Hypoglycemia

72 Hypoglycemia



Andrew A. Palladino, Diva D. DeLeón


Hypoglycemia is often the initial manifestation of a disorder of energy metabolism and regulation. The accurate diagnosis of the underlying condition facilitates institution of disease-specific therapy that can prevent long-term complications such as seizures, developmental delay, permanent brain damage, and even death. In children, the most common cause of persistent hypoglycemia is hyperinsulinism, a disorder affecting approximately 1 in 20,000 children in the United States.



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.


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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.


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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.



Box 72-1 Differential Diagnosis of Hypoglycemia in Infants and Children



• Infant of a diabetic mother

• Prolonged neonatal hypoglycemia
• Perinatal stress-induced hyperinsulinism

• Permanent hypoglycemia
• Congenital hyperinsulinism

• KATP channel hyperinsulinism

• GDH hyperinsulinism

• Glucokinase hyperinsulinism

• SCHAD deficiency hyperinsulinism

• Exercise-induced hyperinsulinism

• Insulinoma

• Other causes of hyperinsulinism
• HN4-alpha mutations associated with familial monogenic diabetes

• Factitious hyperinsulinism

• Beckwith-Wiedemann syndrome

• Anti-insulin and insulin receptor-stimulating antibodies

• Congenital disorders of glycosylation

• PPH (dumping syndrome)

• Disorders of gluconeogenesis
• GSD 1a

• GSD 1b

• F-1,6-Pase deficiency

• Pyruvate carboxylase deficiency

• Disorders of glycogen storage
• GSD 0

• GSD 3

• GSD 6

• GSD 9

• Disorders of fatty acid oxidation

• Pituitary hormone deficiency
• Panhypopituitarism

• Isolated ACTH deficiency

• Isolated growth hormone deficiency

• Primary adrenal insufficiency

• Medication-induced hypoglycemia
• Sulfonylureas

• Ethanol

• β-Blockers

• Salicylates

• Ketotic hypoglycemia

ATCH, adrenocorticotropic hormone; F-1,6-Pase, fructose-1,6-biphosphatase; GDH, glutamate dehydrogenase; GSD 0, glycogen synthase deficiency; GSD 1a, glucose-6-phosphatase deficiency; GSD 1b, glucose-6-phosphate translocase deficiency; GSD 3; debrancher enzyme deficiency; GSD 6, glycogen phosphorylase deficiency; GSD 9, phosphorylase kinase deficiency; KATP, adenosine triphosphate–sensitive potassium; PPH, postprandial hypoglycemia; SCHAD, short-chain 3-hydroxyacyl-CoA dehydrogenase.



Hypoglycemia Secondary to Excessive and Inappropriate Insulin



Infant of a Diabetic Mother


Infants of mothers with uncontrolled diabetes mellitus (DM) during pregnancy (regardless of type) are at risk of hypoglycemia because of transient hyperinsulinism. These infants are almost always large for gestational age. During gestation, the β cells of the fetal pancreas secrete high levels of insulin in response to chronic exposure to elevated glucose. After delivery, there is a sudden removal of the mother’s elevated glucose supply, and hypoglycemia quickly occurs in the newborn, who continues to secrete increased levels of insulin. Hypoglycemia typically resolves in 1 to 2 days as the pancreatic islet cells reduce the insulin secretory rate. Infants exposed to oral hypoglycemic agents (e.g., sulfonylureas) can also develop hypoglycemia because of transient hyperinsulinism.



Prolonged Neonatal Hypoglycemia


When hypoglycemia persists beyond the first 2 or 3 days of life, one must consider the causes of persistent hypoglycemia. The most common cause of prolonged neonatal hypoglycemia is perinatal stress-induced hyperinsulinism (PSIH), a poorly understood, transient disorder that is characterized by dysregulated insulin secretion. PSIH occurs most commonly in neonates exposed to a perinatal stress, such as prematurity, asphyxia, intrauterine growth retardation (IUGR), or maternal toxemia. Newborns with PSIH have high glucose requirements, and during hypoglycemia, they show evidence of hyperinsulinism with insulin levels that are inappropriately detectable, suppressed levels of β-hydroxybutyrate and free fatty acids, and a robust glycemic response to glucagon (≥30 mg/dL increase in blood glucose levels after administration of glucagon). PSIH can last from weeks to months with a median age of resolution of 6 months.



Permanent Hypoglycemia (Congenital Hyperinsulinism)


The most common cause of persistent hypoglycemia in infants and children is congenital hyperinsulinism (CHI). In general, infants with CHI are large for gestational age and develop severe hypoglycemia shortly after birth. They require large amounts of intravenous (IV) glucose to maintain blood glucose above 70 mg/dL. During hypoglycemia (blood glucose <50 mg/dL), these infants have inappropriately normal or elevated serum insulin levels (although insulin levels may not be detected in all assays), suppressed free fatty acids and β-hydroxybutyrate, and a glycemic response to glucagon. Additional laboratory tests that may help distinguish specific forms of hyperinsulinism include ammonia (glutamate dehydrogenase hyperinsulinism), 3-hydroxy-butyrylcarnitine (short chain 3-hydroxacyl Co-A dehydrogenase hyperinsulinism), and abnormally processed transferrin (congenital disorders of glycosylation). Mutations in at least six genes have been associated with hyperinsulinism: the sulfonylurea receptor 1 (SUR-1), potassium inward rectifying channel (Kir6.2), glucokinase (GK), glutamate dehydrogenase (GDH), short-chain 3-hydroxyacyl-CoA dehydrogenase (SCHAD), and ectopic expression on the β-cell plasma membrane of SLC16A1 (encodes monocarboxylate transporter 1 [MCT1]). Ectopic expression of MCT-1 on the plasma membrane of pancreatic β cells leads to exercise-induced hyperinsulinism.


The most common and severe form of CHI is caused by inactivating mutations of the adenosine triphosphate–sensitive potassium (KATP) channel, made up of SUR-1 and Kir6.2. Inactivating mutations in the KATP channel result in constitutive closure of the channel, allowing membrane depolarization and calcium influx into the β cell, resulting in constitutive insulin secretion from the β cell. In about half of cases, the baby has inherited a defective allele from each parent, resulting in diffuse hyperinsulinism. In the remaining cases, a loss of function mutation inherited from the father in combination with loss of heterozygosity with loss of tumor suppressor genes imprinted in the maternal allele results in focal hyperinsulinism.

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Jun 19, 2016 | Posted by in PEDIATRICS | Comments Off on Hypoglycemia

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