Unit 01: Thyroid gland Flashcards
what is the thyroid gland
- had diverse effects on many aspects of metabolic homeostasis
- follicular thyroid cells constitute the majority of thyroid tissue - cells can produce and secrete the classical thyroid hormones thyroxine T4, Triiodothyronine (T3) and reverse triiodothyronine (rT3)
- located in neck inferior to the larynx and spanning the ventral surface of the trachea
*main functions is to produce thyroid hormones T3 and T4 - hormones built on backbone of two tyrosine molecules that are iodinated and connected by an ether linkage
what do thyroid hormones do?
major product of the thyorid gland
major poduct if T4
- T3 and rT3 re largely produced by peripheral tissues by the action of deiodinases, D1 D2 and D3
what are deiodinases
family of enzymes that are important int he activation and deactivation of thyroid hormones
- activation occurs when the prohormone thyroxine is transformed into active hormone T3 through removal of an idoine atom from the outer ring
describe the inactivation of thyroid hormones
occurs when an iodine atom is fromoved from thyroxine or the inner ring to generate inactive rT3
- generally, D1 is important for converting T4 tot he majority of serum T3, D3 converts T4 to T3 locally and D3 converts T4 to biologically inactive rT3
describe the structure thyroid hormones
- Thyroid hormones are synthesized from two derivatized tyrosine molecules that are attached by an ether linkage.
- outer ring is hyroxylated, and inner is linked covalently to thyroglobulin during thyroid hormone synthesis. Iodine is attached to three or four positions of the tyrosine backbone, creating several different substitution patterns
T4: 4 iodines attached, 2 on each ring
T3: two idoines attached to inner ring and only to outer
rT3: has 2 iodines attached to outer and 1 on inner
describe peripheral metabolism of thyroid hormones
T4 is deiodinated by 5′-deiodinases present in target tissues and in the liver.
- the pattern of deiodination produces wither T3 ot rT3
describe the Hypothalamic-Pituitary-Thyroid Axis
- thyroid hormone reg follows a negative regulatory feedback scheme
- TRH is a tripeptide secreted by the hypothalamus that travels via the hypothalamic pituitary portal circulation to the anterior pituitary glang
- it is secreted at an inc rate to promote thermogenesis during cold exposure
- TRH binds to a G rpotein coupled recetpor lecated on PM of nterior pituitary gland thyrotropes or TSH-producing cells, it stimuilates thyrotropes of the anterior pituitarygland to release thyroid stimulating hormone
- this stim a signal transduction cascade that ultimately promotes the synthesis and release of TSH
*TSH is the msot important direct regualtor of thyroid gland function and production of T4 and T3
- thyroid hormones inhibit further release of TRH and TSH by the hypothalamus and anterior pituatiry respectively (neg feedback)
what inhibits production of TSH
TH inhibits further release of TRH and TSH by the hypothalamus and anterior pituitary gland, respectively.
how is iodine collected to synthesize thyroid hormones
- iodine is a trace element thats crucial for thyroid hormones
- thyroif follicular cells synthesize and secrete thyroid hormones, selectively concentrate idoine via Na+/I- symporter located on basolateral membrane of the cell
- once insdie the thyroid gland follicular cells - iodine is transported across apical membrane of cella dn concurrently oxidized by the enzyme thyroif peroxidase
once iodine is present for TH synthesis, what happens to the iodine
- an oxidation reaction creates a reactive iodine intermediate that couples specifically to tyrosine residues on thyroglobulin
- thyroglobulin is a proteins ynthesized by thyroid follicular cells and secreted at the apical surface intot eh colloid space
*process of thyroglobulin iodination is knwon as organification, results in thyroglobulin molecules containing monoiodotyprsine (MIT) and Diiodotyrosine DIT residues
how are T3 and T4 formed
After MITs and DITs are generated within thyroglobulin, thyroid peroxidase also catalyzes coupling between these residues.
An MIT joined to DIT generates T3
joining of two DITs creates T4
These thyroglobulin molecules are then stored in the lumen of the follicle as colloid
- when TSH stimulates the thyroid gland to secrete thyroid hormone, the follicular cells endocytose colloid and it enters lysosomes where proteases digest the contents
*digestion releases free T3 and T4 which are transported across the follicular basolateral membrane intot he blood
describe thyroid hormone synthesis, storage and release
- follicular cells of the thyroid gland concentrate idode I- fromt he plasma via a basloateral membrane Na+/I- symporter
- through organification catalyzed by thyroid peroxidase, intracellular iodide reacts covalently with tyrosine residues on thyroglobulin molecules at the apical membrane
- addition of one I- to tyrosine results in formation of monoiodinated tyrosine MIT, and addition of 2 forms diioinated tyrosine DIT
- MIT and DIT ssociate on thyroglobulin via coupling catalyzed by thyroid peroxidase
- derivitized thyroglobulin is stored as colloid within follicles in the thyroid gland
- when stim by TSH, thyroif follicular cells endocytose collid into lysosomal compartments, where the thyroglobulin is degraded and yield free T4. T3 an uncoupled MIT and DIT
*T3 and T4 are secreted into the plasma, and MIT and DIT are deiodinated intracellularly to yield free iodide for use in new thyroid hormone synthesis (not shown). The thyroid gland secretes more T4 than T3, although T4 is converted to T3 in peripheral tissues
describe the ratios of T3 and T4, how they circulate and elimination
- ratio of 4 T4s for eveery T3 in the thyroid
- majority (99%) circualtes int he blood bound to thyroid binding globulin
- elimination 1/2 life of T4 is 7 days vs one day for T3
- peripheral conversation of T4 to T3 occurs by the enzyme deiodinase
*T3 has 4x the biologic potency as the prohormone T4
where is D1 expressed? where is D2 expressed?
D1 is expressed in the liver, kidney, thyroid, skeletal and cardiac muscle
D2 is expressed primarily in the pituitary gland and brain.
what are teh effects of thyroid hormones
- act on target tissues mediated by nucelar events and proteins ynthesis
- similar to cortisolm thyroid hormone plays a role in the regulation of carbohydrate, lipid and protein metabolism
- Th also affects oxygen consumption by modulating the sodium potassium pump
actions on growth and development (nervous, skeletal and reproductive tissue) and cardiovascular system have been reported
what is hypothyroidism
- most common thyroid disorder
- primary hypothyroidism is most common, involves issue with the thyroid tiself
- secondary hypothyroidism is in the form of TSH insufficiency from the pituitary
- iodine dificienc can also result in hypothyroidism in cildren or adults and is the most common cause of hypothyroid worldwide
wha is cretinism
- Hypothyroidism may also manifest as cretinism
- congenital condition characterized by arrested physical and mental development caused by hypofunction or absence of the thyroid gland
decribe Autoimmune thyroiditis or Hashimoto’s thyroiditis
most common cause of hypothyroidism in first world countries
occurs when autoantibodies against thyroid peroxidase and potentially against thyroglobulin and TSH receptor are produced -> causing destruction of the thyroid gland.
what is iatrogenic hypothyroidism
hypothyroidism as the result of medical intervention
-common causes are surgery, radioactive iodine for hyperthyroid treatment, chemotherapy for toher cancers and drugs like thioamides
what are the signs of hypothyroidism
- slowing of bodily functions including NS, cardiovasuclar system and energy metabolism
common symptoms are lethargy, weakness, fatigue, cold intolerance, decreased libido, weight gain and brady cardia
- severe hypothyroidism or myxedema is dangerous bc it cna cause water intoxication, hypothermia, hypoglycemia, hypoventilation, hyponatremia, shock or even coma
- can also cause goiter - enlargement of thyroid gland - can form due to an iodine deficiency, neoplasms or autoimmune destruction.
what is levothyroxine
synthetic form of the thyroid hormone thyroxine (T4), used for replacement therapy in clinical hypothyroidism
- has a long 1/2 life (7 days) allows for once a day daily dosing
- bc T4 is the main thyroid hormone circulating in the blood it is easily monitored
- steady state levels of T4 requires 6-8 weeks of therapy
what is liothyronine
almost identical to T3 also can be prescribed but not often
what is liotrix
mixture of T4/T3 in a 4:1 ratio
- it is very expensive and high risk patients (long-standing hypothyroidism, elderly and cardiovascular disease) are cautioned to use an initial low dose due to cardiac adverse effect
