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Metabolism CC > Calcium > Flashcards

Calcium Flashcards

1
Q

Blood calcium

A

50% protein bound (40% albumin, 10% globulin)
40% ionised
10% complexes with phosphate/citrate

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2
Q

When does calcium bind to albumin

A

In an alkalotic state e.g. hyperventilation

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3
Q

Calcium signalling

A

Nerve + muscle automaticity
Muscle contraction
Neurotransmitter release
Endocrine/exocrine secretion

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4
Q

Intracellular calcium

A

99% within mitochondrial compartment

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5
Q

Chemical and electrical Ca 2+ gradient

A

Maintained by limited conductance of resting Ca2+ channel and Ca2+/H+ ATPases and Ca2+/Na+ exchangers

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6
Q

Phosphate

A

85% mineralised in bone

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7
Q

Serum phosphate

A

Almost all is ionised

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8
Q

Extracellular Ca

A

Total Serum Conc= 2.5 x 10-3 M
Free Serum Conc= 1.2 x 10-3
Function= bone mineral, blood coagulation, membrane excitability

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9
Q

Intracellular Ca

A 
Conc= 10-7 M
Function= signalling
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10
Q

Extracellular Phosphate

A

Total Serum Conc= 1 x 10-3 M
Free Serum Conc= 0.85 x 10-3 M
Function= Bone mineral

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11
Q

Intracellular Phosphate

A 
Conc= 1.2 x 10-3M
Function= structural, high energy bonds, phosphorylation
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12
Q

PTH processing

A

Processed from polypeptide prohormone PreproPTH
Secreted intact PTH-184 is extensively metabolised by liver + kidney and has circulation half life of only 2 mins
Active PTH portion is N-terminal

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13
Q

PreproPTH –> PTH

A

PreproPTH –> ProPTH in Rough ER

ProPTH –> PTH in Golgi

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14
Q

PTH secretion

A

Released when serum ionised calcium low

PTH levels rise higher when acute fall rather than chronic fall as additional protection against hypocalcaemia

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15
Q

Calcium sensing receptor

A

G-protein coupled receptor

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16
Q

Calcium sensing receptor MOA

A

Activated PLC (phospholipase C)
Blocks stimulation of cAMP
Also activated by magnesium, certain aa’s and calcimimetic compounds

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17
Q

Calcium sensing receptor effects

A

Reduced PTH secretion
Increases breakdown of stored PTH
Suppresses transcription of PTH gene

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18
Q

Parathyroid

A

Oxyphilic and Chief cells

Chief cells release PTH

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19
Q

Inactivating mutations of Calcium sensing receptor

A

Familial Hypocalciuric hypocalcaemia (FHH)

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20
Q

Other determinants of PTH secretion

A

Activated Vit D (calcitriol) suppresses PTH gene transcription
Phosphate stimulates PTH gene transcription
Cinacalcet activates CASR and reduces calcium levels
CASR activation restrain parathyroid proliferation

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21
Q

PTH Actions- KIDNEY

A

Decreases calcium excretion

Increases phosphate excretion

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22
Q

PTH Actions- BONE

A

Increases calcium and phosphate resorption

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23
Q

PTH Actions- INTESTINE

A

Increases absorption of calcium and phosphate

Some evidence of direct effect but mainly through calcitriol

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24
Q

Proximal tubule- calcium handling

A

65% reabsorption
Paracellular
PTH independent
Voltage dependent

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25
Q

Loop of Henle- calcium handling

A 
20% reabsorption
Para/Transcellular
Voltage dependent
Inhibited by loop diuretics
CASR downregulates Na+/K+/2Cl-
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26
Q

Distal tubule- calcium handling

A

10% reabsorption

PTH upregulates - TRPV Ca2+ channels, Calcium ATPase, Na+/Ca2+ exchanger

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27
Q

More Renal PTH effects

A

Down-regulates Na+/Pi transporters –> reduces phosphate reabsorption
Vit D activation- Stimulation 25dihydroxyvitD3–> 1,25-dihydroxyvitD2 (calcitriol)
Acts on increasing 1-alpha hydroxylase activity- can be overridden by calcitriol or hypercalcaemia
Proximal tubule gluconeogenesis
Inhibits sodium/water/bicarb reabsorption via effect on Na+/H+ exchanger and Na+/K+ ATPase

28
Q

Endochondral bone formation

A

Occurs with cartilage model
Generates longitudinal physical growth and embryonic long bone formation
–> chondrocytes produce cartilage which is absorbed by osteoclasts
–> osteoblasts lay down bone on cartilaginous framework
–> forms primary trabecular bone
–> bone deposition occurs on metaphyseal side

29
Q

Intramembranous bone formation

A

Occurs without cartilage model

Leads to embryonic flat bone formation, including subperiosteal surface of long bones

30
Q

Endochondral –>

A

Trabecular bone (spongy)

31
Q

Endochondral + intramembranous –>

A

Cortical bone

32
Q

Bone

A

Collagen + hydroxyapatite

33
Q

Mineralisation

A

Calcium + phosphate + alkaline phosphatase

34
Q

Osteoblasts derived from

A

Mesenchymal cells

35
Q

Osteoclasts from

A

Myeloid origin

36
Q

Osteoblast role

A

Produces mineral

Signal osteoclast to resorb bone

37
Q

Osteoblast when mineralisation is complete

A

Differentiate into osteocytes, encased in mineralised bone

Maintain connections with other osteoblasts in an extended syncytium

38
Q

Osteoblasts release

A

RANKL
CSF-1
–> promote osteoclastogenesis + osteoclast function

39
Q

Other influences on bone remodelling

A

OPG (osteoprotegerin) inhibits osteoclastogenesis
PTH and calcitriol
–> stimulate RANKL production, downregulate OPG

40
Q

PTH

A

Increases RANKL
Decreases OPG
Increases IGF1
Increases IL1

41
Q

Calcitriol

A

Increases RANKL in vitro

Increases gut Ca2+ absorption

42
Q

Glucocorticoid

A

Reduces osteoblast numbers + mineral production

Increases RANKL

43
Q

Oestrogen

A

Epiphyseal closure
Reduces cytokine sensitivity
Inhibits bone remodelling

44
Q

Vit D

A

Not a vitamin
7-dehydrocholesterol –> previtamin D by UV light
—> isomerises to Vit D in 48 hours

45
Q

Prolonged sun exposure

A

Doesn’t cause Vit D exposure and subsequent hypercalcaemia because

  • -> further isomerisation to luminosterol + tachysterol
  • -> pigmentation
46
Q

Vit D2

A

Ergocalciferol

Plant sources

47
Q

Vit D3

A

Cholecalciferol

Animal sources

48
Q

Vit D–> 25(OH)D

A

Liver
Unregulated
Under action of p450 enzymes

49
Q

25(OH)D half life

A

2-3 weeks

50
Q

Conversion to 1,25(OH)D

A

Highly regulated

Produces a hormone with much shorter half life, 6-8 hours

51
Q

Vit D in circulation

A

Albumin

Vit D binding protein (VDBP)- acts as reservoir

52
Q

1 alpha hydroxylase inhibitor

A

Antifungal agent ketoconazole

Used in Vit D toxicity by granulomatous disease

53
Q

Vit D receptor

A

Nuclear receptor
Found on DNA in a heterodimer with a retinoid receptor
Activation inhibits action of 1 alpha hydroxylase, therefore reducing amount of activated Vit D able to bind to receptor

54
Q

Macrophage production of Vit D

A

Positive feedback of activated Vit D production within activated macrophages, to upregulate their cytotoxic capacity
1 alpha hydroxylase not regulated by PTH or downregulated by VDR activation

55
Q

Gut Calcium absorption

A

Calcitriol increases gut calcium and phosphate absorption
Presence of bile salts, FAs in diet, fibre in diet, gastric acidity
PPIs reduce Ca uptake
Across enterocytes- occurs via transcellular, paracellular and vesicular routes

56
Q

Vit D effects

A 
Reduces PTH transcription
Reduces expression type 1 collagen
Increases osteocalcin levels
Increases RANKL
Facilitates osteoclast differentiation
In gut- increases phosphate absorption, increases levels FGF23 to remove it via renal excretion
Increases AA uptake
57
Q

Primary hyperparathyroidism

A

Absence of hypocalcaemia- either normal or high
–> hypercalcaemia- polyuria, polydipsia, kidney stones, osteoporosis, mood disorder
Parathyroid adenoma, carcinoma, hyperplasia

58
Q

Secondary hyperparathyroidism

A

Compensation for hypocalcaemia

59
Q

Tertiary hyperparathyroidism

A

Autonomous PTH production followed by chronic secondary hyperparathyroidism

60
Q

Primary hyperparathyroidism- diagnosis

A

Serum calcium + PTH
24hr urine calcium
Renal ultrasound

61
Q

Primary hyperparathyroidism- asymptomatic patients

A

Low bone mineral density
Renal calculi
Renal impairment
Calcium .3mmol/L

62
Q

Hypoparathyroidism Causes

A 
Iatrogenic
Chronic kidney disease
Vit D deficiency
Genetic
Metabolic disease
Autoimmune
Parathyroid resistance syndromes
63
Q

Hypoparathyroidism effect

A

Hypocalcaemia

–> convulsions, arrhythmias, tetany, paresthesias

64
Q

Hypoparathyroidism Treatment- ACUTE

A

IV or oral calcium replacement

65
Q

Hypoparathyroidism Treatment- CHRONIC

A

Alfacalcidol (1,25 Vit D3) orally

Increases gut absorption of Ca

66
Q

PTH

A

Peptide hormone
Can’t be given orally
Some patients on subcutaneous infusions via an insulin pump

67
Q

FHH

A 
Inactivating mutations of CaSR
Parathyroid can't sense high calcium
PTH not suppressed by high calcium
CaSR in kidney not activated
High serum calcium
Low urine calcium
High serum magnesium

Metabolism CC (29 decks)

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