Non-Islet Cell Tumour Hypoglycaemia

Non-islet cell tumour hypoglycaemia is fasting hypoglycaemia caused by a non-islet tumour, mainly through secretion of incompletely processed insulin like growth factor 2 (big IGF-2), with suppressed insulin.

It is rare and usually involves a large intrathoracic or retroperitoneal mesenchymal tumour, often already known.

Associated tumours are solitary fibrous tumour (including pleural), other mesenchymal tumours, hepatocellular carcinoma, adrenocortical carcinoma, gastrointestinal stromal tumour, large carcinoid and lymphoma.

Pathophysiology.

Big IGF-2 binds poorly to its binding protein complex, so more free peptide reaches tissues and acts at the insulin receptor. This increases glucose uptake, suppresses hepatic glucose production and lowers ketones.

Growth hormone, IGF-1, insulin and C-peptide are suppressed. The ratio of IGF-2 to IGF-1 rises.

• Fasting or early morning neuroglycopenia in a patient with a large tumour, weight loss or cancer.
• Pleural tumour with hypoglycaemia may occur with pulmonary osteoarthropathy.

• Critical sample at glucose under 3.0 mmol/L (54 mg/dL): insulin under 3 microunits/mL (18 pmol/L), C-peptide under 0.6 ng/mL (0.2 nmol/L), proinsulin under 5 pmol/L, with low beta hydroxybutyrate, and a glucose rise of 1.4 mmol/L (25 mg/dL) or more after glucagon.
• IGF-1 low, growth hormone suppressed, and IGF-2 to IGF-1 molar ratio over 10. Total IGF-2 may be normal. Immunoblot for big IGF-2 is a specialist test.
• Cross-sectional imaging (CT chest, abdomen and pelvis, MRI) and PET-CT to find or stage the tumour.
• Morning cortisol to exclude adrenal insufficiency.

Differential diagnosis.

• Insulinoma (insulin raised).
• Factitious insulin or sulphonylurea use.
• Insulin autoimmune syndrome.
• Adrenal insufficiency, hypopituitarism, liver failure, sepsis and starvation.

• Acute hypoglycaemia: 15 to 20 g oral glucose, or intravenous 10% glucose 150 to 200 mL over 15 minutes (or 20% glucose 75 to 100 mL), then a continuous 10% glucose infusion; glucagon 1 mg intramuscularly if no access.
• Definitive: resection of the tumour, which usually corrects hypoglycaemia. Debulking, embolisation, radiotherapy or chemotherapy when resection is not possible.
• Medical control: frequent meals with overnight uncooked cornstarch, and glucocorticoids such as prednisolone (dose varies, start low and titrate to glucose). Glucagon infusion or growth hormone have been used in refractory cases.
• Avoid fasting and monitor glucose closely during any procedure.

Monitoring. Glucose daily, with continuous monitoring if available; imaging follow up for recurrence, as hypoglycaemia often returns with relapse.

Referral and escalation. Oncology, endocrinology and surgery. Palliative care when disease is unresectable.