[W2] Calcium, Phosphate and Magnesium Metabolism Flashcards
Where is the majority of calcium stored?
99% in the bone/skeleton.
What percentage of calcium is stored intracellularly?
1%
What percentage of calcium is stored extracellularly?
0.1%
How is extracellular calcium mainly stored?
It is primarily bound to plasma proteins, especially albumin.
What else is calcium in the extracellular space complexed with?
Some calcium is complexed with small anions.
How can calcium levels be measured?
In the lab or on a point-of-care device.
What are some methods for measuring calcium?
- Spectrophotometric methods (e.g., metallochromic indicators like 5-nitro-5’-methyl-BAPTA, o-cresolphthalein, arsenazo III).
- Ion-selective electrodes (primarily for ionized calcium on blood gas instruments).
What is the reference range for adjusted calcium in adults?
2.20-2.60 mmol/L.
What calcium level indicates hypocalcemia?
Less than 2.20 mmol/L.
What calcium level indicates hypercalcemia?
Greater than 2.60 mmol/L.
Why is adjusted calcium calculated?
Because calcium is largely bound to albumin, and the adjusted calcium accounts for this.
What is the standard equation for adjusted calcium?
Adjusted calcium = measured calcium + ((40 - albumin) x 0.02).
How should labs ideally establish their own adjusted calcium equation?
Labs should establish their own equation based on their own population data.
Where is the majority of phosphorus found in the body?
85% in the bone, 14% in cells, 1% in the blood.
What are some functions of phosphorus?
- Bone mineralization.
- Formation of ATP from ADP.
- Synthesis of nucleic acids.
- Intracellular metabolic pathways.
- Phospholipids.
- Tissue oxygenation.
- Buffer in urine.
- Enzyme cofactor.
- Signaling.
How is phosphorus mainly measured in the lab?
Spectrophotometrically, where phosphate combines with an indicator like ammonium molybdate.
What can increase phosphorus levels in serum samples?
A delay in centrifugation and hemolysis, both due to the release of phosphorus from inside red blood cells.
What is the reference range for phosphorus in adults?
0.8-1.5 mmol/L.
What is the primary function of magnesium?
It acts primarily as an enzyme cofactor.
What are other functions of magnesium?
- Energy metabolism.
- Membrane stabilization.
- Neuromuscular excitability.
- Protein and nucleic acid synthesis.
- Utilization of ATP.
How is magnesium typically measured in the lab?
Spectrophotometrically, by reaction with metallochromatic indicators like Xylidyl blue, calmagite, or chlorophosphanozo III, either measuring an increase or decrease in a colored product.
What is the reference range for magnesium in adults?
0.7-1.0 mmol/L.
What are the major hormones involved in calcium and phosphate regulation?
- PTH (Parathyroid Hormone).
- Vitamin D.
What other hormones are involved in calcium and phosphate regulation?
- PTHrp (Parathyroid Hormone-related Protein).
- Calcitonin.
- FGF23 (Fibroblast Growth Factor 23) for phosphate regulation.
Where is parathyroid hormone (PTH) produced?
In the parathyroid glands, located in the neck.
How does PTH sense calcium levels?
It directly senses free calcium (Ca) levels in the blood.
What happens when calcium levels are low?
Low calcium levels increase PTH production and secretion.
What happens when calcium levels are high?
High calcium levels inhibit PTH production and secretion.
What are the effects of PTH on bone?
PTH causes osteolysis (breakdown of bone) and increases bone resorption, releasing calcium and phosphate from the bone.
What are the effects of PTH on the kidneys?
- PTH increases calcium reabsorption in the kidneys, reducing renal loss of calcium.
- It inhibits phosphate reabsorption, causing phosphate wasting or loss.
How does PTH activate vitamin D?
PTH activates vitamin D (more details on this in the next slide).
What other factors control PTH secretion?
Magnesium (low magnesium inhibits PTH release).
1,25-dihydroxyvitamin D.
Where is PTH-related protein (PTHrp) synthesized?
In tissues such as keratinocytes and the placenta.
What is the role of PTHrp?
It binds to the PTH receptor.
What condition is PTHrp primarily associated with?
It is the principal mediator of hypercalcemia associated with malignancy, as it is released from tumor cells.
Does PTHrp cross-react in PTH assays?
No, it does not cross-react in PTH assays.
Why is PTHrp rarely measured?
It is very unstable and rarely provides additional information about the cause of hypercalcemia.
How is vitamin D mainly circulated in the body?
It circulates bound to globulin or vitamin D binding protein.
What controls the production of 1,25-dihydroxyvitamin D?
The production by 1-alpha-hydroxylase in the kidney is controlled by PTH, phosphate and calcium concentration, and vitamin D itself through negative feedback.
What are the actions of vitamin D on the GI tract?
It stimulates the absorption of both calcium and phosphate from the gut.
What are the actions of vitamin D on bone?
It increases bone resorption, releasing calcium and phosphate.
What are the actions of vitamin D on the kidneys?
It inhibits its own synthesis and stimulates its metabolism.
What effect does vitamin D have on the parathyroid?
It inhibits the synthesis and secretion of PTH through a specific receptor.
What method is primarily used for measuring vitamin D?
Immunoassay.
What other method is available for measuring vitamin D?
Mass spectrometry methods.
What is a limitation when measuring vitamin D?
It is important that both the D2 and D3 forms of vitamin D are detected.
What method is primarily used for measuring PTH?
Immunoassay.
What is a limitation when measuring PTH?
Different assay generations measure different fragments or parts of the PTH molecule.
What is the classic mnemonic for the clinical features of hypercalcemia?
“Bones, stones, moans, and groans” (Bone pain, renal stones, abdominal pain, depression/psychological features).
What are common clinical features of hypercalcemia?
Bone pain, renal stones, abdominal pain, depression/psychological features, hypertension, nausea, and vomiting.
How can you check for true hypercalcemia?
Use the albumin-adjusted formula.
Why should the albumin-adjusted formula be used to check for true hypercalcemia?
Because the majority of calcium is albumin-bound, and variations in albumin concentration can cause variations in total calcium concentration without affecting the free ionized calcium concentration (which is typically not available in most labs).
What other tests should be done to investigate hypercalcemia?
Measure PTH and phosphate levels.
What PTH result indicates an appropriate response to hypercalcemia?
PTH should be decreased (appropriate response to high calcium levels).
What should be checked if hypercalcemia is suspected due to cancer (e.g., myeloma)?
Check serum and urine protein electrophoresis.
What test should be done for Addison’s disease (adrenal insufficiency) if hypercalcemia is suspected?
Check cortisol levels.
What tests are used to check for vitamin D toxicity (rare)?
Measure 25OHD and 1,25OHD levels.
What test should be done to check for granulomatous diseases like sarcoidosis or TB?
Measure angiotensin-converting enzyme (ACE).
What test should be done to check for skeletal metastases in hypercalcemia?
Skeletal imaging.
What test should be done if hypercalcemia is suspected to be due to hyperthyroidism?
Check thyroid function tests.
Which drugs are associated with hypercalcemia?
Thiazide diuretics, lithium, and milk-alkali syndrome (overconsumption of antacids).
What PTH result indicates an inappropriate response to hypercalcemia?
PTH levels normal or increased (inappropriate response to high calcium levels).
What conditions are associated with inappropriate PTH response to hypercalcemia?
- Primary hyperparathyroidism (adenoma, hyperplasia, or carcinoma).
- Familial hypocalciuric hypercalcemia (FHH).
- Tertiary hyperparathyroidism (due to renal pathology).
What are the clinical features of hypocalcemia?
- Neuromuscular hyperexcitability.
- Hypotension and ECG abnormalities.
- Paraesthesia, numbness, cramps, anxiety, tetany.
- Chvostek’s sign (facial twitching) and Trousseau’s sign (arm).
- Prolonged symptoms: convulsions, laryngeal stridor, dystonia, and psychosis.
What should be done initially when suspecting hypocalcemia?
- Ensure it is true hypocalcemia.
- Use the albumin-adjusted formula.
What should be checked for contamination in calcium testing?
Check for contamination with additives from other blood tubes such as EDTA, Sodium Citrate, and Fluoride Oxalate.
Why do additives like EDTA, Sodium Citrate, and Fluoride Oxalate affect calcium testing?
These additives prevent clotting by binding to calcium and magnesium, causing artefactually low results.
What should be measured when hypocalcemia is suspected?
Measure PTH and phosphate levels.
What does a decreased PTH indicate in hypocalcemia?
Inappropriate PTH response to hypocalcemia, such as in:
- Magnesium deficiency (which impairs PTH secretion).
- Hypoparathyroidism (post-surgical damage or genetic causes).
- Infiltrative diseases (e.g., Hemochromatosis, Wilson’s disease).
What are the clinical features of hyperphosphataemia primarily due to?
Binding of calcium.
What are the acute clinical features of calcium binding?
Hypocalcemia leading to hypotension, seizures, and tetany.
What are the chronic clinical features of calcium binding?
Calcification of blood vessels/soft tissue, renal failure, cardiovascular disease (CVD), and secondary hyperparathyroidism.
What 3 factors should be considered to determine if calcium imbalance is genuine?
Use age-related reference ranges (higher in children).
Check for in vitro hemolysis.
Avoid aged samples.
What are some iatrogenic causes of calcium imbalance?
Over-replacement of calcium.
What 4 conditions can cause calcium imbalance due to renal failure?
- Renal failure itself.
- Intravascular hemolysis.
- Rhabdomyolysis.
- Tumor lysis syndrome.
What conditions are associated with low calcium levels?
- Hypoparathyroidism.
- Magnesium deficiency.
What conditions are associated with high calcium levels?
- Malignancy.
- Vitamin D toxicity (rare).
What can cause normal calcium levels despite metabolic disturbances?
Acid-base disturbances, typically acidosis (e.g., diabetic ketoacidosis).
Can mild hypophosphatemia be symptomatic?
No, mild cases can be asymptomatic.
What are the clinical features of hypophosphatemia when levels drop below 0.3 mmol/L?
Muscle weakness, respiratory failure, cardiac and hematological complications.
What are the chronic effects of hypophosphatemia?
Rickets or osteomalacia.
What are the four main mechanisms leading to hypophosphatemia?
- Redistribution into cells
- Redistribution into bone
- Increased loss (renal/GI)
- Decreased intestinal absorption or inadequate intake
How can postprandial state or insulin therapy affect phosphate levels?
They can cause hypophosphatemia.
What should be measured first when investigating hypophosphatemia?
Calcium levels.
What does high calcium in hypophosphatemia suggest, and what should be measured next?
Suggests hyperparathyroidism → Measure PTH.
What does low calcium in hypophosphatemia suggest, and what should be measured next?
Suggests vitamin D deficiency → Measure vitamin D.
What should be assessed if calcium levels are normal in hypophosphatemia?
Other electrolytes such as magnesium (Mg) and potassium (K).
What do normal magnesium levels suggest in hypophosphatemia?
Possible rarer/genetic causes or alkalosis.
What does low magnesium in hypophosphatemia suggest?
Possible alcoholism, malabsorption/malnutrition, GI loss, or refeeding syndrome.
Is hypermagnesaemia common or rare?
Rare.
What are the ECG changes seen in hypermagnesaemia?
Prolonged PR and QRS intervals, peaked T waves.
What severe complications can hypermagnesaemia cause?
Respiratory paralysis and cardiac arrest.
What are the main causes of hypermagnesaemia?
Excessive intake and renal failure (usually with supplements).
What are the symptoms of hypomagnesaemia?
Anorexia, nausea, agitation, confusion, cardiac dysrhythmias, hypokalaemia, hypocalcaemia.
What gastrointestinal conditions can cause hypomagnesaemia?
Malnutrition or malabsorption.
Name three conditions associated with magnesium redistribution.
Refeeding syndrome, pancreatitis, DKA recovery.
What renal issues can lead to hypomagnesaemia?
Renal tubular dysfunction, hyperaldosteronism, osmotic diuresis.
What drug classes are linked to hypomagnesaemia?
PPIs, diuretics, tacrolimus.
What is the function of osteoblasts?
Form new bone.
What is the role of osteoclasts?
Bone resorption and dissolution.
What is the main function of osteocytes?
Maintain mineral homeostasis; they are the majority of formed bone cells.
What are osteogenic cells?
Stem cells in bone that differentiate into other bone cells.
What is osteoporosis?
Low bone mass with structural deterioration of bone tissue.
How is osteoporosis diagnosed?
By measuring bone mineral density using a DEXA scan.
What T-score indicates osteoporosis?
-2.5 SD or below.
What are some secondary causes of osteoporosis?
Endocrine disorders, drugs, malignant disease, malabsorption, etc.
What is the difference between rickets and osteomalacia?
Rickets affects children, while osteomalacia affects adults.
What are the main causes of rickets/osteomalacia?
Vitamin D or phosphate deficiency (and genetic causes).
What blood marker is often elevated in rickets/osteomalacia?
Alkaline phosphatase.
What is Paget’s disease?
A localized bone disorder affecting one or two bones, disrupting the bone remodeling process.
How does Paget’s disease affect bone structure?
It causes faster but disorganized and weaker new bone formation.
What does CKD-MBD stand for?
Chronic Kidney Disease – Mineral and Bone Disorder.
How does reduced renal function contribute to CKD-MBD?
It prevents activation of vitamin D, leading to low calcium and PTH activation, which increases bone resorption.
How does phosphate accumulation in CKD-MBD affect bone?
It also activates PTH, further increasing bone resorption.
What is the long-term effect of CKD-MBD on bones?
Chronic bone resorption reduces bone mineral density.
How are most metabolic bone diseases diagnosed?
Through imaging, but bone turnover markers allow blood test monitoring.
What makes an ideal bone turnover marker?
It is secreted directly by osteoblasts/osteoclasts or is a product of bone turnover.
Can bone turnover markers indicate the location of the affected bone?
No, they do not provide location information.
Why are bone turnover markers useful?
They are non-invasive and cheaper than imaging, helping monitor treatment efficacy and compliance.
What are the disadvantages of bone turnover markers?
Lack of assay standardization, sample stability issues, and high variability.
Name three markers of bone formation.
P1NP (most common), bone-specific ALP, osteocalcin.
What is P1NP, and how is it formed?
A bone formation marker; osteoblasts synthesize procollagen, and when N- and C-terminals are cleaved, P1NP and P1CP are released.
Name three markers of bone resorption.
CTX (most common), NTX, deoxypyridinoline.
What is CTX, and how is it formed?
A bone resorption marker; it is cleaved from type 1 collagen.
