Calcium And Phosphate Metabolism And Homeostasis

Front 1

How much calcium is there in the body?

Where is it distributed?

Back 1

25000 mmol (1kg)

99% is in mineral phase in bone (mechanical strength)

Much higher conc outside cell
extracellular ionised Ca ~1.2 mmol/L
Intracellular cytosolic 10-4 - 10-3 mmol/L

Front 2

What biological roles does calcium have?

Back 2

Biological roles:
muscle contraction
intracellular messenger
nerve excitability
blood coagulation
enzymes of metabolism

Front 3

How is calcium distributed in serum?

Back 3

47% free (unbound/ionised)
47% bound to albumin
6% complexed

Note: Feedback mechanisms are regulated by the free fraction

Normal 2.2-2.6 mmol/L

Front 4

How is serum calcium measured?

Back 4

We can measure either:
-free calcium
-total calcium (bound+free)

If a patient has a low albumin concentration, TOTAL [Calcium] will also be low but the FREE [Calcium] may be normal

In practise we measure total calcium (what serum total calcium would have been if the albumin had been normal)

Ca (adj) = Ca(tot) + [0.02(45-alb)]

Front 5

How is calcium homeostatis maintained (organs and hormones)?

Back 5

Main organs involved
–kidney
–gut
–bone
–parathyroid glands (calcium sensing receptors)

Metabolic control – main hormones
–parathyroid hormone (PTH) - resorption and reabsorption
–1,25 dihydroxyvitamin D (AKA dihydroxycholecalciferol - 1.25DHCC or calcitriol) - absorption

Front 6

How much calcium is needed in the diet?

Back 6

25mmol/day of which 6mmol is absorbed

Front 7

Where is calcium absorbed along the GIT?

Back 7

Mainly in duodenum and jejenum by two mechanisms
-cell mediated active transport controlled by 1.25 DHCC
-passive diffusion depending on Ca conc

Proportion of ingested Ca absorbed varies from 20-60%
1.25DHCC increases fractional absorption
-if dietary intake falls
-during growth, pregnancy and lactation

Front 8

What happens to calcium in the kidney?

Back 8

65 % reabsorbed in proximal tubule - coupled to bulk transport of solutes such as Na and water

Increased by PTH:
-20% reabsorbed in cortical thick ascending loop of Henle
-15% in DCT

Front 9

What is PTH and from where is it released?

Back 9

84 AA polypeptide produced by parathyroid glands

-Secretion regulated by FREE calcium sensed by calcium sensing receptors on parathyroid cells (quick response)
-Main ligand is calcium
-Serve as calciostat for calcium homeostasis
-As Ca increases PTH decreases, as Ca decreases PTH increases

Front 10

Where are calcium sensing receptors found in the body?

Back 10

-G protein coupled receptor found in:

-parathyroid cells - mediates effects of EC ionised Ca on PTH release
-Renal tubule - mediates effect of high peritubular ionised [Ca] to inhibit Ca reabsorption

Activators used clinically to reduce PTH secretion in patients with renal failure and parathyroid cancer

Disorders of this receptor can produce abnormalities in serum calcium concentrations

Front 11

What is the relationship between ionised Ca and PTH?

Back 11

Steep, inverse sigmoidal curve
•Small change in iCa causes significant change in PTH
•Midpoint gives sensitivity of parathyroid gland (CSR) to iCa
•Disorders of the CSR recognised.

Front 12

What are the effects of PTH?

Back 12

•Stimulates renal tubular calcium REABSORPTION
•Promotes bone RESORPTION
•Stimulates formation of 1,25 DHCC in kidney, which enhances calcium ABSORPTION from gut

Front 13

How is vitamin D synthesised

Back 13

?

Front 14

What are two major causes of hypocalcaemia?

Back 14

PTH problem
–Hypoparathyroidism – neck surgery, idiopathic, magnesium deficiency

Vitamin D problem
–Deficiency – malabsorption, little exposure to sunlight
–Renal disease – kidneys fail to make the active form DHCC

Front 15

What are two major causes of hypercalcaemia?

Back 15

PTH problem
–Hyperparathyroidism – adenoma of parathyroid gland
–Calcium increase and PTH increase

Malignancy – PTH related peptide – lung cancer, breast cancer, multiple myeloma
–Calcium increase and PTH suppressed

Vitamin D problem
–Inappropriate dosage

Front 16

Why does the body require phosphate?

Back 16

skeletal development and bone mineralisation

Composition of cell membranes, nucleotide structure, cell signalling

Front 17

Where is phosphate located in the body?

Back 17

85% of total body PO4 mineralised matrix of bone
•Rest predominantly intracellular – bound to lipids and proteins – organic
–Cell membranes, nucleic acids, enzyme cofactors, glycolytic intermediates, ATP

•Only 1% in EC fluids - 30% is inorganic – routinely measured

Front 18

Phosphate transport in/out of cells

Back 18

Phosphate shifts between organic phosphate pool and inorganic pool
Phosphate shifts in and out of cells
e.g. Insulin-mediated entry of glucose into cells after meals results in phosphate shifting into cells

So serum [PO4] # true PO4 stores

Front 19

What are the main organs involved in phosphate homeostasis?

Back 19

Kidney
Gut
Bone

Front 20

What are the main hormones involved in phosphate homeostasis?

Back 20

–Parathyroid hormone (PTH)
–Fibroblast Growth Factor 23 (FGF 23)
–1.25 dihydroxyvitamin D (1.25DHCC)

•ABSORPTION in intestine less rigidly regulated than Ca – entire small intestine – increased by 1.25 DHCC
•Plentiful in diet

Front 21

What is the role of the kidney in phosphate homeostasis?

Back 21

•15-20% phosphate is protein bound, rest filtered by kidney
•75% of filtered phosphate is reabsorbed in PCT and 5-20% in DCT
•PTH and FGF23 INHIBIT the reabsorption of phosphate by renal tubule

Front 22

Other points that influence serum phosphate

Back 22

Several factors influence serum values:
•Marked diurnal variation rhythm, nadir before noon, peak after MN - peak to nadir amplitude ~30%
•Dietary effects – rises post-prandially then falls due to effect of rise in insulin
•Marked age-related changes. Highest values in infancy when growth velocity high