SUN-272 A Rare Dual Paraneoplastic Syndrome: Coexisting 1,25-dihydroxyvitamin D-mediated Hypercalcemia And Igf-2-mediated Hypoglycemia

Abstract Disclosure: D. Ashouri: None. T.E. Angell: None. An 84-year-old female with high functional status presented with acute encephalopathy, nausea, and vomiting. Initial evaluations found hypercalcemia (calcium 17 mg/dL [normal: 8.5-10.3]) and hypoglycemia (glucose 50 mg/dL [normal: 65-99]). Intravenous dextrose was initiated. Further workup showed low PTH (4 pg/mL [normal: 15-65]), low PTHrP (8 pg/mL [normal: 11-20]), and elevated 1,25-dihydroxyvitamin D (1,25-vD, 162 pg/mL [normal: 18-72]). Levels of alkaline phosphatase, 25-hydroxyvitamin D, and AM cortisol were normal. Workup, including angiotensin-converting enzyme, chest imaging, and tuberculosis testing, was negative for granulomatous diseases. Empiric treatment with intravenous fluids, calcitonin, and bisphosphonate normalized serum calcium, resulting in improved mental status. After IV dextrose was discontinued, persistent hypoglycemia recurred, and evaluation during hypoglycemia revealed low insulin (1.5 μIU/mL [normal: <18.4]), low C-peptide (0.3 ng/mL [normal: 0.8-3.85]), low proinsulin (0.2 pmol/L [normal: <10]), low beta-hydroxybutyrate (0.49 mmol/L [normal: <2.7]), negative sulfonylurea screen, and no insulin autoantibodies. Serum glucose rose >30 mg/dL after IV glucagon, excluding malnutrition or hepatic dysfunction; this, along with absence of acidosis, normal liver tests, made tumor burden or Warburg effect unlikely. Abdominal CT revealed a 9.8-cm transverse colon mass with abdominal lymphadenopathy, peritoneal carcinomatosis, and ascites. Ascitic fluid cytology showed malignant lymphoid cells diagnostic of aggressive B-cell lymphoma. IGF-2 was 241 ng/mL (normal: 260-600), and IGF-1 was <10 ng/mL [normal: 34-246], yielding an IGF-2:IGF-1 molar ratio >20. Based on the totality of findings, the patient was diagnosed with 1,25-vD-mediated hypercalcemia and IGF-2-mediated non-islet cell tumor hypoglycemia due to aggressive B-cell lymphoma. The patient was treated with steroids, but deteriorated and died from tumor lysis syndrome. Lymphoma-induced hypercalcemia is a paraneoplastic syndrome caused by tumor overproduction of 1,25-vD, leading to increased osteoclastic bone resorption and renal calcium reabsorption. It carries a poor prognosis and primarily responds to treatment of the underlying malignancy. IGF-2-mediated hypoglycemia from lymphoma is rare, typically occurring in large, highly metabolic tumors that increase glucose uptake and suppress hepatic glucose production. An IGF-2/IGF-1 molar ratio >10 is considered diagnostic, but measuring “big IGF-2” by gel filtration chromatography is ideally performed to confirm bioactive IGF-2 excess. While both hypercalcemia and hypoglycemia can occur independently in lymphoma, their coexistence is exceptionally rare, with only two identified cases in the literature. Clinicians should maintain a high index of suspicion to facilitate early recognition and management. Presentation: Sunday, July 13, 2025