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FHB Endocrinology > L75: Parathyroid and Regulation of Calcium > Flashcards

L75: Parathyroid and Regulation of Calcium Flashcards

1
Q

What is a good indicator of free calcium availability?

A

Albumin levels: calcium bound to albumin

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2
Q

What are the 2 primary regulators of Calcium?

A

Parathyroid Hormone

Vitamin D/Calcitriol

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3
Q

Which organs govern calcium homeostasis?

A

Intestines, Kidney, Bone

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4
Q

Where is the parathyroid gland?

A

On anterior surface of thyroid gland

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5
Q

What cells are found in the parathyroid gland and what do they do?

A

Chief Cells: produce PTH

Oxyphil Cells: unknown, increases with age

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6
Q

How is PTH synthesized?

A

Signal peptide on preproPTH directs peptide to ER -> Processed to Pro-PTH sequence after signal peptide cleaved -> vesicles -> PTH secreted as 84 residue molecule (Active sequence: 1-34, C term fragment: 35-84)

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7
Q

Which part of the secrete PTH binds to the PTH receptor?

A

N terminal fragment 1-34 is the biologically active component

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8
Q

What is unique about the C terminal fragment 35-84 from PTH?

A

Longer half life than biologically active part of PTH and inactive

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9
Q

What is PTHrP

A

PTH related peptide: mimics PTH actions in bone and kdney

is NOT a regulator of plasma Calcium

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10
Q

What usually produces PTHrP?

A

Tumors-> leads to hypercalcemia

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11
Q

What is the primary PTH receptor?

A

PTH 1R: found in osteoblasts and kidney

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12
Q

What kind of receptor is PTH 1R and what does it bind?

A

GPCR: Gas-> AC/cAMP pathway; Gaq->PLC/IP3/DAG

Binds: 1-34 fragment, 1-84, and PTHrP

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13
Q

What is PTH 2R?

A

Another PTH receptor that binds the 1-34 fragment of PTH
Does NOT bind PTHrP
Unclear of importance in humans

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14
Q

What are the targets of PTH and their net effects?

A

Targets: Bone and Kidney

Net EffectS: Increase plasma Calcium and decrease plasma phosphate

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15
Q

Where is the vast majority of calcium present in?

A

99% found in bone

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16
Q

What do osteoblasts do?

A

Bone formation and mineralization

High expression of PTH receptors

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17
Q

Where are osteoblasts derived from?

A

Mesenchymal Stem Cells

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18
Q

What do osteoclasts do?

A

Bone reabsorption

Do NOT express PTH receptors

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19
Q

Where are osteoclasts derived from?

A

hematopoietic stem cells

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20
Q

What are osteocytes?

A

Make up most of bone matrix

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21
Q

Where do osteocytes derive from?

A

Terminally differentiated osteoblasts

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22
Q

How does PTH affect bone remodleing?

A

PTH stimulates M-CSF in osteoblasts-> M-CSF stimulates differentiation of osteoclast precursors -> PTH stimulates RANK-ligand -> osteoclasts mature-> bone reabsorption -> bone degradation leads to release of calcium and phosphate into blood

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23
Q

What is osteoprotegerin (OPG)?

A

Antagonist to RANK ligand ->prevents association with RANK on osteoclast precursors-> prevents maturation of osteoclasts

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24
Q

What regulates OPG?

A

Estrogens stimulate OPG

Glucocorticoids inhibit OPG

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25
Q

How do osteoclasts reabsorb bone?

A

Secrete H+ and acid proteases into lacuna -> dissolves bone mineral and hydrolyze bone matrix proteins

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26
Q

What does the PTH do in the kidney?

A

Stimulate CYP1a(1a-hydroxylase) -> converts to active form of Vitamin D3

Stimulate Calcium channel insertion on the apical membrane of distal tubule

REduce phosphate reabsorption

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27
Q

Where in the kidney does PTH exert its effects?

A

Thick Ascending limb
Distal tubule
Proximal tubule

28
Q

What is CaSR?

A

Calcium sensing receptor
Binds ionized Calcium -> regulates PTH by inhibiting its synthesis at the promoter level

Also stimulates degradation of preformed PTH

29
Q

Where are CaSRs found?

A

Chief Cells, Kidney Tubules, C cells

30
Q

What role does Vitamin D play in PTH regulation?

A

Binds nuclear receptor (VDR) to inhibit PTH synthesis at promoter level

Stimulates CaSR gene transcription -> indirect regulation of PTH

31
Q

How does PTH stimulate Osteoclasts?

A

Indirectly through M-CSF secretion stimulation in osteoblasts

32
Q

What is calciferol?

A

General term for Vitamin D and natural sturctural analogs

33
Q

What is cholecalciferol?

A

Vitamin D3 (animal tissues)

34
Q

What is calcidiol?

A

25-hydroxy-vitamin D (25-D): immediate precursor to active Vitamin D

35
Q

What is Calcitriol?

A

1,25-dihydroxy-vitamin D (1,25-D): active form of Vitamin D

36
Q

What is ergocaliferol?

A

Vitamin D2 from vegetables

37
Q

Where is Vitamin D3 derived from?

A

From cholesterol (steroid hormone)

38
Q

What receptor does Vitamin D3 bind?

A

Nuclear receptor VDR

39
Q

How is Vitamin D3 transported?

A

Bound to vitamin D binding protein

40
Q

How is Vitamin D3 synthesized in the skin?

A

Precursor hormone (7-dehydr/ocholesterol) converted to cholecalciferol in skin by UV -> isomerized -> Vitman D3 -> binds to Vitamin D binding protein in circulation -> transport to liver

41
Q

How do you activate vitamin D3 and vitamin D2 from the diet?

A

1a-hydroxylase enzyme in kdiney via stimulation from PTH

42
Q

How is Vitamin D3 metabolized?

A

VitD3 transported from skin to liver
VitD3 and D2 from diet are transported to liver directly via portal circulation or indirectly via chylomicrons

LIVER: hydroxylated to calcidiol (25- D) -> goes to kidney to convert to active Calcitriol (1,25-D) by 1a-hydroxylase

43
Q

What is the default pathway for Vitamin D3 synthesis?

A

Inactive form 24,25-D

44
Q

What is the sequence in the pathway for active vitamin D3 synthesis?

A

7-dehydrocholesterol(skin) -> UV light -> Cholecalciferol-> liver -> Calcidiol(25-D3) -> Kidney(1a Hydroxylase) -> Calcitriol (1,25D3) active form

45
Q

What conditions lead to the active form pathway for Vitamin D?

A

Key Factors: hypocalcemia and hypophosphatemia

Others: Vitamin D deficiency, Increased PTH

46
Q

What are the effects of Vitamin D on bone?

A

Direct:
mobilize calcium from bone via VDRs on osteoblasts and osteoclasts
stimulate osteoclast proliferation/differentiation

Indirect:
Increase plasma calcium to promote bone mineralization

47
Q

What are the effects of Vitamin D on the intestine?

A

Increase transcellular Calcium absorption in duodenum by increasing expression of TRPV5/6
Stimulate phosphate reabsorption from small intestine

48
Q

How does Vitamin D promote calcium reabsorption transcellularly in the intestine?

A

Vitamin D-> inc TRPV5/6 -> Calcium comes in from luminal side -> binds to Calbindin -> goes through membrane calcium ATPase pump on other side

49
Q

How does Vitamin D promote phosphate absorption in the intestine?

A

Vitamin D -> inc expression of Na+/Pi cotransporter -> secrete 2 Na+ for 1 phosphate

50
Q

Does Vitamin D show pleiotropic effects?

A

Yes

51
Q

What can Vitamin D deficiency lead to?

A 
MS
Asthma
CV disease
DM T2
Colorectal/breast cancer
Depressive disorder
52
Q

How does vitamin D affect immune cells?

A

induces differentiation

53
Q

How is low blood calcium regulatd?

A

Hypocalcemia -> inc PTH =>
inc CYP1a-> inc 1,25D (calcitriol -> inc dietary calcium absorption in intestine, inc bone turnover-> inc blood Ca

inc bone turnover +inc Ca2+ reabsorption and inc phosphate excretion in kidneys -> inc blood Ca2+

54
Q

How are low serum calcium and high serum phosphate dealt with?

A

PTH infusion normalizes them

55
Q

What is the normal range for serum calcium? phosphate?

A

Calcium: 2.2-2.6 mM
Phosphate: 0.8-1.45 mM

56
Q

What is osteoporosis? What cases it?

A

Reduced bone density in trabecular bone

Causes: Genetics, Menopause(low estrogen), Glucocorticoid/stress, low dietary Caclium

57
Q

How do you treat osteoporosis?

A

Estrogen
Calcitonin
Bisphosphonates
Vitamin D

58
Q

What are the 2 forms of hyperparathyroidism?

A

Primary: hyperplasia, carcinoma of Parathyroid gland->leads to hypercalcemia and kidney stones

Secondary: due to chronic renal failure -> reduced Vitamin D -> excess PTH secretion

59
Q

What is seen with hypoparathryoidism?

A

hypocalcemic tetany (low calcium levels lower the threshold for depolarizaiton)

Chvostek Sign

60
Q

What is Chvostek Sign?

A

twitching of facial muscles in response to tapping facial nerve

61
Q

What causes rickets(children)/osteomalacia (adults)?

A

Unmineralized bone due to Vitamin D deficiency leading to decreased bone strength

62
Q

What is calcitonin?

A

Peptide produced in C cells of thyroid gland with unclear importance in normal physiology

63
Q

What happens to calcium levels with thyroidectomy but intact parathyroid glands??

A

No change in normal range of calcium (calcitonin thus is not a major regulator of calcium)

64
Q

What happens to calcium levels with C cell tumors?

A

Tumors -> very high levels of calcitonin -> but no changes seen in calcium levels => calcitnon is not a major regulator of calcium

65
Q

What uses does calcitonin have?

A

Therapeutic: inhibit osteoclast reabsorption of bone and slows bone turnover- > leads to hypocalcemic effect

66
Q

What is Paget disease and how can it be treated?

A

Excessive localized regions of bone resorption and reactive sclerosis leading to very high bone turnover
Treat with calcitonin

67
Q

What is the escape phenomenon in relation to calcitonin

A

Rapid downregulation of calcitonin receptors -> leads to diminished anti-osteoclastic effects of calcitonin -> makes it become less effective treatment option

FHB Endocrinology (10 decks)

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