Calcium and phosphate homeostasis Flashcards
What is the role of the parathyroid glands in Ca2+ and PO4 homeostasis?
- Detect plasma levels of Ca2+ and PO4
- Produce and secrete parathyroid hormone
What is the role of the kidneys in Ca2+ and PO4 homeostasis?
- Ca2+ and PO4 reabsorption from filtrate
- Site of vitamin D activation
What is the role of the gut in Ca2+ and PO4 homeostasis?
Uptake of Ca2+ and PO4
What is the role of the thyroid in Ca2+ and PO4 homeostasis?
Calcitonin synthesis
What is the role of bone in Ca2+ and PO4 homeostasis?
- Storage of Ca2+ and PO4
- Produces fibroblast growth factor
What are the physiological roles of calcium?
- Bone and teeth formation and remodelling
- Muscle contraction
- Nerve function
- Enzyme co-factor
- Intracellular second messenger
- Stabilisation of membrane potentials
What are the roles of parathyroid hormone?
What stimulates its production?
Stimulated by low Ca2+
- Alters 1aOHase to convert 25(OH)D to 1,25(OH)2D in the kidney
- Stimulates increased reabsorption of Ca2+ in the kidney
- Stimulates bone resorption and Ca2+ release from bones.
What are the actions of active vitamin D (1,25(OH)2D)?
- Stimulates Ca2+ and PO4 reabsorption in kidneys
- Increases Ca2+ uptake in gut
- Stimulates bone resorption and release of Ca2+
- Required for osteoblast and osteoclast differentiation
- Regulates immune system
- Increases bone remodelling by promoting resorption
- Essential for cartilage production and bone mineralisation
What are the actions of calcitonin?
What is it synthesised by?
Synthesised by C-cells (neuroendocrine parafollicular cells) in the thyroid gland.
- Acts via g-protein linked receptor
- Inhibits bone resorption by preventing osteoclast activity
- Decreases reabsorption of PO4 and Ca2+ in the kidneys
Which hormones regulate Ca2+ reabsorption from filtrate in the kidneys?
Parathyroid hormone (stimulates)
Vitamin D (stimulates)
Calcitonin (inhibits)
What is the role of the parathyroid glands?
Detect circulating Ca2+ levels
Where is parathyroid hormone produced?
Chief cells in the parathyroid glands
How do calcium sensing receptors in the parathyroid gland stimulate or suppress production of PTH?
When there is sufficient or excess calcium, it is able to bind to the calcium sensing receptor.
High Ca2+:
- Binding to receptor causes activation of phospholipase C which suppresses PTH secretion and gene expression.
- G-protein signalling from the receptor also inhibits adenylate cyclase which then reduces CAMP causing suppression of PTH production.
Low Ca2+:
- Decreased binding to calcium receptor prevents the inhibition of adenylate cyclase; increased CAMP is produced which stimulates production and secretion of PTH.
What can bind to and activate Parathyroid hormone receptor 1 (PTHR1)?
Parathyroid hormone and Parathyroid Hormone Related Peptide
Both have same effect
What are the actions of parathyroid hormone related peptide? (PTHrP)
- Paracrine and autocrine action
- Mimics PTH, binds to PTHR1→ Increases Ca2+ in plasma
- Regulates endochondral bone formation/mineralisation
- Produced by some cancers: hypercalcaemia
- Does not increase activation of vit D
- Calcium regulation in foetus and lactation
How does bone buffer Ca2+ and PO4?
Resorption releases Ca2+ and PO4
Formation deposits Ca2+ and PO4
How is calcium absorbed in the gut in high and low levels?
High levels of Ca2+:
- Paracellular route (when vitamin D levels are low because of high calcium)
Low levels of Ca2+:
- Low levels of Ca2+ triggers Vit D activation
- Vitamin D activates calcium channels (TRPV6) to upregulate calcium absorption.
What are the two routes of active reabsorption of Ca2+ in the GI tract?
Active uptake and extrusion:
- Ca2+ enters activated Ca2+channels (TRPV6) on the luminal membrane of GI epithelial cells.
- Binds to Calcium Binding Protein (CaBP) inside the cell.
- Transported out of the basolateral membrane of the cell via ATPase or Ca2+/Na+ exchanger
Endocytosis and Exocytosis:
- Calcium enters the cell via TRPV6 on the luminal membrane.
- Taken up into vesicles along with CaBP
- Ca2+-CaBP complex Released from the basolateral membrane via exocytosis.
How does vitamin D upregulate absorption of Ca2+?
- Increases production and translocation of TRPV6 and insertion into the luminal membrane.
- Increases available CaBP
- Increases transport mechanisms (ATPase, Ca2+/Na+ transporters)
What are the 2 methods of calcium reabsorption in the kidney?
Where do they occur?
Passive:
- Unregulated paracellular transport.
- Proximal convoluted tubule (60-70%)
- Tall ascending loop of Henle (20-25%)
Active:
- Regulated by Vit D, PTH, calcitonin
- Distal convoluted tubule (5-10%)
- Collecting duct (0.5-1%)
How is Ca2+ reabsorbed in the distal convoluted tubule of the kidney?
- Paracellular by osmosis
- PTH and Vit D upregulate TRPV5 channels on the luminal membrane and basolateral Ca2+ transporters
- Enters the cell via TRPV5, binds to CaBP and exits the cell via ATPase and Ca2+/Na+ transporters
How is vitamin D synthesised and activated?
UV light converts 7-dehydroxycholesterol to colecalciferol (1aOHase) in the skin
1aOHase converts 25(OH)D (inactive vitamin D produced by liver) into 1,25(OH)2D (active vitamin D)
Excess 1,25(OH)2D is inactivated by 24hydroxylase and excreted in urine.
What are the physiological roles of phosphate?
- Intracellular metabolism (e.g. ATP synthesis)
- Phosphorylation (e.g. enzyme activation)
- Phospholipids in membranes
How are phosphate levels regulated?
Low PO4:
- Stimulates activation of 1aOHase which then activates vitamin D
- Stimulates release of klotho which is also activated by 1aOHase
Active vitamin D increases reabsorption of PO4 in kidneys and gut, as well as PO4 (and Ca2+) release from bone through resorption.
Also causes production of FGF-23 (fibroblastic growth factor 23) in bone.
Negative Feedback:
- High PO4 causes FGF-23 and klotho to bind as a complex:
- Inhibits 1aOHase to prevent Vit D activation
- Increases 24hydroxylase to inactivate active Vit D
- Inhibits PO4 reabsorption in the kidneys by inhibiting NPT2a and NPT2c phosphate transporters.
How is phosphate absorbed in the kidney?
How is this stimulated and inhibited?
Through NPTC2a and NPTC2c transporters
- Stimulated by active vitamin D
- Inhibited by FGF-23-klotho complex and PTH
How is phosphate absorbed in the gut?
How is this stimulated and inhibited?
Through NPT2a
- Stimulated by low levels of PO4 and active vitamin D
- Inhibited by high levels of dietary PO4
What are the common causes of hypercalcaemia?
Primary hyperparathyroidism:
- Increased PTH secretion by parathyroid glands causes increased Ca2+
- Usually caused by benign tumour of parathyroids
Malignancy:
- E.g. breast or lung cancer; tumours produce PTHrP which mimics PTH.
What are the symptoms of hypercalcaemia?
- Polyuria/polydipsia
- Tiredness/confusion
- Headaches
- Depression
- Nausea and vomiting
- Constipation
- Muscle weakness
- Abdo pain
- Cardiac arrhythmias: decreased QT interval (severe cases)
- Chronic= bone loss, kidney stones, ectopic calcification
How is hypercalcaemia treated?
- IV fluids + loop diuretic
- Calcitonin
- Bisphosphonates
- Oral phosphate
- Parathyroid surgery (if long term)
What are the common causes of hypocalcaemia?
Hypoparathyroidism (low PTH)
Calcium deficiency
- Usually caused by vitamin D deficiency
- Low dietary calcium intake
How is hypocalcaemia treated?
Acute (neuromuscular symptoms): IV calcium gluconate
Hypoparathyroidism:
- Limited options: lifelong vitamin D supplements, high Ca2+ diet, Ca2+ supplementation
Calcium deficiency:
- Vitamin D deficiency: supplements (colecalciferol-inactive form)
- Active form causes hypercalcaemia: can only be given to renal failure pts.
- Low dietary intake: high Ca2+ diet, supplements
What are the symptoms of hypocalcaemia?
- Paraesthesia (fingers, toes and around mouth usually)
- Tetany
- Carpopedal spasm
- Seizures
- Increased QT interval +/- heartblock/VF (severe cases)
What is secondary hyperparathyroidism?
Caused by hypocalcaemia
Usually caused by kidney disease:
- Kidneys can’t respond to PTH so can’t produce vit D
- Can’t increase absorption of Ca2+ or PO4 from kidneys or gut
- Can’t increase PO4 excretion
- =Gland enlarges and produces unregulated amounts of PTH causing hypercalcaemia
How is secondary hyperparathyroidism caused by kidney disease treated?
- Increase Ca2+ levels
- Calcimimetics
- Parathyroid surgery
What would the following blood results indicate:
Low Ca2+ and high PTH
Low Ca2+ and low/normal PTH
High Ca2+ and high PTH
High Ca2+ and low PTH
Normal Ca2+ and high PTH
Low Ca2+ and High PTH =
- PT responding correctly, hypocalcaemia
Low Ca2+ and low/normal PTH =
- Probable hypoparathyroidism
High Ca2+ and high PTH =
- Hyperparathyroidism (imagine to ?cause)
High Ca2+ and low PTH =
- PT responding correctly, ?cause of high Ca2+
Normal Ca2+ and high PTH =
- Mild hyperparathyroidism
