What does elevated calcium with normal Parathyroid Hormone (PTH) intact levels indicate?

Elevated Calcium with Normal PTH: Diagnostic Implications

Elevated calcium with normal intact parathyroid hormone (PTH) levels most commonly indicates hypercalcemia of malignancy, with other potential causes including vitamin D intoxication, granulomatous disorders, medications, or familial hypocalciuric hypercalcemia.

Differential Diagnosis

When evaluating a patient with hypercalcemia and normal PTH levels, consider the following causes:

1. Malignancy-Related Hypercalcemia

• Most common non-parathyroid cause of hypercalcemia 1
• Mechanisms:
  • Humoral hypercalcemia of malignancy (HHM) via parathyroid hormone-related protein (PTHrP)
  • Local osteolytic hypercalcemia
  • Ectopic production of 1,25-dihydroxyvitamin D (rare lymphomas)
  • Extremely rare: ectopic PTH production by tumors 2

2. Vitamin D-Related Causes

• Vitamin D intoxication
• Granulomatous disorders (sarcoidosis, tuberculosis)
• 1,25-dihydroxyvitamin D production by granulomas

3. Medication-Induced Hypercalcemia

• Thiazide diuretics
• Lithium
• Vitamin A excess
• Calcium supplements
• Newer medications: SGLT2 inhibitors, immune checkpoint inhibitors 1

4. Other Causes

• Thyrotoxicosis
• Adrenal insufficiency
• Immobilization
• Familial hypocalciuric hypercalcemia (FHH)
• Milk-alkali syndrome

Diagnostic Approach

1. Confirm hypercalcemia - Repeat calcium measurement, preferably with ionized calcium 1

2. PTH assessment - Key initial test to differentiate PTH-dependent from PTH-independent causes 1

   • Normal/elevated PTH with hypercalcemia: Primary hyperparathyroidism
   • Suppressed PTH (<20 pg/mL): Non-parathyroid causes

3. Additional laboratory tests:

   • PTHrP measurement
   • 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D levels
   • Complete blood count
   • Serum and urine protein electrophoresis
   • Thyroid function tests
   • 24-hour urinary calcium (to rule out FHH)
   • Renal function tests

4. Imaging studies:

   • Chest X-ray
   • Abdominal imaging (CT/MRI)
   • Bone scan if metastatic disease suspected
   • Mammography in women
   • PET scan if malignancy suspected but not localized

Management Considerations

Acute Management of Symptomatic Hypercalcemia

For severe hypercalcemia (total calcium >14 mg/dL or ionized calcium ≥10 mg/dL):

1. Hydration - IV fluids (normal saline) to restore intravascular volume 1

2. Bisphosphonates - Zoledronic acid or pamidronate for malignancy-related hypercalcemia 1

3. Alternative therapies:

   • Denosumab for patients with renal failure
   • Calcitonin for rapid but short-term effect
   • Glucocorticoids for vitamin D-mediated or granulomatous causes 1
   • Dialysis for severe, refractory cases with renal failure

Long-Term Management

Treatment depends on the underlying cause:

1. Malignancy - Treat the underlying cancer with appropriate therapy 2

2. Medication-induced - Discontinue offending agent if possible

3. Granulomatous disorders - Treat with glucocorticoids

4. Vitamin D intoxication - Discontinue supplements, consider glucocorticoids

Clinical Pearls and Pitfalls

• Pearl: While primary hyperparathyroidism and malignancy account for >90% of hypercalcemia cases, the PTH level is the key discriminator 3, 4

• Pitfall: Rare cases of ectopic PTH production by tumors can present with elevated calcium and normal/elevated PTH, mimicking primary hyperparathyroidism 2

• Pearl: Mild hypercalcemia (calcium <12 mg/dL) is often asymptomatic but may cause fatigue and constipation in about 20% of patients 1

• Pitfall: Familial hypocalciuric hypercalcemia can present with elevated calcium and normal/slightly elevated PTH, but is distinguished by low urinary calcium excretion

• Pearl: In patients with chronic kidney disease, secondary hyperparathyroidism typically presents with normal or low calcium levels and elevated PTH, not hypercalcemia with normal PTH 5, 6

Remember that hypercalcemia with normal PTH represents a PTH-independent process in most cases, and malignancy should be high on the differential diagnosis, especially in patients without a clear alternative explanation.