What is the etiology and workup of elevated intact parathyroid hormone (iPTH) levels?

Etiology and Workup of Elevated iPTH

Elevated intact parathyroid hormone (iPTH) requires a systematic evaluation of calcium, phosphorus, and vitamin D status to determine whether it represents primary, secondary, or tertiary hyperparathyroidism.

Etiologies of Elevated iPTH

Primary Hyperparathyroidism

• Characterized by hypercalcemia with elevated or inappropriately normal iPTH levels 1
• Most common cause: parathyroid adenoma (single gland disease)
• Less common causes: parathyroid hyperplasia (multiple gland disease), parathyroid carcinoma
• Normocalcemic variant (NPHPT): normal serum calcium with elevated iPTH after excluding secondary causes 2

Secondary Hyperparathyroidism

• Physiologic response to conditions that cause hypocalcemia or mineral metabolism disturbances 1
• Common causes:
  • Chronic kidney disease (CKD): decreased vitamin D activation leads to decreased calcium absorption and phosphate retention 3, 4
  • Vitamin D deficiency: low 25(OH) vitamin D levels (<30 ng/mL) 4
  • Renal phosphate wasting
  • Medications (loop diuretics, anticonvulsants, bisphosphonates)
  • Gastrointestinal disorders affecting calcium absorption
  • Magnesium deficiency

Tertiary Hyperparathyroidism

• Autonomous parathyroid function following long-standing secondary hyperparathyroidism
• Typically seen in advanced CKD or after renal transplantation

Normocalcemic Primary Hyperparathyroidism

• Elevated iPTH with consistently normal calcium levels
• Diagnosis of exclusion after ruling out secondary causes 2

Diagnostic Workup

Initial Laboratory Assessment

1. Serum calcium (total and ionized if available)

   • Interpret total calcium in context of albumin levels
   • Elevated in primary hyperparathyroidism
   • Normal or low in secondary hyperparathyroidism

2. Serum phosphorus

   • Low or low-normal in primary hyperparathyroidism
   • Elevated in CKD-related secondary hyperparathyroidism
   • Normal or low in vitamin D deficiency

3. 25(OH) vitamin D levels

   • Target level >30 ng/mL (75 nmol/L) 4
   • Low levels suggest vitamin D deficiency as cause of secondary hyperparathyroidism

4. Renal function tests

   • Serum creatinine and estimated GFR
   • CKD stages correlate with different target iPTH levels 4:
     • CKD G3: <70 pg/mL
     • CKD G4: <110 pg/mL
     • CKD G5: <300 pg/mL
     • CKD G5D (dialysis): 150-600 pg/mL

5. 24-hour urinary calcium

   • Low in vitamin D deficiency and CKD
   • High in primary hyperparathyroidism (hypercalciuria)
   • Helps distinguish causes and assess risk of nephrolithiasis

6. Alkaline phosphatase (ALP)

   • Elevated in high-turnover bone disease
   • Helps assess bone involvement 4

7. Magnesium levels

   • Hypomagnesemia can cause PTH resistance and secondary hyperparathyroidism

Additional Tests Based on Initial Results

1. For suspected primary hyperparathyroidism:

   • Parathyroid imaging if surgical candidate:
     • Ultrasound of neck
     • 99mTc-sestamibi scintigraphy with SPECT/CT 3
   • Bone mineral density (DXA scan)
   • Renal ultrasound if history of kidney stones

2. For suspected secondary hyperparathyroidism:

   • Calculate tubular reabsorption of phosphate (TRP) and TmP/GFR for renal phosphate handling 4
   • 1,25(OH)₂D levels if vitamin D metabolism disorder suspected 5
   • Celiac disease screening if malabsorption suspected

3. For suspected familial disorders:

   • Consider genetic testing for MEN1, MEN2A, or hyperparathyroid-jaw tumor syndrome 3
   • Family history assessment

Management Approach Based on Etiology

Primary Hyperparathyroidism

• Surgical referral for parathyroidectomy if meeting criteria 1:
  • Symptomatic disease
  • Age ≤50 years
  • Serum calcium >1 mg/dL above upper limit of normal
  • Osteoporosis
  • Creatinine clearance <60 mL/min/1.73m²
  • Nephrolithiasis or nephrocalcinosis
  • Hypercalciuria

Secondary Hyperparathyroidism

• Treat underlying cause:
  • CKD: Phosphate restriction (800-1000 mg/day), phosphate binders, vitamin D supplementation 3, 4
  • Vitamin D deficiency: Native vitamin D supplementation (800-1000 IU daily) 4
  • Active vitamin D analogs (calcitriol, alfacalcidol, paricalcitol) for persistent elevation 3, 4, 6
  • Monitor calcium, phosphorus, and iPTH levels regularly based on CKD stage 4

Normocalcemic Primary Hyperparathyroidism

• Conservative approach with monitoring for development of hypercalcemia or end-organ damage 2
• Surgical intervention only if complications develop

Monitoring Recommendations

• Frequency of monitoring depends on CKD stage 4:

  • CKD G3: Calcium, phosphorus, iPTH every 6-12 months
  • CKD G4: Every 3-6 months
  • CKD G5: Every 1-3 months
  • Dialysis: Monthly

• Monitor for complications:

  • Bone disease: Fractures, bone pain
  • Kidney stones or nephrocalcinosis
  • Cardiovascular calcifications in CKD

Common Pitfalls to Avoid

1. Failing to recognize normocalcemic primary hyperparathyroidism
2. Not excluding vitamin D deficiency before diagnosing primary hyperparathyroidism
3. Overlooking medication effects on calcium and PTH levels
4. Inadequate monitoring of calcium levels when initiating vitamin D therapy
5. Misinterpreting iPTH levels in CKD without considering target ranges for each stage
6. Pursuing parathyroidectomy in secondary hyperparathyroidism before optimizing medical management
7. Not recognizing persistent elevated iPTH after parathyroidectomy may indicate inadequate vitamin D levels or renal dysfunction 7