The diagnostic criteria for HI include:
- Fasting and/or post-prandial hypoketotic hypoglycemia (< 2.5 - 3 mmol/l)
- Inappropriate plasma insulin levels (plasma insulin concentration detectable) and c-peptide concomitant to hypoglycemia. Indeed, insulin levels should be undetectable at the time of hypoglycemia. In HI patients, plasma insulin levels are not frequently high during hypoglycemia, and they remain within the normal range of the laboratory. However, normal ranges of insulin levels were set with normal blood glucose.
- An increase in blood glucose greater than 1.7 mmol/L (30 mg/dL) within 30 - 40 minutes after IM or IV administration of 1 mg glucagon. Indeed insulin promotes glycogen storage and inhibits its use. Conversely, glucagon stimulates glycogenolysis. When glucagon increases blood glucose, it proves the paradoxical hepatic glycogen content despite hypoglycemia, and it rules out the differential diagnosis of glycogen storage disease.
- Inappropriately low ketone bodies in plasma and urines and low free fatty acids in plasma even for fasting hypoglycemia (Insulin inhibits lipolysis) .
A major specific but inconstant diagnostic criterion is the glucose infusion rate required to maintain blood glucose above 3 mmol/L. A glucose infusion rate higher than 10 mg/kg.min in a neonate proves an insulin related hypoglycemia. This threshold decreases with age: 7 mg/kg.min in 5 years old children and 4 mg/kg.min in adults. Indeed, most hormones (cortisol, growth hormone, glucagon, epinephrine etc.) and metabolic pathways sustain blood glucose by stimulating hepatic glycogenolysis and gluconeogenesis leading to a physiological glucose output up to 10 mg/kg.min in neonates. Thus, if hypoglycemias are still occurring despite higher glucose infusion rate, the only possible mechanism is insulin. Protein-induced hypoglycemia can be observed in HI, especially in HI/HA syndrome (see HI/HA syndrome below).
Once the diagnosis of hyperinsulinemic hypoglycemias is set, further routine evaluations are necessary to precise the etiology. Indeed, patients may present an "isolated HI" secondary to a primary disorder of insulin secretion or a "syndromic HI" where HI is one symptom in the phenotype of a more generalized disease. Most patients have isolated HI with no other associated symptoms but a subtle facial dysmorphism . Some of these etiologies are screened with routine tests:
- Ammonemia: hyperammonemia may lead to the diagnosis of HI/HA syndrome,
- Urine organic acids (high 3-OH-glutarate) and plasma acylcarnitines (high C4-OH-carnitine), to identify a short-chain-hydroxyacyl-CoA dehydrogenase (SCHAD) deficiency.
- Clinical examination searching for dysmorphic features (hemihypertrophy, overgrowth, fat pads, congenital heart defects etc.) may require further biochemical, imaging or genetics tests to confirm the diagnosis of syndromic HI.
Syndromic HI includes (Table 1
In the following chapters, only the management and the genetics of isolated HI will be reviewed. The management of syndromic HI won't be specifically described, because they are diffuse, usually diazoxide-responsive and require extra care for their supplementary symptoms.