Calcium Phosphate Homeostasis Flashcards
What tissues and hormones regulate Ca2+ and PO4 homeostasis?
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
What are the physiological roles of Ca2+?
Bone formation, growth and remodelling Teeth formation Muscle contraction Nerve function Enzyme co-factor Intracellular 2nd messenger Stabilisation of membrane potentials
How is Ca2+ distributed throughout the body?
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
What are the physiological roles of PO4?
Intracellular metabolism (ATP synthesis)
Phosphorylation (enzyme activation)
Phospholipids in membranes
Talk about the parathyroid gland and hormones
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)
What’s the parathyroid hormone related peptide?
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
Why are strong changes in Ca2+ levels dangerous?
Can cause arrhythmias and cardiac arrest
What does PTH act on to have what effects?
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
What are 3 ways Ca2+ is absorbed in the GI tract?
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
Where is the majority of Ca2+ absorbed?
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
What’s the role of Calcitonin, secreted by C cells of the Thyroid gland?
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
How is Ca2+ absorbed in the kidney?
Passively reabsorbed in PCT
PTH and Vitamin D up regulate TRPV5 in DCT
What’s the role of Vitamin D?
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)
Outline Vitamin D synthesis
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
Outline the distribution of PO4
Actively reabsorbed by kidney; only excreted by kidney
Input = output as redistributed to tissues
84% ionised form
Outline PO4 homeostasis in low PO4 levels
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
What’s the role of FGF-23 and Klotho?
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
How is PO4 reabsorbed in the PCT and Intestine?
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
What are signs/symptoms of Hypercalcaemia?
Poluria
Tiredness, confusion, depression, headaches
Nausea, vomitting
Muscle weakness
Abdominal pain
Loss of bone, kidney stones and ectopic calcification
What are common causes of Hypercalcaemia?
Primary Hyperparathyroidism (increased PTH secretion)
Malignancy (PTHrP production)
Vitamin D excess, Granulomatous conditions
How is Hypercalcaemia managed?
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
What are signs and symptoms of Hypocalcaemia?
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
What are some causes of Hypocalcaemia?
Hypoparathyroidism (insufficient PTH secretion)
Ca2+ deficiency either by vitamin D deficiency or low dietary uptake
Consequences: secondary hyperparathyroidism or Rickets/osteomalacia
How is hypocalcaemia managed?
Acute neuromuscular symptoms: IV calcium gluconate
Oral Calcium (+ Vitamin D often)
Vitamin D
What is osteomalacia?
Softening of bones by impaired bone metabolism (inadequate PO4, Ca2+, vitamin D levels)
What’s secondary hyperparathyroidism?
Low serum Ca2+ stimulates PTH production and secretion (usually associated with kidney disease) - treatment is to increase Ca2+ levels
What’s the significance of kidney disease to Ca2+/PO4 homeostasis?
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
