What is the diagnostic approach to determine primary hyperparathyroidism?

Diagnostic Approach to Primary Hyperparathyroidism

The diagnostic approach to primary hyperparathyroidism (PHPT) should begin with simultaneous measurement of serum calcium (total calcium corrected for albumin) and intact parathyroid hormone (iPTH), with the hallmark finding being hypercalcemia or high-normal calcium with elevated or inappropriately normal PTH levels. 1, 2

Initial Laboratory Evaluation

• Measure serum calcium (total calcium corrected for albumin) and iPTH simultaneously as the cornerstone of diagnosis 1, 2
• Assess vitamin D status (25-hydroxyvitamin D) as deficiency can complicate interpretation of PTH levels 1
• Check serum phosphate, which is typically low or low-normal in PHPT 1
• Measure serum creatinine to evaluate kidney function 1
• Check serum chloride and uric acid levels to evaluate for conditions associated with stone disease 1
• Use assay-specific reference values for PTH measurement, as different assay generations can affect clinical interpretation 3
• Collect blood samples in EDTA tubes for PTH measurement as PTH is most stable in EDTA plasma 1

Confirmatory Testing

• Obtain a 24-hour urine collection for calcium, oxalate, uric acid, citrate, sodium, potassium, and creatinine to evaluate complications and other metabolic abnormalities 1
• Calculate the calcium-to-creatinine clearance ratio to rule out familial hypocalciuric hypercalcemia (FHH), which has a ratio <0.01 4
• Consider measuring PTHrP in cases where malignancy-associated hypercalcemia is suspected 5

Differential Diagnosis

• Secondary hyperparathyroidism: characterized by normal or low serum calcium with elevated PTH, commonly seen in chronic kidney disease or vitamin D deficiency 1, 2
• Tertiary hyperparathyroidism: marked by hypercalcemia with elevated PTH, typically in end-stage renal disease 1, 2
• Familial hypocalciuric hypercalcemia: presents with hypercalcemia, normal or elevated PTH, and low urinary calcium excretion 4
• Malignancy-associated hypercalcemia: typically presents with hypercalcemia and suppressed PTH levels 6
• Medication-induced hypercalcemia: from lithium, thiazide diuretics, or excessive vitamin D or calcium supplementation 6

Imaging Studies (After Biochemical Diagnosis)

• Ultrasound of the neck is recommended as the first-line localization study 1, 2
• Dual-phase 99mTc-sestamibi scintigraphy with SPECT/CT provides high sensitivity for localizing parathyroid adenomas 1, 2
• The combination of ultrasound and sestamibi scan offers the highest sensitivity for localization 1, 2
• MRI or CT scan may be considered if initial imaging is negative 1, 2
• For reoperative cases or suspected ectopic glands, 4D-CT or MRI may be particularly useful 3

Special Considerations

• In patients with suspected multiple endocrine neoplasia (MEN) syndromes, screening for PHPT should begin at age 11 for high-risk variants and age 16 for moderate-risk variants 1, 2
• Consider normocalcemic PHPT in patients with consistently elevated PTH levels but normal calcium levels after excluding secondary causes 7
• For patients with chronic kidney disease, different diagnostic criteria apply, and imaging prior to parathyroidectomy is essential 3

Common Pitfalls to Avoid

• Not assessing vitamin D status when interpreting PTH levels can lead to misdiagnosis 1
• Using different PTH assay generations without considering their varying sensitivity to PTH fragments can result in inaccurate diagnoses 3, 1
• Relying on a single calcium measurement rather than confirming persistent hypercalcemia 7
• Using imaging studies for diagnosis rather than localization (diagnosis is biochemical) 4
• Failing to consider biotin supplements as a potential interferent with PTH assays 1
• Not accounting for factors that influence PTH levels such as race, age, BMI, and vitamin D status 1