Diagnosis: Normocalcemic Primary Hyperparathyroidism (NPHPT)
This patient has normocalcemic primary hyperparathyroidism (NPHPT), defined by persistently elevated intact PTH (35 pg/mL is above the lower reference limit of ~20 pg/mL) with consistently normal serum calcium, after exclusion of secondary causes including low 1,25-hydroxyvitamin D and undetectable PTHrP. 1
Diagnostic Reasoning
Why This Is NPHPT and Not Secondary Hyperparathyroidism
The low 1,25-hydroxyvitamin D (calcitriol) is actually expected in NPHPT and does not indicate secondary hyperparathyroidism. In primary hyperparathyroidism, elevated PTH should stimulate 1α-hydroxylase activity and increase calcitriol production; when calcitriol remains low despite elevated PTH, this suggests parathyroid autonomy with impaired renal response—a feature of primary, not secondary, hyperparathyroidism. 2
Secondary hyperparathyroidism presents with hypocalcemia or low-normal calcium, not normal calcium. The consistently normal serum calcium excludes secondary hyperparathyroidism from chronic kidney disease, vitamin D deficiency, or malabsorption. 3
The undetectable PTHrP excludes humoral hypercalcemia of malignancy. PTHrP-mediated hypercalcemia presents with suppressed PTH (<20 pg/mL), not elevated PTH. 4
Critical Diagnostic Considerations
NPHPT represents the earliest biochemical manifestation of primary hyperparathyroidism, where PTH elevation precedes the development of frank hypercalcemia. Longitudinal studies demonstrate that 40% of NPHPT patients progress to hypercalcemia over 3 years. 5
An intact PTH of 35 pg/mL, while only mildly elevated, is inappropriately normal-to-high in the context of normal serum calcium. In healthy individuals, normal calcium should suppress PTH toward the lower reference range (20-25 pg/mL); failure to suppress indicates autonomous parathyroid function. 4
The low 1,25-hydroxyvitamin D with elevated PTH suggests parathyroid adenoma with impaired renal 1α-hydroxylase response. One case series documented a patient with primary hyperparathyroidism who had markedly increased intact PTH and 1,25-dihydroxyvitamin D with normocalcemia initially, but the combination of elevated PTH with low calcitriol is more consistent with early autonomous parathyroid disease. 2
Essential Next Steps to Confirm Diagnosis
Mandatory Laboratory Exclusions
Measure 25-hydroxyvitamin D to exclude vitamin D deficiency as a secondary cause; levels must be >20 ng/mL (>50 nmol/L) to diagnose NPHPT. Vitamin D deficiency is the most common cause of secondary hyperparathyroidism and must be ruled out. 1
Confirm adequate dietary calcium intake (≈1,000–1,200 mg/day) and measure 24-hour urinary calcium or spot urine calcium/creatinine ratio. Low calcium intake can mimic secondary hyperparathyroidism. 1
Verify normal renal function with eGFR ≥60 mL/min/1.73 m² to exclude chronic kidney disease-related secondary hyperparathyroidism. CKD is a common secondary cause that must be excluded. 1
Repeat serum calcium and intact PTH measurements on at least two separate occasions to confirm persistent normocalcemia and elevated PTH. NPHPT requires consistent biochemical findings, not single measurements. 6
PTH Assay Considerations
Use EDTA plasma rather than serum for PTH measurement, as PTH is most stable in EDTA plasma at 4°C. PTH degrades rapidly at room temperature in serum. 4
Recognize that intact PTH assays vary by up to 47% between different generations; always use assay-specific reference ranges. A PTH of 35 pg/mL may be normal in one assay but elevated in another. 4
Clinical Significance and Management
Why NPHPT Is Not Benign
NPHPT carries a risk profile comparable to hypercalcemic primary hyperparathyroidism, with high prevalence of nephrolithiasis (36%), fragility fractures (12%), and osteoporosis (25%). This is not an indolent disease state. 7
Patients with NPHPT develop more substantial skeletal involvement than typical asymptomatic hypercalcemic PHPT, with 57% meeting WHO criteria for osteoporosis at diagnosis. 5
Over 3 years of follow-up, 40% of NPHPT patients develop progression: 19% become hypercalcemic, 16% develop >10% BMD loss, and others develop kidney stones or fractures. 5
Surgical Indications
Parathyroidectomy is indicated if the patient meets any of the following criteria: corrected calcium >1 mg/dL above upper limit of normal (not applicable here), age <50 years, eGFR <60 mL/min/1.73 m², osteoporosis (T-score ≤-2.5 at any site), history of nephrolithiasis or nephrocalcinosis, or patient preference for definitive treatment. 1, 4
Obtain bone mineral density (BMD) at spine, hip, and distal one-third radius to assess for osteoporosis. NPHPT does not show preferential cortical bone loss; all sites are affected. 5
If surgical criteria are met, refer to both an endocrinologist for medical optimization and a high-volume parathyroid surgeon for preoperative localization imaging (ultrasound and/or 99mTc-sestamibi SPECT/CT). 4
Medical Management for Non-Surgical Candidates
Maintain 25-hydroxyvitamin D levels >20 ng/mL using cholecalciferol or ergocalciferol supplementation to support bone health. 1
Ensure adequate dietary calcium intake (1,000–1,200 mg/day) but avoid total elemental calcium intake exceeding 2,000 mg/day. 4
Monitor serum calcium and PTH every 3–6 months, and repeat BMD every 1–2 years to detect progression. 4
Common Pitfalls to Avoid
Do not assume low 1,25-hydroxyvitamin D indicates secondary hyperparathyroidism. In NPHPT, low calcitriol despite elevated PTH reflects parathyroid autonomy with impaired renal response. 2
Do not order parathyroid imaging before confirming the biochemical diagnosis. Imaging is for surgical planning, not diagnosis. 4
Do not supplement with calcitriol or active vitamin D analogs in NPHPT. These agents are reserved for secondary hyperparathyroidism in CKD and will worsen hypercalcemia if primary hyperparathyroidism is present. 1
Do not dismiss NPHPT as benign or asymptomatic. These patients have substantial skeletal disease and high progression rates. 7, 5