What is the appropriate step‑by‑step work‑up for a patient with hypercalcemia?

Hypercalcemia Work-Up: Step-by-Step Diagnostic Algorithm

Measure serum calcium (corrected for albumin or ionized), intact parathyroid hormone (PTH), basic metabolic panel, phosphorus, albumin, and magnesium as your initial laboratory panel. 1, 2, 3

Step 1: Confirm True Hypercalcemia

• Obtain ionized calcium (normal 4.65–5.28 mg/dL) to avoid pseudo-hypercalcemia from hemolysis or improper sampling. 1, 2 This is the gold standard and eliminates false positives from albumin abnormalities.

• If only total calcium is available, calculate corrected calcium using: Corrected calcium (mg/dL) = Total calcium + 0.8 × [4.0 – Serum albumin (g/dL)]. 1, 2

• Hypercalcemia is defined as corrected calcium >10.2 mg/dL or ionized calcium >5.28 mg/dL. 2

Step 2: Measure Intact PTH Simultaneously with Calcium

PTH is the single most important test to determine the etiology of hypercalcemia—it distinguishes PTH-dependent from PTH-independent causes. 1, 2, 3, 4

Critical PTH Measurement Considerations:

• Use EDTA plasma rather than serum for PTH measurement, as PTH is most stable in EDTA plasma at 4°C. 1, 2

• PTH assays vary by up to 47% between different generations; always use assay-specific reference values. 1, 2

• Biological factors (race, age, BMI, vitamin D status) influence PTH concentration—interpret in clinical context. 2

Step 3: Interpret PTH Results to Guide Further Work-Up

A. Elevated or Inappropriately Normal PTH (PTH-Dependent Hypercalcemia)

This pattern indicates primary hyperparathyroidism in >90% of cases. 2, 3, 4

Essential Additional Tests:

• Measure 25-hydroxyvitamin D to exclude vitamin D deficiency (target >20 ng/mL), which causes secondary hyperparathyroidism and can falsely elevate PTH. 1, 2

• Obtain serum phosphorus (typically low-normal in primary hyperparathyroidism), serum creatinine, and eGFR to assess renal function. 2, 5

• Measure 24-hour urine calcium or spot urine calcium/creatinine ratio to evaluate urinary calcium excretion and assess for nephrolithiasis risk. 1, 2

• Check renal ultrasound for nephrocalcinosis or kidney stones. 2

• Obtain bone density scan (DEXA) if chronic hyperparathyroidism is suspected. 2

Surgical Indications for Primary Hyperparathyroidism:

Refer to endocrinology and an experienced parathyroid surgeon if any of the following criteria are met: 2

• Corrected calcium >1 mg/dL above upper limit of normal (>11.3 mg/dL)
• Age <50 years
• eGFR <60 mL/min/1.73 m²
• Osteoporosis (T-score ≤–2.5 at any site)
• History of nephrolithiasis or nephrocalcinosis
• 24-hour urinary calcium >300 mg/24 hours
• Patient preference for definitive treatment

Common Pitfall:

Do not order parathyroid imaging (ultrasound or sestamibi scan) before confirming the biochemical diagnosis—imaging is for surgical planning, not diagnosis. 2

---

B. Suppressed PTH (<20 pg/mL) (PTH-Independent Hypercalcemia)

This pattern indicates malignancy, granulomatous disease, vitamin D intoxication, or other non-parathyroid causes in >90% of cases. 1, 2, 3, 4

Essential Additional Tests:

• Measure PTH-related protein (PTHrP)—elevated in 80% of malignancy-associated hypercalcemia, particularly squamous cell carcinomas (lung, head/neck), renal cell carcinoma, and breast cancer. 1, 2

• Obtain both 25-hydroxyvitamin D AND 1,25-dihydroxyvitamin D together before any supplementation—their relationship provides critical diagnostic information: 1, 2

  • Vitamin D intoxication: 25-OH vitamin D markedly elevated (>150 ng/mL), 1,25-(OH)₂ vitamin D variable
  • Granulomatous disease (sarcoidosis): 25-OH vitamin D low, 1,25-(OH)₂ vitamin D elevated due to increased 1α-hydroxylase activity in granulomas
  • Malignancy: Both typically low due to PTH suppression

• Check serum protein electrophoresis (SPEP), immunofixation, and serum free light chains if multiple myeloma is suspected (anemia, bone pain, renal insufficiency). 1

• Obtain comprehensive imaging if malignancy is suspected: 1, 2

  • Chest CT (lung cancer is the most common PTHrP-secreting tumor)
  • Abdominal/pelvic CT or MRI
  • PET-CT when available
  • Bone scan if bone metastases suspected

Medication and Supplement History:

Specifically ask about: 1, 2

• Thiazide diuretics (reduce urinary calcium excretion)
• Lithium (increases PTH secretion)
• Calcium supplements (>500 mg/day)
• Vitamin D supplements (>400 IU/day)
• Vitamin A intake
• Calcitriol or vitamin D analogs (cause hypercalcemia in 22.6–43.3% of patients)

Urgent Malignancy Work-Up:

Hypercalcemia of malignancy carries a median survival of approximately 1 month—do not delay imaging and oncology consultation while treating acute hypercalcemia. 1, 2 The work-up must proceed simultaneously with calcium-lowering measures.

---

Step 4: Assess Severity and Symptoms

Severity Classification:

• Mild hypercalcemia: Total calcium <12 mg/dL or ionized calcium 5.6–8.0 mg/dL (1.4–2.0 mmol/L)—usually asymptomatic but may cause fatigue and constipation in 20% of patients. 3

• Moderate hypercalcemia: Total calcium 12–14 mg/dL—associated with polyuria, polydipsia, nausea, confusion, vomiting, abdominal pain, myalgia, and dehydration. 1, 2

• Severe hypercalcemia: Total calcium ≥14 mg/dL or ionized calcium ≥10 mg/dL (≥2.5 mmol/L)—causes mental status changes, bradycardia, hypotension, severe dehydration, acute renal failure, and coma. 1, 2, 3

Electrocardiographic Assessment:

Obtain a 12-lead ECG to identify shortened QT interval (hypercalcemia) and any arrhythmias requiring continuous cardiac monitoring. 1

---

Step 5: Additional Laboratory Monitoring

• Measure serum creatinine and BUN to assess renal function—hypercalcemia causes acute kidney injury and worsens chronic kidney disease. 1, 2

• Check electrolytes (potassium, magnesium) every 6–12 hours during acute treatment—hypomagnesemia and hypokalemia are common and require correction. 1

• Monitor ionized calcium every 4–6 hours during the first 48–72 hours of treatment, then twice daily until stable. 1

---

Key Distinguishing Features: Primary Hyperparathyroidism vs. Malignancy

Primary hyperparathyroidism typically presents with: 4, 5

• Mild hypercalcemia (calcium <12 mg/dL)
• Prolonged duration (>6 months)
• Fewer, subtle symptoms
• Kidney calculi
• Hyperchloremic metabolic acidosis
• No anemia
• Elevated or inappropriately normal PTH

Malignancy-associated hypercalcemia typically presents with: 4, 5

• Rapid onset (days to weeks)
• Higher calcium levels (often >12 mg/dL)
• Severe symptoms
• Marked anemia
• No kidney calculi or metabolic acidosis
• Suppressed PTH (<20 pg/mL)
• Elevated PTHrP in 80% of cases

---

Critical Pitfalls to Avoid

• Do not rely on corrected calcium alone—measure ionized calcium to avoid misclassification from sampling artifacts. 1, 2

• Do not supplement vitamin D until hypercalcemia is resolved—supplementation worsens calcium elevation even when 25-OH vitamin D is low. 1, 2

• Do not order parathyroid imaging before confirming biochemical diagnosis—imaging is for surgical planning only. 2

• Do not delay malignancy work-up while treating acute hypercalcemia—median survival is 1 month in hypercalcemia of malignancy. 1, 2

• Do not use calcitriol or active vitamin D analogs in primary hyperparathyroidism—they increase intestinal calcium absorption and exacerbate hypercalcemia. 2