DESCRIPTION

Hypoglycemia can be defined as a plasma glucose concentration low enough to impair brain function. Evaluation should be undertaken in infants and young children with documented plasma glucose <60 mg/dL and in older children who demonstrate Whipple triad (see below).

EPIDEMIOLOGY

• Healthy newborns undergo a period of transitional hypoglycemia at birth. During the first hours of life, 19% of neonates have plasma glucose concentrations <45 mg/dL.
• By 72 hours of life, plasma glucose concentrations in neonates are like those in older infants, children, and adults.
• Up to 50% of high-risk neonates (small for gestational age [SGA], intrauterine growth restricted, infants of diabetic mothers) have persistent hypoglycemia due to transient hyperinsulinism (HI).
  • Annual incidence of congenital HI estimated at ~1:28,000 to 50,000 live births
  • May be as high as 1:2,500 in select populations (Saudi Arabians, Ashkenazi Jews)
• Congenital hypoglycemia disorders are less frequent. Of these, congenital HI is the most common.

ETIOLOGY

• HI
  • Due to dysregulated insulin secretion
  • Congenital HI is caused by genetic defects in β-cell insulin secretion pathways (>10 identified genes). Most common types are the following:
    • K_ATP-HI: Inactivating mutations in K_ATP channel genes ABCC8 and KCNJ11 (on 11p15) cause the most common and severe forms of HI. Two distinct histologic types:
      • Diffuse HI: mutations inherited in an autosomal recessive or less commonly, autosomal dominant manner; cause abnormal insulin secretion in all β cells throughout the pancreas (40% of cases)
      • Focal HI: A paternally inherited recessive mutation of ABCC8 or KCNJ11 combined with loss of maternal alleles on the imprinted chromosome region 11p15 leads to paternal uniparental disomy; results in a focal adenomatous lesion (60% of cases).
    • Glucokinase (GCK) HI: autosomal dominant–activating GCK mutations, cause a lower glucose threshold for insulin secretion and persistent hypoglycemia
    • Glutamate dehydrogenase (GDH) HI: autosomal dominant–activating mutations of GDH, encoded by GLUD1; known as HI/hyperammonemia (HI/HA) syndrome; characterized by fasting and protein-induced hypoglycemia with elevated ammonia levels
  • HI can also occur in association with perinatal stress (SGA, maternal hypertension, birth asphyxia or congenital heart disease); resolves by 3 to 6 months of life.
  • HI is also associated with certain syndromes (Beckwith-Wiedemann syndrome [BWS], Turner, Kabuki).
• Insulinoma
  • Insulin-producing islet cell tumors; 5–10% malignant
  • Rare in pediatric populations
  • Associated with multiple endocrine neoplasia (MEN) type 1 (inherited disorder due to mutations in the MEN1 gene associated with tumors of the pituitary, parathyroid glands, and pancreas)
• Glycogen storage diseases (GSDs)
  • Heterogeneous disorders due to defects in glycogen synthesis or degradation
  • Various degrees of ketotic hypoglycemia, hepatomegaly
  • Glycogen synthase deficiency (type 0): characterized by postprandial hyperglycemia and fasting ketotic hypoglycemia
  • Glucose-6-phosphatase deficiency (type I): impaired gluconeogenesis and glycogenolysis. Fasting results in severe lactic acidosis, hypoglycemia, hypertriglyceridemia, and hyperuricemia. Type Ib is also associated with neutropenia. Complications include nephropathy and hepatic adenomas.
  • Debrancher enzyme deficiency (type III): significant hepatomegaly, fasting ketotic hypoglycemia, hyperlipidemia, elevated transaminases, myopathy, and cardiomyopathy
  • Liver phosphorylase (type VI) and phosphorylase kinase (type IX): hepatomegaly, fasting ketotic hypoglycemia, growth retardation, elevated transaminases; milder than GSD I and III
• Hormone deficiencies
  • Ketotic hypoglycemia from counterregulatory hormone deficiency
    • Adrenal insufficiency:
      • In infants due to hypopituitarism
      • In older children Addison (autoimmune adrenalitis associated with 21-hydroxylase antibodies) most common
    • Growth hormone deficiency (GHD): Hypoglycemia occurs primarily in infants.
    • Neonatal panhypopituitarism: mimics HI in neonates with low ketones and positive response to glucagon
• Fatty acid oxidation disorders (FAODs)
  • Due to defects in fatty acid transport and β-oxidation
  • Variable presentation and severity
  • Prolonged fasting provokes hypoketotic hypoglycemia, seizures, cardiac and liver dysfunction.
• Idiopathic ketotic hypoglycemia
  • Children, typically 1 to 4 years old, with fasting hypoglycemia but no identifiable metabolic or endocrine abnormality
  • Commonly presents in the setting of illness and decreased oral intake
  • Resolves by school age
• Other
  • Insulin-induced hypoglycemia in persons on insulin for diabetes
  • Munchausen and Munchausen by proxy
    • Hypoglycemia from surreptitious insulin or oral hypoglycemic agent administration
    • Consider with abrupt onset of severe, unpredictable hypoglycemia.
  • Liver failure
  • Infections
    • Sepsis
    • Malaria
  • Postprandial hypoglycemia
    • Occurs in infants following fundoplication surgery or other gastrointestinal surgeries and results in hypoglycemia 1 to 2 hours after bolus feed or meal
    • Due to excessive incretin response to a meal that triggers exaggerated insulin secretion

PATHOPHYSIOLOGY

• In response to fasting, insulin secretion is suppressed, and counterregulatory hormones (glucagon, cortisol, growth hormone, epinephrine) increase.
• These hormonal changes result in hepatic release of glucose through glycogenolysis and gluconeogenesis. Additionally, activation of lipolysis and ketogenesis leads to increases in free fatty acids (FFAs) and ketone bodies. The brain uses ketones as an alternative source of energy as glucose stores are depleted.
• Disruption of these fasting systems results in hypoglycemia.
• Postprandial hypoglycemia is rare yet can be seen in up to 30% of children who undergo fundoplication.
• Autonomic symptoms (sweating, tremors, hunger) appear when plasma glucose falls <55 mg/dL.
• Brain dysfunction (confusion, seizures, coma) can result when plasma glucose is <50 mg/dL.