Insulinoma: important in the differential diagnosis of persistent hypoglycaemia unrelated to diabetes

Hypoglycaemia is a common disorder that is most frequently seen in patients with diabetes on glucose-lowering medication. Owing to the potential for impaired concentration and level of consciousness, hypoglycaemia can be dangerous and has implications for the ability to drive and work.

In an adult patient without diabetes who fulfils Whipple’s triad, further investigation is warranted (Box 4).1 Whipple’s triad requires signs and symptoms consistent with hypoglycaemia and low measured plasma glucose, which resolve after the plasma glucose rises. However, hypoglycaemic unawareness may develop after repeated episodes of hypoglycaemia2 and was the presumed cause for the lack of symptoms in our patient.

An insulinoma is a mostly benign, functioning pancreatic neoplasm. It occurs in up to four people per million in the general population.3 Insulinoma remains challenging to diagnose, often leading to a delay in diagnosis with potentially lethal consequences. In our patient, the diagnosis could have been made earlier, and the car accident may have been avoided, if the previous documented hypoglycaemia had been investigated.

If biochemical test results obtained during a hypoglycaemic episode demonstrate endogenous hyperinsulinaemic hypoglycaemia (Box 1), and sulfonylurea ingestion has been excluded, the most likely diagnosis is an insulinoma, unless there is a history of bariatric surgery causing nesidioblastosis or there are insulin antibodies suggesting the rarer autoimmune-mediated hypoglycaemia (Box 5). If spontaneous hypoglycaemia does not occur, a supervised 72-hour fast is required. Only after biochemical confirmation of endogenous hyperinsulinaemic hypoglycaemia should further imaging to localise a lesion be performed. Five to ten per cent of insulinomas are associated with multiple endocrine neoplasia type 1, and further testing should be considered in individuals with a suggestive personal or family history of endocrinopathies.1

Insulinomas are evenly distributed throughout the pancreas and are often small; imaging therefore sometimes fails to localise the lesion. Computed tomography detects 70–80% of cases; magnetic resonance imaging has an improved rate of 85%. If computed tomography and magnetic resonance imaging fail to identify a lesion, endoscopic pancreatic ultrasonography with fine needle aspiration can be performed (sensitivity > 90%), and positron emission tomography may also be helpful. Other options are selective pancreatic arterial calcium injections (sensitivity, 94–100%), intra-operative pancreatic ultrasonography (80–100%) and palpation of the pancreas by an experienced surgeon (75–95%).3

Most patients with benign insulinomas are cured with surgery, with a good prognosis. If the patient is not suitable for surgery, other methods to improve hypoglycaemia include endoscopic ultrasound-guided ethanol and radiofrequency ablation.1 Medical therapies include octreotide, which binds to somatostatin receptors to inhibit insulin release and may have an additional anti-proliferative effect, and diazoxide, which acts through stimulation of α-adrenergic receptors.4 Glucocorticoids, which inhibit insulin production and increase insulin resistance, are an additional option.5

About 10% of insulinomas are malignant, with a 10-year survival of 29%.4 In addition to liver resection, adjuvant chemoradiotherapy is often required to improve survival.4 Everolimus and sunitinib have shown an improvement in progression-free survival of about 6 months longer compared with placebo.5 Everolimus has the added benefit of inducing hyperglycaemia, which may help symptom control.5

Peptide receptor radionuclide therapy for metastatic or inoperable insulinoma involves specific uptake and retention of radioactive lutetium-177 octreotate by the tumour, resulting in irradiation to the cancer cells.