Hypoglycemia is the most common biochemical emergency in pediatric patients. Therefore, the ability to efficiently evaluate and treat of this condition is essential for the general pediatrician. Four broad categories of problems contribute to the development of hypoglycemia: loss of homeostatic control, inadequate intake of food, intoxication with a substance that induces low blood sugar, and inborn errors in the utilization, production, or release of sugar. When all systems are operating, there is a balance of supply and demand to maintain normal blood sugar (euglycemia) over a broad range of physiologic settings.
Euglycemia is maintained by a balance of glucose intake and production and glucose consumption. In the immediate postprandial period, there is a transient increase in the blood glucose level from glucose provided by digested food. However, this rapidly corrects, primarily through the action of insulin, which promotes the consumption and storage of glucose. In all cells, glucose is consumed primarily through the glycolytic pathway, by which the breakdown of glucose produces energy in the form of adenosine triphosphate (ATP), as well as products that can be further used in the tricarboxylic acid cycle or for lipogenesis. Insulin also promotes the uptake of glucose into the liver, where it is stored in the form of glycogen.
In the typical fasting state, euglycemia is maintained by the provision of glucose. Initially, this is done by glycogenolysis—the fast release of free glucose via the breakdown of liver glycogen. In a long fast, after glycogen stores are exhausted, glucose is synthesized, largely from the breakdown of amino acids and triglycerides. This process is known as gluconeogenesis. As fasting time lengthens, although euglycemia is maintained, the glucose level is lower in comparison to the immediate postprandial level. The maintenance of euglycemia in the face of fasting is coordinated by several hormones, including glucagon, cortisol, epinephrine, and norepinephrine.
Different organ systems have distinct roles in glucose homeostasis. Different organs also have different energy demands and different avidities for glucose as an energy source. Of note is the brain, which preferentially consumes glucose and is responsible for 15% to 18% of glucose consumption. The liver is the most important buffer for blood glucose, storing glucose during times of excess and releasing it during times of fasting. Muscle produces glucose only for local use and cannot release it. Adipose tissue provides energy in the form of fatty acids that can be used during fasting, but it cannot synthesize glucose to be used by other tissues.
Ketogenesis is a key component of the normal physiological response to fasting. Ketones are produced by the breakdown of fatty acids. Ketones are a glucose-sparing energy source, as they can enter the tricarboxylic acid cycle to drive the production of ATP. Ketones are also important in the fasting period, as they provide the ATP needed for gluconeogenesis.
As hypoglycemia develops, catabolic hormones are released as a counterregulatory measure. Chief among these enzymes are epinephrine and norepinephrine. Therefore, the earliest manifestations of hypoglycemia are sympathetic symptoms, such as diaphoresis, pallor, and tachycardia. Because the brain is a major consumer of glucose, if hypoglycemia persists, neurologic symptoms are manifest, including fatigue, altered mental status, seizures, and ultimately coma. These symptoms are neither invariantly present nor specific to hypoglycemia. Therefore clinicians should maintain a low threshold to suspect hypoglycemia, particularly in a child with neurologic manifestations.
Although hypoglycemia is common, controversy exists about laboratory cutoffs for hypoglycemia. Most sources agree that a blood glucose less than 50 mg/dL (40 mg/dL in neonates) warrants urgent correction. This level is chosen because of evidence that lower levels may produce long-term neurologic sequelae. Patients who have symptomatic hypoglycemia should be immediately corrected, regardless of the value of their blood glucose. Diagnostic workup of persistent or recurrent hypoglycemia should be pursued, even if it does not meet this threshold.
Newborns as a population are at special risk of hypoglycemia. There are several reasons for this: (1) Glucose is provided in utero through placental circulation. Within 2 hours of separation from placental circulation, blood glucose nadirs. Glucose does not stabilize until 4 to 6 hours postpartum. (2) The brain is proportionally larger in newborns and therefore there is increased glucose demand per body weight as compared to different age groups. (3) Newborns have small glycogen stores. (4) Several biochemical pathways, including glycogenolysis, ketogenesis, and gluconeogenesis, are immature in the newborn, resulting in poor response to fasting.
In addition to these physiologic factors, several common conditions can lead to hypoglycemia in the newborn. In the normal newborn, primary factors include hypothermia, delayed feeding, or difficultly with breastfeeding. Infants of diabetic mothers may have high insulin levels from placental circulation, predisposing them to hypoglycemia. Infants who have intrauterine growth restriction or who are small for gestational age may have an exaggerated physiologic nadir, with particularly low glycogen stores and particularly high brain to bodyweight ratios.
The symptoms of hypoglycemia may be subtle in newborns. Therefore a low index of suspicion must be maintained and all infants with symptoms such as poor feeding, hypothermia, jitteriness, or lethargy should have a blood glucose checked. To help expedite diagnosis of hypoglycemia in the newborn period, nurseries should have a standard protocol for glucose monitoring that identifies infants at risk for hypoglycemia, including infants of diabetic mothers, infants who are large for gestational age, and infants who are small for gestational age.
It is extremely important to note that hypoglycemia with neurologic symptoms may be the hallmark of other serious problems, including sepsis and inborn errors of metabolism. Neonates in distress who do not respond to or cannot tolerate oral or gavage feedings with breast milk or formula need rapid administration of intravenous dextrose and a full diagnostic evaluation that includes screening for sepsis and inborn errors of metabolism.
Extrinsic causes are among the most frequent cause of hypoglycemia in the pediatric population; most common is ingestion of oral hypoglycemics. These medications affect glucose metabolism through several distinct mechanisms. Thiazolidinediones sensitize target cells to insulin so that glucose clearance from the bloodstream is increased, metformin interferes with glucose production by the liver, and sulfonylureas increase insulin secretion. All these medications may lead to hypoglycemia in a normal child, but the effects of sulfonylurea poisoning can be the most severe.
Insulin overdose should be suspected in diabetic patients. Accidental overdose, misuse of an insulin pump, iatrogenic error, and Munchausen syndrome are all possible causes. Glucagon kits to be used at home are frequently provided to families with diabetic children.
Alcohol may also cause hypoglycemia. Alcohol causes symptoms by blockade of gluconeogenesis. The actual frequency of alcohol-induced hypoglycemia is quite low; however the hypoglycemic effect of alcohol is an important factor in the care of all inebriated children, because they are often unwilling or unable to eat and may have had a prolonged fast by the time they reach medical attention.
The intrinsic causes of hypoglycemia can be loosely grouped into the following subcategories: inborn errors of carbohydrate metabolism, inborn errors of fatty acid oxidation, glycogen storage disorders, deficiencies of counterregulatory hormones, and hyperinsulinism. Patients may also have hypoglycemic crises precipitated by attempted fasting, times of increased caloric need (such as illness), or ingestion of foods that cannot be properly metabolized.
Children with intrinsic metabolic defects tend to present with repeated bouts of hypoglycemia. The degree of hypoglycemia and symptoms may be of a severity out of proportion to the given history. The history and physical examination in patients with suspected inborn errors of metabolism may reveal hepatomegaly due to hepatic steatosis or storage of glycogen, abnormal odors, feeding aversions, events precipitated by specific foods, or unexplained episodes of acidosis during prior illnesses.
A discussion of the numerous inborn errors of metabolism that may present with hypoglycemia is beyond the scope of this chapter. Referral to a specialist in endocrinology or biochemical genetics is required for the diagnosis and management of many of these disorders. However, the principle of immediate treatment in patients with signs and symptoms of hypoglycemia is still useful, even when the underlying disorder is unknown or unfamiliar to the practitioner. The following disease categories provide an overview of the most common and most severe of these disorders seen in children.
The glycogen storage diseases are a family of syndromes caused by defects in glycogen synthesis, storage, degradation of glycogen into glucose, and/or release of glucose. The glycogen storage diseases are diverse in terms of manifestations, based on the different errors in the glycogen metabolism pathway (not all patients with glycogen storage diseases are prone to hypoglycemia). In the most common forms, hepatomegaly is present as a result of glycogen accumulation. However, glycogen storage disease cannot be ruled out in the absence of hepatomegaly, because rare but underdiagnosed forms of glycogen storage disease without hepatomegaly exist. The glycogen storage diseases can affect many tissues, giving children a typical appearance: short stature, rounded face, enlarged abdomen, and wasted extremities. Laboratory studies reflect low glucose in the face of a normal counterregulatory response and brisk increases in circulating ketones at the time of fasting. Lactic acidemia is common in glycogen storage disease type I, caused by deficiency of glucose-6-phosphatase, a key enzyme in both glycogen degradation and gluconeogenesis.
In children with glycogen storage diseases, hypoglycemia occurs when glycogenolysis fails to maintain an adequate blood glucose level. Because these children are unable to use glycogen stores efficiently, their blood sugar may fall within a few hours after starting a fast. Proper management of these patients requires that they avoid prolonged fasting, and for many patients, even sleeping through the night without caloric intake is impossible. The use of uncooked cornstarch for intermittent overnight feedings or nasogastric feedings is required for type I glycogen storage disease. These treatments limit the intervals of fasting to ensure adequate energy reserves. There are many long-term complications with all these disorders, including hyperuricemia, hypertriglyceridemia, renal failure, and hepatic adenomas.1
Hereditary fructose intolerance is caused by inherited defects in the enzymes necessary to convert these sugars to glucose. Children present with hypoglycemia and associated symptoms after ingestion of the offending sugar.
Hereditary fructose intolerance, also known as fructosemia, is caused by a deficiency in fructose-1-phosphate aldolase (aldolase B) and usually presents at the time of first exposure to fructose (such as fruit or fruit juice), typically around 4 to 6 months of age. Ingestion of sucrose-containing substances also exposes the infant to fructose as the sucrose disaccharide is hydrolyzed to glucose and fructose. Without adequate enzymes, fructose-1-phosphate is not catalyzed, allowing this toxic substance to accumulate. These infants present with vomiting, lethargy, and hypoglycemia shortly after ingestion. The hypoglycemia may be severe but is often transient, complicating the laboratory diagnosis. Failure to detect this condition can lead to hepatitis, renal failure, and even death if the patient continues to be fed sucrose- or fructose-containing juices or foods. If the condition is not recognized in infancy, most children develop food aversions that limit or prevent toxic ingestion, but they continue to be at risk any time a novel food containing fructose or sucrose is given to them. Diagnosis requires an accurate dietary history. Targeted history should be obtained in any hypoglycemic child of the correct age range.
Fatty acid oxidation defects interfere with the ability to utilize fatty acids for oxidative metabolism and ketogenesis. Hypoglycemia occurs because patients are overly dependent on glycolysis to produce energy and the substrates for the tricarboxylic acid cycle and are unable to produce ketones as an alternate energy source. There is impairment of gluconeogenesis, which requires ATP, typically derived from ketones.
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
