eMedicine Specialties > Pediatrics: General Medicine > Endocrinology

Hypoglycemia

Author: Robert P Hoffman, MD, Associate Professor of Pediatrics, Department of Pediatrics, Ohio State University College of Medicine
Contributor Information and Disclosures

Updated: Nov 4, 2009

Introduction

Background

Hypoglycemia may be considered a biochemical symptom, indicating the presence of an underlying cause. Because glucose is the fundamental energy currency of the cell, disorders that affect its availability or its use can cause hypoglycemia. Hypoglycemia is a common clinical problem in neonates, is less common in infants and toddlers and is rare in older children. It can be caused by various conditions. The most common cause of mild or severe hypoglycemia in childhood is insulin-treated type 1 diabetes and a mismatch among food, exercise, and insulin.

Clinical symptoms of hypoglycemia may be subtle or overt but are not specific to hypoglycemia and are frequently attributed to other disorders. This is particularly true if the patient has had another neurologic insult, such as head trauma or hypoxia.

Pathophysiology

The body normally defends against hypoglycemia by decreasing insulin secretion and increasing glucagon, epinephrine, growth hormone, and cortisol secretion. These hormonal changes combine to increase hepatic glucose output, to increase alternative fuel availability, and to decrease glucose use (see image below). The increase in hepatic glucose production is initially caused by the breakdown of liver glycogen stores due to lower insulin levels and increased glucagon levels. When glycogen stores become depleted and protein breakdown increases because of increased cortisol levels, hepatic gluconeogenesis replaces glycogenolysis as the primary source of glucose production. This breakdown of protein is reflected by increased plasma levels of the gluconeogenic amino acids, alanine, and glutamine.

Decreased peripheral glucose use again occurs initially because of a fall in insulin levels and later because of increases in epinephrine, cortisol, and growth hormone levels. All 3 events increase lipolysis and plasma free fatty acid levels, which are available as an alternative fuel and competitively inhibit glucose use. Increased plasma and urinary ketone levels indicate the use of fat as an energy source. Plasma free fatty acids also stimulate glucose production.

Hypoglycemia occurs when one or more of these counterregulatory mechanisms fail because of the overuse of glucose (as in hyperinsulinism), the underproduction of glucose (as in the glycogen-storage diseases), or both (as in growth hormone or cortisol deficiency).

Frequency

United States

Hypoglycemic events occur at rate of 24.7 events per 100 infant-days at risk.¹ Hypoglycemia is more common in those neonates born at less than 37 weeks' gestation and in those born at more than 40 weeks' gestation, with incidence rates of 2.4% in neonates born at 37 weeks' gestation, 0.7% in neonates born at 38-40 weeks' gestation, and rates of 1.6% and 1.8% in neonates born at 41 weeks' gestation and 42 weeks' gestation, respectively.² The incidence of hypoglycemia in children older than 6 months in a large urban emergency department was 0.034%.³

Mortality/Morbidity

Hypoglycemia has both acute and long-term consequences (see Clinical). Infants and children with asymptomatic hypoglycemia have been shown to have neurocognitive defects at the time of hypoglycemia, including impaired auditory and sensory-evoked responses and impaired test performance. Many etiologies of hypoglycemia may have the same consequences, complicating the causal distinction.

Long-term consequences of hypoglycemia include decreased head size, lowered intelligence quotient (IQ), and specific regional brain abnormalities revealed by MRI. As many as 50% of patients who survive hyperinsulinemic hypoglycemia of infancy have long-term neurologic complications; this rate has changed little over the last 20 years. This emphasizes the need for early recognition and treatment of these children.

Age

Hypoglycemia is most common in the immediate postneonatal period. The incidence of new cases decreases with increasing age, and true hypoglycemia is extremely rare in adolescents. The age is also helpful in assessing the probable diagnosis of hypoglycemia. Hyperinsulinemia, hypopituitarism, and inborn errors of metabolism are frequent causes of hypoglycemia in infancy. In toddlers, ketotic hypoglycemia is most common. In adolescents, insulin-producing pancreatic tumors are the most common cause of true hypoglycemia.

Clinical

History

Glucose is normally the primary source for brain energy. The brain can also use ketones, but this transition is gradual. Symptoms of hypoglycemia reflect 2 major clinical pathways. The first pathway is caused by activation of the autonomic nervous system, which causes symptoms such as sweating, trembling, flushing, anxiety, heart pounding, and hunger. The second group of symptoms is due to neuroglycopenia and includes inability to concentrate, confusion, tiredness, feeling tearful, difficulty speaking, behavioral changes, incoordination, weakness, and drowsiness. Nonspecific symptoms include mouth tingling, dry mouth, blurred vision, headache, and nausea. These symptoms, of course, vary according to the age of the patient, as follows:

• Neonates
  • Tremulousness
  • Brisk Moro reflex
  • Lethargy
  • Poor feeding
  • Irritability
  • Hypothermia
  • Respiratory distress
  • Apnea
  • Bradycardia
  • Seizure
  • Coma
  • Sudden death
• Older children
  • Dizziness
  • Sweating
  • Hunger
  • Anxiousness
  • Confusion
  • Lethargy
  • Poor feeding
  • Irritability
  • Seizure
  • Coma
  • Sudden death

Physical

• Hypoglycemic reactions are usually, but not always, accompanied by an increased heart rate with bounding pulse due to increased epinephrine secretion. Infants, if awake, may be irritable, tremulous, and cranky.
• If the brain energy supply is severely impaired, the patient's mental status is likely to be impaired with extreme inappropriate affect and mood, lethargy, seizure, or coma.
• Large body size for age in the neonate or older child suggests hyperinsulinism, although some children with hyperinsulinism are born prematurely and are small for gestational age. Decreased subcutaneous fat suggests inadequate glucose stores. Poor linear growth may point to growth hormone deficiency, and midline facial and cranial abnormalities suggest pituitary hormone deficiencies. Liver size should be assessed for evidence of glycogen-storage diseases.

Causes

Disorders of excessive glucose use include the following:

• Hyperinsulinemia
  • Possible causes of hyperinsulinism in children include maternal diabetes in pregnancy, persistent hyperinsulinemic hypoglycemia of infancy, insulin-producing tumors, and child abuse. Hyperinsulinism causes excess glucose use primarily by stimulating skeletal muscle to uptake glucose. This is aggravated by insulin-induced suppression of hepatic glycogenolysis and gluconeogenesis.
  • In infants, hyperinsulinemia may be due to various genetic defects that cause a loss of glucose regulation of insulin secretion. This disorder is known as endogenous-persistent hyperinsulinemic hypoglycemia of infancy (previously termed nesidioblastosis). The most common of these disorders is associated with an inactive or only partially active potassium channel. This channel is composed of 2 parts: the sulfonylurea receptor (SUR1) and the potassium pore (Kir6.2). The former is encoded by the ABCC8 gene and the latter by the KCNJ11 gene.
  • Other rarer genetic causes of hyperinsulinism in infants include the following:
    • Activating defects of the GCK gene for the enzyme glucokinase, which serves as the primary glucose sensor in the β cell are rare Most of these defects are autosomal recessive, but some are autosomal dominant. This defect causes an increased intracellular ATP/ADP ratio and closure of the potassium-ATP channel. 
    • Defects in GLUD1, which encodes the enzyme glutamate dehydrogenase, are usually associated with hyperammonemia and cause hyperinsulinism; however, the relationship is not entirely understood.
    • Recently, a genetic defect in the enzyme short-chain L-3-hydroxyacyl-CoA dehydrogenase was described in patients with hypoketotic hyperinsulinemic hypoglycemia, although this causal relationship is not clear either.
  • No genetic defect is identified in 50% of patients with hyperinsulinism although unusual single nucleotide polymorphisms defects have been found that may be responsible in some infants⁴ .
  • Infants of mothers with diabetes also have high insulin levels after birth due to the high glucose exposure in utero; the poorer the glucose control during pregnancy, the greater the likelihood of hyperinsulinism in the infant.
  • In older children, hyperinsulinemia is rare, but an insulin-producing tumor is the most common cause. Exogenous administration of insulin or oral hypoglycemic agents, either accidental or due to abuse, must be considered.

Glucose-processing defects (Krebs cycle defects, respiratory chain defects) are rare; they interfere with the ability to appropriately generate ATP from glucose oxidation. Lactate levels are high. Defects in alternative fuel production (eg, carnitine acyl transferase deficiency, hepatic hydroxymethyl glutaryl coenzyme A [HMG CoA] lyase deficiency, long-chain and medium-chain acyl-coenzyme A dehydrogenase deficiency, variably in short-chain acyl-coenzyme A dehydrogenase deficiency) interfere with the use of fat as an energy supply, meaning the body depends only on glucose. This becomes a problem during periods of prolonged fasting that frequently accompany GI illness. Sepsis or other hypermetabolic states, such as hyperthyroidism, may cause hypoglycemia.

Disorders of glucose underproduction include the following:

• Inadequate glucose stores are associated with prematurity, infants who are small for gestational age, malnutrition, and ketotic hypoglycemia. After insulin treatment in diabetes, these disorders are the most common causes of hypoglycemia. These disorders are largely diagnoses of exclusion made after other causes of hypoglycemia are ruled out. Prematurity, infants who are small for gestational age, and malnutrition should be readily apparent based on the clinical situation. Ketotic hypoglycemia, which usually affects children who are thin and small and aged 18 months to 6 years, is usually due to disrupted food intake.
• Glycogen synthase deficiency (glycogen-storage disease type 0) is associated with fasting hypoglycemia because of the liver’s inability to store glucose in the immediate postprandial state. Thus, the glucose load from the meal is anaerobically used rather than stored for later use. In this disorder, plasma glucose and lactate levels are high in the immediate postprandial state.
• Disorders of hepatic glucose production include glucose-6-phosphatase deficiency (glycogen-storage disease type I), debrancher deficiency (glycogen-storage disease type III), and hepatic phosphorylase deficiency (glycogen-storage disease type VI, glycogen synthase deficiency, fructose 1,6 diphosphatase deficiency, phosphoenol pyruvate deficiency, pyruvate carboxylase deficiency, galactosemia, hereditary fructose intolerance, maple syrup urine disease). These disorders interfere in glucose production through various defects, including blockage of glucose release or synthesis or blockage or inhibition of gluconeogenesis. Children with these diseases may adapt to their hypoglycemia because of its chronicity.
• Hormonal abnormalities include panhypopituitarism, growth hormone deficiency, and cortisol deficiency (primary or secondary). As described above, growth hormone and cortisol play important roles in generating alternative fuels and stimulating glucose production. Because they are easily treatable abnormalities, early recognition is important.

Toxins and other illnesses (ethanol, salicylates, propranolol, malaria) also cause hypoglycemia. Ethanol inhibits gluconeogenesis in the liver and can thus cause hypoglycemia. This is particularly true in patients with insulin-treated diabetes who are unable to reduce insulin secretion in response to developing hypoglycemia. Salicylate intoxication causes both hyperglycemia and hypoglycemia. The latter is due to augmentation of insulin secretion and inhibition of gluconeogenesis.

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