Calcium Phosphate Homeostasis

Question 1

What tissues and hormones regulate Ca2+ and PO4 homeostasis?

Answer 1

Parathyroid glands secrete PTH to detect plasma levels
Kidneys: vitamin D activation and Ca2+/PO4 reabsorption
Gut: Ca2+ and PO4 uptake
Thyroid: Calcitonin synthesis to detect serum Ca2+ levels
Bone: storage of Ca2+ and PO4 and produces FGF-23

Question 2

What are the physiological roles of Ca2+?

Answer 2

Bone formation, growth and remodelling
Teeth formation
Muscle contraction
Nerve function
Enzyme co-factor
Intracellular 2nd messenger
Stabilisation of membrane potentials

Question 3

How is Ca2+ distributed throughout the body?

Answer 3

99% in the skeleton
1% intracellular
0.1% extracellular: plasma -> ionised or bound Ca2+
Bound Ca2+ to plasma proteins eg Albumin = provides adjusted Calcium levels which are measured

Question 4

What are the physiological roles of PO4?

Answer 4

Intracellular metabolism (ATP synthesis)
Phosphorylation (enzyme activation)
Phospholipids in membranes

Question 5

Talk about the parathyroid gland and hormones

Answer 5

4 glands located on superior surface of Thyroid gland - blood supply is independent so unaffected in thyroidectomy

Parathyroid glands responsible for sensing circulating Ca2+ concentrations by secretion of PTH from chief cells

PTH acts via GPCR (PTHR1)

Question 6

What’s the parathyroid hormone related peptide?

Answer 6

Made by many tissues - paracrine and autocrine function
Mimics PTH: binds to PTHR1 to elevate Ca2+ levels
Produced in some cancers so can cause hypercalcaemia
Doesn’t increase (1,25(OH)2D) levels

Question 7

Why are strong changes in Ca2+ levels dangerous?

Answer 7

Can cause arrhythmias and cardiac arrest

Question 8

What does PTH act on to have what effects?

Answer 8

Directly on bone: stimulate production or resorption
Directly on kidney: increase PO4 loss in urine, decrease Ca2+ loss in urine, promotes activity of 1a-OHase to activate Vitamin D
Indirectly on gut by activated Vitamin D for Ca2+ absorption

Question 9

What are 3 ways Ca2+ is absorbed in the GI tract?

Answer 9

Ca2+ uptake on luminal surface across brush border by TRPV6 proteins:

Active uptake and extrusion (by CaNa exchanger and CaATPase)

Paracellular transport bound to CaBP

Endocytosis and exocytosis of Ca2+-CaBP complex

Question 10

Where is the majority of Ca2+ absorbed?

Answer 10

All Ca2+ intake comes from the intestine, mostly duodenum/upper jejunum

Uptake facilitated by vitamin D
High serum Ca2+ -> paracellular uptake
Low serum Ca2+ -> TRPV6 + 1,25D

Question 11

What’s the role of Calcitonin, secreted by C cells of the Thyroid gland?

Answer 11

Inhibits bone resorption by preventing osteoclast action
Reduces reabsorption of Ca2+ and PO4 in the kidney

Regulated by circulating Ca2+: high Ca2+ sensed by CaSR increases levels of Calcitonin

Question 12

How is Ca2+ absorbed in the kidney?

Answer 12

Passively reabsorbed in PCT

PTH and Vitamin D up regulate TRPV5 in DCT

Question 13

What’s the role of Vitamin D?

Answer 13

Facilitates Ca2+ uptake in gut and Ca2+/PO4 reabsorption in the kidney
Cartilage production and bone mineralisation
Required for osteoblast and osteoclast differentiation
Increases bone remodelling
Regulates immune system (infection and inflammation)

Question 14

Outline Vitamin D synthesis

Answer 14

Converted from cholesterol on our skin by UV radiation
D2 and D3 from our diet

7-dehydro-cholesterol -> colecalciferol (D3) -> calcidiol (25(OH)D) in liver -> calcitriol, 1,25(OH)2D in kidney (by 1a-OHase) -> 24, hydroxyls inactivates it as it’s excreted in urine

Question 15

Outline the distribution of PO4

Answer 15

Actively reabsorbed by kidney; only excreted by kidney

Input = output as redistributed to tissues
84% ionised form

Question 16

Outline PO4 homeostasis in low PO4 levels

Answer 16

Low PO4 stimulates 1,25(OH)D synthesis (from 25(OH)D) to increase PO4 absorption in bone, reabsorption in kidney and bone resorption to release PO4 into serum

Question 17

What’s the role of FGF-23 and Klotho?

Answer 17

FGF-23 (produced by osteoclasts and osteoblasts) is cell surface signalling receptor that needs to bind to Klotho to work

FGF-23-Klotho complex inhibits 1a-OHase to inhibit Vitamin D to aid in reducing levels when they’re too high

FGF-23 is a phosphaturic hormone = increase PO4 in urine and reduce PO4 in blood

Counteracts actions of vitamin D-induced PO4 changes by inhibiting 1a-OHase and activating 24-OHase to inactive Vitamin D

Question 18

How is PO4 reabsorbed in the PCT and Intestine?

Answer 18

PCT: by Na+ dependent PO4 transport protein (NAPT2a and NAPT2c)
PTH and FGF-23 inhibits NAPT2a and NAPT2c to prevent PO4 reabsorption so it’s excreted in urine

Intestine: NPT2b is major transporter, increased by 1,25(OH)D and low dietary PO4

Question 19

What are signs/symptoms of Hypercalcaemia?

Answer 19

Poluria
Tiredness, confusion, depression, headaches
Nausea, vomitting
Muscle weakness
Abdominal pain
Loss of bone, kidney stones and ectopic calcification

Question 20

What are common causes of Hypercalcaemia?

Answer 20

Primary Hyperparathyroidism (increased PTH secretion)
Malignancy (PTHrP production)
Vitamin D excess, Granulomatous conditions

Question 21

How is Hypercalcaemia managed?

Answer 21

Aim is to restore Ca2+ levels and treat emergency symptoms
>3.4 mmol/L
Normal saline fluids
Furosemide loop diuretic
Calcitonin
Bisphosphonates
Oral phosphate
Long term: parathyroid gland surgery

Question 22

What are signs and symptoms of Hypocalcaemia?

Answer 22

Paraesthesia in fingers, toes, around mouth
Tetany (nerve fibres discharge spontaneously by low extracellular Ca2+)
Carpopedal spasm (wrist flexion and fingers drawn together)
Muscle cramps
Seizures

Question 23

What are some causes of Hypocalcaemia?

Answer 23

Hypoparathyroidism (insufficient PTH secretion)
Ca2+ deficiency either by vitamin D deficiency or low dietary uptake

Consequences: secondary hyperparathyroidism or Rickets/osteomalacia

Question 24

How is hypocalcaemia managed?

Answer 24

Acute neuromuscular symptoms: IV calcium gluconate
Oral Calcium (+ Vitamin D often)
Vitamin D

Question 25

What is osteomalacia?

Answer 25

Softening of bones by impaired bone metabolism (inadequate PO4, Ca2+, vitamin D levels)

Question 26

What’s secondary hyperparathyroidism?

Answer 26

Low serum Ca2+ stimulates PTH production and secretion (usually associated with kidney disease) - treatment is to increase Ca2+ levels

Question 27

What’s the significance of kidney disease to Ca2+/PO4 homeostasis?

Answer 27

Kidneys can’t respond to PTH
Can’t make active Vitamin D (1,25(OH)2D)
Unable to increase absorption of Ca2+ in gut or kidneys, can’t increase PO4 excretion in urine
Only way Ca2+ can be increased is from bone

Generally plasma Ca2+ decreases and PO4 levels increase