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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
Loop of Henle- calcium handling
``` 20% reabsorption Para/Transcellular Voltage dependent Inhibited by loop diuretics CASR downregulates Na+/K+/2Cl- ```
26
Distal tubule- calcium handling
10% reabsorption | PTH upregulates - TRPV Ca2+ channels, Calcium ATPase, Na+/Ca2+ exchanger
27
More Renal PTH effects
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
Endochondral bone formation
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
Intramembranous bone formation
Occurs without cartilage model | Leads to embryonic flat bone formation, including subperiosteal surface of long bones
30
Endochondral -->
Trabecular bone (spongy)
31
Endochondral + intramembranous -->
Cortical bone
32
Bone
Collagen + hydroxyapatite
33
Mineralisation
Calcium + phosphate + alkaline phosphatase
34
Osteoblasts derived from
Mesenchymal cells
35
Osteoclasts from
Myeloid origin
36
Osteoblast role
Produces mineral | Signal osteoclast to resorb bone
37
Osteoblast when mineralisation is complete
Differentiate into osteocytes, encased in mineralised bone | Maintain connections with other osteoblasts in an extended syncytium
38
Osteoblasts release
RANKL CSF-1 --> promote osteoclastogenesis + osteoclast function
39
Other influences on bone remodelling
OPG (osteoprotegerin) inhibits osteoclastogenesis PTH and calcitriol --> stimulate RANKL production, downregulate OPG
40
PTH
Increases RANKL Decreases OPG Increases IGF1 Increases IL1
41
Calcitriol
Increases RANKL in vitro | Increases gut Ca2+ absorption
42
Glucocorticoid
Reduces osteoblast numbers + mineral production | Increases RANKL
43
Oestrogen
Epiphyseal closure Reduces cytokine sensitivity Inhibits bone remodelling
44
Vit D
Not a vitamin 7-dehydrocholesterol --> previtamin D by UV light ---> isomerises to Vit D in 48 hours
45
Prolonged sun exposure
Doesn't cause Vit D exposure and subsequent hypercalcaemia because - -> further isomerisation to luminosterol + tachysterol - -> pigmentation
46
Vit D2
Ergocalciferol | Plant sources
47
Vit D3
Cholecalciferol | Animal sources
48
Vit D--> 25(OH)D
Liver Unregulated Under action of p450 enzymes
49
25(OH)D half life
2-3 weeks
50
Conversion to 1,25(OH)D
Highly regulated | Produces a hormone with much shorter half life, 6-8 hours
51
Vit D in circulation
Albumin | Vit D binding protein (VDBP)- acts as reservoir
52
1 alpha hydroxylase inhibitor
Antifungal agent ketoconazole | Used in Vit D toxicity by granulomatous disease
53
Vit D receptor
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
Macrophage production of Vit D
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
Gut Calcium absorption
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
Vit D effects
``` 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
Primary hyperparathyroidism
Absence of hypocalcaemia- either normal or high --> hypercalcaemia- polyuria, polydipsia, kidney stones, osteoporosis, mood disorder Parathyroid adenoma, carcinoma, hyperplasia
58
Secondary hyperparathyroidism
Compensation for hypocalcaemia
59
Tertiary hyperparathyroidism
Autonomous PTH production followed by chronic secondary hyperparathyroidism
60
Primary hyperparathyroidism- diagnosis
Serum calcium + PTH 24hr urine calcium Renal ultrasound
61
Primary hyperparathyroidism- asymptomatic patients
Low bone mineral density Renal calculi Renal impairment Calcium .3mmol/L
62
Hypoparathyroidism Causes
``` Iatrogenic Chronic kidney disease Vit D deficiency Genetic Metabolic disease Autoimmune Parathyroid resistance syndromes ```
63
Hypoparathyroidism effect
Hypocalcaemia | --> convulsions, arrhythmias, tetany, paresthesias
64
Hypoparathyroidism Treatment- ACUTE
IV or oral calcium replacement
65
Hypoparathyroidism Treatment- CHRONIC
Alfacalcidol (1,25 Vit D3) orally | Increases gut absorption of Ca
66
PTH
Peptide hormone Can't be given orally Some patients on subcutaneous infusions via an insulin pump
67
FHH
``` 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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