Hematological Malignancies Associated with Low PTH Levels
Multiple myeloma and non-Hodgkin's lymphoma are the primary hematological malignancies that can present with low PTH levels, occurring when these tumors produce parathyroid hormone-related protein (PTHrP) or excess 1,25-dihydroxyvitamin D, which suppress endogenous PTH secretion through hypercalcemia. 1, 2, 3
Pathophysiologic Mechanism
The suppression of PTH in hematological malignancies occurs through the following mechanism:
- PTHrP production by tumor cells mimics PTH action on bone and kidney, causing hypercalcemia while simultaneously suppressing endogenous PTH production 1
- PTHrP shares considerable homology with parathyroid hormone and binds to the PTH type 1 receptor (PTH1R) with high affinity 1
- The resulting hypercalcemia provides negative feedback to the parathyroid glands, leading to inappropriately low or suppressed PTH levels 1, 4
Specific Hematological Malignancies
Multiple Myeloma
- PTHrP is expressed in myeloma cells and can be detected by immunohistochemistry and in situ hybridization in bone marrow specimens 2
- Approximately one-third of myeloma cells may be PTHrP-positive in affected patients 2
- The biochemical profile shows elevated PTHrP (>3.7 pmol/L) with suppressed PTH and suppressed 1,25(OH)2 vitamin D3 2
- Hypercalcemia occurs through both local osteolytic mechanisms and humoral hypercalcemia of malignancy 2
Non-Hodgkin's Lymphoma
- 62.5% of hypercalcemic NHL patients have significant elevations of PTHrP (mean 70.5 ± 38.5 pmol equivalents per liter) 5
- PTHrP elevation is particularly common in stage IV disease with high-grade pathology (11 of 30 patients with advanced disease) 5
- Concomitant suppression of 1,25(OH)2D3 occurs in 66% of hypercalcemic NHL patients with PTHrP-mediated hypercalcemia 5
- In rare cases, NHL can produce both PTHrP and excess 1,25-dihydroxyvitamin D simultaneously, with tumor tissue demonstrating expression of both PTHrP and CYP27B1 3
Diagnostic Approach
When evaluating a patient with hematological malignancy and suspected hypercalcemia:
- Measure serum intact PTH (will be suppressed in PTHrP-mediated hypercalcemia) 1, 4
- Measure serum PTHrP levels (elevated in humoral hypercalcemia of malignancy) 1, 4
- Measure serum calcium, albumin, phosphorus, and magnesium 4
- Measure 1,25-dihydroxyvitamin D and 25-hydroxyvitamin D levels 4
- The characteristic pattern is: elevated PTHrP, suppressed iPTH, and low or normal calcitriol levels 1, 4
Clinical Pitfalls and Caveats
- Always measure PTH at initial presentation of hypercalcemia in all patients with malignancy, as 10% may have coexisting primary hyperparathyroidism 6
- Patients with parathyroid disease coexisting with malignancy have significantly longer median survival (13 months) compared to those with hypercalcemia due to malignancy alone (3 months) 6
- PTHrP measurement is particularly useful to identify occult malignancy in patients without clinically apparent cancer 6
- In multiple myeloma, bisphosphonate treatment can paradoxically stimulate PTH release by lowering calcium, potentially masking the underlying PTHrP-mediated suppression 7
Prognostic Significance
- Hypercalcemia occurs in 10-25% of cancer patients, being more common in squamous cell lung cancer but also significant in hematological malignancies 1, 4
- The median survival after discovery of malignant hypercalcemia is approximately 1 month in lung cancer patients, emphasizing the grave prognostic significance 1, 4
- Tumor response to chemotherapy is associated with decrease in PTHrP levels, making it a useful marker for treatment response 5