Workup to Distinguish Primary from Secondary Hyperparathyroidism
The distinction between primary and secondary hyperparathyroidism is made biochemically by simultaneously measuring serum calcium (corrected for albumin) and intact PTH: primary hyperparathyroidism presents with hypercalcemia (or high-normal calcium) with elevated or inappropriately normal PTH, while secondary hyperparathyroidism shows normal or low serum calcium with elevated PTH. 1, 2
Essential Initial Laboratory Tests
The following tests must be obtained simultaneously to establish the diagnosis:
- Serum calcium (corrected for albumin) and intact PTH measured at the same time are the cornerstone of diagnosis 1
- Serum phosphate: typically low or low-normal in primary hyperparathyroidism, but elevated (>4.6 mg/dL in CKD stages 3-4) in secondary hyperparathyroidism due to chronic kidney disease 1, 2
- Serum creatinine to evaluate kidney function, as chronic kidney disease is the most common cause of secondary hyperparathyroidism 1, 2
- 25-hydroxyvitamin D level is crucial because vitamin D deficiency can cause secondary hyperparathyroidism and complicate PTH interpretation in both conditions 1, 2
Diagnostic Algorithm Based on Biochemical Pattern
| Laboratory Finding | Primary HPT | Secondary HPT |
|---|---|---|
| Serum Calcium | Elevated or high-normal | Normal or low (<8.4 mg/dL) |
| PTH | Elevated or inappropriately normal | Elevated |
| Serum Phosphate | Low or low-normal | Elevated (in CKD) or low (in vitamin D deficiency) |
| Pathophysiology | Autonomous PTH secretion | Compensatory response to hypocalcemia/hyperphosphatemia |
Additional Confirmatory Tests
Once the pattern suggests primary hyperparathyroidism, obtain:
- Serum chloride and uric acid to assess for stone disease complications 1
- 24-hour urine collection for calcium, oxalate, uric acid, citrate, sodium, potassium, and creatinine to evaluate metabolic abnormalities and stone risk 1
- Alkaline phosphatase: often elevated in secondary hyperparathyroidism, suggesting high bone turnover 2
Critical Pitfalls to Avoid
Vitamin D deficiency is the most important confounder that can mask the true diagnosis:
- Vitamin D deficiency can cause secondary hyperparathyroidism with normal or low calcium and elevated PTH, mimicking other causes of secondary hyperparathyroidism 1, 2
- In primary hyperparathyroidism patients, coexisting vitamin D deficiency can suppress urine calcium excretion and complicate the biochemical picture 1, 3
- Always measure 25-hydroxyvitamin D before interpreting PTH levels 1
PTH assay considerations:
- Different PTH assay generations measure different PTH fragments and yield significantly different values 1, 2
- Use assay-specific reference ranges when interpreting results 1
- Collect blood in EDTA tubes as PTH is most stable in EDTA plasma 1
- Biotin supplements can interfere with PTH assays 1
Special Consideration: Tertiary Hyperparathyroidism
Tertiary hyperparathyroidism presents with hypercalcemia and elevated PTH (similar to primary hyperparathyroidism biochemically) but occurs in patients with longstanding chronic kidney disease or after kidney transplantation, representing autonomous PTH hypersecretion after prolonged secondary hyperparathyroidism 4, 2. The clinical context and history of chronic kidney disease distinguish this from primary hyperparathyroidism 2.
Role of Imaging
Imaging has no role in distinguishing primary from secondary hyperparathyroidism—this is a purely biochemical diagnosis 1. Imaging is only used for preoperative localization after the biochemical diagnosis of primary hyperparathyroidism is established and surgery is planned 4, 1.