18- The Thyroid Gland & Disorders

Question 1

• describe the location and structure of the thyroid gland.
• describe the embryological development of the thyroid gland.
• describe what you see on a histology image of the thyroid gland. Is the colloid extracellular or intracellular?
• are the thyroid and parathyroid glands the same gland? Give their main structural differences.

Answer 1

• lies against and around the front larynx and trachea, below the thyroid cartilage ie Adam’s apple, bow tie shape, the 2 lobes are joined by the isthmus which extends from the 2nd to 3rd rings if the trachea.
• thyroid is the 1st endocrine gland to develop, at 3-4 weeks gestation it appears as a epithelial proliferation at the base of the tongue and takes a few weeks to migrate to its final position. Descends through the thyroglossal duct, during migration it remains connected to the tongue by the thyroglossal duct which then disintegrates.
• thyroid follicles can be seen (big spheres that are light inside- the colloid which is a deposit if thyroglobulin, on outside lined by follicular cells), parafollicular cells form a blob between follicles. colloid is considered extracellular even though it is inside the follicle
• NO, are 2 distinct glands, parathyroid in histology is all cells with principal/ chief cells that produce PTH, thyroid in histology is arranged in follicles lined w follicular cells producing TH, parafollicular cells make calcitonin. Sections can show both glands at the same time since they are in close proximity.

Question 2

• how are thyroid hormones made?
• give the components needed to make T3 and T4 and give their full names.
• what is thyroid peroxidase and what 3 reactions does it regulate?

Answer 2

• 2 tyrosines linked together w iodine at 3 or 4 positions in the aromatic rings. Thyroglobulin protein (from colloid) acts as a scaffold: thyroglobulin leaves the follicular cell, tyrosine residues are within the thyroglobulin, iodide is taken up from the blood and oxidated (iodide -> iodine)so it can then it can iodinate thyroglobulin-tyrosine complex(added on), they then undergo coupling where the MIT or DIT join to form T3 or T4. They enter the thyroid follicle cell via pinocytosis, a lysosome degrades the thyroglobulin which releases the THs that then enter the blood for action.
• T3 (triiodothyronine)=MIT (1) + DIT (2) -> T3.
• T4 (thyroxine)= DIT (2) + DIT (2) -> T4.
• thyroid peroxidase=a membrane bound enzyme. Regulates: 1)oxidation of iodide to iodine (requires H2O2). 2)addition of iodine to tyrosine acceptor residues on thyroglobulin . 3) coupling of MIT or DIT to make THs.

Question 3

• what form of iodide/iodine is taken in via diet and how is it changed as it is absorbed and then added to tyrosine acceptors on thyroglobulin?
• why is iodine found in small amounts in the body and where is most of it?
• give some common sources of iodine.
• give the differences in secretion & activity of T3 and T4. What is converted to what and where does this happen?

Answer 3

• dietary form=iodine but must be reduced to iodide before it can be absorbed in the small intestine. It then enters the blood, then taken up into thyroid epithelial cell (via a Na+/I- symporter or ‘iodine trap’) where its oxidated to iodine before it can do iodination and add into thyroglobulin-tyrosine complex.
• bc only THs and precursors use it, not a huge demand. 95% is in the thyroid gland.
• dairy products, grains, meat, veggies.
• 90% secreted is T4 but T3 has much greater biological activity. Therefore most T4 is converted to T3 in liver & kidneys (80% of T3 in blood came from T4).

Question 4

• what protein must T3 and T4 be bound to for transport through the blood?
• describe how THs are regulated.
• give the main functions of THs.
• describe the structure of TSH and give examples of what it stimulates.

Answer 4

thyroxine-binding globulin.

• regulation of TH secretion is via a negative feedback loop. Hypothalamus senses a decrease, stimulates thyrotropin releasing hormone (TRH), stimulates anterior pituitary to secrete thyroid stimulating hormone (TSH), this acts in thyroid gland to increase secretion of THs to then target tissues. When TH is increased, the anterior pit stops secreting TSH and the hypothalamus stops secreting TRH.
• affects cellular differentiation & development, effects on metabolic. pathways
• TSH= a glycoprotein hormone composed of 2 non covalently bonded subunits (alpha & beta). *the alpha subunit is the same as the one in FSH & LH therefore the beta subunit provides the unique activity of TSH. -mainly, it’s the trigger for TH release but in turn stimulates: iodide uptake, iodide oxidation, thyroglobulin synthesis and iodination, pinocytosis, thyroglobulin degradation/proteolysis, lastly cell metabolism and growth.

Question 5

• TSH can induce 2nd messenger pathways. What are the 2 types of G protein subunits it can bind to and roughly describe its pathway.
• give some general actions of TH then some tissue specific effects of TH.

Answer 5

• TSH can bind to G-alpha S & G-alpha q. It is therefore involved in stimulation of 1) adenylyl cyclase converted ATP to cAMP which stimulates PKA to then stimulate TH synthesis + release. 2) stimulation of phospholipase C which converts PIP2 -> IP3 + DAG where DAG activates PKC and IP3 stimulates Ca2+ release via the IP3 receptor which then also activates PKC, stims TH release.
• general=increases basal metabolic rate and heat production by increasing number abs suez of mitochondria and stimulating ETC. (Most tissues except brain, spleen & testes), stimulates metabolic pathways- generally more catabolic pathways eg lipolysis, B-oxidation of FAs in lipid metabolism. Sympathomimetic effects- increases catecholamine receptor numbers on target cells thus increasing their effect.
• tissue specific=CVS: increased hearts responsiveness to catecholamines which increases CO (also HR + contractility), peripheral vasodilation to increase heat lost at surface. Nervous system: increased myelination of nerves + dev. of neurons.

Question 6

• give some characteristics and functions of thyroid hormone receptors.
• how do thyroid hormones enter cells?
• give the normal plasma levels of THs (free T3, T4 and TSH)

Answer 6

• members of larger family of nuclear receptors, hormone activated transcription factors and act to modulate gene expression. They bind DNA in the absence of TH leading to suppression of transcription. When the hormone binds it causes a conformational change in the receptor causing it to function as a transcriptional activator.
• THs are lipid soluble so can enter cells via thyroid hormone transporters.
• free T3= 3 to 8 pM, free T4= 10-25 pM, TSH= 1 to 15 pM ie v small amounts!!

Question 7

• what is goitre and when can it be seen?
• describe the causes, symptoms and specific diseases (in kids & adults) hypothyroidism can cause.
• describe Hashimoto’s disease and treatment for it.

Answer 7

• goitre is an enlargement of the thyroid gland, it may accompany hyper or hypo thyroidism (not always seen in these conditions). Happens when the gland is overstimulated.
• hypothyroidism causes=general failure of thyroid gland, TSH or TRH deficiency, iodine deficiency, postpartum . Symptoms=obesity, lethargy, cannot tolerate cold, hoarse voice, bradycardia, dry skin, hair loss, constipation. In kids-> cretinism ie dwarfed, mental retardation, poor bone dev. Adults-> thick puffy skin, muscle weak, slow speech.
• hashimoto’s= autoimmune disease resulting in destruction of thyroid follicles, leads to hypothyroidism, v common, more in women, sometimes goitre present, Low T3&T4, high TSH. Treat=oral thyroid hormone (we give T4 since it has a longer half life and fewer doses will be needed)

Question 8

• describe causes and symptoms for hyperthyroidism.
• describe Graves’ disease, incl TH & TSH levels and symptoms associated w it.
• what is thyroid scintigraphy, which isotope is used, comment on the radiation exposure and what is it used for?

Answer 8

• hyperthyroidism causes= autoimmune Graves’ disease, toxic multinodular goitre, toxic adenoma of thyroid gland, ectopic thyroid tissue (sometimes some left in tongue as in gest. it didn’t fully detach). Symptoms=as we have excess TH, we’re doing excess metabolism therefore symptoms of weight loss, irritability, fatigue, heat intolerance, sweaty warm hands, tachycardia (noticeable heartbeat), increased hunger, trembling. Sometimes goitre and bulging eyes.
• Graves’= autoimmune disease resulting in hyperthyroidism, caused by production of thyroid stimulating immunoglobulin (TSI) which continually stimulates TH secretion outside of normal neg feedback control therefore T3 & T4 high, TSH low. (TSI stimulated TH secretion therefore it’s not stopped as it’s not in TSH pathway- anterior pituitary has no control). Symptoms=increase in basal metabolic rate, excess sweating, loss of BW, palpitations. Graves’ opthalmopathy, Graves’ dermopathy.
• technetium-99m used for isotope scanning of the thyroid w a gamma camera. Radiation exposure low as it has a half life of ~1 day, used for bone scans, thyroid, brain.

Question 9

• what are antithyroid drugs used for, what is the most common one and how does it work?
• why may it take a few months before they begin to work?

Answer 9

• anti thyroid drugs are used for treating an overactive thyroid eg Graves’. Carbimazole is a prodrug which is converted to methimazole in the body. It prevents thyroid peroxidase from coupling and iodinating tyrosines on thyroglobulin.
• because theres a big store of TH and iodinated thyroglobulins that need to be used up first.

Question 10

• give 4 investigations for hyper/hypothyroidism.

- what is thyroiditis and what are some causes? Does it cause hyper or hypothyroidism?

Answer 10

• physical thyroid examination (palpate), ultrasound, X ray and CT
• inflammation of the thyroid gland, releases T4 into blood, due to viral infection, after childbirth, medication eg amiodarone. It causes hyperthyroidism as there’s a higher plasma conc of T4