Etiology and Pathogenesis

In children, as in adults, blood glucose levels are maintained within a narrow range in the postabsorptive and fed state. Thus, normal fasting blood glucose levels should be above 70 mg/dL. A lower level of 50 mg/dL is recommended for diagnostic purposes only. The classic diagnostic triad of hypoglycemia, also known as “Whipple’s triad,” consists of a blood glucose level less than 50 mg/dL, symptoms of hypoglycemia, and resolution of symptoms with normalization of the blood glucose level.

To recognize the different causes of hypoglycemia, it is helpful to understand the fundamentals of energy homeostasis (Figure 72-1). In the fed state, as glucose levels increase, so do insulin levels. Insulin stimulates glucose uptake into cells for use as a source of energy and metabolic intermediate or for storage (see Chapter 4, Figure 4-1). Insulin has other effects that influence energy metabolism; in the liver, insulin inhibits glycogenolysis, gluconeogenesis, and ketogenesis. In the fasted state, insulin secretion is suppressed, allowing glycogenolysis and gluconeogenesis to commence, followed by fatty-acid oxidation, which leads to ketogenesis. In the absence of glucose, the brain uses ketones (e.g., β-hydroxybutyrate and acetoacetate) as energy sources. Insulin secretion from pancreatic β-islet cells is suppressed in the fasted state, and there is increased secretion of counterregulatory hormones that maintain blood glucose levels by stimulating glycogenolysis and gluconeogenesis, such as glucagon, cortisol, growth hormone, and epinephrine. Disorders that impair insulin regulation and counterregulatory hormone secretion, as well as storage or production of glucose, can result in hypoglycemia.

Figure 72-1 Intermediary metabolism in the liver cell.

Clinical Presentation

The symptoms of hypoglycemia can result from two different mechanisms. An adrenergic response (e.g., fight or flight) typically is triggered in response to a rapid decrease in blood glucose, as occurs with postprandial hypoglycemia (PPH). By contrast, the slower decline in blood glucose that occurs with fasting hypoglycemia may not trigger an obvious adrenergic response but can manifest as loss of consciousness caused by neuroglycopenia (Figure 72-2). In general, hypoglycemia in infants and children is fasting hypoglycemia. Hypoglycemia in neonates can present with irritability, shakiness, difficulty feeding, hypothermia, pallor, hypotonia, and seizures. In children, symptoms include sweatiness, unsteadiness, headache, hunger, nausea, weakness, tachycardia, change in mentation, and seizures. If symptoms suggestive of hypoglycemia are present, it is imperative, if possible, to send a blood specimen for a glucose level to the laboratory to confirm that hypoglycemia is at the root of the symptoms.

Figure 72-2 Symptoms of hypoglycemia.

Differential Diagnosis

The differential diagnosis of hypoglycemia is expansive and includes not only disorders of carbohydrate metabolism but also disorders of fat oxidation, hormone deficiencies, and medication-induced hypoglycemia (Box 72-1). It is perhaps most useful to separate these disorders into those associated with hyperinsulinism and those associated with appropriately suppressed levels of insulin. Not included in this classification is transient neonatal hypoglycemia, typically seen within the first 6 hours of life, caused by immaturity of fasting mechanisms and poor glucose stores in premature infants and breastfed infants. In these cases, the hypoglycemia improves with feedings and typically resolves within the first day of life.

Evaluation and Management

Glucose can be measured in whole blood or serum (i.e., plasma). In the past, blood glucose values were given in terms of whole blood, but most laboratories now measure and report serum glucose levels. By contrast, point-of-use glucometers typically measure and report whole blood glucose concentrations. Serum has a higher water content than blood cells and consequently contains more dissolved glucose than does whole blood. A calculated serum glucose level can be estimated from the whole-blood glucose by multiplying the blood glucose level by 1.15.

Additional caveats are worth noting. Blood samples that are not processed promptly can have erroneously low glucose levels owing to glycolysis by red and white blood cells (i.e., at room temperature, the decline of whole blood glucose can be 5-7 mg/dL/hr). In addition, hospital bedside glucose monitors and similar home glucose monitors are less precise than clinical laboratory methods and can be expected to have an error range of 10% to 15%. For practical reasons, the authors use the same threshold of 70 mg/dL if using plasma glucose or whole blood, but for diagnostic purposes, all measurements below 60 mg/dL should be verified with a plasma level in the clinical laboratory.

In severely symptomatic or clinically unstable patients with hypoglycemia, the first step should be administration of a 2 mL/kg bolus of 10% dextrose in water IV followed by a continuous infusion of 10% dextrose in an age-appropriate saline concentration at a glucose infusion rate of 6 to 8 mg/kg/min (Box 72-2). Whenever hypoglycemia is suspected in a clinically stable patient, the first step should be to send a “critical” blood sample to the laboratory to confirm hypoglycemia and to obtain the diagnostic tests necessary to establish the underlying cause of hypoglycemia (Box 72-3). If the patient is stable after the critical sample is sent, a glucagon stimulation test will help to refine the differential diagnosis (Figure 72-3).

Figure 72-3 Hypoglycemia diagnostic algorithm.

The initial management, regardless of the etiology, is essentially always the same: dextrose-containing IV fluids. Long-term management of children with hypoglycemia depends on the cause of the hypoglycemia.

Future Directions

In the past few years, significant advances in molecular genetics have contributed to our understanding of the most common causes of hypoglycemia in children. These advances should result in the development of specific, more effective therapies in the next few years that may improve the outcome in these children.