What does hypercalcemia with normal PTH and low vitamin D 25 hydroxy level indicate and how should it be managed?

Hypercalcemia with Normal PTH and Low Vitamin D 25-Hydroxy

This biochemical pattern—calcium 10.3 mg/dL with normal PTH and low 25-hydroxyvitamin D—most likely represents early or mild primary hyperparathyroidism, and you must measure 1,25-dihydroxyvitamin D to exclude granulomatous disease or other causes of PTH-independent hypercalcemia. 1, 2

Diagnostic Interpretation

The combination of hypercalcemia with normal (rather than suppressed) PTH is inappropriately normal and indicates PTH-dependent hypercalcemia, most commonly primary hyperparathyroidism. 1, 2

• In primary hyperparathyroidism, PTH levels are elevated OR inappropriately normal in the presence of hypercalcemia—a normal PTH when calcium is elevated is pathologic because PTH should be suppressed. 1, 2

• The low 25-hydroxyvitamin D is expected in this scenario because hypercalcemia suppresses PTH secretion (even if PTH remains in the "normal" range), which reduces the conversion of 25-OH vitamin D to the active 1,25-dihydroxyvitamin D form. 1

• Vitamin D deficiency itself can cause secondary hyperparathyroidism and must be excluded before confirming primary hyperparathyroidism, as vitamin D-replete individuals have PTH reference values 20% lower than those with unknown vitamin D status. 1

Critical Next Steps

Measure 1,25-Dihydroxyvitamin D

• You must measure both 25-OH vitamin D AND 1,25-(OH)₂ vitamin D levels, as their relationship provides critical diagnostic information to distinguish between causes. 1

• If 1,25-dihydroxyvitamin D is elevated despite low 25-OH vitamin D and normal PTH, consider granulomatous diseases (sarcoidosis, tuberculosis) or lymphomas where ectopic 1α-hydroxylase activity in macrophages or tumor cells produces excessive 1,25(OH)₂D. 1, 3, 4

• If 1,25-dihydroxyvitamin D is low or low-normal, this supports primary hyperparathyroidism with the low vitamin D being a secondary finding. 1

Additional Diagnostic Workup

• Confirm true hypercalcemia by measuring ionized calcium or correcting total calcium for albumin to rule out pseudo-hypercalcemia. 1

• Obtain 24-hour urine calcium or spot urine calcium/creatinine ratio to assess for hypercalciuria and distinguish primary hyperparathyroidism from familial hypocalciuric hypercalcemia. 1, 5

• Perform renal ultrasonography to evaluate for nephrocalcinosis or kidney stones. 1

• Check serum creatinine and calculate GFR, as impaired kidney function (GFR <60 mL/min/1.73 m²) is a surgical indication in confirmed primary hyperparathyroidism. 1

• Review all medications and supplements, particularly thiazide diuretics, calcium supplements, and vitamin D preparations, which can cause or exacerbate hypercalcemia. 1, 2

Management Approach

If Primary Hyperparathyroidism is Confirmed

• Refer to endocrinology and an experienced parathyroid surgeon for surgical evaluation if corrected calcium is >0.25 mmol/L (approximately 1 mg/dL) above the upper limit of normal, indicating more severe disease. 1

• Parathyroidectomy should be considered based on age, serum calcium level, and kidney or skeletal involvement. 2

• In patients older than 50 years with serum calcium less than 1 mg/dL above the upper normal limit and no evidence of skeletal or kidney disease, observation with monitoring may be appropriate. 2

• Do NOT order parathyroid imaging (ultrasound or sestamibi scan) before confirming the biochemical diagnosis—imaging is for surgical planning, not diagnosis. 1

If Vitamin D-Mediated Hypercalcemia is Suspected

• Glucocorticoids are effective for vitamin D-mediated hypercalcemia, such as in sarcoidosis and lymphomas, where they suppress ectopic 1α-hydroxylase activity. 1, 2

• Discontinue any vitamin D supplements immediately, particularly in patients with granulomatous disease or impaired vitamin D metabolism. 1

For Mild Hypercalcemia (10.3 mg/dL)

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

• Mild hypercalcemia (calcium <12 mg/dL) usually does not need acute intervention but requires diagnostic workup to identify the underlying cause. 2

Common Pitfalls

• Do not assume vitamin D deficiency is the primary problem—the low 25-OH vitamin D is likely secondary to the hypercalcemia suppressing PTH-driven conversion to active vitamin D. 1

• Do not supplement vitamin D without first establishing the diagnosis, as vitamin D supplementation can unmask or worsen hypercalcemia in patients with granulomatous disease or impaired vitamin D degradation. 3, 4

• PTH assays differ in antibodies used and can vary up to 47% between different assay generations—use assay-specific reference values and consider biological variation (20% in healthy individuals). 1

• Be aware that PTH measurements can be affected by sampling site, time, race, age, BMI, and vitamin D status—PTH is most stable in EDTA plasma at 4°C. 1