Congenital Hyperinsulinism
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Direct answer
Congenital hyperinsulinism is a group of disorders in which pancreatic beta cells secrete insulin inappropriately during hypoglycaemia, causing persistent and often severe neonatal hypoglycaemia. The diagnosis rests on a critical sample taken during hypoglycaemia, showing detectable insulin with suppressed ketones and fatty acids, together with a high glucose infusion requirement. Diazoxide, which opens the beta cell KATP channel, is the first-line drug, and focal lesions may need surgical treatment.
What you must remember
- Mechanism: the beta cell KATP channel stays closed and fails to open at low glucose, so the cell stays depolarised and keeps secreting insulin; this is most often due to inactivating ABCC8 or KCNJ11 mutations.
- Focal versus diffuse: focal disease is a localised lesion, typically a paternally inherited KATP mutation with loss of the maternal 11p15 allele in the lesion, and can be cured by resection; diffuse disease involves the whole gland.
- Glucose requirement: infusion rates above about 8 mg/kg per minute suggest hyperinsulinism rather than transient neonatal hypoglycaemia.
- Critical sample: at plasma glucose below about 3 mmol/L, insulin is detectable while beta-hydroxybutyrate and free fatty acids are suppressed.
- Diazoxide: first-line medical therapy that works in many but not all patients (inactivating KATP mutations are usually unresponsive), with fluid retention and hypertrichosis as main adverse effects.
- Second-line therapy: octreotide and other agents for diazoxide-unresponsive disease, with early specialist input.
A stepwise route from hypoglycaemia to localisation
The investigative logic is to prove inappropriate insulin during hypoglycaemia, then decide between medical therapy and surgery according to lesion type.
- Document hypoglycaemia: confirm persistent low glucose with a documented trend and glucose infusion requirement, rather than relying on single readings.
- Take the critical sample: draw blood at low glucose and measure insulin, C-peptide, beta-hydroxybutyrate, free fatty acids, growth hormone and cortisol, which also excludes hypopituitarism.
- Interpret suppression: detectable insulin with low ketones and fatty acids during hypoglycaemia indicates hyperinsulinism rather than a counter-regulatory deficit.
- Start diazoxide: begin medical therapy promptly, monitoring for fluid retention and hypertrichosis.
- Test genes: sequence KATP channel genes to classify disease and predict diazoxide responsiveness and surgical need.
- Localise focal disease: 18F-DOPA PET-CT and MRI guide resection for focal lesions, while subtotal pancreatectomy is reserved for refractory diffuse disease. Recurrent hypoglycaemia threatens neurodevelopment, so treatment starts while the investigation is still in progress rather than after it is complete. Parents need feeding routines, glucose monitoring and clear instructions for emergency glucose.
Where the exam tries to catch you
Hyperinsulinism vignettes test whether the candidate proves insulin excess before treating.
- Trap: attributing persistent neonatal hypoglycaemia to transient causes without a critical sample Correct: persistent hypoglycaemia with a high glucose requirement needs testing for hyperinsulinism.
- Trap: judging the insulin level in isolation Correct: insulin must be read against glucose, ketones and fatty acids in the same sample.
- Trap: assuming surgery cures every case Correct: focal lesions may be cured by resection, while diffuse disease usually needs medical therapy.
- Trap: continuing diazoxide for unresponsive disease Correct: unresponsive infants need second-line therapy and specialist review.
Frequently asked questions
What is the critical sample in congenital hyperinsulinism?
The critical sample is blood taken during hypoglycaemia, at glucose below about 3 mmol/L, to measure insulin, ketones and fatty acids. Detectable insulin with suppressed ketones and fatty acids confirms inappropriate insulin secretion.
Why is diazoxide used in congenital hyperinsulinism?
Diazoxide opens the KATP channel in beta cells, reducing insulin secretion, and it is the first-line medical treatment for most children with congenital hyperinsulinism. Its main adverse effects are fluid retention and hypertrichosis.
How is focal congenital hyperinsulinism treated?
Focal congenital hyperinsulinism is treated by resection of the localised lesion, often guided by 18F-DOPA PET-CT, which can cure the child. Surgery is considered when medical therapy fails or when a focal lesion is identified.
What glucose infusion rate suggests congenital hyperinsulinism?
A glucose infusion rate above about 8 mg/kg per minute needed to maintain normoglycaemia suggests congenital hyperinsulinism rather than transient neonatal hypoglycaemia. The rate is interpreted together with insulin levels from a critical sample.
Which genes are most often involved in congenital hyperinsulinism?
ABCC8 and KCNJ11, which encode the subunits of the beta cell KATP channel, are the most common genes involved. Genetic testing helps predict diazoxide response and whether focal surgery is an option.