What is the workup for hypercalcemia?

Workup for Hypercalcemia

The initial workup for hypercalcemia should include corrected calcium calculation, intact parathyroid hormone (iPTH), phosphorus, magnesium, renal function tests, 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D levels, and urinary calcium/creatinine ratio to differentiate PTH-dependent from PTH-independent causes. 1

Initial Assessment

1. Calculate corrected calcium if ionized calcium is not available:

   • Formula: Corrected calcium = Total calcium + 0.8 × (4.0 - serum albumin) 1

2. Measure intact parathyroid hormone (iPTH):

   • Most important initial test to differentiate causes 1, 2
   • Elevated/normal iPTH → PTH-dependent causes (primarily hyperparathyroidism)
   • Suppressed iPTH (<20 pg/mL) → PTH-independent causes (malignancy, etc.)

3. Additional essential laboratory tests:

   • Phosphorus (typically low in hyperparathyroidism)
   • Magnesium
   • Renal function tests (BUN, creatinine)
   • 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D levels
   • Urinary calcium/creatinine ratio (helps identify familial hypocalciuric hypercalcemia)

Diagnostic Algorithm Based on PTH Results

If PTH is elevated or inappropriately normal:

• Primary hyperparathyroidism is likely (responsible for ~90% of hypercalcemia cases along with malignancy) 1, 2
• Consider familial hypocalciuric hypercalcemia if urinary calcium is low 1, 3
• Check for lithium use or thiazide diuretics (can cause PTH-dependent hypercalcemia)

If PTH is suppressed:

1. Evaluate for malignancy (second most common cause) 1, 2

   • Check PTH-related peptide (PTHrP)
   • Consider appropriate imaging based on symptoms/clinical suspicion
   • Look for anemia (common in malignancy-associated hypercalcemia) 4

2. Assess for vitamin D disorders:

   • Check 25(OH)D levels (>150 ng/mL suggests vitamin D toxicity) 1
   • Evaluate for granulomatous disorders (sarcoidosis, tuberculosis) 1
   • Consider lymphoma (can cause vitamin D-mediated hypercalcemia) 1, 4

3. Review medication history:

   • Vitamin A or D supplements
   • Calcium supplements
   • Thiazide diuretics
   • Lithium
   • SGLT2 inhibitors
   • Immune checkpoint inhibitors 2

Clinical Correlation

• Mild hypercalcemia (total calcium <12 mg/dL):

  • Often asymptomatic or with subtle symptoms like fatigue and constipation 1, 2
  • Typically seen in primary hyperparathyroidism
  • Usually present for >6 months 4

• Severe hypercalcemia (total calcium ≥14 mg/dL):

  • More likely to be symptomatic with nausea, vomiting, dehydration, confusion 2
  • Often associated with malignancy
  • Usually rapid in onset 4
  • Requires more urgent intervention

Special Considerations

• Kidney stones and hyperchloremic metabolic acidosis suggest hyperparathyroidism 4
• Anemia with hypercalcemia suggests malignancy 4
• Familial hypocalciuric hypercalcemia should be considered in patients with:
  • Family history of hypercalcemia
  • Low urinary calcium excretion
  • Mildly elevated or normal PTH 1, 3

Common Pitfalls to Avoid

1. Failing to correct calcium for albumin when ionized calcium is unavailable 1
2. Not measuring PTH as the first diagnostic step 1, 2, 3
3. Overlooking medication-induced causes of hypercalcemia 1, 2
4. Missing familial hypocalciuric hypercalcemia, which requires no treatment 1
5. Focusing only on common causes without considering rarer etiologies in challenging cases 1

Follow-up Testing

• For patients with mild hypercalcemia, monitor serum calcium and phosphorus at least every 3 months 1
• If primary hyperparathyroidism is diagnosed, evaluate for end-organ damage:
  • Bone density scan
  • Renal ultrasound for nephrolithiasis
  • 24-hour urine for calcium excretion 1

The diagnostic approach to hypercalcemia should be systematic, starting with PTH measurement to guide further testing. Primary hyperparathyroidism and malignancy account for 90% of cases, but other causes should be considered when clinical presentation is atypical.