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Block 4: Anatomy + Physiology > Calcium + phosphate homeostasis > Flashcards

Calcium + phosphate homeostasis Flashcards

1
Q

Which tissues help to regulate calcium and phosphate homeostasis?

A 
Parathyroid glands 
Thyroid
Kidneys
Gut
Bone
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2
Q

How do parathyroid glands help to regulate calcium and phosphate homeostasis?

A

Make parathyroid hormone (PTH) in response to detected levels of plasma calcium (Ca2+) and phosphate (PO4)

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3
Q

How do the kidneys help to regulate calcium and phosphate homeostasis?

A

Regulate calcium and phosphate reabsorption

Activate vitamin D

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4
Q

How does the gut help to regulate calcium and phosphate homeostasis?

A

Uptake calcium and phosphate (facilitated by vitamin D) - mainly in the duodenum and jejunum
All calcium intake comes from diet

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5
Q

How does the thyroid help to regulate calcium and phosphate homeostasis?

A

Synthesis of calcitonin

Detection of serum calcium levels

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6
Q

How do bones help to regulate calcium and phosphate homeostasis?

A

Storage of calcium and phosphate
Resorption of bone releases calcium and phosphate and formation deposits calcium and phosphate
Make fibroblast growth factor 23 (FGF-23)

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7
Q

What is the role of calcium in the body?

A

Bone (and teeth) formation - growth and remodelling
Muscle contraction (actin filaments)
Nerve function
Enzyme co-factor (clotting)
Intracellular second messenger
Stabilisation of membrane potentials (e.g. in cardiac muscles)

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8
Q

What are the parathyroid glands?

A

4 glands found on the posterior surface of the thyroid gland responsible for sensing the circulating concentrations of calcium (PTH secreted from cheif cells in response to low calcium)
Have an independent blood supply to that of the thyroid gland (meaning that thyroidectomy should not affect parathyroid glands)

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9
Q

What is the distribution of calcium in the body?

A

Approx. 1-2 kg in body (99% of which is stored in the skeleton and 1% intracellularly)
Approx. 2.5 mmol extracellularly in blood plasma (45% ionised and 55% bound e.g. to albumin)

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10
Q

How is calcium normally regulated in the body?

A

Increased PTH secretion in response to low calcium levels
PTH acts on bones, kidneys and vitamin D to increase serum calcium levels
Active vitamin D acts on bone, kidneys and GI tract to increase serum calcium levels
Increased calcium and active vitamin D levels feeds back to parathyroid glands to switch off PTH secretion (negative feedback)

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11
Q

What actions does PTH have in response to low calcium levels?

A
  1. Increases bone resorption for calcium release
  2. Increases calcium reabsorption in the kidneys
  3. Alters enzyme 1apha-hydroxylase to convert inactive vitamin D to its active form
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12
Q

What actions does vitamin D (in its active form) have in response to low calcium levels?

A
  1. Increases bone resorption for calcium release
    2, Increases calcium reabsorption in the kidneys
  2. Increases calcium absorption in the GI tract (through activation of TRPV6 channels)
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13
Q

How does the body respond to high calcium levels?

A

Thyroid gland produces Calcitonin which inhibits bone resorption (by preventing osteoclast action) and calcium and phosphate reabsorption in the kidneys to lower serum calcium levels

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14
Q

How does parathyroid hormone work?

A

Peptide hormone (short half life)
Acts via G-protein coupled receptor
Binds to PTHR1 - activated by both PTH and PTH-related peptide

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15
Q

How are high calcium levels detected and responded to in the blood?

A
  1. Calcium binds to extracellular Calcium-sensing receptors (CaSR) in parathyroid glands (and thyroid)
  2. G-protein pathway activated which inhibits action of adenylate cyclase
  3. Inhibition of AC prevents conversion of ATP to cAMP
  4. Lack of cAMP inhibits production and secretion of PTH
  5. Calcium binds to extracellular CaSR
  6. G-protein pathway inhibits Phospholipase C
  7. Suppression of PTH secretion and gene expression
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16
Q

How are low calcium levels detected and responded to in the blood?

A
  1. Less binding of calcium to extracellular calcium-sensing receptors in parathyroid glands (and thyroid)
  2. ATP converted to cAMP by adenylate cyclase
  3. cAMP involved in producing and secreting PTH

[+ no inhibition of phospholipase C allows for secretion and gene expression of PTH)

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17
Q

What is parathyroid hormone-related peptide (PTHrP)?

A

Made by many tissues (esp. malignant tissues)
Mimics PTH (by binding to PTHR1) thus elevating plasma calcium levels
Can cause hypercalcaemia in cancer
Does not increase activation of vitamin D (unlike PTH)

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18
Q

How is calcium absorbed in the GI tract when blood calcium levels are high?

A

Paracellular transport (meaning absorption levels are fairly low)

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19
Q

How is calcium absorbed in the GI tract when blood calcium levels are low?

A
  1. Calcium enters epithelial cell via TRPV6 channels
  2. Binds to calcium binding proteins
  3. Exported into blood via Calcium ATPase pumps or sodium-calcium exchanger

OR

  1. Calcium enters epithelial cell via TRPV6 channels
  2. Engulfed in vesicle with calcium binding protein
  3. Transported through cell and released by exocytosis into the blood

[+ some paracellular transport]

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20
Q

How does vitamin D increase calcium absorption in the GI tract?

A
  1. Increases production and translocation of TRPV6 and insertion into luminal membrane
  2. Increases amount of calcium binding protein
  3. Increases transport mechanisms out of cell
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21
Q

Where in the kidneys is calcium reabsorbed?

A
  1. Calcium filtered through glomerulus and enters proximal tubule in filtrate
  2. Majority of calcium reabsorbed in proximal tubule
  3. Some reabsorbed in loop of Henle
  4. Reabsorption in distal tubule through active transport
  5. 1-2% excreted in urine
22
Q

How is calcium reabsorbed in the distal tubule?

A
  1. TRPV5 calcium channels in luminal membrane
  2. Transported across basolateral membrane via Calcium ATPase pumps or sodium-calcium exchangers

[+ some paracellular transport]

23
Q

What is vitamin D?

A 
Steroid hormone (not vitamin!) - half-life = hours 
Binds to nuclear receptor 
Transport proteins facilitating uptake into cells 
Endocrine, paracrine and autocrine action
24
Q

What are some functions of vitamin D?

A

Osteoblast + osteoclast differentiation
Bone remodelling (by promoting bone resorption)
Cartilage production
Bone mineralisation
Facilitates calcium uptake from gut and calcium/ phosphate reabsorption in kidney

25
Q

How is vitamin D made?

A
  1. Intake = 10% diet (D2+D3) and 90% sunlight (D3, by conversion of 7-dehydro-cholesterol to colecalciferol)
  2. D2 and D3 hydroxylated in liver to form 25-hydroxy-vitamin D (calcidiol)
  3. 1alpha-hydroxylase converts 25(OH)D into 1,25(OH)2D (calcitriol) - in both kidneys and non-renal tissues (although only that made in kidneys has effect on calcium homeostasis, other tissues are for immune function)
26
Q

What enzyme inactivates vitamin D?

A

24-hydroxylase

Eventually vitamin D is excreted in urine

27
Q

What are the physiological roles of phosphate?

A

Intracellular metabolism (e.g. ATP synthesis)
Phosphorylation (e.g. enzyme activation)
Phospholipids in membranes

28
Q

Where is fibroblast growth factor (FGF) 23 made?

A

Osteocytes and osteoblasts

29
Q

What are the signs and symptoms of hypercalcaemia?

A

Polyuria (increased urination)
Polydipsia (increased thirst)
Tiredness, confusion, depression, headaches
Nausea/ vomiting
Constipation
Anorexia
Muscle weakness
Abdominal pain
Shortened QT interval (in severe cases, leading to arrhythmias)
Loss of bone, kidney stones and ectopic calcification in severe, chronic cases

30
Q

What are the common causes of hypercalcaemia?

A 
Primary hyperparathyroidism (most common)
Malignancy

Less common:
Vitamin D excess
Some drugs
Some genetic causes

31
Q

Why can malignancy cause hypercalcaemia?

A 
Bone loss (osteolytic secondary malignancies)
PTHrP production
32
Q

Why can primary hyperparathyroidism cause hypercalcaemia?

A

Increased PTH secretion
Sustained high levels of PTH causes bone loss
Often a benign tumour in 1+ parathyroid gland

33
Q

How can severe hypercalcaemia be managed?

A

Initial treatment:
Fluids (saline)
Loop diuretic (furosemide)
+ Find cause!

Calcitonin
Bisphosphonates
Oral phosphate
Parathyroid gland surgery

34
Q

What calcium levels are classed as severe/ urgent?

A

> 3.4 mmol/l

35
Q

What can cause hypocalcaemia?

A 
Hypoparathyroidism 
Calcium deficiency (e.g. through low dietary intake, vitamin D deficiency)
36
Q

What are the potential consequences of hypocalcaemia?

A

Rickets/ Osteomalacia

Secondary hyperparathyroidism

37
Q

What are the treatment options for hypoparathyroidism?

A

Lifelong vitamin D analogues
High calcium diet
Calcium supplements
Recombinant human parathyroid hormone

38
Q

What are the actions of fibroblast growth factor (FGF)-23?

A

Prevents vitamin D mediated hyperphosphataemia
Inhibits type II sodium-phosphate co-transporters
Inhibits 1a-hydroxylase (preventing vitamin D activation)
Stimulates 24-hydroxylase (inactivating vitamin D)
Inhibits PTH

39
Q

How is phosphate reabsorption regulated in the PCT?

A

PTH and FGF23 both inhibit sodium-phosphate co-transporters
Preventing reabsorption into blood so phosphate is excreted in the urine
PIT-1/2 = unregulated phosphate transporter

40
Q

How is phosphate absorption regulated in the intestines?

A

Vitamin D increases NPT2b transporter to cause increased uptake of phosphate in the GI tract
PIT-1/2 = unregulated phosphate transporter

41
Q

What factors can result in lack of normal calcium homeostasis?

A

Altered absorption (e.g. due to disease or removal of part of the GI tract)
Vitamin D deficiency (e.g. lack of sunshine or diet)
Hyper/ hypoparathyroidism
Kidney disease

[Resulting in hyper/hypocalcaemia and/or poor bones]

42
Q

What are the signs and symptoms of hypocalcaemia?

A

Paraesthesia (esp. fingers, toes and around mouth)
Tetany (muscle spasms)
Carpopedal spasm (wrist flexion and fingers drawn together)
Muscle cramps
Seizures
Prolonged QT interval (leading to arrthymias)

43
Q

How does secondary hyperparathyroidism occur?

A
  1. Low serum calcium levels stimulates PTH production and secretion (usually as a consequence of kidney disease)
  2. If kidneys are not functioning properly then they cannot respond to PTH; cannot activate vitamin D; cannot increase calcium absorption; cannot increase phosphate excretion
  3. Feedback loop dysfunctional leading to sustained, unregulated PTH production
  4. Can lead to tertiary hyperparathyroidism (as calcium levels eventually rise)
44
Q

What is the difference in calcium, PTH and phosphate levels between primary, secondary and tertiary hyperparathyroidism?

A 
Primary = high calcium, high PTH, low phosphate
Secondary = low/normal calcium, high PTH, low/normal/high phosphate
Tertiary = high calcium, high PTH, high phosphate
45
Q

How can hypocalcaemia be managed?

A

Acutely: IV calcium gluconate, ECG if cardiac symptoms
Chronic: Oral calcium and vitamin D

46
Q

Which form of vitamin D is measured when testing vitamin D levels?

A

25D3

form that liver produces from D2 and D3

47
Q

What vitamin D (25D3) level is classed as deficient?

A

<25/30 nmol/l (differs between trusts)

Supplementation should be given

48
Q

What vitamin D (25D3) level is classed as insufficient?

A

30-50 nmol/l

Supplementation should be given

49
Q

What vitamin D (25D3) level is classed as adequate?

A

> 50 nmol/l

50
Q

What is the most common nutritional deficiency worldwide?

A

Vitamin D deficiency

51
Q

What can cause vitamin D deficiency?

A

Lack of exposure to sunlight
Liver or kidney problems
Diet (to a small extent)

52
Q

What can be done to combat vitamin D deficiency?

A 
Safe sun exposure (difficult to advice on)
Dietary contribution (small impact) 
Supplement: Colecalciferol (D3) - still requires activation so very difficult to overdose

In patients with renal disease: Calcitriol or analogues

Block 4: Anatomy + Physiology (12 decks)

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