How is primary hyperparathyroidism diagnosed?

Diagnosing Primary Hyperparathyroidism

The diagnosis of primary hyperparathyroidism (PHPT) is confirmed by demonstrating persistent hypercalcemia (or high-normal serum calcium levels) with elevated or inappropriately normal serum parathyroid hormone (PTH) levels. 1, 2

Initial Diagnostic Steps

• Measure serum calcium (total calcium corrected for albumin) and intact parathyroid hormone (iPTH) simultaneously, as this is the cornerstone of PHPT diagnosis 1, 2
• Check serum phosphate, which is typically low or low-normal in PHPT 1
• Assess vitamin D status (25-hydroxyvitamin D), as vitamin D deficiency can complicate interpretation of PTH levels 1
• Measure serum creatinine to evaluate kidney function, which is essential in diagnosing PHPT 1
• Check serum chloride and uric acid levels to identify conditions associated with stone disease 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 calcium-to-creatinine clearance ratio to rule out familial hypocalciuric hypercalcemia (FHH) - a ratio <0.01 suggests FHH rather than PHPT 3
• Consider measuring 1,25-dihydroxyvitamin D, which may be elevated in PHPT 3

Biochemical Patterns in PHPT

• Classic PHPT: Hypercalcemia with elevated or inappropriately normal PTH 4, 5
• Normocalcemic PHPT: Normal serum calcium with elevated PTH (after excluding secondary causes of hyperparathyroidism) 5, 6
• Note that PTH has substantial biological variation (within-subject variation of ~20% in healthy people), requiring significant changes (>54%) to confirm true increases 4

Differential Diagnosis

• Secondary hyperparathyroidism: Normal or low serum calcium with elevated PTH, commonly seen in chronic kidney disease or vitamin D deficiency 1, 2
• Tertiary hyperparathyroidism: Hypercalcemia with elevated PTH, typically in end-stage renal disease 1, 2
• Familial hypocalciuric hypercalcemia: Hypercalcemia with inappropriately normal or elevated PTH and low urinary calcium excretion 3, 6
• Hypercalcemia with suppressed PTH: Consider malignancy, granulomatous diseases, vitamin D intoxication, or other endocrinopathies 3

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

Special Considerations

• 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 1
• In patients with suspected PHPT, consultation with a specialist with expertise in this condition is recommended 1

Common Pitfalls to Avoid

• Not assessing vitamin D status when interpreting PTH levels can lead to misdiagnosis 1, 2
• Using different PTH assay generations without considering their varying sensitivity to PTH fragments can result in inaccurate diagnoses 4, 1
• Biotin supplements can interfere with PTH assays, leading to either underestimation or overestimation depending on the assay design 4
• Not accounting for factors that influence PTH levels such as race (higher in Black individuals), BMI (higher in obesity), and age (increases with age) 4
• Failing to calculate calcium-to-creatinine clearance ratio to rule out familial hypocalciuric hypercalcemia 3