How should I evaluate and manage a patient with severe hypercalcemia (serum calcium 2.9 mmol/L) and a low parathyroid hormone level (0.9 pg/mL)?

Evaluation and Management of Severe Hypercalcemia with Suppressed PTH

This patient has PTH-independent hypercalcemia (PTH 0.9 pg/mL with calcium 2.9 mmol/L), which requires immediate aggressive hydration with IV bisphosphonates while simultaneously pursuing an urgent malignancy workup, as this presentation carries a median survival of approximately 1 month if due to humoral hypercalcemia of malignancy. 1

Immediate Diagnostic Workup

Measure the following laboratory tests urgently:

• PTHrP (parathyroid hormone-related peptide) – elevated PTHrP with suppressed PTH defines humoral hypercalcemia of malignancy and signals advanced cancer with poor prognosis 1
• 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D together – the relationship between these two provides critical diagnostic information 1
  • If 25-OH vitamin D is markedly elevated: vitamin D intoxication 1
  • If 25-OH vitamin D is low but 1,25-(OH)₂ vitamin D is elevated: granulomatous disease (sarcoidosis, lymphoma) due to increased 1α-hydroxylase activity 1, 2
• Serum creatinine and eGFR – assess kidney function as hypercalcemia can cause acute kidney injury 1
• Ionized calcium – provides definitive assessment (normal 4.65-5.28 mg/dL or 1.15-1.36 mmol/L) 1

Urgent Imaging for Malignancy

Do not delay the malignancy workup while treating hypercalcemia – imaging and oncology consultation must proceed simultaneously because of the poor prognosis (median survival ≈1 month with PTHrP-mediated hypercalcemia). 1

Obtain immediately:

• Chest CT – squamous cell lung cancer is the most common PTHrP-secreting tumor 1, 3
• Abdominal/pelvic CT or MRI – evaluate for renal cell carcinoma, pancreatic neuroendocrine tumors 1
• PET-CT when available – comprehensive staging for occult malignancy 1
• Consider head/neck imaging if no primary identified, as head-and-neck squamous carcinoma is a common source 1

Acute Management of Severe Hypercalcemia

Initiate treatment immediately:

1. Aggressive IV hydration with isotonic normal saline – cornerstone of acute therapy to restore intravascular volume and promote calciuresis 1, 4

2. IV bisphosphonates (first-line pharmacologic therapy):

   • Zoledronic acid or pamidronate – inhibit osteoclast-mediated bone resorption, achieve calcium reduction within 2-4 days 1, 4

3. Monitor ionized calcium every 4-6 hours during initial treatment phase 1

4. Loop diuretics only after volume restoration – not before adequate hydration 1

Etiology-Specific Considerations

If PTHrP is elevated (>20 pg/mL):

• Confirms humoral hypercalcemia of malignancy 3
• Involve oncology and palliative care immediately given median survival of 1 month 1, 3
• Consider denosumab if bisphosphonates fail or if patient has advanced kidney disease 4, 3

If 25-OH vitamin D is low but 1,25-(OH)₂ vitamin D is elevated:

• Suggests granulomatous disease (sarcoidosis, lymphoma) 1, 2
• Glucocorticoids are first-line treatment – suppress 1α-hydroxylase activity in granulomas 1, 4, 2
• Consider bone marrow biopsy if other workup negative, as sarcoidosis can be isolated to bone marrow 2

If 25-OH vitamin D is markedly elevated:

• Vitamin D intoxication 1
• Discontinue all vitamin D supplements immediately 1
• Glucocorticoids effective for vitamin D-mediated hypercalcemia 1, 4

If all above tests negative:

• Consider immobilization hypercalcemia (though rare in adults) 5
• Evaluate for thyrotoxicosis, adrenal insufficiency 6, 4
• Review medications: thiazides, lithium, calcium/vitamin D supplements 4

Critical Pitfalls to Avoid

• Do not wait for PTHrP results before starting IV hydration and bisphosphonates – severe hypercalcemia requires immediate treatment regardless of etiology 1, 4
• Do not give loop diuretics before adequate volume resuscitation – this worsens dehydration 1
• Do not delay malignancy imaging – the workup must proceed simultaneously with acute treatment given the poor prognosis 1
• Do not assume primary hyperparathyroidism – PTH of 0.9 pg/mL is suppressed (<20 pg/mL), ruling out PTH-dependent causes 1, 4
• Do not measure only 25-OH vitamin D – both 25-OH and 1,25-(OH)₂ vitamin D are needed to distinguish vitamin D intoxication from granulomatous disease 1

Renal Failure Considerations

If eGFR <30 mL/min/1.73m² or patient is anuric:

• Hemodialysis with low-calcium dialysate is indicated for refractory severe hypercalcemia 3
• Denosumab may be preferred over bisphosphonates in advanced kidney disease 4, 3

Monitoring During Treatment

• Ionized calcium every 4-6 hours until stable 1
• Serum phosphorus and electrolytes closely during acute treatment 1
• Reassess renal function regularly (creatinine, eGFR) as hypercalcemia can worsen kidney injury 1