In an adult with hypercalcemia and elevated intact parathyroid hormone due to a parathyroid adenoma, what is the recommended diagnostic work‑up and definitive treatment, and what are the alternatives if surgery is contraindicated?

Management of Parathyroid Adenoma

Parathyroidectomy is the only definitive curative therapy for primary hyperparathyroidism due to parathyroid adenoma and should be performed in all symptomatic patients and most asymptomatic patients. 1, 2

Diagnostic Work-Up

Initial Biochemical Testing

• Measure serum calcium (corrected for albumin) and intact parathyroid hormone (iPTH) simultaneously—the hallmark finding is hypercalcemia or high-normal calcium with elevated or inappropriately normal PTH levels. 3
• Check serum phosphate (typically low or low-normal in primary hyperparathyroidism). 3
• Assess 25-hydroxyvitamin D status, as vitamin D deficiency can complicate PTH interpretation and mask hypercalciuria. 3
• Measure serum creatinine to evaluate kidney function (eGFR). 3

Confirmatory and Risk Assessment Testing

• Obtain 24-hour urine collection for calcium, oxalate, uric acid, citrate, sodium, potassium, and creatinine to evaluate complications and metabolic abnormalities. 3
• Patients with 24-hour urine calcium >400 mg/day are at increased risk for kidney stones and bone complications, which constitutes a surgical indication. 3
• Perform dual-energy x-ray absorptiometry (DEXA) to assess bone mineral density. 2

Important Technical Considerations

• Use assay-specific reference values for PTH measurement, as different assay generations measure different PTH fragments and yield significantly different values between laboratories. 3
• Collect blood samples in EDTA tubes for PTH measurement, as PTH is most stable in EDTA plasma. 3
• Be aware that biotin supplements can interfere with PTH assays. 3

Preoperative Localization Imaging

Imaging has no role in diagnosing hyperparathyroidism but is essential for preoperative localization when surgery is planned. 1, 3

First-Line Imaging

• Ultrasound of the neck is the recommended first-line localization study. 3
• Dual-phase 99mTc-sestamibi scintigraphy with SPECT/CT provides high sensitivity for localizing parathyroid adenomas. 1, 3
• The combination of ultrasound and sestamibi scan offers the highest sensitivity for localization. 3

Advanced Imaging

• Consider MRI or CT scan if initial imaging is negative. 3
• For reoperative cases or suspected ectopic glands, 4D-CT or MRI may be particularly useful. 3
• Avoid preoperative parathyroid biopsy. 2

Definitive Treatment: Parathyroidectomy

Surgical Indications

Surgery is indicated for: 1, 3, 2

• All symptomatic patients (nephrolithiasis, bone pain, recurrent hypercalcemia symptoms)
• Asymptomatic patients meeting any of the following criteria:
  • Age ≥50 years
  • Osteoporosis on DEXA
  • eGFR <60 mL/min/1.73 m²
  • Kidney stones
  • Calcium >0.25 mmol/L (>1 mg/dL) above upper limit of normal
  • 24-hour urine calcium >400 mg/day

Surgical Approach

• Both minimally invasive parathyroidectomy (MIP) with intraoperative PTH monitoring and bilateral neck exploration achieve high cure rates. 1, 2
• For single adenoma localized on imaging, minimally invasive parathyroidectomy with intraoperative PTH monitoring via a reliable protocol is appropriate. 1, 2
• Minimally invasive parathyroidectomy is not routinely recommended for known or suspected multigland disease. 2
• Surgeons who perform high volumes of parathyroid operations have better outcomes. 2
• The possibility of multigland disease should be routinely considered during surgery. 2

Intraoperative Considerations

• Ex vivo aspiration of resected parathyroid tissue may confirm parathyroid tissue intraoperatively. 2
• Devascularized normal parathyroid tissue should be autotransplanted. 2
• Address clinically relevant thyroid disease during the same operation. 2

Postoperative Management

Immediate Monitoring (First 48-72 Hours)

• Monitor ionized calcium every 4-6 hours to detect early hypocalcemia. 1
• If ionized calcium drops below 0.9 mmol/L (corrected total calcium <7.2 mg/dL), initiate intravenous calcium gluconate infusion at 1-2 mg elemental calcium/kg/hour. 1

Transition to Oral Therapy

• Once oral intake is tolerated, switch to calcium carbonate 1-2 g three times daily plus calcitriol up to 2 μg/day to prevent hungry-bone syndrome. 1
• Review serum phosphorus levels and discontinue or reduce phosphate binders when phosphorus falls toward lower normal range. 1

Long-Term Follow-Up

• Assess for cure defined as eucalcemia at more than 6 months postoperatively. 2
• Monitor for hematoma and symptoms of hypocalcemia. 2

Alternatives When Surgery Is Contraindicated

Surgery is more cost-effective than observation or pharmacologic therapy, but medical management is suitable for patients with contraindications to surgery or asymptomatic disease not meeting surgical criteria. 2, 4

Medical Management Options

• Bisphosphonates for skeletal protection (no fracture data available). 4
• Calcimimetic agents to lower serum calcium (no fracture data available). 4, 5
• Hormone replacement therapy or raloxifene in postmenopausal women (no fracture data available). 4
• Close monitoring is safe in asymptomatic patients not meeting surgical criteria. 4

Important Contraindications

• Increased calcium diet is completely contraindicated in hypercalcemia, as it worsens elevated calcium levels. 1

Special Considerations

Atypical Presentations

• Approximately 5-33% of parathyroid adenomas present with hypercalcemia but normal PTH levels, sometimes due to parathyroid hormone-related peptide (PTHrP) production. 6
• Ectopic adenomas (substernal, mediastinal) occur in approximately 5% of cases and may cause persistent or recurrent hyperparathyroidism. 6

Genetic Screening

• For patients with multiple endocrine neoplasia (MEN) syndromes, screening should begin at age 11 for high-risk variants and age 16 for moderate-risk variants. 3