10. Laboratory approaches for the detection of disorders in calcium, magnesium and phosphate homeostasis

From greek.doctor

Calcium

Calcium is an ion in the body.

  • Roles
    • Comprises bone
    • 1 kg in adults
      • 99% in bone
    • Muscle contraction
    • Neurotransmission
    • Membrane transport
    • Enzymes
    • Coagulation
  • 45% free
  • 45% protein bound
  • 10% anion bound
  • Regulation
    • Kidney
    • PTH
      • Decreased calcium stimulates PTH
      • Increased phosphate stimulates PTH
      • Increases Ca2+ reabsorption in tubule
      • Increases phosphate excretion in tubule
      • Increases vitamin D production
      • Increases bone resorption
    • Vitamin D
      • Increases Ca2+ reabsorption in tubule
      • Increases Ca2+ reabsorption in GI tract
      • Decrease phosphate excretion in tubule
      • Increase bone mineralization
    • (Calcitonin)
      • Opposite of PTH
      • Tumor marker


Hypocalcaemia

Hypocalcaemia
DefinitionFree calcium (Ca2+) < 1,15 mmol/L
SymptomsTetany, paraesthesia, Trosseau sign, Chvostek sign
ComplicationsArrhythmia, seizures
CausesDysfunction of parathyroid gland, chronic kidney disease, vitamin D deficiency
TreatmentIV supplementation if severe, followed by oral supplementation. Correction of low magnesium and vitamin D

Hypocalcaemia is a disorder of calcium homeostasis characterised by low levels of calcium (free calcium < 1,15 mmol/L). It's a relatively uncommon electrolyte abnormality and the opposite of hypercalcaemia.

99% of the body's calcium is in the bones. The remaining 1% is in the blood. 40% of calcium in the serum is bound to albumin, 10% is bound to other anions (lactate and citrate), and the remaining 50% exists as free calcium ions (Ca2+) in the serum. It is the free calcium which is biologically active and therefore is used to diagnose hypocalcaemia. Bound calcium is inactive.

Grading of severity

Hypocalcaemia isn't really graded into "mild", "moderate", and "severe" in most sources, instead only using 1,15 mmol/L as the border between normal and abnormal. However, here is one source's grading:

Free calcium level Total calcium level Severity
1,00 - 1,15 1,90 - 2.1 Mild
0,80 - 1,00 Moderate
< 0,80 < 1,90 Severe

Etiology

Hypocalcaemia can be secondary to hypoparathyroidism or it can be secondary to other causes.

The most common causes of hypocalcaemia are surgical destruction of parathyroid glands, chronic kidney disease, and vitamin D deficiency.

Chronic kidney disease, mostly end-stage, causes hypocalcaemia due to loss of vitamin D-synthesis and retention of phosphate, causing hyperphosphataemia.

Acute pancreatitis causes hypocalcaemia due to adiponecrosis is the pancreas, where calcium combines with free fatty acids.

Alkalosis reduces calcium binding to albumin, causing free calcium to increase.

Critical illness, usually as part of severe sepsis or trauma or similar, causes hypocalcaemia due to various mechanisms that are not well known. These may include impaired PTH secretion and dysregulation of magnesium.

Hypomagnesaemia causes PTH resistance in peripheral tissues, which mimics hypoparathyroidism. On the other hand, hypermagnesaemia inhibits PTH secretion.

Hyperphosphataemia causes deposition of calcium phosphate salts, reducing the levels of free calcium.

Pathomechanism

Decreasing levels of calcium increases the neuromuscular excitability, which is the mechanism behind the clinical features and complications.

Clinical features

Mild hypocalcaemia is asymptomatic. As the hypocalcaemia becomes more severe or develops more acutely, tetany, perioral or extremity paraesthesia, and psychiatric disorders like anxiety or depression may occur. Seizures can occur in very severe hypocalcaemia.

Trousseau sign, also called carpopedal spasm, is a clinical sign in hypocalcaemia which occurs due to increased neuromuscular excitability. Inflating a blood pressure cuff above the systolic blood pressure for 2-3 minutes causes the hand to take on a bird's head-like posture where the thumb, wrist, and MCP joints are flexed and the fingers are extended. Video link.

Chvostek sign is another clinical sign due to increased neuromuscular excitability. Tapping on the facial nerve, usually where it exits the skull anterior to the ear, elicits contraction of facial muscles.

Diagnosis and evaluation

Different ways to report calcium levels

There are three different ways the laboratory can report a patient's calcium levels.

Advantage Disadvantage Reference range
Total calcium Easy to measure Inaccurate estimate of free calcium in case of abnormal albumin levels, abnormal parathyroid levels, surgery, blood tranfusion, multiple organ failure, acid-base disorder 2.1 - 2.5 mmol/L
Albumin-corrected calcium Easy to measure and calculate Even more inaccurate estimate of free calcium in case of abnormal albumin levels 2.18 - 2.45 mmol/L
Free calcium The gold standard Requires special sample taking, sample must be cooled, must be processed quickly after sample taking, expensive 1.15 - 1.28 mmol/L

As already stated, only the free calcium matters, and this is therefore the gold standard for diagnosis of calcium disorders. However, measuring the free serum calcium is more difficult (see the table) and more expensive than measuring total calcium.

Because 50% of calcium in the serum is free, one would assume one could simply halve the total calcium value to get the free value. However, as evident from the table, this relationship can change in many cases, most notably in case of hypoalbuminaemia. As such, total calcium levels does not always provide an accurate estimate of the free calcium level. In the absence of the aforementioned complicating factors, total calcium is good enough to evaluate the calcium level.

A formula was developed to "correct" the total calcium level in case of hypoalbuminaemia. This formula, which the lab often calculates for you and reports as a separate, "albumin-corrected" calcium, unfortunately performs poorly clinically and has actually been shown to be a worse estimator of free calcium level than the uncorrected total calcium level.[1][2] This formula overestimates the total calcium level and may therefore give a false diagnosis of hypercalcaemia or mask hypocalcaemia. Its use should therefore be avoided and free calcium should be measured instead.

Checking the heart

Hypocalcaemia can cause QT prolongation, so ECG is indicated.

Determining the cause

Measurement of PTH, vitamin D, magnesium, and phosphorus levels is obligatory as they can help determine the cause. The presence of hypoparathyroidism indicates that hypocalcaemia is secondary to parathyroid gland dysfunction or destruction. Hyperparathyroidism is an appropriate physiological response to hypocalcaemia due to other causes than parathyroid pathology.

Hypercalcaemia

Hypercalcaemi
DefinitionFree calcium > 1,30 mmol/L
SymptomsGastrointestinal symptoms, non-specific symptoms, polyuria, altered mental status
ComplicationsAcute pancreatitis, nephrocalcinosis, diabetes insipidus, peptic ulcer
CausesParathyroid adenoma, malignancy
TreatmentIV hydration, bisphosphonates, calcitonin

Hypercalcaemia is a disorder of calcium homeostasis characterised by high levels of calcium (free calcium > 1,30 mmol/L). It's a relatively common electrolyte abnormality and is the opposite of hypocalcaemia.

A free calcium level of > 2,00 is sometimes called a hypercalcaemic crisis.

99% of the body's calcium is in the bones. The remaining 1% is in the blood. 40% of calcium in the serum is bound to albumin, 10% is bound to other anions (lactate and citrate), and the remaining 50% exists as free calcium ions (Ca2+) in the serum. It is the free calcium which is biologically active and therefore is used to diagnose hypercalcaemia. Bound calcium is inactive.

Grading of severity

Hypercalcaemia isn't really graded into "mild", "moderate", and "severe" in most sources, instead only using 1,30 mmol/L as the border between normal and abnormal. However, here is one source's grading:

Free calcium level Total calcium level Severity
1,30 - 1,50 2,5 - 3,00 Mild
1,50 - 1,70 3,00 - 3,50 Moderate
1,70 - 2,00 > 3,50 Severe
> 2,00 Hypercalcaemic crisis

Etiology

Hypercalcaemia can be secondary to hyperparathyroidism or it can be secondary to other causes. The most common causes (90% of cases) are primary hyperparathyroidism (causes mild hypercalcaemia) and malignancy (causes more severe hypercalcaemia).

In chronic kidney disease, calcium is lost during diuresis, causing hypocalcaemia or normocalcaemia with a compensatory parathyroid hyperplasia causing secondary hyperparathyroidism. However, in some long-standing cases of CKD, the parathyroid hyperplasia may progress regardless of calcium levels. This is called tertiary hyperparathyroidism.

Many malignancies are associated with hypercalcaemia, through multiple mechanisms. The most common mechanism is paraneoplastic syndrome due to secretion parathyroid hormone-related protein (PTHrP) by the tumour. Lytic bone metastases can also release calcium from bone. In multiple myeloma, other osteoclast-stimulating factors than PTHrP are secreted.

Vitamin D intoxication is usually accidental, but certain malignancies and granulomatous disorders like sarcoidosis can cause hypercalcaemia by increased production of 1,25-dihydroxyvitamin D.

Drugs are a rare cause of hypercalcaemia alone, but use of lithium or thiazides, which increase PTH secretion and inhibit urinary excretion respectively, may be the sole etiology in mild cases.

Pathomechanism

Hypercalcaemia decreases neuromuscular excitability and inhibits myocardial depolarisation. It also impairs the kidney's ability to concentrate urine, by reducing the kidney's response to vasopressin.

Clinical features

The symptoms of hypercalcaemia have long been remembered by the phrase "groans, bones, moans, thrones, and psychiatric overtones".

Groans refer to abdominal pain, which can be accompanied by nausea and vomiting.

Bones refer to bone pain.

Stones refer to kidney stones, which may cause renal colic.

Moans refer to fatigue and malaise.

Thrones, as in sitting on a toilet throne (it wasn't me who came up with these I swear) refer to polyuria and constipation. There may also be polydipsia.

Psychiatric overtones refers to symptoms of encephalopathy, including lethargy and confusion.

Diagnosis and evaluation

Checking the heart

Hypercalcaemia can cause QT shortening, so ECG is indicated.

Determining the cause

Measurement of PTH is obligatory as it can help determine the cause. The presence of hyperparathyroidism means a diagnosis of primary hyperparathyroidism is most likely. If the PTH is low, malignancy is the most likely cause and must be ruled out. PTHrP and 1,25-dihydroxyvitamin D should be measured. If PTHrP is elevated, the patient should undergo evaluation for malignancy. If it's negative and 1,25-dihydroxyvitamin D is elevated, granulomatous disease should be ruled out.

Magnesium

  • Normal level: 0,7 - 1.0 mM
  • Roles
    • Enzyme cofactor
    • Calcium homeostasis
      • Magnesium is a calcium antagonist, prevents intracellular accumulation of calcium

Hypomagnesaemia

  • Hypomagnesaemia
    • Malnutrition
    • Laxative abuse
    • Hyperparathyroidism

Hypermagnesaemia

  • Hypermagnesaemia
    • Renal failure
    • Rhabdomyolysis

Phosphate

Phosphate is a group of anions in the body. The normal level is approximately 0,75 - 1,50 mmol/L. Most of phosphate in the body exists in the skeleton as part of hydroxyapatite. Pathologically low or high phosphate levels is called hypophosphataemia and hyperphosphataema, respectively.

Hypophosphataemia

Hypophosphataemia refers to a pathologically low phosphate level, approximately < 0,75 mmol/L. It can be present in case of alcoholism, malnourishment, hyperparathyroidism.

Hyperphosphataemia

Hyperphosphataemia refers to a pathologically high phosphate level, approximately > 1,50 mmol/L. It can be present in case of chronic kidney disease (most common), tumor lysis syndrome, rhabdomyolysis, acidosis.

References

  1. ↑ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8340960/
  2. ↑ https://www.utpjournals.press/doi/full/10.22374/cjgim.v11i3.150