What is the workup and differential for a patient with long-standing hypercalcemia and elevated Parathyroid Hormone (PTH) levels?

Workup and Differential Diagnosis for Long-Standing Hypercalcemia with Elevated PTH

Primary Diagnosis

This patient has primary hyperparathyroidism (PHPT), most likely from a parathyroid adenoma, given the 8-year history of hypercalcemia (10-11 mg/dL) with markedly elevated PTH (258 pg/mL) and normal albumin. 1, 2

Initial Laboratory Workup

Complete the following laboratory tests to confirm PHPT and assess complications:

• Serum phosphate - typically low or low-normal in PHPT 1
• 25-OH vitamin D level - vitamin D deficiency can complicate PTH interpretation and must be assessed 1, 3
• Serum creatinine/GFR - to evaluate renal function (GFR <60 mL/min/1.73 m² is a surgical indication) 1
• 24-hour urine calcium and creatinine - to calculate calcium/creatinine clearance ratio and exclude familial hypocalciuric hypercalcemia (FHH) 2, 4
• Ionized calcium - if total calcium fluctuates or albumin correction is uncertain 3

Critical Differential Diagnosis Considerations

Familial Hypocalciuric Hypercalcemia (FHH)

• Must be excluded as it mimics PHPT but requires no treatment 2
• FHH presents with hypercalcemia, elevated or inappropriately normal PTH, but low urinary calcium excretion 2
• Calculate calcium/creatinine clearance ratio: ratio <0.01 suggests FHH 2
• If suspected, genetic testing for CASR inactivating mutations is indicated 2

PTHrP-Mediated Hypercalcemia

• Your patient's PTHrP is 10.7, which appears mildly elevated (normal is typically <2.0 pmol/L)
• However, PTHrP-mediated hypercalcemia typically presents with suppressed PTH, not elevated PTH 2
• This elevation may represent assay interference or cross-reactivity rather than true malignancy-associated hypercalcemia
• If PTHrP is truly elevated with elevated PTH, consider rare parathyroid carcinoma (though this represents <1% of PHPT cases) 5, 6

Secondary or Tertiary Hyperparathyroidism

• Secondary hyperparathyroidism occurs with hypocalcemia (or normal calcium) in response to chronic kidney disease, vitamin D deficiency, or malabsorption 5
• Your patient has hypercalcemia, excluding secondary hyperparathyroidism
• Tertiary hyperparathyroidism occurs after long-standing secondary hyperparathyroidism (typically post-kidney transplant) with autonomous PTH secretion causing hypercalcemia 5
• No history of chronic kidney disease or transplant makes this unlikely

Imaging Studies for Localization

Imaging should only be performed if surgery is planned, as it has no role in confirming or excluding the diagnosis of PHPT. 5, 3

First-Line Imaging Options

• Neck ultrasound - sensitivity 76-80% for parathyroid adenoma localization 5, 2
• 99mTc-Sestamibi SPECT/CT - dual-phase imaging with SPECT/CT improves sensitivity to 88-93% 5, 2
• Combined ultrasound and sestamibi are typically sufficient for most cases 3, 4

Advanced Imaging (if first-line nonlocalizing)

• 4-D parathyroid CT (noncontrast, arterial, and venous phases) - useful for ectopic adenomas or reoperative cases 5
• Consider if initial imaging is discordant, nonlocalizing, or if ectopic adenoma is suspected 6

Additional Assessments

Evaluate for Complications

• Renal ultrasound - to detect nephrocalcinosis or kidney stones 3
• DXA scan - measure bone mineral density at lumbar spine, femoral neck, total femur, and distal forearm 3
• Assess for symptoms - bone pain, fractures, kidney stones, neurocognitive symptoms, muscle weakness 5

Genetic Testing Considerations

• Consider MEN1 and MEN2A genetic testing if: 4, 6
  • Age <40 years at presentation
  • Family history of hyperparathyroidism or endocrine tumors
  • Multiglandular disease on imaging
  • Recurrent disease after surgery

Surgical Indications

Surgery is indicated for this patient based on the following criteria: 1

• Age considerations - surgery typically indicated even when asymptomatic 5
• Significant hypercalcemia - calcium >0.25 mmol/L (>1 mg/dL) above upper limit of normal 1
• Impaired renal function - GFR <60 mL/min/1.73 m² 1
• Persistent PTH >800 pg/mL with hypercalcemia refractory to medical therapy (though your patient's PTH is 258 pg/mL) 1
• Complications - nephrolithiasis, osteoporosis, fractures 3

Medical Management Considerations

If surgery is delayed or contraindicated:

• Optimize vitamin D - supplement to achieve 25-OH vitamin D >20 ng/mL (50 nmol/L) before surgery 1, 3
• Cinacalcet - calcimimetic agent that can reduce calcium levels in patients unable to undergo surgery 7, 8
  • Dosing: start 30 mg twice daily, titrate every 2 weeks to maximum 90 mg four times daily 7
  • Mean calcium reduction of 1.7-2.3 mg/dL in clinical trials 7

Common Pitfalls to Avoid

• Do not rely on imaging to confirm or exclude PHPT diagnosis - this is a biochemical diagnosis 5
• Do not miss FHH - always measure 24-hour urine calcium to avoid unnecessary surgery 2
• Do not ignore vitamin D status - deficiency complicates PTH interpretation and should be corrected preoperatively 1, 3
• Be aware of PTH assay variability - different assay generations have varying sensitivity to PTH fragments 1
• Consider biotin interference - biotin supplements can interfere with PTH assays 1
• Verify the PTHrP result - true elevation with elevated PTH is extremely rare and may suggest parathyroid carcinoma or assay interference 8, 2