7) Thyroid Gland Flashcards
What are the three structures that produce hormones as part of the thyroid gland?
- Thyroid gland
- Parathyroid gland
- C-cells
Where is the thyroid gland located?
Below the larynx
What are the functional units of the thyroid gland?
Thyroid follicles
What is the structure of thyroid follicles?
Single layer of epithelial cells surrounding a lumen that contains colloid
Are thyroid hormones stored or secreted immediately following synthesis? Why is this particular?
Thyroid hormones are lipophilic, but they are capable of being stored within the colloid of the thyroid follicles (7-8 weeks)
What controls blood flow to the pituitary gland?
Postganglionic sympathetic nerves
What regulates T4 and T3 release?
Blood flow by affecting the delivery of TSH, iodine, and nutrients
How do thyroid follicles differ in the underactive and overactive state?
- Underactive: expansion of the colloid
- Overactive: expansion of the follicles, decrease in colloid
Where are C-cells contained?
Within the walls of the follicle
What are the two biologically active forms of thyroid hormone?
- T4
- T3
What are the two inactive forms of thyroid hormone? How are they produced?
- reverse-T3 (deiodination of T4)
- T2 (deiodination of T3)
What are the six steps required for the synthesis of T3 and T4? (6)
1) Active transport of iodine into the thyroid cell
2) Oxidation of iodide and iodination of thyroglobulin
3) Linking pairs of iodotyrosines in thyroglobulin to form T3 and T4
4) Proteolysis of thyroglobulin to release T3 and T4
5) Deiodination of iodotyrosines in thyroid cell and recycling of iodine
6) Intrathyroidal 5-deiodination of T4 to T3
What is the active transport of iodine into the thyroid cell referred as?
Trapping
What is oxidation of iodide and iodination of thyroglobulin referred as?
Organification
What is iodinated in thyroglobulin?
Tyrosyl residues
What is linking pairs of iodotyrosines in thyroglobulin to form T3 and T4 referred as?
Coupling
How is T4 converted to T3 within the thyroid?
5’-deiodination
What three components must be present for thyroid hormone synthesis?
1) Na+/I- symporter
2) Thyroglobulin
3) Thyroid peroxidase
What are the two major effects of TSH binding to its cognate receptor?
- Growth of the cell
- Synthesis of thyroid hormones
Which GPCRs do TSH-receptors contain?
- Gs
- Gq
How is iodide transported into the thyroid follicle cell from the extracellular fluid?
- Na+/I- symporter
- Na+ is brought back to the extracellular fluid with an ATPase
What are the two functions of thyroid peroxidase?
1) Iodination reaction
2) Couple MIT and DIT on the thyroglobulin molecule itself
What is the function of lysozyme in the synthesis of thyroid hormones?
Proteolytic breakdown of thyroglobulin, releasing compounds for recycling, and T3/T4
Which negative anions in the extracellular fluid block the active transport of iodine?
- ClO4-
- SCN-
- Bromide
- Nitrite
Transport of iodine into the follicular thyroid cell occurs against what type of concentration gradient?
- Steep concentration gradient
- Iodine concentration in the blood plasma is extremely low (30 to 40-fold difference)
What is used to block hyperthyroidism, while acting as an environmental inhibitor of the thyroid gland?
Perchlorate
What may be used to destroy thyroid tissue, in the case of cancer or hyperthyroidism?
Radioactive iodine (I-131)
What are competitive inhibitors of iodine uptake that are present in the diet?
- Bromide
- Nitrite
What may prevent the bioconcentration of radioactive iodine?
- Non-radioactive iodine
- Iodine itself is an inhibitor of the Na+/I- symport
- If an excess of iodine is ingested, paradoxically, hypothyroidism occurs as you inhibit more uptake of iodine
How are TPO and thyroglobulin synthesized?
- TSH stimulates their transcription and translation
- They are co-packaged into vesicles, and exocytosed into the lumen of the follicle
_____ is extensively glycosylated in the Golgi and is 10% carbohydrate by weight.
Thyroglobulin
What carries out the iodination of thyroglobulin (organification)?
Thyroperoxidase (TPO)
How is TPO activated?
At the apical membrane by cofactors
What does TPO require to function?
Hydrogen peroxide
What is the target for many drugs to reduce thyroid hormone production?
TPO
What are inhibiting compounds for TPO that are found in food?
- Goitrogens
- Present in milk from cows fed certain plants, and brassicae
What are the effects of the blockage of iodination by the inhibition of TPO?
- Results in an increased TSH production, as the negative feedback loop is cut-off
- Stimulation of the growth of the follicle, but lack of production of T4 and T3 given the inhibition of iodination
- Results in hyperplasia and goiter
Which residues of thyroglobulin become iodinated?
Tyrosines on the surface (about 1/3)
Which precursors of thyroid hormone are used to produce T3?
- MIT (monoiodotyrosine)
- DIT (diiodotyrosine)
Which precursors of thyroid hormone are used to produce T4?
2 x DIT (diiodotyrosine)
When does the coupling reaction occur based on the iodination reaction?
The coupling reaction occurs simultaneously with the iodination reaction, sometimes within the same molecule
What is the maximum of thyroid hormones produced from each protein molecule?
Four T3 and/or T4 hormones
Which thyroid precursor increases if there is an excess of iodine in the diet? Which thyroid hormone does it synthesize?
- Diiodothyrosine (DIT)
- T4
Which thyroid precursor increases if there is a deficiency of iodine in the diet? Which thyroid hormone does it synthesize?
- Monoiodotyrosine (MIT)
- T3
Why is the synthesis of T3 particularly important when iodine is deficient in the diet?
T3 is more bioactive than T4
Which thyroid hormone is produced when there is a deficiency in iodine? Which thyroid hormone is produced when iodine is in excess?
- Deficiency: T3
- Excess: T4
What is the effect of propylthiouracil (PTU)?
Blocks the iodination of thyroglobulin
Is iodine transported with or against its concentration gradient?
Against its concentration gradient
Which thyroid hormone is produced in a greater quantity?
T4 is produced in a greater quantity than T3
What are indicators of “sick euthyroid syndrome”?
- High levels of r-T3
- Low levels of T3
What is “sick euthyroid syndrome”?
- Thyroid is normally functioning
- Hypothyroidism due to a metabolic adaptation to some other condition (e.g. anorexia, cancer)
What synthesizes the carrier proteins for thyroid hormones?
The liver
Which thyroid hormone is more bound to a carrier protein?
- T4 is more likely to be bound to a carrier protein (less free T4)
- Free thyroid hormones are bioactive
What occurs if a drug competes with the binding to the carrier protein of thyroid hormones? What are the side effects?
- Elevation of free T3 and T4
- Hyperthyroidism
How does the half-life of T3 compare to T4?
T4 has a longer half-life
How does T3 compare to T4 in terms of bioactivity and half-life? How do they compare in terms of the quantity produced?
- T3 is more bioactive than T4 but it has a shorter half-life
- T4 is produced in greater quantities
What determines the free hormone concentration?
The level of binding proteins
Which conditions would result in a greater quantity of binding protein? What occurs?
- Pregnancy
- Oral contraceptives
- More total hormone are required to maintain a free hormone level
Which conditions would result in a lesser quantity of binding protein? What occurs?
- Starvation
- Liver disease
- Less total hormone are required to maintain free hormone level
What mechanisms may allow the body to react to an increased level of binding protein?
- Feedback control
- Tissue action
- Hormone metabolism
- Excretion
What are the effects of starvation on T3, T4, and r-T3?
- Starvation decreases binding proteins
- T3 and T4 decrease as a lesser quantity is required to maintain the free hormones
- r-T3 levels increase
What is the function of a type I deiodinase? Where does it occur?
- T4 –> T3
- Liver, kidney, muscle (peripheral conversion)
What is the function of a type II deiodinase? Where does it occur?
- T4 –> T3
- Brain, pituitary
Which deiodinase is key for the feedback on TRH and TSH?
Type II deiodinase
What is the function of a type III deiodinase?
- T4 –> rT3
- Inactivation if T3 is in excess (rT3 –> T2)
Which rare amino acid do the three deiodinases contain?
Selenocysteine (containing selenium)
What is the mechanism of action of type I and type II deiodinases?
Bioactivate the thyroid hormone by removing a single “outer-ring” iodine atom
What is the mechanism of action of type III deiodinases?
Inactivates the thyroid hormone by removing a single “inner-ring” iodine atom
Describe the basic organization of the selenodeiodinases.
- Membrane-bound proteins, containing an extracellular, transmembrane, and intracellular domain
- Exist as a dimer
What are the three physiological functions of deiodinases?
1) Permit local tissue and cell modulation of the thyroid hormone
2) Aid in the adaptation to changes, including iodine deficiency or chronic illness
3) Regulate thyroid actions during early development
How does type III deiodinase fluctuate during hyperthyroidism and hypothyroidism?
- Increases during hyperthyroidism
- Decreases during hypothyroidism
What occurs to the portion of T4 that is NOT metabolized by deiodination (20%)?
Inactivated by the liver by glucoronidation and biliary secretion
Where is type I deiodinase located within the cell?
Cytosol
Where is type II deoiodinase located within the cell?
Bound to the endoplasmic reticulum
Where is type III deoiodinase located?
Extracellular
What are the two major effects of thyroid hormone?
1) Growth and development
2) Maintenance of basal metabolic rate
Which thyroid hormone receptor modulates gene transcription more than the other thyroid hormone?
T3 > T4
What are the effects of injection of T3 into thyroidectomized rats?
Rapid increase in transcription and translation, as well as tissue growth
How may thyroid hormone receptors influence transcription?
They may activate or inactivate transcription
What are the possible structures of thyroid hormone receptors?
- Monomers
- Homodimers
- Heterodimers
Which two genes encode the T3 and T4 receptor? How many receptors do they each give rise to? How?
- TRA and TRB
- Each gives rise to two receptor proteins by alternative splicing
What modulates the effect of T3 and T4 on different tissues?
Tissue-specific expression of T3 and T4 receptors
Where is the T3/T4 alpha-1 receptor located?
Widely distributed
What is the function of the T3/T4 alpha-2 receptor?
- Acts as an inhibitor
- Binds to TRE sequence, but NOT to T4 or T3
Does the alpha-2 receptor bind to T4 or T3?
No
Where is the T3/T4 beta-1 receptor located?
Widely distributed
Where is the T3/T4 beta-2 receptor located?
Anterior pituitary or specific brain regions
Are there solely four classes of T3/T4 receptors?
No, they may undergo further processing to form other types of receptors
What results from the binding of T3 to the thyroid receptor?
Results in the displacement of the repressor complex, and the assembly of an activator complex to allow transcription to start
How do thyroid hormones act on the mitochondria?
Activate genes associated with thermogenesis
What is the function of T2 in terms of thermogenesis?
T2 binds to cytochrome c to increase oxidative phosphorylation
What is the function of T3 in terms of thermogenesis?
- T3 binds to uncoupling proteins to increase heat production
- T3 binds to the thyroid receptor to increase mitochondrial transcription
In addition to a nuclear receptor, how may T4/T3 act in terms of signal transduction? What are the effects?
- Via a GPCR
- Activates MAPK, STAT, and PLC pathways to alter gene transcription within the cell
What are the physiological effects of thyroid hormone on the heart?
- Increased strength of heart beat
- Increased heart rate
What are the physiological effects of thyroid hormone on adipose tissue?
- Catabolic
- Stimulates lipolysis
What are the physiological effects of thyroid hormone on muscle?
- Catabolic
- Increases protein breakdown
Which tissues do not respond to excess heat production by thyroid hormones?
- Testes
- Uterus
- Lymph nodes
- Spleen
- Anterior pituitary
What is the effect of the calorigenic action of thyroid hormones?
Increase in oxygen consumption and heat production in metabolically active tissues
How does the kinetic calorigenic action of T4 compare to T3? Which thyroid hormone is used in pharmacology?
- The response of T3 is more rapid
- The response of T4 lasts longer
- T4 is used in pharmacology
How does calorigenesis affect nitrogen excretion?
- Increased nitrogen excretion
- Protein turnover increases leading to decreased skeletal muscle
How does calorigenesis affect weight?
Weight loss due to catabolism of fat and protein (unless balanced with food intake)
How does calorigenesis affect growth in children? What is the effect?
- Small doses produce a positive nitrogen balance
- T4 stimulates growth
How does calorigenesis affect vitamin supply?
Increased metabolism requires increased vitamin supply
How is T4 related to carotenemia (yellowish tint of the skin)?
T4 is required for hepatic conversion of carotene to vitamin A in the liver
What is myxedema? What is the cause?
- Puffiness of the skin due to a lack of degradation of proteins, polysaccharides, and hyaluronic acid
- Due to a lack of T4
How does calorigenesis affect erythropoiesis?
Increased erythropoiesis de to increased demand for cellular oxygen
How does calorigenesis affect gut motility? What may that lead to if hyperthyroidic?
- Promotes gut motility
- May lead to hyperdefecation if hyperthyroidic
What are the two heat dissipation mechanisms activated by a rise in body temperature?
1) Cutaneous vasodilation (decreased resistance to peripheral blood flow)
2) Increased of cardiac output (increase pulse pressure and cardiac rate)
Which hormones increase cardiac output?
- T3/T4
- Catecholamines
What triggers the mechanism of action of heart myocytes? Where does it come from? Why?
- T3
- From circulation
- Since myocytes lack the deiodinase to form T3 from T4
Which genes are turned on by T3 within heart myocytes?
- a-myosin heavy chain (high ATPase activity)
- Sarcoplasmic reticulum Ca2+ ATPase
- B-adrenergic receptors
- G-proteins
- Na+-K+-ATPase
- Some K+ channels
Which genes are inhibited by T3 within heart myocytes?
- B-myosin heavy chain (low ATPase activity)
- Two types of adenylyl cyclase
- T3 nuclear receptor
- Na+-Ca2+ exchanger
What is the net result of T3 on heart myocytes?
Increased heart rate and force of contraction
Which myosin heavy chain contracts more rapidly?
The a-myosin heavy chain contracts more rapidly than the B-isoform
How does the action of catecholamines compare to T4 and T3?
- They have similar effects, but of shorter duration
- Increase in metabolic rate, stimulation of the nervous system, cardiovascular effects
How does the injection of T4 influence catecholamines?
Injection of T4 increases toxicity of catecholamines according to rat studies
What is the effect of blocking B-adrenergic receptors on the action of T3 and T4?
Reduces the action of T3/T4
What type of drug is used to treat thyroid storms?
Beta-blockers
What is a thyroid storm?
- Thyroid hormone toxicity induced by infection, trauma, drugs
- May be lethal if not treated immediately
What is the effect of hypothyroidism on the nervous system?
- Slow mentation
- Elevated protein levels in the cerebrospinal fluid
- Usually placid, but can be severely depressed or agitated
Which nervous system cells convert T4 to T3?
Astrocytes
How does hypothyroidism affect responsiveness to catecholamines within the nervous system?
Increased responsiveness to catecholamines
How does a lack of T3/T4 during development affect the nervous system?
- Mental retardation
- Motor rigidity
- Deaf-mutism (cretinism)
How does hyperthyroidism affect skeletal muscle?
- Muscle weakness due to increased protein catabolism
- Thyroxin affects the expression of myosin heavy-chain genes
How does hypothyroidism affect skeletal muscle?
- Muscle weakness
- Cramps
- Stiffness
What are the effects of thyroid hormone on carbohydrate metabolism?
Increase absorption of carbohydrate from the GI tract
What are the effects of thyroid hormone on cholesterol metabolism? Is it dependent or independent of calorigenic action?
Decrease of cholesterol levels (independent of calorigenic action)
Why do cholesterol levels decrease in response to thyroid hormones?
Due to the increase of LDL receptors in the liver (hepatic clearance of cholesterol)
What are thyroid hormones required for in terms of the reproductive system?
- Required for normal follicular development and ovulation
- Required for the normal maintenance of pregnancy
- Required for normal spermatogenesis in the male
What are the effects of thyroid hormones in terms of growth and tissue development?
- Increase in growth and maturation of bone
- Increase in tooth development and eruption
- Increase growth and maturation of the epidermis, hair follicles, and nairs
- Increase rate and force of skeletal muscle contraction
Is hypothyroidism or hyperthyroidism associated with myxedema?
Hypothyroidism
What is myxedema? Why does it occur?
- Puffiness associated with accumulation of mucopolysaccharides under the skin
- Thyroid hormones inhibits the synthesis and increases the degradation of mucopolysaccharides in subcutaneous tissue
What are signs and symptoms of hypothyroidism?
- Deficiency results in slowing-down metabolism
- Fatigue, coldness, weight gain, constipation, low voice
- Cool skin, dry skin, swelling of face/hands/legs, slow reflexes, myxedema
What are the effects of hypothyroidism in infants and children?
- Retardation
- Short stature
- Swelling of face/hands
- Possible deafness
What is primary hypothyroidism?
- Due to a failure of the thyroid gland
- Most common cause
What is secondary hypothyroidism?
- Due to a failure of the pituitary
- TSH deficiency
What is tertiary hypothyroidism?
- Hypothalamic failure
- TRH deficiency
How is the cause of hypothyroidism determined?
Determined by geography
How is primary hypothyroidism diagnosed?
- Low free T4
- High TSH
What must be checked if an individual presents low free T4 and high TSH?
- Must check for antibodies
- Primary hypothyroidism is associated with Hashimoto’s disease (autoimmune disease)
What is Hashimoto’s disease?
- Autoimmune disease
- Thyroid tissue is being destroyed by the immune system
How is secondary or tertiary hypothyroidism diagnosed?
- Low free T4
- Low TSH
- TRH stimulation test
- MRI
What is the treatment of hypothyroidism?
- Levothyroxine (T4)
- T4 is used due to its longer half-life
What may the treatment of hypothyroidism prevent?
- Bone loss
- Cardiomyopathy
- Myxedema
What may cause an iodine deficiency?
- Deficient intake
- Perchlorates and other treatments that inhibit the sodium-iodine symporter
How does iodine deficiency affect goiter?
- Elevated TSH due to a decrease in negative feedback
- Results in the enlargement of the thyroid to increase efficiency of iodine uptake
What is the effect of iodine deficiency during pregnancy?
- Results in neurological damage (cretinism)
- Can easily be prevented by iodine supplements
How do large doses of iodine affect thyroid hormones?
May inhibit synthesis and excretion of thyroid hormones
Which sociological populations are affected by iodine deficiency?
- Underprivileged countries
- Iodine deficiency is still a huge problem worldwide
- But, it may be prevented by iodized salt
How does hypothyroidism affect growth in children? How does it affect GH?
- Slowed bone growth
- Delay of epiphyseal closure
- GH secretion is depressed, as T3/T4 potentiate the effect of GH on tissues
How does euthyroidism affect iodine concentration in the urine, thyroid, and plasma following iodine ingestion?
- Iodine is rapidly absorbed from the oral dose, rising in concentration within the plasma, and then falls off
- Most of the iodine is cleared from our blood via urine
- Some is incorporated into MIT and DIT within the thyroid
How does the quantity of iodine excreted in urine in an hyperthyroidic individual compare to a euthyroid individual?
The amount cleared in the urine is much LESS
How does the quantity of iodine incorporated into the thyroid in an hyperthyroidic individual compare to a euthyroid individual?
The amount incorporated into the thyroid is much HIGHER
How does the quantity of iodine excreted in urine in an hypothyroidic individual compare to a euthyroid individual?
The iodine is cleared at a similar quantity, but at a much slower rate because there is less incorporated into the thyroid gland itself
How does the quantity of iodine incorporated into the thyroid in an hypothyroidic individual compare to a euthyroid individual?
The amount incorporated into the thyroid is much LOWER
What are causes of congenital hypothyroidism?
- Maternal iodine deficiency
- Abnormal development of the fetal thyroid
- Inborn errors of thyroid hormone synthesis
- Maternal anti-thyroid antibodies that cross the placenta
- Fetal hypopituitary hypothyroidism
May growth be restored in hypothyroidic children? How?
Yes, by injecting exogenous T4 or providing iodine (depending on the reason for hypothyroidism)
Which patients typically develop a myxedema coma? When?
- Untreated hypothyroidism that occurs typically in older patients
- During the winter
What are symptoms of a myxedema coma?
- Hypoglycemia
- Hypothermia (hypothyroidism = not responsive to temperature control)
- Eventually, progessing to a coma and death
Which age group possesses the higher level of T4? How does that fluctuate with age?
- T4 is highest in young children
- Decreases to adult levels at puberty, and remains stable until about 60 years old
- Then, gradually decreases, and the elderly are susceptible to hypothyroidism
What is the major cause of hypothyroidism in areas of iodine sufficiency?
Hashimoto’s disease
Is Hashimoto’s disease associated with goiter, or no?
May be associated with goiter, or no goiter
What is the pathogenesis of Hashimoto’s disease?
- Immune system attacks and gradually destroys the thyroid gland
- Circulating antibodies against antigens present in the thyroid
- Infiltration by lymphocytes gradually interfere with normal thyroid function
What is the immune response normally directed against in Hashimoto’s disease?
Thyroid peroxidase and/or thyroglobulin
Which age and sex group is Hashimoto’s disease commonly present?
Females aged 30 to 50 years old
What are the laboratory values of Hashimoto’s disease in terms of TSH, T4, and antibodies?
- High TSH
- High TRH
- Low T4 (thyroid tissue is destroyed)
- Anti-TPO Antibody
- Anti-TG Antibody
How is Hashimoto’s disease treated?
Levothyroxine (T4)
What is the most common cause of hyperthyroidism?
- Grave’s disease
- An overproduction of thyroid hormone, which causes the enlargement of the thyroid
What are signs and symptoms of Grave’s disease?
- Palpitations
- Nervousness
- Fatigue
- Diarrhea
- Sweating
- Heat intolerance (accelerated metabolism)
- Thyroid enlargement
What is the cause of Grave’s disease?
- The immune system produces anti-TSH receptor antibodies
- The binding of the antibody to the receptor induces the signal transduction of the TSH pathway, resulting in more T4
How does Grave’s disease affect TSH secretion?
T4 produced suppresses TSH release from the pituitary by negative feedback
How may the antibodies produced in Grave’s disease affect ophthalmopathy?
- Increase in glycosaminoglycans
- Swelling in muscle and connective tissues behind the eyes
- Causes eye bulging
What are the laboratory values of Grave’s disease in terms of TSH, T4, and antibodies?
- Low TSH
- Normal/high T4
- Anti-TSH receptor antibody
How long does Grave’s disease take to diagnose?
- Symptoms develop slowly
- Grave’s disease requires around 3 years to diagnose
What are the three possible treatments for Grave’s disease?
- Medical: anti-T4 compounds that inhibit the production of MIT, T3, and T4
- Surgical: subtotal thyroidectomy
- Radiation: bioconcentration of a radionucleotide that destroys the thyroid from the inside-out
Which types of tumours may cause hyperthyroidism? Which is common, and which is rare?
- Common: T4-secreting tumours
- Rare: TSH-secreting tumours
What are causes of thyroid storms?
- Thyroid surgery
- Trauma
- Severe illness
- Infections
How does a thyroid storm affect the response to catecholamines?
Increases the response to catecholamines
What is the treatment for a thyroid storm?
- Anti-thyroid drugs
- B-blockers
