Congenital hyperinsulinaemic hypoglycaemia (HH) is characterised by the inappropriate secretion of insulin despite low blood glucose levels.
Hyperinsulinism may be transient or permanent. Transient hyperinsulinism can occur in babies of diabetic mothers who have been exposed to maternal hyperglycaemia before birth. Babies who have sustained perinatal asphyxia and those with intrauterine growth restriction are also at increased risk of transient hyperinsulinism. In a few rare cases transient hyperinsulinism can result from a monogenic aetiology.
Permanent or persistent HH is often associated with macrosomia, due to intrauterine exposure to high levels of insulin. The majority of cases with persistent hyperinsulinism are due to mutations of a single gene. HH may also occur as a feature of a genetic syndrome such as Beckwith–Wiedemann.
Hyperinsulinism most commonly presents in the newborn period, but can also present during infancy and childhood. Hypoglycaemic symptoms vary from non-specific symptoms such as poor feeding, lethargy and irritability to apnoea, seizures or coma in the most severe cases.
Two main histological subtypes have been identified in individuals with hyperinsulinism: focal and diffuse disease. Focal lesions appear as small regions of islet adenomatosis measuring 2–10 mm, which are characterised by beta cells with enlarged nuclei surrounded by normal tissue. In contrast, diffuse pancreatic disease affects all the beta cells within the islets of Langerhans. A few patients have been reported to have ‘atypical histology’. In one patient this was shown to result from somatic mosaicism for segmental uniparental disomy (UPD) of chromosome 11 that unmasked a recessively acting ABCC8 mutation (1). In the remaining patients the genetic aetiology remains unknown.
Diagnosis and Management
Early recognition and prompt, appropriate management are essential to avoid hypoglycaemic brain injury. An intravenous glucose infusion rate of >8 mg/kg per min is virtually diagnostic of hyperinsulinism. Biochemically, HH is diagnosed by the demonstration of an inappropriate concentration of serum insulin (and/or C-peptide) for the level of blood glucose. The metabolic effect of this inappropriate insulin secretion is reflected by the low levels of serum ketone bodies and fatty acids during the hypoglycaemic episode. In some infants the counter-regulatory hormonal response to hypoglycaemia is blunted as demonstrated by inappropriately low serum cortisol and glucagon levels.
For patients that are unresponsive to medical management it is essential to differentiate focal from diffuse disease as the surgical approaches are radically different. The precise preoperative localisation and limited surgical removal of the focal lesion cures the patient. In contrast, patients with diffuse disease may require a near total pancreatectomy, which is associated with a high risk of diabetes mellitus and pancreatic exocrine insufficiency. For these patients insulin and/or enzyme replacement therapy may be required.
In 2016 the Pediatric Endocrine Society published their recommendations for the evaluation and management of persistent hypoglycemia in neonates, infants and children (2). A copy of this paper can be accessed here.
The recent introduction of 18F-L-3,4-dihydroxyphenylalanine positron emission tomography (18F-DOPA-PET scanning) for pancreatic imaging, has revolutionised the ability to localise the focal lesion pre-operatively (3). The principle of the 18FDOPA-PET scan is based on pancreatic islets being able to take up L-3,4-dihydroxyphenylalanine (L-DOPA), and convert it to dopamine by DOPA decarboxylase. The uptake of the positron emitting tracer 18F is increased in beta cells with a high rate of insulin synthesis and secretion compared with unaffected areas, which results in the visualisation of the focal lesion.
(1) Hussain et al An ABCC8 gene mutation and mosaic uniparental isodisomy resulting in atypical diffuse congenital hyperinsulinism. Diabetes. 2008 57(1):259-63. PubMed PMID: 17942822.
(2) Thornton et al Pediatric Endocrine Society. Recommendations from the Pediatric Endocrine Society for Evaluation and Management of Persistent Hypoglycemia in Neonates, Infants, and Children. J Pediatr. 2015 167(2):238-45 doi: 10.1016/j.jpeds.2015.03.057. Epub 2015 May 6. PubMed PMID: 25957977.
(3) Otonkoski et al Noninvasive diagnosis of focal hyperinsulinism of infancy with [18F]-DOPA positron emission tomography. Diabetes. 2006 55(1):13-8. PubMed PMID: 16380471.