In a 67‑year‑old woman with epigastric burning discomfort, nausea, mild hypercalcemia, normal vitamin D, elevated intact parathyroid hormone, hypercalciuria, and a history of tarsal bone fractures, hysterectomy, and endometrial ablation, what is the differential diagnosis for the hypercalcemia?

Differential Diagnosis for Hypercalcemia

This patient's presentation of mild hypercalcemia with elevated PTH and hypercalciuria is most consistent with primary hyperparathyroidism (PHPT), which should be your leading diagnosis given the classic biochemical triad and history of pathological fractures. 1

Primary Diagnosis: Primary Hyperparathyroidism

The biochemical profile—mild hypercalcemia, elevated intact PTH, and hypercalciuria—represents the "typical form" of PHPT that poses little diagnostic difficulty 1. The patient's history of tarsal bone fractures is particularly significant, as PHPT should be suspected in cases of repeated fractures, osteoporosis, and diffuse osteoarticular pain 1. Her gastrointestinal symptoms (epigastric burning, nausea) are consistent with hypercalcemia effects.

Key Supporting Features:

• Elevated PTH with hypercalcemia = inappropriate PTH secretion 2
• Hypercalciuria = PTH excess increases intestinal and bone calcium inputs 1
• History of pathological fracture = target organ involvement 2
• Normal vitamin D = excludes secondary hyperparathyroidism from vitamin D deficiency 2

Critical Differential Diagnoses to Exclude

1. Familial Hypocalciuric Hypercalcemia (FHH)

This is the most important alternative diagnosis to rule out before proceeding to parathyroidectomy. FHH presents with hypercalcemia and elevated PTH but characteristically shows hypocalciuria (not hypercalciuria as in this patient) 1, 3. The presence of hypercalciuria in your patient makes FHH unlikely, but calculate the calcium-to-creatinine clearance ratio if there's any diagnostic uncertainty.

2. Medication-Induced Hypercalcemia

Given her epigastric symptoms, investigate:

• Calcium carbonate antacid overuse (milk-alkali syndrome) 4
• Thiazide diuretics 5, 6
• Lithium 1, 6

However, these typically cause PTH-independent hypercalcemia (suppressed PTH), which doesn't match this patient's elevated PTH 1.

3. Malignancy-Related Hypercalcemia

While malignancy accounts for approximately 45% of hypercalcemia cases 5, it typically presents with:

• Suppressed PTH (PTH <20 pg/mL) 5
• Elevated PTH-related peptide (PTHrP) in solid tumors 6
• More severe, rapidly progressive hypercalcemia 5

The elevated PTH in this patient argues strongly against malignancy 7.

4. Granulomatous Disease (Sarcoidosis)

Sarcoidosis can cause severe hypercalcemia with constitutional symptoms and may mimic malignancy 7. However, it characteristically shows:

• Suppressed PTH 7
• Elevated 1,25-dihydroxyvitamin D 6, 7
• Responds to corticosteroids 5

The elevated PTH excludes this diagnosis.

5. Tertiary Hyperparathyroidism

Check renal function (eGFR) carefully 1. Tertiary hyperparathyroidism develops after prolonged secondary hyperparathyroidism (usually from chronic kidney disease), resulting in autonomous PTH secretion 3. However, this patient would need a history of chronic kidney disease or dialysis.

Diagnostic Algorithm Before Accepting PHPT Diagnosis

Per the 2025 guidelines 1, 2, you must systematically exclude confounding factors:

1. Confirm vitamin D status is adequate (>30 ng/mL for at least 6 months) 2
2. Measure eGFR to exclude renal insufficiency 1
3. Review all medications: thiazides, lithium, bisphosphonates, denosumab, excessive vitamin D/calcium supplements 1
4. Assess for malabsorption: history of bariatric surgery, celiac disease, inflammatory bowel disease 1
5. Measure ionized calcium if total calcium is borderline 2

Common Pitfalls to Avoid

• Do not diagnose normocalcemic PHPT without first correcting vitamin D deficiency for >6 months 2. Vitamin D insufficiency is a frequent cause of secondary hyperparathyroidism that can confound the diagnosis.

• Do not proceed to parathyroidectomy without excluding FHH, as surgery is ineffective for FHH and the condition is benign 3.

• Do not attribute all hypercalcemia with elevated PTH to PHPT in patients with chronic kidney disease—distinguish secondary from tertiary hyperparathyroidism 3.

• In patients with gastrointestinal symptoms, specifically ask about calcium carbonate antacid use, as milk-alkali syndrome is resurfacing as a common cause of hypercalcemia 4.

Next Steps for This Patient

Confirm PHPT diagnosis by:

• Verifying 25(OH)vitamin D level is adequate (>30 ng/mL)
• Checking serum creatinine/eGFR
• Obtaining ionized calcium if total calcium is only mildly elevated
• Reviewing medication list for interfering drugs
• Calculating 24-hour urinary calcium excretion to confirm hypercalciuria and exclude FHH

Once PHPT is confirmed, assess for surgical indications 2:

• Age <50 years
• Serum calcium >1 mg/dL above upper normal limit
• Evidence of skeletal disease (osteoporosis, fractures)
• Evidence of renal disease (nephrolithiasis, reduced eGFR)

Given this patient's history of pathological fractures, parathyroidectomy is likely indicated 2, 8.