What is the most likely diagnosis and recommended next step for a patient with persistent hypercalcemia predating GLP‑1 receptor agonist therapy and a parathyroid lesion on CT?

Primary Hyperparathyroidism (PHPT) with Parathyroid Adenoma

The most likely diagnosis is primary hyperparathyroidism due to a parathyroid adenoma, and the next step is to measure serum PTH (parathyroid hormone) to confirm the diagnosis, followed by localization imaging (ultrasound plus either 99mTc-sestamibi scintigraphy or 18F-choline PET-CT) if surgery is indicated. 1

Diagnostic Confirmation

Your patient's persistent hypercalcemia (calcium 10.1 mg/dL) that predates GLP-1 therapy, combined with a parathyroid lesion on CT, strongly suggests PHPT. The temporal relationship rules out medication-induced hypercalcemia from the GLP-1 agonist 2.

Required Laboratory Testing

Measure serum PTH immediately alongside calcium. The diagnosis of PHPT is confirmed when:

• PTH is elevated or inappropriately normal in the setting of hypercalcemia
• This represents the hallmark biochemical pattern 1, 3

Additional baseline labs should include:

• 24-hour urine calcium (to assess hypercalciuria and rule out familial hypocalciuric hypercalcemia)
• Serum creatinine/eGFR
• 25-OH vitamin D level (correct any deficiency before finalizing the diagnosis) 1, 3

Assessment of Target Organ Damage

Once PHPT is biochemically confirmed, systematically evaluate for complications that would mandate surgical intervention 1:

Renal assessment:

• Non-contrast low-dose CT urinary tract (more sensitive than ultrasound for detecting nephrolithiasis or nephrocalcinosis) 1
• Calculate eGFR
• Measure 24-hour urine calcium

Skeletal assessment:

• Bone densitometry (DXA) of spine, hip, and distal radius 1
• Consider spine imaging for asymptomatic vertebral fractures

Surgical Indications

Surgery should be offered if ANY of the following criteria are present 1:

• Serum calcium >10 mg/dL (0.25 mmol/L) above the upper limit of normal
• eGFR <60 mL/min/1.73 m²
• Kidney stones, nephrocalcinosis, or history of renal colic
• Bone density T-score ≤-2.5 at any site
• Fragility fracture
• 24-hour urine calcium >250 mg/day (women) or >300 mg/day (men)
• Age <50 years (though not explicitly stated, younger patients typically warrant surgery)

Given that your patient already has a calcium of 10.1 mg/dL and chronic kidney disease is a possibility (you mention "lesion in parathyroid area"), she likely meets surgical criteria.

Preoperative Localization Imaging

If surgery is planned, proceed with localization imaging 1:

First-line approach (perform both):

• Parathyroid ultrasound by experienced operator
• PLUS either:
  • Dual-isotope 123I/99mTc-sestamibi scintigraphy with SPECT/CT, OR
  • 18F-choline PET-CT (excellent performance, particularly useful if multi-glandular disease suspected) 1

If initial imaging is negative or discordant, consider 18F-choline PET-CT as second-line if sestamibi was performed first 1.

Important Caveats

Do not perform localization imaging if surgery is not planned 1. The imaging is to guide surgical approach, not to confirm diagnosis.

Rule out secondary causes before finalizing PHPT diagnosis:

• Correct vitamin D deficiency (maintain >6 months) 1
• Review medications: thiazides, lithium, calcium/vitamin D supplements 4, 5
• Assess for chronic kidney disease causing secondary hyperparathyroidism 1

The parathyroid "lesion" on CT is supportive but not diagnostic—biochemical confirmation with PTH is mandatory. CT alone cannot distinguish adenoma from carcinoma or even confirm parathyroid origin 6, 7, 8.

Management Algorithm

1. Measure PTH now (with simultaneous calcium, creatinine, vitamin D)
2. If PTH elevated/normal with hypercalcemia → Confirm PHPT diagnosis
3. Assess for surgical indications (renal imaging, bone densitometry, labs)
4. If surgical criteria met → Obtain localization imaging (US + functional imaging)
5. Refer to experienced endocrine surgeon for parathyroidectomy 1

Parathyroidectomy is the only curative treatment and should be performed by a surgeon experienced in endocrine surgery 1, 9. Success is confirmed by intraoperative PTH monitoring showing >50% decline from baseline 8.

If the patient refuses surgery or has prohibitive comorbidities, pharmacological management (calcimimetics, bisphosphonates) may be considered, but this is second-line 1.