Hypercalcemia

Background

• Hypercalcemia is a serum calcium level above the upper limit of normal. While reference ranges vary by laboratory, it is usually defined as ionized fraction of calcium > 5.6 mg/dL (1.4 mmol/L) or total calcium > 10.6 mg/dL (2.6 mmol/L) in adults (slightly higher in children).
• Hypercalcemia is often asymptomatic and detected during routine screening or during monitoring for underlying conditions such as osteoporosis or nephrolithiasis.
• Primary hyperparathyroidism and malignancy are the most common causes of hypercalcemia in adults. Less common causes include granulomatous disease (both infectious and noninfectious), vitamin D or vitamin A excess, milk-alkali syndrome, medications, immobilization, and certain benign tumors.
• Hypercalcemia is rare in children and the underlying etiology may be much broader.
• Complications of hypercalcemia include altered mental status, pancreatitis, peptic ulcer disease, hypertension and vascular calcifications, dehydration, bone pain and fractures, and renal dysfunction such as nephrogenic diabetes insipidus, nephrolithiasis, and chronic kidney disease.

Evaluation

• The clinical presentation depends on the severity of hypercalcemia.
  • Mild hypercalcemia:
    • defined as ionized calcium 5.6-8 mg/dL (1.4-2 mmol/L) or total calcium 10.6-12 mg/dL (2.6-3 mmol/L)
    • usually asymptomatic
  • Moderate hypercalcemia:
    • defined as ionized calcium 8-10 mg/dL (2-2.5 mmol/L) or total calcium 12-14 mg/dL (3-3.5 mmol/L)
    • presentation may include fatigue, malaise, anorexia, impaired mental concentration, constipation, polyuria, and polydipsia
  • Severe hypercalcemia (also known as hypercalcemic crisis):
    • defined as ionized calcium > 10 mg/dL (2.5 mmol/L) or total calcium > 14 mg/dL (3.5 mmol/L)
    • presentation may include symptoms of moderate hypercalcemia in addition to nausea, vomiting, dehydration, pancreatitis, peptic ulcers, arrhythmias, cardiac arrest, altered mental capacity, stupor, or coma
    • considered a life-threatening emergency requiring hospital admission for IV hydration and treatment
• Diagnosing the underlying cause of hypercalcemia:
  • Initial blood tests should include an assessment of concurrent serum calcium, albumin, estimated glomerular filtration rate (GFR), and intact parathyroid hormone (PTH) level.
  • If PTH is inappropriately normal (should be suppressed in hypercalcemia) or high, perform a 24-hour urine collection for calcium and creatinine and measure concurrent serum creatinine and calcium to calculate a creatinine clearance ratio (CaCrCl).

    CaCrCl = (Urinary calcium × Serum creatinine) ÷ (Serum calcium × Urinary creatinine)

    • If GFR is < 60 mL/minute, consider impaired renal function as the cause of low urinary calcium excretion.
    • If GFR is > 60 mL/minute:
      • CaCrCl < 0.01 suggests familial hypocalciuric hypercalcemia
      • CaCrCl 0.01-0.02 suggests either primary hyperparathyroidism or familial hypocalciuric hypercalcemia; genetic testing will often be necessary for diagnosis
      • CaCrCl > 0.02 suggests primary hyperparathyroidism
  • If PTH is appropriately suppressed, proceed with workup for malignancy.
    • Measure parathyroid hormone-related peptide (PTHrP), 1,25-dihydroxyvitamin D (calcitriol), and 25-hydroxyvitamin D (calcidiol).
      • If PTHrP is elevated, malignancy is the most likely cause.
      • If PTHrP is normal and calcitriol is elevated, causes may include lymphoma or granulomatous disease (such as sarcoidosis).
      • If PTHrP and calcitriol are normal and calcidiol is elevated, the most likely cause is vitamin D intoxication.
    • If PTHrP, calcitriol, and calcidiol are all normal, measure serum protein electrophorese (SPEP), urine protein electrophoresis (UPEP), and/or serum-free light chain assay.
    • If SPEP, UPEP, and serum-free light chain assay are abnormal, underlying cause may be multiple myeloma.
    • If malignancy workup is positive, imaging studies should be performed, including:
      • chest x-ray to evaluate for sarcoid, often with biopsy of appropriate tissue
      • bone scans to evaluate for metastatic lesions
    • If malignancy workup is negative, consider lymphoproliferative or granulomatous disorders and test for other endocrinopathies, including:
      • thyroid function tests to rule out hyperthyroidism
      • cortisol to rule out adrenal insufficiency
      • insulin-like growth factor-1 to evaluate for biochemical evidence of acromegaly
      • vitamin A to test for vitamin A intoxication
• Additional testing in patients with confirmed hyperparathyroidism:
  • Imaging studies should be performed after biochemical diagnosis of hyperparathyroidism, including:
    • thyroid/parathyroid ultrasound and sestamibi scan (usually with single photon emission computed tomography [SPECT]) to localize parathyroid adenomas
    • dual-energy x-ray absorptiometry (DXA) to measure bone mineral density, including of the forearm
  • Genetic testing may be indicated when primary hyperparathyroidism is suspected to arise from an inherited endocrinopathy, including in patients with:
    • family history of hypercalcemia
    • familial hypocalciuric hypercalcemia
    • unusually low age at presentation (< 45 years)

Management

• If the history or physical suggests a modifiable underlying cause (such as medications), discontinue the exposure to the potential causative agent and recheck the serum calcium. If the patient is taking thiazide diuretics, stop the diuretic and repeat the serum calcium in 1 month, as high-dose thiazide diuretics can unmask primary hyperparathyroidism.
• Patients with severe hypercalcemia (> 14 mg/dL [3.5 mmol/L]) or acutely rising symptomatic hypercalcemia require immediate treatment.
  • Provide IV rehydration with normal saline (2-4 L/day for 1-3 days) for moderate-to-severe hypercalcemia (oral hydration may be sufficient for mild hypercalcemia).
  • Bisphosphonates suppress osteoclast activity and are the treatment of choice for moderate-to-severe hypercalcemia of various etiologies.
    • Bisphosphonates may take 24-48 hours to take effect.
    • In hypercalcemic emergency, fluids, loop diuretics, and calcitonin can be used to manage symptoms while waiting for bisphosphonates to take effect.
  • Glucocorticoids can be used for hypercalcemia due to granulomatous disease or lymphoma until primary treatment of malignancy takes effect.
  • Denosumab may be the preferred treatment option over bisphosphonates (either as a monotherapy or initially combined with calcitonin) in patients with severe kidney dysfunction and moderate-to-severe hypercalcemia of malignancy.
  • Options for medication-resistant hypercalcemic crisis include hemodialysis or, in patients with primary hyperparathyroidism, urgent parathyroidectomy.
• Management of patients with chronic symptomatic moderate hypercalcemia (12-14 mg/dL [3-3.5 mmol/L]) is similar to management of severe cases, but treatment is less urgent.
• Interventions for mild hypercalcemia or to reduce risk for recurrence following treatment of severe hypercalcemia may include:
  • discontinuing any medications associated with hypercalcemia, if possible
  • encouraging adequate hydration
  • encouraging mobilization
  • reviewing dietary calcium and vitamin D intake
• Medical management of hypercalcemia of malignancy in adults:
  • In adults with moderate hypercalcemia of malignancy and symptomatic or an acute increase in serum calcium:
    • Treat with denosumab or IV bisphosphonate (such as pamidronate or zoledronic acid) over no treatment with either antiresorptive medication (Strong recommendation).
    • Consider treatment with denosumab over treatment with IV bisphosphonate (Weak recommendation).
  • In adults with severe hypercalcemia of malignancy, consider a combination of calcitonin (for 2-3 days due to tachyphylaxis) plus IV bisphosphonate or denosumab for initial treatment over IV bisphosphonate or denosumab monotherapy for initial treatment (Weak recommendation).
  • In adults with refractory or recurrent hypercalcemia of malignancy after treatment with IV bisphosphonate, consider treatment with denosumab over treatment without denosumab (Weak recommendation).