What is the appropriate work‑up for a patient with an elevated intact parathyroid hormone (iPTH) level?

Work-Up for Elevated Intact Parathyroid Hormone (iPTH)

When you encounter an elevated iPTH, immediately measure serum calcium (albumin-corrected or ionized), serum phosphorus, 25-hydroxyvitamin D, and estimated glomerular filtration rate (eGFR) to distinguish primary hyperparathyroidism from secondary causes. 1, 2, 3

Initial Laboratory Panel

The first step requires a focused biochemical assessment to determine whether the elevated PTH represents autonomous parathyroid overactivity or an appropriate physiologic response:

• Serum calcium (albumin-corrected or ionized): This single measurement determines your diagnostic pathway. Hypercalcemia with elevated PTH indicates primary hyperparathyroidism, while normal calcium suggests secondary hyperparathyroidism or normocalcemic primary hyperparathyroidism. 4, 2, 3

• Serum phosphorus: Low or low-normal phosphorus points toward primary hyperparathyroidism, whereas elevated phosphorus suggests chronic kidney disease-related secondary hyperparathyroidism. 2, 3

• 25-hydroxyvitamin D: Deficiency (< 30 ng/mL) is the most common and frequently missed reversible cause of secondary hyperparathyroidism. This must be measured and corrected before pursuing any other diagnosis. 1, 4, 2, 3

• Estimated glomerular filtration rate (eGFR): PTH rises early in chronic kidney disease (often when eGFR falls below 60 mL/min/1.73 m²), frequently before calcium or phosphorus abnormalities appear. 1, 2, 3

Diagnostic Algorithm Based on Calcium Status

Elevated Calcium with Elevated PTH (Primary Hyperparathyroidism)

If serum calcium is elevated (> 10.2 mg/dL) with elevated or inappropriately normal PTH, the diagnosis is primary hyperparathyroidism. 4, 5

Additional confirmatory steps:

• Verify vitamin D status: Even in primary hyperparathyroidism, ensure 25-hydroxyvitamin D is > 20 ng/mL to exclude concurrent vitamin D deficiency that could be driving part of the PTH elevation. 1, 4

• Measure 24-hour urinary calcium or spot urine calcium-to-creatinine ratio: If the calcium-to-creatinine clearance ratio is < 0.01, consider familial hypocalciuric hypercalcemia rather than primary hyperparathyroidism. 4, 5

• Assess for surgical indications: Refer to endocrinology and an experienced parathyroid surgeon if the patient meets any of these criteria: corrected calcium > 1 mg/dL above upper limit of normal, age < 50 years, eGFR < 60 mL/min/1.73 m², osteoporosis (T-score ≤ -2.5), history of nephrolithiasis or nephrocalcinosis, or 24-hour urinary calcium > 300 mg. 4

Critical pitfall: Do not order parathyroid imaging (ultrasound or sestamibi scan) before confirming the biochemical diagnosis. Imaging is for surgical planning only, not for diagnosis. 4

Normal Calcium with Elevated PTH (Secondary vs. Normocalcemic Primary Hyperparathyroidism)

When PTH is elevated but calcium is normal, systematically exclude all secondary causes before considering normocalcemic primary hyperparathyroidism. 3, 6

Step 1: Rule Out Vitamin D Deficiency

• Measure 25-hydroxyvitamin D: If < 30 ng/mL, supplement with cholecalciferol or ergocalciferol to achieve levels ≥ 30 ng/mL, then remeasure PTH after 3–6 months. 1, 2, 3, 6

• Dosing: For deficiency, use ergocalciferol 50,000 units orally every month for 6 months if eGFR < 30 mL/min/1.73 m², or standard cholecalciferol 1,000–2,000 IU daily for patients with normal kidney function. 1

Step 2: Assess Kidney Function

• If eGFR < 60 mL/min/1.73 m²: The elevated PTH likely represents chronic kidney disease-related secondary hyperparathyroidism. Evaluate and correct modifiable factors including hyperphosphatemia, hypocalcemia, high phosphate intake, and vitamin D deficiency. 1, 2, 3

• Monitoring frequency for CKD patients: Measure calcium and phosphorus every 6–12 months for CKD G3a–G3b, every 3–6 months for CKD G4, and every 1–3 months for CKD G5. 2, 3

Step 3: Evaluate Dietary Calcium Intake

• Assess daily calcium intake: Inadequate dietary calcium (< 1,000–1,200 mg/day) can cause secondary hyperparathyroidism even with normal vitamin D and kidney function. 4, 6, 7

• Calcium challenge test: If dietary intake is low, supplement with calcium carbonate 600 mg twice daily and remeasure PTH after 2–3 weeks. Normalization of PTH confirms that insufficient calcium intake was the cause. 7

Step 4: Check for Medications and Other Causes

• Review medications: Lithium salts, thiazide diuretics, and antiresorptive osteoporosis therapies (bisphosphonates, denosumab) can elevate PTH. 6

• Assess for hypercalciuria: Measure 24-hour urinary calcium or spot urine calcium-to-creatinine ratio. Hypercalciuria with normal serum calcium and elevated PTH may indicate renal calcium leak causing secondary hyperparathyroidism. 6

• Consider malabsorption: Conditions such as celiac disease, inflammatory bowel disease, or prior bariatric surgery can impair calcium absorption and drive secondary hyperparathyroidism. 6

Step 5: Consider Normocalcemic Primary Hyperparathyroidism

If all secondary causes are excluded—specifically, 25-hydroxyvitamin D ≥ 30 ng/mL, eGFR ≥ 60 mL/min/1.73 m², adequate dietary calcium intake (≥ 1,000–1,200 mg/day), and no interfering medications—then normocalcemic primary hyperparathyroidism is the diagnosis. 4, 6

• Calcium loading test: Administer intravenous calcium and measure PTH response. In normocalcemic primary hyperparathyroidism, PTH fails to suppress appropriately when serum calcium rises above the upper limit of normal. 6, 8

• Clinical significance: Normocalcemic primary hyperparathyroidism is not benign; it carries a risk profile comparable to hypercalcemic primary hyperparathyroidism, including bone loss, nephrolithiasis, and neurocognitive symptoms. 4

Special Considerations and Common Pitfalls

PTH Assay Variability

• Use assay-specific reference ranges: Intact PTH assays differ by up to 47% between generations due to variations in antibodies used. Always interpret results using the reference range provided by your specific laboratory. 1, 4

• Prefer EDTA plasma over serum: PTH is most stable in EDTA plasma at 4°C. If possible, request that your laboratory use EDTA plasma for PTH measurement. 4

Biological Factors Affecting PTH

• Race, age, BMI, and vitamin D status influence PTH concentration: Reference values are approximately 20% lower in vitamin D-replete individuals compared to those with unknown vitamin D status. 4

• Biological variation is substantial: PTH varies by approximately 20% in healthy individuals, so differences must exceed 54% to be clinically significant. Serial measurements should be interpreted with this variability in mind. 4

Rare Presentations

• Suppressed or low-normal PTH with hypercalcemia: In rare cases, primary hyperparathyroidism can present with inappropriately low or even undetectable PTH levels due to secretion of PTH molecular species not detected by standard assays. If clinical suspicion is high (hypercalcemia, nephrolithiasis, osteoporosis), pursue imaging with sestamibi scan despite low PTH. 9

Monitoring During Treatment

For CKD-Related Secondary Hyperparathyroidism

• During active treatment: Check serum calcium and phosphorus monthly for the first 3 months, then every 3 months. Measure PTH every 3 months for 6 months, then every 3–6 months thereafter. 2, 3

• Avoid calcitriol or vitamin D analogs in CKD G3a–G5 not on dialysis: These agents increase the risk of adynamic bone disease and hypercalcemia. Reserve them only for severe and progressive hyperparathyroidism in CKD G4–G5. 1, 3

For Primary Hyperparathyroidism

• If surgery is not pursued: Monitor serum calcium every 3 months for patients with confirmed primary hyperparathyroidism who are not surgical candidates. 4

• Post-parathyroidectomy: Measure ionized calcium every 4–6 hours for the first 48–72 hours to detect "hungry bone syndrome," a rapid fall in calcium that can occur after removal of hyperfunctioning parathyroid tissue. If ionized calcium drops below 0.9 mmol/L (≈ 3.6 mg/dL), start intravenous calcium gluconate infusion at 1–2 mg elemental calcium per kg per hour. 4, 2