Hypercalcaemia
Exam Tips
- In OSCE/viva, classify severity numerically: mild >2.6 to <3.0, moderate 3.0-3.5, severe >3.5 mmol/L.
- Use PTH as the key branching test: high/inappropriately normal PTH = PTH-mediated; suppressed PTH = search for malignancy, vitamin D-mediated, or drug causes.
- For acute severe hypercalcaemia, prioritise IV 0.9% saline first, then IV bisphosphonate; mention ECG monitoring and strict fluid balance.
- Differentiate primary hyperparathyroidism from familial hypocalciuric hypercalcaemia with urinary calcium (low in FHH).
- A sudden decline in a patient with known cancer plus dehydration/confusion should trigger urgent treatment for possible hypercalcaemic emergency.
Definition
Hypercalcaemia is a biochemical disorder in which albumin-adjusted serum calcium is persistently elevated (typically >=2.6 mmol/L on at least two samples). In UK practice it is often graded as mild (2.6 to <3.0 mmol/L), moderate (3.0 to 3.5 mmol/L), and severe (>3.5 mmol/L), with symptoms determined more by speed of rise than the absolute value.
Pathophysiology
Calcium homeostasis is regulated by parathyroid hormone (PTH), vitamin D, renal handling of calcium, gut absorption, and bone turnover. Hypercalcaemia develops when calcium entry into plasma (bone resorption, gut absorption, renal retention) exceeds renal excretion. The two dominant mechanisms are (1) PTH-driven disease, usually primary hyperparathyroidism (classically a solitary adenoma), causing increased osteoclast-mediated bone resorption, increased distal tubular calcium reabsorption, and increased 1,25-dihydroxyvitamin D activity; and (2) malignancy-related pathways, most often PTH-related peptide secretion (humoral hypercalcaemia) or osteolytic metastases/myeloma. Less common mechanisms include vitamin D excess or ectopic calcitriol production (e. g, lymphoma, granulomatous disease), endocrine causes (thyrotoxicosis, adrenal insufficiency), and medication effects (thiazides, lithium). See Figure: PTH-vitamin D-calcium feedback loop (standard endocrine textbook calcium homeostasis diagram).
Risk Factors
- Primary hyperparathyroidism (older age, female sex, MEN syndromes/familial endocrine disease)
- Known malignancy, especially advanced disease (multiple myeloma, breast, lung, renal, squamous cancers)
- Thiazide diuretic therapy
- Lithium therapy
- Excess calcium and/or vitamin D intake (including milk-alkali syndrome)
- Granulomatous disease (sarcoidosis, tuberculosis)
- Hyperthyroidism
- Prolonged immobilisation with high bone turnover states
Clinical Features
Symptoms
- Often asymptomatic when mild/chronic and detected incidentally
- Fatigue, lethargy, proximal muscle weakness
- Thirst, polyuria, polydipsia, nocturia, dehydration
- Constipation, nausea, vomiting, abdominal pain, anorexia, weight loss
- Renal colic from nephrolithiasis
- Low mood, anxiety, cognitive slowing, confusion; severe cases may progress to delirium/coma
- Bone pain or fragility fracture history
Signs
- Clinical dehydration and reduced skin turgor
- Confusion, reduced GCS, or delirium in severe hypercalcaemia
- Short QT interval on ECG (sometimes PR prolongation/arrhythmia in severe disease)
- Hypertension
- Skeletal tenderness/deformity in longstanding bone disease
- Signs of underlying malignancy (cachexia, lymphadenopathy, organ-specific findings)
Investigations
Management
Lifestyle Modifications
- Stop or reduce reversible contributors: thiazides, lithium (with specialist input), calcium/vitamin D supplements, dehydration
- Encourage oral hydration if mild and stable; avoid prolonged immobilisation
- Urgent hospital assessment for symptomatic, rapidly rising, or severe hypercalcaemia (especially >=3.0 mmol/L, and emergency if >3.5 mmol/L)
Pharmacological Treatment
Volume expansion
- Sodium chloride 0.9% IV, typically 4-6 L in first 24 hours (adjust to age, cardiac/renal status)
First-line in acute severe hypercalcaemia. Monitor fluid balance closely; caution in heart failure and advanced CKD to avoid fluid overload.
Intravenous bisphosphonates
- Zoledronic acid 4 mg IV infusion over at least 15 minutes, single dose
- Pamidronate disodium 30-90 mg IV infusion (dose by calcium level), usually over 2-4 hours
- Ibandronic acid 2-4 mg IV infusion, single dose
Main antiresorptive therapy in malignancy-related hypercalcaemia after rehydration. Onset usually 24-48 hours, nadir by 4-7 days. Contraindications/cautions: severe renal impairment (dose adjust/avoid per product guidance), hypocalcaemia risk, osteonecrosis of jaw (dental assessment in recurrent use), acute phase reactions.
Calcitonin (selected severe cases)
- Calcitonin (salmon) 4 IU/kg SC or IM every 12 hours (can increase to 8 IU/kg every 6-12 hours short term)
Rapid but short-lived calcium reduction; useful as bridging therapy while bisphosphonate takes effect. Tachyphylaxis limits use beyond 48-72 hours.
Glucocorticoids for vitamin D-mediated hypercalcaemia
- Prednisolone 20-40 mg orally once daily
- Hydrocortisone 100 mg IV every 6 hours in severe inpatient presentations
Useful in lymphoma/sarcoidosis/TB-related calcitriol excess; not routine for PTH-driven disease. Screen infection risk and hyperglycaemia; taper according to response.
RANKL inhibition (refractory or renal-limited cases)
- Denosumab 120 mg subcutaneously on day 1, 8, 15, then every 4 weeks
Consider when bisphosphonates fail or are unsuitable. High risk of hypocalcaemia (especially CKD); ensure vitamin D repletion if appropriate and monitor calcium frequently.
Dialysis
- Haemodialysis with low-calcium dialysate in life-threatening, refractory hypercalcaemia
Reserved for severe cases with renal failure, fluid overload, or failure of medical therapy.
Surgical / Interventional
- Parathyroidectomy for primary hyperparathyroidism when symptomatic or when guideline criteria are met (e. g, renal stones, osteoporosis/fracture, significant hypercalcaemia, reduced renal function, younger age)
- Oncological treatment of underlying malignancy (systemic therapy/radiotherapy/surgery) to reduce recurrence risk
Complications
- Acute kidney injury and chronic renal impairment
- Nephrolithiasis and nephrocalcinosis
- Cardiac arrhythmias and reduced consciousness/coma in severe cases
- Pancreatitis and peptic ulcer disease (uncommon)
- Osteoporosis and fragility fractures
- Hypercalcaemic crisis with dehydration and multi-organ dysfunction
Prognosis
Outcome depends on cause and reversibility. Primary hyperparathyroidism generally has an excellent outlook with surgery (cure rates typically >95% for single adenoma), while conservatively managed disease can progress over time in a minority. Hypercalcaemia of malignancy is a poor prognostic marker because it often reflects advanced cancer, although modern cancer therapies and antiresorptives have improved short-term outcomes.
Sources & References
🏥BMJ Best Practice(5)
💊BNF Drug References(24)
- Adrenaline with articaine hydrochloride[cautions]
- Alfacalcidol[contraindications]
- Bendroflumethiazide[contraindications]
- Calcifediol monohydrate[contraindications]
- Calcitonin (salmon)[management.pharmacological]
- Calcitriol[contraindications]
- Calcium acetate with magnesium carbonate[contraindications]
- Chlortalidone[contraindications]
- Colecalciferol[contraindications]
- Co-tenidone[contraindications]
- Digoxin[cautions]
- Ergocalciferol[contraindications]
- Hydrochlorothiazide[contraindications]
- Ibandronic acid[management.pharmacological]
- Indapamide[contraindications]
- Metolazone[contraindications]
- Pamidronate disodium[management.pharmacological]
- Paricalcitol[contraindications]
- Testosterone[contraindications]
- Testosterone enantate[contraindications]
- Testosterone propionate[contraindications]
- Testosterone undecanoate[contraindications]
- Xipamide[contraindications]
- Zoledronic acid[management.pharmacological]
✅NICE Guidelines(1)
- Hypercalcaemia[overview]