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Endo/Repro I Exam 1 > Lecture 6: Regulation of Calcium and Phosphate Metabolism > Flashcards

Lecture 6: Regulation of Calcium and Phosphate Metabolism Flashcards

1
Q

What is the % distribution of total calcium among ECF, plasma, ICF, bones/teeth?

A

ECF: 0.1%

Plasma: <0.5%

ICF: 1%

Bones/teeth: 99%

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2
Q

What is the biologically active form of calcium and what is its distribution?

A

Free, ionized Ca2+ is biologically active

Protein bound: 40%

Ultrafilterable: 60% —> Non-ionized complexed to anions (10%) and Ionized Ca2+ (50%)

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3
Q

How do changes in the plasma calcium concentration influence membrane excitability, hypocaclemia and hypercalcemia?

A

Hypocalcemia: hyperreflexia, spontaneous twitching, muscle cramp, tingling and numbness

Hypercalcemia: decreased QT interval, constipation, lack of appetite, polyuria, polydipsia, muscle weakness, hyporeflexia, lethary, coma

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4
Q

What are the two “signs” used to indicate hypocalcemic state?

A

Chvostek sign: twitching of the facial muscles elicited by tapping on the facial nerve

Trousseau sign: carpopedal spasm upon inflation of a blood pressure cuff

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5
Q

How does Hypocalcemia influence the membrane excitability; affect on sensory and motor neurons?

A
  • Reduces the activation threshold for Na+ channels -> easier to evoke AP
  • Results in increased membrane excitability (spontaneous APs)
  • Generation of spontaneous AP is the physical basis for hypocalcemic tetany (spontaneous muscle contractions due to low extracellular Ca2+)
  • Produces: tingling and numbness (on sensory neurons) and spontaenous muscle twitches (on motorneurons and muscle)
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6
Q

How does Hypercalcemia influence membrane excitiability?

A
  • Opposite of hypocalcemia mechanism (decreased membrane excitability)
  • Nervous system becomes depressed and reflex responses are slowed
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7
Q

How do changes in plasma protein concentrations alter total Ca2+ concentrations?

A
  • Alter total Ca2+ concentration in the same direction
  • Increased plasma protein concentration = increased total Ca2+ concentration
  • No change in Ca2+ ionized
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8
Q

How do changes in anion concentrations alter total Ca2+ concentrations?

A
  • If you increase anions, such as the phosphate concentration, you decrease the ionized Ca2+ concentration
  • Anions will pick up the ionized Ca2+ increase the amount complexed in non-ionized form
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9
Q

How does acidemia alter the ionized Ca2+ concentration?

A
  • In acidemia there is more H+ which competes w/ Ca2+ for binding sites on albumin.
  • Increased H+ will lead to an increase in free ionized Ca2+
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10
Q

How does alkalemia alter the ionized Ca2+ concentration?

A
  • Less H+ in the blood allows for more free ionized Ca2+ to bind to albumin
  • This leads to a decrease in the amount of free ionized Ca2+ in the blood, often accompanied by hypocalcemia.
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11
Q

What 3 organ systems and 3 hormones are involved in regulating calcium homeostasis?

A

Organs: kidney, bone, and intestine

Hormones: PTH, calcitonin, vitamin D (calcitriol)

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12
Q

What hormone stimualtes the absorption of Calcium from the intestine?

A

Vitamin D

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13
Q

What hormones have an affect on bone resorption?

A

Activators: PTH and Vitamin D

Inhibitors: Calcitonin

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14
Q

How do the kidneys function to maintain Ca2+ balance; which hormone stimulates reabsorption of Ca2+ from the kidneys?

A
  • Kidneys must excrete the same amount of Ca2+ that is absorbed by the GI tract
  • PTH
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15
Q

How is the extracellular concentration of phosphate related to that of Ca2+ and what hormones do the regulation?

A
  • Extracellular concentration of Pi is regulated by the same hormones that regulate Ca2+ concentration
  • Concentration of Pi is inversely related to that of Ca2+
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16
Q

What is the % distribution of Pi in the bones, plasma, and ICF?

A
  • Bone: 85%
  • Plasma: <1%
  • 84% ionized
  • 10% protein bound
  • 6% complexed
  • ICF: 15%
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17
Q

Where is the parathyroid gland located anatomically and what is secreted from here; specifically what cells?

A
  • Posterior side of the thyroid gland
  • Chief cells secrete PTH
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18
Q

Describe the structure of PTH; where is it synthesized and how is it made into active form?

A
  • Peptide hormone w/ 1-34th AA being biologically active
  • Syntheszied on ribosomes as preproPTH then cleaved to form proPTH followed by transport to Golgi and further cleavage to form PTH before packed into secretory granules
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19
Q

What are the 4 classic regulators of phosphate metabolism?

A
  1. Dietary phosphate intake and absorption.
  2. Calcitriol - increases phosphorus resorption from bone and absorption from intestine. Increases Pi reabsorption in kidney.
  3. PTH - phosphorus resorption directly from bone, and indirectly activates intestinal absorption through stimulation of calcitriol production.
  4. Renal tubular reabsorption of phosphorus, which is stimulated by tubular filtered
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20
Q

What is FGF-23 and why it important in the regulation of phosphate concentrations in the plasma?

A
  • Derived from bone
  • Phosphate and Vitamin D levels regulated its expression, which in turns regulates phosphate homeostasis
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21
Q

What are the 3 renal effects of FGF-23?

A

1) Directly downregulates NaPi transporters in kidney
2) Stimulates PTH to downregulate NaPi transporter in kidney
3) Decreases 1,25-dihydroxyD3 (calcitriol) produciton in the kidney

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22
Q

What is the primary stimulus for the secretion of PTH?

A

Low plasma ionized Ca2+

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23
Q

How is PTH production and secretion regulated by the parathyroid gland; how can it sense Ca2+ levels?

A
  • Calcium-sensing receptor (CaSR)
  • Hypercalcemia will causes downstream signaling to block PTH gene and block the release of PTH
  • Hypocalcemia will stimulate PTH secretion
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24
Q

How does 1,25-vitamin D have an effect on the parathyroid gland?

A
  • Can cross the membrane into cells of parathyroid and either inhibit the PTH gene
  • Can also upregulate the transcription of CaSR gene leading to increased CaSR’s on the surface of the cell membrane
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25
Q

What can mutations in the CaSR gene cause?

A

Familial hypocalciuric hypercalcemia (FHH)

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26
Q

How does chronic hypercalcemia affect PTH?

A
  • Decrease synthesis and storage of PTH
  • Increased breakdown of stored PTH and release of inactive PTH fragment into circulation
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27
Q

How does chronic hypocalcemia affect PTH?

A
  • Increase synthesis and storage of PTH
  • Hyperplasia of parathyroid glands (2° hyperparathyroidism)
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28
Q

How does Magnesium, especially severe hypomagnesemia affect PTH?

A
  • Severe hypomagnesemia (result of chronic Mg2+ depletion, as in alcoholism)
  • Inhibits PTH synthesis, storage, and secretion
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29
Q

PTH signals through which receptor and what pathways?

A
  • GPCR
  • Gs —-> cAMP —-> PKA
  • Gq —-> IP3/DAG —–> increase Ca2+ and PKC
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30
Q

When plasma [Ca2+] is low and PTH secretion increases, what are the effects on bone, kidney, and intestine?

A

Bone: increased bone resorption

Kidney: decreased Pi reabsorption (phosphaturia), increased Ca2+ reabsorption, and increased urinary cAMP

Intestine: increased Ca2+ absorption (indirect via calcitriol)

*ALL work towards increasing [Ca2+] toward normal

31
Q

Where does Vitamin D exert its actions and what are its functions?

A
  • Has actions in: intestine, kidney, and bone
  • Increases both [Ca2+] and [Pi] in plasma
  • Promotes mineralization of new bone
32
Q

What are the opposing effects of Vitamin D on Pi levels via action on kidneys and intestine?

A
  • Can induce both FGF-23 and Klotho to increase urinary excretion of Pi and lower serum phosphate levels
  • Increased intestinal absorption of phosphate to increase serum [Pi]
33
Q

What is the main circulating form of vitamin D and what needs to be done to make it active; what is the enzyme and where does the activation occur (be specific)?

A
  • 25-OH-cholecalciferol is main circulating form (inactive)
  • In PROMXIMAL tubule of kidney is converted to 1,25-dihydroxycholecalciferol (1,25-(OH)2-cholecalciferol) = active, by the enzyme 1α-hydroxylase
  • Can also be converted to, inactive, 24-25-(OH2)-cholecalciferol in te kidney by 24-hydroxylase

*1α-hydroxylase = CYP1α*

34
Q

What activates 1α-hydroxylase in the kidneys?

A
  • Decreased [Ca2+]
  • Increased PTH
  • Decreased [Phosphate]
35
Q

What form of Vitamin D do we ingest in our diets and then what happens in the body?

A
  • Cholecalciferol (inactive)
  • Converted in the liver to 25-OH-cholecalciferol (inactive form) by 25-hydroxlase
36
Q

Explain how kidney 1α-hydroxylase is tightly regulated at the transcriptional level by 1,25-dihydroxyD, [Ca2+], and PTH?

A
  • 1,25-dihydroxyD inhibits 1α-hydroxylase and sitmulates 24-hydroxylase expression
  • High [Ca2+] inhibits 1α-hydroxylase expression
  • PTH stimulates 1α-hydroxylase
37
Q

Vitamin D is what kind of hormone and how does it assert its effects on a cell at a transcriptional level?

A
  • Steroid hormone that binds a cytosolic and nuclear vitamin D receptor (VDR)
  • In genomic response: binds to to nuclear VDR leading to heterodimerization of the VDR w/ the retinoid X receptor (RXR) and binding to vitamin D response element (VDREs) in the promoters of target genes affects transcription
38
Q

Where are the PTH receptors in bone located and what are the short-term vs. long-term actions?

A
  • On the osteoblasts NOT osteoclasts

Short term: bone formation (via direct action on osteoblast)

  • Basis for use of intermittent synthetic PTH administration in osteoporosis tx

Long term: increased bone resorption (indirect action on osteoclasts mediated by cytokines released from osteoblast)

39
Q

What are the actions of vitamin D on bone, specifically w/ PTH?

A

Acts synergistically w/ PTH to stimulate osteoclast activity and bone resorption

40
Q

Explain the long-term action when PTH binds to osteoblasts, what are the key players (M-CSF, Vitamin D, RANKL, and RANK)?

A
  • PTH binds to osteoblasts which secrecte M-CSF, inducing stem cells to differentiate into osteoclast precursors, mononuclear osteoclasts, and finally, mature, multinucleated osteoclasts.
  • Vitamin D and PTH promote release of RANK ligand, which is a receptor activator for NF-kB ligand, and the primary mediator of osteoclast formation. RANKL binds to RANK on osteoclasts and osteoclast precursors
  • Multi-nucleated osteoclasts are now able to facilitate bone resorption through the secretion of acids that breaks the osteoid
41
Q

Explain how osteoblasts are able to put a break on the actions of osteoclasts, what are the key players (i.e., OPG)?

A
  • Osteoblasts are also able to put a break on the system by producing a decoy receptor for RANKL, called OPG, which inhibits the RANKL/RANK interaction
  • This short-term action will be increased bone formation via the actions of osteoblasts
42
Q

What are the speicific actions of PTH and vitamin D on RANKL and OPG?

A

PTH: increases RANKL and decreases OPG

Vitamin D: increases RANKL

43
Q

Where does RANKL come from?

A

Cell surface protein produced by: osteoblasts, bone lining cells and apoptotic osteocytes

44
Q

How does PTH affect Pi reabsorption in the Proximal Tubule of the Kidney, which receptors/pathways?

A
  • PTH binds its receptor at basolateral membrane of proximal tubule, which is coupled via Gs protein to adenylyl cyclase
  • Adenylyl cyclase produces cAMP, which activates series of protein kinases, which then phosphorylate intracellular proteins
  • Phosphorylation of the luminal Na+-Pi (NPT) co-transporter inhibits Na+-Pi co-transport leading to decreased Pi reabsorption and increased Pi excretion (phosphaturia)
45
Q

Why is the cAMP produced during the binding of PTH to its receptors in the proximal tubule of the kidney significant?

A

cAMP generated in the cells of the proximal tubule is excreted in urine, and urinary cAMP can be measured to assess how the PTH system is functioning

46
Q

What is the second renal action of PTH; where does it occur?

A

- Increase in reabsorption of Ca2+ in the DCT

- Complements the increase in plasma [Ca2+] that resulted from increased bone resorption and phosphaturia

47
Q

What are the actions of vitamin D on the kidney?

A

Stimulates both Ca2+ and Pi reabsorption

*Remember that PTH increased reabsorption of Ca2+, but inhibits the reabsorption of Pi*

48
Q

What is the mechanism of action for Vitamin D on the intestine; what transporters does it induces synthesis of?

A
  • Vit D induces the synthesis of an intracellular calcium-binding protein called Calbindin
  • Induces synthesis of Na-Pi transporter and Ca2+ channel on the luminal side, needed for absorption of Pi and Ca2+
  • Induces synthesis of the Na+-Ca2+ antiporter on the basolateral side
  • Induces synthesis of the Ca2+-ATPase on the basolateral side
49
Q

What sensitizes osteoblasts to PTH and regulates osteoid production and calcification?

A

Vitamin D

50
Q

What organs does Calcitonin primarily act on; major stimulus; what are its functions?

A
  • Bone and kidney
  • Increased plasma [Ca2+] = major stimulus
  • Decreases blood [Ca2+] and [Pi] by inhibiting bone resorption (effect only occurs at high circulating levels of the hormone)
  • Promotes renal excretion of calcium and phosphate
51
Q

Where are the calcitonin receptors found in bone and what are its actions here?

A
  • On osteoclasts
  • Decreases activity and decreases number of osteoclasts
52
Q

What conditions prove that calcitonin has no role in chronic (minute-to-minute) regulation of plasma [Ca2+]?

A

Thyroidectomy: decreases calcitonin, but no effect in Ca2+ metabolism

Thyroid tumors: increased calcitonin, but no effect in Ca2+ metabolism

53
Q

What effect does Estradiol-17β have on Ca2+ in the kidneys, intestines, and what are its effects on bone?

A
  • Stimulates intestinal Ca2+ absorption and renal tubular Ca2+ reabsorption
  • One of the most potent regulators of osteoblast and osteoclast function
  • Promotes survival of osteoblasts and apoptosis of osteoclasts; favoring bone formation > resorption
54
Q

What effect do adrenal glucocorticoids (i.e., cortisol) have on bone and Ca2+; how does this affect patients treated w/ these drugs?

A
  • Promotes bone resorption
  • Promotes renal Ca2+ wasting
  • Inhibits intestinal Ca2+ absorption
  • Pt’s tx w/ high levels of a glucocortcoid can develop glucocorticoid-induced osteoporosis
55
Q

What is Primary hyperparathyroidism; normal treatment?

A
  • Parathyroid problem resulting in hypersecretion of PTH
  • Pt’s excrete excessive amounts of Pi, cAMP, and Ca2+ = Ca2+-oxalate stones
  • Increased GI Ca2+ absorption (mediated by Vit D)
  • Increased renal calcium reabsorption

- “Stone,” “bones,” and “groans”

  • Tx usually requires a parathyroidectomy
56
Q

What is Secondary hyperparathyroidism; causes?

A
  • Increase in PTH levels is secondary to low [Ca2+] in blood
  • Causes for the low [Ca2+] in blood include:
  • Renal failure
  • Vit D deficiency
57
Q

How do the levels of PTH, Ca2+, Pi, and vitamin D differ in secondary hyperparathyroidism due to renal failure vs. vitamin D deficiency?

A
58
Q

What are the causes of hypoparathyroidism and what are most symptoms associated with; treatment?

A
  • Thyroid surgery, Parathyroid surgery, and autoimmune/congenital
  • Most sx’s are associated w/ decreased Ca2+
  • Muscle spasm/cramping, numbness, tingling, or burning around mouth and fingers, seizures, and poor teeth development in kids
  • Tx: oral Ca2+ supplement and active form of Vit D
59
Q

What are the levels of PTH, Ca2+, Pi, and Vit D in hypoparathyroidsim?

A
  • Decreased PTH
  • Decreased Ca2+
  • Increased Pi
  • Decreased Vit D
60
Q

What is Albright hereditary osteodystrophy (pseudohypoparathyroidism type 1a)?

A
  • Inherited autosomal dominant disorder; Gs for PTH in bone and kidney is defective
  • Hypocalcemia and hypophosphatemia develop
  • Increased PTH levels (but can’t exert its function)
  • Administration of exogenous PTH produces no phosphaturic response and no increase in urinary cAMP
61
Q

What are the PTH, Ca2+, Pi, and Vit D levels in Pseudohypoparathyroidism?

A
  • PTH is increased
  • Ca2+ is decreased
  • Pi is increased
  • Vit D is decreased
62
Q

What disease causes this phenotype?

A
  • Pseudohypoparathyroidism
  • Short stature, short neck, obesity, subcutaneous calcification, and shortened metatarsals and metacarpals
63
Q

What is humoral hypercalcemia or malignancy; what is produced and how does it exert its effects?

A
  • Hypercalcemic syndrome associated w/ malignancy
  • PTH-related peptide (PTHrP) is a peptide produced by tumors w/ close homology in the N-terminal to PTH
  • Binds and activates same receptor as PTH (type 1 PTH receptor)
64
Q

What levels do we see in humoral hypercalcemia or malignancy; and how is it different from primary hyperparathyroidism?

A

Similarities:

  • Increased urinary Ca2+, Pi, and cAMP
  • Increased blood Ca2+, decreased blood Pi

Differences:

  • Decreased PTH levels
  • Decreased Vit D (in cancer, Vit D levels are normally suppressed)
65
Q

What is the treatment for humoral hypercalcemia or malignancy?

A
  • Furosemide (inhibits renal Ca2+ reabsorption and increases Ca2+ excretion)
  • Etidronate (inhibitor of bone resorption)
66
Q

What is Familial hypocalciuric hypercalcemia (FHH); inheritance pattern; results in?

A
  • Autosomal dominant disorder
  • Mutations that inactivate CaSR in parathyroid glands and paracellular Ca2+ receptors in the ascending limb of the kidney
  • Results in decreased urinary Ca2+ excretion (hypocalciuria) and increased serum [Ca2+]
  • Fairly mild condition and most patients are asymptomatic
67
Q

What is the pathophysiology of Rickets-Osteomalacia?

A

Impaired Vit D metabolism:

  • Dietary deficiency
  • Absence of 1α-hydroxylase or mutations in Vit D receptor
  • GI disorders, chronic renal failure, and Pi depletion can lead to pathophysiological changes in Vit D metbaolism
68
Q

What are the 2 congenital disorders that can lead to Rickets in children?

A

1) Pseudovitamin D-deficientt rickets or vitamin D-dependent rickets type I (decreased 1α-hydroxylase)
2) Pseudovitamin D-deficientt rickets or vitamin D-dependent rickets type II (decreased vitamin D receptor (VDR))

69
Q

What are the characteristics of Osteomalacia?

A
  • New bone fails to mineralize
  • Characterized by bending and softening of weight-bearing bones
70
Q

What are the treatments for Rickets-Osteomalacia?

A
  • Vitamin D2 (ergocalciferol) or D3 (cholecalciferol)
  • Ca2+
  • Sunlight
  • 1,25-(OH)2-D3 (calcitriol)
71
Q

What are the levels of PTH, Ca2+ Pi, Urine, and Bone in Vitamin D deficiency?

A
  • Increased PTH (2°)
  • No change or decreased Ca2+
  • Decreased Pi
  • Increased urine Pi and cAMP
  • Increased bone resorption
72
Q

Why do women often experience Osteoporosis before men?

A
  • After menopause women have very decreased levels of estrogen
  • Estrogen is important for stimulating intestinal Ca2+ absorption and renal tubular reabsorption
  • Estrogen is also one of the most potent regulators of osteoblast and osteoclast function; favoring bone formation
73
Q

What are the anabolic therapies and antiresorptive therapies for Osteoporosis?

A

Anabolic:

  • PTH

Antiresorptive:

  • Bisphosphonates
  • Estrogen
  • Selective estrogen receptor modulators
  • Calcitonin
  • RANKL inhibitors

Endo/Repro I Exam 1 (12 decks)

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