What is the appropriate workup and management for a patient with elevated parathyroid hormone (PTH) levels, considering potential underlying causes such as vitamin D deficiency, chronic kidney disease, or primary hyperparathyroidism?

Workup for Elevated Parathyroid Hormone

Begin by measuring serum calcium, phosphorus, creatinine/GFR, and 25-hydroxyvitamin D levels simultaneously with the PTH to determine the underlying etiology—this single panel distinguishes primary hyperparathyroidism (high PTH with hypercalcemia) from secondary hyperparathyroidism (high PTH with normal/low calcium) and guides all subsequent management. 1, 2

Initial Laboratory Assessment

Core diagnostic panel:

• Serum calcium (ionized or corrected total): Hypercalcemia indicates primary hyperparathyroidism; normal or low calcium suggests secondary hyperparathyroidism 2, 3
• Serum phosphorus: Typically low in primary hyperparathyroidism, elevated in CKD-related secondary hyperparathyroidism 1, 3
• Serum creatinine and GFR: Essential to identify chronic kidney disease as the cause; begin monitoring when GFR falls below 60 mL/min/1.73 m² 1
• 25-hydroxyvitamin D: Vitamin D deficiency is a common reversible cause of secondary hyperparathyroidism, particularly in elderly patients 2, 4
• Alkaline phosphatase: Elevated levels suggest high bone turnover and add predictive value when interpreting PTH, particularly for assessing severity of bone disease 1, 3

Critical technical consideration: Intact PTH assays overestimate biologically active PTH by detecting C-terminal fragments that may have inhibitory activity; use assay-specific reference values as different generations vary significantly 1

Diagnostic Algorithm Based on Calcium Levels

High PTH with Hypercalcemia (Calcium >10.5 mg/dL)

This pattern indicates primary hyperparathyroidism 2, 3

Additional workup:

• 24-hour urinary calcium excretion: Low urinary calcium (<100 mg/24h) with hypercalcemia suggests familial benign hypocalciuric hypercalcemia (FBHH) rather than primary hyperparathyroidism 3
• Imaging for surgical planning: Preoperative localization with ultrasound and/or 99mTc-sestamibi scintigraphy with SPECT/CT if parathyroidectomy is being considered 5

Indications for parathyroidectomy: Osteoporosis, symptomatic disease, or inability to undergo medical management 5

High PTH with Normal or Low Calcium

This pattern indicates secondary hyperparathyroidism—identify the underlying cause 2, 3

Determine etiology:

If GFR <60 mL/min/1.73 m²: CKD-related secondary hyperparathyroidism 1

• Monitor calcium, phosphorus, and PTH every 3 months initially 6
• Target PTH ranges vary by CKD stage: 150-300 pg/mL for dialysis patients (Stage 5) 6, 1, 5
• Critical pitfall: Never target normal PTH levels (<65 pg/mL) in dialysis patients—this causes adynamic bone disease with increased fracture risk 1

If 25-hydroxyvitamin D <30 ng/mL: Vitamin D deficiency 6, 2

• Supplement with ergocalciferol 50,000 IU monthly and recheck 25(OH)D annually once replete 1
• This is the most common reversible cause in elderly patients 4

If both GFR and vitamin D are normal: Consider malabsorption syndromes, chronic liver disease, or medication effects 7, 4

CKD-Specific Management Algorithm

For CKD Stage 3-4 (GFR 15-59 mL/min/1.73 m²):

Step 1: Control phosphorus first 1, 5

• Restrict dietary phosphorus to 800-1,000 mg/day 1
• Add phosphate binders if dietary restriction fails; restrict calcium-based binders 5
• Target serum phosphorus 3.5-5.5 mg/dL 1
• Monitor phosphorus monthly after initiating therapy 1

Step 2: Correct vitamin D deficiency 1, 5

• Supplement with ergocalciferol if 25(OH)D <30 ng/mL 1
• Do not initiate active vitamin D therapy (calcitriol) until serum phosphorus falls below 4.6 mg/dL—this prevents vascular calcification 1

Step 3: Consider active vitamin D analogs only for severe, progressive hyperparathyroidism 5

• Reserve calcitriol and vitamin D analogs for CKD G4-5 with PTH >110 pg/mL (Stage 4) on more than 2 consecutive measurements despite phosphorus control and vitamin D repletion 6, 5
• Calcitriol and vitamin D analogs should not be routinely used in non-dialysis CKD patients 5

For CKD Stage 5 (Dialysis patients):

If PTH >300 pg/mL: 6, 5

• Initiate active vitamin D sterol (calcitriol, alfacalcidol, paricalcitol, or doxercalciferol) 6, 5
• Intermittent intravenous calcitriol is more effective than daily oral calcitriol for lowering PTH 6, 5
• Target PTH 150-300 pg/mL 6, 1, 5
• Monitor calcium and phosphorus every 2 weeks for 1 month, then monthly 6, 5
• Monitor PTH monthly for 3 months, then every 3 months once target achieved 6, 5

If PTH remains >300 pg/mL despite vitamin D therapy:

• Add calcimimetics (cinacalcet starting at 30 mg once daily with food) 1, 8
• Titrate cinacalcet every 2-4 weeks through sequential doses of 30,60,90,120, and 180 mg once daily 8
• Monitor calcium within 1 week of dose adjustment 8

Dose adjustments during vitamin D therapy: 6

• If PTH falls below target: Hold vitamin D until PTH rises above target, then resume at half the previous dose 6
• If calcium >9.5 mg/dL: Hold vitamin D until calcium <9.5 mg/dL, then resume at half dose 6
• If phosphorus >4.6 mg/dL: Hold vitamin D, increase phosphate binder, resume vitamin D once phosphorus <4.6 mg/dL 6

Surgical Indications

Parathyroidectomy should be considered when: 6, 2, 5

• PTH persistently >800 pg/mL with hypercalcemia and/or hyperphosphatemia refractory to medical therapy after 3-6 months of optimized treatment 6, 1, 5
• Surgical options include subtotal parathyroidectomy or total parathyroidectomy with autotransplantation 6, 2, 5
• Total parathyroidectomy may have lower recurrence rates but higher risk of permanent hypoparathyroidism 1, 2

Post-parathyroidectomy monitoring: 6, 2, 5

• Monitor ionized calcium every 4-6 hours for first 48-72 hours, then twice daily until stable 6, 2, 5
• If ionized calcium <0.9 mmol/L, initiate calcium gluconate infusion at 1-2 mg elemental calcium/kg/hour 6, 5
• When oral intake possible, provide calcium carbonate 1-2 g three times daily and calcitriol up to 2 μg/day 6, 5

Common Pitfalls to Avoid

Never start active vitamin D therapy with uncontrolled hyperphosphatemia—this worsens vascular calcification and increases calcium-phosphate product 1

Never target normal PTH levels in dialysis patients—PTH should be maintained at 2-9 times the upper normal limit (approximately 150-300 pg/mL) to prevent adynamic bone disease 1, 5

Do not overlook vitamin D deficiency as a reversible cause—measure 25-hydroxyvitamin D in all patients with elevated PTH, as deficiency is extremely common and easily correctable 1, 4

Consider primary hyperparathyroidism even with low-normal calcium if severe vitamin D deficiency is present—vitamin D deficiency can mask hypercalcemia in primary hyperparathyroidism 9