What is hypercalcemia?

Hypercalcemia Definition and Management

Hypercalcemia is defined as an albumin-corrected serum calcium level above the upper limit of normal (typically >10.5 mg/dL or >2.6 mmol/L), with severe hypercalcemia defined as levels ≥12 mg/dL (≥3 mmol/L). 1

Classification of Hypercalcemia

Hypercalcemia can be classified based on severity:

• Mild hypercalcemia: Total calcium <12 mg/dL (<3 mmol/L) or ionized calcium of 5.6-8.0 mg/dL (1.4-2 mmol/L) 2
• Moderate to severe hypercalcemia: Albumin-corrected serum calcium ≥12 mg/dL 1
• Severe hypercalcemia: Total calcium ≥14 mg/dL (>3.5 mmol/L) or ionized calcium ≥10 mg/dL (≥2.5 mmol/L) 2
• Hypercalcemic crisis: Total calcium >3.5 mmol/L with severe symptoms 3

Etiology

Hypercalcemia can be categorized based on the underlying mechanism:

1. PTH-dependent causes (elevated or normal PTH):

   • Primary hyperparathyroidism (PHPT) - most common cause in outpatients (90% of cases) 2
   • Tertiary hyperparathyroidism (occurs in chronic kidney disease patients after prolonged secondary hyperparathyroidism) 1

2. PTH-independent causes (suppressed PTH <20 pg/mL):

   • Malignancy-associated hypercalcemia - most common cause in hospitalized patients 2
     • Humoral hypercalcemia: Due to PTH-related protein (PTHrP) production
     • Osteolytic hypercalcemia: Due to bone invasion
   • Granulomatous disorders (sarcoidosis)
   • Vitamin D toxicity
   • Medication-induced (thiazide diuretics, calcium supplements, vitamin D/A supplements)
   • Immobilization
   • Endocrinopathies (thyroid disease)

Clinical Presentation

• Mild hypercalcemia: Often asymptomatic, but may present with fatigue and constipation in approximately 20% of patients 2
• Severe hypercalcemia: Nausea, vomiting, polyuria, dehydration, confusion, somnolence, and coma 2

Diagnostic Approach

1. Calculate corrected calcium:

   • Corrected calcium (mg/dL) = Total calcium (mg/dL) + 0.8 × [4 - Serum albumin (g/dL)] 1

2. Initial laboratory evaluation:

   • Intact parathyroid hormone (iPTH) - critical for differentiating causes
   • Complete blood count
   • Urinalysis
   • Thyroid-stimulating hormone (TSH)
   • Liver function tests
   • Parathyroid hormone-related protein (PTHrP)
   • Vitamin D metabolites (25-OH and 1,25-OH2)
   • Serum calcium, albumin, magnesium, and phosphorus 1

Management

Mild Asymptomatic Hypercalcemia

• Observation with monitoring if due to PHPT in patients >50 years with serum calcium <1 mg/dL above upper normal limit and no evidence of skeletal or kidney disease 2
• Discontinuation of offending agents (thiazide diuretics, calcium supplements, vitamin D/A supplements) 1

Symptomatic or Severe Hypercalcemia

1. Immediate measures:

   • Aggressive IV fluid resuscitation with normal saline 1
   • Loop diuretics (only after volume restoration) to enhance calcium excretion 1
   • Calcitonin for immediate short-term management of severe symptomatic hypercalcemia 1

2. Bisphosphonates:

   • Zoledronic acid 4 mg IV over 15 minutes is the preferred first-line treatment for moderate to severe hypercalcemia 1
   • Alternative: Pamidronate 90 mg IV 1
   • Dose adjustments not necessary for mild-to-moderate renal impairment (serum creatinine <4.5 mg/dL) 1

3. For renal impairment:

   • Denosumab is preferred over bisphosphonates in patients with severe renal impairment 1
   • Consider dialysis with calcium-free or low-calcium solution for patients with renal failure 1

4. For specific causes:

   • Glucocorticoids for vitamin D toxicity, granulomatous disorders, or some lymphomas 1
   • Parathyroidectomy for PHPT depending on age, serum calcium level, and evidence of kidney or skeletal involvement 1

Monitoring and Follow-up

• Regular monitoring of serum calcium, phosphate, magnesium, renal function, and electrolytes 1
• Retreatment with zoledronic acid 4 mg may be considered if serum calcium does not normalize after initial treatment (minimum 7 days before retreatment) 1
• For malignancy-associated hypercalcemia, continue bone-targeting treatment (bisphosphonates or denosumab) for up to 2 years 1

Common Pitfalls to Avoid

• Failing to correct calcium for albumin, leading to inaccurate diagnosis
• Inadequate hydration before bisphosphonate administration
• Using diuretics before correcting hypovolemia
• Not monitoring for hypocalcemia after treatment, especially with denosumab
• Treating the laboratory value without addressing the underlying cause
• Delaying treatment of severe hypercalcemia 1