Hypocalcaemia

What is hypocalcaemia?¹

Whilst ranges vary slightly between laboratories, the normal range for total serum calcium is usually between 2.1 and 2.6 mmol/L.²

Derangements above (hypercalcaemia) and below (hypocalcaemia) this level interfere with the normal function of many cells, but nerve and muscle cells in particular.

About 45% of plasma calcium is bound to proteins, particularly albumin. 15% is bound to small anions such as phosphate and citrate. It is the unbound, ionised fraction of calcium which is important physiologically (the "active state"),³ and the level for serum calcium is usually reported as both uncorrected and corrected (where adjustment is made for changes in albumin levels). Particular care should be taken where the measured albumin concentration is less than about 20 g/L, because of the known inaccuracy of albumin measurement at low levels.

Hypocalcaemia is less common than hypercalcaemia but is potentially life-threatening if not treated promptly.³

Epidemiology

Evidence for overall incidence is sparse. The condition spans all ages and both sexes. It has a prevalence of 18% in all patients in hospital and 85% in the intensive care unit.⁴The reported prevalence of transient hypocalcaemia after thyroidectomy varies between 6.9% and 49%, whilst between 0.4% and 33% report permanent hypocalcaemia.³

Hypocalcaemia causes (aetiology)³

Causes of hypocalcaemia fall into two main classes.

With low parathyroid hormone (PTH) levels (hypoparathyroidism)

• Post-surgical. About 75% of cases of hypoparathyroidism occur after thyroidectomy, parathyroidectomy or radical neck surgery.

• Autoimmune disorder. Parathyroid autoantibodies are the commonest immunological cause of hypoparathyroidism.

• Parathyroid agenesis. Abnormal parathyroid development can be seen in several genetic disorders, including but not limited to DiGeorge's syndrome, Charge syndrome, and MELAS.

• Parathyroid destruction. Irradiation, infiltration by metastases or systemic disease such as Wilson's disease, sarcoidosis, and amyloidosis can cause destruction of the parathyroid gland. Some chemotherapeutic agents such as nivolumab and l-asparaginase also cause parathyroid destruction.

With high PTH levels (secondary hyperparathyroidism)

• Vitamin D deficiency. Vitamin D improves calcium absorption so its deficiency (caused by reduced intake, malabsorption, inadequate sun exposure, liver or kidney disease) can cause hypocalcaemia.

• Chronic kidney disease. This can cause impaired phosphate excretion and conversion of 25-hydroxy vitamin D to 1,25-dihydroxy vitamin D. This drives PTH secretion causing secondary hyperparathyroidism. However, due to reduced vitamin D metabolism and high phosphorus levels, the serum calcium remains low despite the high PTH.

• Pseudohypoparathyroidism. This causes end-organ resistance to parathyroid hormone.

Other causes of hypocalcaemia

• Hypo- or hyper-magnesaemia.

• Drugs. Drugs which can cause hypocalcaemia include: bisphosphonates, denosumab, cinacalcet, and cisplatin.

• Acute pancreatitis.

• Acute phosphataemia.

• Massive blood transfusion.

• Acute rhabdomyolysis.⁵

• Malignancy - tumour lysis (following chemotherapy) or osteoblastic metastases (most common in prostate and breast cancers).

Hypocalcaemia is extremely common in patients in hospital and correlates with the severity of their illness.⁶There is little evidence of benefit from treating the hypocalcaemia in these patients and some evidence of harm - it may be a marker of the severity of their illness rather than a cause of it. ⁷

Hypocalcaemia presentation⁸

Hypocalcaemia symptoms

Hypocalcaemia symptoms generally correlate with the magnitude and rapidity of the fall in serum calcium: mild hypocalcaemia (2.00-2.12 mmol/L) can be asymptomatic, whereas life-threatening symptoms can develop in the more severe form (<1.9 mmol/L).³

Symptoms include:

• Seizures. These usually occur in very severe hypocalcaemia.

• Tetany. This usually occurs following a rapid fall in serum calcium levels, usually alongside respiratory alkalosis.

• Paraesthesia. This is usually perioral or in the extremities.

• Muscle cramps.

• Psychiatric symptoms. Anxiety, depression, and emotional lability are uncommon manifestations of hypocalcaemia.

Hypocalcaemia signs⁸

• Carpopedal spasm. Also known as Trousseau's sign, this. It increased neuromuscular excitability and is seen as a spasm of the hand characterized by flexion of the thumb, wrist, and metacarpophalangeal joints with extension of the fingers when a sphygmomanometer is inflated above systolic blood pressure for 2 to 3 minutes.

• Chvostek's sign. Another manifestation of heightened neuromuscular excitability, tapping of the facial nerve in front of the ear causes ipsilateral contraction of the facial muscles.

• QTc prolongation. This can lead to torsades de pointes (a potentially fatal ventricular tachycardia).

• Laryngospasm.

• Bronchospasm.

With prolonged hypocalcaemia⁸

• Subcapsular cataract.

• Papilloedema.

• Abnormal teeth.

• Ectopic calcification (for example, in basal ganglia may cause extrapyramidal neurological symptoms).

• Dementia and confusion.

Differential diagnosis

Investigations

• Is the patient really hypocalcaemic? Ensure use of an adjusted calcium value. Sometimes fasting is recommended but this has limited evidence. Prolonged tourniquet use may affect the results.⁹

If the calcium levels are very low or the patient is symptomatic, admission is required for any further tests. Tests can often be performed in primary care, if there are no acute concerns. Further tests include:

• U and Es.

• Magnesium.

• Phosphate.

• PTH.

• Vitamin D.

• Amylase (although possible acute pancreatitis needs emergency admission).

• Creatine kinase.

• Perform an ECG to exclude dysrhythmias and prolonged QT interval.

Management³

Acute hypocalcaemia

• Admission for urgent treatment where symptomatic (seizures, tetany) or at high risk of complications with a serum calcium <1.90 mmol/L. Treatment usually involves giving 10 ml (2.25 mmol) of calcium gluconate 10% by slow intravenous (IV) injection initially followed by repeated doses or by infusion of calcium gluconate 10% infusion - 40 ml (9 mmol)/24 hours.

• Oral calcium preparations may need to be given as supplements to IV treatment or where IV access is difficult.

• Monitor serum calcium concentrations regularly to judge response.

• If it is likely to be persistent, give vitamin D by mouth.

• If hypomagnesaemic, it is necessary to correct the magnesium level before the hypocalcaemia will resolve.

Persistent hypocalcaemia

• Initially, supplementary calcium (10-20 mmol calcium bd-qds) and vitamin D; however, calcium may be discontinued once stabilised.

• Calcitriol (oral 1,25(OH)₂D₃) is more expensive than the parent vitamin D compounds, vitamin D₂ (ergocalciferol), and vitamin D₃, but is used first-line in patients with renal impairment because it does not require hydroxylation by the kidney for activation.

• Closely monitor the patient's serum and urine concentration. In some hypoparathyroid individuals, calcium levels may remain permanently unstable and it is important that the maintenance dose be regularly monitored and adjusted.

• These patients should remain under the care of an endocrinologist.

Prevention

• Ensure adequate dietary intake or consider supplementation in those with necessary dietary exclusions - eg, lactose-intolerant.¹⁰

• Giving 1,25(OH)₂D₃ and calcium for several days before elective subtotal parathyroidectomy may prevent extreme hypocalcaemia.