What is the diagnostic approach for hyperparathyroidism?

Diagnostic Approach for Hyperparathyroidism

The essential diagnostic tests for hyperparathyroidism include serum calcium, phosphorus, and intact parathyroid hormone (iPTH) measurements, with iPTH being the most critical diagnostic test. 1

Types of Hyperparathyroidism

Hyperparathyroidism is classified into three main types:

1. Primary Hyperparathyroidism (PHPT):

   • Characterized by autonomous PTH production
   • Typically presents with hypercalcemia or normal-high serum calcium with elevated or inappropriately normal PTH levels 2
   • Most common cause of hypercalcemia 3

2. Secondary Hyperparathyroidism:

   • Occurs due to chronic hypocalcemia (vitamin D deficiency, CKD, etc.)
   • Compensatory increase in PTH secretion 4

3. Tertiary Hyperparathyroidism:

   • Autonomous parathyroid function after long-standing secondary hyperparathyroidism
   • Often seen in severe chronic renal failure 4

Diagnostic Algorithm

Step 1: Initial Laboratory Testing

• Serum calcium (total and ionized)
• Serum phosphorus
• Intact parathyroid hormone (iPTH)
• 25-OH vitamin D level
• Renal function tests (BUN, creatinine, eGFR)
• Magnesium level 1

Step 2: Interpretation of Results

For Primary Hyperparathyroidism:

• Elevated or inappropriately normal PTH with hypercalcemia
• Often low or low-normal phosphorus
• Calculate calcium-to-creatinine clearance ratio (if <0.01, consider familial hypocalciuric hypercalcemia) 2

For Secondary Hyperparathyroidism:

• Elevated PTH with normal or low calcium
• Check for:
  • Vitamin D deficiency (25-OH vitamin D <20 ng/ml)
  • Chronic kidney disease (reduced eGFR)
  • Intestinal malabsorption
  • Medications (e.g., phosphate binders) 1, 4

For Tertiary Hyperparathyroidism:

• Elevated PTH with hypercalcemia
• History of long-standing secondary hyperparathyroidism
• Usually associated with end-stage renal disease 4

Step 3: Additional Testing Based on Initial Results

If PHPT is suspected:

• 24-hour urinary calcium excretion
• Bone mineral density (DEXA scan)
• Renal ultrasound (to detect nephrolithiasis/nephrocalcinosis)
• Parathyroid imaging (for localization, not diagnosis) 2, 3

If secondary hyperparathyroidism is suspected:

• Additional testing based on suspected cause:
  • For CKD: phosphorus levels, frequency based on CKD stage:
    • Stage 3: Every 6-12 months
    • Stage 4: Every 3-6 months
    • Stage 5: Every 1-3 months
    • Dialysis: Monthly 1
  • For vitamin D deficiency: 1,25-dihydroxy vitamin D levels
  • For malabsorption: celiac panel, stool studies 1

Special Considerations

Potential Pitfalls in Diagnosis

1. Vitamin D Status:

   • Vitamin D deficiency can cause secondary hyperparathyroidism
   • Always measure 25-OH vitamin D when evaluating PTH levels
   • Correct vitamin D deficiency before making definitive diagnosis 1

2. Laboratory Interference:

   • Biotin supplements can interfere with PTH assays
   • Consider biotin interference in discordant results 1

3. Familial Hypocalciuric Hypercalcemia:

   • Can mimic PHPT but has low urinary calcium excretion
   • Calculate calcium-to-creatinine clearance ratio (if <0.01, suspect FHH)
   • Genetic testing may be needed 2

4. Medications:

   • Thiazide diuretics can cause hypercalcemia
   • Lithium can cause hyperparathyroidism
   • Always review medication history 1, 2

When to Consider Genetic Testing

• Young age at presentation (<40 years)
• Family history of hypercalcemia
• Multiple endocrine neoplasia syndromes
• Multigland disease 3

Indications for Surgical Referral in PHPT

Referral to a parathyroid surgeon is indicated when patients have:

• Symptomatic hypercalcemia
• Severe hypercalcemia
• Osteoporosis
• Age <50 years
• Creatinine clearance <60 mL/min/1.73 m²
• Nephrolithiasis or nephrocalcinosis 1

Monitoring Recommendations

• For diagnosed hyperparathyroidism without immediate surgical indication:

  • Serum calcium and PTH every 6 months
  • Bone mineral density annually
  • Renal ultrasound every 1-2 years if history of stones 1, 5

• For secondary hyperparathyroidism in CKD:

  • Target PTH levels based on CKD stage:
    • CKD G3: <70 pg/mL
    • CKD G4: <110 pg/mL
    • CKD G5: <300 pg/mL
    • CKD G5D: 150-600 pg/mL 1

By following this structured diagnostic approach, clinicians can accurately diagnose and classify hyperparathyroidism, leading to appropriate management decisions that improve patient outcomes.