What does it mean to have hypercalcemia and low Parathyroid Hormone (PTH) levels?

Hypercalcemia with Low PTH: Diagnostic Implications

Hypercalcemia with suppressed parathyroid hormone (PTH) levels indicates a parathyroid-independent cause of hypercalcemia that requires investigation for underlying malignancy or other non-parathyroid disorders. 1

Common Causes of Hypercalcemia with Low PTH

• Malignancy-associated hypercalcemia is the most common cause of PTH-independent hypercalcemia, accounting for approximately 90% of cases alongside primary hyperparathyroidism 1
• Parathyroid hormone-related peptide (PTHrP) production by tumors, particularly squamous cell carcinomas, is a frequent mechanism of malignancy-associated hypercalcemia 2
• Osteolytic bone metastases from various cancers can release calcium from bone tissue independent of PTH action 2
• Lymphomas may produce 1,25-dihydroxyvitamin D, leading to increased intestinal calcium absorption 2
• Granulomatous disorders like sarcoidosis can cause hypercalcemia through excessive production of 1,25-dihydroxyvitamin D 1

Diagnostic Approach

• Measure PTHrP when PTH is suppressed (<26 ng/L) in the setting of hypercalcemia, as this is highly predictive of PTHrP-mediated hypercalcemia 3
• Check 25-OH vitamin D and 1,25-dihydroxyvitamin D levels to evaluate for vitamin D intoxication or disorders of vitamin D metabolism 4
• Assess kidney function with creatinine and GFR measurements, as kidney dysfunction can contribute to hypercalcemia 4
• Evaluate phosphorus levels, which are typically low in PTHrP-mediated hypercalcemia but may be elevated in vitamin D toxicity 4
• Consider medication review for agents that can cause hypercalcemia, including thiazide diuretics, lithium, vitamin A, and calcium or vitamin D supplements 1

Rare Considerations

• Primary hyperparathyroidism with undetectable PTH can occur in rare cases due to genetic mutations in the PTH gene within parathyroid adenomas 5
• Jansen's metaphyseal chondrodysplasia can present with hypercalcemia due to gain-of-function mutations in the PTH/PTHrP receptor (PTHR1) 2
• Familial hypocalciuric hypercalcemia should be considered, especially if there is a family history of hypercalcemia 5
• Immobilization can cause hypercalcemia through increased bone resorption, particularly in patients with high bone turnover 1

Management Principles

• Severity assessment is crucial - mild hypercalcemia (total calcium <12 mg/dL) may be asymptomatic, while severe hypercalcemia (≥14 mg/dL) requires urgent treatment 1
• Hydration with intravenous fluids is the initial management for symptomatic or severe hypercalcemia 1
• Intravenous bisphosphonates (zoledronic acid or pamidronate) are effective for treating malignancy-associated hypercalcemia 1
• Denosumab may be considered in patients with kidney failure when bisphosphonates are contraindicated 1
• Glucocorticoids are effective when hypercalcemia is due to excessive vitamin D production (as in granulomatous disorders or some lymphomas) 1
• Dialysis may be necessary in severe cases with kidney failure 1

Clinical Pitfalls to Avoid

• Failing to consider rare cases of primary hyperparathyroidism with undetectable PTH - parathyroid imaging may still be warranted in select cases 5
• Ordering PTHrP before confirming hypercalcemia and measuring PTH - PTHrP testing is most informative when PTH is suppressed 3
• Not accounting for biological variation in PTH levels, which can affect interpretation 4
• Ignoring the possibility of medication-induced hypercalcemia, which is common and potentially reversible 1
• Failing to treat the underlying cause rather than just managing the hypercalcemia 6

Remember that while malignancy is the most common cause of hypercalcemia with suppressed PTH, a thorough evaluation for other causes is essential for appropriate management and treatment of the underlying condition 6.