Thyroid and Parathyroid/Calcium Physiology

Question 1

What are the hormones of the thyroid gland? What is the major function of each?

Answer 1

• triiodothyronine (T3) and tetraiodothyronine AKA thyroxine (T4)
• T3/T4 have an effect on virtually every organ system: increase BMR, O2 consumption, body temp, metabolism, cardiac output, bone formation, brain development
• (T3/T4 secretion triggered by AP’s TSH, which is triggered by hypothalamic TRH)
• in addition, thyroid’s C cells (parafollicular cells) secrete calcitonin (lowers serum Ca2+)

Question 2

What is the difference between T3 and T4?

Answer 2

• T3 is much more active than T4, but the thyroid secretes 10x as much T4 because it is synthesized more quickly
• in the target peripheral tissue, however, T4 is converted into T3 by the removal of an iodine by 5’-deiodinase

Question 3

Where does T3/T4 synthesis occur in the thyroid? What is required in large amounts for their synthesis? Where are the hormones stored until needed?

Answer 3

• T3/T4 is made in the follicles of the thyroid gland
• iodine is required in large amounts for their synthesis
• once made, the hormones are stored EXTRACELLULARLY in the lumen of the follicles (they are stored as colloid)

Question 4

What are the steps involved in T3/T4 synthesis?

Answer 4

• 1) the follicular epithelial cells of the thyroid make thyroglobulin (TG), which is exocytosed into the follicular lumen
• 2) iodine (I-) is actively pumped into the cell from the blood supply and gets oxidized into I2 by thyroid peroxidase as it enters the follicular lumen
• 3) thyroid peroxidase then joins I2 and thyroglobulin (organification) to form mono- and di-iodotyrosine (MIT, DIT)
• 4) thyroid peroxidase then joins 2 DITs to form T4, and joins 1 DIT and 1 MIT join to form T3 (the joining of 2 DITs is 10x faster, hence more T4 is made)
• synthesis stimulated by anterior pituitary’s TSH

Question 5

How does T3/T4 travel in the blood? What does this mean in terms of the hormones’ activity?

Answer 5

• the majority of T3/T4 travels the blood bound to TBG (thyroxine-binding globulin)
• some T3/T4 also binds to albumin
• the remaining small amount travels free
• only the free T3/T4 is active, so TBG’s role is to provide a large reservoir of circulating T3/T4

Question 6

What happens to T3/T4 synthesis in hepatic failure? What about in pregnancy? Why?

Answer 6

• hepatic failure: decreased liver synthesis of TBG (thyroxine-binding globulin) results in increased concentration of free (active) T3/T4, which will lead to decreased synthesis of T3/T4 because of negative feedback inhibition of TSH
• pregnancy: increased estrogen levels result in diminished TBG degradation and the raised TBG levels yield decreased concentration of free T3/T4, which will lead to increased synthesis of T3/T4

Question 7

What type of hormone is T3/T4 and what signaling mechanism does it use?

Answer 7

• T3 and T4 are both amine hormones

- although they are amines, they use the steroid receptor signaling mechanism (they enter the nucleus and act as TFs)

Question 8

T3/T4 utilize the steroid receptor signaling mechanism - which genes/proteins do they increase transcription of? What effect will these have?

Answer 8

• most tissues will increase the number of Na+-K+-ATPase pumps; this will increase basal metabolic rate (BMR), O2 consumption, and heat production
• myocardial cells will increase myosin, beta-1 receptors, and Ca2+-ATPase; this will increase heart rate and contractility (positive ionotropism)
• liver and adipose tissue will increase transcription of metabolic enzymes; this will increase metabolism

Question 9

What are the effects of T3/T4?

Answer 9

• increase basal metabolic rate (BMR) and metabolism, increase beta adrenergic effects (heart rate and contractility), increase bone growth, and increase brain maturation; the 4 B’s: BMR, beta adrenergic, bone growth, brain maturation
• BMR is increased (increased O2 consumption and body temperature)
• metabolism is increased (glycogenolysis, gluconeogenesis, lipolysis are increased) to match the availability of substrates with the increased O2 consumption
• cardiac output is increased (beta-1 receptor increase means increased sensitivity to sympathetic activity) to also match the increased O2 consumption
• bone formation occurs as a result of synergy with GH and IGF-1
• required for normal brain maturation

Question 10

What will result from T3/T4 deficiency? T3/T4 excess?

Answer 10

• deficiency: cretinism in child (severe mental and physical retardation), weight gain (without increased intake), cold intolerance, bradycardia, slowed movement and speech, hyporeflexia, somnolence, lethargy, slowed mental activity, constipation
• excess: weight loss (with increased food intake), heat intolerance and increased sweating, tachycardia, tremor, nervousness, weakness, hyperreflexia, diarrhea

Question 11

What are the major hormones of the parathyroid glands? What is the major function of each?

Answer 11

• PTH: monitors and regulates serum Ca2+ by acting on the bones, kidneys, and (indirectly) gut to increase the concentration of free, ionized Ca2+
• PTH is secreted by the parathyroid’s chief cells

Question 12

What is the normal concentration of Ca2+ in the blood? How is it carried in the blood? What is the biologically active form of calcium?

Answer 12

• normal serum concentration is 10 mg/dL
• 40% of this plasma calcium is bound to proteins (such as albumin)
• the remaining 60% of plasma calcium is not bound to protein and is therefore ultra filterable; 10% forms complexes with anions (mainly phosphate, but also citrate and sulfate), 50% is free and in its ionized form
• only the free, ionized form of Ca2+ is biologically active; this is what the parathyroid monitors
• (note that 99% of total calcium is actually in the bone; the remaining 1% is split, found in SR and ER or in the ECF; the percentages above refer to the levels in the ECF/plasma)

Question 13

Why is hypercalcemia often associated with acidemia?

Answer 13

• acidemia is characterized by excess H+
• albumin, being negatively charged, can bind to Ca2+ or to H+, so when the amount of H+ increases, more albumin will bind to H+ and less will bind to Ca2+
• this increases the pool of free ionized Ca2+ (the biologically active form)
• (conversely, in alkalemia, more albumin will bind to Ca2+, resulting in hypocalcemia)

Question 14

How does Ca2+ regulate PTH secretion?

Answer 14

• (remember that only the free ionized form of Ca2+ is biologically active)
• Ca2+ binds to Gq receptors on the parathyroid, activating phospholipase C and IP3/Ca2+
• activation of this pathway results in the INHIBITION of PTH secretion

Question 15

What effects does PTH have on the body? How do these effects take place? What signaling mechanism is used by PTH?

Answer 15

• PTH uses the adenylyl cyclase/cAMP mechanism
• increases phosphate secretion: PTH acts on the renal proximal tubule to inhibit Na+-phosphate cotransport (the cotransporter normally reabsorbs both)
• increases Ca2+ reabsorption: acts on renal distal convoluted tubule
• increases Ca2+ absorption from the gut: stimulates renal activation of vitamin D (by activating 1alpha-hydroxylase)
• increases bone resorption: stimulates osteoblasts to activate osteoclasts (note that in small doses, PTH actually increases bone formation)

Question 16

Why is PTH’s effect on phosphate secretion so important in regulating serum Ca2+?

Answer 16

• PTH’s effects on the gut and bone increase serum concentrations of both Ca2+ and PO43-
• this does NOT increase the free ionized (biologically active) form of Ca2+ as the phosphate joins the calcium
• therefore, by increasing the secretion (excretion) of phosphate, this issue is avoided and free Ca2+ levels will rise

Question 17

What will result from PTH deficiency? PTH excess?

Answer 17

• (most symptoms are a result of the calcium levels)
• deficiency causes hypocalcemia: hyperreflexia, twitching, muscle cramps (tetany), tingling and numbness
• excess causes hypercalcemia: constipation, polyuria, polydipsia, hyporeflexia, lethargy, coma, nephrolithiasis

Question 18

Calcium is needed for muscle contraction, so why does hypocalcemia (due to PTH deficiency) result in HYPER-reflexia?

Answer 18

• hypocalcemia refers to the concentration of EXTRACELLULAR Ca2+, not the intracellular concentration (only the intracellular Ca2+ is responsible for contraction)
• the drop in extracellular Ca2+ results in a lowered threshold potential for depolarization, so muscles and nerves have increased excitability

Question 19

In addition to PTH, what other two hormones play a role in calcium/phosphate regulation? What does each do?

Answer 19

• calcitonin and vitamin D
• calcitonin: decreases serum Ca2+ by inhibiting osteoclastic activity; secreted by thyroid’s C cells in setting of hypercalcemia
• vitamin D: increases serum Ca2+ and PO43- to be used in new bone formation by increasing gut absorption of both (vitamin D increases the synthesis of calcium binding calbindin D-28K in absorptive epithelial gut cells); cholecalciferol obtained by UV light and diet, converted into active vitamin D in liver and kidneys

Question 20

How is vitamin D activation regulated?

Answer 20

• vitamin D activation is mainly regulated at the kidney’s hydroxylation step (so the 2nd step, 1st step is in liver)
• the enzyme 1alpha-hydroxylase catalyzes the final activation step of vitamin D; it is stimulated by PTH, hypocalcemia, and hypophosphatemia

Question 21

What percent of calcium is reabsorbed? Where does it get reabsorbed and where does PTH act to regulate reabsorption?

Answer 21

• 98% of calcium is reabsorbed
• 70% always occurs at the proximal tubule (PASSIVE)
• 20% always occurs at the loop of Henle (PASSIVE)
• up to 8% can be absorbed at the distal convoluted tubule (ACTIVE); this is where PTH acts (additionally, PTH increases PO43- excretion in the proximal tubule)