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Endocrinology Year 2 > Calcium and Phosphate regulation > Flashcards

Calcium and Phosphate regulation Flashcards

1
Q

State some roles of calcium in the body.

A
  • Control of neuromuscular excitability
  • Muscle Contraction
  • Strength in bone; calcium reservoir in bone
  • Blood clotting
  • Intracellular second messenger/co-enzyme
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2
Q

Where and how is calcium mainly stored? What are the other sites?

A

99% of calcium in the body is stored in bone in the form of complex hydrated calcium phosphate salts called hydroxyapatite crystals.
Found in all cells (low in cytoplasm and relatively high in specialised organelles), + blood and other extracellular fluids.

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3
Q

How is calcium present in the blood, and in what proportions? Which is the bio-active component?

A

Unbound ionised calcium (Ca2+) = 1.25mM = 50%
Bound to plasma proteins = 1.15mM = 45%
Tiny bit as soluble salts

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4
Q

What is the usual daily intake of calcium? Briefly describe how this calcium is absorbed into the blood from the gut.

A

1000 mg/day

  1. Trans-cellular transport (mainly) in the duodenum involving specific binding proteins.
  2. Passive para-cellular transport throughout small intestine (especially when calcium intake is high)
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5
Q

State the main organs involved in the fine regulation of plasma calcium, and what other tissue is also involved

A

Kidneys

and bone

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6
Q

Where, and in what proportions, is calcium reabsorbed in the nephron?

A
  • PCT = 70%

Principal component which is regulated:

  • Ascending limb of LoH = 20%
  • DCT
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7
Q

What two hormones raise plasma calcium concentration?

A 
Parathyroid Hormone (PTH)
Calcitriol (1,25-dihydroxycholecalciferol)
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8
Q

State and describe the two receptors of PTH

A

PTHR1 and PTHR2
GPCRs
Activation => increased adenyl cyclase activity => increased synthesis of cAMP => activation of PKA pathway
Found particularly in bone and kidneys

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9
Q

Where is PTH synthesised/stored?

A

PTH is synthesised and stored in chief cells of the parathyroid glands (two superior and two inferior glands located at the back of the thyroid)

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10
Q

Describe the effect of PTH on bone to explain its role in raising plasma calcium (and hence phosphate) concentration

A
  • PTH binds to PTHR1 receptors on osteoblasts
  • Stimulates their release of osteoclast-activating factors (which include the cytokines RANKL and M-CSF)
  • Once activated, osteoclasts release acids and proteolytic enzymes into the nearby osteoid => bone resorption = release of Ca2+ (and phosphate) into ECF and blood
  • PTH (when bound) also decreases synthesis of osteoprotegerin by osteoblasts (a molecule which decreases RANKL binding to its receptor reducing osteoclast formation and activation)
  • Note that PTH also promotes osteoclast/osteoblast development form precursors
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11
Q

Describe the effect of PTH on the kidneys (concerning calcium and phosphate reabsorption)

A

Acting through its PTHR1 receptor, PTH:

  1. Stimulates calcium reabsorption; 65% PCT, 20% thick limb of LoH, 15% DCT
  2. Promotes phosphate ion excretion (and sodium ion excretion) via down-regulation of sodium-phosphate co-transporters.
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12
Q

Why is the PTH-induced excretion of phosphate by the kidneys important?

A
  • Overall, considering the effects of PTH on bone and the kidneys, plasma calcium concentration is increased but the plasma phosphate concentration is maintained.
  • Therefore, the likelihood that calcium phosphate salts will be deposited in the soft tissues decreases, since the dissociation constant is maintained (between the ions and their salt)
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13
Q

Describe the effect of PTH on the kidneys (concerning calcitriol synthesis)

A
  • PTH acts on endocrine cells (via PTHR1) found between the cells of the PCT.
  • Stimulates calcitriol synthesis by acting as a transcription factor for the 1α-hydroxylase enzyme.
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14
Q

Describe the control of the synthesis and release of PTH (stimulating and inhibiting factors)

A
  • Chief cells respond to changes in circulating Ca2+ by means of a calcium-sensing receptor (CaR) on its cell membrane.
    CaR = GPCR that, when activated by ligand (Ca2+) binding, inhibits the adenyl cyclase-cAMP pathway and stimulates the PLC-IP3, DAG pathway.
  • Therefore, a fall in plasma calcium concentration => reduction in ligand binding => decreased activation of the PLC pathway => decreased release of Ca2+ from intracellular stores => decreased inhibition of PTH release.

ALSO;
- Catecholamines (by binding to beta receptors)

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15
Q

What type of molecule is calcitriol? What is it derived form?

A

Steroid hormone

Bioactive derivative/metabolite of vitamin D3 (cholecalciferol)

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16
Q

What are the ways in which vitamin D3 may be obtained?

A
  • Ingested in the diet
  • Synthesised in the skin (epidermis and dermis layers) from its early precursor 7-dehydrocholesterol; UVB light brings about the conversion

Note: ergocalciferol (vitamin D2) found in certain algae/fungi may also be utilised.

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17
Q

Describe the synthesis and transport of calcitriol

A
  • Cholecalciferol once synthesised is transported in the circulation mainly (85%) bound to cholecalciferol- binding protein, CBP / vitamin D–binding protein, VDBP; also albumin (with less than 0.5% free/bioactive)
  • It reaches the liver where it gets rapidly hydroxylated in various positions, the main hydroxylation being catalysed by a 25-hydroxylase enzyme, forming 25-hydroxycholecalciferol (25 OH-D3).
  • 25 OH-D3 is stored in the liver which normally contains at least 3 months’ supply of it, and which accounts for the liver being a good source of vitamin D3.
  • The 25 OH-D3 (from the circulation) is then 1α-hydroxylated in various tissues, but mainly in epithelial cells of the renal PCTs.
  • The 1α-hydroxylase activity is the determining factor for the production of calcitriol (aka 1,25 (OH)2 cholecalciferol)
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18
Q

Why is calcitriol not stored to any significant extent in the cells where it is produced?

A

(Like its precursors), it is a steroid hormone and hence it is lipophilic.
Therefore it is only synthesised when the proximal tubular cells are appropriately stimulated

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19
Q

State the half life of calcitriol

A

Between 3 and 6 hours

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20
Q

Describe the general receptor-mediated mechanism of action of calcitriol

A
  • Calcitriol binds to specific intracellular receptors (vitamin D3 receptors, VDR) which also bind related ligands such as the 25 OH-D3 metabolite.
  • These receptors are part of the retinoic acid family of receptors.
  • Once bound to its receptor, it acts as a transcription factor modulating gene activity => new protein synthesis, but it does so only after forming a complex with the retinoid X receptor.
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21
Q

State the tissues/organs that calcitriol has an effect on

A

Intestinal tract (duodenum and jejunum) MAINLY
Bone
Kidneys
Parathyroid glands

22
Q

Describe the effect of calcitriol on the small intestine

A
  1. Stimulates the trancellular and paracellular processes of calcium absorption:
    - e.g. once the calcium ions have entered the enterocytes, they bind to intracellular proteins such as calmodulin and calbindin (directed to the brush border by calcitriol) and are transported to the serosal membrane; calcium ions are finally secreted out of the cells by a calcitriol-inducible, ATPase-dependent, calcium (and magnesium) pump
  2. Calcitriol also stimulates intestinal phosphate absorption
23
Q

Describe the effect of calcitriol on the kidneys

A
  1. Stimulates the synthesis of proximal tubular calcium channels and promotes the reabsorption of Ca2+ through them
  2. Inhibits phosphate reabsorption/increased loss of phosphate indirectly, mainly in the PCT, by stimulating the synthesis of fibroblast growth factor-23 (FGF-23) in osteocytes
24
Q

What are the actions of FGF-23? What stimulates its production?

A
  • FGF-23 is an important endocrine factor that inhibits sodium phosphate co-transporters in the brush borders of both enterocytes and proximal tubular cells => decreased uptake across the small intestine and decreased reabsorption in the proximal tubules
  • Stimulated by phosphate in the diet and in the circulation, as well as by calcitriol
25
Q

Describe the effect of calcitriol on bone

A

Stimulates osteoblasts which synthesise osteoclast-activating factors => increased bone resorption
(note a very minimal effect on bone)

26
Q

Describe the effect of calcitriol on the parathyroid glands/PTH synthesis

A

Has clear genomic effects on chief cells, including the inhibition of cell proliferation and the synthesis of PTH.
Therefore, has a direct negative feedback effect on PTH.

27
Q

Describe the control of the synthesis and release of calcitriol

A

Calcitriol synthesis is regulated mainly by PTH, but is also influenced by FGF-23 (negative feedback), phosphate, calcium and calcitriol itself.

28
Q

What hormone decreases the circulating calcium ion concentration?

A

Calcitonin

29
Q

Where is calcitonin synthesised?

A

Parafollicular cells located within the thyroid gland

30
Q

How is calcitonin transported in the blood and where is it metabolised?

A

Circulates in the blood, principally unbound and bioactive.

It is metabolised mainly in the kidneys, but also in the liver.

31
Q

State the name and type of receptor for calcitonin

A

G protein–coupled calcitonin receptor

32
Q

Explain why calcitonin decreases plasma calcium concentration

A

KIDNEYS:
- Receptors are located mainly in the proximal tubules where calcitonin decreases reabsorption of calcium and sodium

BONE:
- Inhibits osteoclast activity and stimulates osteoblast proliferation and activity, resulting in an increase in bone osteoid formation.

33
Q

State a physiological benefit of calcitonin

A

Calcitonin is protective of bone, for instance in situations when excessive bone resorption might be potentially harmful such as during pregnancy and lactation.

34
Q

What stimulates and inhibits the synthesis of calcitonin in the parafollicular cells?

A

Stimulated by:

  • Increase in circulating calcium ion levels (MAINLY)
  • Certain gastrointestinal hormones
  • β-receptor agonists such as adrenaline, and glucocorticoids

Inhibited by:

  • Somatostatin
  • Calcitriol
35
Q

List the causes of vitamin D deficiency

A
  • Diet
  • Lack of sunlight
  • GI malabsorption
    e. g. coeliac disease, inflammatory bowel disease,
  • Renal failure
  • Liver failure
  • Vitamin D receptor defects (autosomal recessive, rare, resistant to vitamin D treatment)

Re-emerging as problem in UK due mainly to inadequate diet and lack of sunlight

36
Q

State the effect of hypocalcaemia and hypercalcaemia on muscle excitability

A

HYPERcalcaemia:
- Ca2+ blocks Na+ influx, so LESS membrane excitability

HYPOcalcaemia
- Enables GREATER Na+ influx, so MORE membrane excitability

37
Q

State the normal range of serum Ca2+

A

~ 2.2–2.6mmol/L

38
Q

What are the signs and symptoms associated with hypocalcaemia

A

Parasthesia (hands, mouth, feet, lips)
Convulsions
Arrhythmias
Tetany

[CATs go numb]

39
Q

What is CHVOSTEK’S SIGN?

A
  • Tap facial nerve just below zygomatic arch
  • Positive response = twitching of facial muscles
  • Indicates neuromuscular irritability due to hypocalcaemia
40
Q

What is TROUSSEAU’S SIGN?

A

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

41
Q

List the potential causes of hypocalcaemia

A
  • Vitamin D deficiency
  • Low PTH levels => hypoparathyroidism; due to e.g. neck surgery, auto-immune, magnesium deficiency
  • PTH resistance e.g. pseudohypoparathyroidism
  • Renal failure => impaired 1a-hydroxylation => decreased production of 1,25(OH)2D3
42
Q

What are the signs and symptoms associated with hypercalcaemia

A

Stones (renal effects):

  • Polyuria & thirst
  • Nephrocalcinosis, renal colic, chronic renal failure
Abdominal moans (GI effects):
- Anorexia, nausea, dyspepsia, constipation, pancreatitis
Psychic groans (CNS effects):
- Fatigue, depression, impaired concentration, altered mentation, coma (usually >3mmol/L)
43
Q

List the potential causes of hypercalcaemia

A
  • Primary hyperparathyroidism
  • Hypercalcaemia of malignancy i.e. tumours/metastases often secrete a PTH-like peptide
  • Conditions with high bone turnover (hyperthyroidism, Paget’s disease of bone => immobilised patient)
  • Vitamin D excess (rare)
44
Q

How would you diagnose primary hyperparathyroidism?

A

Tumour of the parathyroid gland:
- Autonomous PTH secretion despite hypercalcaemia, so no negative feedback
=> Raised calcium, Low phosphate, Raised (unsuppressed) PTH

45
Q

How would you diagnose hypercalcaemia of malignancy?

A

Negative feedback is fine so:

  • Raised calcium
  • Suppressed PTH
46
Q

How would you diagnose secondary hyperparathyroidism?

A

Vitamin D deficiency => Low serum calcium => PTH increases to try to normalise serum calcium

47
Q

Vitamin D deficiency leads to what important conditions?

A

In children - RICKETS
In adults - OSTEOMALACIA

In general, results in:

  • Lack of mineralisation in bone => bone deformities, bone pain, increased fracture risk
  • Severe proximal myopathy (muscle cells synthesise VDRs)
  • Normal stresses on abnormal bone cause insufficiency fractures - Looser zones
  • Waddling gait - typical
48
Q

What are the biochemical findings vitamin D deficiency?

A
  • Plasma [25(OH)D3] usually low (NB we don’t measure 1,25 dihydroxy vitamin D (1,25 (OH)2 D) to assess body vitamin D stores)
  • Plasma [Ca2+] low (may be normal if secondary hyperparathyroidism has developed)
  • Plasma [PO43-] low (reduced gut absorption)
  • [PTH] high
49
Q

How would you treat vitamin D deficiency (in patients with normal renal function)?

A
  • Give 25 hydroxy vitamin D (ergocalciferol or cholecalciferol)
  • Patient converts this to 1,25 dihydroxy vitamin D via 1a-hydroxylase
50
Q

How would you treat vitamin D deficiency (in patients with renal failure)?

A
  • Inadequate 1a hydroxylation, so can’t activate 25 hydroxyl vitamin D preparations
  • Give Alfacalcidol (1a hydroxycholecalciferol)
51
Q

State the causes and effects of excess vitamin D?

A
  • Can lead to hypercalcaemia and hypercalciuria due to increased intestinal absorption of calcium

Can occur as a result of:

  • excessive treatment with active metabolites of vitamin D e.g. Alfacalcidol
  • granulomatous diseases such as sarcoidosis, leprosy and tuberculosis (macrophages in the granuloma produce 1a hydroxylase to convert 25(OH) D to the active metabolite 1,25 (OH)2 D)

Endocrinology Year 2 (18 decks)

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