CH4 Thyroid Gland Flashcards
What regulates production of Thyroid Hormone?
TSH & Iodine
What are inhibitors of Thyroid Hormone synthesis? Where do they cause inhibition?
T4 & T3 (feedback inhibition) at TRH & TSH; dopamine, somatostain, & glucocorticoids inhibit at TSH
What are the major cells of the Thyroid Gland? What do they do?
Follicular (epithelial) Cells - thyroid hormone synthesis, Parafollicular (C) Cells - production of calcitonin
What is the functional unit of the Thyroid Gland? What is it composed of?
thyroid follicle: layer of thyroid epithelial cells arranged around a large central cavity filled with colloid (thyroglobulin Tg)
What occurs at the apical and basolateral ends of thyroid epithelial cells?
basolateral (facing circulation) - iodide uptake & T4 (tetraiodothyronine) deiodination; apical (facing colloid) - iodide efflux & iodination mechanisms (iodination of tyrosine residues on protein Tg)
What do Parafollicular Cells do?
secrete the hormone Calcitonin
What is the vasculature of the Thyroid Gland?
superior & inferior thyroid arteries; superior, middle, & inferior thyroid veins
What innervates the Thyroid Gland?
Middle & Inferior cervical ganglia of the Sympathetic Nervous System
Which polar end of Thyroid Follicular Cells are TSH receptors located?
basolateral end (facing circulation)
What type of receptor is the TSH receptor? What happens when bound to TSH?
Gs AND Gq; PKA regulates iodide uptake, activity of the Sodium-Iodide (Na+/I-) Symporter, & transcription of Thyroglobulin TG + Thyroid Peroxidase TPO; Ca++ regulates iodide efflux (Apical Iodide Channel), H2O2 production, and Thyroglobulin Tg iodination
What is Grave’s Disease?
thyroid autoimmune disease - Antibodies to the receptor act as agonists mimicking the actions of TSH (hyperthyroidism); can see hyperplasia of thyroid gland (enlargement/ aka goiter)
What is Hashimoto Thyroiditis?
thyroid autoimmune disease - Antibodies to the receptor act as ANTagonists (hypothyroidism)
How does TSH cause thyroid hyperplasia?
via hyperthyroidism. Growth and function of the thyroid are stimulated by rise in cAMP production via TSH stimulation
What is the mechanism of T3/T4 negative feedback inhibition?
Circulating T4 is taken in by cells of the hypothalamus & pituitary gland. Type II Deiodinase converts T4 –> T3. T3 exerts its inhibitory effects.
How does the Thyroid Gland concentrate iodide?
energy-dependent Sodium-Iodide (Na+/I-) Symporter; 2:1 ratio
How does Iodide get into the follicular lumen?
efflux of iodide is achieved by the Iodide Channel, which was opened when TSH bound (Gq - Ca++ effects)
Describe how Organification of Iodine occurs.
Organification of Iodine is the use of Iodide, Hydrogen Peroxide, & a tyrosine residue of Tg (via Thyroid Peroxidase) to form Monoiodotyrosine (MIT) or Diiodotyrosine (DIT).
Describe Thyroid Hormone Synthesis, starting with binding of TSHs to basolateral TSH receptors & ending with secretion of Thyroid Hormones.
TSH binds to TSH receptors (both Gs & Gq). Gs (adenylate cyclase) pathway stimulates Iodide Uptake (Na+/I- symporter 2:1), transcription of Tg + TPO. Gq (phospholipase C) pathway stimulates iodide efflux (Iodide Channels), H2O2 production, & Tg iodination. Iodide is taken in via 2:1 Na/I symporter (driven by Na/K ATPase). Iodide diffuses to apical membrane & out of Iodide channels. Thyroid Peroxidase oxidizes iodide to iodine (I+) using Hydrogen Peroxide & then iodinates tyrosine resides (3’ or 5’) on Tg. (“organification”) This forms Monoiodotyrosine (MIT) & Diiodotyrosine(DIT) resides. Residues are enzymatically coupled (Thyroid Peroxidase) into Triiodothyronine (T3) or Tetraiodothyronine (thyroxine, T4). Colloid is endocytosed, Tg is degraded (phagolysosomes), & free T4 & T3 is released into bloodstream.
What is the Wolff-Chaikoff Effect?
An autoregulatory occurrence of inhibition of Organification of Iodine due to elevated circulating levels of iodide. (only lasts a few days, alleviated by ‘escape phenomenon’)
Comparing T4 & T3 thyroid hormones, which has higher circulating levels, half-life, and potency?
T4 has a lower affinity for thyroid receptor and a higher affinity for Thyroid-Binding Protein, so it has higher circulating levels and half life (7 days) but is less potent. T3 is more potent, has less circulating levels and a shorter half life. (approx. 1 day).
What system ensures dynamic equilibrium of free & protein-bound thyroid hormone?
hypothalamic-pituitary-thyroid axis is controlled by the amount of free hormone available (negative feedback). (e.g. decrease in free thyroid hormone due to increase of plasma binding proteins will stimulate release of TSH from anterior pituitary.)
How is Thyroid Hormone Metabolized in peripheral tissues?
T4 & T3 are sequentially deiodinated. T4 can be deiodinated to T3 or rT3 (inactive) which are then deiodinated to T2 (inactive) by Deiodinases.
List the Deiodinases & their functions.
Deidonases remove iodide from Carbon 5 from either the inner or outer rings of Thyroid Hormone. Type I (both inner and outer ring deiodination), Type II (ONLY outer ring deiodination; therefore can only do T4–>T3 & rT3 –> T2), Type III (ONLY inner ring deiodination; therefore can only do T4 –> rT3 & T3 –> T2)
Which Deiodinase is responsible for negative feedback inhibition in the hypothalamus and pituitary?
Type II Deiodinase (T4 –> T3) (also does rT3 –> T2)
Which Deiodinase is stimulated by TSH?
Type I (responsible for peripheral T4 –> T3)
What kinds of biologic effects do Thyroid Hormones elucidate?
genomic effects (transcriptional regulation) & nongenomic effects (stimulation of Ca++-ATP ATPase, Na+/H+ antiporter, & increase O2 consumption)
Which two transporters have particular specificity for Thyroid Hormones?
OATP1C1 has a preference for T4; MCT8 has a preference for T3
What happens when a Thyroid Hormone binds to its receptor?
Receptor is usually bound to Thyroid Hormone Response elements (corepressor proteins) that dissociate upon binding of TH. Complex then recruits co-activators to modulate gene transcription.
How does Thyroid Hormone effect Bone?
stimulates growth and development (osteoclast/osteoblast activity)
How does hyperthyroidism effect bone?
increased risk of osteoperosis
How does Thyroid Hormone effect the Cardiovascular System?
Cardiac inotropic (increase str. of contraction) & chronotropic (change heart rate) effects: increases cardiac output + blood volume, decreases systemic vascular resistance (vasodilation)
How does Thyroid Hormone effect adipose tissue?
INDUCES white adipose tissue differentiation, lipogenic enzymes, and intracellular lipid accumulation; STIMULATES adipocyte proliferation, uncoupling proteins (generates heat by dissipating mitochondrial proton gradient)
How does hyperthyroidism effect adipose tissue?
enhances lipolysis (Increased thyroid hormone levels stimulate fat mobilization, leading to increased concentrations of fatty acids in plasma. They also enhance oxidation of fatty acids in many tissues.)
How does hypothyroidism effect adipose tissue?
decreases lipolysis
How does Thyroid Hormone effect the pituitary gland?
Stimulates Growth Hormone production; Inhibits TSH production
How does Thyroid Hormone effect the brain?
axonal growth & development (myelination, cell differentiation, migration, signaling)
What are symptoms of hypothyroidism?
cretinism (stunted growth), cold intolerance, hair loss, brittle nails, dry coarse skin, reduced stroke volume and heart rate, decreased cardiac output, enlarged heart, slowing of mental function, impaired memory, thickened features
Patient presents with symptoms of hypothyroidism & labs show high TSH & low T4 & normal T3. What is the diagnosis?
Primary Hypothyroidism
What laboratory values would a patient with Primary Hypothyroidism show?
high TSH, low T4 & normal or low T3
What laboratory values would a patient with Secondary Hypothyroidism show?
low TSH, low T4, low T3
A patient presents with symptoms of hypothyroidism, but normal circulating levels of TSH, T4, & T3 (euthyroid). What is the likely cause of the symptoms?
Thyroid Hormone Resistance
In Graves Disease (toxic goiter), what is stimulating the TSH receptor?
immunoglobulin G
Exopthalmos (protruding eyes) and accumulation of hyaluronate are typically symptoms of what?
Graves Disease
What are symptoms of hyperthyroidism?
palpations, tachycardia, increase in blood volume, enlarged thyroid gland, heat intolerance, tenseness, warm moist skin
What laboratory values would a patient with Primary Hyperthyroidism have?
low TSH, high T4, high T3
What laboratory values would a patient with a pituitary TSH-secreting adenoma have?
high TSH, high T4, high T3 (hyperthyroidism)
What is Euthyroid Sick Syndrome?
Patient has altered thyroid function but appears euthyroid. Caused by increase in deidionise III activity (inner ring only). Patients present with decreased T4 binding to thyroid-binding globulin, decreased T3 concentration, & increased rT3 concentration. All else appears normal. [can also be caused by impaired conversion of T4 –> T3 due to pharmacologics such as Propranolol & Amiodarone]
What is the required amount of iodine for thyroid hormone synthesis?
150 ug
How does Perchlorate affect the Thyroid Gland?
inhibits iodine transport into follicular cells
How does Methimazole affect the Thyroid Gland?
inhibits iodide uptake & organification of iodine
How does Thiouracil affect the Thyroid Gland?
inhibits iodine organification
How does Propythiouracil affect the Thyroid Gland?
inhibits iodine organification & peripheral conversion of T4 –> T3
What is Thyroiditis?
inflammation of the thyroid gland. can be acute or chronic. Acute Thyroiditis presents with a painful thyroid; chills and fever; hot, enlarged, palpable gland; and initially with hyperthyroidism; increased levels of rT3. Chronic Thyroiditis is an autoimmune disease characterized by lymphocyte infiltration and circulating autoimmune antibodies that inhibit the Na/I symporter.
What is the normal TSH, T4, & T3 values?
0.4-4.5 uU/mL; 5-12 ug/dL; 60-180 ng/dL
