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FHB Block 4 > Calcium and Phosphate Regulation > Flashcards

Calcium and Phosphate Regulation Flashcards

1
Q

List the general functions of calcium

A 
Membrane stability and cell function
Neuronal transmission
Bone structure/formation
Blood coagulation
Muscle function
Hormone secretion
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2
Q

List the general functions of phosphate

A 
Cellular energy metabolism (ATP)
Intracellular signaling pathways
Nucleic acid backbone
Bone structure
Enzyme activation/deactivation
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3
Q

What is a good indicator of free calcium availability?

A

Albumin levels - calcium is bound to albumin

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4
Q

What is the most abundant cation?

A

Calcium! tightly regulated in plasma (.2-2.6 mM)

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5
Q

What can result from hypocalcemia?

A

Muscle failure, tetany, convulsions, death

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6
Q

What can result from hypercalcemia?

A

renal dysfunction, calcification of soft tissues, muscle weakness, coma

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7
Q

What would result in hyperphosphatemia?

A

Crush injury- 10x more phosphate than Ca in soft tissue

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8
Q

What are the two primary regulators of calcium?

A

PTH
Vit D/Calcitriol (skin, diet)

Calcitonin (thyroid) probably not important in humans

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9
Q

What are the three organs regulating Ca homeostasis?

A

Kidneys
Gut
Bone

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10
Q

Discuss the daily calcium turnover in humans

A

Intake ~1000mg

Gut takes up ~500 but also secrets some, making the net absorption only ~200mg

Urinary excretion same as gut absorption

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11
Q

Discuss the general anatomy of the PT glands

A

paired glands, 4 total, located at posterior borders on lateral lobes of the thyroid gland, usually embedded in a capsule

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12
Q

What kind of cells synthesizes PTH?

A

Chief cells (aka principal cells)

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13
Q

What are oxyphil cells?

A

no known function, increase with age and chronic kidney disease

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14
Q

What directs newly synthesized PTH to the ER?

A

signal peptide

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15
Q

What is the form of PTH that is a clinically important measurement, and what is its half life?

A

Intact 1-84 fragment, half life of 4 minutes

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16
Q

What is the biologically active form of PTH?

A

N-terminal 1-34 fragment, binds to the PTH receptor

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17
Q

What segment of PTH has the longest half life? Is it active or inactive?

A

C-terminal 35-84, inactive

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18
Q

What is the role of parathyroid hormone related peptide?

A

mimics activity of PTH in bone and kidney

normally very low concentrations, does not regulate plasma Ca

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19
Q

What produces abnormally high concentrations of PTHrP?

A

many tumors, resulting in hypercalcemia

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20
Q

what is the primary receptor of PTH?

A

PTH 1R

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21
Q

Where is PTH 1R found?

A

Bone and kidney

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22
Q

What are the secondary signaling pathways that PTH 1R utilizes?

A

GPCR

G-alpha-s: adenylyl cyclase/cAMP

G-alpha-q: PLC/IP3/DAG

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23
Q

What does PTH 1R bind?

A

1-34 fragment, 1-84, PTHrP

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24
Q

What is an additional PTH receptor?

A

PTH 2R

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25
Q

What is the function of PTH 2R and what does it bind?

A

function unclear

binds 1-34 fragment, does not bind PTHrP

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26
Q

What does PTH target?

A

Bone and kidneys

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27
Q

What is the overall effects of PTH?

A

Increase in plasma Ca

Decrease in plasma phosphate

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28
Q

Where is the majority of body Ca found?

A

99% body Ca2+ content in bone

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29
Q

What is the function of osteoblasts?

A

bone formation and mineralization

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30
Q

What do osteoblasts express at high concentrations

A

Receptors for PTH

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31
Q

What are osteoblasts derived from?

A

mesenchymal stem cells

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32
Q

What is the function of osteoclasts?

A

Bone resorption

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33
Q

What are osteoclasts derived from?

A

hematopoietic stem cells

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34
Q

Do osteoclasts express PTH receptors?

A

NO!

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35
Q

what are osteocytes and what are the derived from?

A

make up most of the bone matrix

terminally differentiated from osteoblasts

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36
Q

What does PTH stimulate in osteoblasts?

A

macrophage colony stimulating factor (M-CSF)

RANK Ligand

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37
Q

What does M-CSF stimulate?

A

differentiation of osteoclast precursors

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38
Q

How does PTH stimulate osteoclasts?

A

Indirectly! via M-CSF

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39
Q

What does RANK ligand do?

A

leads to maturation of osteoclasts and bone resorption

40
Q

What is the overall result of bone resorption?

A

release of calcium and phosphate to the systemic circulation

41
Q

What is osteoprotogerin?

A

a “soluble decoy” that is an antagonist of RANK ligand

42
Q

How do osteoclasts resorb bone?

A

secrete H+ and acid proteases into the lacuna

43
Q

What are the regulators of osteoprotogerin?

A

Estrogens stimulate (protective)

glucocorticoids inhibit (increased osteoclast activity)

44
Q

What does PTH stimulate in the kidney?

A

CYP1-alpha

calcium channel insertion in apical membrane of distal tubule

45
Q

What does CYP1alpha do?

A

encodes 1-alpha-hydroxylase which converts the active from of vitamin D

46
Q

What regulates PTH?

A

CaSR (calcium sensing receptor)

Vitamin D

47
Q

Where is CaSR located?

A

Chief cells, kidney tubules, C cells

48
Q

what does CaSR do?

A

binds ionized calcium

inhibits PTH synthesis at the promoter level

stimulates degradation of preformed PTH

49
Q

What does Vitamin D bind?

A

binds the nuclear receptor VDR

50
Q

How does vit D regulate PTH?

A

inhibits PTH synthesis at the promoter level

stimulates CaSR gene transcription (indirect PTH regulation)

51
Q

What is calciferol?

A

general term for vitamin D and other natural structural analogs

52
Q

What is cholecalciferol?

A

specifically refers to vitamin D3 (from animal tissues)

53
Q

What is calcidiol (calcifidiol)?

A

25-hydroxy-vitamin D (25-D) = 25-hydroxy-cholecalciferol

immediate precursor

54
Q

What is calcitriol (calcifitriol)?

A

1,25-dihydroxy-vitamin D (1,25-D) = 1,25-dihydroxycholecalciferol

55
Q

What is the active form of vit D?

A

1,25-dihydroxy-vitamin D (1,25-D) = 1,25-dihydroxycholecalciferol

56
Q

What is ergocalciferol?

A

Vit D2, from vegetables

57
Q

What is vit D derived from?

A

Cholesterol (steroid hormone)

58
Q

what is the receptor for vit D, and what kind of receptor is it?

A

nuclear receptor VDR

59
Q

what is vit D bound to in plasma?

A

Vit D binding protein (VDBP)

60
Q

How is vitamin D3 synthesized in the skin?

A

The precursor hormone 7-dehydrocholesterol is converted to cholecalciferol in the skin by UV light and then isomerized to form vitamin
D3

61
Q

Where is vitamin D3 processed after being formed in the skin?

A

the liver

62
Q

what does bioactivation of vit D3 and D2 (from diet) require?

A

1-alpha hydroxylase (stimulated by PTH)

63
Q

how is vit D3 transported from the skin the the liver?

A

VDBP

64
Q

how are vit D3 and D2 transported from the gut to the liver?

A

either directly via portal circulation or indirectly via chylomicrons (via lymphatics)

65
Q

What happens to vit D in the liver?

A

converted to 25-hydroxyvitamin D via 25-hydroxylase

66
Q

where does conversion to the active form occur, and what does it require?

A

in the kidney, requires enzyme 1-alpha-hydroxylase

67
Q

what is the default pathway of vit D processing?

A

the inactive pathway that forms 24,25-(OH)2-D3

68
Q

what are primary factors that drive conversion to the active from of vit D?

A

hypocalcemia and hypophosphatemia

69
Q

What organs does vit D target?

A

bone, kidneys, and gut

70
Q

what are the direct effects of Vit D on bone?

A

mobilize calcium from the bone

stimulate osteoclast proliferation/differentiation

71
Q

What has VDR in the bone?

A

osteoclasts and osteoblasts

72
Q

What is an indirect effect of vit D on bone?

A

increases plasma Ca which stimulates mineralization

73
Q

what does vit D do in the intestines?

A

increases transcellular Ca absorption in duodenum

stimulates phosphate reabsorption in the small intestine

74
Q

How does vit D result in increased absorption of calcium in the gut?

A

increases expression of TRPV5/6 (luminal transporter), calbindin (intracellular binding protein), and basolateral membrane calcium ATPase pump

75
Q

How does vit D result in increased reabsorption of phosphate in the gut?

A

increases expression of Na/P cotransporter

76
Q

What is a deficiency of vit D linked to?

A 
MS
Asthma
Cardiovascular disease
Type II Diabetes mellitus
Colorectal/breast cancer
Major Depressive Disorder (MDD)
77
Q

What is a normal serum calcium level?

A

2.2-2.6 mM or 8.8-10.3 mg/100 ml

78
Q

What is a normal serum phosphate level?

A

0.8-1.45 mM or 2.4-4.1 mg/100 ml

79
Q

What is osteoporosis?

A

reduced bone density, especially trabecular bone

80
Q

What are causes of osteoporosis?

A

genetic, menopause (low estrogen), glucocorticoid therapy/chronic stress, low dietary Ca

81
Q

What is the treatment of osteoporosis?

A

estrogens, calcitonin, bisphosphonates (inhibit bone resorption), vit D

82
Q

what is primary hyperparathyroidism due to?

A

hyperplasia or carcinoma of the PT gland

83
Q

What is the result of primary hyperparathyroidism?

A

hypercalcemia and kidney stones

84
Q

What is secondary hyperparathyroidism a result of?

A

due to chronic liver failure

85
Q

What is the result of secondary hyperparathyroidism?

A

reduced vit d leads to excess PTH synthesis

86
Q

what is a result of hypoparathyroidism?

A

hypocalcemic tetany

Chvostek sign: twitching of facial muscles in response to tapping of facial nerve

87
Q

what is Rickets (children)/Osteomalacia (adults)?

A

unmineralized bone due to vit D deficiency

decreased bone strength (bowing in children)

88
Q

What is pseudohypoparathyroidism?

A

congenital defect in G protein that associates with PTH R1

89
Q

what is a result of pseudohypoparathyrodism?

A

general resistance to PTH, LH, FSH, TSH

90
Q

What are some clinical signs of pseudohypoparathyroidism?

A

Low ca, high phosphate, elevated PTH, short stature

91
Q

How could you normalize low plasma Ca and high plasma P?

A

PTH infusion

92
Q

What is a urinary marker for enhanced bone resorption?

A

hydroxyproline

93
Q

What is calcitonin?

A

a 32AA peptide produced by C cells of the thyroid gland

may help in inhibiting calcium resorption in bone

94
Q

What does therapeutic use of calcitonin result in?

A

Used to treat Paget disease (high bone turnover):

inhibits osteoclast resorption and slows bone turnover (hypocalcemic action)

95
Q

What is the escape phenomenon?

A

rapid downregulation of calcitonin receptors cause the antiosteoclastic actions of calcitonin to diminish within a few hours making this a less effective treatment option

96
Q

Why are some findings that make the physiological function of calcitonin unclear?

A

Complete thyroidectomy (with parathyroids left intact) does not alter normal physiological range of Ca2+.

C-cell tumors – extremely high calcitonin – does not affect Ca2+ levels

FHB Block 4 (13 decks)

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