SUN-043 - A Case of IGF-2-Mediated Non-Islet Cell Tumor Hypoglycemia in Hepatocellular Carcinoma

Introduction:
Non-islet cell tumor hypoglycemia (NICTH) is a rare paraneoplastic syndrome in which tumors secrete large amounts of insulin-like growth factor-2 (IGF-2) causing hypoglycemia. Complete resection of the tumor is curative when feasible.

Case:
A 44-year-old male with a history of HIV, cirrhosis, and diffuse infiltrative hepatocellular carcinoma (HCC) was brought in by EMS after being found down and was hypoglycemic to 37 mg/dL on admission. Workup revealed an insulin level of 0.52 microU/mL, C-peptide < 0.10 ng/mL, beta-hydroxybutyrate (BHOB) < 0.01 mmol/L, IGF-1 < 10 ng/mL (52-328), IGF-2 of 155 ng/mL (267-616), and IGF-2/IGF-1 of 15.5. NICTH was suspected given an IGF‑2:IGF‑1 ratio >10. The patient was not a candidate for surgical resection, targeted embolization, or systemic therapy. He was started on oral prednisone 40 mg daily, with the dose titrated up to 80 mg daily. Due to recurrent hypoglycemia on prednisone 80 mg, recombinant human growth hormone (rhGH) was initiated at 3 mg daily, alongside a D10 dextrose infusion at 25 mL/hr. When the dextrose infusion was discontinued, the patient experienced recurrent hypoglycemia, prompting an increase in rhGH to 5 mg daily. He was on dexamethasone 12 mg daily and somatropin 5 mg daily on discharge, with limited hypoglycemia. He was discharged to inpatient hospice care, and expired 3 days after discharge.


Discussion:
NICTH is usually seen with mesenchymal or epithelial cell types. Among tumors of epithelial cell origin, HCC are most common. IGF-2 activates insulin receptors in skeletal muscle to increase glucose uptake and inhibits hepatic gluconeogenesis, glycogenolysis, and ketogenesis in the liver. IGF-2 binds to IGF-1 and insulin receptors on pancreatic α-cells, leading to suppression of glucagon secretion. The initial step in diagnosis is to confirm hypoglycemia using Whipple’s triad, followed by biochemical testing. Biochemical testing typically reveals low insulin, proinsulin, C-peptide levels, and BHOB. A ratio of IGF-2 to IGF-1 above 10 is highly suggestive of IGF-2-mediated hypoglycemia. Tumor resection remains the cornerstone of management. If inoperable, local tumor–directed therapies such as percutaneous ethanol injection or trans-arterial chemoembolization are recommended, as well as systemic chemotherapy. In cases where the underlying malignancy cannot be treated, glucocorticoids may be used, most commonly prednisone at daily doses of 30–60 mg. These agents promote lipolysis, decrease peripheral glucose utilization, increase hepatic gluconeogenesis, and may reduce tumor production of pro–IGF-2. RhGH at supraphysiological doses of 3–12 mg daily have demonstrated efficacy. This case highlights the importance of considering NICTH in patients with refractory hypoglycemia in the context of malignancy, as well as the therapeutic challenges in non-surgical candidates.

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