Malignant hypercalcaemia

• Overview:

  • Hypercalcaemia is defined as an adjusted serum calcium of >2.6 mmol/L
  • Hypercalcaemia of malignancy if the most common life-threatening metabolic disorder in cancer patients
• Three main mechanisms result in hypercalcaemia of malignancy:

  • Secretion of parathyroid hormone-related protein (PTHrP)
  • Osteolytic metastases
  • Secretion of 1,25-dihydroxyvitamin D (calcitriol)
• Calcitriol = active form of vitamin D = increases calcium levels
• PTHrP secretion:

  • most common cause of hypercalcaemia in malignancy
  • Associated with - renal, ovarian, endometrial and squamous cell cancer
  • PTHrP stimulates osteoclastic resorption and inhibits osteoblast formation of bone = excessive calcium release
  • Also acts on kidney to reduce calcium clearance
• Osteolytic metastases:

  • Associated with breast cancer and multiple myeloma
  • Local release of cytokines and chemokines results in increased osteoclast activity
  • Excessive calcium release overwhelms the kidney's ability to clear it from the body
• Calcitriol mediated hypercalcaemia:

  • Can occur in most lymphomas
  • Over expression of the enzyme responsible for converting 25-hydroxyvitamin D to calcitriol
  • Excessive production of calcitriol (active from of vitamin D), resulting in increased intestinal absorption of calcium and increased osteoclast activity
• Cancers associated with hypercalcaemia:

  • Multiple myeloma: via osteolytic metastases
  • Breast cancer: via PTHrP and osteolytic metastases
  • Lung cancer (squamous cell carcinoma): via PTHrP
  • Renal cancer: via PTHrP
  • Thyroid cancer (squamous cell carcinoma): via PTHrP
  • Lymphomas (all types): via calcitriol
• Medications that worsen hypercalcaemia:

  • Thiazide like diuretics
  • Lithium
  • Over the counter supplements containing calcium or vitamin D
• Hypercalcaemia often presents with vague symptoms:

  • Confusion
  • Nausea and vomiting
  • Fatigue
  • Thirst: due to increased urine production causing dehydration
  • Polyuria: due to increased urine production via nephrogenic diabetes insipidus
  • Constipation
  • Anorexia
  • Bone pain: either due to the hypercalcaemia or due to bony metastases 
  • Abdominal pain
  • Renal colic
• The common presenting features are often remembered as stones, bones, groans and psychiatric moans (renal calculi, bone pain, abdominal pain and psychiatric features).
• Typical examination findings may include:

  • Signs of dehydration: dry mucous membranes, sunken eyes, reduced skin turgor
  • Hyporeflexia
  • Tongue fasciculations
  • Abdominal distension due to constipation
  • Bony tenderness
• The key investigation is the adjusted serum calcium level, with a result >2.6 mmol/L considered abnormal. Hypercalcaemia can then be further categorised according to severity:

  • Mild: <3.0 mmol/L
  • Moderate: 3 – 3.5 mmol/L
  • Severe: >3.5 mmol/L
• Bedside investigations:

  • ECG
  • Bradycardia
  • Shorted QT interval
  • Heart block
• Lab investigations:

  • U&Es - for AKI and planning treatment
  • PTH - will be suppressed in malignancies producing PTHrP
  • PTHrp
  • Bone profile - phosphate
  • Calcitriol
  • Vitamin D
  • Immunoglobulins and electrophoresis - if myeloma suspected
• Relevant imaging investigations include:

  • Chest X-ray: if underlying lung cancer is suspected
  • CT scan: to help stage any underlying cancer or assess for bony metastases
• Management:

  • Stop any contributing medications e.g. thiazide diuretics
  • Consider stopping nephrotoxic medications
  • Rehydration - IV fluids with target of at least 3L in the first 24 hours
  • Bisphosphonates - IV zoledronic acid (do not immediately reduce calcium so dont repeat dose until at least day 5)
• Asymptomatic patients with adjusted calcium <3 mmol/L can be considered for outpatient management
• Complications of hypercalcaemia of malignancy include:

  • Transient flu-like syndrome due to bisphosphonate treatment
  • Acute kidney injury (AKI)
  • Acute pancreatitis
  • Cardiac arrhythmias
  • Seizures
  • Coma
• Hypercalcaemia is also a poor prognostic indicator for patients with cancer, with a mean survival of 2-3 months