What is the likely cause of hypercalcemia in a patient with a serum albumin of 3.5 and a prealbumin of 12?

Severe Hypercalcemia: Likely Causes and Diagnostic Approach

A serum calcium of 14 mg/dL with normal albumin (3.5 g/dL) and low prealbumin (12 mg/dL) most likely indicates malignancy-associated hypercalcemia or primary hyperparathyroidism, with the low prealbumin suggesting either malignancy with cachexia or chronic illness. 1

Immediate Diagnostic Priority

The single most important test is intact parathyroid hormone (PTH) to distinguish between PTH-dependent and PTH-independent causes 1, 2:

• Elevated or normal PTH (>20 pg/mL): Primary hyperparathyroidism 1
• Suppressed PTH (<20 pg/mL): Malignancy or other non-PTH-mediated causes 1, 3

Clinical Context Analysis

Calcium Level Interpretation

• Calcium 14 mg/dL is severe hypercalcemia (>3.5 mmol/L), which causes nausea, vomiting, dehydration, confusion, somnolence, and potential coma 1
• With albumin 3.5 g/dL (low-normal), no correction is needed—this represents true severe hypercalcemia 4
• The corrected calcium formula: Corrected calcium = 14 + 0.8 × [4.0 - 3.5] = 14.4 mg/dL 4, 5

Prealbumin Significance

• Prealbumin 12 mg/dL is significantly low (normal 18-40 mg/dL), indicating:
  • Malnutrition from malignancy (most concerning) 1
  • Chronic inflammatory state 1
  • Acute illness with cachexia 1

Most Likely Etiologies in Order of Probability

1. Malignancy (Most Likely Given Low Prealbumin)

• Accounts for 90% of inpatient hypercalcemia when combined with primary hyperparathyroidism 1, 6
• Low prealbumin strongly suggests malignancy with cachexia 1
• Mechanisms include PTHrP secretion (most common), osteolytic metastases, or lymphoma with 1,25-vitamin D production 1, 3
• Median survival approximately 1 month once hypercalcemia develops 2

2. Primary Hyperparathyroidism

• Most common cause of outpatient hypercalcemia 1, 6, 3
• Less likely here given severity (calcium 14 mg/dL) and low prealbumin 1
• Typically presents with mild, chronic hypercalcemia rather than acute severe elevation 1

3. Tertiary Hyperparathyroidism (If CKD Present)

• Autonomous PTH secretion in chronic kidney disease patients 7
• Would show elevated PTH with hypercalcemia 7
• CKD itself causes hypocalcemia, not hypercalcemia—elevated calcium indicates iatrogenic causes or tertiary disease 7

Essential Diagnostic Workup

Immediate Laboratory Panel

• Intact PTH (most critical) 1, 2
• PTHrP (if PTH suppressed) 2, 3
• 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D (measure both together for accuracy) 2
• Phosphorus (low in hyperparathyroidism, variable in malignancy) 2, 3
• Serum creatinine and BUN (assess renal function) 2, 3
• Alkaline phosphatase (elevated in bone disease) 3
• Ionized calcium (avoid pseudo-hypercalcemia from hemolysis) 2, 3

Additional Investigations Based on PTH Result

• If PTH elevated/normal: Imaging for parathyroid adenoma 1
• If PTH suppressed: Chest X-ray, CT chest/abdomen/pelvis for malignancy, serum protein electrophoresis for multiple myeloma 1, 3

Critical Pitfalls to Avoid

• Do not assume CKD causes hypercalcemia—CKD causes hypocalcemia; elevated calcium indicates iatrogenic causes (calcium binders, vitamin D) or tertiary hyperparathyroidism 7
• Do not rely on corrected calcium alone—measure ionized calcium to avoid pseudo-hypercalcemia from improper sampling 2, 7
• Do not delay treatment while awaiting workup—calcium 14 mg/dL requires immediate aggressive IV hydration and bisphosphonates 2, 5, 1
• Measure BOTH 25-hydroxyvitamin D AND 1,25-dihydroxyvitamin D together for diagnostic accuracy in granulomatous disease or lymphoma 2

Medication History Red Flags

• Thiazide diuretics: Can cause severe hypercalcemia, especially with calcium supplements 8, 3
• Lithium: Causes PTH-mediated hypercalcemia 1, 3
• Calcium supplements >500 mg/day or vitamin D >400 IU/day 2
• Calcium-based phosphate binders with vitamin D analogs in CKD patients (causes hypercalcemia in 22.6-43.3%) 7

Immediate Management Required

This patient requires emergency treatment regardless of etiology 5, 1:

• Aggressive IV normal saline targeting urine output 100-150 mL/hour 2, 5
• Zoledronic acid 4 mg IV over 15 minutes (preferred bisphosphonate, normalizes calcium in 50% by day 4) 2, 5, 1
• Monitor calcium, creatinine, electrolytes every 6-12 hours until stabilized 5
• Discontinue all calcium and vitamin D supplements immediately 2