What is the diagnostic approach for a patient with hypercalcemia and elevated parathyroid hormone (PTH) levels, suspected of having primary hyperparathyroidism?

Diagnostic Workup for High Calcium and High PTH

In a patient with hypercalcemia and elevated PTH, the diagnostic approach should begin with simultaneous measurement of serum calcium (corrected for albumin) and intact PTH to confirm primary hyperparathyroidism, followed by assessment of vitamin D status, renal function, and 24-hour urine calcium to exclude secondary causes and evaluate complications. 1

Initial Biochemical Confirmation

The hallmark finding is hypercalcemia or high-normal calcium with elevated or inappropriately normal PTH levels. 1 Measure these tests simultaneously in the following order:

• Serum calcium (total calcium corrected for albumin) - confirms hypercalcemia 1
• Intact parathyroid hormone (iPTH) - elevated or inappropriately normal in primary hyperparathyroidism 1
• Serum phosphate - typically low or low-normal in primary hyperparathyroidism 1
• 25-hydroxyvitamin D - crucial because vitamin D deficiency can complicate PTH interpretation and cause secondary hyperparathyroidism 1
• Serum creatinine and eGFR - essential to evaluate kidney function and exclude secondary hyperparathyroidism from chronic kidney disease 1

Critical Technical Considerations

Collect blood samples in EDTA tubes for PTH measurement, 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. 2 Be aware that biotin supplements can interfere with PTH assays and lead to under or overestimation depending on the assay design. 1

Secondary Laboratory Tests

Once primary hyperparathyroidism is biochemically confirmed, obtain:

• Serum chloride and uric acid - may suggest underlying conditions associated with stone disease 1
• 24-hour urine collection for calcium, oxalate, uric acid, citrate, sodium, potassium, and creatinine - helps evaluate complications and metabolic abnormalities 1

Patients with 24-hour urine calcium >400 mg/day are at increased risk for kidney stone formation and bone complications, which is a surgical indication for parathyroidectomy. 2

Differential Diagnosis Exclusions

Before confirming primary hyperparathyroidism, exclude these conditions:

• Secondary hyperparathyroidism - characterized by normal or low serum calcium with elevated PTH, commonly seen in chronic kidney disease or vitamin D deficiency 1
• Tertiary hyperparathyroidism - marked by hypercalcemia with elevated PTH in end-stage renal disease 1
• Familial hypocalciuric hypercalcemia - if urinary calcium-to-creatinine clearance ratio is <0.01, consider this genetic cause 3

Vitamin D deficiency causes secondary hyperparathyroidism and must be excluded before diagnosing primary hyperparathyroidism. 2 PTH reference values are 20% lower in vitamin D-replete individuals compared to those with unknown vitamin D status. 2

Imaging Studies (Only After Biochemical Diagnosis)

Imaging has no utility in confirming or excluding the diagnosis of hyperparathyroidism, but is used only for localization after biochemical diagnosis is established. 1 When surgery is planned:

• Ultrasound of the neck - first-line localization study 1
• Dual-phase 99mTc-sestamibi scintigraphy with SPECT/CT - provides high sensitivity for localizing parathyroid adenomas 1
• Combination of ultrasound and sestamibi scan - offers the highest sensitivity for localization 1
• MRI or CT scan - consider if initial imaging is negative 1

For reoperative cases or suspected ectopic glands, 4D-CT or MRI may be particularly useful. 1

Common Pitfalls to Avoid

Not assessing vitamin D status when interpreting PTH levels can lead to misdiagnosis. 1 Vitamin D deficiency can suppress urine calcium excretion in primary hyperparathyroidism patients, potentially masking hypercalciuria. 2 Using different PTH assay generations without considering their varying sensitivity to PTH fragments can result in inaccurate diagnoses. 1 Never order parathyroid imaging before confirming biochemical diagnosis, as imaging is for surgical planning, not diagnosis. 2

When to Refer

Seek advice from a specialist with expertise in primary hyperparathyroidism once biochemical diagnosis is confirmed. 1 Refer to endocrinology and an experienced parathyroid surgeon for surgical evaluation when surgical criteria are met, including corrected calcium >1 mg/dL above upper limit of normal, impaired kidney function (GFR <60 mL/min/1.73 m²), osteoporosis, history of nephrolithiasis, 24-hour urine calcium >400 mg/day, or age <50 years. 2, 4