What is the next step in evaluating a patient with mild hypercalcemia (serum calcium 10.4 mg/dL, normal phosphorus) when serum creatinine, intact parathyroid hormone, and 25‑hydroxy vitamin D levels are not available?

Next Step: Measure Intact PTH and 25-Hydroxyvitamin D Immediately

The immediate next step is to measure serum intact parathyroid hormone (PTH) and 25-hydroxyvitamin D levels to determine whether this mild hypercalcemia is PTH-dependent (primary hyperparathyroidism) or PTH-independent (other causes). 1, 2

Why PTH Is the Critical First Test

• PTH distinguishes the two major pathways of hypercalcemia: An elevated or inappropriately normal PTH (typically >20 pg/mL) in the setting of hypercalcemia confirms primary hyperparathyroidism, while a suppressed PTH (<20 pg/mL) indicates a PTH-independent cause such as malignancy, vitamin D intoxication, or granulomatous disease. 1, 2

• Approximately 90% of hypercalcemia cases are due to either primary hyperparathyroidism or malignancy, making PTH the single most important discriminating test. 2

• The patient's calcium of 10.4 mg/dL represents mild hypercalcemia (defined as total calcium <12 mg/dL), which is typically asymptomatic but warrants diagnostic evaluation. 2

Why 25-Hydroxyvitamin D Must Be Measured Simultaneously

• Vitamin D deficiency can mask the true severity of hypercalcemia in primary hyperparathyroidism and can independently elevate PTH, creating diagnostic confusion. 1, 3

• Severe vitamin D deficiency with concurrent primary hyperparathyroidism can present with only borderline-elevated calcium (as low as 10.8 mg/dL), but vitamin D repletion can unmask severe hypercalcemia (up to 14.4 mg/dL), requiring urgent management. 3

• The Endocrine Society recommends measuring 25-hydroxyvitamin D at first encounter in patients with elevated PTH to exclude vitamin D deficiency as a secondary cause of PTH elevation. 1

• Vitamin D levels >20 ng/mL (>50 nmol/L) are required to confidently diagnose primary hyperparathyroidism, because deficiency below this threshold can cause secondary hyperparathyroidism that mimics the biochemical picture. 1

Additional Essential Laboratory Tests

While awaiting PTH and vitamin D results, the following should be obtained:

• Serum creatinine and estimated GFR to assess renal function, as chronic kidney disease (CKD) significantly alters calcium metabolism and PTH interpretation. 1

• Serum albumin to calculate corrected calcium using the formula: Corrected calcium (mg/dL) = Total calcium + 0.8 × [4.0 – Serum albumin (g/dL)]. 4, 1

• Ionized calcium if albumin is abnormal, to avoid pseudo-hypercalcemia and obtain the most accurate assessment. 1, 5

• 24-hour urine calcium or spot urine calcium-to-creatinine ratio to evaluate urinary calcium excretion and distinguish primary hyperparathyroidism from familial hypocalciuric hypercalcemia. 1

Interpretation Algorithm Based on PTH Result

If PTH Is Elevated or Inappropriately Normal (>20 pg/mL):

• Primary hyperparathyroidism is confirmed when hypercalcemia coexists with elevated or inappropriately normal PTH. 1, 2

• Check if 25-hydroxyvitamin D is <20 ng/mL: If deficient, vitamin D repletion is needed but must be done cautiously because supplementation can unmask severe hypercalcemia. 1, 3

• Refer to endocrinology and an experienced parathyroid surgeon for surgical evaluation, especially if the patient meets criteria: corrected calcium >1 mg/dL above upper limit of normal (i.e., >11.3 mg/dL), age <50 years, impaired kidney function (GFR <60 mL/min/1.73 m²), osteoporosis, or history of nephrolithiasis. 1

• Obtain preoperative localization imaging (ultrasound and/or 99mTc-sestamibi SPECT/CT) only after biochemical diagnosis is confirmed—imaging is for surgical planning, not diagnosis. 1

If PTH Is Suppressed (<20 pg/mL):

• Measure PTH-related protein (PTHrP), 1,25-dihydroxyvitamin D, and 25-hydroxyvitamin D to identify the cause. 1, 5

• Elevated PTHrP indicates malignancy-associated hypercalcemia, which carries a poor prognosis (median survival ≈1 month) and requires urgent imaging (chest CT, abdominal/pelvic CT or MRI, PET-CT) to identify the primary tumor. 1, 5

• Low 25-hydroxyvitamin D with elevated 1,25-dihydroxyvitamin D suggests granulomatous disease (e.g., sarcoidosis), where increased 1α-hydroxylase activity in granulomas drives hypercalcemia. 1, 5

• Markedly elevated 25-hydroxyvitamin D indicates vitamin D intoxication, which responds to corticosteroids and discontinuation of supplements. 1, 5

Critical Pitfalls to Avoid

• Do not order parathyroid imaging before confirming the biochemical diagnosis with PTH and calcium measurements—imaging is for surgical planning, not diagnosis. 1

• Do not supplement with vitamin D until the cause of hypercalcemia is identified, as supplementation can worsen hypercalcemia in primary hyperparathyroidism or other PTH-independent causes. 4, 1

• Do not assume mild hypercalcemia is benign—even asymptomatic hypercalcemia requires diagnostic evaluation to identify the underlying cause and prevent progression. 2

• Do not rely on corrected calcium alone if albumin is abnormal—measure ionized calcium to avoid misclassification. 1, 5

Monitoring During Workup

• Ensure adequate oral hydration and discontinue any calcium supplements, vitamin D, or thiazide diuretics during the diagnostic evaluation. 1

• Measure serum calcium every 3 months if the workup is delayed or if the patient is being observed without immediate intervention. 1

• Assess for symptoms of hypercalcemia (polyuria, polydipsia, nausea, constipation, fatigue, confusion) at each visit, as symptom development may prompt more urgent intervention. 1, 2