Thyroid Gland Physiology (Lopez)

Question 1

What are the hormones secreted from thyroid gland and what is its general structure?

Answer 1

• hormones: prohormone is thyroxine (T4) and active hormone triiodothyronine (T3)
• thyroid follicle is functional unit, surrounded by single layer of epithelial cells while lumen is filled w/ colloid, size of epithelial cells and amnt of colloid change w/ activity
• thyroid also contains parafollicular C cells that secrete calcitonin (decrease Ca2+ levels)
• thyroid is highly vascularized

Question 2

Where are thyroid hormones synthesized?

Answer 2

• synthesis is by follicular epithelial cells sitting on basal lamina on periphery of colloid
• colloid is composed of newly synthesized thyroid hormones attached to thyroglobulin

Question 3

What is the relationship between iodine and thyroid hormones?

Answer 3

• thyroid hormones are stored as iodinated tyrosines of thyroglobulin: 8000 μg total, 600 μg is T4 and T3; 60 μg of new hormone secreted/day; enough hormone stored as iodinated thyroglobulin to last body for 2-3 months
• thus, secretory hormones are iodothyronines (contains a lot of iodine): T3 is DIT+MIT which yields a 3 iodine molecule, while T4 is DIT+DIT which yields a 4 iodine molecule (~10x more T4 is prod than T3)
• when availability of iodine is restricted, T3 is favored (less iodine to produce T3)

Question 4

How is T4 converted to T3?

Answer 4

• occurs through action of enzyme, deiodinase: ~80-90% of T3 is produced by peripheral conversion, ~10-20% of T3 is produced directly by thyroid gland (DIT+DIT)

(process is beneficial to provide circulating T3 for uptake by other issues if T3 is too low)

• certain clinical states a/w reduction of conversion of T4 into T3: fasting, medical/surgical stress, catabolic dz

Question 5

How are thyroid hormones synthesized?

Answer 5

(occurs both intracellularly (follicular epithelial cell) and extracellularly (follicular lumen, apical membrane))

1. tyrosine converted to thyroglobulin via rough ER and Golgi (intracellularly) and sent extracellularly
2. iodine trap brings iodine into the cell from the blood on the basolateral side
3. iodine is transported via pendrin pump to the follicular lumen, where it is converted to I2 via peroxidase
4. thyroglobulin + I2 converted to TG + MIT and DIT by peroxidase (organification)
5. TG + MIT and DIT converted to TG + T4, T3, MIT, DIT by peroxidase (stored as colloid)
6. colloid storage brought back into cell via pinocytosis (where TSH stimulation occurs)
7. T4 and T3 are broken down into free form to go into blood circulation by proteases (lysosomes)
8. the “leftover” MIT and DIT from the colloid storage and T3/T4 breakdown is put back into the cycle to start back at step 1 by intrathyroidal deiodinase (deficiency of deiodinase mimics iodine deficiency)

Question 6

• a chloride/iodine pump that is used within thyroid hormone synthesis to move iodine out of the follicular epithelial cell into the follicular lumen of apical membrane (where this pump is located)
• mutation of gene (SLC26A4 or PDS): causes defects in transport across apical membrane, affects cochlea (sensorineural hearing loss), and usually results in hypothyroidism w/ goiter

Answer 6

pendrin pump

Question 7

What is a common tx for hyperthyroidism and what can high levels of iodine lead to?

Answer 7

• Propylthiouracil (PTU) is common med used to tx of hyperthyroidism: it blocks iodine entry into follicular epithelial cell and blocks peroxidase in moving iodine out of the cell into follicular lumen and from converting TG + I2 > TG + MIT and DIT
• Wolff-Chaikoff effect: occurs when there are high levels of iodine, which inhibits organification and synthesis of thyroid hormones

Question 8

How can the activity (and thereby associated conditions) of thyroid hormones be assessed diagnostically?

Answer 8

• via a radioactive iodine test
• normal: shows a gradual peak of iodine uptake that levels off after 24 hr
• hyperthyroidism: shows a quick, sharp peak that levels off but is still above physiological normal over 24 hr period
• hypothyroidism: shows reduced uptake that remains consistent over 24 hr period

Question 9

How are thyroid hormones transported within circulation?

Answer 9

• circulate in BS either bound to plasma (99%) or free (1%)
• equilibrium exists between bound and free circulating hormones in BS
• binding proteins: thyroxine-binding globulin (TBG, 70%) is syn in liver and affinity T4 > T3; transthyretin (TTR, 10-15%), and albumin (15-20%)

Question 10

How can circulating levels of TBG be indirectly assessed?

Answer 10

• T3 resin uptake test
• exogenous T3 that is unbound and labeled is added into body
• unbound TBG sites bind labeled T3
• anti-T3 antibody or non-specific resin absorbs left over unbound T3
• the antibody or resin is precipitated (T3 uptake), while the labeled T3 bound to TBG is removed
• amount of TBG can be subtracted from the T3 uptake

(refer to image on how TGB levels and T3 uptake will present in different conditions)

Question 11

How does TGB alter the amnt of free thyroid hormones, and how is this demonstrated in hepatic failure and pregnancy?

Answer 11

• increase in TGB leads to decrease in free T3/T4 and vice versa
• hepatic failure (decrease in TBG): transient increase in free T3/T4, followed by inhibition of synthesis of T3/T4 (due to negative feedback on TRH and TSH)
• pregnancy (increase in TBG): increase in bound T3/T4 and decrease in free T3/T4; transient decrease in free T3/T4 causes increase in syn/secretion of T3/T4; leads to increased total levels of T3/T4, but levels of free/physiological active thyroid hormones are normal (clinically euthyroid)

Question 12

How is the HPT axis regulated?

Answer 12

• TSH: released from anterior pituitary, stimulates growth of thyroid fland (trophic effect) and secretion of thyroid hormones
• TSH regulation: thyrotropin-releasing hormone (TRH) stimulates TSH prod/release; free T3 inhibits prod/release; secretion occurs at a steady state
• T3 inhibition: inhibits ant pit production of TSH and hypothalamic production of TRH

Question 13

How does TSH act on the thyroid gland?

Answer 13

• increases synthesis/secretion of thyroid hormones
• trophic effect on thyroid gland (Gs protein and increase in cAMP production)

Question 14

What are the stimulatory and inhibitory factors on thyroid hormone secretion?

Answer 14

• stimulatory: TSH, thyroid-stimulating immunoglobulins, increased TBG levels (e.g. pregnancy)
• inhibitory: iodine deficiency, deiodinase deficiency, excessive iodine intake (Wolff-Chaikoff effect), perchlorate/thiocyanate (inhibit Na+ and I- cotransport), propylthiouracil (PTU, inhibits peroxidase enzyme), decreased TBG levels (e.g. liver dz)

Question 15

What proteins do the thyroid hormones stimulate the synthesis of?

Answer 15

• in general: Na+-K+ ATPase, transport proteins, β1-adrenergic receptors, lysosomal enzymes, proteolytic enzymes, structural proteins
• cardiac muscle cells: myosin, β1-adrengergic receptors, Ca+ ATPase
• liver and adipose tissue: key metabolic enzymes

Question 16

What physiological actions result from thyroid hormone stimulation?

Answer 16

• growth, bone maturation
• CNS maturation
• BMR: increased Na+-K+ ATPase, O2 consumption, heat production, BMR
• metabolism: increased glucose absorption, glycogenolysis, gluconeogenesis, lypolysis, protein syn/degradation (net catabolic)
• cardiovascular: increased cardiac output (upregulation of β1-adrenergic receptors)

Question 17

How do thyroid hormones increased basal metabolic rate (BMR)?

Answer 17

• they increase activity of Na+-K+ ATPase which leads to increase O2 consumption and heat production
• increase in BMR by single dose of thyroxine (T4) occurs after several hours but is long-lasting (>6 hours)

Question 18

How do thyroid hormones affect lipid and carbohydrate metabolism?

Answer 18

• lipid: stimulate fat mobilization > increased conc of fatty acids (FA) in plasma; enhance oxidation of FA; plasma conc of cholesterol/trigs are inversely correlated w/ thyroid hormones (increased blood cholesterol seen in hypothyroidism); lipid breakdown required for coversion of carotene to vitamin A (hypothyroidism patients can suffer from blindness and yellowing of skin)
• carb: increase gluconeogenesis and glycogenolysis to generate free glucose; enhance insulin-dependent entry of glucose into cells

Question 19

How do thyroid hormones affect the cardiovascular system?

Answer 19

• direct: increase cardiac muscle, myosin heavy chain α/β ratio, Na+-K+ ATPase, sarcoplasma Ca-ATPase, β-adrenergic signaling, G-protein stimulatory/inhibitory ratio; increases ventricular contractility/function; decreases peripheral vascular resistance
• indirect: increase heat production/CO2 in tissues, decreases peripheral vascular resistance, decreases diastolic blood pressure, reflex increase in adrenergic stimulation (when thyroid hormone levels are high, myocardium has increased β1 receptors (norepi), thus is more sensitive to sympathetic ANS stimulation)
• together, direct and indirect effects increase cardiac rate/output and blood volume

Question 20

What are the effects of thyroid hormones on growth and CNS?

Answer 20

• growth: act synergistically w/ growth hormone and somatomedins to promote bone formation
• CNS: important for CNS maturation; deficiency can lead to abnormal development of synpases and decreased dendritic branching/myelination, neural changes induced by thyroid hormone deficiency during perinatal period are irreversible and lead to cretinism unless replacement therapy is started soon after birth

Question 21

Answer 21

Question 22

• due to thyroid hormone overproduction (thyrotoxicosis)
• primary: Graves’ dz (most common cause)
• secondary: TSH-secreting pituitary tumor
• TSH levels: decreased due to negative feedback from T3 on anterior pituitary; if defect is in anterior pituitary TSH levels are elevated
• sx: increased metabolism, weight loss, sweating, tachycardia, heart palpitations, hypertension, diarrhea

Answer 22

hyperthyroidism

Question 23

• condition that causes overproduction of thyroid hormones due to thyroid-stimulating immunoglobulins that bind to TSH receptor, causing unregulated overproduction of thyroid hormones
• clinical signs: exophthalmos (abnormal protrusion of eyeball) and periorbital edema (due to recognition by anti-TSH receptor antibodies of similar epitope within orbital cells)
• dx: elevated serum free and total T4 or T3 level and clinical signs of goiter and ophthalmopathyl presence of TSI (thyroid-stimulating immunoglobulins) helps distinguish this condition from adenoma of pituitary thyrotrophs

Answer 23

Graves’ disease

Question 24

What are the causes and treatment for primary hypothyroidism?

Answer 24

• gland destruction (e.g. surg removal, irradiation, autoimmune dz, idiopathic atrophy), Hashimoto’s thyroiditis is most common cause of hypothyroidism in iodine-sufficient areas of the world
• inhibition of thyroid hormones syn/release (e.g. iodine deficiency, inherited enzyme defects, drugs that interfere)
• transient (e.g. after surg or therapeutic radioiodine, postpartum, thyroiditis
• others: hypothalamic dz, pituitary dz (Sheehan’s syndrome), resistance to thyroid hormones
• tx: replacement doses of T4 (b/c metabolism of T4 decreases and plasma 1/2 life increases w/ age higher doses are required in younger patients; in women beyond menopause overprescribing T4 can contribute to development of osteoporosis)

Question 25

• thyroid hormone synthesis is impaired by thyroglobulin or TPO antibodies, which leads to decreased T3/T4 secretion
• TSH levels are high and have a trophic effect (causes goiter)

Answer 25

Hashimoto’s thyroiditis

Question 26

What are the causes and sx of congenital hypothyroidism?

Answer 26

• causes: untreated postnatal hypothyroidism, iodine deficiency, maternal intake of anti-thyroid meds, impaired development of thyroid gland, inherent deficit in synthesis of thyroid hormones
• sx: feeding probs, respiratory difficulty, protruding tongue, curse facial features growth retardation, mental retardation, jaundice, dry skin, hypotonia

Question 27

How would hypothyroidism due to iodine deficiency present clinically?

Answer 27

• transient decrease in synthesis of thyroid hormones, TSH levels elevated, goiter likely present
• if gland maintains nml levels of thyroid hormones patient will be euthyroid and asymptomatic
• if gland cannot maintain nml levels, patient exhibits hypothyroidism

Question 28

• postpartum hypopituitarism due to necrosis of pituitary gland
• most patients present w/ agalactorrhea and/or difficulties in lactation
• amenorrhea commonly present
• some patients present w/ hypothyroidism
• other endocrine dysfunction may be present

Answer 28

Sheehan syndrome

Question 29

• can develop in response to multiple imbalances and disease within HPT axis
• hyperthyroidism: Graves’ dz, TSH-producing tumor (secondary hyperthyroidism)
• primary hypothyroidism: iodine deficiency, sporadic hypothyroidism, chronic thyroiditis (Hashimoto’s or autoimmune-induced)

Answer 29

goiter

Question 30

TSH test results and associated diagnoses:

Answer 30