What causes elevated calcium levels and what additional tests are needed to evaluate hypercalcemia in a patient?

Causes of Elevated Calcium and Required Diagnostic Tests

Primary hyperparathyroidism and malignancy account for approximately 90% of all hypercalcemia cases, making intact parathyroid hormone (PTH) the single most critical initial test to guide your diagnostic workup. 1

Major Causes of Hypercalcemia

PTH-Dependent Causes (Elevated or Inappropriately Normal PTH)

• Primary hyperparathyroidism is characterized by elevated or inappropriately normal PTH levels in the presence of hypercalcemia, typically caused by parathyroid adenoma or hyperplasia 2, 1
• Primary hyperparathyroidism tends to present with lower calcium levels (<12 mg/dL), longer duration (>6 months), kidney stones, hyperchloremic metabolic acidosis, and no anemia 3

PTH-Independent Causes (Suppressed PTH <20 pg/mL)

• Malignancy (solid tumors and hematological) represents 49.1% and 16.5% of hospitalized hypercalcemia cases respectively, with oral cavity carcinoma and multiple myeloma being most common 4
• Malignancy-associated hypercalcemia presents with rapid onset, higher calcium levels (often >12 mg/dL), severe symptoms, marked anemia, but never kidney stones or metabolic acidosis 3, 5
• Vitamin D toxicity (definite 8%, probable 3.5%) has emerged as an increasingly important iatrogenic cause over the past decade 4
• Granulomatous diseases such as sarcoidosis cause hypercalcemia in approximately 6% of patients through increased 1α-hydroxylase production by granulomatous macrophages 2, 4
• Medications including thiazide diuretics, lithium, calcium supplements, vitamin D supplements, vitamin A, calcitriol, and vitamin D analogues 1, 6
• Chronic kidney disease accounts for 4.9% of cases 4

Essential Diagnostic Algorithm

First-Line Laboratory Tests (Order Immediately)

• Serum intact PTH - this is your most important discriminating test 2, 7, 1
• Total serum calcium and albumin to calculate corrected calcium using: Corrected calcium (mg/dL) = Total calcium + 0.8 × [4.0 - Serum albumin (g/dL)] 8, 7
• Ionized calcium (normal 4.65-5.28 mg/dL) for definitive assessment, especially when albumin is abnormal 8, 7
• Serum creatinine and BUN to assess renal function 7, 1
• Serum phosphorus (typically low-normal in primary hyperparathyroidism) 8, 7
• Serum magnesium 7

Second-Line Tests Based on PTH Results

If PTH is elevated or inappropriately normal (suggesting primary hyperparathyroidism):

• 25-hydroxyvitamin D - must be measured because vitamin D deficiency causes secondary hyperparathyroidism and must be excluded before diagnosing primary hyperparathyroidism 2, 8
• 1,25-dihydroxyvitamin D - measure together with 25-hydroxyvitamin D as their relationship provides critical diagnostic information 7
• 24-hour urine calcium or spot urine calcium/creatinine ratio to assess for hypercalciuria and kidney stone risk 8, 7
• Renal ultrasonography to evaluate for nephrocalcinosis or kidney stones 8
• Bone density scan if chronic hyperparathyroidism is suspected 8

If PTH is suppressed (<20 pg/mL, indicating PTH-independent cause):

• PTH-related protein (PTHrP) - elevated in humoral hypercalcemia of malignancy 8, 7, 5
• 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D together - in sarcoidosis, 25-OH vitamin D is typically low (84% of patients) while 1,25-(OH)2 vitamin D is elevated (11% of patients) due to extrarenal 1α-hydroxylase activity 2, 7
• Serum protein electrophoresis and immunofixation if multiple myeloma suspected 4
• Chest imaging if lung cancer or sarcoidosis suspected 4

Critical Interpretation Nuances

PTH Assay Considerations

• PTH measurements can vary up to 47% between different assay generations (second vs. third generation), so always use assay-specific reference values 2, 8
• PTH is more stable in EDTA plasma than serum and at 4°C than room temperature - specify EDTA plasma collection 2, 8
• Biological variation of PTH is substantial (20% in healthy individuals), so differences must exceed 54% to be clinically significant 8
• PTH reference values are 20% lower in vitamin D-replete individuals compared to those with unknown vitamin D status 2, 8

Vitamin D Pattern Recognition

• Primary hyperparathyroidism: Elevated PTH, elevated 1,25-(OH)2 vitamin D (PTH stimulates conversion), variable 25-OH vitamin D 2
• Sarcoidosis/granulomatous disease: Suppressed PTH, low 25-OH vitamin D (84%), elevated 1,25-(OH)2 vitamin D (11%) 2, 7
• Malignancy: Suppressed PTH, decreased 25-OH vitamin D (hypercalcemia suppresses PTH which normally drives conversion to active form) 8
• Vitamin D toxicity: Suppressed PTH, elevated 25-OH vitamin D, variable 1,25-(OH)2 vitamin D 1

Race, Age, and BMI Adjustments

• PTH concentrations are higher in Black individuals compared to White individuals 2
• PTH increases with age due to declining GFR, resulting in higher PTH in patients over 60 years 2
• PTH concentration is higher in obese patients (BMI-dependent) 2

Common Diagnostic Pitfalls to Avoid

• Never rely on corrected calcium alone - always measure ionized calcium when albumin is abnormal to avoid pseudo-hypercalcemia from hemolysis or improper sampling 8, 9
• Never order parathyroid imaging before confirming biochemical diagnosis - imaging (ultrasound, 99mTc-sestamibi SPECT/CT) is for surgical planning only, not diagnosis 8
• Never diagnose primary hyperparathyroidism without excluding vitamin D deficiency first - vitamin D deficiency causes secondary hyperparathyroidism with elevated PTH 2, 8
• Always measure BOTH 25-hydroxyvitamin D AND 1,25-dihydroxyvitamin D together - their relationship is diagnostically critical, especially for granulomatous diseases 9, 7
• Check medication list thoroughly - thiazides, lithium, calcium supplements (>500 mg/day), vitamin D (>400 IU/day), vitamin A, calcitriol, and calcium-based phosphate binders are common culprits 9, 1, 6

Special Population Considerations

• Chronic kidney disease patients: Distinguish secondary hyperparathyroidism (hypocalcemia or normal calcium with elevated PTH) from tertiary hyperparathyroidism (autonomous hypercalcemia with elevated PTH) 8, 7
• Patients on dialysis: Consider dialysate calcium concentration effects on PTH and calcium balance 8, 7
• Dehydration: Can concentrate blood components causing falsely elevated calcium - check serum osmolality (>300 mOsm/kg indicates dehydration) 7