Endocrine 8: Calcium and Phosphate; PTH Flashcards

1
Q

List functions of calcium

A
  • most abundant cation (because it is in bone)
  • tightly regulated
  • membrane stability
  • neuronal transmission
  • bone formation
  • blood coagulation
  • muscle function
  • hormone secretion
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2
Q

List functions of phosphates.

A
  • energy metabolism
  • intracellular signalling pathway
  • nucleic acid backbone
  • bone structure
  • enzyme activation/deactivation
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3
Q

What can hypocalcemia lead to?

A
  • muscle failure
  • tetany
  • convulsions
  • death
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4
Q

What can hypercalcemia lead to?

A
  • renal dysfunction
  • calcification of soft tissue
  • muscle weakness
  • coma
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5
Q

What can lead to hyperphosphatemia?

A

crush injury

- severe tissue injury leaks phosphate

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6
Q

How is calcium transported in the blood?

A
  • free
  • albumin (since 50:50 ratio, measuring albumin is a good indicator of calcium)
  • few complexed (phosphates, citrates)
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7
Q

How is phosphate transported in the blood?

A
  • mostly free

- some protein

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8
Q

What are the primary regulators of calcium?

A
  • PTH

- vitamin D (calcitriol)

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9
Q

Define rapidly exchangeable pool.

A
  • constant bone remodeling utilizes calcium storage

- main storage in bones, gut, and kidney

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10
Q

List the primarily cells in the PTH.

A
  • chief cells - make PTH

- oxyphil cells - increase with age and kidney decline

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11
Q

Where is the parathyroid gland located?

A

on the back of the thyroid

  • 4 lobes
  • small
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12
Q

Describe the structure of PTH.

A
  • total 1-84 AA secreted
  • peptide hormone (prepro => pro => hormone)
  • 1-34 AA is biologically active, binds to PTH1R
  • 35-84 fragment is not active, but has long half-life
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13
Q

Define PTHrP.

A

PTH-related-peptide

  • highly analagous to 1-34AA
  • mimics PTH in bone and kidney
  • many tumors produce this => hypercalcemia
  • paracrine effect
  • binds with equal affinity to PTH1R
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14
Q

Differentiate PTH1R and PTH2R.

A
PTH1R can bind with equal affinity to PTH and PTHrP
- primary receptor
- found on osteoclasts and kidney
- GPCR
- binds 1-34, 1-84, and PTHrP
PTH2R can bind only to PTH
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15
Q

What is the net effect of PTH?

A
  • increase plasma Ca (via bone resorption)

- decrease plasma Pi

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16
Q

Define osteoblasts.

A
  • support bone mineralization and bone formation
  • PTH target (high expression of PTH1R)
  • derived from mesenchymal stem cells
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17
Q

Define osteoclasts.

A
  • bone breakdown/resorption
  • derived from HSCs
  • do NOT express PTH1R
18
Q

Define osteocytes.

A
  • terminally differentiated osteoblasts

- found in bone matrix

19
Q

What does PTH do in the bone?

A
  1. PTH binds to PTH receptors on osteoblasts
  2. stimulates macrophage-colony stimulating factor (M-CSF) from osteoblasts
  3. M-CSF stimulates osteoclast differentiation
  4. stimulates osteoblast expression of RANK-Ligand
  5. RANKL stimulates RANK expression on osteoclast
  6. further osteoclast differentiation and bone resorption => release of Ca and Pi from bone into plasma
  7. osteoblasts take released Ca and Pi and use it to make new bone mineralization
20
Q

Define OPG.

A

OsteoProteGerin

  • soluble decoy
  • antagonist to RANKL
  • prevents differentiation of osteoclasts
  • no bone resorption, maintains bone
21
Q

What regulates OPG?

A
  • estrogen stimulates OPG => prevent bone resorption; protective in pre-menopausal women
  • cortisol inhibits OPG => allow RANK activation => bone resorption
22
Q

What does PTH do in the kidney?

A
  • transcription of CYP1a gene
  • encodes CYP1a/1a-hydroxylase enzyme
  • required for activation of Vitamin D (converts to 1,25-OH-cholecaciferol)
  • allows for calcium channel insertion on apical membranes of distal tubule (increase calcium reabsorption)
23
Q

What is the primary regulator of PTH?

A
  • plasma calcium levels monitored by CaSr on parathyroid gland chief cells, kidney, and thyroid calcitonin C cells
  • high calcium = low PTH
  • low calcium = high PTH
24
Q

Define CaSR.

A

Calcium Sensing-Receptor

  • found on chief cells, kidney, C cells
  • binds free Ca in the blood
  • downstream signaling cascade inhibits PTH gene transcription and promotes degradation of preformed PTH
25
Q

How does Vitamin D regulate PTH?

A
  • inhibits PTH gene transcription
  • promotes transcription of CaSR
  • increases PTH sensitivity to Ca (even if little Ca in the blood…will think there is enough..no PTH)
26
Q

Define calciferol.

A

any Vitamin D analog

27
Q

Define cholecalciferol.

A

Vitamin D3 from animal tissues.

28
Q

Define ergocalciferol.

A

Vitamin D2 from plant tissues

29
Q

Define calcidiol.

A

25-OH-Vitamin D (25-OH-cholecalciferol)

  • immediate precursor to active Vitamin D
  • default inactive pathway
30
Q

Define calcitriol.

A

1, 25 -OH-cholecalciferol

  • active form
  • activated by CYP1a or 1a-hydroxylase in the kidney
31
Q

How is active vitamin D synthesized?

A
  1. endogenous cholesterol derivative is activated to vitamin D3 via UV light
  2. transported to liver via vitamin-D binding protein or chylomicron in blood
  3. liver converts it to the immediate inactive precursor (25-OH-D)
  4. transported in peripheral blood attached to DBP
  5. activated in the kidney via 1a-hydroxylase to 1,25-OH-D
32
Q

What regulates vitamin D activation?

A
  • calcium levels (low calcium => PTH increase => bone resorption => increase plasma calcium)
  • phosphate levels
  • low Vitamin D
33
Q

What are targets of Vitamin D?

A

bone
kidney
gut

34
Q

Describe Vitamin D effects in bone.

A
  • mobilize Ca from bone
  • stimulate osteoclast differentiation directly via nuclear receptors
  • indirect: by increasing calcium absorption and reabsorption in the kidney => increase plasma calcium => promote bone mineralization
35
Q

Describe Vitamin D effects in gut.

A
  • increase transcellular calcium absorption by promoting transcription of TRPV5/6 and PMCA transport proteins
36
Q

What happens in hypocalcemic situations?

A
  1. low Ca stimulates PTH release
  2. PTH
    ===> activates CYP1a in kidney ==> Vit. D activation ==> bone resorption, dietary absorption
    ===> bone resorption ===> increase plasma Ca
    ===> reabsorption at the kidney ===> increase plasma Ca
  3. negative feedback
    ===> vitamin D blocks PTH release
    ===> increased blood Ca blocks PTH and CYP1a
37
Q

Define osteoporosis

A

Causes

  • genetic
  • menopause (loss of estrogen => loss of OPG => continuous RANK stimulation => continuous resorption)
  • stress/glucocorticoids (cortisol increases bone resorption)
  • low dietary Ca

Sx: reduced bone density
Tx: estrogen, calcitonin, dietary Ca, bisphosphonates (inhibit bone resorption but can lead to fractures), Vitamin D

38
Q

Define hyperparathyroidism.

A

Primary Causes = hyperplasia, carcinoma at parathyroid
- Sx: kidney stones, hypercalcemia
Secondary Causes = chronic renal failure
- reduced vitamin D production => constant PTH release

39
Q

Define pseudohyperparathyroidism.

A
  • congenital defect in PTH1R G-protein
  • also leads to generalized resistance to PTH, LH, FSH, TSH (same G protein)
  • Sx: low calcium, high phosphate, high PTH, short stature
40
Q

Define hypoparathyroidism.

A

Sx: tetany, low Ca, Chvostek sign of twitching facial nerve

41
Q

Define rickets/osteomalacia.

A

rickets = bow legged, children; osteomalacia = adults

  • Vitamin D deficiency => unmineralized bone (soft)
  • decreased bone strength
42
Q

Define source and effects of calcitonin.

A
  • thyroid C cells
  • inhibits bone resorption
  • hypocalcemia actions