What are the steps to diagnose primary hyperparathyroidism?

Diagnosing Primary Hyperparathyroidism

The diagnosis of primary hyperparathyroidism (PHPT) is primarily biochemical, characterized by hypercalcemia or high-normal calcium levels with elevated or inappropriately normal parathyroid hormone (PTH) levels. 1, 2

Initial Diagnostic Steps

• Simultaneously measure serum calcium (total calcium corrected for albumin) and intact parathyroid hormone (iPTH) - this is the cornerstone of diagnosis 1
• Check serum phosphate levels, which are typically low or low-normal in PHPT 1
• Assess vitamin D status by measuring 25-hydroxyvitamin D, as vitamin D deficiency can complicate interpretation of PTH levels 1, 3
• Measure serum creatinine to evaluate kidney function, which is essential in the diagnostic workup 1
• Check serum chloride and uric acid levels to help identify underlying conditions associated with stone disease 1

Biochemical Interpretation

• Classic PHPT presentation (70% of cases): Concomitant elevation of both calcium (≥10.5 mg/dL) and PTH (≥65 pg/dL) 4
• Normocalcemic PHPT (21% of cases): Normal calcium (≤10.5 mg/dL) with elevated PTH (≥65 pg/dL) 4
• Normohormonal PHPT (6% of cases): Elevated calcium (≥10.5 mg/dL) with PTH in normal range (≤65 pg/dL) 4
• Atypical PHPT (3% of cases): Both calcium and PTH within reference ranges but PTH inappropriately normal for the calcium level 4

Confirmatory Testing

• Collect a 24-hour urine sample for calcium, oxalate, uric acid, citrate, sodium, potassium, and creatinine to evaluate complications and other metabolic abnormalities 1
• Calculate calcium-to-creatinine clearance ratio - a ratio <0.01 suggests familial hypocalciuric hypercalcemia rather than PHPT 2
• Consider measuring 1,25-dihydroxyvitamin D levels, which are often elevated in PHPT 2

Differential Diagnosis Considerations

• Secondary hyperparathyroidism: Normal or low serum calcium with elevated PTH, commonly seen in chronic kidney disease or vitamin D deficiency 1
• Tertiary hyperparathyroidism: Hypercalcemia with elevated PTH, typically in end-stage renal disease 1
• Familial hypocalciuric hypercalcemia: Hypercalcemia with normal or elevated PTH but low urinary calcium excretion (calcium-to-creatinine clearance ratio <0.01) 2
• Other causes of hypercalcemia with suppressed PTH: Malignancy, granulomatous diseases, vitamin D intoxication, hyperthyroidism, and medication effects (e.g., thiazides, lithium) 2

Imaging Studies (After Biochemical Diagnosis)

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

Special Considerations

• PTH assay generation matters: Different PTH assays recognize different PTH fragments, which can affect interpretation 3
• Preanalytical conditions can influence PTH measurement - EDTA plasma is recommended over serum for PTH measurement 3
• Biotin supplements can interfere with PTH assays, leading to under or overestimation 3
• The biological variation of PTH is substantial (approximately 20% in healthy people), which must be considered when interpreting results 3
• For patients with multiple endocrine neoplasia (MEN) syndromes, screening for PHPT should begin at age 11 for high-risk variants and age 16 for moderate-risk variants 3, 1

Common Pitfalls to Avoid

• Not assessing vitamin D status when interpreting PTH levels can lead to misdiagnosis 1, 3
• Using different PTH assay generations without considering their varying sensitivity to PTH fragments 3, 1
• Failing to calculate calcium-to-creatinine clearance ratio to rule out familial hypocalciuric hypercalcemia 2
• Relying solely on imaging for diagnosis - PHPT diagnosis is biochemical, and imaging is only for localization after biochemical diagnosis is established 2, 5
• Not considering medication effects (thiazides, lithium) that can affect calcium and PTH levels 2