Calcium, Phosphate and Magnesium Homeostasis Flashcards
What is EDTA? What is its use?
A chemical that binds metal ions such as calcium, magnesium, lead and iron
What colour lid does a sample bottle containing EDTA have?
Purple
Function of EDTA in medicine?
- Prevent blood samples clotting
- Removes calcium and lead from the body
- Keeps bacteria from forming a biofilm
If a calcium sample is contaminated with EDTA, what can this result in?
This can cause a falsely low result; EDTA has bound to calcium
What tis the physiological importance of calcium?
- Blood clotting
- Muscle contraction
- Neuronal excitation
- Enzyme activity (Na/K ATPase, hexokinase etc.)
How is calcium involved in clotting?
Calcium ions (Ca2+) play a major role in the tight regulation of coagulation cascade that is paramount in the maintenance of haemostasis.
Other than platelet activation, calcium ions are responsible for complete activation of several coagulation factors, including coagulation Factor XIII (FXIII)3
Weight of calcium in human body?
Calcium accounts for 1 to 2 percent of adult human body weight.
Over 99 percent of total body calcium is found in teeth and bones.
Describe the distribution of calcium in the human body
99% bone
1% intracellular
0.1% extracellular
Regarding total plasma calcium:
a) What are normal ranges?
b) How is total plasma calcium distributed?
c) What form is biologically active?
d) What plasma protein is calcium predominantly bound to?
a) 2.2-2.6 mmol/L
b) 50% ionised ‘free’ Ca2+, 41% bound to plasma proteins, 9% complexed t anions
c) Ionised ‘free’ Ca2+
d) albumin
Above and below which levels for calcium is a medical emergency?
Calcium <1.6 or >3.5 mmol/L
How does low albumin levels affect calcium?
- Ionised calcium remains the same
- Protein-bound calcium decreases
- Total calcium decreases
- As albumin levels increases, so does total calcium
When should calcium levels be adjusted? Why?
The calcium level should be corrected in patients with low serum albumin levels:
Adjusted Ca = Total Ca + [(40 - Alb) x 0.025]
Why should calcium levels be adjusted in patients with low albumin?
Relationship between albumin and calcium isn’t valid at such a low value
What should be used for calcium measurement instead in patients with low albumin?
In these cases; recommend measuring ionised calcium on a point-of-care blood gas analyser.
Is phosphate predominantly intracellular or extracellular?
Intracellular
Physiological importance of phosphate?
o The P in ATP – our fuel!
o Intracellular signalling
o Cellular metabolic processes e.g. glycolysis
Structural importance of phosphate?
o Backbone of DNA
o Component of hydroxyapatite Ca₁₀(PO₄)₆(OH)₂
o Membrane phospholipids
Describe the distribution of calcium in the human body
85% bone
14% intracellular
1% extracellular
What are the 2 forms of phosphorus in the blood?
- Organic form (covalently bound) 70%
2. Inorganic form as phosphate 30%
If an analyte (e.g. calcium or phosphate) is above or below the reference range, what are the 3 main questions to ask?
- Is it due to increased/decreased intake?
- Is it due to increased/decreased output?
- Is it due to tissue redistribution/storage?
What are the 2 main controlling factors for calcium homeostasis?
o Parathyroid hormone (PTH)
o Vitamin D and metabolites
Where is PTH released from?
Released from 4 parathyroid glands in neck
What is PTH released in response to?
Low serum calcium
Which mineral is required for the secretion of PTH?
magnesium
PTH has 2 direct actions and 1 indirect action.
What are the 2 direct actions?
- Bone: drives resorption –> releases Ca and PO4 from bone mineral
- Kidney: increases reabsorption of Ca from filtrate but increases excretion of PO4
What is indirect action of PTH on kidneys?
Increases conversion of vitamin D to its active form –> this then increases Ca and PO4 absorption from the gut
What are the net effects of PTH on serum calcium and phosphate?
o Increase serum calcium
o Decrease serum phosphate (effect on kidneys is larger)
What is the feedback loop of Ca on PTH?
o High calcium inhibits PTH release by negative feedback (via CaSR)
o Low calcium stimulates PTH release
How does a high phosphate affected PTH release?
PTH release is also stimulated (to a lesser extent) by high phosphate
What is the active form of vitamin D?
1,25(OH)2
Calcium homeostasis is also affected by FGF23. What is this? How does it affect calcium?
FGF23 is a member of the fibroblast growth factor (FGF) family:
1) Suppresses activation of vitamin D by kidney
2) Increases renal phosphate excretion (i.e. suppresses reabsorption)
What is FGF23 secreted by?
Secreted by osteocytes in response to increase in active form of vitamin D
Calcium homeostasis is also affected by calcitonin.
How does calcitonin affect calcium levels?
What is calcitonin secreted by?
Secreted by c cells of thyroid gland in response to increased serum calcium
Opposes the effect of PTH by acting on osteoclasts to inhibit bone resorption
Function is usually insignificant in the regulation of normal calcium homeostasis
Calcium homeostasis is also affected by oestrogen.
What is effect of oestrogen on calcium?
Inhibits bone resorption; reduced bone density after menopause
What is calcium and phosphate homeostasis the result of a balance of?
o GI uptake
o Bone storage
o Renal clearance
What are the 2 ways humans get vitamin D?
- Obtained from diet
* Can be made from cholesterol by action of UV-B sunlight on skin
How is vitamin D synthesised in humans?
• Can be made from cholesterol by action of UV-B sunlight on skin
o This requires hydroxylation in liver (this is the main circulating form)
o This is further hydroxylated in kidney (this is now the active form)
What is the activation of vitamin D in the kidney stimulated by?
PTH
When measuring vitamin D levels, which form is measured? Why?
•The vitamin D hydroxylated by the liver is the one that is measured
o More stable
o Present in circulation at much greater concentration
What are the effects of vitamin D on the:
a) intestine?
b) bone?
c) immune cells
a) Increases absorption of Ca2+ and phosphate
b) Increases bone mineralisation
c) Induces differentiation
What are the effects of vitamin D on cancer?
Inhibits proliferation
Induces differentiation
Inhibits angiogenesis
What % of 4-18 year olds in the UK have insufficient vitamin D levels?
29%; recent resurgence of rickets
What factors affect vitamin D levels?
o Season o Latitude/climate o Clothing o Use of sunscreen o Time spent indoors/outdoors o Skin tone o Age o Diet o Body fat & BMI o Malabsorption (e.g. Crohn’s)
What are the 4 main causes of hypocalcaemia?
- Vitamin D deficiency
- Inadequate dietary calcium intake
- High phosphate (can complex with calcium)
- Hypoparathyroidism
What are the major causes of vitamin D deficiency?
o Dietary / lack of sunlight / malabsorption
o Liver or renal disease; causes deficiency of active vitamin D
Why can hypomagnesaemia lead to hypoparathyroidism?
Magnesium required for secretion of PTH
What are the spurious causes of hypocalcaemia?
o EDTA contamination
o Citrate contamination
What are the signs and symptoms of hypocalcaemia?
- Tetany
- Paraesthesia in the extremities
- Cramps
- Convulsions
- Psychosis
By which 2 signs can latent tetany be demonstrated?
- Chvostek’s sign
2. Trousseau’s sign
What is Trousseau’s sign?
Carpopedal spasm which involves flexion of wrist, thumb and MCP joints along with hyperextension of the IP joints when blood pressure cuff is inflated
What is Chvostek’s sign?
Twitching of the facial muscles in response to tapping over the area of the facial nerve
Contamination of blood specimens with potassium EDTA is a major problem for the Clinical Biochemistry department.
What are the effects of EDTA contamination?
Increased potassium- leading to an invalid interpretation of potassium status.
Decreased calcium, magnesium and alkaline phosphatase
Why is potassium EDTA the anticoagulant primarily used?
The cellular components and morphology of the blood
cells are preserved and is the recommended anticoagulant for haematology.
Clinical Case 1:
- Potassium is high
- Adjusted calcium is low
- Alk Phos is low
- Magnesium is low
What does this suggest?
• This sample has been contaminated with EDTA
o Anticoagulant is K+ EDTA; explains high potassium
o EDTA has collated the calcium and the magnesium
o Alk Phos is low; EDTA has collated the zinc and magnesium which are essential for this enzyme’s activity
In a patient with chronic renal disease describe the levels of:
a) urea?
b) creatinine?
c) active vitamin D?
d) phosphate?
a) elevated
b) elevated
c) low
d) high
As calcium levels fall, how does this affect PTH?
PTH levels should increase
When are reference ranges for PTH only applicable?
When calcium is in the normal range; if you have a low calcium, a PTH above the reference range is appropriate
Why are vegans at higher risk of low calcium and high PTH?
Likely due to vitamin D deficiency and low calcium intake
Why can patients experience hypoparathyroidism post thyroidectomy?
Removal of thyroid glands may also remove parathyroid tissue
What does a low adjusted calcium AND a low PTH indicate?
Hypoparathyroidism
What does a low adjusted calcium and a high PTH indicate?
Vitamin D deficiency?
What are the 2 most common causes of hypercalcaemia?
- Hyperparathyroidism (e.g. parathyroid adenoma secreting PTH)
- Malignancy
What are the 3 ways in which malignancy can cause hypercalcaemia?
- Tumours secreting PTHrp
- Tumours secreting osteoclast-activating cytokines (with or without bone metastases)
- Cells with 1α hydroxylase activity
How can tumours secreting PTHrp result in hypercalcaemia?
PTH related peptide; has similar action on bone as PTH
How can tumours secreting osteoclast-activating cytokines result in hypercalcaemia?
Causes increase in bone resorption
How can cells with 1α hydroxylase activity result in hypercalcaemia?
Causes activation of vitamin D; increase calcium absorption from gut) e.g. lymphoma
Which medications can lead to hypercalcaemia?
Thiazides, lithium
How can vitamin D levels lead to hypercalcaemia?
Vitamin D excess (e.g. over-supplementation)
What is sarcoidosis? How can it affect calcium levels?
A disease involving abnormal collections of inflammatory cells that form granulomas.
Cells have 1α hydroxylase activity; key enzyme in vitamin D metabolism –> increased calcium absorption from intestine and reabsorption in kidney
What is effect of 1α hydroxylase activity?
Key enzyme in vitamin D metabolism –> increased calcium absorption from intestine and reabsorption in kidney
What is effect of hyperthyroidism on calcium level?
Can cause hypercalcaemia
What are the signs and symptoms of hypercalcaemia?
Stones, bones, moans, groans
Explain ‘stones, bones, moans and groans’ behind hypercalcaemia?
Stones: renal stones due to hypercalciuria, causing renal colic
Bones: Bone pain & osteoporosis (due to inappropriately high PTH)
Moans: Lethargy, fatigue, depression
Groans: (GI) Abdominal pain, constipation, nausea, vomiting
Why can hypercalcaemia also cause dehydration?
High calcium causes renal resistance to ADH –> increase in urine production
What would the results of PTH and calcium be in metastatic small cell lung cancer?
hypercalcaemia of malignancy:
high adjusted Ca
PTH is appropriately suppressed
What would the results of PTH and calcium be in a parathyroid adenoma?
Primary hyperparathyroidism:
- hypercalcaemia
- inappropriately high PTH
What are the initial investigations for hypo- or hypercalcaemia?
Simultaneous measurement of Ca & PTH –> Is PTH appropriate or inappropriate for adjusted calcium?
What are the investigations for hypo- or hypercalcaemia?
- Simultaneous measurement of Ca & PTH
- Consider the adjusted calcium equation - look at the albumin concentration; Measure the ionised calcium on a blood gas analyser
- Bone profile (adjusted calcium, phosphate, ALP)
- Vitamin D
- Magnesium
When conducting a bone profile in hypo- or hypercalcaemia, what could a high ALP indicate?
o Elevated ALP may indicate increased turnover of bone
o ALP may also be from the hepatobiliary system; be careful
What are the 3 categories of causes of phosphate deficiency?
- Low intake
- Excess losses
- ECF/ICF redistribution
What can cause a low intake of phosphate?
o Malnutrition
o Malabsorption
o Alcoholism
What can cause excess losses of phosphate?
o Hyperparathyroidism
o Renal tubular damage (Fanconi syndrome)
o Diarrhoea
How can hyperparathyroidism cause excess phosphate loss?
PTH drives calcium resorption but phosphate excretion at kidney
What is Fanconi syndrome?
A syndrome of inadequate reabsorption in the proximal renal tubules of the kidney.
How can Fanconi syndrome affect phosphate levels?
Excess loss of phosphates as cannot be reabsorbed
What can cause ECF/ICF redistribution of phosphate?
o Refeeding syndrome
o Alkalosis
How can alkalosis affect phosphate levels?
Rise in pH stimulates glycolytic pathway which requires phosphate (so phosphate moves inside cells)
What is the most common cause of hypophosphatemia?
Alcoholism
Signs and symptoms of phosphate deficiency?
- Haemolysis, thrombocytopenia and poor granulocyte function
- Severe muscle weakness, respiratory muscle failure and rhabdomyolysis
- Convulsions, coma, death
- Chronic phosphate deficiency will cause rickets (children) / osteomalacia (adults)
Why can phosphate deficiency lead to muscle problems?
Adequate phosphate is essential for ATP
What is rhabdomylosis?
Rhabdomyolysis is a serious syndrome due to a direct or indirect muscle injury. It results from the death of muscle fibres and release of their contents into the bloodstream. This can lead to serious complications such as renal failure. This means the kidneys cannot remove waste and concentrated urine.
Why can chronic phosphate deficiency cause rickets (children) / osteomalacia (adults)?
Due to inadequate bone mineralisation
If confirmed, what is the treatment for acute phosphate deficiency?
o Oral phosphate
o IV phosphate
What is the most common cause of hyperphosphataemia?
Renal failure; either AKI or CKD
As the GFR falls toward CKD stages 4-5 (low), hyperphosphatemia develops from the inability of the kidneys to excrete the excess dietary intake.
Effect of PTH on phosphate?
PTH inhibits renal phosphate reabsorption
Hypoparathyroidism effect on phosphate?
Causes hyperphosphataemia
What are the spurious causes of hyperphosphataemia?
Phosphate has a much higher conc inside cells than in the plasma:
- Haemolysis: phosphate will appear to be higher in a haemolysed sample as phosphate has leaked out of blood cells
- Delayed separation of sample; phosphate will appear to be higher in an older sample as phosphate has leaked out of blood cells
- Assay interference e.g. Myeloma; high conc of antibodies in patient serum can cause interference with assay
How will contamination of sample of Mg with EDTA affect result?
contamination will result in low result
Physiological importance of Mg in the body?
o Cofactor for ATP – our fuel!
o Neuromuscular excitability
o Enzymatic function
o Regulates ion channels
Which plasma protein is Mg predominantly bound to in the blood?
Albumin
How do magnesium levels affect PTH?
PTH release is stimulated by a decrease in magnesium and inhibited by an increase in magnesium (but calcium is a much more potent stimulus)
BUT PTH release is magnesium-dependent
How will severe hypomagnesaemia affect PTH?
Will inhibit PTH, causing hypocalcaemia
Hypocalcaemia will be resistant to supplementation unless magnesium is replenished
Causes of hypomagnesaemia?
- Inadequate intake
- Renal loss
- GI loss
- Redistribution into cells
- Spurious causes (EDTA)
Which drugs can cause renal loss of magnesium?
o Drugs; nephrotoxic medication o Antibiotics - gentamicin / carbenicillin o Chemotherapy, esp. cisplatin o Diuretics o FK506 (Tacrolimus)
How can refeeding syndrome lead to hypomagnesaemia / hypokalaemia / hypophosphataemia?
- During prolonged restriction of carbohydrate intake, insulin is decreased and glucagon is increased –> fat and proteins are metabolised to produce energy
- This results in intracellular loss of electrolytes; potassium, phosphate and magnesium without the serum levels dropping much
- Upon carbohydrate intake, insulin is released and glycolysis is kickstarted; requires potassium, phosphate and magnesium to move into cells along with glucose, leaving a markedly reduced concentration in extracellular fluid
- Drop in minerals can cause many problems; heart and respiratory problems
Why is hypermagnesaemia rare?
since kidneys have a large capacity to excrete excess
Why is hypermagnesaemia usually iatrogenic?
o Cardiac surgery; cardio-protective
o Pre-eclampsia; prevents fits
