What is the differential diagnosis for hypercalcemia with normal Parathyroid Hormone (PTH) levels?

Differential Diagnosis for Hypercalcemia with Normal PTH

Hypercalcemia with normal (inappropriately normal) PTH most commonly indicates primary hyperparathyroidism, as a normal PTH in the setting of hypercalcemia represents failure of appropriate PTH suppression and should be interpreted as pathologically elevated. 1, 2

Understanding "Normal" PTH in Hypercalcemia

The key diagnostic principle is that PTH should be suppressed (low) in hypercalcemia unless the parathyroid glands are the source of the problem. A "normal" PTH level in the presence of elevated calcium is physiologically inappropriate and diagnostic of primary hyperparathyroidism. 1, 2

• In healthy individuals, hypercalcemia from any non-parathyroid cause should suppress PTH to undetectable or very low levels 2
• When PTH remains in the "normal range" despite hypercalcemia, this represents autonomous parathyroid hormone secretion 1, 2
• Primary hyperparathyroidism is defined as hypercalcemia with elevated or inappropriately normal PTH concentration 1, 2

Primary Differential Diagnosis

PTH-Mediated (Normal or Elevated PTH)

Primary Hyperparathyroidism - This is the diagnosis when PTH is normal or elevated with hypercalcemia:

• Caused by parathyroid adenoma or hyperplasia producing autonomous PTH secretion 1
• Confirmed by corrected calcium >0.25 mmol/L (approximately 1 mg/dL) above upper limit of normal with inappropriately normal or elevated PTH 2
• Must exclude vitamin D deficiency first, as this causes secondary hyperparathyroidism with elevated PTH but typically normal or low calcium 1, 2

PTH-Independent (Suppressed PTH) - If PTH is Actually Low

If repeat testing shows PTH is truly suppressed (not normal), consider:

Malignancy-Associated Hypercalcemia:

• Occurs in 10-25% of patients with lung cancer, especially squamous cell carcinoma 2
• Measure PTHrP (parathyroid hormone-related protein), which is elevated in 76-82% of malignancy-associated hypercalcemia 3, 4
• PTHrP is elevated in 100% of squamous cell carcinomas of lung, esophagus, skin, and breast cancer 4
• Median survival approximately 1 month after diagnosis 2

Granulomatous Disease (especially Sarcoidosis):

• Characterized by elevated 1,25-dihydroxyvitamin D with low or normal 25-hydroxyvitamin D 2
• Increased 1α-hydroxylase activity in granulomas converts 25-OH vitamin D to active 1,25-(OH)₂ vitamin D 2
• Responds to glucocorticoid therapy 2

Lymphoma:

• Most commonly causes hypercalcemia through excess 1,25-dihydroxyvitamin D production 5
• Rarely, can co-secrete both PTHrP and 1,25-dihydroxyvitamin D 5

Vitamin D Intoxication:

• Elevated 25-hydroxyvitamin D levels (>150 ng/mL typically) 2
• History of excessive supplementation 2

Medications:

• Thiazide diuretics (should be discontinued) 2
• Calcium-based supplements 2
• Lithium (can cause hyperparathyroidism)

Diagnostic Algorithm

Step 1: Confirm True Hypercalcemia

• Measure corrected calcium or ionized calcium to exclude pseudo-hypercalcemia 2
• Corrected calcium = measured calcium + 0.8 × (4.0 - albumin in g/dL) 2

Step 2: Measure Intact PTH Using EDTA Plasma

• Use EDTA plasma rather than serum for most stable PTH measurement 1, 2
• Use assay-specific reference values, as PTH measurements can vary up to 47% between assay generations 2
• Biological variation of PTH is substantial (20% in healthy individuals), so differences must exceed 54% to be clinically significant 2

Step 3: Interpret PTH Level

If PTH is Normal or Elevated:

• Diagnose primary hyperparathyroidism 1, 2
• Check 25-hydroxyvitamin D to exclude vitamin D deficiency causing secondary hyperparathyroidism 2
• PTH reference values are 20% lower in vitamin D-replete individuals 2
• Consider coexisting malignancy if clinical suspicion exists (occurs in 3.9-10% of cases) 3, 4

If PTH is Suppressed (<20 pg/mL typically):

• Measure PTHrP to evaluate for malignancy 2, 3
• Measure 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D 2
• Pattern: Low 25-OH vitamin D with high 1,25-(OH)₂ vitamin D suggests granulomatous disease 2
• Pattern: High 25-OH vitamin D suggests vitamin D intoxication 2
• Pattern: Elevated PTHrP suggests malignancy 3, 4

Step 4: Additional Workup Based on Initial Results

• 24-hour urine calcium or spot urine calcium/creatinine ratio 2
• Serum creatinine and estimated GFR 2
• Consider imaging only after biochemical diagnosis is confirmed 2
• In malignancy cases, tissue immunohistochemical staining can demonstrate PTHrP and CYP27B1 expression 5

Critical Pitfalls to Avoid

• Do not interpret "normal" PTH as excluding hyperparathyroidism - this is the most common diagnostic error. Normal PTH with hypercalcemia IS hyperparathyroidism. 1, 2
• Do not order parathyroid imaging before confirming biochemical diagnosis - imaging is for surgical planning, not diagnosis 2
• Always check vitamin D status - vitamin D deficiency can elevate PTH and confound the diagnosis 1, 2
• Consider coexisting conditions - 10% of patients with malignancy have concurrent parathyroid disease, and these patients have better prognosis (median survival 13 months vs 3 months) 3
• Account for biological factors affecting PTH - race (higher in Black individuals), age, BMI, and kidney function all influence PTH levels 1
• Measure both PTH and PTHrP when malignancy is suspected - this combination changes the diagnosis in 10% of cases 3, 4

Management Implications

• Primary hyperparathyroidism with normal PTH requires surgical evaluation if patient meets criteria: age <50 years, corrected calcium >1 mg/dL above upper limit, GFR <60 mL/min/1.73 m², osteoporosis, or history of kidney stones 1, 2
• Immediate treatment priorities for moderate-severe hypercalcemia: IV crystalloid hydration, bisphosphonates (zoledronic acid or pamidronate), and glucocorticoids if granulomatous disease suspected 2
• Discontinue offending agents: calcium supplements, vitamin D, thiazide diuretics 2