Regulation of calcium and phosphate

Question 1

What is the most abundant metal in the body?

Answer 1

Calcium

Question 2

How is calcium distributed in the body?

Answer 2

99% in skeleton and teeth as calcium hydroxyapatite crystals
1% Intracellular
0.1% Extracellular
- Plasma (Ionised Ca2+ and Bound Ca2+)
- Bound to plasma proteins 45% and

Question 3

Why is calcium important?

Answer 3

Neuromuscular excitability
• Muscle contraction
• Bone strength
• Intracellular 2nd messenger
• Intracellular co-enzyme
• Hormone/neurotransmitter
stimulus-secretion coupling
• Blood coagulation (factor IV)

Question 4

Why is phosphate important?

Answer 4

Essential component of:
High energy compounds e.g. ATP 2nd messengers
Fundamental molecules eg DNA,
RNA, phospholipids
Extracellular phosphate is inversely proportional to extracellular calcium – so both regulated by same hormones

Question 5

Which hormone decreases calcium?

Answer 5

Calcitonin secreted thyroid parafollicular cells

Can reduce calcium acutely but lack of hormone does not cause any negative effects

Question 6

What are the two form of Vitamin D?

Answer 6

Ergocalciferol- Diet

Cholecalciferol- Sunshine

Question 7

How is Vitamin D made?

Answer 7

UVB light from the sun shines on skin cells
Triggers a series of reactions 
Precursor- 7-dehydrocholesterol
CONVerted to pre-vitamin D3
Converted to Vitamin D3

Question 8

Where is the first step of Vitamin D synthesis?

Answer 8

Liver
D3 or D2 from diet is hydroxylates to form 25 hydroxycholecalciferol
(not active)

Question 9

Where does the second step of Vitamin D synthesis take place?

Answer 9

Kidney
Second hydroxylation using 1 alpha hydroxylase producing
1,25 dihydroxycholecalciferol

Question 10

Where is the first step of Vitamin D synthesis?

Answer 10

Liver
D3 from skin or D2 from diet is hydroxylates to form 25 hydroxycholecalciferol
(not active)

Question 11

Where does the second step of Vitamin D synthesis take place?

Answer 11

Kidney
Second hydroxylation using 1 alpha hydroxylase producing
1,25 dihydroxycholecalciferol
Active form 
AKA Calcitrol

Question 12

How is vitamin D production regulated?

Answer 12

Negative feedback from calciferol on 1 alpha hyroxylase

Question 13

What are the effect of calcitorol?

Answer 13

Works on kidney to increase calcium and phosphate reabsorption
Works on the small intestine to stimulate the absorption of Ca2+ from the gut
Increases reabsorption from bone and stimulates osteoblasts

Question 14

How is parathyroid hormone produced?

Answer 14

Chief cells in parathyroid glands secrete a large precursor (pre-pro-PTH) and cleaved to PTH
G-protein couples calcium sensing receptor on chief cells detect change
G-protein coupled calcium sensing receptor on chief cells detects change in circulating calcium concentration
PTH is directly proportional to serum calcium

Question 15

Why is it called parathyroid hormone?

Answer 15

Parathyroid glands sit at the back of the thyroid gland

Nothing to do with the production of thyroid hormone

Question 16

How is calcium regulated by PTH?

Answer 16

Increase in extracellular calcium
Ca binds to G protein coupled receptors on chief cells
Inhibits PTH secretion

Decrease in extracellular calcium
Less CA2+ binding to receptors on parathyroid cells
More PTH secreted

Question 17

How does PTH increase calcium in kidney?

Answer 17

Works on kidney by increasing calcium reabsorption in the kidney
Increase phosphate secretion
Stimulates 1-alpha hydroxylase activity
Increase in production of active Vitamin D

Question 18

How does PTH increase calcium in bones?

Answer 18

Works on the bones by increasing osteoclast activity, reabsorbing more calcium
Converts osteoblast to osteoclasts
PTH stimulates activating factors for conversion

Question 19

How does PTH increase calcium in gut?

Answer 19

Indirectly- increased cacitrol production

Increased calcium reabsorption in the gut

Question 20

What are osteoblasts?

Answer 20

OsteoBlasts- build bones

Question 21

What are osteoclasts?

Answer 21

OsteoClasts- consume bones and release calcium

Question 22

How is PTH regulated?

Answer 22

Negative feedback loop

As extracellular Ca falls, less binding, more PTH produced
Action on kidney, gut and bone
Indirect action by stimulating enzyme producing calciferol

Increase in calcium decreased PTH secretion
Chief cells have calcitriol receptors negatively feedbacks on parathyroid cells

Question 23

How many parathyroid glands are there?

Answer 23

4

Question 24

What are the main features of calcitonin?

Answer 24

Secreted from parafollicular cells of the thyroid gland
Reduces serum calcium
Physiological role in calcium homeostasis in humans unclear
Removal of thyroid gland does not affect serum calcium
Unclear how critical it is

Question 25

What are the actions of calcitonin?

Answer 25

As Ca2+ rises Increasing Ca2+ excretion from kidney Reduces action of osteoclasts

Question 26

How is serum phosphate regulated?

Answer 26

PTH inhibits phosphate reabsorption in kidney | Inhibits sodium/phosphate co-transporter

Question 27

How is serum phosphate regulated by FGF23?

Answer 27

Fibroblast growth factor Inhibits phosphate reabsorption 1. Inhibits sodium/phosphate co-transporter 2. Inhibits caclitriol production, less phosphate reabsorption in the gut

Question 28

What is high serum calcium?

Answer 28

Hypercalcaemia

Question 29

What is low serum calcium?

Answer 29

Hypocalcaemia

Question 30

What are the effects of hypercalcaemia?

Answer 30

Ca2+ blocks Na+ influx, so less membrane excitability

Question 31

What are the effects of hypocalcaemia?

Answer 31

Enables greater Na+ influx, so more membrane excitability

Question 32

What are the symptoms of hypocalcaemia?

Answer 32

``` Paraesthesia (pins and needles) hands, mouth, feet, lips Convulsions Arrhythmais Tetany CATs go numb ```

Question 33

What is Chvostek's sign?

Answer 33

Tap facial nerviest just below zygomatic arch Postive response- twitching of facial muscles Indicates neuromuscular irritability due to hypocalcaemia

Question 34

What is Trousseau's sign?

Answer 34

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

Question 35

What are the causes if hypocalcaemia?

Answer 35

``` Hypoparathyroidism Surgical- neck surgery Auto-immune Magnesium deficiency Congenital (agenesis, rare) Vitamin D deficiency ```

Question 36

What are the causes of Vitamin D deficiency?

Answer 36

``` Malabsorption or dietary insufficiency Inadequate sun exposure Liver disease Renal disease Vit D receptor defects (rare) ```

Question 37

What is the consequence of vitamin D deficiency?

Answer 37

Lack of non mineralisation= soft bones In children - rickets In adults - osteomalacia (fractures, proximal myopathy)

Question 38

What are the signs of hypercalcaemia?

Answer 38

Stones, abdominal moans and psychic groans | Reduced neuronal excitability- atonal muscles

Question 39

Explain the symptoms of hypercalcaemia?

Answer 39

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)

Question 40

What are the causes of hypercalcaemia?

Answer 40

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 • Certain cancers (eg squamous cell carcinomas) secrete PTH-related peptide that acts at PTH receptors Vitamin D excess (rare)