hypercalcaemia
in review
4 min read
Updated 2026-08-23
Contents
approach to hypercalcaemia
Corrected calcium >2.6 mmol/L (or ionised >1.35 mmol/L). Primary hyperparathyroidism and malignancy account for >90% of cases. The single most useful branch point: is PTH elevated/inappropriately normal (PTH-mediated) or suppressed (PTH-independent)?
do not miss
- Severe hypercalcaemia (Ca²⁺ >3.5 mmol/L) → IV normal saline aggressively; risk of cardiac arrest, coma
- Hypercalcaemia of malignancy — often presents with Ca²⁺ >3.0 mmol/L, rapid onset, poor prognosis (median survival weeks to months if underlying malignancy untreated). Check PTHrP.
- ECG changes — shortened QTc, bradycardia, heart block; risk of VF at very high levels
classification
PTH-mediated (PTH ↑ or inappropriately normal)
| cause | features |
|---|---|
| primary hyperparathyroidism | most common outpatient cause; often incidental finding; mild hypercalcaemia (<3.0), low-normal phosphate, elevated 24-h urine calcium |
| tertiary hyperparathyroidism | autonomous PTH secretion after prolonged secondary HPT (CKD, post-transplant) |
| familial hypocalciuric hypercalcaemia (FHH) | autosomal dominant CaSR mutation; mild lifelong hypercalcaemia with low urine calcium; calcium:creatinine clearance ratio <0.01 — distinguish from PHPT to avoid unnecessary surgery |
| lithium | shifts CaSR set point; PTH-mediated; may unmask adenoma |
PTH-independent (PTH suppressed)
| cause | mechanism |
|---|---|
| malignancy — PTHrP | humoral hypercalcaemia of malignancy (squamous cell, renal, breast); PTHrP ↑ |
| malignancy — osteolytic | direct bone destruction (multiple myeloma, breast mets); PTHrP may be normal |
| malignancy — calcitriol | lymphoma (autonomous 1,25-OH₂D production) |
| granulomatous disease | sarcoidosis, TB, fungal — autonomous 1,25-OH₂D production by macrophages |
| vitamin D toxicity | exogenous (supplements, often >10,000 IU/day); 25-OH-D markedly elevated |
| thiazide diuretics | reduce renal calcium excretion; usually mild |
| immobilisation | increased bone resorption; especially in Paget disease or young patients |
| milk-alkali syndrome | excessive calcium + absorbable alkali intake |
| thyrotoxicosis, adrenal insufficiency | uncommon; mild |
workup
first-pass
- Corrected calcium = total Ca + 0.02 × (40 − albumin in g/L). Or measure ionised calcium directly.
- PTH — the critical branch point
- Phosphate — low in PHPT and PTHrP-mediated; high in vitamin D excess and CKD
- Creatinine — renal function; CKD changes the differential
- 25-OH vitamin D — exogenous vitamin D excess
- 1,25-OH₂ vitamin D — elevated in granulomatous disease and lymphoma
second-pass (directed by PTH result)
| PTH elevated/normal | PTH suppressed |
|---|---|
| 24-h urine calcium + creatinine (Ca:Cr clearance ratio to exclude FHH) | PTHrP |
| sestamibi/US neck (localise adenoma) | 1,25-OH₂D (granulomatous/lymphoma) |
| consider lithium history | SPEP/UPEP (myeloma) |
| CT chest/abdomen if malignancy suspected |
management
acute (symptomatic or Ca²⁺ >3.5 mmol/L)
- IV normal saline — 200–300 mL/h initially; most patients are profoundly volume-depleted from nephrogenic DI. Adjust for cardiac reserve.
- Calcitonin 4 IU/kg SC/IM q12h — rapid onset (4–6 h) but tachyphylaxis by 48 h. Useful as a bridge.
- Zoledronic acid 4 mg IV over 15 min — onset 2–4 days, duration weeks. First-line for malignancy-associated hypercalcaemia. Avoid if eGFR <35 (or use with dose adjustment and slow infusion).
- Denosumab 120 mg SC — alternative when bisphosphonates contraindicated (renal impairment). Onset 4–10 days.
loop diuretics — not routine
Furosemide for calciuresis is a legacy practice. It is only indicated for volume overload during saline resuscitation, not as a primary treatment. Giving furosemide to a volume-depleted patient worsens hypercalcaemia.
by cause
- Primary HPT → parathyroidectomy (curative). Medical management with cinacalcet if surgery declined or contraindicated.
- Malignancy → treat underlying malignancy; zoledronic acid or denosumab for bone-related hypercalcaemia
- Granulomatous disease → corticosteroids (prednisone 20–40 mg/day) — suppress macrophage 1-alpha-hydroxylase; rapid response
- Vitamin D toxicity → stop supplementation; corticosteroids if severe; hydration
- FHH → no treatment needed (benign); counsel against unnecessary parathyroidectomy
traps
- FHH misdiagnosed as PHPT → unnecessary surgery — always check a calcium:creatinine clearance ratio before referring for parathyroidectomy. Ratio <0.01 favours FHH. Prevalence ~1:78,000, but matters because surgery cures PHPT and fails in FHH.
- Assuming hypercalcaemia = primary HPT — in the inpatient setting, malignancy is more common. PHPT dominates in the outpatient population.
- Forgetting myeloma — osteolytic lesions from multiple myeloma cause hypercalcaemia without PTHrP elevation (bone destruction is direct). SPEP/UPEP should be part of the workup when PTH is suppressed and PTHrP is normal.
- Volume status before bisphosphonates — give adequate saline first. Bisphosphonates take 2–4 days to work; a dehydrated patient with Ca²⁺ >4.0 needs saline now, not just zoledronic acid.
- Thiazides as the sole explanation — thiazides cause mild hypercalcaemia (<2.8 mmol/L). If calcium is significantly elevated on a thiazide, there is usually an underlying cause (often PHPT) that the thiazide has unmasked.
related: multiple myeloma · acute kidney injury