TBL6 Calcium

Question 1

Calcium is found in 3 forms in blood serum.

Answer 1

1. Ionised calcium (free and bioactive)
2. Bound to albumin
3. Calcium complexed to serum constituents

Question 2

Most calcium is found in bone as ________, thus it serves as a major reservoir.

Answer 2

hydroxyapatite crystals

Question 3

Any changes in concentration of ________ affects the concentration of ionised calcium in the blood.

Answer 3

albumin

- changes in albumin causes changes in the amount of calcium bound to albumin, hence total calcium concentration.

Question 4

Binding of calcium to albumin is pH-dependent. (Acidosis/alkalosis) increases calcium binding to protein.

Answer 4

Alkalosis increases calcium binding to protein

=> decreased ionised calcium proportion => increased neuromuscular excitability

Question 5

(increased/decreased) ionised calcium concentration increases neuromuscular excitability.

Answer 5

Decreased ionised calcium concentration

• Calcium ions inhibits sodium transport. Thus, lower calcium levels will increase neuromuscular excitability, caused by increased sodium transport leading to depolarisation.

Question 6

Clinical conditions that cause changes in total but not ionised calcium

Answer 6

1. Hypo/hyperalbuminemia

2. Multiple myeloma - causes elevated calcium levels due to increased renal calcium reabsorption

Question 7

Clinical conditions that causes changes to ionised calcium but not total calcium

Answer 7

1. Acid-base disorders
2. PTH disorders
   - promotes bone resorption that increases blood serum ionised calcium levels
3. Hyperhosphataemia
   - Phosphate complexes serum calcium, leading to lower levels of normal ionised calcium

Question 8

Vitamin D3 (calcitriol) is acquired from 2 main sources.

Answer 8

1. Diet

2. Skin (via UV radiation)

Question 9

Vitamin D3 (Calcitriol) synthesis occurs in ________ where ________ is photoconverted to previtamin D3, which is then converted to Vitamin D3.

Answer 9

• occurs in skin keratinocytes

- 7-dehydrocholesterol (precursor) –> pre-vitamin D3 –> vitamin D3 (Calcitriol)

Question 10

2-step reaction to convert inactive Vitamin D3 to active metabolite ____________.

1. Hydroxylation reaction in the _____ to produce 25-hydroxyvitamin D
2. Hydroxylation reaction in the _______ to produce the active metabolite.

Answer 10

active metabolite 1,25-dihydroxyvitaamin D/cholecalciferol

1. Hydroxylation reaction in the liver
   (Vitamin D3 –> 25-hydroxyvitamin D)
2. Hydroxylation reaction in the kidneys
   (25-hydroxyvitamin D –> 1,25-dihydroxyvitamin D)
   by enzyme 1a hydroxylase

Question 11

In calcitriol synthesis, negative feedback occurs as 1,25-dihydroxyvitamin D inhibits _________ enzyme to reduce the production.

Answer 11

1,25-dihydroxyvitamin D inhibits 1a-hydroxylase enzyme (in the kidneys)

Question 12

Calcitriol is a principal regulator of calcium. It mainly acts on _______ and bones.

Answer 12

Calcitriol
- mainly acts on intestines to increase intestinal calcium absorption
- acts on bones to increase bone resorption
=> increases total serum calcium levels

Question 13

PTH is synthesised and secreted by the _______

Answer 13

chief cells of the parathyroid glands

Question 14

The dominant regulator of PTH is _______.

Answer 14

plasma calcium

- High calcium levels inhibit PTH secretion.

Question 15

How does calcium concentration affect PTH secretion?

Answer 15

• via membrane-bound calcium-sensing receptors (CASR) present on chief cells
• calcium binds, activating PLC and inhibiting adenylyl cyclase
• increases intracellular calcium concentration
  => prevents exocytosis of PTH-containing granules

Question 16

The overall action of PTH is to (increase/decrease) plasma calcium levels and (increase/decrease) phosphate levels.

Answer 16

PTH:

• increase plasma calcium levels
• decrease plasma phosphate levels

Question 17

Action of PTH:

1. on bone
2. on kidneys
3. on intestines (indirectly)

Answer 17

1. [bone] increases bone resorption by osteoclasts
2. [kidneys] increases renal calcium reabsorption in the distal tubules and stimulate phosphate excretion
3. [intestines] stimulate 1,25-dihydroxyvitamin D3 synthesis by stimulating 1a hydroxylase
   => intestinal effects of calcitriol

Question 18

If excess 1,25-dihydroxyvitamin D3 is produced, _________ catalyses the 24-hydroxylation of calcitriol, inactivating it.

Answer 18

CYP24 (cytochrome P450 enzyme)

Question 19

Calcitonin is synthesised and secreted by __________.

Answer 19

parafollicular cells of thyroid gland

Question 20

Calcitonin is stimulated mainly by

Answer 20

increased plasma calcium levels

- the overall action of calcitonin is to decrease plasma calcium levels.

Question 21

Main effects of calcitonin on:

1. bone

Answer 21

• inhibits osteoclast motility and inactivates them

=> inhibits bone resorption

Question 22

Calcitonin is a useful histological marker for ________.

Answer 22

medullary thyroid carcinomas

Question 23

_______ mainly functions to regulate phosphate concentration in plasma.

Answer 23

Fibroblast Growth Factor 23 (FGF23)

- secreted by osteocytes

Question 24

Main effects of FGF23

Answer 24

1. Inhibits PTH secretion
2. Inhibits calcitriol synthesis
3. Suppresses phosphate reabsorption

Question 25

PTH stimulates osteoBlast to secrete _______, increasing osteoClastic activity and increased bone resorption.

Answer 25

RANKL

Question 26

Negative feedback by calcitriol:

Answer 26

- inhibits PTH gene expression by upregulating the calcium sensor - represses CYP1a and stimulates CYP24

Question 27

______________ (clinical condition) involves mutations of the calcium-sensing receptor in chief cells, leading to inappropriate release of PTH secretion and elevated serum calcium.

Answer 27

Familial benign hypocalciuric hypercalcemia (FBHH)

Question 28

PTH binds to transmembrane receptors which activate ________ and _________.

Answer 28

PTH: activates both adenylyl cyclase (leading to increased cAMP) and PLC (increased IP3)

Question 29

Osteoblasts are involved in bone (synthesis/breakdown). | Osteoclasts are involved in bone (synthesis/breakdown).

Answer 29

Osteoblasts - bone synthesis Osteoclasts - bone breakdown

Question 30

In bones, PTH receptors are found only on _________. => how to activate osteoclasts..?

Answer 30

osteoblasts (involved in bone matrix synthesis) - inhibited in their main activity, but stimulated to produce osteoclast activating factors which stimulate osteoclasts to increase bone resorption.

Question 31

Stimuli of PTH production

Answer 31

1. Decreased plasma calcium levels | 2. Catecholamines

Question 32

PTH production is negatively feedbacked by

Answer 32

1. Calcium | 2. Calcitriol (via raised Ca2+)

Question 33

Calcitriol effect on bones

Answer 33

(opposite of PTH) | - increases bone osteoblast activity to increase bone matrix synthesis, leading to the storage of Ca2+

Question 34

Calcitriol effect on small intestines

Answer 34

1. increases calcium reabsorption | 2. increases phosphate reabsorption

Question 35

Calcitonin and PTH are ________ hormones.

Answer 35

polypeptide

Question 36

Calcitonin mainly acts on the bone to __________. | It also has effects on the kidney.

Answer 36

Calcitonin: - inhibits osteoclastic breakdown of bone matrix => reduces bone resorption and release of calcium and phosphate into the blood 2. Effects on kidneys => natriuretic hormone as it increases excretion of Na+, Ca2+ and phosphate.

Question 37

Administration of _______ helps to stimulate calcitonin production from parafollicular cells to test their function.

Answer 37

gastrin

Question 38

Stimuli for calcitonin release:

Answer 38

1. gastrin | 2. increased plasma calcium concentration

Question 39

3 other hormones affecting calcium metabolism

Answer 39

1. thyroid iodothyronines 2. adrenal glucocorticoidds (cortisol) 3. sex steroids

Question 40

Hypocalcaemia may present with ______.

Answer 40

tetany - low calcium levels that causes neuromuscular excitability => intermittent muscular spasms

Question 41

3 endocrine causes of hypocalcemia

Answer 41

1. hypoparathyroidism 2. pseudohypoparathyroidism 3. vitamin D deficiency

Question 42

Hypomagnesaemia (low magnesium levels) can cause (hypo/hyper)parathyroidism.

Answer 42

Hypomagnesaemia causes hypoparathyroidism. Low Mg --> more calcium released from SR --> high Ca2+ levels --> inhibits PTH release --> hypoparathyroidism

Question 43

__________ occurs due to target organ resistance to PTH. (not actually low PTH levels) This is mainly believed to be due to _________.

Answer 43

Pseudohypoparathyroidism - due to defective Gs protein => no response to PTH binding can occur

Question 44

Vitamin D deficiency presents as _____ in children and ______ in adults.

Answer 44

rickets in children; osteomalacia in adults (softening of the bones due to decreased mineralisation of bone matrix)

Question 45

Treatment of acute hypocalcemia

Answer 45

IV calcium gluconate to replenish calcium

Question 46

Treatment of chronic hypocalcemia

Answer 46

- oral supplements - IV calcium salts - in combination with vit D preparations, bisphosphonates, oestrogens, calcitonin

Question 47

3 endocrine causes of hypercalcemia

Answer 47

1. Primary hyperparathyroidism 2. Tertiary hyperparathyroidism 3. Vitamin D toxicosis

Question 48

Primary hyperparathyroidism

Answer 48

- increased PTH levels resulting in increased Ca2+ levels | - loss of negative feedback

Question 49

Causes of primary hyperparathyroidism

Answer 49

- Parathyroid adenoma | - Chief cell hyperplasia

Question 50

Secondary hyperparathyroidism

Answer 50

- (physiological) increased PTH levels in response to hypocalcemia

Question 51

Causes of secondary hyperparathyroidism (hypocalcemia)

Answer 51

- renal failure (cannot reabsorb calcium) | - vitamin D deficiency

Question 52

Tertiary hyperparathyroidism

Answer 52

- long-standing secondary hyperparathyroidism leading to autonomous production of PTH and thus increased Ca2+ - loss of negative feedback with persistent stimulation

Question 53

Causes of tertiary hyperparathyroidism

Answer 53

- Autonomous parathyroid hyperplasia | - chronic renal failure