Regulation Of Calcium + Phosphate

Question 1

Calcium requirements

Answer 1

Most abundant metal in the body
Diet should meet all requirements (dairy/ oily fish/ broccoli)
Recommended adult intake - 1000mg/day

Question 2

Calcium distribution in the body

Answer 2

99% in skeleton and teeth as calcium hydroxyapatite crystals
1% intracellular
0.1% extracellular and tightly regulated:
2.5mmol/L Plasma - ionised Ca2+ biologically active component 45%
- bound Ca2+ plasma proteins 45% + anions

Question 3

Hormones which regulate Calcium and Phosphate

Answer 3

Parathyroid hormone (parathyroid glands)
Vitamin D aka Calcitriol (synthesis in skin or intake via diet)
- main regulators of calcium and phosphate homeostasis via actions in kidney, bone and gut
Calcitonin (thyroid parafollicular cells)
- can reduce calcium acutely, but no negative effect if parafollicular cells are removed

Question 4

Sources of Vitamin D

Answer 4

Diet - vitamin D2 Ergocalciferol
Skin Synthesis Sunshine - vitamin D3 Cholecalciferol

Slight structural difference

Question 5

Vitamin D metabolism

Answer 5

UVB light from sun shines on skin stimulating conversion from 7-dehydrocholesterol to pre-vitamin D3 to Vitamin D3 which is taken by the blood supply from the skin to the liver.
Vitamin D2 from the diet absorbed by the gut and transported to liver by blood supply.
First hydroxylation step takes place in liver where vitamin D2/3 reacts via enzyme 25-hydroxylase producing 25(OH)cholecalciferol.
Second hydroxylation step takes place in kidney undertaken by 1 alpha-hydroxylase converting inactive 25-hydroxy-cholecalciferol into active 1,25-dihydroxy-cholecalciferol aka CALCITRIOL

Question 6

Effects of Calcitriol

Answer 6

Increased Ca2+ reabsorption from bone,
Increased Ca2+ and PO4 3- reabsorption from kidney
Increased Ca2+ and PO4 3- absorption in gut (from food)

Question 7

Parathyroid Hormone (PTH)

Answer 7

Chief cells in parathyroid glands in the thyroid
Secreted as a large precursor (pre-pro-PTH) and cleaved to PTH
G-protein coupled Ca2+ sensing receptor on chief cells detecting change in circulation Ca2+ concentration
PTH secretion inversely proportional to serum calcium

Question 8

Calcium sensing receptor and PTH secretion

Answer 8

High Ca2+ extracellular fluid:
Ca2+ binds to receptors on parathy cells so PTH secretion inhibited

Low Ca2+ extracellular fluid:
Less Ca2+ binding to receptors on parathyroid cells so PTH secreted

Question 9

Actions of PTH

Answer 9

Increased bone reabsorption 
Kidney:
Increased Ca2+ reabsorption,
Increased PO4 3- excretion 
Increased 1-a-hydroxylase activity -> needed for synthesis of Calcitriol 
Gut:
Increased Ca2+ absorption
Increased PO4 3- absorption 

Altogether increased plasma Ca2+

Question 10

PTH action in bone

Answer 10

Osteoblasts - important for bone formation
Have receptors which recognise PTH which when binding stimulates osteoblasts to make osteoclasts activation factors causing osteoclasts to breakdown bone and increase Ca2+
Osteoclasts - important for bone consumption by releasing powerful digestive enzymes which dissolve bone to release calcium

Question 11

Calcitriol action on Bone

Answer 11

Calcitriol receptors on osteoblasts attach Calcitriol which again stimulates osteoclast activating factors and so osteoclasts to release more Ca2+

Calcitriol effects on bone is dependant on serum calcium:
Low serum calcium - calcitriol increases calcium reabsorption from bone osteoclasts
Normal serum calcium - calcitriol works to increase bone formation via osteoblasts

Question 12

PTH Regulation

Answer 12

Negative feedback system
Decreased plasma Ca2+ so more PTH released causing increased plasma Ca2+ via bone reabsorption
PTH increases Calcitriol production which then also increases plasma C2+
Negative feedback system with vitamin D receptors when calcitriol levels are too high PTH levels are decreased

Question 13

Calcitonin

Answer 13

Secreted from parafollicular cells of the thyroid gland
Reduces serum calcium
Physiological role in calcium homeostasis is unclear as removal of thyroid gland does not affect serum calcium

Question 14

Calcitonin actions & regulation

Answer 14

Increased plasma Ca2+ detected by parafollicular cells of thyroid causes release of Calcitonin
This causes increased Ca2+ excretion from kidneys (via urine) and decreased osteoclast activity (less bone consumption) which altogether causes a decrease in plasma Ca2+ (limited effect)

Question 15

FGF23

Answer 15

Fibroblast Growth Factor 23 hormone

Question 16

Regulation of serum phosphate by FGF23

Answer 16

Normally PO43- is reabsorbed in proximal convoluted tubule of the kidney by Na/PO co-transporter
FGF23 inhibits the co-transporter so less PO is reabsorbed and so is excreted more via urine (PTH also does this)
FGF23 also inhibits Calcitriol action which causes less reabsorption of PO from the gut
Altogether prevents PO levels in bloodstream via these two ways

Question 17

Abnormal Calcium Metabolism

Answer 17

High serum Calcium = HYPERCALCAEMIA
Low serum Calcium = HYPOCALCAEMIA

Action potential generation in nerves/skeletal muscle requires Na+ influx across cell membrane
HYPER - Ca2+ blocks Na2+ influx so LESS membrane excitability
HYPO - enables greater Na+ influx so MORE membrane excitability

Question 18

Hypocalcaemia

Answer 18

Sensitises excitable tissues; muscle cramps, tingling 
Signs + Symptoms
- Paraesthesia (hands/mouth/feet/lips)
- Convulsions
- Arrhythmias
- Tetany

Question 19

Chvostek’s Sign

Answer 19

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

Question 20

Trousseau’s Sign

Answer 20

Try and induce tetany
Inflation of BP cuff for several minutes induces carpopedal (fingers) spasm = neuromuscular irritability due to hypocalcaemia

Question 21

Causes of Hypocalcaemia

Answer 21

Low PTH levels = hypoparathyroidism 
-Surgical neck surgery 
-Auto-immune 
-Magnesium deficiency 
-Congenital 
Vitamin D deficiency

Question 22

Causes of Vitamin D deficiency

Answer 22

1. Malabsorption or Dietary insufficiency (ergocalciferol)
2. Inadequate sun exposure (cholecalciferol)
3. Liver Disease (first hydroxylation step)
4. Renal Disease (second hydroxylation step)
5. Vitamin D receptors defects (can’t be recognised and used)

Question 23

Consequences of Vitamin D deficiency

Answer 23

Lack of bone mineralisation = ‘soft’ bones
Children - rickets (bowing of bones)
Adults - osteomalacia (fractures, proximal myopathy)

Question 24

Hypercalcaemia

Answer 24

Signs + Symptoms
Stones: renal effects (nephrocalcinosis)
Abdominal moans: GI effects (anorexia, nausea, dyspepsia, constipation + pancreatitis)
Psychic groans: CNS effects (fatigue, depression, impaired concentration, altered mentation, coma)
Reduced neuronal excitability - atonal muscles

Question 25

Causes of Hypercalcaemia

Answer 25

Primary hyperparathyroidism:
- too much PTH
- usually due to a parathyroid gland adenoma
- no negative feedback (high PTH but high Calcium)
Malignancy:
- bony metastasis produce local factors to activate osteoclasts, increasing Calcium reabsorption from bone
Vitamin D excess (rare)