What are the diagnostic steps for primary hyperparathyroidism?

Diagnosing Primary Hyperparathyroidism

The diagnosis of primary hyperparathyroidism (PHPT) requires 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

Initial Diagnostic Steps

• Measure serum calcium (total calcium corrected for albumin) and intact parathyroid hormone (iPTH) simultaneously 1
• Check serum phosphate, which is typically low or low-normal in PHPT 2
• 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 2
• Consider checking serum chloride and uric acid levels which may suggest underlying conditions associated with stone disease 2

Confirmatory Testing

• Diagnosis is confirmed by demonstrating persistent hypercalcemia (or high-normal calcium) with inappropriately normal or elevated PTH levels 3
• Calculate calcium-to-creatinine clearance ratio to rule out familial hypocalciuric hypercalcemia (FHH) - a ratio <0.01 suggests FHH rather than PHPT 3
• Consider 24-hour urine collection for calcium, oxalate, uric acid, citrate, sodium, potassium, and creatinine to evaluate for complications and other metabolic abnormalities 2

Differential Diagnosis Considerations

• Secondary hyperparathyroidism: characterized by normal or low serum calcium with elevated PTH (common in chronic kidney disease, 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 and low urinary calcium excretion 3
• Medication-induced changes: thiazide diuretics, lithium, excessive vitamin D or calcium supplementation 4

Imaging Studies (After Biochemical Diagnosis)

• Ultrasound of the neck is recommended as first-line localization study 1
• Dual-phase 99mTc-sestamibi scintigraphy with SPECT/CT provides high sensitivity for localizing parathyroid adenomas 1
• 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
• Note: Imaging is used for localization of abnormal parathyroid tissue, not for diagnosis of PHPT 3

Clinical Scenarios Requiring PHPT Evaluation

• Patients with nephrolithiasis or nephrocalcinosis 3, 5
• Bone pain, subperiosteal resorption, or pathologic fractures 3
• Osteoporosis or osteopenia on DEXA scan 3
• History of neck irradiation 3
• Family history of multiple endocrine neoplasia syndrome (types 1 or 2) 3
• Patients with cognitive or psychiatric disorders 4

Common Pitfalls to Avoid

• Not assessing vitamin D status when interpreting PTH levels 1
• Using different PTH assay generations without considering their varying sensitivity to PTH fragments 2, 1
• Relying solely on imaging for diagnosis rather than biochemical confirmation 3
• Failing to consider medication effects (thiazides, lithium) on calcium and PTH levels 4
• Not calculating calcium-to-creatinine clearance ratio to distinguish PHPT from familial hypocalciuric hypercalcemia 3

Special Considerations

• Normocalcemic PHPT: elevated PTH with consistently normal calcium levels after excluding secondary causes of hyperparathyroidism 6
• In patients with suspected primary hyperparathyroidism, seek advice from a specialist with expertise in this condition 2
• For patients with MEN syndromes, screening for PHPT should begin at age 11 for high-risk variants and age 16 for moderate-risk variants 1