Thyroid Flashcards
what is the function of the thyroid gland and where is it located
endocrine organ specialized in secretion of thyroid hormones
located below larynx
the thyroid gland has a large …. and is innervated by ….
blood supply and is innervated by sympathetic nerves
what are the functional units of the thyroid gland? what are their structure?
thyroid follicles consisting of a single layer of epithelial cells surrounding a lumen that contains colloid
what are the parafollicular cells a source of?
calcitonin
why is the important blood supply important in regards to the thyroid gland?
the blood flow regulates the thyroid hormones release by affecting the delivery of TSH, iodine and nutrients
what causes the release of thyroid hormones?
the delivery of thyroid stimulating hormones TSH, iodine and nutrients
which nerves control the blood flow through the Thyroid gland
postganglionic sympathetic nerves
what are the 2 biologically active forms of the thyroid hormones?
T4 (thyroxine) and T3 (triiodothyronine)
what is rT3
metabolically inactive form of thyroid hormone generated from T4 via the type 3 5′-deiodinase enzyme
what is T2
hormone precursor and byproduct of the thyroid hormone synthesis
where are rT3 and T2 formed
in the peripheral tissue
T4 and T3 secreted by …. through the singling of … on …. have …. feedback at the pituitary and hypothalamus level
the thyroid gland through the signaling of TRH on TSH have a negative feedback
steps in the synthesis of T4 and T3
- TRAPPING = active transport of iodine into the thyroid cell -> - TSH binds to TSHR: cAMP activating sodium-iodine symporter NIS (influx of iodine and sodium in epithelial cell)
- ORGANIFICATION: oxidation of iodine and iodination of tyrosyl residues in thyroglobulin (Tg)
- COUPLING: linking pairs of iodotyrosines in thyroglobulin to form T3 and T4
- proteolysis of Tg to release T3 and T4
- deiodination of iodotyrosines and recycling of I-
- intrathyroidal 5’-deiodination of T4 to T3
what are the RDAs for iodine?
adults: 150microg
during pregnancy: 200 microg
children: 90-120microg
how is the iodine transported from ECF to cytoplasm of thyroid epithelial cell
via NIS stimulated by TSH
-> symport: co-transport of Na+ and I- driven by the Na+ gradient [iodine concentration in the blood plasma is extremely low: 30-40 fold difference]
…. block uptake of iodine
anions (ClO4-)
… can be used to block hyperthyroidism
perchlorate
what can be used to destroy thyroid tissue in case of cancer or hyperthyroidism
radioactive iodine (oral I131)
… and … are competitive inhibitors of iodine causing apparent iodine deficiency in some areas of the world
bromide (Br-) and nitrite (NO2-)
what is ThyroShield Potassium Iodide
It is thyroid blocking used in a radiation emergency only. It contains 65mg potassium iodide per mL. Helps prevent radioactive iodine from getting into the thyroid gland during a nuclear radiation emergency
[not more than 1 dose in 24hrs]
characteristics of thyroglobulin Tg
large glycoprotein, homodimer, each Tg contains 140 tyrosine residues
how is Tg synthesized
- TSH stimulates its transcription/translation in the follicular cells of the thyroid
- It is extensively glycosylated in the Golgi (10% carbohydrate by weight
- Packed into vesicles, exocytosed into the lumen of follicle (colloid)
in which step of T4 and T3 synthesis does iodination of thyroglobulin occur
organification
how is the iodination of thyroglobulin during organification carried out
carried out by thyroperoxidase TPO which is packaged in an inactive form together with thyroglobulin into vesicles in the Golgi
how is thyroperoxidase activated
activated at the apical membrane by co-factor H2O2
TPO + I- + Tg-protein + H2O2 =
= I.TPO.Tg-protein complex -> TPO + I-Tg-protein
how do you reduce thyroid hormone production?
by inhibiting thyroglobulin iodination by targeting thyroperoxidase TPO
how does hyperplasia and goiter occur?
block of iodination results in TSH production resulting eventually in hyperplasia and goiter
what do we call the inhibiting compounds used for inhibiting iodination?
goitrogens
how are thyroid hormones produced from Tg
tyrosine residues on thyroglobulin are iodinated which causes a structural change leading to the formation of triiodothyronine T3 and thyroxine T4 within the structure of thyroglobulin
which protein catalyzes the coupling step in TH synthesis
Thyroperoxidase
MIT + DIT =
T3
DIT + DIT =
T4
… occurs simultaneously with the iodination reaction
coupling
maximum of … T3 and/or T4 hormones within each thyroglobulin are formed
4
how does the degradation of Tg and release of TH occur?
T3-T4-TG-MIT-DIT complex is taken into the cytoplasm through pseudopods into colloid droplets
lysosomes and proteases act on colloid droplet cleaving MIT/DIT and T3/T4 off of Tg
MIT/DIT are deionized and T3 and T4 diffuse out of through the basal membrane into circulation where they bind to carrier proteins (lipophilic)
what is the “sick euthyroid syndrome”
high levels of r-T3 [inactive] in blood in conjunction with low levels of T3 [active] i.e. thyroid normal function but hypothyroidism as a metabolic adaption to some other condition - anorexia/cancer
where are thyroid carrier proteins synthesized
liver
which are the thyroid carrier proteins
- thyroxine binding globulin TBG
- transthyretin (thyroxine-binding prealbumin TAPA)
- albumin
what are the effects of drugs treating epilepsy and inflammation and in turn the side effect
these drugs compete with binding to the carrier protein and therefore elevate free T4 and T3 -> hyperthyroidism
… is 2-10 times more active than …
T3 more active than T4
total … is only about 2% of ,,,,
T3 2% of T4
what does a stronger binding of T4 imply?
it kales the free concentration T3 about 30% of that of free T4 although total T3 is only 2% of T4
serum T3 is more important than serum T4. True or false
False. Although T3 is 2-10 times more active than T4, total T3 is only about 2% of T4. But, the stronger binding of T4 makes that the free concentration of T3 about 30% of that of free T4
overall serum T3 and T4 are equally important
all T4 and T3 comes from thyroid gland. true or false
False, all T4 comes from thyroid gland but not T3
production, affinity for binding, free form, and half-life of T4 vs T3
everything: T4>T3
what does a high biding protein content mean?
when binding protein is high, more total hormone is required to maintain free hormone level
in which cases are binding proteins high?
during pregnancy and oral contraceptive use
what does a low binding protein content mean?
when binding protein is low, less total hormone required to maintain free hormone level
in which cases are binding proteins low
starvation and liver disease
what determine the free hormone concentration
the level of binding proteins
type 1 deiodination of T4 by deiodinases
T4 -> T3
Liver, kidney, muscle
Peripheral conversion
type 2 deiodination of T4 by deiodinases
T4 -> T3
brain, pituitary
key for feedback on TRH and TSH
Type 3 deiodination of T4 by deiodinases
T3 -> rT3/T2
inactivation if T3 is in excess
what is the particularity of all three deiodinases?
they contain selenium in the form of the rare amino acid selenocysteine (21st AA, codon UGA). [only 25 selenocysteine containing proteins have so far been identified, 11 in thyrocytes
what is the physiological importance of deiodinases
- it permits local tissue modulation of thyroid hormone
- helps animal to adapt to changes including iodine deficiency or chronic illness
- regulate thyroid actions during early development
about 80% of T4 is metabolized by deiodination - 35% to T3 and 45% to rT3. What about the other 20%?
the rest is inactivated by liver by glucuronidation and biliary secretion
what is the function of thyroid hormones
- growth and development
2. maintenant of basal metabolic rate
what kind of receptor is the thyroid hormone receptor
nuclear receptor bu also found in mitochondria - ligand dependent transcription factor => may activate/inactivate transcription
what is an example of the transcription factor function of the THR
activation of GH transcription, inactivation of TSH transcription
what is the most common heterodimer partner of THR
RXR
how is the effect of T3 and T4 modulated
tissue specific expression of the receptors modulates the effect of T3 and T4 on different tissues
ligand aka thyroid hormone enters neutron by passive diffusion because it is lipophilic, it does not require a transporter. true or false
true but some tissues express transporters MCT 8 and 10
T4 and T3 receptors are encoded by one gene. true or false
false, two genes encode T3/T4 receptors: THRA and THRB
THRA gene found in chromosome 17 has 2 isoforms. which are they and what are there respective functions
alpha1-receptor - widely distributed
alpha2-receptor - acts as an inhibitor (binds to TRE sequence but not ligand - transcriptional repression)
THRB gene found on chromes 13 has 2 isoforms. which are they and what are there respective functions
beta1-receptor - widely distributed
beta2-receptor - anterior pituitary and specific brain regions
T2 binds to cytochrome c in mitochondria to ….
increase oxidative phosphorylation
T3 binds to uncoupling proteins to ….
increase thermogenesis
THRs to …
increase mitochondrial transcription
T4 and T3 singling though membrane receptors
PLC - PKC - MAPK - ERK1/ERK2 - serine phosphorylation and protein trafficking
effects of T3/T4 on growth and tissue developemnt
- increase growth and maturation of bone
- increase growth and maturation of epidermis, hair follicles, and nails
- increases rate and force of skeletal muscle contraction
inhibits synthesis and increases degradation of mucopolysaccharides in subcutaneous tissue
what is myxodema
hypothyroidism with puffiness associated with mucopolysaccharides accumulation under skin
effects of T3/T4 on metabolism
- effects on CHO metabolic: thyroid hormones increase absorption of CHO from GI
- effects 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 can the calorigenic action of thyroid hormones be explained
- increase of O2 consumption and heat production in metabolically active tissues
- exceptions are adult brain, testes, uterus, lymph nodes, spleen, and anterior pituitary (pituitary - feedback inhibition by T4)
- some calorigenic effects are due to FA metabolization and increase of Na/K ATPase activity
what are the effects of subcutaneous injections of T4 and T3
T3: lower dose, faster response in increase metabolism but not long lasting
T4: measurable effect in several hours, lasts for 6 days or more
effect of T3/T4 on secondary calorigenesis
- increases nitrogen excretion (protein turnover increases leading to decreased skeletal muscle)
- weight loss due to catabolism of fat and protein (unless balanced by food intake)
- in children, small doses produce a positive nitrogen balance sign T4 stimulates growth
role of T4 in vitamin A production in liver
T4 is required for the conversion of carotene to vitamin A in the liver
what is the effect of T3/T4 on the cardiovascular system
- rise in body temperature activates heat dissipation mechanisms
- > cutaneous vasodilation - decreased resistance to peripheral blood flow - increase of renal Na and H2O reabsorption to expand blood volume
- > increase of cardiac output by T3/T4 and catecholamines shorten circulation time of blood by increased pressure and cardiac rate
-what is the mechanism of action of thyroid hormone on heart myocytes
- triggered by T3 (from circulation since myocytes lack the deiodinase to form T3 from T3)
- genes turned on: alpha-myosin heavy chain (high ATPase activity), sarcoplasmic reticulum Ca ATPase, beta-adrenergic receptors, G-proteins, Na-K ATPase, and some K channels
- genes inhibited: beta-myosin heavy chain (low ATPase activity), 2 types of adenyl cyclase, t3 nuclear receptor, Na-Ca exchanger
=> INCREASED HEART RATE AND FORCE OF CONTRACTION
How are catecholamines similar to T4/T3
increase in metabolic rate, stimulation of nervous system, cardiovascular effects
what are thyroid storms
untreated or undertreated hyperthyroidism. During thyroid storm, an individual’s heart rate, blood pressure, and body temperature can soar to dangerously high levels
induced by infection, trauma, drugs
lethal if not treated
what is used to treat thyroid storms
beta-blockers
what are the effects of T3/T4 on nervous system
astrocytes convert T4 to T3
increased responsiveness to catecholamines
- lack of T3/T4 during development: mental retardation, motor rigidity, deaf-mutism
what is the effect of hyperthyroidism on skeletal muscle
muscle weakness due to increased protein catabolism
what is the effect of hypothyroidism on skeletal muscle
muscle weakness, cramps, stiffness due to decreased metabolic rate
what role does thyroid hormones play on the reproductive system (3)
- required for normal follicular development and ovulation in the female
- required for the normal maintenance o pregnancy
- required for normal spermatogenesis in the male
what is the impact of hypothyroidism on the metabolism
deficiency in thyroid hormone results in slowing down metabolism
what are the 4 different types of hypothyroidism
- primary: thyroid gland failure (most common cause)
- secondary: pituitary failure (TSH deficiency)
- tertiary: hypothalamic failure (TRH deficiency)
- peripheral resistance to action of thyroid hormones (non responsiveness fo receptors)
what is the treatment for hypothyroidism
levothyroxine (T4) due to longer half life
what are the consequences of iodine deficiency [hypothyroidism]
iodine deficiency at <50microgram/day causes elevated TSH levels due to decreased negative feedback eventually causing an enlargement of the thyroid
what happens in hypothyroid children
thyroid hormones are essential for growth and neural development
-> growth hormone secretion is depressed therefore, hypothyroid children have slowed bone growth and there’s a delay of EPIPHYSIAL closure => mental retardation, stunted growth, delayed puberty
what does thyropause refer to
when T4 levels gradually decrease by 50% in elderly and gradually develop hypothyroidism causing myxedema
what is Hashimoto’s disease
autoimmune disease against TPO and/or Thyroglobulin causing hypothyroid disorders in areas of iodine sufficiency
-> Goiter in younger patients
treatment of Hashimoto’s disease
Levothyroxine T4 [synthetic T4]
what is the most common cause of hyperthyroidism
Graves’ disease
what is Graves’ disease
immune system produces anti-TSH receptor antibodies and binding of antibody to the receptor induces signal transduction of SH pathway resulting in T4/T3 production without TSH
T4 suppresses TSH release from pituitary [negative feedback]
