Regulation of calcium and phosphate Flashcards
What is the recommended adult intake for calcium?
1000mg/day
Calcium is the most abundant metal in the body
How is calcium distributed in the body?
Skeleton + teeth (99%)
Intracellular (1%)
Extracellular (0.1%)
How is calcium stored in skeleton and teeth?
calcium hydroxyapatite crystals
How does extracellular calcium exist?
~2.5 mmol/L in plasma
45% is ionised Ca2+
65% is bound Ca2+
Of bound Ca2+: 45% plasma proteins, 65% anions (bicarbonate, phosphate, lactate)
unbound/ionised calcium is the biologically active component
Which hormones increase calcium and phosphate?
Parathyroid hormone (PTH) Vitamin D
Where is parathyroid hormone secreted?
parathyroid glands
Where do we get Vit D from?
synthesised in skin (sunshine)
intake via diet
Where do PTH and vit D act?
kidney, bone and gut
What hormone decrease calcium and phosphate?
Calcitonin
Where is calcitonin secreted?
thyroid parafollicular cells
What does calcitonin do?
Can reduce calcium acutely, but no negative effect if parafollicular cells are removed eg thyroidectomy
What are the key hormones in control of serum calcium and phosphate?
Parathyroid hormone (PTH) Vitamin D
What are the sources of vitamin D?
Vitamin D2 (Ergocalciferol) - diet Vitamin D3 (Cholecalciferol) - skin synthesis/sunshine These two have different slightly different structures
(See diagram 6/32)
What is the mechanism of vit D metabolism?
UVB -> 7-dehydrocholesterol -> pre-vitamin D3 -> Vitamin D3 -> carried from skin to blood to liver into 25(OH)cholecalciferol by 25-hydroxylase -> 1,25(OH)2 cholecaliferol by 1 alpha-hydroxylase 25(OH)cholecalciferol is an inactive precursor
(See diagram 7/32)
What is a good indicator of body vitamin D status?
serum 25-OH vitamin D
How does 1,25(OH)2 vitamin D (calcitriol) regulate its own synthesis?
by decreasing the transcription of 1 alpha hydroxylase
What is the active form of vitamin D?
calcitriol
What are the effects of calcitriol?
↑ Ca2+ reabsorption in bone
↑ Ca2+ and PO43- reabsorption in kidney
↑ Ca2+ absorption in gut
↑ PO43- absorption in gut
(See diagram 8/32)
Which cells secrete PTH?
Chief cells in parathyroid glands
What is PTH secreted as?
a large precursor (pre-pro-PTH) and cleaved to PTH
What do G-protein coupled calcium sensing receptor on chief cells do?
detect change in circulating calcium concentration
How is PTH secretion related to serum calcium?
it is inversely proportional
Where are the parathyroid glands?
How many are there?
back of thyroid glands
4 (2 on each lobe)
(See diagram 9/32)
When is PTH secretion inhibited?
high ECF [Ca2+] Ca2+ binds to calcium sensing receptors on parathyroid cells
(See diagram 10/32)
When is PTH secreted?
Low ECF [Ca2+] Less Ca2+ binding to calcium sensing receptors on parathyroid cells
What are the actions of PTH?
↑ bone reabsorption
(in kidneys:) ↑ Ca2+ reabsorption, ↑ PO43- excretion,↑ 1-a-hydroxylase activity -> ↑ 1,25 (OH)2D3 synthesis (affecting the gut)
(in gut:) ↑ Ca2+ absorption ↑PO43- absorption
(See diagram 12/32)
How does PTH regulate serum calcium and phosphate?
↑ Ca2+ mobilisation in bones, ↑ Ca2+ reabsorption in kidneys, ↑ PO43- excretion in kidneys -> ↑ plasma Ca2+
↑ 1,25 (OH)2D3 synthesis in kidneys -> ↑ Ca2+ absorption in gut, ↑PO43- absorption in gut -> ↑ plasma Ca2+
(See diagram 13/32)
Describe PTH action in bone.
PTH binds to PTH receptor on osteoblast -> Osteoclast Activating Factors (OAFs) - e.g. RANKL; Receptor activator of nuclear factor kappa-B ligand) -> activates osteoclasts -> bone resorption
What do osteoblasts do?
Build bone
What do osteoclasts do?
consume bone release digestive enzymes through ruffled border at the bottom and dissolve bone to release calcium
(see diagram 14/32)
What does calcitriol do in bones?
calcitrol binds to calcitriol receptor on osteoblast -> Osteoclast Activating Factors OAFs (e.g. RANKL; Receptor activator of nuclear factor kappa-B ligand) -> activate osteoclast -> bone resorption
What changes the calcitriol effects on bone?
serum calcium
What happens at low serum calcium?
calcitriol increases calcium reabsorption from bone osteoclasts > osteoblasts increase calcium in body
What happens at high serum calcium?
calcitriol works to increase bone formation osteoblasts > osteoclasts
How is PTH regulated?
↓ plasma Ca2+ -> PTH -> ↑ plasma Ca2+ -> negative feedback to parathyroid glands PTH -> ↑ 1,25 (OH)2D3 synthesis -> ↑ plasma Ca2+ -> negative feedback to parathyroid glands and negative feedback from calcitriol to reduce PTH
(See diagram 16/32)
Where is calcitonin secreted?
parafollicular (C) cells of the thyroid gland
See diagram 17/32
What is the role of calcitonin?
reduce serum calcium
the physiological role in calcium homeostasis in humans unclear
Removal of thyroid gland does not affect serum calcium (there are no negative effects of having no calcitonin)
What are the actions and regulation mechanism of calcitonin?
↑ plasma Ca2+ (detected by parafollicular cells of thyroid) -> Calcitonin
Calcitonin -> ↑ Ca2+ excretion in kidneys, ↓ osteoclast activity in bones -> ↓ plasma Ca2+ (limited effect)
How does Fibroblast Growth Factor 23 (FGF23) regulate serum phosphate?
- main job is to reduce phosphate in circulation
- does this in 2 ways normally, phosphate is reabsorbed in the proximal convoluted tubule by the Na+/PO43- co-transporter
- FGF23 inhibits the co-transporter -
inhibits calcitriol production therefore, less phosphate reabsorption in the gut
(See diagram 19/32)
What is hypercalcaemia?
high serum calcium
What is hypocalcaemia?
low serum calcium
What happens with hyper/hypocalcaemia?
Action potential generation in nerves/skeletal muscle requires Na+ influx across cell membrane.
HIGH extracellular calcium (HYPERcalcaemia) Ca2+ blocks Na+ influx, so LESS membrane excitability
LOW extracellular calcium (HYPOcalcaemia) enables GREATER Na+ influx, so MORE membrane excitability
What are the signs and symptoms of hypocalcaemia?
Sensitises excitable tissues; muscle cramps, tetany, tingling
- Paraesthesia (hands, mouth, feet, lips)
- Convulsions
- Arrhythmias
- Tetany –> increased excitability
Mnemonic - [CATs go numb]
What is Chvostek’s sign?
Tap facial nerve just below zygomatic arch
Positive response = twitching of facial muscles
Indicates neuromuscular irritability due to hypocalcaemia
(See diagram 23/32)
What is Trousseau’s sign?
Inflation of BP cuff for several minutes induces carpopedal spasm = neuromuscular irritability due to hypocalcaemia
(See diagram 24/32)
Causes of hypocalcaemia?
Low PTH levels = hypoparathyroidism
- Surgical – neck surgery
- Auto-immune
- Magnesium deficiency
- Congenital (agenesis, rare)
Vitamin D deficiency
Causes of vitamin D deficiency?
- malabsorption of dietary insufficiency
- inadequate sun exposure
- liver disease
- renal disease
- vit D receptor defects (rare)
(See diagram 27/32)
What are the consequences of vitamin deficiency?
Lack of bone mineralisation = ‘soft’ bones
In children – rickets (bowing of bones)
In adults – osteomalacia (fractures, proximal myopathy)
(See diagram 28/32)
What are the signs and symptoms of hypercalcaemia?
‘Stones, abdominal moans and psychic groans’
Reduced neuronal excitability – atonal muscles
Stones – renal effects
• Nephrocalcinosis – kidney stones, renal colic
Abdominal moans - GI effects
• Anorexia, nausea, dyspepsia, constipation, pancreatitis
Psychic groans - CNS effects
• Fatigue, depression, impaired concentration, altered mentation, coma (usually >3mmol/L)
What are the causes of hypercalcaemia?
Primary hyperparathyroidism
• Too much PTH
• Usually due to a parathyroid gland adenoma
• No negative feedback - high PTH, but high calcium
Malignancy
• Bony metastases produce local factors to activate osteoclasts, increasing calcium reabsorption from bone
Vitamin D excess (rare)
