What are the possible causes of an elevated parathyroid hormone level (88 pg/mL) with normal serum calcium (9.1 mg/dL) and sufficient 25‑hydroxyvitamin D (55 ng/mL)?

Normocalcemic Primary Hyperparathyroidism (NPHPT)

Your laboratory values—PTH 88 pg/mL with normal calcium (9.1 mg/dL) and sufficient vitamin D (55 ng/mL)—most likely represent normocalcemic primary hyperparathyroidism (NPHPT), though secondary causes must be rigorously excluded before confirming this diagnosis.

Diagnostic Framework

This biochemical pattern requires systematic evaluation because elevated PTH with normal calcium can represent either:

• Normocalcemic primary hyperparathyroidism (NPHPT): Autonomous parathyroid dysfunction despite normal calcium 1, 2
• Secondary hyperparathyroidism (SHPT): Physiologic PTH elevation responding to an underlying stimulus 3

The Endocrine Society emphasizes that NPHPT is diagnosed only after excluding all secondary causes of PTH elevation 1, 4.

Essential Exclusion Criteria

Before diagnosing NPHPT, you must systematically rule out:

1. Vitamin D Status (Already Adequate)

• Your 25-hydroxyvitamin D of 55 ng/mL exceeds the required threshold of >20 ng/mL (>50 nmol/L), effectively excluding vitamin D deficiency as a cause 1, 4
• However, recent research suggests measuring free 25-hydroxyvitamin D may reveal occult deficiency: one study found 20% lower free vitamin D levels in NPHPT subjects despite normal total levels, with free vitamin D inversely correlating with PTH (r = -0.42) 5
• PTH reference values are 20% lower when established in vitamin D-replete populations 4

2. Dietary Calcium Intake

• Confirm daily calcium intake of 1,000–1,200 mg through dietary history 1, 4
• Insufficient calcium intake is a common and reversible cause: a 2022 case series demonstrated that 9 patients with PTH 80.6 ± 13.4 pg/mL and normal calcium normalized their PTH to 51.0 ± 10.6 pg/mL after just 17.6 days of calcium supplementation (600 mg twice daily) 6
• The Endocrine Society states that low calcium intake can mimic secondary hyperparathyroidism 1

3. Renal Function

• Measure serum creatinine and calculate eGFR 1, 2
• An eGFR ≥60 mL/min/1.73 m² is required to exclude chronic kidney disease-related secondary hyperparathyroidism 1, 4
• PTH begins rising when GFR falls below 60 mL/min/1.73 m², even before overt hyperphosphatemia develops 4

4. Serum Phosphorus

• Obtain fasting serum phosphorus 7
• Low-normal phosphorus supports primary hyperparathyroidism, whereas elevated phosphorus suggests secondary hyperparathyroidism from renal dysfunction 2
• Phosphate retention is the fundamental initiating factor in CKD-related secondary hyperparathyroidism 4

5. Medication Review

• Discontinue thiazide diuretics, lithium, bisphosphonates, or denosumab if present, as these can elevate PTH 1
• Avoid biotin supplements before PTH measurement, as they interfere with assays 4

6. Malabsorptive Conditions

• Screen for history of bariatric surgery or intestinal disease (celiac disease, inflammatory bowel disease) 1, 4
• Post-bariatric surgery patients develop secondary hyperparathyroidism from impaired calcium and vitamin D absorption 4

PTH Assay Considerations

Critical caveat: PTH assays vary markedly between generations, with differences up to 47% reported 1, 2. Your PTH of 88 pg/mL may be interpreted differently depending on:

• Assay-specific reference ranges: Always use the laboratory's specific normal range 1, 2
• Sample type: PTH is most stable in EDTA plasma at 4°C rather than serum 1, 2
• Biological factors: PTH is higher in Black individuals, increases with age (especially >60 years), and correlates positively with BMI 4

The K/DOQI guidelines note that "intact PTH" assays detect biologically inactive PTH fragments (amino acids 7-84), leading to spuriously elevated levels 7.

Clinical Significance of NPHPT

NPHPT is not benign—despite normal calcium, it carries comparable risks to hypercalcemic primary hyperparathyroidism 1:

• Occult renal calcifications: A 2022 study found nephrocalcinosis or urolithiasis in 26.5% of asymptomatic NPHPT patients, associated with higher PTH (176 vs. 99 pg/mL), higher 1,25-dihydroxyvitamin D (97 vs. 62 pg/mL), and higher 24-hour urinary calcium (182 vs. 118 mg/day) 8
• Bone loss: NPHPT affects bone mineral density similarly to hypercalcemic disease 1
• Neurocognitive symptoms: Depression, emotional lability, impaired cognition, and memory loss are recognized target-organ manifestations 1

Recommended Diagnostic Workup

Order the following tests immediately:

1. Repeat serum calcium (albumin-corrected or ionized) on at least two separate occasions to confirm persistent normocalcemia 1, 2
2. Serum creatinine and eGFR to exclude CKD 1, 2
3. Fasting serum phosphorus 7, 2
4. 24-hour urinary calcium or spot urine calcium/creatinine ratio to assess for hypercalciuria (>300 mg/24 hours is a surgical indication) 1, 8
5. Consider free 25-hydroxyvitamin D if available, as total vitamin D may be misleading 5
6. Detailed dietary calcium assessment (aim for 1,000–1,200 mg/day) 1, 6

If secondary causes are excluded, proceed with:

1. Parathyroid imaging (ultrasound and/or 99mTc-sestamibi SPECT/CT) only after biochemical diagnosis is confirmed—imaging is for surgical planning, not diagnosis 1
2. Renal ultrasonography to detect occult nephrocalcinosis or stones 1, 8
3. Bone density scan (DXA) to assess for osteoporosis (T-score ≤-2.5 is a surgical indication) 1

Management Algorithm

If Secondary Hyperparathyroidism is Confirmed:

• Optimize calcium intake to 1,000–1,200 mg/day through diet or supplementation 1, 6
• Recheck PTH after 2–4 weeks of adequate calcium intake; normalization confirms dietary insufficiency as the cause 6
• Maintain 25-hydroxyvitamin D >20 ng/mL with cholecalciferol or ergocalciferol 1, 4
• Avoid calcitriol or active vitamin D analogs, as they increase intestinal calcium absorption and can precipitate hypercalcemia 1

If NPHPT is Confirmed:

Refer to endocrinology and an experienced parathyroid surgeon if any of the following surgical indications are present 1:

• Age <50 years
• eGFR <60 mL/min/1.73 m²
• Osteoporosis (T-score ≤-2.5 at any site)
• 24-hour urinary calcium >300 mg (or >400 mg indicates severe hypercalciuria)
• History of nephrolithiasis or nephrocalcinosis
• Disabling neurocognitive symptoms (depression, cognitive impairment, functional disability)
• Patient preference for definitive treatment

For non-surgical candidates or observation:

• Maintain 25-hydroxyvitamin D >20 ng/mL with supplementation 1
• Ensure normal calcium intake (1,000–1,200 mg/day); avoid high or low extremes 2
• Monitor serum calcium every 3 months 1
• Repeat bone density scan every 1–2 years 1
• Reassess renal function and urinary calcium annually 1

Common Pitfalls to Avoid

1. Do not order parathyroid imaging before confirming biochemical diagnosis—imaging is for surgical planning, not diagnosis 1
2. Do not assume normal total vitamin D excludes deficiency—consider measuring free vitamin D 5
3. Do not overlook inadequate dietary calcium intake—this is a simple, reversible cause that resolves with supplementation 6
4. Do not use assay-independent PTH cutoffs—PTH measurements vary up to 47% between assays 1, 2
5. Do not supplement with calcitriol in suspected NPHPT—it will worsen hypercalcemia if primary hyperparathyroidism is present 1
6. Do not delay renal imaging—occult nephrocalcinosis is present in >25% of asymptomatic NPHPT patients 8

Immediate Next Steps

Start with a calcium challenge: Given your normal vitamin D and calcium levels, the most cost-effective and rapid diagnostic maneuver is to ensure adequate calcium intake (1,200 mg/day total from diet plus supplements) and recheck PTH in 2–4 weeks 6. If PTH normalizes, the diagnosis is secondary hyperparathyroidism from insufficient calcium intake. If PTH remains elevated despite adequate calcium, vitamin D, and normal renal function, proceed with full NPHPT workup including urinary calcium, renal imaging, and bone density assessment before surgical referral 1, 8.