Hypercalcaemia

Contents

Overview

Hypercalcaemia is a corrected serum calcium above 2.6 mmol/L. Severe hypercalcaemia (>3.5 mmol/L) causes a constellation of neurological, gastrointestinal, renal, and cardiac effects that can be life-threatening. The two most common causes — primary hyperparathyroidism and malignancy — account for over 90% of cases. Identification of the underlying aetiology guides definitive management beyond acute resuscitation.

Calcium Physiology

Serum calcium exists in three fractions:

  • Ionised (free): ~50% — the biologically active form
  • Protein-bound (principally to albumin): ~40%
  • Complexed (to citrate, phosphate, bicarbonate): ~10%

Only ionised calcium is physiologically active. Total serum calcium must be corrected for albumin: Corrected Ca = Measured Ca + 0.02 × (40 − albumin g/L). In critically ill patients with hypoalbuminaemia, measured calcium underestimates true ionised calcium; ionised calcium measured directly on ABG is preferred in the ICU.

Regulation:

  • Parathyroid hormone (PTH) increases calcium by stimulating osteoclastic bone resorption, increasing renal calcium reabsorption, and activating vitamin D (calcitriol) production in the kidney
  • Calcitriol increases intestinal calcium absorption
  • Calcitonin (from thyroid C cells) lowers calcium by reducing osteoclast activity — physiological role is minor in adults
  • FGF-23 reduces phosphate reabsorption and inhibits calcitriol production

Aetiology

Primary hyperparathyroidism: The most common cause overall (90% of outpatient cases). Usually a solitary parathyroid adenoma. Causes mild-to-moderate asymptomatic hypercalcaemia; symptomatic crisis is less common. PTH is elevated (or inappropriately normal relative to the calcium level).

Malignancy: The most common cause of severe or symptomatic hypercalcaemia in hospitalised patients. Mechanisms:

  • PTHrP (PTH-related peptide): secreted by solid tumours (squamous cell carcinomas of lung, head and neck, oesophagus, breast, renal, bladder). Binds PTH receptor, mimicking PTH. Most common mechanism. PTH is suppressed.
  • Osteolytic metastases: direct bone destruction by metastases (breast, myeloma, lymphoma). Local cytokine-mediated osteoclast activation.
  • 1,25-dihydroxyvitamin D production: by lymphoma and granulomas (extrarenal calcitriol synthesis). Causes elevated calcitriol.

Sarcoidosis and granulomatous disease: Activated macrophages in granulomas express 1-alpha-hydroxylase, converting 25-OH vitamin D to active calcitriol. PTH is suppressed. Also seen in TB, histoplasmosis, berylliosis.

Vitamin D toxicity: Excessive supplementation or calcitriol in CKD.

Milk-alkali syndrome: Excessive calcium and absorbable alkali intake (antacids, calcium carbonate).

Thiazide diuretics: Reduce renal calcium excretion; usually mild.

Immobilisation: Especially in Paget's disease or with high bone turnover. Uncoupling of bone formation and resorption.

Other endocrine: Thyrotoxicosis (excess osteoclast activity), Addison's disease, acromegaly, phaeochromocytoma.

Clinical Features

Remembered as Bones, Stones, Groans, Psychic Moans:

Bones: Bone pain, pathological fractures, osteitis fibrosa cystica (in prolonged hyperparathyroidism).

Stones: Nephrolithiasis (calcium oxalate or phosphate), nephrocalcinosis, polyuria and polydipsia from nephrogenic diabetes insipidus (hypercalcaemia reduces collecting duct responsiveness to ADH).

Groans: Nausea, vomiting, constipation, anorexia, pancreatitis, peptic ulcer disease.

Psychic moans: Confusion, lethargy, depression, psychosis, and in severe cases stupor and coma.

Cardiac: Shortened QT interval on ECG (as distinct from hypocalcaemia, which prolongs QT). Bradycardia, PR prolongation, and cardiac arrest in severe hypercalcaemia.

Severity does not correlate perfectly with calcium level — the rate of rise matters as much as the absolute level.

Investigations

Initial:

  • Serum calcium (corrected), ionised calcium (blood gas)
  • PTH (intact)
  • Phosphate (low in primary hyperparathyroidism, variable in malignancy)
  • Renal function and eGFR
  • Albumin
  • ALP (elevated in bone disease, Paget's)

Second line:

  • PTHrP (if malignancy suspected and PTH suppressed)
  • 25-OH vitamin D and 1,25-OH vitamin D
  • Urinary calcium excretion (24-hour collection or spot calcium:creatinine ratio)
  • Serum protein electrophoresis and immunofixation (myeloma)
  • TSH, cortisol (if thyrotoxicosis or Addison's suspected)
  • ACE (sarcoidosis)
  • CT chest/abdomen/pelvis, bone scan — tumour search if PTHrP elevated or malignancy suspected

Interpretation:

  • Elevated PTH + hypercalcaemia = primary hyperparathyroidism (or tertiary in CKD)
  • Suppressed PTH + hypercalcaemia + elevated PTHrP = malignancy (humoral)
  • Suppressed PTH + hypercalcaemia + elevated calcitriol = granulomatous disease or lymphoma

Management

Acute Severe Hypercalcaemia

Corrected calcium >3.5 mmol/L, or symptomatic at lower levels, requires urgent treatment.

IV fluids: 0.9% sodium chloride at 200–500 mL/hour to restore intravascular volume and promote urinary calcium excretion. Dehydration is universal (polyuria, reduced oral intake) and must be corrected first. Target urine output 100–150 mL/hour.

Bisphosphonates: Once rehydrated, IV bisphosphonate is the cornerstone of definitive calcium-lowering treatment.

  • Zoledronic acid 4 mg IV over 15 minutes: most potent, most rapid onset (calcium falls within 2–4 days, nadir at 7–10 days). Preferred agent.
  • Pamidronate 60–90 mg IV over 2–4 hours: alternative if zoledronate is unavailable or contraindicated.
  • Avoid in severe renal impairment (eGFR <30) — use with caution and reduce dose.

Bisphosphonates inhibit osteoclast-mediated bone resorption. They do not act immediately; other measures are needed while they take effect.

Calcitonin: Rapid onset (hours), but effect is modest and short-lived (tachyphylaxis within 48–72 hours). Salmon calcitonin 4–8 IU/kg IM/SC 6–12 hourly provides a bridge while bisphosphonates take effect. Useful in severe symptomatic hypercalcaemia.

Corticosteroids: Effective in hypercalcaemia due to vitamin D-mediated mechanisms — sarcoidosis, lymphoma, vitamin D toxicity. Prednisolone 40–60 mg/day. Not effective in primary hyperparathyroidism or PTHrP-mediated hypercalcaemia.

Furosemide: Traditionally used to promote urinary calcium excretion after rehydration. Evidence for benefit is weak; routine use is not recommended. Reserve for patients with fluid overload despite rehydration.

Denosumab: Anti-RANKL monoclonal antibody, increasingly used in malignant hypercalcaemia refractory to bisphosphonates or where bisphosphonates are contraindicated. Works independently of renal function.

Haemodialysis: Effective rapid calcium reduction in life-threatening hypercalcaemia, particularly in renal failure where fluids and bisphosphonates are contraindicated.

Definitive Treatment

Directed at the underlying cause:

  • Primary hyperparathyroidism: parathyroidectomy
  • Malignancy: treat underlying cancer; bisphosphonates/denosumab for skeletal morbidity
  • Sarcoidosis: corticosteroids; hydroxychloroquine for chronic disease

Viva Questions

How do you differentiate between the common causes of hypercalcaemia biochemically?

The key discriminating test is the intact PTH level. In primary hyperparathyroidism, PTH is elevated or inappropriately normal relative to the high calcium level — PTH should be suppressed when calcium is elevated, so even a "normal" PTH in the context of hypercalcaemia is abnormal. In malignancy-associated hypercalcaemia, PTH is suppressed. PTHrP is elevated in humoral hypercalcaemia of malignancy (squamous carcinomas, renal, breast, bladder). If PTH is suppressed and PTHrP is negative, elevated calcitriol suggests granulomatous disease (sarcoidosis, TB) or lymphoma, where ectopic 1-alpha-hydroxylation of vitamin D occurs. Phosphate is typically low in primary hyperparathyroidism (PTH promotes phosphaturia) and variable in other causes. ALP is elevated in Paget's disease and bone metastases. Urinary calcium excretion distinguishes familial hypocalciuric hypercalcaemia (FHH — very low urinary calcium) from primary hyperparathyroidism, which is important because FHH does not benefit from parathyroidectomy.

What is the immediate management of severe symptomatic hypercalcaemia?

The first step is aggressive IV fluid resuscitation with 0.9% sodium chloride. Patients with severe hypercalcaemia are invariably volume-depleted from polyuria, vomiting, and reduced oral intake. Rehydration is essential both to restore haemodynamics and to promote urinary calcium excretion — urine output should target 100–150 mL/hour. Calcitonin (salmon calcitonin 4–8 IU/kg IM or SC 6–12 hourly) provides rapid but short-lived calcium lowering within hours, and is useful as a bridge while waiting for bisphosphonates to work. Zoledronic acid 4 mg IV is given once the patient is rehydrated — it reaches its maximal effect over 2–4 days. Corticosteroids are added if the mechanism is vitamin D-mediated (sarcoidosis, lymphoma, vitamin D toxicity). In the context of renal failure or life-threatening hypercalcaemia refractory to the above, haemodialysis provides the most rapid calcium reduction. Cardiac monitoring is essential — the shortened QT and risk of arrhythmia require continuous ECG monitoring until calcium normalises.

What is the mechanism and clinical significance of hypercalcaemia in malignancy?

Malignancy causes hypercalcaemia through two principal mechanisms. The most common is humoral hypercalcaemia of malignancy (HHM), mediated by PTH-related peptide (PTHrP). PTHrP is structurally homologous to the N-terminus of PTH and binds the PTH receptor, stimulating osteoclastic bone resorption and renal calcium reabsorption, while suppressing endogenous PTH. It is most commonly produced by squamous cell carcinomas (lung, head and neck, oesophagus), renal cell carcinoma, and breast cancer. The second mechanism is osteolytic metastases, where direct tumour invasion of bone and local cytokine release (including RANKL) drive localised osteoclast activation; myeloma, breast, and lung metastases are the typical causes. A third mechanism — ectopic calcitriol production — occurs in some lymphomas. Clinically, malignant hypercalcaemia is often severe and rapidly progressive, presenting with confusion, dehydration, renal failure, and cardiac arrhythmias. It carries a poor prognosis in the context of advanced malignancy — median survival after diagnosis of malignant hypercalcaemia is 30 days without treatment of the underlying cancer — though acute treatment with bisphosphonates relieves symptoms and may restore function pending oncological management.