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Calcium and Phosphate Regulation Flashcards

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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
What is the function of PTH 2R and what does it bind?
function unclear binds 1-34 fragment, does not bind PTHrP
26
What does PTH target?
Bone and kidneys
27
What is the overall effects of PTH?
Increase in plasma Ca Decrease in plasma phosphate
28
Where is the majority of body Ca found?
99% body Ca2+ content in bone
29
What is the function of osteoblasts?
bone formation and mineralization
30
What do osteoblasts express at high concentrations
Receptors for PTH
31
What are osteoblasts derived from?
mesenchymal stem cells
32
What is the function of osteoclasts?
Bone resorption
33
What are osteoclasts derived from?
hematopoietic stem cells
34
Do osteoclasts express PTH receptors?
NO!
35
what are osteocytes and what are the derived from?
make up most of the bone matrix terminally differentiated from osteoblasts
36
What does PTH stimulate in osteoblasts?
macrophage colony stimulating factor (M-CSF) RANK Ligand
37
What does M-CSF stimulate?
differentiation of osteoclast precursors
38
How does PTH stimulate osteoclasts?
Indirectly! via M-CSF
39
What does RANK ligand do?
leads to maturation of osteoclasts and bone resorption
40
What is the overall result of bone resorption?
release of calcium and phosphate to the systemic circulation
41
What is osteoprotogerin?
a "soluble decoy" that is an antagonist of RANK ligand
42
How do osteoclasts resorb bone?
secrete H+ and acid proteases into the lacuna
43
What are the regulators of osteoprotogerin?
Estrogens stimulate (protective) glucocorticoids inhibit (increased osteoclast activity)
44
What does PTH stimulate in the kidney?
CYP1-alpha calcium channel insertion in apical membrane of distal tubule
45
What does CYP1alpha do?
encodes 1-alpha-hydroxylase which converts the active from of vitamin D
46
What regulates PTH?
CaSR (calcium sensing receptor) Vitamin D
47
Where is CaSR located?
Chief cells, kidney tubules, C cells
48
what does CaSR do?
binds ionized calcium inhibits PTH synthesis at the promoter level stimulates degradation of preformed PTH
49
What does Vitamin D bind?
binds the nuclear receptor VDR
50
How does vit D regulate PTH?
inhibits PTH synthesis at the promoter level stimulates CaSR gene transcription (indirect PTH regulation)
51
What is calciferol?
general term for vitamin D and other natural structural analogs
52
What is cholecalciferol?
specifically refers to vitamin D3 (from animal tissues)
53
What is calcidiol (calcifidiol)?
25-hydroxy-vitamin D (25-D) = 25-hydroxy-cholecalciferol | immediate precursor
54
What is calcitriol (calcifitriol)?
1,25-dihydroxy-vitamin D (1,25-D) = 1,25-dihydroxycholecalciferol
55
What is the active form of vit D?
1,25-dihydroxy-vitamin D (1,25-D) = 1,25-dihydroxycholecalciferol
56
What is ergocalciferol?
Vit D2, from vegetables
57
What is vit D derived from?
Cholesterol (steroid hormone)
58
what is the receptor for vit D, and what kind of receptor is it?
nuclear receptor VDR
59
what is vit D bound to in plasma?
Vit D binding protein (VDBP)
60
How is vitamin D3 synthesized in the skin?
The precursor hormone 7-dehydrocholesterol is converted to cholecalciferol in the skin by UV light and then isomerized to form vitamin D3
61
Where is vitamin D3 processed after being formed in the skin?
the liver
62
what does bioactivation of vit D3 and D2 (from diet) require?
1-alpha hydroxylase (stimulated by PTH)
63
how is vit D3 transported from the skin the the liver?
VDBP
64
how are vit D3 and D2 transported from the gut to the liver?
either directly via portal circulation or indirectly via chylomicrons (via lymphatics)
65
What happens to vit D in the liver?
converted to 25-hydroxyvitamin D via 25-hydroxylase
66
where does conversion to the active form occur, and what does it require?
in the kidney, requires enzyme 1-alpha-hydroxylase
67
what is the default pathway of vit D processing?
the inactive pathway that forms 24,25-(OH)2-D3
68
what are primary factors that drive conversion to the active from of vit D?
hypocalcemia and hypophosphatemia
69
What organs does vit D target?
bone, kidneys, and gut
70
what are the direct effects of Vit D on bone?
mobilize calcium from the bone | stimulate osteoclast proliferation/differentiation
71
What has VDR in the bone?
osteoclasts and osteoblasts
72
What is an indirect effect of vit D on bone?
increases plasma Ca which stimulates mineralization
73
what does vit D do in the intestines?
increases transcellular Ca absorption in duodenum stimulates phosphate reabsorption in the small intestine
74
How does vit D result in increased absorption of calcium in the gut?
increases expression of TRPV5/6 (luminal transporter), calbindin (intracellular binding protein), and basolateral membrane calcium ATPase pump
75
How does vit D result in increased reabsorption of phosphate in the gut?
increases expression of Na/P cotransporter
76
What is a deficiency of vit D linked to?
``` MS Asthma Cardiovascular disease Type II Diabetes mellitus Colorectal/breast cancer Major Depressive Disorder (MDD) ```
77
What is a normal serum calcium level?
2.2-2.6 mM or 8.8-10.3 mg/100 ml
78
What is a normal serum phosphate level?
0.8-1.45 mM or 2.4-4.1 mg/100 ml
79
What is osteoporosis?
reduced bone density, especially trabecular bone
80
What are causes of osteoporosis?
genetic, menopause (low estrogen), glucocorticoid therapy/chronic stress, low dietary Ca
81
What is the treatment of osteoporosis?
estrogens, calcitonin, bisphosphonates (inhibit bone resorption), vit D
82
what is primary hyperparathyroidism due to?
hyperplasia or carcinoma of the PT gland
83
What is the result of primary hyperparathyroidism?
hypercalcemia and kidney stones
84
What is secondary hyperparathyroidism a result of?
due to chronic liver failure
85
What is the result of secondary hyperparathyroidism?
reduced vit d leads to excess PTH synthesis
86
what is a result of hypoparathyroidism?
hypocalcemic tetany Chvostek sign: twitching of facial muscles in response to tapping of facial nerve
87
what is Rickets (children)/Osteomalacia (adults)?
unmineralized bone due to vit D deficiency decreased bone strength (bowing in children)
88
What is pseudohypoparathyroidism?
congenital defect in G protein that associates with PTH R1
89
what is a result of pseudohypoparathyrodism?
general resistance to PTH, LH, FSH, TSH
90
What are some clinical signs of pseudohypoparathyroidism?
Low ca, high phosphate, elevated PTH, short stature
91
How could you normalize low plasma Ca and high plasma P?
PTH infusion
92
What is a urinary marker for enhanced bone resorption?
hydroxyproline
93
What is calcitonin?
a 32AA peptide produced by C cells of the thyroid gland may help in inhibiting calcium resorption in bone
94
What does therapeutic use of calcitonin result in?
Used to treat Paget disease (high bone turnover): inhibits osteoclast resorption and slows bone turnover (hypocalcemic action)
95
What is the escape phenomenon?
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
Why are some findings that make the physiological function of calcitonin unclear?
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

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