Patient with parathyroid hormone 88 pg/mL, normal serum calcium 9.1 mg/dL, normal phosphorus 4 mg/dL, adequate 25‑hydroxy‑vitamin D 55 ng/mL, normal gamma‑glutamyl transferase 21 U/L and normal serum protein electrophoresis—what is the most likely diagnosis and what are the appropriate next steps?

Normocalcemic Primary Hyperparathyroidism (NPHPT)

This patient has normocalcemic primary hyperparathyroidism (NPHPT), defined by persistently elevated PTH (88 pg/mL) with consistently normal calcium (9.1 mg/dL) after excluding all secondary causes—and despite the adequate vitamin D level (55 ng/mL), normal renal function (normal phosphorus, GGT), and normal SPEP, this represents autonomous parathyroid disease that warrants endocrinology referral and surgical evaluation. 1

Diagnostic Confirmation

Why This Is NPHPT, Not Secondary Hyperparathyroidism

• Vitamin D sufficiency (55 ng/mL) excludes the most common cause of secondary hyperparathyroidism, as levels >20 ng/mL are required to rule out vitamin D deficiency as the driver of PTH elevation. 1, 2
• Normal calcium (9.1 mg/dL) with elevated PTH (88 pg/mL) represents "inappropriately normal" PTH for the calcium level—in a healthy individual, calcium at 9.1 mg/dL should suppress PTH well below 88 pg/mL. 1, 3
• Normal phosphorus (4 mg/dL) and normal GGT (21 U/L) suggest preserved renal function, making chronic kidney disease–related secondary hyperparathyroidism unlikely (though formal eGFR measurement is still needed). 1, 2
• Normal SPEP excludes multiple myeloma and other paraproteinemias that can cause hypercalcemia or confound calcium measurement. 1

The Diagnostic Threshold

• PTH of 88 pg/mL is clearly elevated when calcium is only 9.1 mg/dL—this represents autonomous parathyroid secretion that fails to suppress appropriately. 1, 3
• NPHPT is not a benign entity; despite normal serum calcium, it carries a risk profile comparable to hypercalcemic primary hyperparathyroidism, including bone loss, kidney stones, and neurocognitive symptoms. 1

Essential Next Steps

Immediate Laboratory Work-Up

1. Measure serum creatinine and calculate eGFR to definitively exclude chronic kidney disease (eGFR ≥60 mL/min/1.73 m² is required for NPHPT diagnosis). 1, 2

2. Obtain 24-hour urine calcium or spot urine calcium/creatinine ratio to assess for hypercalciuria—urinary calcium >300 mg/24 hours (or >400 mg/24 hours in some guidelines) is a surgical indication even with normocalcemia. 1, 2

3. Measure ionized calcium (normal 4.65–5.28 mg/dL) for definitive assessment, as total calcium can be misleading if albumin is abnormal. 1

4. Check serum phosphorus again (if not already done with a comprehensive metabolic panel)—low or low-normal phosphorus supports the diagnosis of primary hyperparathyroidism. 2

Critical Exclusions Before Confirming NPHPT

• Confirm adequate dietary calcium intake (1,000–1,200 mg/day for adults), as low calcium intake can mimic secondary hyperparathyroidism with low urinary calcium. 1
• Verify that eGFR is ≥60 mL/min/1.73 m², as PTH begins to rise when GFR falls below this threshold. 1, 2
• Ensure PTH measurement was performed in EDTA plasma (not serum) and stored at 4°C, as PTH is most stable under these conditions; also verify that the patient was not taking biotin supplements, which can interfere with PTH assays. 1, 2

Surgical Indications in NPHPT

Parathyroidectomy is indicated in NPHPT when any of the following are present: 1, 2

• Age <50 years 1, 2
• Impaired kidney function (eGFR <60 mL/min/1.73 m²) 1, 2
• Osteoporosis (T-score ≤–2.5 at any site) 1, 2
• History of nephrolithiasis or nephrocalcinosis 1, 2
• 24-hour urinary calcium >300 mg (or >400 mg in some guidelines) 1, 2
• Disabling neurocognitive symptoms (refractory depression, emotional lability, impaired cognition, "brain fog," memory loss) that represent target-organ manifestations of primary hyperparathyroidism 1
• Patient preference for definitive treatment is recognized as a valid indication for surgical referral in NPHPT 1

Imaging for Surgical Planning (Not Diagnosis)

• Do not order parathyroid imaging before confirming the biochemical diagnosis—imaging is for surgical planning, not diagnosis. 1
• Once NPHPT is confirmed and surgery is planned, obtain preoperative localization with ultrasound and/or 99mTc-sestamibi scintigraphy with SPECT/CT to enable minimally invasive parathyroidectomy. 1, 2
• Identification of a solitary adenoma on imaging enables minimally invasive parathyroidectomy (MIP), which is associated with shorter operative times, faster recovery, and lower costs. 1

Referral Strategy

Refer this patient to both an endocrinologist and a high-volume parathyroid surgeon: 1

• The endocrinologist will confirm the diagnosis, exclude secondary causes, assess surgical candidacy, and coordinate medical management if surgery is deferred. 1
• All patients meeting surgical criteria should be referred to an experienced, high-volume parathyroid surgeon, as outcomes—including cure rates and complication profiles—are significantly better with specialized expertise. 1
• Re-operations on the parathyroid gland have lower cure rates and higher complication rates, underscoring the importance of achieving cure during the initial surgery. 1

Medical Management if Surgery Is Deferred

If the patient does not meet surgical criteria or declines surgery: 1

• Maintain 25-hydroxyvitamin D levels >20 ng/mL using cholecalciferol or ergocalciferol supplementation to support bone health. 1
• Ensure normal calcium intake (1,000–1,200 mg/day) and avoid high or low calcium diets; total elemental calcium intake should not exceed 2,000 mg/day. 1
• Avoid calcitriol or other active vitamin D analogs, as they increase intestinal calcium absorption and can exacerbate hypercalcemia. 1
• Monitor serum calcium every 3 months for patients with eGFR >30 mL/min/1.73 m². 1
• Obtain bone density scan (DXA) to assess for osteoporosis, which would change management to surgical candidacy. 1, 2

Common Pitfalls

• Assuming elevated PTH is always due to vitamin D deficiency—this patient's vitamin D is 55 ng/mL, well above the 20 ng/mL threshold needed to exclude secondary hyperparathyroidism. 1, 2
• Waiting for hypercalcemia to develop before diagnosing primary hyperparathyroidism—NPHPT is a distinct entity with similar risks to hypercalcemic disease. 1
• Ordering parathyroid imaging before biochemical confirmation—imaging cannot diagnose hyperparathyroidism and should only be used for surgical planning. 1
• Not measuring 24-hour urine calcium—severe hypercalciuria (>300–400 mg/24 hours) is a surgical indication even with normocalcemia and signals high risk for nephrocalcinosis. 1, 2
• Using different PTH assay generations without considering assay-specific reference ranges—PTH assay results can vary by up to 47% between different assay generations. 1, 2