Background: Primary hyperinsulinism is a rare but important cause of hypoglycemia in infants and children. It is the most common cause of neonatal hypoglycemia following the first few hours of life.

The clinical presentation varies with the age of the child. Early diagnosis and treatment are essential to prevent seizures and neurologic sequelae. Persistent hypoglycemia and inappropriately high concentrations of insulin are diagnostic findings. The concentrations of free fatty acids and ketones (ie, beta-hydroxybutyrate, acetoacetate) are low. Several genetic causes of persistent hyperinsulinism recently have been identified.

Pathophysiology: The differential diagnosis of hypoglycemia is extensive, and determining the underlying cause often is difficult. An understanding of glucose homeostasis can help narrow the differential diagnosis. In the fasting state, glucose is provided through glycogenolysis in the liver. After a few hours of fasting, insulin levels fall, and increased lipolysis creates free fatty acids and glycerol. Fatty acids do not cross the blood brain barrier and, therefore, are not used by the brain. However, fatty acids are used by the heart and muscle. Increased free fatty acids result in production of ketones, and the brain is able to metabolize ketones as an alternative source of fuel.

Disorders that result from defective glycogenolysis in the liver lead to hypoglycemia within a few hours of fasting. This hypoglycemia occurs in the setting of low insulin levels.

Disorders of fat metabolism result in the unavailability of free fatty acids and ketones as alternative fuels. Hypoglycemia occurs after several hours of fasting. Circulating insulin levels also are low.

Growth hormone deficiency and hypocortisolemia also can cause hypoglycemia associated with low insulin levels, possibly by unopposed insulin action and decreased ketogenesis.

Hypoglycemia associated with elevated insulin levels makes defects in glucose, free fatty acid, ketone metabolism, growth hormone, and cortisol deficiency unlikely. Conversely, hypoglycemia associated with ketonuria makes hyperinsulinism less likely. Ketonuria does not rule out hyperinsulinemia.

Glucose and several amino acids stimulate insulin secretion under physiologic conditions, and the sequence of events leading to insulin secretion is well delineated. The rate of insulin secretion is dependent on the ATP/ADP ratio in the beta cell. The rate of glucose entry into the beta cell is facilitated by a glucose transporter and exceeds its rate of oxidation.

The first step in glycolysis (ie, conversion of glucose to glucose-6-phosphate by glucokinase) is the rate-limiting step in glucose metabolism; thus, it regulates the rate of glucose oxidation and subsequent insulin secretion. An increase in the intracellular ATP/ADP ratio activates ATP-sensitive potassium dependent channels (KATPs) in the cell membrane. KATP consists of 2 subunits, the sulfonylurea receptor (SUR-1) and the potassium inward rectifier (Kir6.2). Activation leads to closure of the potassium channel and depolarization of the cell membrane. Opening of a voltage-gated calcium channel allows influx of calcium and results in insulin secretion.

Transient hyperinsulinism usually results from environmental factors such as maternal diabetes and birth asphyxia. However, children with persistent hyperinsulinism may have a genetic defect that results in inappropriate secretion of insulin.

Frequency:

• In the US: Hyperinsulinemia is estimated to occur in 1 out of every 50,000 live births.

• Internationally: Autosomal recessive forms of hyperinsulinemic hypoglycemia are more common in inbred populations of Saudi Arabia and among Ashkenazi Jews.

Mortality/Morbidity: Glucose is the primary substrate used by the CNS. Free fatty acids do not cross the blood-brain barrier; however, the brain can metabolize ketones. Unrecognized or poorly controlled hypoglycemia may lead to persistent severe neurological damage. Patients with hyperinsulinism are at high risk of developing seizures, mental retardation, and permanent brain damage.

Age: Transient hyperinsulinism is relatively common in neonates. An infant of a diabetic mother, an infant who is small or large for gestational age, or any infant who has experienced severe stress may have high insulin concentrations. In contrast, congenital hyperinsulinism is rare.

History:

• Pregnancy and birth history may reveal risk factors that could predispose an infant to hyperinsulinism. Maternal diabetes, poor fetal growth, and birth asphyxia all can lead to excessive insulin release.

• Signs and symptoms associated with hyperinsulinemic hypoglycemia result from 2 physiologic processes. Hypoglycemia triggers autonomic nervous system activation and epinephrine release. Central nervous system glucopenia also leads to neurologic manifestations.

• Infants may present with cyanosis, respiratory distress, apnea, lethargy, sweating, hypothermia, jitteriness, irritability, poor feeding, seizures, tachycardia, and vomiting.

• Older children may present with sweating, shakiness, anxiety, hunger and increased appetite, staring or strabismus, lethargy, nausea and vomiting, headache, behavior and mental status changes, inattention, loss of consciousness, tachycardia, hypothermia, and seizures.

Physical:

• Macrosomia reflects the anabolic effects of prolonged hyperinsulinemia in utero in infants who are large for their gestational age and in infants of diabetic mothers.

• Microsomia can occur in infants who are small for their gestational age (particularly those who have experienced maternal toxemia). Infants with microsomia may require high rates of glucose infusion initially to maintain euglycemia.

• Some neonates have physical signs consistent with Beckwith-Wiedemann syndrome. Signs may include fetal overgrowth, omphalocele, macroglossia, visceromegaly, and creases of the ear lobe.

Causes:

• Classification of hyperinsulinism of infancy is based on the following:

• Transient
  • Infant of the diabetic mother
  • Small for gestational age infant
  • Perinatal stress/asphyxia
  • Erythroblastosis fetalis
  • Sepsis
  • Beckwith-Wiedemann syndrome
  • Drug-induced hyperinsulinism
    1. Surreptitious insulin administration
    2. Oral hypoglycemic ingestion
    3. Blood transfusion
  • Umbilical artery catheter placement

• Persistent
  • Adenoma
  • Focal islet cell hyperplasia
  • Generalized beta-cell hyperplasia

• Classification of hyperinsulinism of childhood is based on the following:
  • Adenoma
  • Islet cell hyperplasia

• Transient causes
  • Infants of diabetic mothers: During gestation, glucose is transferred freely across the placenta. Prolonged hyperglycemia in poorly controlled maternal diabetes results in fetal hyperglycemia. Fetal hyperglycemia induces fetal pancreatic beta-cell hyperplasia with resultant hyperinsulinemia and macrosomia. Withdrawal of transplacental supply of glucose after birth leads to a precipitous drop in the concentration of glucose. When neonates present with signs and symptoms of hypoglycemia, many require infusion of large quantities of glucose to maintain normal blood glucose levels. Hyperinsulinism typically resolves within 1-2 days following birth. For a full discussion, see chapter Infant of Diabetic Mother.

• Prolonged hyperinsulinism in infants who are small for gestational age (SGA) and asphyxiated newborns: Infants who are SGA, experience maternal toxemia, or have birth asphyxia are at increased risk for developing hypoglycemia. These infants have high rates of glucose metabolism and may require dextrose infusions as high as 20 mg/kg/min to maintain euglycemia. Some evidence suggests that this may be due to hyperinsulinemia, although the exact mechanisms are still unclear. These patients may have prolonged hypoglycemia for as long as 2-4 weeks following birth. Afterwards, the hypoglycemia appears to resolve completely.

• Erythroblastosis fetalis: Neonates with severe Rh isoimmunization have islet cell hyperplasia and hyperinsulinism. The cause of hyperinsulinism is unknown. Researchers hypothesize that elevated levels of glutathione from massive hemolysis may serve as a stimulus for insulin release.
• Drug-induced hyperinsulinism
  • Surreptitious insulin administration: This phenomenon is rare but may occur in the setting of Munchausen syndrome by proxy. The timing of hypoglycemia is unpredictable and occurs when the offender has access to the patient. Laboratory evaluation reveals elevated insulin levels and a low serum C-peptide level.
  • Ingestion of oral hypoglycemic agents: Toddlers may accidentally ingest drugs prescribed for adult diabetics (eg, sulfonylureas). Depending on the half-life of the preparation ingested, the duration of hypoglycemia varies. Glucose infusion (to maintain normoglycemia) is the treatment of choice. On rare occasions, diazoxide may be needed to suppress insulin secretion.
  • Blood transfusion: Certain preparations of blood products (eg, citrated blood) have large amounts of dextrose. During transfusion, the high glucose load triggers insulin secretion. Problems arise when the transfusion is completed. Elevated insulin levels could lead to a precipitous drop in blood glucose levels. This fall typically occurs about 2 hours posttransfusion.

• Umbilical artery catheter placement: Malposition of the umbilical artery catheter in neonates may be associated with hypoglycemia and hyperinsulinemia. Repositioning of the catheter usually resolves the hypoglycemia and hyperinsulinemia. Theoretically, this problem may be caused by a high glucose load administered to the celiac axis. Localized hyperglycemia would induce insulin secretion and result in hypoglycemia in the systemic circulation.

• Congenital causes

• Beckwith-Wiedemann syndrome includes signs of omphalocele, macroglossia, and visceromegaly.
• These infants have generalized islet cell hyperplasia.
• Hyperinsulinemic hypoglycemia may be difficult to control. These patients require large quantities of glucose. Treatment with diazoxide often is needed to control hyperinsulinemia. Hyperinsulinism usually resolves spontaneously when the infant is aged several weeks or months.

• Focal causes
  • Islet adenomatosis and beta-cell adenoma: Few cases have been reported of patients with congenital hyperinsulinism who demonstrate histologic finding of islet adenomatosis or beta-cell adenoma. Patients older than 1-2 years who present with hyperinsulinemic hypoglycemia are more likely to have a focal cause of hyperinsulinism. A recent study employing preoperative pancreatic catheterization and intraoperative histologic studies suggests that as many as half of all neonates presenting with congenital hyperinsulinism have focal islet-cell hyperplasia. Focal causes of hyperinsulinism can be treated with partial pancreatectomy.
  • Patients with genetic defects of beta-cell regulation have a condition known as persistent hyperinsulinemic hypoglycemia of infancy (PHHI). Other terms used but have fallen out of favor include leucine sensitive hypoglycemia, islet cell dysmaturation syndrome, and nesidioblastosis.

   

• At least 6 genetic forms of congenital hyperinsulinism exist.

• Autosomal recessive
  • Recessive mutations on chromosome 11 lead to alterations in the potassium channel on the plasma membrane of pancreatic beta cells. Two adjacent genes encode SUR and Kir6.2. Mutations in these genes create a nonfunctional potassium channel with membrane depolarization and unchecked insulin secretion. Mutations of the SUR gene are more common than mutations of the Kir6.2 gene. SUR mutations have been found more frequently in less heterogenous populations in Saudi Arabia and in Ashkenazi Jews.
  • These patients present with high birth weights from the anabolic effects of insulin in utero. These disorders cannot be controlled with diazoxide, which acts to block the SUR gene to suppress insulin secretion. Near-total pancreatectomy often is required.

• Autosomal dominant: Mutations of the glucokinase gene and the glutamate dehydrogenase gene transmitted in an autosomal dominant inheritance can lead to hyperinsulinemia. The molecular defects in other autosomal dominant inherited forms of hyperinsulinism are yet to be elucidated. These infants tend to have less severe hypoglycemia and respond more favorably to diazoxide.

• Mutation of the glucokinase gene: A mutation of the glucokinase gene has been associated with hyperinsulinism. This mutation increases the affinity of glucokinase for glucose. Accelerated rates of glycolysis result in increased ATP/ADP ratio and insulin secretion. These patients have a milder form of hyperinsulinism compared to those with potassium channel defects. These patients also respond well to diazoxide treatment. In some patients, treatment can be discontinued after several years.

• Hyperinsulinism and hyperammonemia: Several infants have been reported to have hyperinsulinism and hyperammonemia. They presented with hypoglycemic seizures at a few months of age.

• Mutation of the glutamate dehydrogenase gene: Molecular studies have revealed a mutation of the glutamate dehydrogenase (GDH) gene. Two metabolic pathways use GDH. Leucine GDH-mediated oxidation in beta cells leads to ATP production and insulin release. GDH also prevents formation of glutamate in liver cells, which could prevent the conversion of ammonium to urea. Excessive activity of GDH increases the rate of insulin release and impairs the detoxification of ammonia. Patients with a GDH gene mutation present with low blood glucose levels and persistent mild elevations of serum ammonia to 100-200 mol/L.

Other Problems to be Considered:

Patients with hyperinsulinism usually have elevated levels of insulin for their glucose concentration (ie, even if they do not have hypoglycemia, their insulin level is inappropriately high for their glucose levels). In contrast, patients with the following disorders have an appropriate concentration of insulin for the simultaneous glucose concentration:

• Adrenal insufficiency
   
• Disorders of branched-chain amino acids
   
• Enzymatic block in the Cori and alanine cycles
   
• Fatty acid release/oxidation disorders
   
• Ketone utilization disorders
   
• Fructosemia
   
• Galactosemia
   
• Glycerokinase deficiency
   
• Glycogen storage disease type Ia and type Ib (von Gierke disease, glucose-6-phosphatase deficiency)
   
• Glycogen storage disease type III (Cori disease; amylo-1, 6-glucosidase deficiency)
   
• Glycogen storage disease type VI (Hers disease, phosphorylase deficiency)
   
• Growth hormone deficiency