What is the initial work-up and treatment for a patient with hypercalcemia and elevated Parathyroid Hormone (PTH) levels?

Work-up for Hypercalcemia with Elevated PTH

Initial Diagnostic Approach

In a patient with hypercalcemia and elevated PTH, the diagnosis is primary hyperparathyroidism (PHPT) until proven otherwise, and the initial work-up should focus on confirming this diagnosis and excluding secondary causes of PTH elevation. 1, 2

Essential Laboratory Tests

Measure the following labs immediately:

• Serum calcium (total and ionized) - Ionized calcium (normal: 4.65-5.28 mg/dL) provides definitive assessment and avoids misleading results from abnormal albumin levels 2
• Intact PTH (iPTH) - Use EDTA plasma rather than serum, as PTH is most stable in EDTA plasma 2. PTH measurements can vary up to 47% between different assay generations, so use assay-specific reference values 1, 2
• 25-hydroxyvitamin D - Critical to exclude vitamin D deficiency, which causes secondary hyperparathyroidism and must be ruled out before diagnosing PHPT 1, 2. Aim for levels >20 ng/mL (50 mmol/L) 1
• Serum phosphorus - Typically low-normal in PHPT 2
• Serum creatinine and eGFR - To assess kidney function, as impaired GFR <60 mL/min/1.73 m² is a surgical indication 1, 2
• 24-hour urine calcium or spot urine calcium/creatinine ratio - Low urinary calcium suggests calcium deprivation (calcium and/or vitamin D deficiency) rather than PHPT 1, 2

Critical Interpretation Points

The combination of hypercalcemia with elevated or inappropriately normal PTH confirms PHPT. 1, 2, 3 Even PTH values as low as 40-50 pg/mL can represent PHPT when calcium is elevated, as any detectable PTH in the setting of hypercalcemia is inappropriate 4. In contrast, a suppressed PTH (<20 pg/mL) indicates PTH-independent hypercalcemia from malignancy, granulomatous disease, or vitamin D toxicity 5, 3, 6

Exclude Secondary Hyperparathyroidism

Before confirming PHPT, evaluate for conditions that elevate PTH appropriately:

• Vitamin D deficiency - Patients with elevated PTH should be evaluated for vitamin D deficiency and supplemented if necessary 1. Reference values of PTH are 20% lower in vitamin D-replete individuals 1, 2
• Dietary calcium deficiency - Ensure patients meet age-related recommended dietary allowance for calcium intake through dietary evaluation 1
• Chronic kidney disease - PTH increases with declining GFR, particularly in patients over 60 years old 1

Additional Considerations

Account for biological factors that influence PTH:

• PTH concentrations are race-dependent (higher in Black individuals), correlate with BMI, and increase with age 1
• Biological variation of PTH is substantial (20% in healthy individuals), so differences must exceed 54% to be clinically significant 2
• Sampling site matters: central blood has higher PTH concentrations than peripheral blood 2

Imaging Studies

Do NOT order parathyroid imaging before confirming the biochemical diagnosis. 2 Imaging is for surgical planning, not diagnosis.

Once PHPT is biochemically confirmed and surgery is being considered:

• Ultrasound and/or 99mTc-sestamibi scintigraphy with SPECT/CT for preoperative localization 2
• Renal ultrasonography to assess for nephrocalcinosis or kidney stones 2
• Bone density scan (DEXA) if chronic hyperparathyroidism is suspected to evaluate for osteoporosis 2

Surgical Indications

Refer to endocrinology and an experienced parathyroid surgeon if the patient meets ANY of the following criteria: 1, 2

• Corrected calcium >1 mg/dL (>0.25 mmol/L) above upper limit of normal
• Age <50 years
• Impaired kidney function (GFR <60 mL/min/1.73 m²)
• Osteoporosis (T-score ≤-2.5 at any site)
• History of nephrolithiasis or nephrocalcinosis
• Hypercalciuria (>300 mg/24hr)

Medical Management for Non-Surgical Candidates

For patients who cannot undergo surgery or decline parathyroidectomy:

• Cinacalcet is FDA-approved for hypercalcemia in adult patients with primary hyperparathyroidism for whom parathyroidectomy would be indicated based on serum calcium levels but who are unable to undergo surgery 7
• Starting dose: 30 mg twice daily, titrated every 2-4 weeks to normalize serum calcium 7
• Monitor serum calcium within 1 week after initiation or dose adjustment 7
• Once maintenance dose established, monitor calcium every 2 months 7

Dietary recommendations:

• Maintain normal calcium intake (1000-1200 mg/day); avoid high or low calcium diets 2
• Total elemental calcium intake should not exceed 2000 mg/day 2
• Ensure adequate vitamin D (>20 ng/mL) with supplementation if needed 1

Common Pitfalls to Avoid

• Do not assume vitamin D deficiency is the sole cause if PTH is elevated with hypercalcemia - this combination suggests PHPT with concurrent vitamin D deficiency 1, 2
• Do not order parathyroid imaging before biochemical confirmation - imaging cannot diagnose PHPT 2
• Do not use calcium-based phosphate binders in patients with hypercalcemia and CKD, as these worsen hypercalcemia 5, 2
• Do not overlook multiglandular disease - patients with PTH ≤50 pg/mL have higher rates of multiglandular disease (58.9%) and should be considered for bilateral exploration 4
• Do not assume observation is safe - even asymptomatic PHPT requires monitoring every 3 months for calcium, phosphorus, and kidney function 2