Hypocalcaemia is defined as a serum corrected calcium concentration < 2.2 mmol/L.
Hypocalcaemia can lead to dangerous cardiac arrhythmias and requires urgent identification and treatment. The normal serum calcium concentration is 2.2-2.6 mmol/L and this should be corrected for albumin.
Hypocalcaemia is a common electrolyte abnormality with a wide range of causes. It is commonly seen in chronic kidney disease (CKD) and vitamin D deficiency. Acute symptomatic hypocalcaemia is most often seen following thyroidectomy (removal of the thyroid gland) that can disrupt the parathyroid glands that are needed for in parathyroid hormone (PTH) secretion.
Acute hypocalcaemia can be further divided as follows:
Calcium binds to albumin in the serum.
Due to calcium binding to albumin, a corrected calcium level needs to be determined taking into account the albumin level. With modern laboratories, a corrected calcium result is normally automated.
It is estimated that the serum calcium concentration falls by 0.25 mmol/L (0.8 mg/dL) for every 10 g/L (1 g/L) reduction in serum albumin concentration. The can be calculated manually using the following formula:
Corrected calcium (mg/dL) = serum calcium (mg/dL) + 0.8 x (4.0 - serum albumin [g/dL])
In the context of hypoalbuminaemia, the total calcium concentration is a not a reflection of ionised calcium. Ionised calcium refers to the ‘free’ pool of calcium.. A normal free ionised calcium in the context of hypocalcaemia is known as pseudohypocalcaemia. Therefore, measurement of albumin and ionised calcium helps differentiate true hypocalcaemia from pseudohypocalcaemia.
Calcium is distribuited between bone and the intra- and extra-cellular compartments.
The majority of body calcium, 99%, is stored in bone.
1% of total body calcium is found within the intracellular compartment. Here it plays a key role in intracellular signalling.
0.1% of total body calcium is found within the extracellular pool, this is divided into:
The balance between stored calcium and the extracellular pool of calcium is a closely regulated process. It is controlled by the interaction of three hormones; parathyroid hormone (PTH), vitamin D and calcitonin.
Decreased extracellular calcium is detected by the calcium-sensing receptor (CaSR) on the parathyroid gland. The parathyroid glands respond to the fall in serum calcium by releasing PTH. PTH stimulates the resorption of calcium from bone, activation of vitamin D (leads to calcium absorption from enterocytes) and increased renal tubular reabsorption of calcium.
Conversely, a rise in extracellular calcium detected by the CaSR has the opposite effect. It leads to a reduction in the release of PTH and stimulates the release of calcitonin. This combined effect helps decrease bone resorption and promotes calcium excretion in the kidneys.
Major causes of hypocalcaemia can be determined in relation to the parathyroid hormone concentration.
There are multiple causes of hypocalcaemia that are broadly be divided into four groups:
Hypomagnesaemia is a common cause of hypocalcaemia because it impairs the action of PTH leading to resistance. This predominantly occurs at markedly low magnesium levels (< 0.4 mmol/L). In more severe hypomagnesaemia it can cause a reduction in PTH secretion. Therefore, when assessing a patient with hypocalcaemia it is important to check and replace magnesium. If severe hypomagnesaemia is present, calcium will not improve without normalisation of magnesium.
Rarely, hypermagnesaemia (markedly high level >2.5 mmol/L) can cause hypocalcaemia through suppression of PTH secretion.
Several medications can cause hypocalcaemia by various mechanisms:
In these causes, PTH is secreted in response to low calcium in an attempt to restore normal calcium levels.
This is a very common cause of hypocalcaemia. Linked to poor diet and absence of ultraviolet light.
CKD is a major cause of hypocalcaemia as part of a wider calcium-phosphate handling disorder known as ‘CKD mineral and bone disorders’.
This can cause hypocalcaemia through:
CKD can lead to a marked rise in PTH known as secondary hyperparathyroidism.
When peripheral tissue is unresponsive to the effects of PTH due to an alteration in the PTH receptor, the condition is known as pseudohypoparathyroidism. The condition presents in childhood with characteristic features.
The reason for the term is because the biochemical picture is similar to a lack of PTH (hypoparathyroidisim) with hypocalcaemia and hyperphosphataemia. However, due to resistance rather than reduced secretion, the PTH is elevated.
Many conditions lead to the sequestration of calcium. This causes hypocalcaemia and an appropriate rise in PTH in an attempt to normalisation the serum calcium concentration.
Hypocalcaemia secondary to low PTH is classicalyl seen following thyroid surgery.
Hypocalcaemia with a low PTH is most commonly related to surgery, which can occur following any neck surgery (e.g. thyroid, parathyroid, dissection from cancer). Post-surgical hypocalcaemia can be divided into three types:
This is most commonly an autoimmune disorder that results in immune-mediated destruction of the parathyroid glands. Also occurs due to autoantibodies that bind to the calcium-sensing recepto (CaSR), which decreases PTH secretion.
Rare causes of hypocalcaemia can be due to damage to the parathyroid glands by infiltration or radiation. Additionally, abnormal parathyroid gland development, as seen in DiGeorge syndrome, can result in hypocalcaemia.
Untreated, hypocalcaemia can cause dangerous cardiac arrhythmias and seizures.
Calcium is essential for the functionl of normal cells. This includes stability of membrane potential, neural transmission, boney structures, coagulation and intracellular signalling. Hypocalcaemia can lead to neuromuscular irritability and tetany, which describes muscle spasms. In severe hypocalcaemia life-threatening arrhythmia and seizures can develop.
Acute hypocalcaemia is characterised by paraesthesia and muscle spasms.
This usually occurs at calcium concentrations < 1.9 mmol/L
Two classical eponymous signs are associated with hypocalcaemia:
* Carpopedal spasm refers to flexion at the wrist and metacarpophalangeal joints, extension of the interphalangeal joints and adduction of the thumb
The diagnosis of hypocalcaemia is based on a serum corrected calcium < 2.2 mmol/L.
It is important to distinguish whether the cause of hypocalcaemia is acute or chronic. Acute severe hypocalcaemia (< 1.9 mmol) is a medical emergency that requires urgent treatment and cardiac monitoring.
Usual investigations to determine the underlying cause include:
Other investigations are guided by the clinical presentation. For example, a lipase or amylase in suspected acute pancreatitis or a uric acid level if tumour lysis syndrome is suspected.
Acute severe hypocalcaemia (< 1.9 mmol/L) is a medical emergency.
The management of acute hypocalcaemia depends on whether it is mild or severe. Please note, most centres performing thyroid or parathyroid surgery will have set local protocols for the monitoring and management of hypocalcaemia around the time of surgery.
Mild hypocalcaemia (≥ 1.9 mmol/L)
Severe hypocalcaemia (< 1.9 mmol/L or symptomatic at any level)
Patients with chronic hypocalcaemia require investigation into the underlying cause, which is most commonly due to CKD or vitamin D deficiency. In these cases, treatment of the underlying cause and management with vitamin D supplementation is usually sufficient. Patients with CKD may require additional measures due to secondary hyperparathyroidism.
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