Endo 13: Calcium and phosphate regulation Flashcards
Relevance of vit D to calcium homeostasis
Vit D–> liver hydroxylated to 25-OH vit. D –> kidney to 1,25-OH vit. D
This hydroxlated from of vit D increases calcium and phosphate absorption from the gut
AND
maintains calcium in bone (difference to PTH!!)
AND
increases reabsorption of Ca2+ in kidney
NEGATIVE FEEDBACK ON PTH
How does parathyroid hormone work in calcium homeostasis
Kidneys increase retention of calcium
Bones to release calcium
The enzyme performing the second hydroxylation of vit D (1 alpha hydroxylase) in the kidney is regulated by PTH so you cna get more calcitriol
Outline regulation of phosphate levels
PO43- absorbed back into the blood from filtrate in the kidneys by Na+/PO43- symporter in PCT
PTH inhibits this transporter, increasing phosphate excretion and sodium excretion
FGF23 (derived from osteocytes) also inhibits this transporter, and also inhibits calcitriol, thus reducing phosphate absorption in the gut
Role of FGF23 in phosphate regulation
FGF23 from osteocytes inhibits reabsorption of phosphate from urine…..
FGF 23 inhibits calcitriol (which is involved in reabsorption in the gut!)
T/F FGF 23 reduced PO43- absorption from the kidney
T and also from the gut via reduced calcitriol
Outline regulatin of PTH secretion
Ca2+ binding to the calcium sensing receptor on parathyroid cell, inhibiting PTH release
Low Ca2+ will mean that the calcium sensing receptor isnt activated so you get more PTH
How is vit D produced
7-dehydrocholesterol (in skin) –> (with UV light cholecalciferol
cholecalciferol is then converted to calcitriol via liver and kidney
(other source of cholecalcferol is from the diet)
t/f 25 OH-D3 is biologically active
No… only the 1, 25 OH D3 is active…… converted from 25 OH D3 to 1 25 OHD3 by 1 alpha hydroxylase in the kidneys… REGULATED BY PTH!!!!!
Action of calcitriol
Ca++ absorption
in gut
Ca++ maintenance
in bone
Increased renal Ca++ reabsorption
Why doesnt Ca2+ just keep on increases
Becase calcitriol has negarive feedback on the PTH (as does high Ca2+, inhibiting PTH release)
Cause of vit D deficiency
Diet
Lack of sunlight
GI malabsorption
eg coeliac disease, inflam bowel disease,
Renal failure, Liver failure (due to hydroxylation)
Vitamin D receptor defects (autosomal recessive, rare, resistant to vitamin D treatment)
HOW DO CHANGES IN EC CALCIUM AFFECT NERVE AND SKELETAL MUSCLE EXCITABILITY?
AP in nerves and skel muscle needs high Na+ influx across cell membrane…..
High calcium (hypercalc.), ca2+ blocks Na+ influx, so LESS membrane excitability
LOW ec calcium (HYPOcalcaemia) = enables GREATER Na+ influx, so MORE membrane excitability
Normal serum ca2+
2.2–2.6mmol/L
Signs and symptoms of hypocalcaemia
Parasthesia (hands, mouth, feet , lips)
Convulsions
Arrhythmias
Tetany
[CATs go numb]
it sensitises excitable tissues (less Ca2+ competing with Na+) –? muscle cramps/tetany/tinglng
What is CHVOSTEK’S SIGN
Tap facial nerve just below zygomatic arch
Positive response = twitching of facial muscles
Indicates neuromuscular irritability due to hypocalcaemia
TROUSSEAU’S SIGN
Inflation of BP cuff for several minutes induces carpopedal spasm = neuromuscular irritability due to hypocalcaemia
Casues of hypocalcaemia
Vit. D defic.
Low PTH (surigcal,autoimmune or Mg defic. remember it’s Mg dependent!!)
PTH resistance (pseudohypoparathyroidism)
Renal failure
Impaired 1a hydroxylation
decreased production of 1,25(OH)2D3
Hypercalcaemia signs and symptoms
Stones, abdominal moans and
psychic groans
reduced neuronal excitability so atonal muscles
STONES (renal effect) –> Polyuria & thirst
Nephrocalcinosis, renal colic, chronic renal failure
Abdominal moans: GI effects (anorexia, nausea, dyspepsia, constipation, pancreatitis)
Psychic groans (Fatigue, depression, impaired concentration, altered mentation, coma (usually >3mmol/L)
Hypercalcaemia causes
Primary hyperparathyroidism
Malignancy – tumours/metastases often secrete a PTH-like peptide (paraneoplastic)
Conditions with high bone turnover (hyperthyroidism, Paget’s disease of bone – immobilised patient)
Vitamin D excess (rare)
Primary hyperparathyroidism diagnosis
Due to a busy parathyroid gland
HYPERCALCAEMIA
Low phosphate
Raised (unsuppressed- negative feedback doesn’t work) PTH
Hypercalcaemia of malignancy
Raised calcium Suppressed PTH (PTH like peptide instead!)
Define vit D defic.
lack of mineralisation in bone
ricets in kids and osteomalacia in adults
Softening of bone, bone deformity, proximal myopathy, pain
Treatment of primary hyperparathyroidism
PARATHYROIDECTOMY
Secondary hyperparathyroidism
Vitamin D deficiency –> low calcium (HYPOCALCAEMIA)
and
PTH INCREASES TO TRY TO NORMALISE SERUM CALCIUM
i.e. this is a NORMAL PHYSIOLOGICAL RESPONSE
Biochemical findings in vit D deficiency
Plasma [25(OH)D3] usually low (NB we don’t measure 1,25 dihydroxy vitamin D (1,25 (OH)2 D) to assess body vitamin D stores….bcause it’s hard to measure, 25 cholecalciferol is measured instead )
Plasma [Ca2+] low (may be normal if 2o hyperparathyroidism has developed)
Plasma [PO43-] low (reduced gut absorption)
[PTH] high (2o hyperparathyroidism)
Treatment of vit D def.
In patients with normal renal function Give 25 hydroxy vitamin D (25 (OH) D) Patient converts this to 1,25 dihydroxy vitamin D (1,25 (OH)2 D) via 1a hydroxylase Ergocalciferol 25 hydroxy vitamin D2 Cholecalciferol 25 hydroxy vitamin D3
In patients with renal failure - inadequate 1a hydroxylation, so can’t activate 25 hydroxyl vitamin D preparations
Give Alfacalcidol - 1a hydroxycholecalciferol… which is active vitamin D (very potent)
Cause and consequence of vitamin D excess
Can lead to hypercalcaemia and hypercalciuria due to increased intestinal absorption of calcium
Can occur as a result of:
- excessive treatment with active metabolites of vitamin D eg Alfacalcidol
- granulomatous diseases such as sarcoidosis, leprosy and tuberculosis (macrophages in the granuloma produce 1a hydroxylase to convert 25(OH) D to the active metabolite 1,25 (OH)2 D
