What are the common causes of hypercalcemia and how should it be evaluated?

Why Calcium is Elevated: A Systematic Approach

Elevated calcium (hypercalcemia) occurs primarily due to two main mechanisms: PTH-dependent causes (most commonly primary hyperparathyroidism) and PTH-independent causes (most commonly malignancy), with the PTH level being the critical first test to distinguish between them. 1, 2

Initial Diagnostic Framework

The evaluation of hypercalcemia must begin with simultaneous measurement of serum calcium and intact PTH 1. This single decision point determines your entire diagnostic pathway:

PTH-Dependent Hypercalcemia (PTH elevated or inappropriately normal)

Primary hyperparathyroidism (PHPT) is the most common cause in outpatients, affecting approximately 90% of hypercalcemia cases in ambulatory settings 3. PHPT is particularly frequent in postmenopausal women and increases with age 1.

The typical biochemical presentation includes:

• Hypercalcemia with elevated or "normal" PTH (which is inappropriate for the calcium level)
• Increased urinary calcium or calcium excretion fraction >2%
• Often accompanied by hypophosphatemia 1, 2

Critical pitfall: Before confirming PHPT, you must exclude factors that can mask or induce secondary hyperparathyroidism 2:

• Vitamin D deficiency (measure 25-OH vitamin D)
• Renal insufficiency (calculate eGFR)
• Malabsorption (inflammatory bowel disease, celiac disease, bariatric surgery)
• Medications: thiazide diuretics, lithium, excessive vitamin D or calcium supplementation 2

Hypercalcemia with Hypocalciuria (PTH elevated, urine calcium low)

When fractional excretion of calcium is ≤2%, consider familial hypocalciuric hypercalcemia (FHH) due to inactivating mutations in CASR, GNA11, or AP2S1 genes 2. An oral calcium loading test and Pro-FHH score can help differentiate this from PHPT 1.

PTH-Independent Hypercalcemia (PTH suppressed <20 pg/mL)

Malignancy is the second most common cause overall and the most common cause in hospitalized patients 3. The mechanisms include:

1. Humoral hypercalcemia of cancer: PTH-related peptide (PTH-rP) secretion from solid tumors (epidermoid, neuroendocrine)

   • Causes increased bone resorption
   • Associated with hypophosphatemia (distinguishes from osteolytic metastases)
   • No visible osteolytic lesions on imaging 2

2. Osteolytic metastases: Direct bone destruction (breast cancer, myeloma)

   • Often accompanied by hyperphosphatemia (opposite of PTH-rP)
   • Visible bone lesions on imaging 2

3. Hypervitaminosis D: Excessive calcitriol production

   • Granulomatous diseases (sarcoidosis, tuberculosis)
   • Lymphomas
   • Vitamin D intoxication
   • CYP24A1 gene mutations (impaired vitamin D catabolism) 2

4. Endocrine causes:

   • Thyrotoxicosis
   • Adrenal insufficiency 2

5. Immobilization hypercalcemia: Particularly in young adults after spinal cord trauma or elderly with prolonged bed rest, occurring 4-6 weeks after immobilization begins 2

6. Medications:

   • Thiazide diuretics
   • Lithium
   • Vitamin A toxicity
   • Calcium supplements (milk-alkali syndrome) 2

Practical Clinical Algorithm

Step 1: Measure serum calcium and intact PTH simultaneously

Step 2: If PTH is elevated or inappropriately normal:

• Check 25-OH vitamin D, eGFR, and review medications
• Measure 24-hour urine calcium or spot urine calcium-to-creatinine ratio
• If urine calcium is low (FeCa ≤2%), consider FHH and genetic testing
• If urine calcium is normal/high, diagnose PHPT

Step 3: If PTH is suppressed (<20 pg/mL):

• Evaluate for malignancy (history, physical exam, age-appropriate cancer screening)
• Check phosphate level:
  • Hypophosphatemia → suspect PTH-rP (humoral hypercalcemia)
  • Hyperphosphatemia → suspect osteolytic metastases or vitamin D excess
• Measure 25-OH vitamin D and 1,25-dihydroxy vitamin D if granulomatous disease suspected
• Consider imaging for bone metastases if clinically indicated 2

Common Diagnostic Pitfalls

1. Assuming "normal" PTH excludes hyperparathyroidism: A PTH in the normal range is inappropriate when calcium is elevated and indicates PHPT 1

2. Missing vitamin D deficiency: This can mask PHPT by preventing hypercalciuria and must be corrected before finalizing the diagnosis 2

3. Overlooking medication causes: Always discontinue thiazides, lithium, and excessive supplements before extensive workup 2, 4

4. Confusing PTH-rP with osteolytic disease: Check phosphate—hypophosphatemia points to PTH-rP, while hyperphosphatemia suggests bone metastases 2