Nesidioblastosis

Nesidioblastosis is diffuse beta cell hypertrophy and islet hyperplasia causing endogenous hyperinsulinaemic hypoglycaemia. In infants it is the diffuse form of congenital hyperinsulinism. In adults it is rare and is also called non-insulinoma pancreatogenous hypoglycaemia syndrome.

Congenital hyperinsulinism occurs in about 1 in 50,000 live births, and more often in consanguineous or isolated populations. Adult disease is rare, usually presents after meals and is reported more often in men.

Causes in infants are variants in ABCC8 and KCNJ11 (most common), GCK, GLUD1, HADH, HNF4A and HNF1A. In adults the cause is usually unknown. Hypoglycaemia after gastric bypass is a separate entity.

Pathophysiology.

Beta cells secrete insulin at low glucose. Loss of function of the ATP-sensitive potassium channel (ABCC8, KCNJ11) keeps the cell depolarised, so insulin release is continuous.

Diffuse islet enlargement with large nuclei is found, usually without a discrete tumour. Excess insulin suppresses lipolysis and ketogenesis, so the brain lacks alternative fuel and injury occurs quickly.

• Adults: neuroglycopenic symptoms (confusion, visual disturbance, behaviour change, seizure) 2 to 4 hours after meals, less often fasting.
• Infants: jitteriness, poor feeding, hypotonia, seizures and apnoea, often large for gestational age, with a glucose infusion requirement over 8 mg/kg/min.

Red flags.

• Seizure, coma or recurrent severe episodes.
• Persistent hypoglycaemia in the first days of life.

• Critical sample at glucose under 3.0 mmol/L (54 mg/dL): insulin 3 microunits/mL (18 pmol/L) or more, C-peptide 0.6 ng/mL (0.2 nmol/L) or more, proinsulin 5 pmol/L or more, beta hydroxybutyrate 2.7 mmol/L or less, and a glucose rise of 1.4 mmol/L (25 mg/dL) or more after glucagon. Add a sulphonylurea and meglitinide screen.
• Adults: mixed meal test (a 72-hour fast is often normal). Imaging (CT, MRI, endoscopic ultrasound, and exendin based PET where available) is negative or shows no discrete lesion.
• Selective arterial calcium stimulation with hepatic venous sampling: at least a doubling of insulin in more than one arterial territory supports diffuse disease.
• Infants: genetic testing of ABCC8, KCNJ11, GCK, GLUD1, HADH, HNF4A and HNF1A, and fluorine-18 dihydroxyphenylalanine PET-CT to separate focal from diffuse disease.

Differential diagnosis.

• Insulinoma (single lesion on imaging or on arterial stimulation).
• Hypoglycaemia after bariatric surgery.
• Insulin autoimmune syndrome, factitious insulin use and sulphonylurea use.
• Non-islet cell tumour hypoglycaemia (insulin suppressed), adrenal insufficiency and hypopituitarism.
• Fatty acid oxidation defects and glycogen storage disease in infants (ketones present).

• Acute hypoglycaemia: 15 to 20 g oral glucose, repeat at 15 minutes; intravenous 10% glucose 150 to 200 mL over 15 minutes (or 20% glucose 75 to 100 mL); glucagon 1 mg intramuscularly (0.5 mg if under 25 kg). In infants keep plasma glucose at 3.9 mmol/L (70 mg/dL) or more with a continuous glucose infusion.
• Adults: small frequent low-glycaemic-index meals. Acarbose 50 to 100 mg with each main meal.
• Diazoxide: adults 3 to 8 mg/kg daily in two or three divided doses; infants 5 to 15 mg/kg daily (maximum 20 mg/kg daily). Add a thiazide diuretic for fluid retention. Watch for hypertrichosis, hyperuricaemia, and pulmonary hypertension or heart failure in infants. It does not work in most recessive ABCC8 or KCNJ11 disease.
• Octreotide 50 micrograms subcutaneously every 8 hours, titrated up to 100 micrograms; infants 5 to 25 micrograms/kg daily in three or four divided doses. Long acting somatostatin analogues monthly once the dose is stable.
• Refractory disease: pancreatectomy. In adults a subtotal resection (80 to 95%) risks diabetes and exocrine insufficiency, so use only after medical failure. In infants focal lesions are resected; diffuse disease unresponsive to drugs needs specialist centre surgery.

Special groups. Infants: hypoglycaemia is an emergency because of brain injury. Target glucose 3.9 mmol/L (70 mg/dL) or more, manage in a specialist centre and offer genetic counselling (recessive forms carry a 25% recurrence risk).

Monitoring. Glucose by continuous monitoring, growth and development in infants, HbA1c and faecal elastase after pancreatic resection.

Referral and escalation. Specialist hyperinsulinism or endocrine centre for infants and for any adult needing surgery.