Regulation of Calcium and Phosphate

Question 1

Where does calcium come from and what is the recommended daily amount?

Answer 1

Is the most abundant metal in the body and should get recommended intake from diet. 1000mg daily.

Question 2

Describe calcium distribution in the body

Answer 2

99% resides in skeleton and teeth as calcium hydroxyapatite crystals. Extracellular calcium (tiny amount of total body calcium) is tightly regulated.
‘Unbound’ ionised calcium is biologically active component and constitutes 45% of plasma calcium. This constantly alternates between bound and unbound forms where the bound form can be found in plasma proteins and anions.

Question 3

What hormones are involved in the control of serum calcium?

Answer 3

Parathyroid hormone (PTH) (secreted by parathyroid glands) mainly increase plasma calcium levels. Vitamin D is synthesised in skin or intake via diet and is one of the main regulators of calcium & phosphate homeostasis via actions on kidney, bone and gut. Calcitonin (secreted by thyroid parafollicular cells) can reduce calcium acutely, but is not a major hormone involved in the control of calcium as people with a thyroidectomy do not observe negative effects caused by absence of calcitonin.

Question 4

What are the sources of vitamin D?

Answer 4

Vitamin D2 received from diet is called ergocalciferol and slightly different in structure stereoisomerically. Vitamin D3 made in the skin is known as cholecalciferol.

Question 5

Describe how vitamin D is metabolised in the body

Answer 5

Vitamin D2 gained from the diet and enters the bloodstream through ileum. 7-dehydrocholesterol acted on by UVB in the skin forming pre-vitamin D3 and then vitamin D3 synthesised in the skin. This then enters the bloodstream. From here, vitamin D taken to the liver where 25-hydroxylase acts on vitamin D. Forms 25(OH)cholecalciferol which is transported to the kidney. Where it is synthesised into 1,25(OH)2 cholecalciferol by action of 1 alpha-hydroxylase. Active form of vitamin D known as calcitriol.

Question 6

How is calcitriol synthesis regulated?

Answer 6

1,25(OH)2 vitamin D (calcitriol) regulates its own synthesis by decreasing transcription of 1 alpha hydroxylase through a negative feedback loop. Serum 25-OH vitamin D is a good indicator of body vitamin D status. 1,25-calcitrol is hard to measure from bloodstream as its very unstable. Therefore, to measure body stores of vitamin D we measure precursor 25-hydroxycholecalciferol instead.

Question 7

What are the effects of calcitriol?

Answer 7

1. Increases calcium reabsorption from bones
2. Increases calcium absorption from the ileum
3. Increases calcium and phosphate absorption in the kidneys as well as ileum.

Question 8

Where is parathyroid hormone secreted and how is it regulated?

Answer 8

Secreted by chief cells in parathyroid glands. It is secreted as a large precursor (pre-pro-PTH) & cleaved to PTH. Regulated by G-protein coupled calcium-sensing receptors on chief cells which detect changes in circulating calcium concentration and PTH is secreted in an inversely proportional way to serum calcium.

Question 9

How does the calcium-sensing receptor on the parathyroid gland work?

Answer 9

When there are high ECF levels [Ca2+], Ca2+ binds to receptors on parathyroid cells, PTH secretion is inhibited. When there are low ECF levels [Ca2+], less Ca2+ binding to receptors on parathyroid cells occurs and so PTH is secreted.

Question 10

What are the actions of the parathyroid hormone?

Answer 10

1. Increases calcium reabsorption from the bone.
2. Increases calcium reabsorption from the kidneys, increases phosphate excretion from the kidneys.
3. increases 1-alpha-hydroxylase activity so calcitriol synthesis increased. Increase in 1-alpha-hydroxylase activity increases calcium and phosphate reabsorption from the ileum.

Question 11

How does PTH act on bones?

Answer 11

PTH binds to receptors on osteoblasts, stimulating them to release osteoclast activating factors such as RANKL (Receptor activator of nuclear factor kappa-B ligand.) This activates the osteoclast causing bone breakdown and absorption of calcium from the bones.

Question 12

How does calcitriol act on bones?

Answer 12

Calcitriol effects on bone depend on serum calcium.
When there is low serum calcium, calcitriol increases calcium reabsorption from bone. Osteoclast activity exceeds osteoblasts. When there is normal serum calcium, calcitriol works to increase bone formation.
Osteoblast activity exceeds osteoclasts.

Question 13

How is PTH regulated?

Answer 13

Decreased plasma calcium causes increase in PTH secretion by parathyroid gland, this increased 1,25 (OH)2D3 synthesis and thus plasma calcium. Howeve, this is a negative feedback loop as increased calcitriol levels increases calcium levels and thus inhibits PTH levels.

Question 14

Describe calcitonin synthesis and its role

Answer 14

It is secreted from the parafollicular cells of the thyroid gland. Reduces serum calcium but physiological role in calcium homeostasis in humans unclear. Removal of thyroid gland does not affect serum calcium.

Question 15

How does calcitonin act and how is it regulated?

Answer 15

Increases calcium excretion from the kidneys and decreases osteoclast activity. Parafollicular cells stimulated to produce it when high plasma calcium levels detected.

Question 16

How does FGF23 work?

Answer 16

FGF23 is a hormone derived from the bone. It inhibits the NaPO transporters in the cuboidal epithelia of the proximal tubule. Therefore, the phosphate can’t be absorbed from the filtrate. FGF23 also inhibits calcitriol, further decreasing phosphate reabsorption. PTH inhibits renal phosphate reabsorption – so in primary hyperparathyroidism, serum phosphate is low due to increased urine phoshate excretion.

Question 17

What are the possible conditions resulting from abnormal calcium metabolism?

Answer 17

Hypercalcemia is when there is an excess of serum calcium. Ca2+ blocks Na+ influx, so less membrane excitability when there is high extracellular calcium. Hypocalcemia occurs when there is low serum calcium. This enables greater Na+ influx, so more membrane excitability.

Question 18

What are the symptoms of hypocalcaemia?

Answer 18

Characterised by excitable tissues; muscle cramps, tetany, tingling. Symptoms are: Paraesthesia (hands, mouth, feet , lips), Convulsions, Arrhythmias, Tetany. Check for Chvostek’s sign (Tap facial nerve just below zygomatic arch. Positive response = twitching of facial muscles. Indicates neuromuscular irritability due to hypocalcaemia.) Check for Trousseau’s sign (Inflation of BP cuff for several minutes induces carpopedal spasm = neuromuscular irritability due to hypocalcaemia)

Question 19

What are the causes of hypocalcaemia?

Answer 19

Low PTH levels = hypoparathyroidism. Causes can be:
1. Surgical – neck surgery - damage to parathyroid
2. Auto-immune - most common
3. Magnesium deficiency - required to make PTH
4. Congenital (agenesis, rare)
Vitamin D deficiency

Question 20

What can cause vitamin D deficiency?

Answer 20

1. Malabsorption or dietary insufficiency (not enough ergocalciferol)
2. Inadequate sun exposure (7-dehydrocholesterol not made into vitamin D3)
3. Liver disease (so first hydroxylation reaction doesn’t occur)
4. Renal disease (1-alpha-hydroxylase stimulated by PTH but may not function)
5. Problems with vitamin D receptors in sites of actions

Question 21

What is the consequence of a vitamin D deficiency?

Answer 21

Lack of bone mineralisation leading to soft bones. Known as rickets in children characterised by a bowing of bones. Known as osteomalacia in adults characterised by fractures and proximal mylopathy.

Question 22

What are the signs and symptoms of hypercalcaemia?

Answer 22

1. Renal effects
   Nephrocalcinosis – kidney stones, renal colic
2. GI effects
   Anorexia, nausea, dyspepsia, constipation, pancreatitis
3. CNS effects
   Fatigue, depression, impaired concentration, altered mentation, coma (usually >3mmol/L)

Question 23

What are the causes of hypercalcaemia?

Answer 23

1. Primary hyperparathyroidism - Too much PTH, usually due to a parathyroid gland adenoma. No negative feedback system so there is a high PTH but also a high calcium level.
2. Malignancy - Bony metastases produce local factors to activate osteoclasts, increasing calcium reabsorption from bone
3. Vitamin D excess