What are the diagnostic tests for hyperparathyroidism?

How to Test for Hyperparathyroidism

Measure serum calcium (corrected for albumin), intact parathyroid hormone (PTH), and serum phosphorus simultaneously—these three tests form the diagnostic cornerstone for hyperparathyroidism. 1, 2

Core Diagnostic Laboratory Tests

Essential Initial Tests

• Serum calcium (total calcium corrected for albumin) should be measured as the primary screening test, with hypercalcemia being the hallmark of primary hyperparathyroidism 2

• Intact parathyroid hormone (PTH) must be measured simultaneously with calcium—elevated or inappropriately normal PTH in the setting of hypercalcemia confirms primary hyperparathyroidism 1, 2

• Serum phosphorus should be measured, as hyperparathyroidism typically causes hypophosphatemia or low-normal phosphorus 1, 2

• Serum creatinine and blood urea nitrogen are essential to assess kidney function, as hypercalcemia can cause kidney damage and chronic kidney disease alters the interpretation of PTH levels 1, 2

Critical Supplementary Tests

• 25-hydroxyvitamin D must be measured because vitamin D deficiency can cause secondary hyperparathyroidism with elevated PTH and complicate interpretation—this is a common pitfall that leads to misdiagnosis 1, 2

• Urine calcium/creatinine ratio in a random spot urine should be evaluated to assess for hypercalciuria and to exclude familial hypocalciuric hypercalcemia (a genetic condition that mimics hyperparathyroidism but requires no treatment) 1

Interpretation Algorithm

For Primary Hyperparathyroidism

• Elevated serum calcium + elevated or inappropriately normal PTH + low/low-normal phosphorus = Primary hyperparathyroidism 2
• PTH should be elevated relative to the calcium level; a "normal" PTH in the setting of hypercalcemia is inappropriate and diagnostic 2

For Secondary Hyperparathyroidism

• Normal or low serum calcium + elevated PTH = Secondary hyperparathyroidism, commonly from chronic kidney disease or vitamin D deficiency 2
• In patients with CKD and GFR <60 mL/min/1.73 m², measure calcium, phosphorus, and intact PTH regularly to monitor for secondary hyperparathyroidism 3

For Tertiary Hyperparathyroidism

• Elevated calcium + elevated PTH in end-stage renal disease = Tertiary hyperparathyroidism (autonomous parathyroid function after prolonged secondary hyperparathyroidism) 2

Important Technical Considerations

PTH Assay Differences

• Use assay-specific reference ranges for PTH interpretation, as different assay generations measure different PTH fragments and can yield significantly different results 3, 1, 2
• PTH assays lack complete standardization, leading to remarkable differences between laboratories even when using the same assay generation 3
• Collect blood in EDTA tubes for PTH measurement, as PTH is most stable in EDTA plasma 2

Factors Affecting PTH Levels

• Race, age, and BMI affect PTH levels—PTH is higher in Black individuals, increases with age, and is elevated in obese patients 3, 1, 2
• Biotin supplements (vitamin B7/B8) can interfere with PTH assays, causing falsely elevated or decreased results depending on assay design 3, 1, 2
• PTH has substantial biological variation (within-subject variation ~20% in healthy people), so changes must exceed 54% to be considered clinically significant 3

Additional Confirmatory Testing

When Initial Tests Are Diagnostic

• 24-hour urine collection for calcium, oxalate, uric acid, citrate, sodium, potassium, and creatinine can evaluate complications and metabolic abnormalities 2
• Serum chloride may be helpful—elevated chloride supports primary hyperparathyroidism in the differential diagnosis 2
• Alkaline phosphatase can serve as a marker of severity of hyperparathyroid bone disease, though its predictive power when used with PTH is not fully established 3

When Diagnosis Is Uncertain

• If PTH is between 100-500 pg/mL (11.0-55.0 pmol/L) in CKD patients with unexplained hypercalcemia, bone pain, or increased bone alkaline phosphatase, bone biopsy may be useful for accurate assessment 3
• PTHrP (parathyroid hormone-related peptide) should only be measured if PTH is low or low-normal (≤26 ng/L), as it helps differentiate malignancy-related hypercalcemia from primary hyperparathyroidism 4

Common Pitfalls to Avoid

• Not measuring vitamin D status when interpreting PTH levels is the most common error leading to misdiagnosis of primary hyperparathyroidism when secondary hyperparathyroidism from vitamin D deficiency is actually present 1, 2

• Measuring PTHrP before confirming low PTH is wasteful—if PTH is not low or low-normal, PTHrP testing is uninformative 4

• Ignoring kidney function when interpreting PTH—chronic kidney disease causes secondary hyperparathyroidism and requires different diagnostic criteria 2

• Using different PTH assays interchangeably without considering their varying sensitivity to PTH fragments can result in inaccurate diagnoses 3, 2

Monitoring Frequency

• For patients with CKD Stage 3-5, measure calcium, phosphorus, and PTH based on CKD stage—more frequently if receiving treatment for abnormalities 3
• For patients on treatment for secondary hyperparathyroidism, monitor calcium and phosphorus at least monthly for the first 3 months, then every 3 months thereafter 1