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Maintenance of plasma glucose depends on a normal endocrine system, functional enzyme levels for glycogenolysis, gluconeogenesis and other processes, and there must be an adequate supply of endogenous fat, glycogen and substrates of gluconeogenesis. Neonatal hypoglycemia should be defined as serum glucose less than 2.2 mmol/L in the first 72 h of life and less than 2.5 mmol/L thereafter. The purpose of this paper is to review the more uncommon causes of hypoglycemia in the full term, apparently healthy neonate. Most of these conditions are inborn errors of metabolism. A protocol for investigation of these conditions and some of the more common diseases, such as hyperinsulinism, is provided, with a rationale explaining why these tests may be helpful.
La prise en charge du glucose dans le plasma dépend d’un système endocrinien normal, de taux enzymatiques fonctionnels pour la glycogénolyse, la néoglucogenèse et d’autres processus, et d’une quantité suffisante de lipides endogènes, de glycogènes et de substrats de la néoglucogenèse. L’hypoglycémie néonatale se définit par une glycémie inférieur à 2,2 mmol/L au cours des premières 72 h de vie et à 2,5 mmol/L par la suite. Le présent article vise à étudier les causes plus rares d’hypoglycémie chez le nouveau-né à terme et apparemment en santé. La plupart de ces pathologies sont causées par des erreurs innées du métabolisme. On fournit un protocole d’investigation de ces pathologies et de quelques-unes des maladies plus courantes, comme l’hyperinsulinisme, et on explique l’utilité de ces tests.
Before birth, the fetus receives glucose through the maternoplacental circulation at a daily amount of 7 g/kg (1). When the umbilical cord is clamped, the neonate must meet several metabolic challenges, two of which are the maintenance of adequate circulating levels of glucose or alternate fuels to the brain and other organs, and adaptation to intermittent milk feedings. If these processes fail to occur, neonatal hypoglycemia develops (2). The physiological serum glucose values in healthy newborns range between 3.3 and 5 mmol/L. Neonatal hypoglycemia should be defined as serum glucose less than 2.2 mmol/L in the first 72 h of life and less than 2.5 mmol/L thereafter. Lower values for defining hypoglycemia that were suggested in the past represent ‘statistical normals’ based on older studies of infants subjected to what now would be considered prolonged periods of fasting (3).
Maintenance of physiological plasma glucose concentration depends on a normal endocrine system that integrates and modulates substrate mobilization, interconversion and utilization. Enzymes of glycogenolysis, gluconeogenesis and other metabolic fuels must be functional, and there must be an adequate supply of endogenous fat, glycogen and gluconeogenic substrates (amino acids, glycerol, lactate) (4). Preterm, small for gestational age and intrauterine growth-retarded infants, and infants with hyperinsulinism (infants of diabetic mothers, Beckwith-Wiedemann syndrome), asphyxia, sepsis or other medical conditions, such as cardiopulmonary disease, are at risk of developing hypoglycemia (2,5,6). Management of neonates with hypoglycemia related to these conditions is not the focus of this paper; there are several articles available that discuss these topics (2,5,6). However, when a full term, apparently healthy neonate without the predisposing signs and symptoms of the above conditions develops hypoglycemia, the etiology may not be immediately obvious. The more uncommon causes of hypoglycemia, such as inborn errors of metabolism, should be considered. This paper briefly reviews some of the inborn errors of metabolism that present with neonatal hypoglycemia. The clinical diagnosis of inborn errors of metabolism presenting as hypoglycemia is often difficult because blood and urine samples may not be helpful unless collected at the time of the acute symptoms. This difficulty in diagnosis occurs because the disorder may produce only intermittent abnormalities (7). Table 1 lists many, but not all, of the causes of neonatal hypoglycemia.
The signs of neonatal hypoglycemia are nonspecific but reflect the involvement of two systems primarily, adrenergic stimulation of the sympathetic nervous system (tachycardia, diaphoresis, pallor, tremulousness) and impaired central nervous system function (lethargy, seizures, apnea, coma). Some infants may be asymptomatic while hypoglycemic (3). Glucose test strips are useful for screening neonates suspected of being hypoglycemic. All abnormal or suspicious test strips should be confirmed with a serum glucose sample.
Glycogen is the storage form of glucose in virtually all animal cells, especially liver and muscle. When plasma glucose is low, the liver releases glucose from glycogen (glycogenolysis) for use by other tissues that cannot make significant amounts, such as the brain (7). Glycogen storage diseases (GSD) are a group of inherited conditions that affect glycogen metabolism in muscle, the liver or both, so that glycogen is abnormal in quantity or quality. The hepatic GSD present with hypoglycemia and hepatomegaly (7). Galactose-1-phosphate-uridyl-transferase deficiency, the cause of classical galactosemia, presents with vomiting and diarrhea within a few days of the introduction of milk; hypoglycemia may be associated (7). Fructose, a six-carbon reducing sugar, is used in the liver, kidney and small intestine because it can be converted into intermediates for the glycolytic-gluconeogenic pathway. Of course, symptoms only occur after fructose is introduced into the diet; it is present in some infant formulas. Fructose 1,6-bisphosphatase is a key enzyme for gluconeogenesis because it allows the endogenous formation of glucose from lactate, glycerol and amino acids such as alanine (7,8). In the first week of life, the neonate is very dependent on gluconeogenesis for glucose production (4).
The mitochondria play a major role in energy production because this is the organelle where fatty acids are degraded by the sequential removal of two-carbon fragments (known as acetyl-CoA) from the carboxylterminal end of the molecule. This process is known as beta oxidation. The liver uses 90% of its acetyl-CoA to form ketone bodies that can be used as auxiliary fuel for many tissues, including the brain. Fatty acids are also metabolized in peroxisomes and in the cytoplasm by omega oxidation (9).
Medium chain acyl-CoA dehydrogenase (MCAD) deficiency, an autosomal recessive condition, is the most common defect of fatty acid oxidation with an incidence of 1/20,000 (1/16,400-1/46,000) (10). It may present as early as day four of life, usually following a prodromal illness with episodic hypoketotic hypoglycemia, apnea, Reye-like encephalopathy or sudden infant death syndrome (11). Metabolic acidosis, hyperammonemia, elevated liver function tests, elevated acylcarnitine:free carnitine ratio and secondary carnitine deficiency are associated laboratory findings. The acylcarnitine profile is unique because cis-4-decenoate is seen in the plasma of patients when ill or well (10). The gene is located on chromosome 1p31, and the most common mutation is A985G (12). The combination of DNA analysis and acylcarnitine profile can reliably detect all patients with MCAD deficiency (12).
Carnitine palmitoyltransferase deficiency types I and II (CPT I and CPT II) may present in the neonatal period with hypoketotic hypoglycemia. The plasma carnitine is normal to increased and the plasma acylcarnitine is normal in CPT I. The plasma carnitine is decreased and the plasma acylcarnitine is increased in CPT II (13).
Long chain 3-OH acyl-CoA dehydrogenase (LCHAD) deficiency may present as early as the first day of life with hypoketotic hypoglycemia, liver dysfunction, hypotonia and variable hypertrophic cardiomyopathy. Metabolic acidosis and urine dicarboxylic aciduria may be associated. When the fetus has LCHAD deficiency, the heterozygous mother may have had HELLP (hemolysis, elevated liver enzymes and low platelets), hyperemesis gravidarum or fatty liver of pregnancy (13).
Hyperinsulinism, regardless of the cause, increases glucose utilization and glycogen formation. It reduces the gluconeogenic precursors, including amino acids, free fatty acids and ketone bodies. The diagnosis is confirmed when the insulin to glucose ratio is greater than 38.7 pmol/L:mmol/L (7,14,15). Glucagon produces an elevated glycemic response because of the large glycogen stores (7). The anterior pituitary hormones are important in energy production. Growth hormone (GH) acts to stabilize glucose and stimulate the release of free fatty acids from adipose tissue during episodes of hypoglycemia, stress or fasting. Adrenocorticotropin hormone (ACTH) also stimulates the release of free fatty acids and releases cortisol, which stimulates gluconeogenesis. GH levels less than 8 μg/L and cortisol levels less than 500 nmol/L suggest abnormal hypothalamic-pituitary function. Male neonates with a microphallus and neonates with abnormalities of the palate or ADH secretion may have hypopituitarism (15).
The following protocol is for investigation of persistent hypoglycemia in a neonate when the cause is unclear or the hypoglycemia is unexpectedly severe. The investigations will aid in the diagnosis of the conditions reviewed in this paper and listed in Table 1.
Treatment of the hypoglycemic infant may begin while investigations continue. If the neonate is asymptomatic and the hypoglycemia is mild (serum glucose 1.7 to 2.2 mmol/L), oral feeding of glucose, 0.5 to 1.0 g/kg, may be appropriate. If the neonate is symptomatic or the serum glucose is less than 1.7 mmol/L, an intravenous bolus of 10% dextrose in water (2 mL/kg) given over 5 mins may be indicated. This should be followed by an infusion of 10% dextrose in water at 5 to 10 mg/kg/min, or 90 mL/kg/24 h to maintain serum glucose over 3.3 mmol/L (3).
The highest glucose concentration that can be administered through a peripheral vein is 12.5% dextrose in water. Central venous access is required for more concentrated solutions. When venous access is difficult or when glucagon is indicated, 0.3 mg/kg/dose to a total dose of 1.0 mg/kg/day may be used (16). Steroid therapy is somewhat controversial in the treatment of persistent neonatal hypoglycemia of unknown etiology. Steriods are not effective in hyperinsulinism or other disorders not due to adrenal insufficiency. Diazoxide may be used in cases of hyperinsulinism (3).