring
structure of T3 and T4 and what positions I
T4- thyroxine, 2 diiodotyrosines together
T3: 3,5,3’ triiodothyronine, 1 mono and 1 diiodotyrosine
to what forms peropheral tissues convert T3 and T4
Describe synthesis of T3 and T4
Na/K ATPase creates a gradient of Na (low inside the follicle)
- NIS: 2Na and 1I are brought into the cell(symporter) due to gradient of Na
- PDS: a trasnporter that transfers I from the follicle into the colloidal
- Meanwile: TSHR (receptor of TSH),which functions through GPCR and IP3/Ca system induces transcription and trasnfer of thyroglobulin(Tg) into the colloidal
- Ca in the cytoplasm induces production of H2O2 into the colloidal by taking H from NADPH
- Thyroid peroxidase with H2O2 puts I on Tg in the colloidal
- Now Tg have T3,T4 and precursors
- Iodinated Tg is taken inside the follicle and undergoes hydrolysis
- mono and diiodotyrosine are recycles and I is given off to colloid again
- T4 and T3 is transported into the circulation. Not sure what transporter, but the candidate is MCAT10
What 3 parts are essential for thyroid hormone synthesis in thyroid gland
NIS (Na+/I- symporter),
TG (thyroglobulin), TPO (thyroid peroxidase)
how thyroid feedback works
What is trapping? what is organification? what is coupling?
1) active transport of iodine into the thyroid
cell (“trapping”)
2) oxidation of iodide and iodination of
tyrosyl residues in thyroglobulin
(organification)
3) linking pairs of iodotyrosines in
thyroglobulin to form T3 and T4
(coupling)
Is T3 or T4 more bioactive?
T3
What other organ apart from thyroid gland cna trap I
Salivary gland
What can block NIS and how this is used for treatment?
Anions (such as ClO4-) block uptake of iodine; perchlorate
can be used to block hyperthyroidism (also environmental
inhibitor of thyroid
Radioactive iodine is used for
Radioactive iodine (oral I131) can be used to destroy thyroid tissue (in case of cancer or hyperthyroidism)
What is the structure of Tg
Dimer
contains about 140 tyrosines
What are psot translational modifications of Tg
v Extensively glycosylated in the Golgi (10% carbohydrate
by weight)
v Packaged into vesicles, exocytosed into the lumen of the
follicle
how iodination of Tg occurs
Thyroperoxidase is Packaged in an inactive form together with thyroglobulin (Tg) into vesicles in the Golgi
v Activated at the apical membrane by co-factors
Drugs inhibiting iodination are targeted on
Thyroperoxidase is the target for many drugs to reduce
thyroid hormone production e.g. thiocarbamide
inhibitors
Name of compounds that block thyroperoxidase and where they are found
and the result of blockage
Several inhibiting compounds (goitrogens) are present in
food (e.g. milk from cows fed certain plants, brassicae).
v Block of iodination results in increased TSH production,
resulting eventually in hyperplasia and goiter
What tyrosines become iodinated
Only the tyrosines on the surface of the Tg become
iodinated (about 1/3rd)
What stimulates coupling of MIT and DIT
TPO
How much of T3 and T4 is in 1 Tg
- Maximum of four T3 and/or T4 hormones within each Tg molecule are formed.
- The kinetics is such that it keeps the level of T3 (the active form of the thyroid hormones) steady despite fluctuations in the dietary intake of iodine.
Why thyroid gland have cilia
For endocytic mechanism for uptake of iodinated Tg
High levels of r-T3 and low levels of T3 what does it indicate
(“sick euthyroid syndrome” i.e. thyroid normal function but
hypothyroidic as a metabolic adaption to some other condition
e.g. anorexia, cancer
How T3 and T4 are transported int he blood?
Lipophilic therefore bound to carrier proteins
synthesized in the liver (99%)
– Thyroxine binding globulin (TBG)
– Transthyretin (thyroxine-binding prealbumin i.e. TBPA)
– Albumin
Why some drugs for treating epilepsy and inflammation are causing hyperthyroidism
Some drugs compete with binding to the carrier protein
and therefore elevate free T4 and T3
Difference between T3 and T4 (half life, how active, importance)
- Half-life 1-3 days for T3 and 5-7 days for T4
- rT3 is cleared rapidly with a half-life of 5h
- T3 is 2-10 times more active than T4
- Total T3 is only about 2% of T4. However, stronger binding of T4 makes that the free concentration of T3 is about 30% of that of free T4
- Overall serum T3 and T4 are equally important (not counting tissue specific conversion)
Why free thyroid hormone is important
Cells can only take up the free thyroid hormones, but
not the carrier proteins → Free hormone concentration
is important
v The level of binding proteins determines the free
hormone concentration.
What will be the amount of binding protein in pregnancy, oral contraception? Starvation, liver disease?
v Binding protein high → More total hormone required to
maintain free hormone level
v Binding protein low → Less total hormone required to
maintain free hormone level
What enzyme is needed for T4 deiodination?
deiodinase
how maany types of deodinase are there and what is particular about them
All three deiodinases contain selenium in the form of the rare amino acid selenocysteine, the 21st amino acid (codon UGA)
Describe 3 types of deiodinase
deiodinase functions as
As a dimer
trasnmembrane protein
Physiological importance of deiodinase
v permit local tissue and cell modulation of thyroid
hormone
v help animal to adapt to changes including iodine
deficiency or chronic illness e,g, D3 increases during
hyperthyroidism and decreases during hypothyroidism
v regulate thyroid actions during early development
How most of T4 is deactivated and what happens to the rest
v about 80 % of T4 is metabolized
by deiodination (35 % to T3 and
45 % to rT3)
v rest inactivated by liver by
glucuronidation and biliary
secretion
Why thyroid hormone is unique (storage)
T4 and T3 are lypophylic-> usually not stored
vThe thyroid is unique by virtue of the large store of
hormone
vthe reservoir provides prolonged protection in case
synthesis ceases.
vThe stored amount is enough to maintain a
euthyroid state for at least 50 days.
What is thyroid storm hyperthyrotoxicity
If dome trauma and all reserved hormones are released in circulation
What are the effects of thyroid hormone and who modulate the action more
Thyroid hormone receptor is _____
Nuclear receptor-> ligand dependent TF
How Thyroid hormone receptor function
Acts as monomer, homodimer or
heterodimers
v Most common heterodimer partner – RXR
what are genes for T3/T4 receptors and how they give rise to different receptor isoforms
Two genes encode T3/T4 receptors:
THRA (NR1A1) and THRB (NR1A2)
v Each gives rise to two receptor isoforms
by alternative splicing
Where THR are found
Tissue specific expression of these
receptors modulates the effect of T3
and T4 on different tissues
v Localization: Nuclear (Class II NR)
v Found also in mitochondria
How TH gets to its receptor
Ligand entry by passive diffusion, but
in certain cells it may be aided by
special transport systems
What happens to T3, when there is plenty
When T3 is plenty, rT3 is formed and
readily cleared.
Difference between THR alpha 1 and alpha 2
Difference between B1 and B2 receptors
what happens in nucleus ,when T3/T4 bind
Repressor proteins are exchanged to activators and initiation proteins can bind
is T3 and T4 cna target only nucleus?
No, also genes in mitochondria
How thyroid hormones can influence mitochondria
v T2 binds to cytochrome c to increase oxidative phosphorylation
v T3 binds to uncoupling proteins to increase heat production
T4/T3 signaling not through HRE
PKC/PLC->MAPK pathway
GPCR?
How TH influence heart
Increses hesrt rate and force
How TH influence adipose tissue and muscle
How thyroid hormone influences bone and nervous system
How thyroid gland influence gut, lipoprotein and other organism
Why there is calorogenic effects if thyroid hormones
Some calorigenic effects
are due to fatty acid
mobilization and increase
of Na+/K+ ATPase Activity
How long is the effect of T4 on metabolism
Single dose of T4 → Measurable effect in
several hours, lasts for 6 days or more
What is the exception of calorigenic action of TH
Exceptions are adult brain,
testes, uterus, lymph
nodes, spleen and anterior
pituitary (pituitary →
feedback inhibition by T4)
Effects Secondary to Calorigenesis
Increased nitrogen excretion (protein turnover increases
leading to decreased skeletal muscle)
v Weight loss due to catabolism of fat and protein (unless
balanced by food intake)
increased erythropoiesis (increased demand for O2)
T4 is will promote ___ in children
positive nitrogen
balance since T4 stimulates growth.
How T 4 can lead to increased vitamin A in circulation
T4 is required for hepatic conversion of carotene to
vitamin A in the liver → carotenemia
Lack of T4 will lead to
myxedema (puffiness of the skin due to lack
of degradation of proteins, polysaccharides and hyaluronic
acid)
rise in body temperature by T3/T4 will lead to
vCutaneous vasodilation → Decreased resistance to
peripheral blood flow → Increase of renal Na+ and
H2O reabsorption to expand blood volume
vIncrease of cardiac output by T3/T4 and
catecholamines shorten circulation time of blood by
increasing pulse pressure and cardiac rate
what hormone (t3 or t4) will stimuate myocytes
T3 from circulation since myocytes lack
the deiodinase to form T3 from T4
What genes are going to be inhibited and activated in CVS with T3
- Genes turned on: α-myosin heavy chain (high ATPase
activity), sarcoplasmic reticulum Ca2+ ATPase, β-
adrenergic receptors, G-proteins, Na+-K+ ATPase,
some K + channels. - Genes inhibited: β-myosin heavy chain (low ATPase
activity), two types of adenyl cyclase, T3 nuclear
receptor, Na+-Ca2+ exchanger - Net result: Increased heart rate and force of
contraction
what hormones have similar action to T3/T4
vCatecholamines have similar effects as T4/T3
but of shorter duration
Increase in the metabolic rate, stimulation of the
nervous system, cardiovascular effects
Why beta-blockers are used to treat thyroid storms
vBlocking β-adrenergic receptors reduces action
of T3/T4
vThyroid hormone toxicity induced by infection,
trauma, drugs etc. Molecular mechanism unclear but
high temp. up to 106 F, heart rate 200 bpm etc.
vMay be lethal if not treated immediately
what can astocytes do with thyroid hormones, what will be there action and what will happen if there is lack of T3/T4 during developement
- v Astrocytes convert T4 to T3
- Increased responsiveness to catecholamines
- Lack of T3/T4 during development → Mental
retardation, motor rigidity, deaf-mutism (cretinism
Muscle weakness can be result of ____ and what is the action of hyper anadd hypothyroidism on muscles
vHyperthyroidism: Muscle weakness due to
increased protein catabolism.
vHypothyroid: Muscle weakness, cramps,
stiffness.
vIn both cases relationship between myopathy
and thyroxin levels unclear.
vEffects on Carbohydrate Metabolism
– Thyroid hormones increase
absorption of carbohydrate from the
gastrointestinal tract
vEffects on Cholesterol Metabolism:
– Decrease of cholesterol levels
independent of calorigenic action
– Due to the increase of LDL receptors
in the liver (→ hepatic clearance of
cholesterol)
How catecholamines act on thyroid hormones
Synergetic
Modulate the response
Effects Of The Thyroid Hormones On The
Reproductive System
vRequired for normal follicular development
and ovulation in the female
vRequired for the normal maintenance of
pregnancy
vRequired for normal spermatogenesis in the
male
Effects Of The Thyroid Hormones In Growth
and Tissue Development
v Increase growth and maturation of bone
v Increase growth and maturation of epidermis, hair
follicles and nails
v Increase rate and force of skeletal muscle contraction
v Inhibits synthesis and increases degradation of
mucopolysaccharides in subcutaneous tissue
Similar action to GH
Hypothyroidism result in
v Symptoms – fatigability, coldness, weight gain,
constipation, low voice
v Signs – Cool skin, dry skin, swelling of face/hands/legs,
slow reflexes, myxedema
v infants and children – Retardation, short stature,
swelling of face/hands, possible deafness
Types of hypothyroidism
Types of Hypothyroidism
v Primary – Thyroid gland failure (most common cause)
v Secondary – Pituitary failure (TSH deficiency)
v Tertiary – Hypothalamic failure (TRH deficiency)
v Peripheral resistance to action of thyroid hormones
Treatment of hypothyroidism
Treatment: Levothyroxine (T4) due to longer half life
iodine deficiency cna be caused by
perchlorates and
other treatments
Elevated TSH is the result of and leads to
Elevated TSH (decreased negative
feedback) results eventually in
enlargement of the thyroid.
Iodine deficiency during pregnancy leads to
neurological damage
(cretinism: intellectual impairment,
deafness, paralysis).
Large doses of iodine can lead to
may inhibit
synthesis and excretion of thyroid
hormones
Is iodine deficiency stil a problem?
Yes
What happens with thyroid hormone levels with aging
vT4 levels gradually
decrease by as much as
50 % in elderly
vThey may gradually
develop hypothyroidism
(“thyropause”)
vbecome more susceptible
to winter
Untreated hypothyroidism during
the winter :
- progressive weakness,
- hypoventilation,
- hypoglycemia,
- Hypothermia,
- progressing to coma and death
What is Hashimoto’s disease, difference between younger and older patients, what will be lab values, treatment
- Autoimmune disease
- Major cause of hypothyroid
disorders in areas of iodine
sufficiency - Goiter in younger patients
- No goiter in older patients
- Autoimmune response is against TPO and/or Tg
- Lab values:
High TSH, Low T4, Anti-TPO Ab,Anti-TG Ab - Treat with Levothyroxine (T4)
what is grave’s disease, signs and symptoms, cause
Symptoms – Palpitations, nervousness, fatigue, diarrhea,
sweating, heat intolerance i.e. accelerated metabolism
Signs – Thyroid enlargement (?), tremor
- Result of immune system producing anti-TSH receptor
antibodies - Binding of Ab to receptor
induces signal transduction of
TSH pathway resulting in T4/T3
production without TSH - T4 suppresses TSH release from
pituitary (i.e. negative feedback)
