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Clinical pathology specialities: Clinical Biochemistry > Clinical Biochemistry: Laboratory investigation of disorders of calcium and phosphate metabolism > Flashcards

Clinical Biochemistry: Laboratory investigation of disorders of calcium and phosphate metabolism Flashcards

1
Q

What are Osteoblasts?

A
  • Cells that form new bone
  • They are derived from mesenchymal stem cells 
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2
Q

What are Osteoclasts?

A
  • Cell that digests/breaks down tissue
  • They are derived from haematopoietic stem cells 
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3
Q

What are Osteocytes?

A
  • They are terminally differentiated osteoblasts
  • They’re encased in bone mineral matrix (lacunae) 
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4
Q

Describe the process of bone remodelling

A
  • Small stress fractures detected by osteocytes
  • Osteocytes activate osteoclasts leading to osteoclast differentiation from osteoclast progenitors
  • Osteoclasts dissolve/digest old bone - specifically digest collagen matrix of old bone by secreting enzymes.
  • ​This leads to them releasing minerals from digested bone into extracellular fluid
  • Reversal occurs when apoptosis of the osteoclasts occurs at the same time as osteoblast differentiation
  • Osteoblasts will then lay down new bone (osteoid)
  • Osteoblasts will mineralise osteoid to form new bone
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5
Q

Describe the induction of Osteoclast differentiation by the RANK ligand

A
  • RANK (receptor activator of nuclear factor kappa-B): surface receptor on pre-osteoclasts
  • RANK-ligand which is produced by pre-osteoblasts and osteocytes; binds to RANK and stimulates osteoclast differentiation
  • NOTE: There’s also OPG (osteoprotogerin) present
    • OPG is a decoy receptor produced by osteocytes; binds to RANK-L, preventing activation of RANK
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6
Q

Describe Osteoblast differentiation

A
  • Osteoblast differentiation controlled by Wnt signalling pathway
  • Complex signal pathway, highly conserved, involved in animal development
  • Wnt is a signalling protein that has a receptor called frizzled
  • Wnt also has a co-receptor called LRP5/6
  • Wnt binds to frizzled and LRP5/6 which activates the intracellular cascades which lead to osteoblast differentiation
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7
Q

How is osteoblast differentiation prevented?

A
  • Osteoblast differentiation prevented by DKK (dickkopf) and sclerostin (SOST) binding to LRP5/6 co-receptor
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8
Q

What other factors can promote/inhibit Osteoclast differentiation?

A
  • Macrophage-colony stimulating factor (M-CSF) released by osteocytes PROMOTES osteoclast differentiation
  • Nitric oxide released by osteocytes INHIBITS osteoclast differentiation
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9
Q

What other factors can promote/inhibit Osteoblast differentiation?

A
  • PGE2, Nitric oxide and ATP released by osteocytes PROMOTE osteoblast differentiation
  • SFRP1 released by osteocytes INHIBIT osteoblast differentiation
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10
Q

What are some sources of calcium and phosphate?

A
  • Both calcium and phosphate are acquired from the diet
  • They are absorbed via the gut
  • Both calcium and phosphate absorption requires calcitriol (vitamin D)
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11
Q

What is the body’s response to the extracellular calcium level going down?

A
  • PTH will increase vitamin D activation
  • This will increase calcium absorption in the gut
  • PTH will cause calcium reabsorption in the renal tubules
  • PTH and vitamin D will promote bone remodelling which will release minerals, including calcium, into the extracellular fluid
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12
Q

What effect does PTH have on phosphate levels?

A
  • PTH causes the excretion of phosphate so causes phosphate levels to decrease
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13
Q

What role does FGF-23 play in phosphate regulation?

A
  • FGF-23 is secreted from osteocytes
  • It promotes excretion of phosphate
  • It also inhibits the actions of calcitriol (vitamin D)
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14
Q

What is Osteomalacia?

A
  • Loss of bone mineralisation
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15
Q

What is the most common cause of osteomalacia?

A
  • Vitamin D deficiency
  • Usually due to combination of low dietary intake and lack of exposure to sunlight
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16
Q

Use the following information to provide a diagnosis to this patient

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: reference range

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 mmol/L (60 - 110)

A
  • Serum investigations show patient has the following:
  • Low calcium
  • Low phosphate
  • High alkaline phosphatase (sign of increased bone turnover)
  • These all suggest patient has vitamin D deficiency
  • Fact she’s a vegetarian and doesn’t really leave home (lack of sunlight) further suggest vitamin D deficiency
  • Lack of vitamin D would cause low Calcium/phosphate as vitamin D needed for calcium/phosphate absorption
17
Q

What is Vitamin D?

A
  • Calcitriol (really a steroid hormone - binds to a nuclear receptor, so not a vitamin)
18
Q

Where is vitamin D synthesised?

A
  • Synthesised in skin in response to exposure to UV
19
Q

How is vitamin D activated?

A
  • Vitamin D3 undergoes 25 hydroxylation in liver to form 25OH D3 (major circulating metabolite)
  • 25OH D3 then undergoes 1α hydroxylation in the kidney to produce 1,25(OH)2 D3, or calcitriol, the active hormone
20
Q

Describe the levels of Calcium, phosphate, 25 OH D3 and 1,25(OH)2 D3 as a result of vitamin D deficiency; renal disease; 1α hydroxylase mutation and vitamin D receptor mutation

A
21
Q

Why are levels of calcitriol (1,25(OH)2 D3) normal during vitamin D deficiency?

A
  • Less 25 OH D3 means less initial conversion into calcitriol (1,25 (OH)2 D3)
  • Less initial calcitriol means less absorption of calcium and vitamin D
  • Low calcium increases PTH levels
  • Increased PTH cause increased conversion of 25 OH D3 into calcitriol which is why levels remain normal
22
Q

Explain why calcitriol levels are very low as a result of a 1α hydroxylase mutation

A
  • Calcitriol levels very low because 1α hydroxylase mutation means it’s dysfunctional
  • This means 25 OH D3 can’t be converted into calcitriol 1,25 (OH)2 D3
23
Q

Explain why calcitriol levels are very high as a result of a vitamin D receptor mutation

A
  • No problem in 25 OH D3 being converted into calcitriol
  • Mutation in vitamin D receptor means calcitriol can’t perform its effects
  • Because of this calcium and phosphate reamain low as caclitriol needed for their absorption
  • This means PTH reamins high and so will increases conversion of 25 OH D3 into calcitriol
24
Q

What is hypophoaphataemia?

A
  • Low levels of phosphate
25
Q

Describe the levels of Calcium, phosphate, 25 OH D3 and 1,25(OH)2 D3 as a result of: X-linked hypopho-phataemic rickets; Autosomal dominant hypopho-phataemic rickets and Oncogenic osteomalacia

A
26
Q

What is FGF-23?

A
  • A hormone secreted by osteocytes that ahs a central role in phosphate homeostasis
27
Q

What is Hypophosphatemic rickets?

A
  • Rare phosphate-wasting conditions leading to bone mineralization defects (osteomalacia)
28
Q

Describe the structure of FGF-23

A
  • Precusor 251 amino acids long
  • Active form 226 amino acids long
  • Cleavage site present in active peptide causes 2 inactive fragments to be fromed when enzymatically cleaved
29
Q

How does the mutation in FGF-23 that leads to Autosomal dominant hypopho-phataemic rickets affects its half-life?

A
  • Mutation in cleavage site of FGF-23 means it’s not recognised by enzymes
  • This means active form of FGF-23 remains in circulation (increased half-life)
30
Q

Describe the effects of FGF-23 on Phosphate, PTH and calcitriol (vitamin D)

A
  • Increase in phosphate causes increase in FGF-23
  • FGF-23 causes increased excretion of phosphate (negative feedback)
  • FGF-23 inhibits conversion of 25 OH D3 into calcitriol (vitamin D)
  • Increase in calcitriol causes increase in FGF-23
  • PTH causes increase in FGF-23
  • FGF-23 causes decrease in PTH
31
Q

Explain how renal osteodystrophy develops

A
  • Decrease in renal function will decrease activation of calcitriol
  • This will cause a decrease in absorption of calcium from gut and in calcium reabsorption in the kidneys
  • Both these effects cause a decrease in Plasma calcium level
  • This causes an increase in PTH
  • Maintained high level of PTH leads to bone erosion
  • Decrease in renal function also causes decrease in H+ excretion which leads to metabolic acidosis
  • Metabolic acidosis also leads to bone erosion
    *

Clinical pathology specialities: Clinical Biochemistry (7 decks)

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