What is the appropriate workup and management for a patient with elevated Parathyroid Hormone-related Protein (PTHrP) and hypercalcemia?

Workup for Elevated PTHrP and Hypercalcemia

Elevated PTHrP with hypercalcemia indicates malignancy-associated hypercalcemia and requires urgent evaluation for underlying cancer, with PTH expected to be suppressed (not elevated). 1

Critical Diagnostic Clarification

If you are seeing both elevated PTHrP AND elevated PTH, this is biochemically inconsistent and suggests either:

• Laboratory error requiring repeat testing 1
• Two separate processes occurring simultaneously (extremely rare)
• Misinterpretation of "normal" PTH as "elevated" PTH 2

PTHrP-mediated hypercalcemia from malignancy characteristically presents with suppressed PTH (<20 pg/mL), not elevated PTH. 3, 1

Immediate Laboratory Workup

Confirm the Biochemical Pattern

• Repeat PTH and PTHrP simultaneously using EDTA plasma (PTH is most stable in EDTA) to verify the pattern 1
• Measure ionized calcium (normal: 4.65-5.28 mg/dL) for definitive assessment rather than relying solely on corrected calcium 1
• Obtain 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D levels to exclude vitamin D-mediated causes 1, 2
• Check serum creatinine and eGFR to assess kidney function 1
• Measure 24-hour urine calcium or spot urine calcium/creatinine ratio to evaluate urinary calcium excretion 1

Expected Pattern for PTHrP-Mediated Hypercalcemia

• PTH: Suppressed (<20 pg/mL) 1, 2
• PTHrP: Elevated 1, 2
• 25-hydroxyvitamin D: Low or normal (hypercalcemia suppresses PTH, which normally stimulates 1,25-dihydroxyvitamin D production) 1
• 1,25-dihydroxyvitamin D: Low or normal 3, 1

Malignancy Evaluation

PTHrP-mediated hypercalcemia occurs in 10-25% of patients with lung cancer, most commonly squamous cell carcinoma, with median survival approximately 1 month after discovery. 1, 2

Imaging and Cancer Screening

• CT chest/abdomen/pelvis to evaluate for lung cancer (especially squamous cell), renal cell carcinoma, or other solid tumors 1
• Consider mammography in women (breast cancer can cause PTHrP-mediated hypercalcemia) 3
• Evaluate for multiple myeloma with serum protein electrophoresis, though this typically causes local osteolytic hypercalcemia rather than PTHrP-mediated 1

Severity Assessment and Immediate Management

Mild Hypercalcemia (10.2-12 mg/dL)

• Ensure adequate oral hydration (2-3 liters daily) 1
• Discontinue calcium supplements, vitamin D, and thiazide diuretics 1
• Monitor serum calcium weekly until diagnosis established 3

Moderate to Severe Hypercalcemia (≥12 mg/dL)

• Initiate aggressive IV crystalloid hydration with normal saline to restore intravascular volume 1, 2
• Administer loop diuretics (furosemide) only after adequate volume repletion 2
• Give IV bisphosphonates (zoledronic acid 4 mg or pamidronate 60-90 mg) as primary therapy 1, 2
• Consider calcitonin (4-8 IU/kg SC/IM every 6-12 hours) as temporizing measure for rapid calcium reduction while awaiting bisphosphonate effect 2

Severe Symptomatic Hypercalcemia (≥14 mg/dL or mental status changes)

• Hospital admission required 3
• Initiate hypertonic 3% saline IV in addition to aggressive hydration for acute symptomatic cases with mental status changes, bradycardia, or hypotension 2
• Monitor ionized calcium every 4-6 hours initially 3

Definitive Treatment

Treat the underlying malignancy urgently with chemotherapy or radiation, as this is the definitive treatment for malignancy-associated hypercalcemia. 2

Bisphosphonates are effective for malignancy-related bone disease but serve as bridge therapy while treating the cancer. 3, 2

Common Pitfalls to Avoid

• Do not order parathyroid imaging if PTH is suppressed—this indicates PTH-independent hypercalcemia, not primary hyperparathyroidism 1
• Do not assume primary hyperparathyroidism based on hypercalcemia alone; PTH must be elevated or inappropriately normal (>20 pg/mL) for this diagnosis 3, 1
• Do not supplement with vitamin D until hypercalcemia resolves, as this worsens calcium absorption 1, 2
• Recognize the poor prognosis: median survival is approximately 1 month in lung cancer patients with PTHrP-mediated hypercalcemia, emphasizing need for aggressive symptom management and goals-of-care discussions 1, 2