Hypocalcaemia

Introduction

Hypocalcaemia is a corrected serum calcium below 2.2 mmol/L. It is common in hospital practice - present in a substantial proportion of critically ill patients - and ranges from an asymptomatic biochemical finding to a genuine emergency with laryngospasm, seizures and arrhythmia.¹

Physiologically, calcium is regulated by PTH (which raises calcium by mobilising bone, increasing renal reabsorption and activating vitamin D) and calcitriol (which increases gut absorption). Almost every cause of hypocalcaemia is a failure of one of these two axes, a problem with phosphate, or chelation of calcium out of the circulation - and that framework makes the causes far easier to recall.

Causes

Vitamin D related

• Vitamin D deficiency - much the commonest cause; from poor dietary intake, limited sun exposure, darker skin pigmentation, covering clothing, older age and institutionalisation. Causes osteomalacia in adults and rickets in children
• Malabsorption - coeliac disease, Crohn's disease, chronic pancreatitis, bariatric surgery, cholestatic liver disease
• Chronic kidney disease - impaired 1-alpha-hydroxylation of vitamin D, together with phosphate retention
• Liver disease - impaired 25-hydroxylation
• Anticonvulsants - phenytoin, carbamazepine and phenobarbital induce hepatic enzymes and accelerate vitamin D metabolism

Parathyroid related

• Post-surgical hypoparathyroidism - the commonest cause of true hypoparathyroidism, following total thyroidectomy, parathyroidectomy or radical neck surgery. May be transient or permanent, and calcium must be monitored closely after such operations
• Autoimmune hypoparathyroidism - isolated, or as part of autoimmune polyglandular syndrome type 1 (with Addison's disease and mucocutaneous candidiasis)
• DiGeorge syndrome (22q11 deletion) - congenital absence of the parathyroids, with thymic aplasia, cardiac defects and cleft palate
• Infiltration - haemochromatosis, Wilson disease, metastases
• Radiation to the neck
• Pseudohypoparathyroidism - end-organ resistance to PTH, so calcium is low and PTH is HIGH. Albright hereditary osteodystrophy gives the classic phenotype: short stature, round face, shortened fourth and fifth metacarpals, obesity and learning difficulties. Pseudopseudohypoparathyroidism has the same phenotype but normal biochemistry
• Hungry bone syndrome - profound, prolonged hypocalcaemia after parathyroidectomy (or thyroidectomy for thyrotoxicosis), as demineralised bone avidly takes up calcium, phosphate and magnesium

Other causes

• Hypomagnesaemia - impairs both PTH secretion and its peripheral action. Common with diuretics, proton pump inhibitors, alcohol dependence, diarrhoea and refeeding
• Acute pancreatitis - calcium is saponified by free fatty acids released by fat necrosis; hypocalcaemia is a marker of severity in scoring systems
• Tumour lysis syndrome - massive phosphate release binds calcium
• Rhabdomyolysis - calcium deposits in damaged muscle (with rebound hypercalcaemia during recovery)
• Massive blood transfusion - citrate in stored blood chelates calcium; a recognised issue in major haemorrhage protocols
• Drugs - bisphosphonates, denosumab (particularly if vitamin D deficient), calcitonin, cinacalcet, foscarnet, and phosphate-containing enemas
• Sepsis and critical illness
• Respiratory alkalosis from hyperventilation - lowers ionised calcium without changing the total
• Osteoblastic metastases - prostate and breast cancer, where calcium is deposited into bone

Clinical features

Hypocalcaemia causes neuromuscular irritability, because a low extracellular calcium lowers the threshold for nerve and muscle depolarisation. Mild hypocalcaemia is frequently asymptomatic; the rate of fall matters as much as the absolute level, and a rapid drop after thyroid surgery may be far more symptomatic than a chronically low calcium in CKD.

• Perioral paraesthesiae and tingling of the fingers and toes - typically the earliest symptom
• Muscle cramps, twitching and carpopedal spasm
• Tetany - sustained involuntary muscle contraction
• Laryngospasm and bronchospasm - potentially life-threatening stridor and airway compromise
• Seizures - hypocalcaemia is a genuinely reversible cause and should be excluded in new-onset seizures
• Anxiety, irritability, depression, confusion and, in chronic cases, cognitive impairment
• Cardiac - prolonged QT interval predisposing to torsades de pointes, and reduced myocardial contractility causing heart failure and hypotension that is refractory to inotropes until calcium is corrected
• Chronic hypocalcaemia - cataracts, dry skin, brittle nails, coarse hair, basal ganglia calcification (occasionally with parkinsonism), dental hypoplasia and papilloedema
• Features of the cause - the scar of a recent thyroidectomy, bowed legs and growth failure in rickets, proximal myopathy and bone pain in osteomalacia

The two eponymous signs

Investigations

• Corrected calcium - repeat to confirm, and always correct for albumin
• Serum magnesium - check in every case; hypomagnesaemia causes refractory hypocalcaemia
• Phosphate - the key discriminator (see above)
• PTH - low or inappropriately normal confirms hypoparathyroidism; raised indicates vitamin D deficiency, CKD or PTH resistance
• 25-hydroxyvitamin D - to diagnose deficiency
• U&Es and creatinine - chronic kidney disease
• Alkaline phosphatase - raised in osteomalacia and rickets, and normal in hypoparathyroidism
• ECG - looking for a prolonged QT interval
• Amylase or lipase - if acute pancreatitis is suspected
• Creatine kinase, urate, potassium and phosphate - for rhabdomyolysis and tumour lysis syndrome
• Coeliac serology and malabsorption screen - where vitamin D deficiency is unexplained
• Blood gas - to assess pH, since alkalosis lowers ionised calcium
• Genetic testing and specialist assessment - for suspected pseudohypoparathyroidism or DiGeorge syndrome
• Post-operative calcium monitoring - routine after total thyroidectomy, typically at intervals over the first 24-48 hours

Management

Severe or symptomatic hypocalcaemia

Treat urgently if there is tetany, carpopedal spasm, laryngospasm, seizures, a prolonged QT or arrhythmia, or if the corrected calcium is below about 1.9 mmol/L even without symptoms.²

1. Secure the airway if there is laryngospasm or stridor, and call for senior and anaesthetic help
2. IV calcium gluconate 10%, 10-20 mL (1-2 ampoules, containing 2.25 mmol calcium per 10 mL) diluted in 50-100 mL of 5% dextrose or 0.9% saline, given over 10-20 minutes, with continuous cardiac monitoring
3. Follow with a calcium gluconate infusion - typically 100 mL of 10% calcium gluconate in 1 litre of 5% dextrose or 0.9% saline over 24 hours, titrated to serum calcium
4. Recheck calcium every 4-6 hours initially
5. Correct magnesium simultaneously - typically magnesium sulphate 20 mmol IV; without this the calcium will not stay corrected
6. Treat the underlying cause and start oral replacement once stable

Chronic and mild hypocalcaemia

Complications

• Laryngospasm and airway obstruction - the most immediately life-threatening consequence
• Seizures - hypocalcaemia is a reversible cause and should always be excluded
• Prolonged QT and torsades de pointes, and other ventricular arrhythmias
• Heart failure and hypotension - from impaired myocardial contractility, characteristically refractory to inotropes until calcium is corrected
• Tetany and carpopedal spasm with significant distress
• Cataracts - a recognised consequence of chronic hypocalcaemia
• Basal ganglia calcification - occasionally causing extrapyramidal features
• Papilloedema and raised intracranial pressure
• Osteomalacia and rickets - with bone pain, proximal myopathy, fractures, bowed legs and growth failure in children
• Dental hypoplasia and enamel defects in childhood-onset disease
• Complications of treatment - hypercalciuria, nephrocalcinosis and renal stones from long-term calcium and active vitamin D therapy (so urinary calcium must be monitored), tissue necrosis from extravasated calcium chloride, and metastatic calcification if calcium is given in hyperphosphataemic states

Red flags

Prognosis

Acute symptomatic hypocalcaemia responds rapidly and completely to intravenous calcium, with tetany, paraesthesiae and ECG changes resolving within minutes to hours. Provided the airway is protected and arrhythmia avoided, there is usually no lasting consequence, and the prognosis then depends entirely on the underlying cause.

Most causes are readily and durably treatable. Vitamin D deficiency, by far the commonest, corrects fully with colecalciferol, with resolution of biochemical abnormalities within weeks and of osteomalacic bone pain and proximal myopathy over months. Hypomagnesaemia-related hypocalcaemia corrects promptly once magnesium is replaced, and post-thyroidectomy hypoparathyroidism is transient in the majority, with parathyroid function recovering over weeks to months.

Permanent hypoparathyroidism is the exception, and carries a genuine long-term burden. It requires lifelong treatment with active vitamin D analogues and calcium, and unlike most endocrine deficiencies it cannot be replaced with the missing hormone in routine practice, so control is often imperfect. The main long-term hazard comes from treatment rather than the disease: because PTH normally promotes renal calcium reabsorption, patients lacking it develop hypercalciuria when calcium is raised towards normal, with consequent nephrocalcinosis, renal stones and progressive chronic kidney disease. For this reason the therapeutic target is deliberately a low-normal serum calcium - enough to abolish symptoms rather than to normalise the number - and urinary calcium and renal function must be monitored long term. Other recognised long-term complications include cataracts and basal ganglia calcification, and quality of life is often reported as poorer than the biochemistry alone would suggest.