Congenital Hyperinsulinaemic hypoglycaemia (CHI) is a cause of severe and persistent hypoglycaemia in the newborn period. Biochemically it is characterized by the inappropriate secretion of insulin in the presence of a low blood glucose concentration. HI has two main characteristics: a high glucose requirement to correct hypoglycemia and a responsiveness of hypoglycemia to exogenous glucagon.
The congenital forms of CHI (congenital hyperinsulinism) lead to severe and profound hypoglycaemia in the newborn period and occur due to defects in key genes involved in regulating insulin secretion. Neonatal onset HI is usually severe while late onset and syndromic HI are generally responsive to a medical treatment. The delay in the diagnosis and inappropriate management of congenital hyperinsulinism is a major cause of hypoglycaemic brain injury.
Glycemia must be maintained within normal ranges to avoid brain damages, initially with glucose administration and glucagon infusion then, once the diagnosis is set, with specific HI treatment. Oral diazoxide is a first line treatment. In case of unresponsiveness to this treatment, somatostatin analogues and calcium antagonists may be added, and further investigations are required for the putative histological diagnosis: pancreatic 18F fluoro-L-DOPA PET–CT and molecular analysis. Indeed, focal forms consist of a focal adenomatous hyperplasia of islet cells, and will be cured after a partial pancreatectomy. Diffuse HI involves all the pancreatic β cells of the whole pancreas. Diffuse HI resistant to medical treatment (octreotide, diazoxide, calcium antagonists and continuous feeding) may require subtotal pancreatectomy which post-operative outcome is unpredictable.
The genetics of focal islet-cells hyperplasia associates a paternally inherited mutation of the ABCC8 or the KCNJ11 genes, with a loss of the maternal allele specifically in the hyperplasic islet cells. The genetics of diffuse isolated HI is heterogeneous and may be recessively inherited (ABCC8 and KCNJ11) or dominantly inherited (ABCC8, KCNJ11, GCK, GLUD1, SLC16A1, HNF4A and HADH). Syndromic HI are always diffuse form and the genetics depend on the syndrome. Except for HI due to potassium channel defect (ABCC8 and KCNJ11), most of these HI are sensitive to diazoxide. The most common cause of medically unresponsive congenital hyperinsulinism is inactivating mutations in the genes ABCC8 and KCNJ11.
Recently advances in imaging techniques such as 18F-DOPA-PET/CT have radically changed the diagnostic approach to patients with diffuse and focal forms of congenital hyperinsulinism. Laparoscopic pancreatectomy (partial and near total) is now also possible for patients with congenital hyperinsulinism.