What does it mean for a patient to have high parathyroid hormone (PTH) levels with normal calcium levels?

High PTH with Normal Calcium: Diagnostic Interpretation

A patient with elevated parathyroid hormone (PTH) and normal calcium most likely has either normocalcemic primary hyperparathyroidism or secondary hyperparathyroidism due to vitamin D deficiency or early chronic kidney disease. 1, 2

Essential Diagnostic Framework

The combination of high PTH with normal calcium requires systematic evaluation to distinguish between three primary entities:

1. Secondary Hyperparathyroidism (Most Common)

This represents a compensatory physiologic response where PTH appropriately increases to maintain calcium homeostasis 2:

• Vitamin D deficiency is the most common cause and must be evaluated first 1, 2
• Chronic kidney disease (even mild GFR reductions) disrupts calcium-phosphate homeostasis, triggering compensatory PTH elevation 2
• Malabsorption disorders reducing calcium availability 3

Key distinguishing features:

• Normal or low serum calcium (not high-normal) 1
• Low 25-hydroxyvitamin D levels (typically <30 ng/mL) 1
• Elevated serum creatinine or reduced eGFR 1
• Serum phosphate typically normal or elevated (not low) 1

2. Normocalcemic Primary Hyperparathyroidism (15% of PHPT cases)

This represents autonomous PTH overproduction despite normal calcium levels 2, 4:

• PTH is inappropriately elevated for the calcium level 2
• Calcium remains in the normal range (2.12-2.62 mmol/L or 8.5-10.5 mg/dL) but often high-normal 4
• Ionized calcium may be elevated in 86% of cases even when total calcium is normal 5
• Patients remain at risk for complications including osteoporosis, kidney stones, and fractures similar to hypercalcemic PHPT 4, 2

Key distinguishing features:

• Serum phosphate is low or low-normal 1, 4
• 25-hydroxyvitamin D is adequate (>30 ng/mL) 4
• Normal kidney function (eGFR >60 mL/min/1.73 m²) 1
• Elevated bone turnover markers may be present 6
• 24-hour urine calcium often shows hypercalciuria (>250-300 mg/day) 6

3. Tertiary Hyperparathyroidism

This occurs when hyperplastic parathyroid glands become autonomous after longstanding secondary hyperparathyroidism 2:

• Most commonly seen after kidney transplantation in patients with prior CKD 3
• Characterized by hypercalcemia with elevated PTH (not normocalcemia) 1
• PTH levels decline slowly post-transplant, with 50% normalizing by 3-6 months 3

Critical Diagnostic Algorithm

Step 1: Measure ionized calcium

• If ionized calcium is elevated, this is likely normocalcemic PHPT with masked hypercalcemia 5
• Correcting total calcium for albumin is essential if albumin is abnormal 1

Step 2: Assess vitamin D status (25-hydroxyvitamin D)

• If <30 ng/mL, vitamin D deficiency is the likely cause of elevated PTH 1, 2
• Failure to check vitamin D is the most common diagnostic pitfall 1, 2

Step 3: Evaluate kidney function

• Measure serum creatinine and calculate eGFR 1
• Even mild CKD (GFR <60 mL/min/1.73 m²) can elevate PTH 2

Step 4: Check serum phosphate

• Low or low-normal phosphate suggests primary hyperparathyroidism 1, 4
• Normal or elevated phosphate suggests secondary hyperparathyroidism from CKD 1

Step 5: Measure 24-hour urine calcium

• Hypercalciuria (>250-300 mg/day) supports normocalcemic PHPT 6
• Low urine calcium (<100 mg/day) suggests calcium/vitamin D deficiency 3

Important Technical Considerations

PTH Assay Interpretation

Different PTH assays yield significantly different results (up to 47% variation between generations), so always use assay-specific reference ranges 1, 2. Several biological factors influence PTH levels:

• Age: PTH increases with age due to declining kidney function 2
• Race: PTH levels are 20% higher in Black individuals 2
• BMI: Obesity increases PTH concentrations 2
• Vitamin D status: PTH reference values are 20% lower in vitamin D-replete individuals 2
• Sample handling: PTH is most stable in EDTA plasma stored at 4°C 1, 2
• Biotin interference: Supplements can cause falsely low or high PTH depending on assay design 1

Common Diagnostic Pitfalls to Avoid

1. Not measuring ionized calcium when total calcium is normal—86% of normocalcemic PHPT patients have elevated ionized calcium 5

2. Ordering parathyroid imaging before biochemical diagnosis is confirmed—imaging is for surgical localization only, not diagnosis 3, 1

3. Assuming normal calcium excludes primary hyperparathyroidism—15% of PHPT presents with normal calcium 4

4. Not recognizing that "inappropriately normal" PTH in the setting of high-normal calcium is abnormal—PTH should be suppressed when calcium is at the upper limit of normal 7

5. Ignoring vitamin D deficiency, which can mask hypercalcemia in PHPT and complicate interpretation 3, 2

Clinical Significance and Natural History

Normocalcemic PHPT is not a benign condition. Despite normal calcium, these patients demonstrate:

• Similar rates of osteoporosis compared to hypercalcemic PHPT 4
• Equivalent frequency of kidney stones 4
• Comparable fracture risk 4
• Potential progression to hypercalcemic PHPT over time 8

In one long-term follow-up case, a patient with normocalcemic PHPT eventually developed multiple parathyroid adenomas requiring sequential surgeries over 10 years 8.

When to Consider Specialist Referral

Refer to endocrinology when:

• Normocalcemic PHPT is confirmed after excluding secondary causes 1
• PTH remains elevated despite vitamin D repletion and normal kidney function 3
• Patient has complications (osteoporosis, kidney stones, fractures) 1

Imaging for surgical localization should only be obtained after biochemical diagnosis is established and surgery is being considered 3, 1. First-line localization includes neck ultrasound and 99mTc-sestamibi scintigraphy with SPECT/CT 1.