How do we differentiate primary from secondary hyperparathyroidism?

Differentiating Primary from Secondary Hyperparathyroidism

The key to differentiating primary from secondary hyperparathyroidism lies in the pattern of calcium, phosphate, and PTH levels, with primary hyperparathyroidism characterized by hypercalcemia with inappropriately elevated PTH, while secondary hyperparathyroidism shows normal or low calcium with elevated PTH in response to an underlying cause. 1, 2

Laboratory Findings

Primary Hyperparathyroidism

• Calcium: Elevated or high-normal
• PTH: Elevated or inappropriately normal (not suppressed despite hypercalcemia)
• Phosphate: Usually low or low-normal
• Vitamin D: Often low (25-hydroxyvitamin D)

Secondary Hyperparathyroidism

• Calcium: Normal or low
• PTH: Elevated (appropriate response to low calcium)
• Phosphate: Variable (elevated in CKD, normal or low in vitamin D deficiency)
• Vitamin D: Usually low (25-hydroxyvitamin D <30 ng/mL)

Underlying Causes

Primary Hyperparathyroidism

• Parathyroid adenoma (80-85% of cases)
• Parathyroid hyperplasia (10-15%)
• Parathyroid carcinoma (rare, <1%)
• Multiple endocrine neoplasia syndromes (MEN 1, MEN 2A)

Secondary Hyperparathyroidism

• Chronic kidney disease (most common cause) 3
• Vitamin D deficiency
• Malabsorption syndromes
• Bariatric surgery
• Chronic liver disease
• Medications (e.g., loop diuretics)

Clinical Assessment

When evaluating a patient with elevated PTH:

1. Check calcium levels first:

   • Hypercalcemia + elevated PTH = Primary hyperparathyroidism
   • Normal/low calcium + elevated PTH = Secondary hyperparathyroidism

2. Evaluate for underlying causes of secondary hyperparathyroidism:

   • Measure eGFR to assess kidney function
   • Check 25-hydroxyvitamin D levels (target >30 ng/mL) 3
   • Assess for malabsorption or history of bariatric surgery
   • Review medication list for drugs affecting calcium metabolism

3. Additional tests to consider:

   • 24-hour urinary calcium (typically high in primary, low in secondary)
   • Phosphate levels (typically low in primary, high in CKD-related secondary)
   • Calcium-to-creatinine clearance ratio (helpful in familial hypocalciuric hypercalcemia)

Special Considerations

Tertiary Hyperparathyroidism

• Develops after longstanding secondary hyperparathyroidism
• Characterized by hypercalcemia with elevated PTH
• Most commonly occurs in patients with chronic kidney disease, especially after kidney transplantation 4
• Parathyroid glands become autonomous despite resolution of the initial stimulus

Normocalcemic Primary Hyperparathyroidism

• Elevated PTH with normal calcium levels
• Must rule out secondary causes before making this diagnosis
• May represent an early form of primary hyperparathyroidism 5

Monitoring Recommendations

For suspected secondary hyperparathyroidism:

• Monitor calcium, phosphorus, and PTH levels based on CKD stage 3:
  • Stage 3 CKD: Every 6-12 months
  • Stage 4 CKD: Every 3-6 months
  • Stage 5 CKD: Every 1-3 months
  • Dialysis patients: Monthly

Common Pitfalls to Avoid

1. Failing to check vitamin D status: Vitamin D deficiency can mask primary hyperparathyroidism by lowering serum calcium.

2. Not considering medication effects: Thiazide diuretics can increase calcium levels; loop diuretics can decrease calcium levels.

3. Missing familial hypocalciuric hypercalcemia: This genetic condition can mimic primary hyperparathyroidism but has low urinary calcium excretion.

4. Overlooking tertiary hyperparathyroidism: In patients with CKD history who develop hypercalcemia with high PTH.

5. Not accounting for assay variability: Different PTH assays may yield different results, affecting interpretation 1.

By systematically evaluating calcium, PTH, phosphate, and vitamin D levels, along with kidney function and clinical context, clinicians can accurately differentiate between primary and secondary hyperparathyroidism and provide appropriate management.