In a patient with elevated parathyroid hormone, normal 25‑hydroxyvitamin D, normal serum creatinine, normal serum calcium and phosphate, and normal 24‑hour urine calcium, what is the most likely diagnosis?

Normocalcemic Primary Hyperparathyroidism (NPHPT)

The most likely diagnosis is normocalcemic primary hyperparathyroidism (NPHPT), a variant of primary hyperparathyroidism characterized by elevated PTH with persistently normal serum calcium after excluding all secondary causes of hyperparathyroidism. 1, 2

Diagnostic Confirmation Algorithm

Step 1: Exclude Secondary Hyperparathyroidism

Before confirming NPHPT, you must systematically rule out all secondary causes:

• Verify vitamin D status: Measure 25-hydroxyvitamin D and ensure levels are >20 ng/mL (>50 nmol/L), as vitamin D deficiency is the most common cause of secondary hyperparathyroidism 1, 3
• Assess dietary calcium intake: Ensure the patient meets age-related recommended dietary allowance (1000-1200 mg/day for adults), as low urinary calcium suggests calcium deprivation 1, 3
• Confirm normal renal function: The normal serum creatinine you report supports this, but verify eGFR >60 mL/min/1.73 m² to exclude CKD-related secondary hyperparathyroidism 1, 3
• Review medications: Exclude thiazide diuretics, lithium, bisphosphonates, and denosumab, which can affect PTH and calcium levels 4

Step 2: Confirm Persistent Biochemical Pattern

NPHPT requires documentation of:

• Persistently elevated PTH on multiple measurements (not a single value) 2, 5
• Persistently normal serum calcium (albumin-corrected) on multiple measurements 2, 6
• Normal 24-hour urine calcium (typically <400 mg/24h), which you have confirmed and helps exclude familial hypocalciuric hypercalcemia 7, 4

Step 3: Calculate Calcium-to-Creatinine Clearance Ratio

Although your 24-hour urine calcium is normal, calculate the calcium-to-creatinine clearance ratio to definitively exclude familial hypocalciuric hypercalcemia (FHH):

• Ratio <0.01 suggests FHH, though clinical context usually excludes this without genetic testing 7
• Ratio ≥0.01 supports NPHPT 7

Clinical Significance and Natural History

NPHPT is not a benign condition despite normal calcium levels. 1, 2

• Frequency: NPHPT represents approximately 15% of all primary hyperparathyroidism cases 6
• Progression risk: A significant proportion of NPHPT patients progress to hypercalcemic primary hyperparathyroidism over time 5
• Complications: Despite the more favorable biochemical profile (lower PTH, higher phosphate, higher vitamin D compared to hypercalcemic PHPT), patients with NPHPT have similar rates of osteoporosis, nephrolithiasis, and low-energy fractures as hypercalcemic PHPT 6, 4
• Occult kidney stones: There is a 20% prevalence of silent kidney stones detected by routine ultrasonography in NPHPT patients 4

Recommended Evaluation

Essential Additional Testing

• Bone density scan (DXA): Measure BMD at lumbar spine, femoral neck, total hip, and distal third of radius to assess for osteoporosis (T-score ≤-2.5) 3, 8
• Renal imaging: Obtain renal ultrasonography to screen for occult nephrolithiasis or nephrocalcinosis, given the 20% prevalence of silent stones 4, 3
• Serum phosphate: Typically low-normal in NPHPT 6, 8
• Bone turnover markers: Consider measuring bone-specific alkaline phosphatase and CTX 6

PTH Measurement Considerations

Critical technical point: Use EDTA plasma rather than serum for PTH measurement, as PTH is most stable in EDTA plasma at 4°C 3, 8. Always use assay-specific reference values, as PTH assays can vary up to 47% between different generations 1, 3, 8.

Management Approach

Surgical Candidacy Evaluation

Refer to endocrinology and an experienced parathyroid surgeon if any of the following criteria are met 3, 8:

• Age <50 years
• Osteoporosis (T-score ≤-2.5 at any site)
• eGFR <60 mL/min/1.73 m²
• History of nephrolithiasis or nephrocalcinosis (including occult stones)
• 24-hour urine calcium >400 mg/day (not present in your case)
• Patient preference for definitive treatment

Important Surgical Considerations

Be aware that NPHPT patients present unique surgical challenges: They more frequently have negative preoperative localization studies and multiglandular disease compared to hypercalcemic PHPT, which complicates surgical management 2. Four-gland hyperplasia is more common when calcium-to-creatinine clearance ratio is <0.01 7.

Medical Management for Non-Surgical Candidates

If surgery is not indicated or declined:

• Maintain adequate vitamin D: Keep 25-hydroxyvitamin D >20 ng/mL with cholecalciferol or ergocalciferol supplementation 1, 3
• Ensure appropriate calcium intake: 1000-1200 mg/day from diet, avoiding both high and low calcium diets 3
• Monitor regularly: Measure serum calcium and PTH every 3-6 months, and repeat DXA every 1-2 years 3

Common Pitfalls to Avoid

• Do not dismiss elevated PTH as insignificant simply because calcium is normal—NPHPT carries similar complication risks as hypercalcemic PHPT 6, 4
• Do not order parathyroid imaging before confirming the biochemical diagnosis—imaging is for surgical planning only, not diagnosis 3
• Do not assume a single normal calcium measurement excludes progression—NPHPT can evolve to hypercalcemic PHPT 5
• Do not overlook occult kidney stones—routine renal ultrasonography is warranted given the 20% prevalence 4
• Do not interpret PTH levels without knowing vitamin D status, as vitamin D deficiency causes secondary hyperparathyroidism and PTH reference values are 20% lower in vitamin D-replete individuals 1, 3, 8