Unit 01: Thyroid gland

Question 1

what is the thyroid gland

Answer 1

• 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

Question 2

what do thyroid hormones do?

Question 3

major product of the thyorid gland

Answer 3

major poduct if T4

• T3 and rT3 re largely produced by peripheral tissues by the action of deiodinases, D1 D2 and D3

Question 4

what are deiodinases

Answer 4

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

Question 5

describe the inactivation of thyroid hormones

Answer 5

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

Question 6

describe the structure thyroid hormones

Answer 6

• 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

Question 7

describe peripheral metabolism of thyroid hormones

Answer 7

T4 is deiodinated by 5′-deiodinases present in target tissues and in the liver.

• the pattern of deiodination produces wither T3 ot rT3

Question 8

describe the Hypothalamic-Pituitary-Thyroid Axis

Answer 8

• 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)

Question 9

what inhibits production of TSH

Answer 9

TH inhibits further release of TRH and TSH by the hypothalamus and anterior pituitary gland, respectively.

Question 10

how is iodine collected to synthesize thyroid hormones

Answer 10

• 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

Question 11

once iodine is present for TH synthesis, what happens to the iodine

Answer 11

• 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

Question 12

how are T3 and T4 formed

Answer 12

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

Question 13

describe thyroid hormone synthesis, storage and release

Answer 13

• 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

Question 14

describe the ratios of T3 and T4, how they circulate and elimination

Answer 14

• 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

Question 15

where is D1 expressed? where is D2 expressed?

Answer 15

D1 is expressed in the liver, kidney, thyroid, skeletal and cardiac muscle

D2 is expressed primarily in the pituitary gland and brain.

Question 16

what are teh effects of thyroid hormones

Answer 16

• 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

Question 17

what is hypothyroidism

Answer 17

• 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

Question 18

wha is cretinism

Answer 18

• Hypothyroidism may also manifest as cretinism
• congenital condition characterized by arrested physical and mental development caused by hypofunction or absence of the thyroid gland

Question 19

decribe Autoimmune thyroiditis or Hashimoto’s thyroiditis

Answer 19

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.

Question 20

what is iatrogenic hypothyroidism

Answer 20

hypothyroidism as the result of medical intervention

-common causes are surgery, radioactive iodine for hyperthyroid treatment, chemotherapy for toher cancers and drugs like thioamides

Question 21

what are the signs of hypothyroidism

Answer 21

• 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.

Question 22

what is levothyroxine

Answer 22

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

Question 23

what is liothyronine

Answer 23

almost identical to T3 also can be prescribed but not often

Question 24

what is liotrix

Answer 24

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

Question 25

what is hyperthyroidism

Answer 25

• elevated thyroid hormone aka thyrotoxicosis
• usually caused by graves disease - afects the thyroid and causes it to enlarge giving it the alternative name of “diffuse toxic goiter”
• grves is an autoimmune disease where the immunoglobulin G antibody binds and activates the TSH receptor in the thyroid -> The secretion of T4 and T3 is in, this dec levels of TSH due to the negative feedback loop.

Overall, the result is high levels of circulating thyroid hormone.

Question 26

what causes graves disease

Answer 26

iatrogenic effects (due to oversupplementation of T4)

neoplasms such as benign adenomas

infection/inflammation of the thyroid.

Destruction of thyroid tissue can cause hormone release which is usually transient, and supportive therapy may be used to treat the symptoms.

Question 27

what are teh clincal signs of hyperthyroidism

Answer 27

• speeds up bodily functions
• individuals are usually hyperactive or agitated, nervous, have insomnia, are intolerant to heat, have rapid HR, experience weight loss, frail due to muscle wasting and experience exophthalmos (bug eyed appearance)
• diagnose base on these symptoms and high circulating free T4/T3 and low TSH
• radioiodine uptake scan such as an MRI or ultrasound can be helpful in identifying nodules versus the whole gland as a culprit.

Question 28

how is hyperthyroidism treated

Answer 28

• with antithyroid drugs
• most useful in younger patients with mild disease and can also be used to stabilize patients for other types of hyperthyroid procedures.
  ex: methimazole, propylthiouracil

Question 29

what are Methimazole and propylthiouracil

Answer 29

• thioamides
• used to control thyrotoxicosis
• both administered roally, but methimazole is 10x as potent as propyluracil
• drugs inhibit thyroid peroxidase organification and iodotyrosine coupling steps which block hormone uptake

Question 30

what is iodinated contrast media

Answer 30

form of intravenous radiographic dye

can be used to inhibit the conversion of T4 to T3

used when other drugs are contraindicated or short term therapy is required, and it is generally considered safe.

Question 31

why are beta blockers like propranolol and calcium channel blockers like diltiazem prescribed to pateints with hyperthyroidism

Answer 31

to aid with the cardiovascular symptoms associated with hyperthyroidism, but may also inhibit the conversion of T4 to T3.

Question 32

what is the preferred treatment for pateints with hyperthyroidism

Answer 32

radioiodine therapy (I131)

• antithyroid drugs may or may not be indicated ebfore treatment to stabilize the aptient
• therapy is given orally as a solution and has a high uptake by the thyorid gland
• effect observed is due to emission of ß rays and cell destruction. Some patients might require a second treatment and approximately 80% of patients get hypothyroidism following treatment.

Question 33

what is the treatment of choice for hyperthyroid patients with alrge thyroid glands

Answer 33

• near-total thyroidectomy is the treatment of choice for patients with very large glands, thyroid cancer, or multinodular goiters.

Antithyroid drugs and potassium iodide are administered pre-surgery to lower T4 and reduce vascularity of the gland respectively to simplify the surgery.

In most cases, replacement T4 therapy will also be needed following surgery.