Hypercalcaemia

Hypercalcaemia is a raised corrected serum calcium, graded broadly as mild (up to about 3.0 mmol/L), moderate (3.0–3.4 mmol/L) and severe (≥3.4 mmol/L, or any level with significant symptoms).

Because roughly 40% of calcium is albumin-bound, the corrected value must be used, or hypercalcaemia will be missed in hypoalbuminaemic patients and over-diagnosed in others.

Primary hyperparathyroidism and malignancy together account for around 90% of cases, and the distinction is usually straightforward: primary hyperparathyroidism tends to be chronic, mild and asymptomatic in an outpatient, while malignancy-associated hypercalcaemia is usually higher, symptomatic and of shorter history.

Other causes include granulomatous disease (sarcoidosis, tuberculosis), vitamin D toxicity, thiazides, lithium, thyrotoxicosis, immobilisation, milk-alkali syndrome and familial hypocalciuric hypercalcaemia.

The classic summary of "bones, stones, abdominal groans and psychic moans" remains a useful memory aid.

• Renal: polyuria and polydipsia (nephrogenic diabetes insipidus), nephrolithiasis, nephrocalcinosis, and acute kidney injury from volume depletion
• Gastrointestinal: anorexia, nausea, vomiting, constipation, abdominal pain, peptic ulceration and pancreatitis
• Neuropsychiatric: fatigue, poor concentration, depression, confusion, and in severe hypercalcaemia drowsiness, stupor and coma
• Musculoskeletal: bone pain, proximal muscle weakness, and in longstanding hyperparathyroidism osteitis fibrosa cystica
• Cardiac: shortened QT interval, bradycardia, and arrhythmia in severe cases, with increased digoxin sensitivity

Volume depletion is central to the pathophysiology and drives a vicious cycle: hypercalcaemia causes polyuria and vomiting, which cause dehydration, which reduces renal calcium excretion, which raises calcium further. Breaking that cycle with fluid is the first therapeutic priority.

• Corrected calcium, repeated to confirm, alongside albumin. Ionised calcium is preferable where available and where the correction is unreliable, as in critical illness or acid-base disturbance
• PTH is the single most useful discriminating test: an inappropriately normal or raised PTH indicates primary (or tertiary) hyperparathyroidism, while a suppressed PTH points to a non-parathyroid cause, principally malignancy
• If PTH is suppressed: PTHrP (humoral hypercalcaemia of malignancy), vitamin D metabolites (raised 1,25-dihydroxyvitamin D suggests granulomatous disease or lymphoma), myeloma screen, and imaging directed by the clinical picture
• Renal function, phosphate, magnesium, alkaline phosphatase
• ECG for QT shortening
• 24-hour urinary calcium and the calcium-creatinine clearance ratio to identify familial hypocalciuric hypercalcaemia, an important benign mimic in which parathyroidectomy is inappropriate and which is otherwise easily mistaken for mild primary hyperparathyroidism
• Review medications, particularly thiazides, lithium, calcium and vitamin D supplements

Differentials: the practical task is usually to separate parathyroid-driven from non-parathyroid causes and then to identify the specific underlying disease.

Severe or symptomatic hypercalcaemia:

• Intravenous isotonic saline is the first and most important step, typically several litres over the first 24 hours, correcting volume depletion and promoting calciuresis. This alone often produces a substantial fall
• Loop diuretics are no longer recommended routinely and should be used only once the patient is genuinely volume replete and where fluid overload is a concern; giving furosemide to a dehydrated hypercalcaemic patient worsens the problem
• Intravenous bisphosphonate (zoledronic acid or pamidronate) for malignancy-associated hypercalcaemia, with the important caveat that the effect takes 2–4 days, so it does not substitute for fluid in the acute phase. Dose adjustment is needed in renal impairment
• Calcitonin works within hours and is useful as a bridge while awaiting bisphosphonate effect, though tachyphylaxis limits it to a few days
• Denosumab is an option in bisphosphonate-refractory hypercalcaemia or significant renal impairment
• Corticosteroids are effective specifically in granulomatous disease, lymphoma and vitamin D toxicity, where the mechanism is excess 1,25-dihydroxyvitamin D
• Haemodialysis for severe hypercalcaemia with renal failure or where the patient is unable to tolerate fluid loading
• Stop contributing drugs and mobilise the patient where possible

Underlying cause:

• Primary hyperparathyroidism: parathyroidectomy where criteria are met; cinacalcet where surgery is not appropriate
• Malignancy: treat the underlying disease, recognising that hypercalcaemia of malignancy carries a poor prognosis and that discussion of goals of care is often appropriate alongside treatment

Referral: endocrinology for parathyroid disease; oncology or palliative care for malignancy-associated hypercalcaemia; nephrology for dialysis or severe renal impairment.