Key Facts

The first investigation in hypercalcaemia is PTH — it divides causes into PTH-mediated and non-PTH-mediated. Aggressive IV hydration is the cornerstone of acute management. IV bisphosphonates are highly effective for malignancy-associated hypercalcaemia.

Epidemiology

Common: found in ~1-3% of hospitalised patients. Primary HPT: ~1-3 per 1,000 population. Malignancy-associated: affects ~20-30% of cancer patients at some point.

Aetiology

PTH-mediated: primary hyperparathyroidism, tertiary HPT (chronic CKD), lithium, FHH. Non-PTH-mediated (PTH suppressed): malignancy (PTHrP, bone metastases, ectopic 1,25-D), vitamin D excess (intoxication, granulomatous disease — sarcoidosis, TB), thyrotoxicosis, immobilisation, Addison disease, drugs (thiazides, vitamin A), milk-alkali syndrome.

Pathophysiology

Hypercalcaemia causes polyuria (nephrogenic DI — calcium blocks aquaporin-2) → dehydration → worsening hypercalcaemia (reduced renal calcium excretion). This vicious cycle can lead to severe hypercalcaemia. Effects: GI smooth muscle hypotonia (constipation), CNS depression, shortened QT interval, renal (stones, nephrocalcinosis, AKI).

Mild (<3.0 mmol/L)

• Often asymptomatic (detected incidentally)
• Fatigue, mild constipation

Moderate (3.0-3.5 mmol/L)

• Polyuria, polydipsia
• Nausea, vomiting, anorexia
• Constipation
• Confusion, depression, cognitive impairment
• Bone pain

Severe (>3.5 mmol/L) — Emergency

• Severe dehydration
• Renal failure
• Abdominal pain, pancreatitis
• Cardiac arrhythmias (shortened QT)
• Drowsiness → coma

Red Flags

• Ca²⁺ >3.5 mmol/L → emergency
• Acute renal failure with hypercalcaemia
• Reduced consciousness
• Cardiac arrhythmia

Essential

• Adjusted calcium: >2.6 mmol/L (adjust for albumin)
• PTH: KEY discriminator — raised = HPT; suppressed = non-PTH cause
• Phosphate: low in HPT; variable in malignancy
• ALP: raised in bone metastases, HPT with bone disease
• U&Es: renal function, dehydration
• 25-OH vitamin D: excess or deficiency
• 1,25(OH)₂D₃: raised in sarcoidosis, lymphoma

If PTH Suppressed

• PTHrP: if malignancy suspected
• Protein electrophoresis (SPEP), urinary BJP: myeloma
• CXR, CT: malignancy, sarcoidosis
• ACE level: sarcoidosis

If PTH Raised

• 24-hour urine Ca:Cr clearance ratio: exclude FHH
• Sestamibi scan, USS neck: adenoma localisation

Other

• ECG: short QT interval
• TFTs: thyrotoxicosis
• Myeloma screen: if appropriate

Acute Severe Hypercalcaemia (>3.5 mmol/L or Symptomatic)

1. IV 0.9% NaCl: aggressive rehydration (3-4L in first 24 hours; adjust for cardiac status)
2. IV bisphosphonate: zoledronic acid 4mg IV over 15 minutes (preferred — more potent) OR pamidronate 60-90mg IV over 2-4 hours; onset 2-4 days; lasts 2-4 weeks
3. Loop diuretics (furosemide): ONLY if fluid-overloaded (NOT routine — may worsen dehydration)
4. Monitor U&Es, calcium 12-24 hourly

Refractory/Specific Causes

• Denosumab 120mg SC: if bisphosphonate-resistant or renal impairment
• Corticosteroids (prednisolone 40mg/day): sarcoidosis, lymphoma, vitamin D excess, myeloma (reduces 1,25-D production/direct tumour effect)
• Calcitonin 4 units/kg SC/IM 12-hourly: rapid but temporary effect (tachyphylaxis within 48h); useful bridge while awaiting bisphosphonate effect
• Dialysis: refractory severe hypercalcaemia with renal failure

Definitive

• Treat underlying cause: parathyroidectomy (HPT), chemotherapy/radiotherapy (malignancy)

Referral Criteria

• Endocrinology: primary HPT
• Oncology: malignancy-associated
• Renal: severe renal impairment

Depends on underlying cause. Primary HPT: excellent prognosis after parathyroidectomy. Malignancy-associated hypercalcaemia: often indicates advanced disease; median survival ~3 months (varies with cancer type). Sarcoidosis: responds well to corticosteroids. Mild chronic hypercalcaemia: generally well-tolerated. Severe hypercalcaemia (>4.0 mmol/L): medical emergency with significant mortality if untreated.

Causes of Hypercalcaemia by PTH Level

Acute Hypercalcaemia Treatment Steps