Calcium and phosphate regulation

Question 1

What are the two key hormones in calcium and phosphate regulation

Answer 1

Vitamin D

PTH

Question 2

How does calcium exist in bone

Answer 2

99% of calcium in the body is stored as complex hydrated calcium phosphate salts (hydroxyapatite crystals).
In the blood, calcium exists in three forms:
Free ions- 50% (1.25 mol/l)
dynamically bound to globulin and albumin
diffusible salts such as citrate and phosphate

Question 3

Describe the importance of the dynamic equilibrium that exists between calcium and phosphate ions with their salts.

Answer 3

When the concentration of Ca2+ and PO43- falls in the blood, the dynamic equilibrium between their free ion and salt concentrations is disturbed such that dissociation of the salt to its constituent ions occurs, restoring the equilibrium.
The concentration of calcium is much higher in the blood than in the cells- so we need to regulate the expression of calcium channels to restore the equilibrium.

Question 4

Describe the effects of PTH on bone

Answer 4

The osteoclasts (involved in bone resorption) have no PTH receptors. 
Instead PTH binds to PTH1 receptors on osteblasts, stimulating the release  of osteoclast activating factors (RANK-L and M-CSF) and decreasing the inhibitory osteoprotegrin synthesis , resulting in the activation of osteoclasts.
Consequently,  the osteoid is broken down and Ca2= and PO43- are released into the general circulation.

Question 5

Describe the renal effects PTH on calcium and phosphate reabsorption

Answer 5

PTH stimulates calcium reabsorption;
PCT (65%)
Ascending limb (20%)
DCT and CT (15%)

Increases phosphate excretion by decreasing their reabsorption (approximately 80%) in the PCT- also a small amount in the DCT.

PTH inhibits the Na+/PO43- co-transporter, and so also has some natrieurtic activity.

Question 6

Why is it important to excrete phosphate whilst reabsorbing calcium

Answer 6

To prevent the restoration of the dynamic equilibrium i.e preventing Ca2+ and PO43- from forming their constituent salts, which would decrease the Ca2+ again.

3Ca2+ + 2PO43- — {(Ca2+)3(PO43-)2]

Question 7

Describe another important renal effect of PTH

Answer 7

Increases calcitriol synthesis

Question 8

Describe the renal effects of calcitriol.

Answer 8

PCT- Increases the synthesis of calcium channels to promote its reabsorption
DT- Calbindin protein synthesis is stimulated to enhance calcium reabsorption.
Stimulates synthesis of FGF23 from osteocytes- which works with PTH to increases phosphate excretion.
However, FGF23 also has negative feedback on calcitriol- thus it will reduce calcium and phosphate reabsorption from the small intestine.

Question 9

Describe the regulation of PTH secretion

Answer 9

Main stimulus for PTH release from the chief cells of the parathyroid gland is a low circulating calcium ion concentration.
They have a calcium sensing receptor (GPCR), and activation of this receptor leads to inhibition of the AC/cAMP pathway and stimulation of the PLC IP3/DAG pathways.
A low Ca2+ therefore dis-inhibits the AC/cAMP pathway hence leading to the secretion of PTH.

Question 10

Describe the different ways in which calcitriol can be synthesised

Answer 10

In the epidermis and dermis layers of the skin, 7-dehydrocholesterol is converted to Vitamin D3 by UVB light (melanin, clothing, glass, low sun and grey skies will decrease the amount of cholecalciferol in the skin. Cholecalciferol can then enter the circulation (bound to cholecalciferol-binding protein) and reaches the liver- where it is hydroxylated by 25-hydroxylase to form 25-hydroxycholecalciferol.
You can also get Vitamin D2 from diet (ergocalciferol) which can then be converted to 25-hydroxycholecalciferol in the liver.
The liver can store this for up to 3 months.
The 25 OH-D3 also circulates in the blood bound to the binding protein CBP to reach the kidney.
in the epithelial cells of the PCT- renal 1a-hydroxylase (stimulated by PTH) converts 25 OH-D3 to 1,25 oH D3 (calcitriol).

Question 11

Describe the actions of calcitriol

Answer 11

Increased renal Ca2+ reabsorption
Negative feedback on PTH
Ca2+ and PO43- reabsorption in the gut
Ca2+ maintenance in bone (but will stimulate some Ca2+ and PO43- release).

Question 12

Outline the causes of Vitamin D deficiency

Answer 12

Diet
Lack of sunlight
GI malabsorption
eg coeliac disease, inflam bowel disease,
Renal failure, Liver failure
Vitamin D receptor defects (autosomal recessive, rare, resistant to vitamin D treatment)

Question 13

Describe the issue with vitamin D deficiency in the UK

Answer 13

Re-emerging as problem in UK due mainly to inadequate diet and lack of sunlight
Food isn’t fortified with Vitamin D
Our latitude and distance from the sun means that we don’t get enough sunlight.

Question 14

When if FGF23 synthesised

Answer 14

Fibroblast growth factor 23 (FGF23): vitD3 stimulates phosphate absorption, and if gets too high then FGF23 stimulated - protects against high phosphate

Question 15

How do changes in EC calcium affect nerve and skeletal muscle excitability

Answer 15

To generate an AP in nerves/skeletal muscle requires Na+ influx across cell membrane
HIGH ec calcium (HYPERcalcaemia) = Ca2+ blocks Na+ influx, so LESS membrane excitability
LOW ec calcium (HYPOcalcaemia) = enables GREATER Na+ influx, so MORE membrane excitability

Question 16

What is the normal range for Ca2+

Answer 16

normal range serum Ca2+ ~ 2.2–2.6mmol/L

Question 17

Describe the signs and symptoms of hypocalcaemia

Answer 17

Sensitises excitable tissues;
muscle cramps/tetany,
tingling

Parasthesia (hands, mouth, feet , lips)
Convulsions
Arrhythmias - Ca2+ needed for contraction of the heart
Tetany

Question 18

Describe Chvostek’s sign

Answer 18

Tap facial nerve just below zygomatic arch
Positive response = twitching of facial muscles
Indicates neuromuscular irritability due to hypocalcaemia

Question 19

Describe trousseaus sign

Answer 19

Inflation of BP cuff for several minutes induces carpopedal spasm = neuromuscular irritability due to hypocalcaemia

Question 20

Describe the causes of hypocalcaemia

Answer 20

Vitamin D deficiency
Low PTH levels = hypoparathyroidism
Surgical – neck surgery- can damage Parathryoid gland
Auto-immune
Magnesium deficiency (needed for PTH synthesis and release).
PTH resistance eg pseudohypoparathyroidism
Renal failure
Impaired 1α hydroxylation
decreased production of 1,25(OH)2D3

Question 21

What causes the symptoms of hypercalcaemia

Answer 21

‘Stones, abdominal moans and 
psychic groans’ 
Reduced neuronal 
excitability;
atonal muscles

Question 22

Describe the symptoms of hypercalaemia

Answer 22

Stones – renal effects
Polyuria & thirst
Nephrocalcinosis (calcium deposits causing kidney stones)., renal colic, chronic renal failure

Abdominal moans - GI effects (the gut is a muscular tube, slows down in hypercalcaemia)
Anorexia, nausea, dyspepsia, constipation, pancreatitis

Psychic groans - CNS effects
Fatigue, depression, impaired concentration, altered mentation, coma (usually >3mmol/L)

Question 23

What is the cause of hypercalcaeima 90% of the time

Answer 23

Primary hyperparathyroidism (parathyroid adenoma)
Malignancy – tumours/metastases often secrete a PTH-like peptide
Tumours often metastasise to bone- thus increasing bone turnover.

Question 24

Describe two other causes of hypercalcaemia

Answer 24

Conditions with high bone turnover (hyperthyroidism, Paget’s disease of bone – immobilised patient)
Vitamin D excess (rare)

Question 25

Outline a diagnostic approach to primary hypercalcaemia

Answer 25

``` NO negative feedback Autonomous PTH secretion DESPITE hypercalcaemia Raised calcium Low phosphate Raised (unsuppressed) PTH ```

Question 26

Outline a diagnostic approach to hypercalcamia of malignancy

Answer 26

Raised calcium Suppressed PTH- PTH comes from ectopic source PTH-rp will be high

Question 27

What is meant by vitamin D deficiency

Answer 27

Definition: lack of mineralisation in bone | Results in “softening” of bone, bone deformities, bone pain; severe proximal myopathy.

Question 28

What are the PTH-independent hypercalcaemias

Answer 28

PTH-independent (PTH suppressed/low) – malignancy, vitamin D excess/intoxication, increased bone turnover

Question 29

What does vitamin D deficiency result in in adults and in children

Answer 29

In children - RICKETS- bones (tibia and femur- bow- can't take the waste of the body). In adults - OSTEOMALACIA- increased risk of fractures

Question 30

What is the main treatment for primary hyperparathyroidism

Answer 30

Surgery Need to use ultrasound and sets-mibi scanning to identify the overactive glands, if the scans are not concordant- surgeon needs to decide whilst in the surgery. MEN1- risk of recurrent disease is common- wait until patient has severe hypercalcaenmia- then remove all the overactive and leave half of the normal one.

Question 31

Describe what happens in secondary hyperparathyroidism

Answer 31

Vitamin D deficiency causes a low Ca2+ PTH INCREASES TO TRY TO NORMALISE SERUM CALCIUM = SECONDARY HYPERPARATHYROIDISM

Question 32

Summarise the biochemical findings in vitamin D deficiency

Answer 32

Plasma [25(OH)D3] usually low (NB we don’t measure 1,25 dihydroxy vitamin D (1,25 (OH)2 D) to assess body vitamin D stores)- hard to measure calcitriol. Plasma [Ca2+] low (may be normal if 2o hyperparathyroidism has developed) Plasma [PO43-] low (reduced gut absorption) [PTH] high (2o hyperparathyroidism)

Question 33

What may radiological findings show in vitamin D deficiency

Answer 33

o Radiological findings may show widened osteoid seams or “Brown Tumours” – bone lesions showing excessive osteoclastic bone resorption.

Question 34

How do we treat vitamin D deficiency in patients with normal renal function

Answer 34

In patients with normal renal function Give 25 hydroxy vitamin D (25 (OH) D) Patient converts this to 1,25 dihydroxy vitamin D (1,25 (OH)2 D) via 1α hydroxylase Ergocalciferol 25 hydroxy vitamin D2 Cholecalciferol 25 hydroxy vitamin D3 Plasma alkaline phosphatase often elevated

Question 35

How do we treat vitamin D deficiency in patients with impaired renal function

Answer 35

In patients with renal failure - inadequate 1α hydroxylation, so can’t activate 25 hydroxyl vitamin D preparations Give Alfacalcidol - 1α hydroxycholecalciferol Patients with vitamin D deficiency and secondary hyperparathyroidism due to chronic renal failure may need supplementation with active vitamin D metabolites, as they have impaired one alpha hydroxylation due to their renal disease, so can’t convert 25(OH)2D to calcitriol. eg Alfacalcidol – 1 alphahydroxycholecalciferol.

Question 36

How are treatments for vitamin D administered

Answer 36

Supplements are usually oral, but intramuscular preparations may be useful eg for malabsorptive states.

Question 37

What happens in vitamin D excess (intoxication)

Answer 37

Can lead to hypercalcaemia and hypercalciuria due to increased intestinal absorption of calcium

Question 38

What can cause vitamin D excess (intoxication)

Answer 38

Can occur as a result of: excessive treatment with active metabolites of vitamin D eg Alfacalcidol granulomatous diseases such as sarcoidosis, leprosy and tuberculosis (macrophages in the granuloma produce 1α hydroxylase to convert 25(OH) D to the active metabolite 1,25 (OH)2 D

Question 39

Explain some causes of vitamin D deficiency

Answer 39

Increased breakdown of vitamin D to inactive metabolites eg. anti-convulsants Vitamin D receptor defects –Hereditary vitamin D –resistant rickets, rare autosomal recessive disease caused by mutations in the vitamin D receptor (VDR)