Extreme Secretion of PTHrP From a Pancreatic Neuroendocrine Tumor, A Shift From Severe Hypercalcemia to Hypocalcemia

Background: PTHrP-secreting pancreatic neuroendocrine tumors (PNET) are a recognized cause of malignancy associated hypercalcemia. Herein, we report a case of severe hypercalcemia due to an extreme elevation of PTHrP from a PNET, where after treatment of the hypercalcemia, symptomatic hypocalcemia occurred. Clinical Case: A 59 year-old-woman with a recurrent PNET with liver metastases undergoing an evaluation for multi-visceral transplant presented with acute confusion, nausea and vomiting. Diagnostic testing identified an extreme elevation of total calcium (Ca) [>20.1 mg/dL (8.5 - 10.2)] from two different samples [serum albumin 4.1 g/dL (3.9 - 4.9)]. The total Ca level one month earlier was 8.3 mg/dL with a serum albumin of 3.1 g/dL. Total Ca measurements were performed with the Ca Gen.2 assay on a cobas c702 chemistry analyzer (Roche Diagnostics). Results greater than the analytical measurement range (0.8 – 20.1 mg/dL) were diluted with saline and confirmed (22.6 mg/dL). A Radiometer ABL 800 Flex blood gas analyzer was used to determine the ionized Ca concentration [2.94 mmol/L (1.08 - 1.30)]. Upon presentation the serum creatinine (Cr) was 2.07 mg/dL (0.58 - 0.96); eGFR utilizing the MDRD equation 24 mL/min/1.73m(2); baseline serum Cr 0.78 mg/dL. Her serum 25-OH vitamin D was 31 ng/mL (31.0 - 80.0), PTH 12 pg/mL (15 - 65), phosphate 4.3 mg/dL (2.7 - 4.8) and 1, 25-OH vitamin D 39.1 (15.0 - 60.0). PTHrP measurements were performed by ARUP Laboratories via liquid chromatography tandem mass spectrometry (LC-MS/MS) and resulted in a reported value of >2500 pmol/L (0.0 - 3.4). Her symptoms resolved and the corrected Ca gradually decreased to 8 mg/dL after treatment with IV fluids, calcitonin 200 units sc every 12 hours for 48 hours, 60 mg IV pamidronate, and five sessions of hemodialysis. Within thirteen days of receiving pamidronate, her corrected Ca slowly increased to 12mg/dL; thus, she received a single dose of 120 mg sc denosumab. Nine days later, the patient developed symptomatic hypocalcemia (7.3 mg/dL) manifested by paresthesia in the hands and feet and perioral numbness. She then received multiple doses of oral and intravenous Ca along with 50,000 units of oral ergocalciferol twice weekly. The corrected Ca normalized (8.1 mg/dL) and symptoms resolved. The patient was discharged with plans for future treatment of her underlying malignancy. Conclusion: This is the first report of a PNET producing an extreme elevation of PTHrP of higher than 2500 pmol/L, resulting in a concordant extreme elevation of total calcium within a month of documented normocalcemia. Treatment of hypercalcemia with denosumab may result in the development of hypocalcemia requiring treatment.