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Endocrinology > Endocrine control of calcium metabolism > Flashcards

Endocrine control of calcium metabolism Flashcards

1
Q

What is the most abundant metal in the body

A

Calcium is the most abundant metal in the human body (fifth most abundant element).

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2
Q

Describe the importance of calcium in humans

A

Essential element.

Diet should meet all requirements (or supplements can be used).

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3
Q

List some of the roles of calcium in the body

A

Neuromuscular excitability
Muscle contraction
Strength in bones- calcium salts constitute bones
Intracellular second messenger
Intracellular co-enzyme
Hormone/neurotransmitter stimulus-secretion coupling- carries vesicle to the membrane.
Blood coagulation (factor IV)

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4
Q

What is the most important function of calcium

A

Maintenance of neuromuscular activity (MOST IMPORTANT). o Ca2+ ions tend to sit outside and block sodium channels. o If you become hypocalcaemic, more sodium channels become available for influx of sodium causing depolarization – hyperexcitability (of nerves and muscles).
Calcium regulates the sodium ion and prevents muscles from spasming.

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5
Q

Which food is a very good source of calcium

A

Broccoli

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6
Q

How is calcium stored in the bone

A

In the form of complex hydrated calcium phosphate salts called hydroxyapatite crystals, which gives bone its rigidity and strength.

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7
Q

Why is it important that a low concentration of calcium is maintained in cells

A

Calcium is an important secondary messenger, hence a low concentration needs to be maintained in cells so that an influx of calcium can elicit a response inside the cell.

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8
Q

Explain how a low concentration of calcium is maintained inside cells

A

The control of calcium channels is important in regulating the diffusion of calcium ions down its concentration gradient, from either intracellular organelles or extracellular fluid into the cytoplasm. Calcium ions are also transported actively from intracellular organelles into the cytoplasm, or from cytoplasm into the ECF, or by secondary transport mechanisms, such as sodium-calcium counter-transport

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9
Q

Describe the different forms of calcium found in the body

A

Most calcium is present in the body as calcium salts
It is mainly found in bone (99%, approx. 1kg) as complex hydrated calcium salt (hydroxyapatite crystals)
In blood, some is present as ionized calcium (Ca2+), some bound to protein and the tiny bit left as soluble salts (citrate and phosphate)
Only the free (unbound) Ca2+ is bioactive

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10
Q

Describe the forms of calcium in the blood

A

99% of Calcium is found in BONE (1kg) as complex hydrated calcium salts – hydroxyapatite crystals.
▪ 1% of Calcium left is present in the blood as:
o Ionised Ca2+ (BIOACTIVE). - 50%
o Bound to plasma proteins.- 45%
o (tiny bit) as soluble salts (citrate, lactate, phosphate)- 5%
▪ Ionised unbound form ~1.25mM/L. ▪ Calcium is present in dynamic equilibrium.

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11
Q

What is the concentration of calcium in the plasma

A

2.5mM

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12
Q

Describe the organs involved in calcium metabolism

A

GI tract absorption from diet (occurs both ways) - ~1000mg/24h. Some calcium enters the GI from the blood from exocrine secretions of digestive enzymes.
Around 850mg/24h lost in faeces.
Calcium passes to the kidneys which regulates content.
4. 150mg/24h excreted from the kidneys to maintain equilibrium.
5. Hydroxyapatite crystals can be broken down to increase levels of calcium in the blood.
We also have minute losses of calcium from dead cells (hair, nails, skin) when they are shed.
If the activity of osteoclasts and osteoblasts is normal, no uptake or loss of calcium from bone.

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13
Q

What is the difference between osteoclasts and osteoblasts

A

Osteoclasts- break down bone

Osteoblasts- make bone

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14
Q

What is the body more concerned with in terms of calcium homeostasis

A

A low calcium concentration

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15
Q

Which hormones can increase calcium concentration

A

PARATHYROID HORMONE (PTH)

1,25 (OH)2 VITAMIN D3 (DIHYDROXY- CHOLECALCIFEROL, or CALCITRIOL)

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16
Q

Which hormone decrease calcium concentration

A

Calcitonin (its effects are less potent, significant and less well defines than that of calcitriol and PTH.

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17
Q

Where are the parathyroid glands found

A

4 parathyroid glands located on the posterior of the thyroid gland.
2 superior and 2 inferior. Each gland is encapsulated and lies on the surface of the thyroidal tissue.
The total number of parathyroid glands can vary in individuals.

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18
Q

What is the role of the parathyroid glands

A

To synthesise parathyroid (parathormone) PTH.

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19
Q

Where is calcitonin released

A

Inside the thyroid gland, there are parafollicular cells in-between the follicles. o These are the site of synthesis of Calcitonin.

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20
Q

Describe the control of the synthesis and release of PTH

A

The main stimulus for the release of PTH is a decrease in circulating calcium ion concentration.
The chief cells respond to circulating levels of calcium ions by means of a calcium-sensing receptor (CaR) in the plasma membrane.
The receptor is G-protein linked, and activation of the receptor by Ca2+ results in the inhibition of the adenyl cyclase cAMP pathway and stimulation of phospholipase C- IP3/DAG pathways.
A low Ca2+ results in reduced ligand binding and is associated with the dis-inhibition of the adenyl cyclase pathway and decreased activation of the PLC pathway, leading to the synthesis of PTH.

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21
Q

Describe PTH synthesis

A

Initially synthesized as protein pre-proPTH
PTH is a polypeptide of 84 aas
Binds to transmembrane G-protein linked receptors
Activation of adenyl cyclase, but also probably PLC as second messenger systems- depending on where the tissue is located.

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22
Q

Describe the mechanisms of action of PTH on the kidney.

A

PTH stimulates calcium reabsorption in the kidney.
It also stimulates phosphate excretion (=more calcium reabsorption) Phosphate reabsorption is dependent on sodium-phosphate co-transporters, whose activity is down regulated by PTH. Hence sodium reabsorption is also down regulated.
b. Synthesise 1a-hydroxylase which creates calcitriol (has important effects on the small intestine → increased absorption of calcium and phosphate). Helps to synthesise the active form of vitamin D3 by adding the final hydroxyl group

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23
Q

What is Vitamin D3 concerned with

A

Getting more calcium out of your diet.

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24
Q

What are the effects of PTH on bone

A
  1. PTH has an effect on the bone:
    a. Stimulates osteoclasts (reabsorption of bone matrix and release of calcium from hydroxyapatite crystals into the gut).
    b. Inhibits osteoblasts.
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25
Q

Where are PTH receptors found in bone

A

On the osteoblasts

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26
Q

Describe PTH action in bone

A

PTH binds to PTH receptor on osteoblasts.
Osteoblasts release osteoclast activation factors (OAFs) such as receptor activator of nuclear kappa B ligand (RANKL) and macrophage colony-stimulating factor (M-CSF) which activate osteoclasts. IL1B is also released which stimulates the differentiation of osteoclasts from their progenitor cells.
OAFs stimulate osteoclasts to breakdown bone matrix to create free calcium.

27
Q

When calcium and phosphate are released from the breakdown of bone by osteoclasts, why don’t they re- associate to form their salts again.

A

The PTH-induced excretion of phosphate by the kidneys, maintaining the dissociation constant between the ions and their salts.

28
Q

Describe PTH regulation

A

PTH increases plasma concentrations of calcium ions and stimulates the synthesis of calcitriol, both of which have negative feedback effects on the synthesis of PTH.
There are beta-receptors on the parathyroid cells so they can be stimulated by catecholamines to secrete PTH.
Low plasma concentration of calcium stimulates the synthesis and release of PTH.

29
Q

Describe the synthesis of calcitriol

A

The precursor is vitamin D3 (cholecalciferol).
Cholecalciferol is obtained from the diet (fish, oils, milk, eggs and butter) or can be synthesised in the skin from its early precursor, 7-dehydrocholesterol, under the influence of vitamin d3.
CHOLECALCIFEROL— 25 HYDROXY-CHOLECALCIFEROL 25 (OH) D3
(synthesized in LIVER and stored in this form) — 1,25 DI-HYDROXY-CHOLECALCIFEROL 1,25 (OH)2 D3
synthesized in KIDNEYS main BIOACTIVE form
(also known as CALCITRIOL)

30
Q

What else can be utilised instead of vitamin d3

A

Vitamin D2, ergocalciferol which is found in certain algae and fungi, this can also be utilised,

31
Q

Describe the UV light required to synthesise Vitamin D3

A

UVB light
285-315nm
melanin, glass, clothing, the low sun of winter, and grey skies decrease the amount of vitamin D3 synthesised in the skin.

32
Q

Which enzyme is responsible for the synthesis for the bioactive form of vitamin d3

A

1a-hydroxylase (stimulated by PTH).

33
Q

Describe the differences in action of vitamin D3 and PTH

A

Vitamin D3 has a more chronic effect on increasing calcium levels, PTH has a more rapid effect. D3 acts as a transcription factor (it takes time to synthesise proteins),

34
Q

Describe the physiological roles of Vitamin D3

A

Major effect is on the small intestine, where it increases calcium and phosphate reabsorption. These are then combined to form salts which are laid down in bone, stimulating osteoblast activity to build bone. In the kidney, it increases calcium and phosphate reabsorption.

35
Q

What is the role of fibroblast growth factor 23

A

It is involved in the homeostasis of phosphate metabolism.

36
Q

What is vitamin D3 trying to protect.

A

Bone.

37
Q

When is fibroblast growth factor 23 released

A

When phosphate levels are high and it is not being used to make bone, calcitriol is used to synthesise FGF 23 to decrease phosphate levels. FGF23 has a negative feedback effect on calcitriol- inhibiting 1a-hydroxylase activity.

38
Q

Describe how FGF 23 decreases phosphate levels

A

It inhibits the activity of the Na+/PO43- cotransporter (along with PTH) in the proximal tubular cells, increasing excretion of sodium and phosphate.

39
Q

Describe calcitonin

A

▪ Synthesised as a pre-procalcitonin. ▪ Calcitonin is a 32 amino-acid polypeptide. ▪ Calcitonin acts via a transmembrane G-protein linked receptor. ▪ Activation of Adenyl cyclase or phospholipase C as a secondary messenger system (depending on the cell type).

40
Q

Why is it believed that calcitonin only plays a minor role in the regulation of calcium metabolism

A

Its effects are relatively weak and short-lived,

41
Q

When giving calcitonin as a drug, from which animal to we obtain the calcitonin from

A

Salmon- its effects are more effective than the human form.

42
Q

Describe the actions of calcitonin

A

▪ Calcitonin works on bone and INHIBITS osteoclast activity (decreases release of calcium from bone into the bloodstream. ▪ Calcitonin works on the kidneys by increasing excretion of sodium ions which increases urinary retention of calcium and phosphate ions. ▪ This is good so during pregnancy, you have enough milk for the child (as calcium retained). Calcitonin is stimulated by an increase in plasma concentration of calcium so overall effect is to decrease plasma ion concentration.

43
Q

What else stimulates the release of calcitonin

A

Gastrin- which is released in the increased secretion of stomach acid (a sign of high calcium) hence high calcium levels can lead to stomach ulcers.

44
Q

What are the endocrine causes of hypocalcaemia

A

HYPOPARATHYROIDISM
PSEUDOHYPOPARATHYROIDISM
VITAMIN D DEFICIENCY

45
Q

Describe the two different ways in which hypocalcaemia can be demonstrated

A

Both examples are known as tetany
▪ Trousseau’s Sign (main d’accoucheur) – 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 and you get muscles to contract.
Muscles spasm easily as there is less calcium blocking the entry of sodium ions, meaning that action potentials are more likely to be generated, leading to increased stimulation of the muscles and consequently spasms.

46
Q

What are the causes of hypoparathyroidism

A

IDIOPATHIC- low PTH
HYPOMAGNESAEMIA- low plasma concentration of plasma magnesium (GI problems, renal problems, nutritional deficiencies, alcoholic’s) needed for synthesis and downstream reactions of PTH.
(SUPPRESSION BY RAISED PLASMA CALCIUM CONCENTRATION)- negative feedback.
Removal of parathyroid glands -surgery, autoimmune attack.

47
Q

What is pseudohypoparathyroidism essentially a case of

A

PTH resistance

48
Q

What is pseudohypoparathyroidism also known as

A

ALLBRIGHT HEREDITARY OSTEODYSTROPHY

49
Q

What is pseudohypoparathyroidism caused by

A

target organ resistance to PTH (multiple underlying causes). Believed due to defective Gs protein (needed to increase cAMP intracellularly in response to PTH receptor activation). Hence, it has a syndromic effect, as Gs proteins are common throughout the body.

50
Q

Describe the symptoms of pseudohypoparathyroidism

A

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).

51
Q

How would you differentiate clinically between pseudohypoparathyroidism and surgical or idiopathic hypoparathyroidism

A

If you were to give cAMP to someone with idiopathic or surgical Hypoparathyroidism, they would get an increase in urinary retention of cAMP but this would not occur with Pseudohypoparathyroidism as they have resistance to PTH.

52
Q

Describe the consequences of a vitamin D deficiency

A

o Can cause rickets in children and osteomalacia in adults. o Clinical Features include: ▪ Softening of bone due to decreased calcification of bone matrix which leads to bowing of bones in children or fractures in adults.

53
Q

Describe what you would expect to see in hypoparathyroidism

A

Low Ca
High phosphate
Low PTH

54
Q

Describe what you would expect to see in pseudohypoparathyroidism

A

Low Ca
High phosphate
Normal or high PTH

55
Q

Describe what you would expect to see in vitamin D deficiency

A

Low Ca
Low phosphate
High PTH

56
Q

What are the endocrine causes of hypercalcaemia

A

PRIMARY HYPERPARATHYROIDISM
TERTIARY HYPERPARATHYROIDISM
VITAMIN D TOXICOSIS

57
Q

Describe primary hyperparathyroidism

A

A tumour in the parathyroid → increase in PTH secretion. o Tumors are unlikely to be regulated by normal negative feedback – it will continue to produce PTH leading to increased plasma ion concentration. o Presents with CLUBBED FINGERS.
The tumour is usually an adenoma

58
Q

Describe secondary hyperparathyroidism

A

Secondary hyperparathyroidism is NOT associated to hypercalcaemia as it is a low plasma calcium ion concentration (not high) possibly due to reasons like renal failure – loss of calcium in the urine which will stimulate PTH release to maintain plasma calcium level.
Renal failure prevents reabsorption of calcium and synthesis of calcitriol.

59
Q

Describe tertiary hyperparathyroidism

A

Initial chronic low plasma calcium ion concentration. o The parathyroid gland is stimulated for a long time so the PTH production becomes autonomous and the gland stops responding to negative feedback. o This is similar to primary as it causes an increase in plasma calcium ion levels.
Often develops from secondary hyperparathyroidism (glands become hyperplastic), when renal failure is cured (transplant, improved nutrition) parathyroid glands are autonomous and the PTH is effective, causing hypercalcaemia

60
Q

What are the renal effects of excess PTH

A

o Polyuria. o Renal stones. o Nephrocalcinosis

61
Q

What are the effects of excess PTH on the GI tract

A

o Gastric acid synthesis → duodenal ulcers (can’t be neutralised in the duodenum as effectively)

62
Q

What are the effects of excess PTH on bone

A

o Bone lesions. o Bone rarefaction. o Fractures.

Thinning of bones

63
Q

What will an X-ray of patients with primary hyperparathyroidism show

A

Clubbing of
finger
Marked periosteal bone erosion in the terminal phalanges

Endocrinology (11 decks)

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