Calcium, Phosphate & Magnesium Homeostasis Flashcards
What is the biochemistry of calcium?
What chemical is used to remove it from the blood?
it is a divalent cation - Ca2+
EDTA is a chemical that binds and holds on to minerals and metals
When they are bound, they cannot have any effects on the body and are removed
EDTA is used to lower blood levels of calcium when they have become dangerously high
For what reasons is calcium physiologically important?
- blood clotting
- muscle contraction
- neuronal excitation
- enzyme activity (Na/K ATPase, hexokinase etc.)
Why is calcium structurally important?
hydroxyapatite - Ca10(PO4)6(OH)2
this is the predominant mineral in bone
What is the total body calcium and how is it distributed?
total body calcium is around 1 kg
99% of this is located in bone
1% is intracellular
0.1% is extracellular
What is total plasma calcium?
How is this distributed?
total plasma calcium is 2.2 - 2.6 mmol / L
41% is bound to plasma proteins (predominantly albumin)
9% is complexed to anions (e.g. phosphate, citrate, bicarbonate)
50% is ionised “free” Ca2+ that is biologically active
What calcium levels define a medical emergency?
calcium < 1.6 or > 3.5 mmol / L
is a medical emergency and requires immediate treatment
What is the equation or total calcium?
total Ca = ionised Ca + bound Ca + complexed Ca
this is the total plasma calcium
What are the concentrations of ionised, protein-bound and complexed calcium in a healthy patient?
- ionised calcium - 1.2 mmol / L
- protein-bound calcium - 1.0 mmol / L
- complexed calcium - 0.2 mmol/L
total calcium = 2.4 mmol/L
What would the concentration of ionised, protein-bound and complexed calcium be in a patient with low albumin?
- ionised calcium - 1.2 mmol/L
- protein-bound calcium - 0.5 mmol /L
- complexed calcium - 0.2 mmol / L
total calcium - 1.9 mmol / L
What is the relationship between total calcium and albumin?
as the concentration of albumin increases, the total calcium also increases
What equation is used to correct calcium values for changes in albumin?
calcium values can be corrected for changes in albumin
adjusted Ca = total Ca + [(40 - Alb) x 0.025]
What is the reference range for adjusted calcium?
When is the equation not valid?
reference range for adjusted calcium is 2.2 - 2.6 mmol/L
equation is not valid if albumin is < 20 g/L
recommended measuring ionised calcium on a point-of-care blood gas analyser
Where is phosphate predominantly found?
PO43-
it is predominantly intracellular
What is the physiological importance of phosphate?
the P in ATP - it is the fuel for the body
involved in intracellular signalling
important in cellular metabolic processes e.g. glycolysis
What is the structural importance of phosphate?
it is involved in the backbone of DNA
component of hydroxyapatite
membrane phospholipids
severe deficiency of phosphate can be fatal
What is total body phosphorous?
How is it distributed?
total body phosphorous is 23 mol (700 g)
85% is within bone
14% is intracellular
1% is extracellular
How is extracellular phosphate distributed?
What is the reference range for blood phosphate?
adult reference range for phosphate is 0.8 - 1.5 mmol / L
70% of blood phosphorous is in its organic form and covalently bound (e.g. phospholipids)
30% is in the inorganic form as phosphate
What is normal calcium concentration?
calcium is normally tightly regulated
2.20 - 2.60 mmol / L
What are the 2 key controlling factors in homeostasis of calcium?
- parathyroid hormone
- vitamin D and metabolites
What is calcium homeostasis a result of?
- GI uptake
- bone storage
- renal clearance
Where and when is parathyroid hormone secreted?
PTH is secreted from the parathyroid glands in states of low calcium
magnesium plays a key role here
How does parathyroid hormone exert an effect in states of low calcium?
- PTH acts on bone to drive reabsorption of Ca and PO4
- PTH acts on the kidneys to increase reabsorption of Ca from the filtrate and increase excretion of PO4
- it also increases conversion of vitamin D to its active form in the kidneys
- this increases Ca and PO4 absorption from the gut
What is the net effect of PTH?
to increase serum calcium
and
decrease serum phosphate
How is PTH release affected by high and low calcium levels?
high calcium inhibits PTH release by negative feedback (via CaSR)
low calcium stimulates PTH release
PTH release is also stimulated (to a lesser extent) by high phosphate
What is the role of vitamin D in the intestine, bone, immune cells and tumour microenvironment?
intestine:
- increases absorption of Ca2+ and Pi
bone:
- increases bone mineralisation
immune cells:
- induces differentiation
tumour microenvironment:
- inhibits proliferation
- induces differentiation
- inhibits angiogenesis
For bone health what is a normal level of vitamin D?
25-OH Vitamin D < 75 nmol/L is deficient or depleted
25-OH Vitamin D > 75 nmol/L is sufficient
25-OH Vitamin D > 500 nmol/L suggests toxicity
What lifestyle factors affect vitamin D level?
- season
- latitude / climate
- clothing
- use of sunscreen
- time spent indoors / outdoors
What non-lifestyle factos affect vitamin D level?
- skin tone
- age
- diet
- body fat and BMI
- malabsorption
What are the 5 regulators of calcium and phosphate homeostasis?
- PTH
- Vitamin D
- FGF23
- calcitonin
- oestrogen
What is the role of FGF23?
it increases renal phosphate excretion
How does calcitonin work?
it opposes the effect of PTH by acting on osteoclasts to inhibit bone reabsorption
function is usually insignificant in the regulation of normal calcium homeostasis
What are common causes of hypocalcaemia?
- vitamin D deficiency
- inadequate dietary calcium intake
- hypoparathyroidism
- hypoalbuminaemia
- high phosphate (can complex with calcium`)
- spurious causes
What causes vitamin D deficiency?
- dietary / lack of sunlight / malabsorption
- liver or renal disease
What causes hypoparathyroidism?
- primary
- hypomagnesaemia
- pseudo-hypoparathyroidism (end-organ resistance to PTH)
What are the 2 spurious causes of hypocalcaemia?
- EDTA contamination
- citrate contamination
What are the signs and symptoms of hypocalcaemia?
- tetany
- paraesthesia in the extremities
- cramps
- convulsions
- psychosis
How may latent tetany be demonstrated?
by Chvostek’s sign or Trousseau’s sign
What are common causes of hypercalcaemia?
- hyperparathyroidism
- malignancy
- medications
- vitamin D excess
- hyperthyroidism
- bone disease / immobilisation
What is a common cause of hyperparathyroidism?
parathyroid adenoma
What types of malignancy would cause hypercalcaemia?
- tumours secreting PTHrp
- tumours secreting osteoclast-activating cytokines (with or without bone metastases)
- cells with 1a hydroxylase activity (activation of vit D) - e.g. lymphoma
What medications cause hypercalcaemia?
thiazides and lithium
What causes vitamin D excess?
over-supplementation
sarcoidosis (1a hydroxylase activity)
What are the signs and symptoms of hypercalcaemia?
stones:
- renal stones due to hypercalciuria, causing renal colic
bones:
- bone pain and osteoporosis (in cases of hypercalcaemia due to inappropriately high PTH)
moans:
- lethargy, fatigue, depression
groans (GI):
- abdominal pain, constipation, nausea, vomiting
hypercalcaemia also causes dehydration via renal resistance to ADH
What are the first line biochemical investigations for hypo- or hypercalcaemia?
- simultaneous measurement of Ca and PTH
- consider the adjusted calcium equation and look at albumin concentration
measure the ionised calcium on a blood gas analyser
- bone profile (adjusted calcium, phosphate, ALP)
- vitamin D
- magnesium
What are the 3 categories of causes of phosphate deficiency?
- low intake
- excess lossess
- ECF / ICF redistribution
Why might someone have a phosphate deficiency through low intake?
- malnutrition
- malabsorption
- alcoholism
Why might someone have phosphate deficiency due to excess losses?
- hyperparathyroidism
- renal tubular damage (Faconi syndrome)
- diarrhoea
Why might someone have a phosphate deficiency due to ECF/ICF redistribution?
- refeeding syndrome
- alkalosis
What are the signs and symptoms of phosphate deficiency?
- severe muscle weakness, respiratory muscle failure and rhabdomolysis
- haemolysis, thrombocytopenia and poor granulocyte function
- convulsions, coma, death
What will chronic phosphate deficiency cause in children and adults?
chronic phosphate deficiency will cause rickets in children and osteomalacia in adults
If confirmed, what is the treatment for acute phosphate deficiency?
oral phosphate or IV phosphate
treatment for acute phosphate deficiency is essential
What are common causes of hyperphosphataemia?
renal failure - acute kidney injury (AKI) or chronic kidney disease (CKD)
hypoparathyroidism
What are spurious causes of hyperphosphataemia?
What are most of the signs and symptoms due to?
- haemolysis
- delayed separation of sample
- assay interference
signs and symptoms are usually due to hypocalcaemia
What is the physiological importance of Magnesium (Mg2+)?
- cofactor for ATP
- neuromuscular excitability
- enzymatic function
- regulates ion channels
What is the structural importance of magnesium?
it comprises 0.5-1% of bone matrix
What is total body magnesium?
How is it distributed?
total body magnesium is 1.1 mol
54% is in bone
45% is intracellular
1% is extracellular
How is magnesium distributed in the blood?
What is the reference range for plasma magnesium concentration?
60% is ionised “free” Mg2+
25% is bound to plasma proteins - predominantly albumin
15% is complexed to anions e.g. phosphate, citrate, bicarbonate
reference range is 0.7 - 1.0 mmol / L
Where is homeostasis of magnesium carried out?
predominantly by the kidneys
How is homeostasis of magnesium by the kidneys carried out?
the mechanism for control of magnesium homeostasis is not completely understood
PTH release is stimulated by a decrease in magnesium and inhibited by an increase in magnesium
PTH release is magnesium-dependent, so severe hypomagnesaemia will inhibit PTH release and cause hypocalcaemia
What is hypomagnesaemia associated with?
In what types of patients is it more prevalent?
hypomagnesaemia is quite prevalent in hospitalised patients
its often associated with hypokalaemia, hyponatraemia, hypophosphataemia and hypocalcaemia
What are the categories of causes of magnesium depletion?
- inadequate intake
- renal loss
- GI loss
- redistribution into cells
- spurious causes
Why might someone have magnesium depletion due to inadequate intake?
- malnutrition (especially alcoholism)
- malabsorption
- total parenteral nutrition (IV)
Why might someone have magnesium depletion due to renal loss?
drugs:
- antibiotics - gentamicin / carbenicillin
- chemotherapy -esp. cisplatin
- diuretics
- FK506 (tacrolimus)
rare inherited disorders
Why might someone have magnesium depletion due to GI loss, redistribution into cells or spurious causes?
GI loss:
- diarrhoea
- PPIs
redistribution into cells:
- refeeding syndrome
spurious causes:
- EDTA contamination
What are the signs and symptoms of magnesium depletion?
- neuromuscular excitability - tremor, tetany, convulsions
- muscle weakness
- CNS - depression, psychosis
- cardiovascular - ECG changes, reduced contractility, arrhythmia
- GI - nausea, anorexia
- biochemical consequences - hypokalaemia, hypocalcaemia, with associated signs and symptoms
Why is hypermagnesaemia rare?
What usually causes it?
it is rare since the kidneys have a large capacity to excrete excess
it is usually iatrogenic - cardiac surgery, pre-eclampsia
