What is the appropriate workup and management for a patient with hypercalcemia and a normal intact parathyroid hormone (PTH) level?

Hypercalcemia with Normal PTH: Diagnostic Workup and Management

When PTH is normal in the setting of hypercalcemia, this represents "inappropriately normal" PTH and should be approached as either PTH-independent hypercalcemia or primary hyperparathyroidism with normal-range PTH values. 1

Initial Diagnostic Approach

The cornerstone of evaluation is distinguishing between two fundamentally different scenarios:

1. True PTH-Independent Hypercalcemia (Suppressed PTH Expected)

Measure PTH-related protein (PTHrP) immediately to evaluate for malignancy-associated hypercalcemia, which is characterized by suppressed PTH and elevated PTHrP. 2 Malignancy is the most common cause of hypercalcemia in hospitalized patients, with a median survival of approximately 1 month after discovery in lung cancer patients. 2

Obtain both 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D levels simultaneously before any vitamin D supplementation, as their relationship provides critical diagnostic information. 1 In vitamin D intoxication, 25-OH vitamin D is markedly elevated, whereas in sarcoidosis/granulomatous disease, 25-OH vitamin D is low but 1,25-(OH)₂ vitamin D is elevated due to increased 1α-hydroxylase activity in granulomas. 2

2. Primary Hyperparathyroidism with "Normal" PTH

Normal PTH in the presence of hypercalcemia is actually inappropriate because PTH should be suppressed by elevated calcium. 1 This represents primary hyperparathyroidism where the parathyroid glands autonomously secrete PTH despite elevated calcium. 1

• Elevated or inappropriately normal PTH in the presence of hypercalcemia confirms primary hyperparathyroidism. 1
• Patients with hypercalcemia and PTH in the normal range can still have primary hyperparathyroidism, and cure rates are similar to those with elevated PTH. 1
• Case reports document parathyroid adenomas presenting with sustained hypercalcemia (2.51-3.03 mmol/L) and normal serum intact PTH levels (21.95-40.15 pg/mL), with normalization of calcium immediately after parathyroidectomy. 3

Essential Laboratory Workup

Complete the following tests before determining management:

• Corrected calcium or ionized calcium (normal: 4.65-5.28 mg/dL) for definitive assessment 1
• Intact PTH using EDTA plasma (most stable at 4°C) with assay-specific reference values 1
• PTHrP if PTH is truly suppressed or low-normal 2
• 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D measured together 1, 2
• Serum phosphorus (typically low-normal in primary hyperparathyroidism) 1
• Serum creatinine and eGFR to assess kidney function 1
• 24-hour urine calcium or spot urine calcium/creatinine ratio 1

Critical Pitfall: Exclude Vitamin D Deficiency First

Vitamin D deficiency causes secondary hyperparathyroidism and must be excluded before diagnosing primary hyperparathyroidism. 1 PTH reference values are 20% lower in vitamin D-replete individuals compared to those with unknown vitamin D status. 1 Ensure 25-hydroxyvitamin D levels are >20 ng/mL (ideally ≥30 ng/mL) to exclude vitamin D deficiency as a secondary cause of elevated PTH. 1

Management Algorithm Based on Etiology

If PTHrP is Elevated (Malignancy-Associated)

Initiate aggressive IV crystalloid hydration with normal saline to restore intravascular volume and promote calciuresis for moderate to severe hypercalcemia (Total Calcium ≥12 mg/dL). 2

Administer IV bisphosphonates (zoledronic acid or pamidronate) as primary therapy for PTH-independent hypercalcemia. 1, 2

• Loop diuretics (furosemide) should only be given after adequate volume repletion to enhance calcium excretion. 2
• Consider calcitonin as a temporizing measure for rapid calcium reduction while awaiting bisphosphonate effect. 2
• For acute symptomatic severe hypercalcemia (Total Calcium ≥14 mg/dL), initiate hypertonic 3% saline IV in addition to aggressive hydration. 2

Treat underlying malignancy urgently with chemotherapy or radiation as this is the definitive treatment. 2

If 1,25-Dihydroxyvitamin D is Elevated (Granulomatous Disease)

Glucocorticoids are the primary treatment when hypercalcemia is due to excessive intestinal calcium absorption from vitamin D. 2 This is effective for vitamin D-mediated hypercalcemia, such as in sarcoidosis and lymphomas. 1

If Primary Hyperparathyroidism is Confirmed

Refer to both endocrinology and an experienced high-volume parathyroid surgeon for surgical evaluation. 1 Surgical indications include:

• Corrected calcium >1 mg/dL above upper limit of normal 1
• Age <50 years 1
• Impaired kidney function (eGFR <60 mL/min/1.73 m²) 1
• Osteoporosis (T-score ≤-2.5 at any site) 1
• History of nephrolithiasis or nephrocalcinosis 1

Preoperative localization imaging with ultrasound and/or 99mTc-sestamibi scintigraphy with SPECT/CT should be performed if surgery is planned. 1 However, do not order parathyroid imaging before confirming biochemical diagnosis, as imaging is for surgical planning, not diagnosis. 1

Immediate Actions Required

Discontinue all calcium supplements, vitamin D therapy, and thiazide diuretics immediately. 1, 2 Vitamin D supplementation can exacerbate hypercalcemia by increasing intestinal calcium absorption. 1

Ensure adequate oral hydration and maintain normal calcium intake (1000-1200 mg/day) while avoiding high or low calcium diets. 1 Total elemental calcium intake should not exceed 2000 mg/day. 1

In patients with chronic kidney disease, reduce or discontinue calcium-based phosphate binders if corrected calcium exceeds 10.2 mg/dL. 1 Avoid calcium-based phosphate binders in CKD patients with hypercalcemia. 2

Monitoring Strategy

Monitor serum calcium every 1-2 weeks until stable. 2 For patients with CKD stage G3 and confirmed primary hyperparathyroidism who are not surgical candidates, monitor serum calcium every 3 months. 1

Measure serum calcium 2-4 weeks after discontinuing vitamin D to assess whether hypercalcemia resolves. 1 If calcium normalizes, vitamin D supplementation was the primary culprit. 1

Special Considerations for CKD Patients

Parathyroidectomy should be recommended in patients with severe hyperparathyroidism (persistent serum levels of intact PTH >800 pg/mL) associated with hypercalcemia and/or hyperphosphatemia that are refractory to medical therapy. 4 Consider parathyroidectomy for tertiary hyperparathyroidism (persistent hypercalcemic hyperparathyroidism) despite optimized medical therapy. 2

Avoid using calcitriol or vitamin D analogues in CKD G3a-G5 not on dialysis, reserving them only for severe and progressive hyperparathyroidism in CKD G4-G5. 1