W3: Calcium, Magnesium & Phosphate Metabolism

Question 1

how are Ca & Mg important? - enzymatic

Answer 1

cofactor: clotting, phosphatases, phosphorylases

Question 2

how are Ca & Mg important? - structure

Answer 2

mineralisation of teeth & bones

Question 3

how are Ca & Mg important? - signalling

Answer 3

intracellular 2nd messenger
adenyl cyclase (cAMP)

Question 4

how are Ca & Mg important? - neuromuscular

Answer 4

muscle contraction
neuromuscular excitability
neurotransmitter release

Question 5

how is PO4 important?

Answer 5

Substrate for mineralisation – prod of hydroxyapatites

Metabolism of sugars & intermediates – especially 2,3DPG.

High energy phosphates, ATP, GTP

Acid-base – a way of excreting H+

Question 6

why is 2,3 DPG important?

Answer 6

Low PO4 reduces ability to form 2,3DPG

Low 2,3DPG moves Hb-O2 dissociation curve to left – increases binding of O2 by Hb

Diff at any given pO2 btwn Hb & Myoglobin (red) curve is less hence myoglobin less able to pull in O2

Result = inadequate O2 delivery to tissues

Question 7

what is so special about calcium?

Answer 7

Divalent Ca2+: Chelates into active sites and binding sites.

3CaCl2 + 2Na3PO4 -> 6NaCl + Ca3(PO4)2

At biological concs [Ca] x [PO4] or
[Ca] x [Oxalate] are close to solubility product -> Tendency to precipitate as stones & calcify tissues

Question 8

effect of Ca on aortic valve

Answer 8

calcification/stenosis
blockages

Question 9

calcium economy (bone)

Answer 9

1Kg calcium, 25,000 mmoles
100 mmol of this is ready exchangeable with ECF
Turnover 500 mmol/day
Most of Ca is structural – lifelong investment in bone strength

7.5 mmol/day bone resorption & formation

Question 10

bone structure

Answer 10

compact bone
trabecular (spongy) bone - metabolically active

Question 11

bone metabolic cycle

Answer 11

W/in trabecular bone, Osteocytes mature to:

Osteoclasts - resorb bone, releasing Ca, PO4 & degraded collagen

& then to

Osteoblasts - Lay down new, re- modelled bone. Raised alkaline phosphatase

Results in bone turnover.

Question 12

how does amount of bone mineral change over a person’s lifetime?

Answer 12

increase until late teenage yrs
decrease at ~50 yrs old

Question 13

what hormone regs calcium levels in blood

Answer 13

parathyroid hormone (PTH)

Question 14

too much calcium causes + form in what 2 places

Answer 14

calcium phosphate crystals
- in thin limb of loop of henle - get stuck
- in papilla - calcium oxalate deposits

Question 15

absorption of calc reg by

Answer 15

vit D

Question 16

bone in middle yrs vs aging bone

Answer 16

middle – steady state. Bone as source of mineral for homeostasis.

Aging bone = catabolism = negative calcium balance

bone loss reaches threshold where fractures – esp biologically and mechanically vulnerable locations e.g. neck of femur – become high risk. Importance of weight-bearing exercise

Question 17

name a metabolic bone disease

Answer 17

osteoporosis

Question 18

demographic affected by osteoporosis

Answer 18

avg age of menopause: 51 - assoc w osteoporosis
occurs when bone mineral density falls 2.5SD below main BMD for young female adult
15% women 50% had osteoporosis

Question 19

calcium economy - kidney

Answer 19

Filters 240 mmol/day
Reabsorbs 234 mmol/day, urine loss 6 mmol/day
Highly responsive to PTH to achieve tight homeostasis within very short time scales

Susceptible to damage by high levels & precipitation
Reduces ability to concentrate urine & polyuria

Question 20

renal stones

Answer 20

calcium-phosphate crystal initiate in loop of henle

Question 21

calcium economy - GI tract

Answer 21

Food intake 25 mmol/day
Secretions 6 mmol/day
Absorption 12 mmol/day
Faeces 19 mmol/day

Absorption facilitated by Vit D
Presence of fatty acids gives non-absorbed Ca soaps. (e.g. Pancreatitis, fat malabsorption)

Question 22

key molecules of economy

Answer 22

Parathyroid hormone (PTH)

Vitamin D, 25(OH) Calciferol
1,25(OH)2 Vitamin D (Calcitriol)

Question 23

measuring pth

Answer 23

competitive immunoassay
sandwich immunoassay

Question 24

PTH receptor

Answer 24

PTH - NH2 terminal 1-34 fragment binds to extracellular receptor site. Receptor is a trans-membrane adenyl cyclase.

Effector = intracellular adenyl-cyclase (Mg++ dependant)

Stimulates renal tubular Calcium reabsorption and Phosphate excretion
Secondarily stimulates 1 hydroxylation of Vit D

Question 25

hyperparathyroidism

Answer 25

Hyperparathyroidism: Uncontrolled production of PTH – approx 1:1000. Usually parathyroid adenoma (benign tumour with good differentiation, produces usual products of tissue but without normal feedback control.)

Bones continually dissolved: Fractures
Kidney retains calcium: High serum calcium
Dilute urine but high calcium filtered load leads to high urine calcium: Stones
Nerve function: Neuromuscular weakness
Psychiatric symptoms

Question 26

hypocalcaemia

Answer 26

Neuromuscular excitability
Tetany – muscle rigidity
If stimulates PTH response then get bone resorption and high phosphate.

Question 27

causes of hypocalcaemia

Answer 27

Hypoparathyroidism
Magnesium deficiency – reduced PTH release and
ineffective actions of PTH
Kidney failure Secondary hyperparathyroidism
Vitamin D deficiency:
Adults – osteomalacia
Children - rickets

Question 28

rickets

Answer 28

Poor mineralisation during
growth means bones are
weak under load. “Green”
bones in childhood bend
and on subsequent
mineralisation give
permanent deformity