12- Endocrine Control Of Calcium Metabolism

Question 1

What are some roles of calcium

Answer 1

The most important role of calcium is in the control of neuromuscular excitability
If you don’t have sufficient calcium in the blood then your nerves and muscles become hyperactive
Calcium ions tend to sit outside and block the sodium channels
If you become hypocalcaemic, more sodium channels become available for influx of sodium causing depolarisation - hyperexcitability
• Muscle contraction
• Strength in bone
• Intracellular second messenger
• Intracellular co-enzyme
• Hormone/neurotransmitter stimulus-secretion coupling
• Blood coagulation (Calcium is Factor IV)

Question 2

Where is calcium found in the body

Answer 2

Most calcium is present in the body as calcium salts
• It is mainly found in BONE (99% - approximately 1 kg) as complex hydrated
calcium salt (hydroxyapatite crystals are embedded in the bone matrix and serve as a reservoir)
• Calcium is present in the blood as:
Ionised calcium (Ca2+) Bound to plasma proteins Tiny bit is left as soluble salts
• ONLY THE FREE UNBOUND Ca2+ IS BIOACTIVE

Question 3

What is the normal intake of calcium and how much is lost in faeces

Answer 3

Normal intake = 1000 mg/24h

• Around 850 mg/24h of the calcium intake will be lost as faeces

Question 4

What happens when calcium enters the blood

Answer 4

Once in the blood, the calcium can pass to the kidneys which regulates the
content of the blood
• A lot of the calcium passing into the kidneys will return to the blood
• About 150 mg/24h is excreted from the kidneys per day - this maintains
equilibrium
• The hydroxyapatite crystals in the bone can be broken down to increase blood
calcium levels

Question 5

Which 2 hormones raise blood calcium

Answer 5

PARATHYROID HORMONE (PTH) 1,25-dihydroxycholecalciferol (or CALCITRIOL)
• NOTE: Calcitriol is a steroid and is also called 1,25-dihydroxy vitamin D3

Question 6

Which hormone decreases blood calcium

Answer 6

CALCITONIN
• This doesn’t seem to have a major effect in the long run
• No one really knows the importance of calcitonin
• Calcitonin is NOT the main controlling influence on calcium ions

Question 7

What is parathyroid hormone

Answer 7

Initially synthesised as protein pre-proPTH
• PTH is a polypeptide with 84 amino acids
• Binds to transmembrane G-protein linked receptors
• Binding of parathormone to the G-protein linked receptor leads to activation
of adenylate cyclase (with phospholipase C acting as a second messenger)

Question 8

Describe the action of parathyroid hormone

Answer 8

PTH stimulates the kidneys to excrete more phosphates
• People used to think that as PTH causes the loss of free phosphates from the
kidneys, the equation is no longer in equilibrium so the phosphate salt will dissociate to make amends for the phosphate that has been excreted and so calcium concentration increases secondarily to the replenishment of phosphate levels
• We have since found out that PTH actually has direct effects on the calcium in the kidneys
• The OVERALL effect is an increase in calcium reabsorption
• PTH has another important effect in the kidneys: stimulates the synthesis of
1α HYDROXYLASE
• 1α Hydroxylase is involved in the synthesis of calcitriol
• Calcitriol has an important effect on the small intestines: controls the
absorption of calcium and phosphate (increases absorption)
• PTH also has an effect on bone:
Stimulates osteoclasts - causes resorption of the bone matrix and release of calcium from hydroxyapatite crystals into the gut
Inhibits osteoblasts
• THIS ALL LEADS TO AN INCREASE IN BLOOD CALCIUM CONCENTRATION

Question 9

Describe PTH action in bone

Answer 9

Osteoclasts are activated by PTH but
NOT directly
• PTH works on osteoblasts and inhibits
various activities
• However, PTH stimulates osteoblasts
to produce various OSTEOCLAST
ACTIVATING FACTORS (OAFs)
• OAFs move to the osteoclasts and stimulates the breakdown of bone matrix to RELEASE CALCIUM
• One of the OAFs is called RANKL which links PTH via the osteoblasts to the main target which are the osteoclasts
• REMEMBER: PTH binds directly to osteoblasts but has an INDIRECT effect on OSTEOCLASTS

Question 10

How is pth regulated

Answer 10

Overall effect of PTH: raise calcium ion concentration
• PTH stimulates an enzyme that leads to the synthesis of calcitriol
• Increased synthesis of calcitriol also leads to increased plasma calcium
concentration
• The cells in the parathyroid gland which produce PTH respond to changes in
plasma calcium concentration - they have calcium ion receptors
• These receptors are activated whenever there is a fall plasma calcium
concentration
• Calcitriol also has a negative feedback effect on PTH
• There are Beta Receptors on the cells that produce PTH so they can be
stimulated by catecholamines to secrete PTH

Question 11

How is calcitrol synthesised

Answer 11

Cholecalciferol has TWO main sources:
Diet
• Different types of vitamin D come from the diet (Vitamin D2 = plants and fungi/ Vitamin D3 = meat/milk)
Sunlight
• UV B works on the skin
• UV B converts 7-dehydrocholesterol to cholecalciferol REMEMBER THESE TWO IMPORTANT SOURCES OF CHOLECALCIFEROL: DIET and SUNLIGHT
• Cholecalciferol is Vitamin D3
• Vitamin D3 is a steroid which circulates around the body and is taken up by the
liver
• The liver has an enzyme called 25-hydroxylase which converts cholecalciferol
to 25-hydroxy-cholecalciferol which is then stored in the liver
• 25-hydroxy-cholecalciferol is stored in the liver but then circulates from the liver and reaches the kidneys where you find 1α hydroxylase (which is
stimulated by PTH)
• 1a hydroxylase is responsible for the conversion of 25-hydroxy-cholecalciferol to 1,25-dihydroxy-cholecalciferol (calcitriol)

Question 12

Describe the action of calcitrol

Answer 12

Main action is on the SMALL INTESTINE: stimulates calcium and phosphate absorption (through separate pathways)
• It has minor effect on bone - it stimulates osteoblast activity (secondary effect of raising the plasma calcium concentration - by raising the calcium level in the blood, the calcium is there to be stored (e.g. in the bone))
• Kidneys - calcitriol increases calcium reabsorption and decreases phosphate reabsorption

Question 13

How is phosphate reabsorbed

Answer 13

nhibits this transporter so phosphate will NOT be reabsorbed so it will be
excreted in the urine
• Calcitriol also has an effect on phosphate reabsorption
• Through the FGF23 (fibroblast growth factor 23 (from osteocytes)) molecule,
calcitriol can block the phosphate transporter
• So PTH and Calcitriol (via FGF23) inhibit phosphate reabsorption in the kidneys

Question 14

What is calcitonin

Answer 14

Synthesised as pre-procalcitonin
• Calcitonin is a 32 amino acid polypeptide
• Calcitonin acts via transmembrane G-protein linked receptors
• Activation of adenyl cyclase or phospholipase C as second messenger systems

Question 15

What are the actions and regulation of calcitonin

Answer 15

Calcitonin works on bone and inhibits osteoclast activity - thus decreasing the release of calcium from bone into the blood
• Calcitonin also affects the kidneys: increases the excretion of sodium ions which, in turn, an increase in the urinary excretion of calcium and phosphate ions
• The effects of calcitonin are relatively small and short-lived
• Physiological benefit:
Plasma calcium levels are raised in PREGNANCY when you need more calcium ions (e.g. in milk)
Calcitonin protects the bone from being broken down to provide calcium
• Calcitonin is stimulated by an increase in plasma calcium concentration and its overall effect is to decrease plasma calcium ion concentration

Question 16

Name some endocrine causes of. Hypocalacemia

Answer 16

Hypoparathyroidism (insufficient PTH)
• Pseudohypoparathyroidism (associated with resistance to PTH)
• Vitamin D Deficiency

Question 17

What are the 2 signs of hypocalacaemia

Answer 17

Trousseau’s Sign (main d’accoucheur)
• Put slight pressure on the arm and the hand can go into contraction
Chvostek’s Sign
• Tap the facial nerve at the angle of the jaw you get the muscles to contract
These are both forms of TETANY

Question 18

What are the causes of Hypoparathyroidism

Answer 18

Idiopathic
• Hypomagnesaemia
• Suppression by raised plasma calcium concentration

Question 19

What is Pseudohypoparathyroidism

Answer 19

Also known as ALLBRIGHT HEREDITARY OSTEODYSTROPHY
• Characterised by target organ resistance to PTH (there are multiple underlying causes) - believed to be due to defective Gs proteins
• Features include:
Particular physical appearance (short stature, round face)
Low IQ
Subcutaneous calcification and various bone abnormalities (e.g. shortening of metacarpals)
Associated endocrine disorders (e.g. hypothyroidism, hypogonadism)

Question 20

What are Features of Hypoparathyroidism

Answer 20

There is a very abnormal 4th metacarpal
• If you give someone PTH, you get an
increase in urinary excretion of cAMP - this is what you’d expect in a normal person
• In people with idiopathic hypoparathyroidism and surgical hypoparathyroidism you get normal results because their target cells are still sensitive to PTH
• Pseudohypoparathyroidism you get no change because of target resistance to
PTH

Question 21

What does vitamin d deficiency cause

Answer 21

Rickets in children
• Osteomalacia in adults
• Clinical feature is the decreased calcification of bone matrix resulting in
softening of the bone
• This leads to BOWING of the bones in children or FRACTURES in adults
• Elderly people are less likely to get sunlight and hence are more likely to suffer
from vitamin D deficiency

Question 22

How can you tell the difference between these 3 conditions

Answer 22

In the kidneys, PTH increases the
excretion of phosphate thereby
reducing the blood plasma
concentration so in
hypoparathyroidism you get an
increase in plasma phosphate
concentration because PTH isn’t
stimulating the excretion of phosphate from the kidneys
• Pseudohypoparathyroidism - the parathyroid glands are producing sufficient PTH so PTH levels are normal but the target organs are resistant to PTH and hence plasma calcium ion concentration is low
• Vitamin D Deficiency - phosphate levels are low, plasma calcium concentration is normal and PTH is normal

Question 23

What is Primary Hyperparathyroidism

Answer 23

• a tumour in the parathyroid causes a large increase in PTH secretion
  Because it is a tumour it is unlikely to be regulated by the normal negative feedback - it will continue to produce large amounts of PTH leading to an increased plasma calcium ion concentration

Question 24

What is Secondary Hyperparathyroidism

Answer 24

Some people have low plasma calcium concentration for a variety of other reasons such as renal failure
Renail failure leads to loss of calcium in the urine which will stimulate the parathyroid to release PTH which will do its best to maintain the plasma calcium ion level

Question 25

What is Tertiary Hyperparathyroidism

Answer 25

Initial chronic low plasma calcium ion concentration
The parathyroid gland is being massively stimulated for a long time Eventually, the PTH becomes autonomous and it stops responding to the negative feedback
This is similar to primary hyperparathyroidism as it causes an increased plasma calcium ion level

Question 26

The external surface of bone is known as endosteum [a]
Osteoclasts are bone-resorbing cells [b]
There are usually four parathyroid glands in humans [c]
Parathyroid hormone (PTH) stimulates the urinary excretion of phosphate [d]
PTH receptors are present on osteoclasts [e]

Answer 26

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Question 27

Excess circulating PTH lowers the serum calcium concentration [a]
PTH secretion is stimulated by a fall in circulating calcium ion concentration [b]
25-hydroxyvitamin D is produced in the kidneys [c]
1,25 dihyroxyvitamin D stimulates calcium absorption from the gut [d]
Hypocalcaemia causes tetany [e]

Answer 27

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Question 28

Pseudohypoparathyroidism may be associated with distinct physical, as well as metabolic, characteristics [a]
In secondary hyperparathyroidism the serum calcium concentration is high [b]
Hypercalcaemia causes polyuria and polydypsia [c]
Calcitonin is produced by the parathyroid glands [d]
Hypercalcaemia can cause renal calculi [e]

Answer 28

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