What are the potential causes of hypercalcemia in a patient with normal parathyroid hormone (PTH) levels?

Causes of Elevated Calcium with Normal PTH

When hypercalcemia occurs with normal (or inappropriately normal) PTH levels, the most likely diagnosis is primary hyperparathyroidism, as a "normal" PTH in the setting of hypercalcemia is physiologically inappropriate and indicates autonomous parathyroid hormone secretion. 1, 2

Understanding "Normal" PTH in Hypercalcemia

The key diagnostic principle is that PTH should be suppressed (typically <20 pg/mL) in the presence of hypercalcemia. 3 A PTH level in the normal reference range when calcium is elevated represents inappropriate PTH secretion and is diagnostic of PTH-dependent hypercalcemia. 1, 2

PTH-Dependent Causes (Normal or Elevated PTH)

Primary Hyperparathyroidism (PHPT)

• Accounts for approximately 90% of outpatient hypercalcemia cases 3
• Characterized by elevated or inappropriately normal PTH levels with hypercalcemia 1, 2
• Single parathyroid adenoma causes 80% of cases, with 15-20% from multigland hyperplasia 2
• The parathyroid glands autonomously secrete PTH despite elevated calcium 1
• Cure rates are similar whether PTH is overtly elevated or in the "normal" range 1

Familial Hypocalciuric Hypercalcemia (FHH)

• Presents with mildly elevated PTH levels that may appear normal 4
• Distinguished by low urinary calcium excretion (calcium/creatinine ratio) 1
• Genetic disorder requiring different management than PHPT 4

Critical Diagnostic Pitfall

Vitamin D deficiency must be excluded before confirming PHPT, as it causes secondary hyperparathyroidism with elevated PTH but typically normal or low calcium. 1, 2 However, if calcium is already elevated, vitamin D deficiency is unlikely to be the primary cause.

PTH Assay Considerations

PTH measurements can vary up to 47% between different assay generations, which may cause truly elevated PTH to appear "normal." 5, 1

Key factors affecting PTH measurement:

• Use assay-specific reference values rather than generic ranges 5
• PTH is most stable in EDTA plasma rather than serum 5, 1
• Biological variation is substantial (20% in healthy individuals) 1
• Race, age, BMI, and vitamin D status all influence PTH concentration 5
• PTH reference values are 20% lower in vitamin D-replete individuals 1

Diagnostic Algorithm for Hypercalcemia with "Normal" PTH

Step 1: Confirm true hypercalcemia

• Measure ionized calcium (normal: 4.65-5.28 mg/dL) for definitive assessment 1
• Correct total calcium for albumin if albumin is abnormal 1, 3

Step 2: Interpret PTH in context

• If PTH is in the normal range (not suppressed <20 pg/mL), this indicates PTH-dependent hypercalcemia 3, 4
• Consider this diagnostic of PHPT until proven otherwise 1, 6

Step 3: Exclude secondary causes of PTH elevation

• Measure 25-hydroxyvitamin D to exclude vitamin D deficiency 1
• Calculate 24-hour urine calcium or spot calcium/creatinine ratio to exclude FHH 1, 4
• Review medications (thiazides, lithium, calcium supplements, vitamin D) 3

Step 4: Confirm PHPT diagnosis

• Measure serum phosphorus (typically low-normal in PHPT) 1
• Assess kidney function (creatinine, eGFR) 1
• Consider parathyroid imaging (ultrasound, sestamibi SPECT/CT) only after biochemical diagnosis is confirmed 1

Step 5: Assess surgical candidacy Refer to endocrinology and experienced parathyroid surgeon if any of the following: 1, 2

• Corrected calcium >1 mg/dL above upper limit of normal
• Age <50 years
• Impaired kidney function (GFR <60 mL/min/1.73 m²)
• Osteoporosis (T-score ≤-2.5)
• History of nephrolithiasis or nephrocalcinosis
• Hypercalciuria (>300 mg/24hr)

Common Clinical Pitfalls

Do not dismiss "normal" PTH as excluding PHPT. A case report documented a parathyroid adenoma causing sustained hypercalcemia (2.51-3.03 mmol/L) with PTH levels consistently in the normal range (21.95-40.15 pg/mL), which resolved immediately after parathyroidectomy. 6

Do not order parathyroid imaging before confirming biochemical diagnosis, as imaging is for surgical planning, not diagnosis. 1

Do not supplement with vitamin D until hypercalcemia resolves, and discontinue all vitamin D therapy if calcium exceeds 10.2 mg/dL. 1

Management Approach

For confirmed PHPT with normal PTH:

• Refer to endocrinology for confirmation and surgical candidacy assessment 1
• Refer to high-volume parathyroid surgeon if surgical criteria met 1
• Maintain normal calcium intake (1000-1200 mg/day), avoiding extremes 1
• Ensure adequate hydration and discontinue calcium supplements, vitamin D, or thiazide diuretics 1
• Monitor serum calcium every 3 months if not a surgical candidate 1