What is Hypercalcemia?

Hypercalcemia is abnormally high calcium levels in the blood. Normal serum calcium is 8.5-10.5 mg/dL (total) or 4.6-5.3 mg/dL (ionized). Hypercalcemia is defined as total calcium >10.5 mg/dL or ionized calcium >5.6 mg/dL.

Common Causes:

Mnemonic: "CHIMPANZEES" (though simplified, the TWO most common causes account for 90%):

• Primary Hyperparathyroidism (PHPT) – 50-60% of cases (outpatient)
• Malignancy – 30-40% of cases (inpatient/hospitalized)

Other Causes:

• Medications:
  • Thiazide diuretics
  • Lithium
  • Vitamin D or Vitamin A intoxication
  • Calcium supplementation (milk-alkali syndrome)
• Granulomatous Diseases: Sarcoidosis, tuberculosis (produce calcitriol)
• Endocrine: Hyperthyroidism, pheochromocytoma, adrenal insufficiency
• Immobilization: Prolonged bed rest (bone resorption exceeds formation)
• Familial Hypocalciuric Hypercalcemia (FHH): Benign genetic condition
• Paget's Disease: If immobilized

Malignancy-Associated Hypercalcemia (MAH):

• Humoral Hypercalcemia of Malignancy: Tumor secretes PTHrP (PTH-related peptide)—mimics PTH. Common in lung, breast, kidney cancers
• Osteolytic Metastases: Cancer in bones directly destroys bone (breast, multiple myeloma)
• Lymphomas: Produce calcitriol

Symptoms ("Stones, Bones, Groans, and Psychiatric Overtones"):

Mild Hypercalcemia (10.5-12 mg/dL): Often asymptomatic or mild symptoms

Moderate to Severe Hypercalcemia (>12-14 mg/dL):

• Renal ("Stones"): Kidney stones, polyuria (excessive urination), polydipsia (thirst), dehydration, kidney failure
• Skeletal ("Bones"): Bone pain, fractures, osteoporosis
• Gastrointestinal ("Groans"): Nausea, vomiting, constipation, abdominal pain, pancreatitis, peptic ulcers
• Neuropsychiatric ("Psychiatric Overtones"): Fatigue, weakness, confusion, depression, "brain fog", altered mental status, coma (if severe)
• Cardiovascular: Hypertension, shortened QT interval, arrhythmias

Diagnosis:

Confirm Elevated Calcium:

• Total Serum Calcium: >10.5 mg/dL (correct for albumin if low)
• Ionized Calcium: >5.6 mg/dL (most accurate; not affected by albumin)

Find the Cause (Initial Workup):

• PTH (Parathyroid Hormone): KEY TEST
  • PTH Elevated or Inappropriately Normal: Primary Hyperparathyroidism or Familial Hypocalciuric Hypercalcemia (FHH)
  • PTH Suppressed (Low): Malignancy, Vitamin D toxicity, granulomatous disease, other non-PTH causes
• PTHrP: If PTH low and malignancy suspected
• 25-OH Vitamin D, 1,25-Vitamin D (Calcitriol): Check for Vitamin D toxicity or granulomatous disease
• Phosphorus: Low in PHPT, variable in other causes
• Alkaline Phosphatase: Elevated in bone disease, malignancy
• Kidney Function (Creatinine, eGFR)
• 24-Hour Urine Calcium: To differentiate PHPT from FHH
  • PHPT: High or normal urine calcium
  • FHH: Low urine calcium (calcium/creatinine clearance ratio <0.01)< /li>

If Malignancy Suspected:

• Chest X-ray, CT scans
• Serum protein electrophoresis (SPEP), urine protein electrophoresis (UPEP) for multiple myeloma
• Cancer-specific workup based on history/symptoms

Treatment:

Depends on Severity and Cause

Mild Hypercalcemia (<12 mg/dL, Asymptomatic):

• Treat underlying cause (e.g., surgery for PHPT)
• Hydration, avoid dehydration
• Avoid thiazides, calcium/Vitamin D supplements
• Monitor

Moderate to Severe Hypercalcemia (>12-14 mg/dL or Symptomatic):

1. Aggressive IV Hydration (First-Line):

• Normal saline (0.9% NaCl) 200-300 mL/hour initially
• Promotes calcium excretion in urine
• Corrects dehydration (common in hypercalcemia)

2. Loop Diuretics (Furosemide):

• ONLY after adequate hydration
• Increases urinary calcium excretion
• Monitor electrolytes closely

3. Bisphosphonates (for Malignancy or Severe Cases):

• Zoledronic Acid (Reclast®): 4 mg IV over 15 minutes (most potent)
• Pamidronate: 60-90 mg IV over 2-4 hours
• Inhibit bone resorption
• Takes 2-4 days to work; lasts weeks

4. Calcitonin (Rapid but Short-Lived):

• 4-8 IU/kg IM or SC every 6-12 hours
• Works within hours but effect wanes after 48 hours (tachyphylaxis)
• Useful as bridge while waiting for bisphosphonates to work

5. Denosumab (Prolia®, Xgeva®):

• For bisphosphonate-refractory malignancy-associated hypercalcemia
• 120 mg SC

6. Glucocorticoids:

• For Vitamin D toxicity, granulomatous disease, lymphomas
• Prednisone 40-60 mg/day

7. Dialysis:

• For life-threatening hypercalcemia unresponsive to other therapies or if kidney failure present

8. Treat Underlying Cause:

• PHPT: Parathyroidectomy (surgery)
• Malignancy: Chemotherapy, radiation, targeted therapy
• Stop Offending Medications: Thiazides, lithium, Vitamin D/A

Hypercalcemic Crisis (Medical Emergency):

• Calcium >14-15 mg/dL with severe symptoms (altered mental status, arrhythmias, acute kidney injury)
• Requires ICU-level care
• Aggressive IV hydration, calcitonin, bisphosphonates, possible dialysis
• High mortality if untreated