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Clinical Biochemistry > Disorders of Calcium and Phosphate Metabolism > Flashcards

Disorders of Calcium and Phosphate Metabolism Flashcards

1
Q

1.Explain how osteoblast differentiation is induced by the RANK ligand?

A

• RANK (receptor activator of nuclear factor kappa-B) surface receptor on pre-osteoclasts stimulates osteoclast differentiation when RANK-L binds to it.
o RANK-ligand: produced by pre-osteoblasts, osteoblasts and osteocytes.
• OPG (osteoprotogerin): decoy receptor produced by osteocytes that binds to RANK-L to prevent the activation of RANK and so inhibits osteoclast differentiation.

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2
Q
  1. What inhibits osteoclast differentiation?
A

OPG (osteoprotogerin): decoy receptor produced by osteocytes that binds to RANK-L to prevent the activation of RANK and so inhibits osteoclast differentiation.

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3
Q
  1. What is the WNT signalling pathway?
A
  • A highly conserved, complex signal pathway that is involved in animal development - Drosophila wingless gene (1987)
  • WNT binds to the frizzled receptor which requires the co-factor LRP5/6 to become activated. The activated receptor activates B-catenin which migrates to the nucleus to bind to transcription factors (e.g. TGF)- osteoblast differentiation
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4
Q
  1. What is the WNT negatively signalled by?
A

DKK (dickkopf) and sclerostin (SOST).

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5
Q
  1. What is osteoCLAST differentiation:
    - Promoted by
    - Inhibited by
A
  • Promoted by RANK-L/M-CSF

- Inhibited by NO/OPG.

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6
Q
  1. What is osteoBLAST differentiation :
    - Promoted by
    - Inhibited by
A
  • Promoted by NO/ATP/PGE2

- Inhibited by SOST/DKK1/SFRP1

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7
Q
  1. Calcium homeostasis has already been covered in another lecture so a quick overview
    - What % of body calcium is in bone and intracellular
    - What amount of extracellular plasma is there?
    - How much is bound, how much is free?
    - What maintains Ca balance
A
  • 99% of body calcium is in bone and the remaining 1% is mainly intracellular
  • Extracellular: plasma Ca 2.2-2.6 mmol L-1
  • About half is free [Ca2+] (physiologically active), half protein bound (mainly albumin).
  • Hormonal control of the tiny (<0.1%) extracellular fraction is what maintains Ca balance.
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8
Q
  1. Where is Ca absorbed from and how?
A

•Ca is absorbed from the gut using vitamin D which is produced by PTH (PTH causes Ca reabsorption from the kidneys/gut and release from the bone).

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9
Q
  1. What % of the bodies phosphorus is in the bone?
A

•85% of body phosphorus is in bone and remainder is mainly intracellular

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10
Q
  1. What form is extracellular phosphorus in?
A

H2PO4^-, HPO4^2-

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11
Q
  1. What amount of plasma Phosphate should there be? What is an appropriate reference range?
A

2.5 - 4.5 mg dL-1 (0.75-1.45 mmol L-1)

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12
Q
  1. Where is Pi absorbed from and how?
A

•Pi is absorbed from the gut via vitamin D which is produced by PTH (PTH causes Pi excretion from the kidneys).

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13
Q
  1. How is Pi regulated by FGF-23?
A

•Pi is also regulated by FGF-23 from osteoclast which promote Pi excretion and inhibits vitamin D activation.

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14
Q
  1. Case Study:
    A 75 year old widow was investigated for bone pain and muscle weakness. She told the GP that she was vegetarian and rarely left her home.
Serum investigations:		               	
Total calcium	1.82 mmol/l	 (2.20 - 2.52)
Phosphate 0.70 mmol/L (0.75 - 1.50)
Albumin	39 g/L  (35 - 48)
Alkaline phosphatase  187 U/L	  (30 - 100)
Creatinine 69 umol/L (60 - 110)

Interpret these results?

A

LOW calcium
LOW phosphate
HIGH alkaline Phosphatase

• Vitamin D deficiency (diet and sunlight) causes low Ca and Pi – increase PTH to try to increase vitamin D.

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15
Q
  1. What is another name for vitamin D?
A

Calcitriol

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16
Q
  1. Is vitamin D a vitamin or a steroid hormone?
A

Steroid Hormone

17
Q
  1. How is Vit D synthesised and then activated?
A

• Synthesised in skin in response to exposure to UV (‘sunshine vitamin’) and activated by 2 metabolic steps
o 25 hydroxylation in liver to form 25OH D3, major circulating metabolite
o 1α hydroxylation of 25 OH D3 in kidney produces 1,25(OH)2 D3, or calcitriol, the active hormone

18
Q
  1. What is the difference between type 1 and type 2 dependant rickets?
A

Type 1 :
-Lack of 1 alpha hydroxylase enzyme

Type 2 :

  • Lack of Calcitriol receptors
  • 1 alpha hydroxylase enzyme is present
19
Q
  1. What levels (ie high or low) would you see of :
    -Ca
    -Pi
    - 25 OH D3
    - 1,25 (0H)2 D3
    -PTH
    Would you see in VIt D deficiency ?
A
  • Ca = LOW
  • Pi = LOW
  • 25 OH D3 = LOW
  • 1,25 (0H)2 D3 = NORMAL
  • PTH = HIGH

How can calcitriol be normal in Vit D deficiency? Point is, it’s inappropriately normal – with low Ca and Pi it should be higher.

20
Q
  1. What levels (ie high or low) would you see of :
    -Ca
    -Pi
    - 25 OH D3
    - 1,25 (0H)2 D3
    -PTH
    Would you see in Renal disease ?
A
  • Ca = LOW
  • Pi = HIGH
  • 25 OH D3 = NORMAL
  • 1,25 (0H)2 D3 = LOW
  • PTH = VERY HIGH
21
Q
  1. What levels (ie high or low) would you see of :
    -Ca
    -Pi
    - 25 OH D3
    - 1,25 (0H)2 D3
    -PTH
    Would you see in 1 alpha hydroxylase mutation ?
A
  • Ca = LOW
  • Pi = LOW
  • 25 OH D3 = NORMAL
  • 1,25 (0H)2 D3 = VERY HIGH
  • PTH = HIGH
22
Q
  1. What levels (ie high or low) would you see of :
    -Ca
    -Pi
    - 25 OH D3
    - 1,25 (0H)2 D3
    -PTH
    Would you see in Vit D receptor mutation ?
A
  • Ca = LOW
  • Pi = LOW
  • 25 OH D3 = NORMAL
  • 1,25 (0H)2 D3 = VERY HIGH
  • PTH = HIGH
23
Q
  1. How can a mutation result in hypophosphataemia ?
A

Mutation leading to excess FGF-23 activity

Ectopic FGF secretion (benign tumour)

24
Q 
24. What levels (ie high or low) of:
Ca
Pi
25 OH D3
1,25 (OH)2 D3
PTH
FGF-23
would you expect to see in X-linked hypopho-phataemic rickets , Autosomal dominant hypopho-phataemic rickets  
and 
Oncogenic osteomalacia ?
A 
Ca = Low / Normal
Pi = Low
25 OH D3 = Normal
1,25 (OH)2 D3 = Low/Normal
PTH = High/Normal
FGF-23 = High
25
Q
  1. Where is FGF-23 secreted from?
A

Osteocytes

26
Q
  1. When was FGF-23 discovered
A

2000

27
Q
  1. What is Hypophosphatemic rickets?
A

A rare phosphate-wasting conditions leading to bone mineralization defects (osteomalacia)

28
Q
  1. What causes Hypophosphatemic rickets?
A

Consortium investigating autosomal-dominant HR (ADHR) traced mutation in gene that turned out to be FGF-23

29
Q
  1. Which hormone plays a central role in phosphate homeostasis?
A

FGF-23

30
Q
  1. Explain the structure of FGF-23 ?
A

glycoprotein with 251 amino acids

signal peptide of 24 amino acids in the N-terminal portion

Next to the signal peptide is the FGF homology region

And then the C terminus

Furin cleaves the active form into inactive

31
Q
  1. What is the half life of FGF-23 normally and when there is a mutation?
A

o Normally: short half-life due to enzymatic cleavage (Furin).

o Recognition sequence mutation: enzyme can’t recognise the cleavage sites, so the peptide remains in circulation for longer causing excessive Pi excretion and excessive inhibition of Vit D production.

32
Q
  1. Explain the actions and interactions of FGF-23?
A
  • FGF-23 action: reduced PTH, reduced active vitamin D production and Pi excretion.
  • FGF production is increased by PTH, increased Pi and increased vitamin D.
  • PTH causes Pi excretion and vitamin D production.
  • Vitamin D causes Pi reabsorption and PTH inhibition of PTH production.
33
Q
  1. What is Renal Osteodystrophy
A

alteration of bone morphology–> Reduced renal function

34
Q
  1. What causes Renal Osteodystrophy?
A
  • Reduced production of activated vitamin D which causes hypocalcaemia (reduced reabsorption), this increases PTH production which causes bone erosion/resorption.
  • Reduced H+ excretion causes metabolic acidosis which also causes bone erosion
35
Q
  1. How does renal phosphate reabsorption work?
A

Sodium-phosphate co-transporter

Requires association with Na-H exchanger regulatory factor (NHERF)

Clinical Biochemistry (7 decks)

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