3 Thyroid Flashcards
Largest endocrine gland
Thyroid
10-20g, 2 lobes joined by isthmus
The thyroid is highly vascularized, and receives _____ of total blood flow
2%
Receives entire cardiac output in ~1 hour
By what gestational age is the hypothalamus-pituitary-thyroid axis functional?
12 weeks
Thyroid secretion in utero is critical in …
Myelination of the CNS, neural sprouting, and growth of fetus
Deficiency during gestation leads to cretinism (severe growth and cognitive defects)
What is the functional unit of the thyroid?
Follicle
Follicular cells surround a lumen filled with colloid, the storage site for hormones
Also contains parafollicular cells that release calcitonin
Reabsorption of colloid is altered in the diseased state
What are the four major steps involved in the synthesis of thyroid hormones
Uptake of iodide
Incorporation (organification) of iodide into tyrosine
Coupling of iodinated tyrosine to form the thyroid hormone
Diffusion of thyroid hormones into the blood
Thyroid hormone synthesis and release are under feedback control by …
The hypothalamic-pituitary-thyroid axis
TRH binds to a receptor on the thyrotrophs, resulting in the release of TSH
TSH is transported to the thyroid gland, where it binds to a TSH receptor on the basolateral membrane of the follicular cell
TSH receptor activation results in …
The stimulation of all steps in thyroid hormone synthesis, including iodide uptake, organification, and release of thyroid hormones
Biologic effects of TSH include stimulation and gene transcription of…
Na+ Iodide Symporter (NIS)
Thyroglobulin (Tg), the glycoproteins that serves as a scaffold for tyrosine iodination as well as storage of thyroid hormone
Thyroid peroxidase (TPO), the enzyme involved in the oxidation of iodide and its incorporation into tyrosine residues of Tg
Synthesis of thyroid hormones T4 and T3
Where does synthesis of T4 and T3 occur?
Within the cytosol of the follicular cell and the colloid
It is both intracellular and extracellular
_____ is the major product of thyroid synthesis.
T4
T4 is a prohormone, and not the most active form of thyroid hormone
Peripheral conversion of T4 to T3 is facilitated by…
Specific peripheral deiodinases
They are responsible for deactivation of thyroid hormones as well
Iodide must be supplied from…
Diet
The body stores it but doesn’t produce it.
Daily intake of iodide is ______, but only _____ is taken up by the thyroid.
400µg, but only 80µg taken up
Total iodide content of thyroid
~7500 µg in the form of iodothyronine
~70-80µg is released as HI or free
Large ratio (100:1) of iodide in the form of hormone to amount the turned over daily protects from iodide deficiency
How long does the body’s stores of iodide last before deficiency symptoms begin?
~2 months
Tyrosine and iodide are taken up from the blood by…
The follicular cells
Tyrosine is endogenous, while iodide is obtained from diet and taken up by the Na+ iodide symporter (NIS)
Where are NIS found?
On basal surface membrane of the follicular cell
2 Na+ ions are transported into the cytosol of the follicular cell with each iodide molecule where it is concentrated
Na+ moves down its concentration gradient, maintained by the Na+K+ATPase
How does iodide get from the follicular cell into the colloid
Facilitated in part by effluent through the iodide channel anoctamin-1 on the apical membrane
One of the effects of TSH (after binding to receptor) is to open both the NIS and anoctamin-1 channels
Activity of the NIS is modulated by…
Diet and Disease states
Low iodide diet —> NIS is increased to compensate for deficiency
Kidneys will compensate to reduce excretion of iodide
If iodide is absent, this leads to hypothyroidism
Mutations in NIS cause hypothyroidism
NIS is an autoantigen in autoimmune disease
Why do you get a goiter with hypothyroidism?
NIS activity is increased when iodide is lacking in the diet but the goiter is the result of enhanced TSH activity on its receptor, enhancing the tropic effect. Because little thyroid hormone is being produced, there is no negative feedback shutoff of TSH
Congenital iodide transport defects are the result of mutations in …
NIS gene
ITD is characterized by hypothyroidism, goiter, and reduced uptake of radio-iodide
Six ITD-causing mutations of NIS have been identified
Other than in the thyroid gland, where else do NIS exist?
In the gastric mucosa, placenta, and lactating mammary glands where it mediates uptake of iodide
In the lactating gland, NIS plays a role by concentrating iodide in milk, thereby supplying newborns with iodide for thyroid hormone synthesis
The transport of iodide in these tissues is NOT under TSH regulation
What causes Grave’s disease?
Autoantibodies are produced against the TSH receptor and NIS. Thyroid-stimulating immunoglobulins bind to and activate the receptor, stimulating growth —> hyperthyroidism
How is radioactive iodine uptake (RAIU) used to measure thyroid function?
NIS reflects activity of the thyroid gland
Tracer dose of I-123 labeled iodine is given and uptake measured by gamma detection
In normal conditions, 15% uptake after 6 hours
You’ll see an organification defect when perchlorate is administered (because iodine cannot be incorporated into tyrosine)
Once iodide is inside the cell, it is transported to the apical membrane by ______.
Pendrin, which belongs to the solute carrier family (SLC26A), and secretes iodide into the follicular lumen.
Pendrin is also expressed in the inner ear and is important in endocochlear potential and structural development
At the apical luminal membrane, iodide is oxidized to iodine by…
Thyroid peroxidase (TPO)
The oxidizing agent is H2O2
Mutations in the Pendrin gene lead to…
Pendred Syndrome (150 mutations have been reported with high heterogeneity)
Goiter develops during childhood. Variability in the expression of the phenotype.
Hearing loss also evident
If iodide intake is scarce, patients with Pendred syndrome develop goiter and overt hypothyroidism
Glycoproteins produced in the cytosol of the follicular cell and containing 132 tyrosine residues
Thyroglobulin (Tg)
Within the colloid, iodine attaches to a tyrosine on Tg
Tg is contained in vesicles and transferred to apical membrane for thyroid hormone synthesis
~20% of residues are iodinated, and only ~5% will become coupled to become active thyroid hormones
The vesicles containing Tg also contain TPO
Iodination of Tg by iodine is catalyze by…
TPO
Iodine bonds to carbon 3 or 5. Iodination yields monoiodinated tyrosine (MIT) and diiodinated tyrosine (DIT)
Iodine metabolism within the cell can also be regulated independently of TSH. This is important when plasma iodide levels are elevated (15-20x above normal) b/c this effect inhibits organification.
What is this effect called?
Wollf-Chaikoff Effect
Excess iodine (ie from diet) inhibits organification and downstream synthesis of thyroid hormones (less T4 is released)
Inhibition is temporary - may last for a few days, until intrathyroidal levels of iodine drop and iodine resumes the normal synthesis of thyroid hormones
After iodination of tyrosine, the next step in thyroid hormone synthesis is…
Coupling of iodinated tyrosine residues (enzymatically catalized by TPO)
Two DIT molecules can couple to form T4 (Tetraiodothyronine), or one MIT and one DIT couple to form T3 (triiodothyronine)
The Tg molecule, along with T3 and T4, remain stored in colloid until the cell is stimulated by TSH
Following stimulation by TSH, follicular cells…
Engulf colloid containing Tg and T3/T4 by megalin
Lysosomes target the engulfed colloid and protease split the iodinated products from the thyroglobulin
T3 and T4 diffuse out into the blood
In follicular cells, MIT and DIT are deiodinated by …
Intrathyroidal deiodinases —> allowing free iodine to be recycled for de novo synthesis of T3/T4
Minor levels of Tg leaking into the plasma is …
Normal
Hyperthyroidism is associated with higher Tg levels in plasma though.
What are the inhibitors of synthesis of Tg and iodide uptake?
Perchlorate and this ya ate
What is the inhibitor of Oxidation of iodide, organification, and coupling?
Propylthiouracil
____% of thyroid gland output is T4, ____% is T3, and ____% is rT3
~90% is T4
~10% is T3 (ACTIVE)
<1% is rT3
In the plasma, T3 and T4 bind to …
Thyroxine-binding globulin (TBG)***
Albumin
Transthyretin
Lipoprotein
_____% of circulating T4 is bound
_____% of circulating T3 is bound
- 98% T4 is bound (only 0.02% free)
99. 5% T3 is bound (0.5% free and ACTIVE)
T4 has 4 iodine molecules
T3 has been deiodinated in the ______ position and rT3 in the ________ position
T3 = outer 5’ (it still has an inner 5)
rT3 = inner 5 (it still has an outer 5’)
Deiodinases 1 and 2 perform ______ ring deiodination, converting T4 to _____ by removing the iodine in the ______ position.
Outer ring deiodination
T3 (active)
Outer 5’
Deiodinase type 3 performs ______ ring deiodination, converting T4 to _____ by removing the iodine in the ______ position.
Inner ring deiodination
rT3 (inactive)
Inner 5
Sequential deiodination results in conversion of …
T4 to T3
T4 to rT3
T3 to T2
rT3 to T2
Thyroid hormones can undergo conjugation in the ______.
Liver
Hepatic sulfa- and glucuronide conjugation increases their solubility and biliary excretion
Effects of thyroid hormones are primarily…
Genomic effects - mediated primarily by the transcription regulation of target genes
Nongenomic effects of thyroid hormones include…
Ca2+ ATPase at the plasma membrane and SR
Na+/H+ anti porter in muscle
Oxygen consumption
In other words, rapid effects on ION FLUXES (predominantly in the CV system)
What transporters allow thyroid hormones to enter cells?
Na+ taurochlorate cotransporting peptide (NTCP)
Na+-independent organic anion transporting polypeptide (OATP)***preference for T4
L- and T-type amino acid transporters (LAT)
Monocarboxylate transporters (MCT)***preference for T3
Mutations in the _________ are associated with psychomotor retardation and thyroid hormone resistance
MCT class (MCT8 gene)
Once free extracellular thyroid hormone enters a cell, T4 is deiodinated so that T4 and T3 levels are equal. Then what happens?
Thyroid hormone receptors bind to nuclear DNA on the Thyroid Response Element (TRE) in the promoter region of genes regulated by T3 and T4. Binding to the TR regulates transcription.
Thyroid receptors have a __________ affinity for T3 than T4
10-fold greater
This makes T3 more potent, and it is responsible for 90% of occupancy of TRs
Calorigenic actions of thyroid hormones
Increased O2 consumption —> increased BMR and body temperature
Mechanism: increasing activity of the Na-K ATPase pump
Calorigenic effects of thyroid hormone occur in all tissue except…
Brain
Gonads
Spleen
Physiologic effects of thyroid hormones on metabolism
Increased glucose absorption from gut
Increased gluconeogenesis
Increased lipolysis
Increased protein synthesis and proteolysis (futile cycling)
Net degradation of tissue protein (negative nitrogen balance)
Physiologic effects of thyroid hormone on CV system
T3 increases cardiac output and ventilation
T3 is chronotropic and inotropic
T3 reduces vascular resistance
Physiologic effects of thyroid hormones on Sympathetic nervous system
Increased synthesis of ß adrenergic receptors in cardiac/skeletal muscles and adipocytes (heterologous up-regulation)
During fetal development, thyroid hormones work synergistically with…
GH and growth factors, to promote bone formation
Anabolic in nature —> stimulates protein synthesis
TH also essential for normal maturation of the CNS, axonal growth, and myelination
Low thyroid status during development is detrimental and detection is critical (dysfunction at birth can be reversed with rapid treatment).
Secretion of thyroid hormone is regulated by…
TRH, dopamine, somatostatin, TSH, and peripheral T4/T3
T4 and T3 inhibit release of _____ by down-regulating the TRH receptor on thyrotrophs
TSH
The key hormone for negative feedback on TSH is free T3 from plasma
Treatment options for hyperthyroidism
Surgical removal of gland/part of gland
Radioactive I-131 to destroy gland
ß-adrenergic antagonists to decrease the effects of excessive adrenergic stimulation
Propulthiouracil (PTU) to inhibit oxidation, coupling, and decreasing conversion of T4 to T3
Why does hyperprolactinemia sometimes co-occur with hypothyroidism?
The lack of negative feedback means TSH is high and TRH is continuing to secrete. TRH increases prolactin synthesis.
BMR in hypo vs hyper thyroid
Hypo: Decreased
Hyper: Increased
Carb metabolism in hypo vs hyper thyroid
Hypo: decreased gluconeogenesis and glycogenolysis but NORMAL serum glucose
Hyper: increased gluconeogenesis and glycogenolysis but NORMAL serum glucose
Protein metabolism in hypo vs hyper thyroid
Hypo: decreased synthesis and proteolysis
Hyper: increased synthesis and proteolysis, + muscle wasting
Lipid metabolism in hypo vs hyper thyroid
Hypo: decreased lipogenesis and lipolysis but INCREASED serum cholesterol
Hyper: increased lipogenesis and lipolysis but DECREASED serum cholesterol
Thermogenesis in hypo vs hyper thyroid
Hypo: decreased
Hyper: increased
Autonomic nervous system in hypo vs hyper thyroid
Hypo: NORMAL levels of catecholamines
Hyper: Expression of ß adrenoreceptors —> increased SENSITIVITY to catecholamines (but serum levels remain normal)
