Education Resource from the Society for Endocrinology

Hypoglycaemic paediatric disorders

Prof David Dungar

University of Cambridge

Summer School 11-14 July 2006
The Møller Centre, Storeys Way, Cambridge, UK

The age at presentation of hypoglycaemic disorders during childhood reflects developmental changes in glucose demand and tolerance of fasting. Glucose turnover in the newborn is 6mg/Kg/min compared with 2mg/Kg/min in adults and the vast majority of the glucose is used by the brain. Ketones provide an essential substrate for the brain in the absence of glucose. Hypoglycaemia in the newborn can arise because of a lack of glycogen stores, as in babies born after intrauterine growth retardation or because of metabolic disorders affecting glycogen synthesis, glycogen degradation and gluconeogenesis. In many of these congenital metabolic disorders there will be other biochemical changes such as lactic acidosis, changes in plasma amino acids or the urinary organic acid profile. Hyperinsulinism is a cause of neonatal hypoglycaemia associated with reduced plasma ketones, which can arise in offspring of mothers with diabetes, those with Beckwith syndrome, and in some infants born after intrauterine growth retardation. Persistent hyperinsulinaemic hypoglycaemia (PHHI) results from diffuse or focal islet cell hyperplasia which may be linked to mutations of the sulphonylurea receptor (SUR1) or the inwardly-rectifying potassium channel (Kir 6.2), subunits of the pancreatic beta cell ATP sensitive potassium channel. Mutations are more commonly identified in those presenting in the new born period than during infancy and as they do not respond to Diazoxide, an agonist to the beta cell KATP channel, they usually require surgery. Identification of subjects with focal disease can be achieved with 18F-DOPA PET scanning and in those cases less extensive surgery is required but this can only be performed in a few centres. Diazoxide responsive PHHI includes subjects with mutations in glutamate dehydrogenase 1 (GLUD1) who also exhibit mild hyperammonaemia. It is essential in PHHI cases that medical management using intravenous glucose, Nifedipine, Glucagon or Octreotide is instituted early and effectively to prevent brain damage, whilst a decision is made on definitive treatment.

Tolerance to fasting is relatively poor in the newborn but improves during childhood and it is dependent on appropriate counterregulation which leads to increased hepatic glucose production, mobilisation of free fatty acids and enhanced ketogenesis. Defects in the breakdown of fatty acids (medium-chain acyl-CoA dehydrogenase and long-chain acyl-CoA dehydrogenase deficiencies) will lead to an abnormal free fatty acid/ketone body ratio, a disordered acylcarnitine profile and abnormal urinary organic acids. Lack of adequate counterregulation can arise from pituitary disorders such a GH and ACTH deficiency, primary adrenal disorders such as congenital adrenal hyperplasia (CAH), Addison’s and ACTH unresponsiveness, or rarer defects such as glucagon deficiency. These conditions will present as ketotic hypoglycaemia, usually after prolonged fasting or during intercurrent illness. The diagnosis is usually quite straight forward if appropriate screening tests to check hormone levels, free fatty acids, plasma amino acids, urinary organic acids, and the acylcarnitine profile are carried at the time of the episode. Rarely, recurrent ketotic hypoglycaemia may be caused by defects in the ability to make or utilise ketone bodies such as HMG - Co A synthase and Lyase deficiencies. There remain a number of children presenting with recurrent ketotic hypoglycaemia where a clear diagnosis cannot be made and the majority of these can be managed by avoidance of prolonged fasting.

The commonest cause of hypoglycaemia during childhood is iatrogenic resulting from mismatch between insulin administration, caloric intake and glucose demand in subjects with type 1 diabetes. A particular problem is asymptomatic nocturnal hypoglycaemia resulting from inappropriately high insulin levels and reduced counterregulation. Risk of hypoglycaemia can be reduced using insulin analogues or continuous subcutaneous insulin infusion therapy (CSII) but hypoglycaemic unawareness remains a problem which can result in children presenting with neuroglycopenia rather than the classical symptoms associated with activation of the autonomic nervous system.

The opinions expressed in this paper are those of the speaker and do not necessarily reflect the views of the Society

Revised: 23-Aug-2006