Persistent Hyperinsulinaemic Hypoglycaemia of Infancy

Persistent hyperinsulinaemic hypoglycaemia of infancy, also called congenital hyperinsulinism, is a group of genetic disorders in which pancreatic beta cells secrete insulin inappropriately despite low glucose. It is the commonest cause of persistent hypoglycaemia in infancy and a major cause of brain injury from hypoglycaemia.

Incidence is about 1 in 25 000 to 50 000 live births and higher in populations with consanguinity. Presentation is usually in the first days of life but can occur later.

Variants in ABCC8 and KCNJ11, which encode the beta cell ATP-sensitive potassium channel, are the commonest cause and give diazoxide unresponsive disease. Other causes include variants in GLUD1 (with hyperammonaemia), GCK, HADH, HNF4A and HNF1A. Disease is diffuse or focal, and focal disease is cured by resection.

Pathophysiology.

Insulin secretion is normally switched off when glucose falls. In channel defects, beta cell membranes stay depolarised, calcium enters and insulin is released regardless of glucose.

Excess insulin suppresses lipolysis and ketogenesis, and blocks glycogenolysis and gluconeogenesis. The brain is left without glucose or ketones, so injury occurs at higher glucose levels than in ketotic hypoglycaemia.

• Jitteriness, poor feeding, hypotonia, apnoea, seizures and coma, or no symptoms.
• Macrosomia, hepatomegaly and a round face in some infants.
• Very high glucose requirement, usually over 8 mg/kg/min (normal 4 to 6 mg/kg/min).
• GLUD1: hyperammonaemia and leucine sensitive hypoglycaemia. Features of syndromes such as Beckwith-Wiedemann or Kabuki syndrome may be present.

Red flags.

• Seizures or coma with glucose under 2.6 mmol/L.
• Glucose requirement over 12 mg/kg/min.
• Hypoglycaemia that persists beyond 7 days of age.

• Critical sample at glucose under 3.0 mmol/L: insulin over 2 mU/L (detectable insulin with low glucose), beta hydroxybutyrate under 1.5 mmol/L, free fatty acids under 1.5 mmol/L and a rise in glucose of over 1.7 mmol/L within 30 minutes of glucagon 1 mg IM or 200 micrograms/kg IV.
• Cortisol, growth hormone, lactate, ammonia, acylcarnitines and urine organic acids to exclude other causes.
• Genetic testing of ABCC8, KCNJ11, GLUD1, GCK, HADH, HNF4A and HNF1A. Rapid testing guides the choice between medical and surgical treatment.
• 18F-DOPA positron emission tomography with CT in diazoxide unresponsive disease to locate focal lesions.

Differential diagnosis. Transient hyperinsulinism (small for gestational age, perinatal stress, maternal diabetes), hypopituitarism, adrenal insufficiency, fatty acid oxidation defects, glycogen storage disease, galactosaemia and hereditary fructose intolerance.

Emergency treatment.

• IV glucose 10% 2 mL/kg bolus, then continuous infusion at 8 to 15 mg/kg/min or more, using a central line when concentrations over 12.5% are needed.
• Glucagon 200 micrograms/kg IM or SC (maximum 1 mg) for urgent rescue, or infusion at 10 to 20 micrograms/kg/h (about 1 mg/day).
• Maintain glucose at 3.9 mmol/L or over, and prevent seizures and brain injury.

Medical treatment.

• Diazoxide 5 to 15 mg/kg/day orally in 2 or 3 divided doses, with a 5-day test of response. Adverse effects: fluid retention, pulmonary hypertension (especially in preterm infants), hypertrichosis and neutropenia. Give chlorothiazide 7 to 10 mg/kg/day in 2 divided doses to limit fluid retention. Do an echocardiogram before and during treatment in preterm infants and those with cardiac disease.
• Octreotide 5 to 30 micrograms/kg/day SC in 3 or 4 divided doses or by infusion. Tachyphylaxis is common and necrotising enterocolitis has been reported.
• Long acting somatostatin analogues and sirolimus are specialist options.
• Dietary: frequent feeds, with continuous gastric feeding or gastrostomy where needed.

Surgery. Focal disease: resection of the lesion with preserved pancreas, which is usually curative. Diffuse disease unresponsive to medical treatment: near total pancreatectomy, with later diabetes and exocrine insufficiency.

Monitoring. Glucose and ketones frequently, fasting tolerance tests of 12 to 18 hours before stopping medicine, growth and neurodevelopment.

Referral and escalation. Refer to a specialist paediatric endocrine and surgical centre at once for any infant needing over 12 mg/kg/min glucose or failing diazoxide.

Special groups. Preterm infants and those with heart disease need echocardiography before diazoxide.