11. Calcium Regulation Flashcards
Where is calcium found in the body?
Calcium found in functionally distinct pools in body;
- Bony skeleton: 99%
- Intracellular pool: ~1%
- Extracellular pool: ~0.1%
Describe calcium uptake
Only in = dietary calcium;
- dietary habits
- supplements
Intestinal absorption;
- absorbed across int epith cell’s brush border membrane
- TRPV6 channel proposed: k/o didn’t change uptake
- TRPM7 linked: k/o = strongly reduced Ca in serum/bones (prob for bulk intest uptake)
After cell uptake Ca bound to calbindin (vit D dependent Ca binding protein);
- transfers to cells ER
- transports to basal membrane on opposite side of cell (doesn’t enter cytosol/ICF)
Ca pumps (PMCA1) actively TP Ca into body;
- occurs primarily in duodenum when Ca intake low
- passive paracellular TP in jejunum + ileum when Ca intake high (independent of vit D level)
Active absorption from gut regulated by calcitriol in blood;
- increases rate of absorption
Why does Ca need to be regulated?
Excitable cells, e.g. neurons, v sensitive to changes in Ca+ conc;
Hypercalcemia = progressive depression of nervous system
Hypocalcemia = progressive excitation of nervous system
Where is phosphate found in the body?
- Bones: 85%
- ICF: 15%
- ECF: <1%
What role do the bones play in calcium homeostasis?
Bones serve as large reservoirs;
- release Ca when ECF conc decreases
- store excess Ca
Describe serum Ca
Ref range: 2.2-2.6mmol/L
Required for normal neuromuscular function
Only ~50% exists as free ions - rest mostly bound to albumin (bio-inactive)
- physiological functions depend on ionised Ca not the total Ca (inc bound)
List the circulating calcium fractions in the serum
50% ionised (free) - biologically active
40% protein-bound, non-diffusable - biologically inactive + not excreted
10% complexed with phosphate, bicarbonate + citrate
Describe Dr Sydney Ringers experiments on calcium
Experiments on calcium + frog heart contraction 1883
Recorded frog heart contractions when perfused with blood mixture;
- substituted blood for saline: amplitude of contractions declined
- when calcium chloride was added to the solution the contractions recovered to almost normal amplitude
Describe the findings in early publications on calcium ion concentration by McClean + Hastings 1934
“frog’s heart sensitive to changes in conc of Ca2+ but not to changes in conc of Ca2+ in non-ionised form”
Showed ionised/free Ca2+ correlated with heart contraction;
- protein/citrate-bound Ca2+ had no effect
Developed first assay for ionised/free Ca2+
Showed in blood this was closely regulated (humans: 1.18mmol/L)
What are the components of separated whole blood?
Plasma;
- if anticoagulant present: contains fibrinogen
Serum;
- no anticoagulant present
Clot;
- formed encapsulating cells
How is blood correctly collected + stored for calcium testing?
Preferred specimen for total Ca2+ = free flowing venous sample;
- serum
- lithium heparin-plasma
Avoid anti-coagulants, e.g. EDTA/oxalate, as bind Ca2+ tightly + interfere with measurement
Loss of CO2 increases pH = samples need to be collected anaerobically
Serum from sealed evacuated tubes can be used if clotting + centrifugation are done quickly (<30min) at room temperature
Describe the lab methods for Ca2+ measurement
Colorimetric;
- Ca2+ released from protein carrier by acidification if sample before dye-binding reaction
- ortho-cresophthaleine complexone (CPC) or arseno III dye forms complex with Ca2+
- CPC method uses 8-hydroxyquinoline to prevent Mg2+ interference
AAS (atomic absorption spectroscopy) is reference method for total Ca2+ but rarely used clinically
Commercial analysers use ISEs to measure free Ca2+;
- use membranes with molecules that selectively + reversibly bind Ca2+ ions
- as Ca2+ binds membranes, electric potential develops proportional to ionised Ca2+ conc
When measuring Ca2+ why and how do we adjust for albumin?
Ca2+ = metabolically active
40-50% of measured total Ca bound to albumin (inactive);
- serum albumin must be considered when assesing Ca2+
Labs use formula to adjust measured Ca2+ relative to albumin levels;
- “adjusted Ca” = approximation of metabolically active Ca2+
Adjusted calcium = measured calcium + 0.02 (40 - albumin conc)
Errors are greatest at extremes of albumin concentration + when there is a suspicion/evidence of acidosis/alkalosis
How does the reference range for calcium vary?
Total Ca2+ varies with age;
- higher in adolescence when bone growth most active
Ionised Ca2+ changes from day 1-3 of life then stabilises at relatively high levels with gradual decline through adolescence
Describe calcium balance + its consequences
Calcium balance: intake = output
Negative balance: output>intake = osteoporosis
Positive balance: intake>output = occurs during growth
Why is calcium considered essential?
We can’t synthesis it, must acquire through diet
Which organ systems are involved in calcium metabolism?
Skeleton
GI tract
Kidneys
Define calciotrophic hormone
Any hormone with a major role in bone growth + remodelling
List the main calciotrophic hormones
Parathyroid hormone (PTH)
Vitamin D (1, 25 dihydroxycholecalciferol)
Calcitonin (CT)
Parathyroid hormone related protein (PTHrP)
Describe the general pathway of calcium in the body beginning at ingestion
Ca2+ ingested
PTH promotes active vit D formation in kidney;
- vit D promotes absorption in small intestine
- unabsorbed Ca2+ is lost in faeces
Ca2+ lost in the urine at kidney;
- PTH promotes Ca2+ reabsorption from urine
Ca2+ removed from blood by osteoblasts in bone;
- PTH promotes Ca2+ release into blood by osteoclasts
- calcitonin inhibits Ca2+ release into blood by osteoclasts
Discuss PTH + its role in calcium homeostasis
Parathyroid hormone;
- peptide hormone
- manufactured in parathyroid glands behind thyroid
Normally tight feedback loop b/n PTH release + serum Ca2+;
- PTH release stimulated by fall in Ca2+ = acts to restore Ca2+
- preserve serum Ca2+ through actions on bone + kidney
Example of negative feedback control
How many parathyroid glands are there + what are the consequences of thyroid surgery?
4 parathyroid glands
Difficult to locate during thyroid surgery;
- total/subtotal thyroidectomy usually = parathyroid removal
Loss of 2 = usually no major physiologic impact
Loss of 3 = transient hypoparathyroidism
Any remaining parathyroid tissue: hypertrophy
How is PTH biosynthesis + secretion regulated by Ca2+?
Secretion determined chiefly by serum ionised calcium concentration through negative feedback inhibiting PTH gene transcription
Parathyroid cell CaSR (G-protein couple receptor) on surface bind extracell Ca
- high conc Ca initiates phospholipase C pathway via Gq G-protein
- hydrolyses PIP2 > liberates intracell messengers IP3 + DAG
IP3 + DAG (diacylglycerol) result in release of extracell Ca from intracell stores into cytoplasmic space
High extracell Ca -> increase in cyto Ca in parathyroid cells;
- inhibits fusion of vesicles containing granules of preformed PTH with cell membrane = inhibits release of PTH
What are the 4 main actions of PTH during low serum Ca2+ (ie when it is actively secreted)?
- BONE: INCREASED OSTEOCLAST ACTIVITY = MORE BONE RESORPTION/ REDUCED OSTEOBLAST ACTIVITY = LESS BONE DEPOSITION
- stimulates Ca2+ release;
- initial osteocyte mobilisation of Ca2+ from bone > ECF
- continued slow release of bone Ca2+ + phosphate from osteoblast breakdown of bone matrix
- also reduces osteoblast activity - KIDNEY: LESS URINARY CALCIUM EXCRETION = CONSERVATION OF Ca
- increases rate of Ca2+ reabsorption from renal tubules
- less excreted in urine - KIDNEY: MORE URINARY PHOSPHATE EXCRETION = PREVENTS HYDROXYAPATITE FORMATION = LESS BONE DEPOSITION
- increases urinary phosphate excretion
- lowers plasma phosphate
- reduces tendency for Ca2+ + phosphate to react (ppts) - KIDNEY
- upregulates transcription of 1-alpha hydroxylase for vit D activation in kidney
- increases rate of vit D conversion to active form calcitriol (1, 25-dihydroxycholecalciferol)
