Hypocalcaemia

Hypocalcaemia
Definition	Free calcium (Ca2+) < 1,15 mmol/L
Symptoms	Tetany, paraesthesia, Trosseau sign, Chvostek sign
Complications	Arrhythmia, seizures
Causes	Dysfunction of parathyroid gland, chronic kidney disease, vitamin D deficiency
Treatment	IV 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.

• Hypoparathyroidism
  • Surgical destruction of the parathyroid glands, either intentional (as treatment for hyperparathyroidism) or accidental (during other thyroid surgery)
  • Autoimmune hypoparathyroidism
• Unrelated to hypoparathyroidism
  • Severe vitamin D deficiency
  • End-stage kidney disease
  • Acute pancreatitis
  • Alkalosis (respiratory or metabolic)
  • Critical illness
  • Hypomagnesaemia or hypermagnesaemia
  • Hyperphosphataemia

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. 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.

Management

Asymptomatic hypocalcaemia, unless severe (<0,8), does not require treatment.

Symptomatic hypocalcaemia requires treatment. An initial IV bolus, followed by an intravenous infusion, of calcium chloride or calcium gluconate is indicated. Calcium chloride is highly irritative and so the infusion should be given in a large vein. While the IV infusion is ongoing, the patient should be startet on a maintainance dose of oral calcium supplement until the calcium level is corrected.

Hypomagnesaemia and vitamin D deficiency maintain hypocalcaemia, and so these must be managed concomitantly.

Complications

Severe acute hypocalcaemia can cause epileptic seizures and, because of QT prolongation, fatal cardiac arrhythmia, as well as vasopressor-refractory hypotension.

Chronic hypocalcaemia, usually due to hypoparathyroidism, can cause cataract, calcification of the basal ganglia, parkinsonism, and dementia.