Hypoglycemia

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Chapter 86 Hypoglycemia

Glucose has a central role in fuel economy and is a source of energy storage in the form of glycogen, fat, and protein (Chapter 81). Glucose, an immediate source of energy, provides 38 mol of adenosine triphosphate (ATP) per mol of glucose oxidized. It is essential for cerebral energy metabolism because it is usually the preferred substrate and its utilization accounts for nearly all the oxygen consumption in the brain. Cerebral glucose uptake occurs through a glucose transporter molecule or molecules that are not regulated by insulin. Cerebral transport of glucose is a carrier-mediated, facilitated diffusion process that is dependent on blood glucose concentration. Deficiency of brain glucose transporters can result in seizures because of low cerebral and cerebrospinal fluid (CSF) glucose concentrations (hypoglycorrhachia) despite normal blood glucose levels. To maintain the blood glucose concentration and prevent it from falling precipitously to levels that impair brain function, an elaborate regulatory system has evolved.

The defense against hypoglycemia is integrated by the autonomic nervous system and by hormones that act in concert to enhance glucose production through enzymatic modulation of glycogenolysis and gluconeogenesis while simultaneously limiting peripheral glucose utilization. Hypoglycemia represents a defect in one or several of the complex interactions that normally integrate glucose homeostasis during feeding and fasting. This process is particularly important for neonates, in whom there is an abrupt transition from intrauterine life, characterized by dependence on transplacental glucose supply, to extrauterine life, characterized ultimately by the autonomous ability to maintain euglycemia. Because prematurity or placental insufficiency may limit tissue nutrient deposits, and genetic abnormalities in enzymes or hormones may become evident in the neonate, hypoglycemia is common in the neonatal period.

Definition

In neonates, there is not always an obvious correlation between blood glucose concentration and the classic clinical manifestations of hypoglycemia. The absence of symptoms does not indicate that glucose concentration is normal and has not fallen to less than some optimal level for maintaining brain metabolism. There is evidence that hypoxemia and ischemia may potentiate the role of hypoglycemia in causing permanent brain damage. Consequently, the lower limit of accepted normality of the blood glucose level in newborn infants with associated illness that already impairs cerebral metabolism has not been determined (Chapter 101). Out of concern for possible neurologic, intellectual, or psychologic sequelae in later life, most authorities recommend that any value of blood glucose <50 mg/dL in neonates be viewed with suspicion and vigorously treated. This is particularly applicable after the initial 2-3 hr of life, when glucose normally has reached its nadir; subsequently, blood glucose levels begin to rise and achieve values of 50 mg/dL or higher after 12-24 hr. In older infants and children, a whole blood glucose concentration of <50 mg/dL (10-15% higher for serum or plasma) represents hypoglycemia.

Significance and Sequelae

Metabolism by the adult brain accounts for the majority of total basal glucose turnover. Most of the endogenous hepatic glucose production in infants and young children can be accounted for by brain metabolism.

Because the brain grows most rapidly in the 1st yr of life and because the larger proportion of glucose turnover is used for brain metabolism, sustained or repetitive hypoglycemia in infants and children can retard brain development and function. Transient isolated and asymptomatic hypoglycemia of short duration does not appear to be associated with these severe sequelae. In the rapidly growing brain, glucose may also be a source of membrane lipids and, together with protein synthesis it can provide structural proteins and myelination that are important for normal brain maturation. Under conditions of severe and sustained hypoglycemia, these cerebral structural substrates may become degraded to energy-usable intermediates such as lactate, pyruvate, amino acids, and ketoacids, which can support brain metabolism at the expense of brain growth. The capacity of the newborn brain to take up and oxidize ketone bodies is about 5-fold greater than that of the adult brain. The capacity of the liver to produce ketone bodies may be limited in the newborn period, especially in the presence of hyperinsulinemia, which acutely inhibits hepatic glucose output, lipolysis, and ketogenesis, thereby depriving the brain of any alternate fuel sources. Although the brain may metabolize ketones, these alternate fuels cannot completely replace glucose as an essential central nervous system (CNS) fuel. The deprivation of the brain’s major energy source during hypoglycemia and the limited availability of alternate fuel sources during hyperinsulinemia have predictable adverse consequences on brain metabolism and growth: decreased brain oxygen consumption and increased breakdown of endogenous structural components with destruction of functional membrane integrity.

The major long-term sequelae of severe, prolonged hypoglycemia are mental retardation, recurrent seizure activity, or both. Subtle effects on personality are also possible but have not been clearly defined. Permanent neurologic sequelae are present in 25-50% of patients with severe recurrent symptomatic hypoglycemia who are younger than 6 mo of age. These sequelae may be reflected in pathologic changes characterized by atrophic gyri, reduced myelination in cerebral white matter, and atrophy in the cerebral cortex. These sequelae are more likely when alternative fuel sources are limited, as occurs with hyperinsulinemia, when the episodes of hypoglycemia are repetitive or prolonged, or when they are compounded by hypoxia. There is no precise knowledge relating the duration or severity of hypoglycemia to subsequent neurologic development of children in a predictable manner. Although less common, hypoglycemia in older children may also produce long-term neurologic defects through neuronal death mediated, in part, by cerebral excitotoxins released during hypoglycemia.

Substrate, Enzyme, and Hormonal Integration of Glucose Homeostasis

In the Newborn (Chapter 101)

Under nonstressed conditions, fetal glucose is derived entirely from the mother through placental transfer. Therefore, fetal glucose concentration usually reflects but is slightly lower than maternal glucose levels. Catecholamine release, which occurs with fetal stress such as hypoxia, mobilizes fetal glucose and free fatty acids (FFAs) through β-adrenergic mechanisms, reflecting β-adrenergic activity in fetal liver and adipose tissue. Catecholamines may also inhibit fetal insulin and stimulate glucagon release.

The acute interruption of maternal glucose transfer to the fetus at delivery imposes an immediate need to mobilize endogenous glucose. Three related events facilitate this transition: changes in hormones, changes in their receptors, and changes in key enzyme activity. There is a 3- to 5-fold abrupt increase in glucagon concentration within minutes to hours of birth. The level of insulin usually falls initially and remains in the basal range for several days without demonstrating the usual brisk response to physiologic stimuli such as glucose. A dramatic surge in spontaneous catecholamine secretion is also characteristic. Epinephrine can also augment growth hormone secretion by α-adrenergic mechanisms; growth hormone levels are elevated at birth. Acting in concert, these hormonal changes at birth mobilize glucose via glycogenolysis and gluconeogenesis, activate lipolysis, and promote ketogenesis. As a result of these processes, plasma glucose concentration stabilizes after a transient decrease immediately after birth, liver glycogen stores become rapidly depleted within hours of birth, and gluconeogenesis from alanine, a major gluconeogenic amino acid, can account for about 10% of glucose turnover in the human newborn infant by several hours of age. FFA concentrations also increase sharply in concert with the surges in glucagon and epinephrine and are followed by rises in ketone bodies. Glucose is thus partially spared for brain utilization while FFAs and ketones provide alternative fuel sources for muscle as well as essential gluconeogenic factors such as acetyl coenzyme A (CoA) and the reduced form of nicotinamide-adenine dinucleotide (NADH) from hepatic fatty acid oxidation, which is required to drive gluconeogenesis.

In the early postnatal period, responses of the endocrine pancreas favor glucagon secretion so that blood glucose concentration can be maintained. These adaptive changes in hormone secretion are paralleled by similarly striking adaptive changes in hormone receptors. Key enzymes involved in glucose production also change dramatically in the perinatal period. Thus, there is a rapid fall in glycogen synthase activity and a sharp rise in phosphorylase after delivery. Similarly, the amount of rate-limiting enzyme for gluconeogenesis, phosphoenolpyruvate carboxykinase, rises dramatically after birth, activated in part by the surge in glucagon and the fall in insulin. This framework can explain several causes of neonatal hypoglycemia based on inappropriate changes in hormone secretion and unavailability of adequate reserves of substrates in the form of hepatic glycogen, muscle as a source of amino acids for gluconeogenesis, and lipid stores for the release of fatty acids. In addition, appropriate activities of key enzymes governing glucose homeostasis are required (see Fig. 81-1).

In Older Infants and Children

Hypoglycemia in older infants and children is analogous to that of adults, in whom glucose homeostasis is maintained by glycogenolysis in the immediate postfeeding period and by gluconeogenesis several hours after meals. The liver of a 10 kg child contains 20-25 g of glycogen, which is sufficient to meet normal glucose requirements of 4-6 mg/kg/min for only 6-12 hr. Beyond this period, hepatic gluconeogenesis must be activated. Both glycogenolysis and gluconeogenesis depend on the metabolic pathway summarized in Figure 81-1. Defects in glycogenolysis or gluconeogenesis may not be manifested in infants until the frequent feeding at 3-4 hr intervals ceases and infants sleep through the night, a situation usually present by 3-6 mo of age. The source of gluconeogenic precursors is derived primarily from muscle protein. The muscle bulk of infants and small children is substantially smaller relative to body mass than that of adults, whereas glucose requirements/unit of body mass are greater in children, so the ability to compensate for glucose deprivation by gluconeogenesis is more limited in infants and young children, as is the ability to withstand fasting for prolonged periods. The ability of muscle to generate alanine, the principal gluconeogenic amino acid, may also be limited. Thus, in normal young children, the blood glucose level falls after 24 hr of fasting, insulin concentrations fall appropriately to levels of <5-10 µU/mL, lipolysis and ketogenesis are activated, and ketones may appear in the urine.

The switch from glycogen synthesis during and immediately after meals to glycogen breakdown and later gluconeogenesis is governed by hormones, of which insulin is of central importance. Plasma insulin concentrations increase to peak levels of 50-100 µU/mL after meals, which serve to lower the blood glucose concentration through the activation of glycogen synthesis, enhancement of peripheral glucose uptake, and inhibition of glucose production. In addition, lipogenesis is stimulated, whereas lipolysis and ketogenesis are curtailed. During fasting, plasma insulin concentrations fall to ≤5-10 µU/mL, and together with other hormonal changes, this fall results in activation of gluconeogenic pathways (see Fig. 81-1). Fasting glucose concentrations are maintained through the activation of glycogenolysis and gluconeogenesis, inhibition of glycogen synthesis, and activation of lipolysis and ketogenesis. It should be emphasized that a plasma insulin concentration of >5 µU/mL, in association with a blood glucose concentration of ≤40 mg/dL (2.2 mM), is abnormal, indicating a hyperinsulinemic state and failure of the mechanisms that normally result in suppression of insulin secretion during fasting or hypoglycemia.

The hypoglycemic effects of insulin are opposed by the actions of several hormones whose concentration in plasma increases as blood glucose falls. These counter-regulatory hormones, glucagon, growth hormone, cortisol, and epinephrine, act in concert by increasing blood glucose concentrations via activating glycogenolytic enzymes (glucagon, epinephrine); inducing gluconeogenic enzymes (glucagon, cortisol); inhibiting glucose uptake by muscle (epinephrine, growth hormone, cortisol); mobilizing amino acids from muscle for gluconeogenesis (cortisol); activating lipolysis and thereby providing glycerol for gluconeogenesis and fatty acids for ketogenesis (epinephrine, cortisol, growth hormone, glucagon); and inhibiting insulin release and promoting growth hormone and glucagon secretion (epinephrine).

Congenital or acquired deficiency of any one of these hormones is uncommon but will result in hypoglycemia, which occurs when endogenous glucose production cannot be mobilized to meet energy needs in the postabsorptive state, that is, 8-12 hr after meals or during fasting. Concurrent deficiency of several hormones (hypopituitarism) may result in hypoglycemia that is more severe or appears earlier during fasting than that seen with isolated hormone deficiencies. Most of the causes of hypoglycemia in infancy and childhood reflect inappropriate adaptation to fasting.

Clinical Manifestations (Chapter 101)

Clinical features generally fall into 2 categories. The 1st includes symptoms associated with the activation of the autonomic nervous system and epinephrine release, usually seen with a rapid decline in blood glucose concentration (Table 86-1). The 2nd category includes symptoms due to decreased cerebral glucose utilization, usually associated with a slow decline in blood glucose level or prolonged hypoglycemia (see Table 86-1). Although these classic symptoms occur in older children, the symptoms of hypoglycemia in infants may be subtler and include cyanosis, apnea, hypothermia, hypotonia, poor feeding, lethargy, and seizures. Some of these symptoms may be so mild that they are missed. Occasionally, hypoglycemia may be asymptomatic in the immediate newborn period. Newborns with hyperinsulinemia are often large for gestational age; older infants with hyperinsulinemia may eat excessively because of chronic hypoglycemia and become obese. In childhood, hypoglycemia may present as behavior problems, inattention, ravenous appetite, or seizures. It may be misdiagnosed as epilepsy, inebriation, personality disorders, hysteria, and retardation. A blood glucose determination should always be performed in sick neonates, who should be vigorously treated if concentrations are <50 mg/dL. At any age level, hypoglycemia should be considered a cause of an initial episode of convulsions or a sudden deterioration in psychobehavioral functioning.

Table 86-1 MANIFESTATIONS OF HYPOGLYCEMIA IN CHILDHOOD

FEATURES ASSOCIATED WITH ACTIVATION OF AUTONOMIC NERVOUS SYSTEM AND EPINEPHRINE RELEASE*

Anxiety ^†

Perspiration ^†

Palpitation (tachycardia)^†

Angina (with normal coronary arteries)

FEATURES ASSOCIATED WITH CEREBRAL GLUCOPENIA

Headache ^†

Mental confusion ^†

Visual disturbances (↓ acuity, diplopia)^†

Organic personality changes ^†

Inability to concentrate ^†

Ataxia, incoordination

Somnolence, lethargy

Seizures

Coma

Stroke, hemiplegia, aphasia

Decerebrate or decorticate posture

* Some of these features will be attenuated if the patient is receiving β-adrenergic blocking agents.

^† Common.

Many neonates have asymptomatic (chemical) hypoglycemia. The incidence of symptomatic hypoglycemia is highest in small for gestational age infants (Fig. 86-1). The exact incidence of symptomatic hypoglycemia has been difficult to establish because many of the symptoms in neonates occur together with other conditions such as infections, especially sepsis and meningitis; central nervous system anomalies, hemorrhage, or edema; hypocalcemia and hypomagnesemia; asphyxia; drug withdrawal; apnea of prematurity; congenital heart disease; or polycythemia.

Figure 86-1 Incidence of hypoglycemia by birthweight, gestational age, and intrauterine growth.

(From Lubchenco LO, Bard H: Incidence of hypoglycemia in newborn infants classified by birthweight and gestational age, Pediatrics 47:831–838, 1971.)

The onset of symptoms in neonates varies from a few hr to a wk after birth. In approximate order of frequency, symptoms include jitteriness or tremors, apathy, episodes of cyanosis, convulsions, intermittent apneic spells or tachypnea, weak or high-pitched cry, limpness or lethargy, difficulty feeding, and eye rolling. Episodes of sweating, sudden pallor, hypothermia, and cardiac arrest and failure also occur. Frequently, a clustering of episodic symptoms may be noted. Because these clinical manifestations may result from various causes, it is critical to measure serum glucose levels and determine whether they disappear with the administration of sufficient glucose to raise the blood sugar to normal levels; if they do not, other diagnoses must be considered.

Classification of Hypoglycemia in Infants and Children

Classification is based on knowledge of the control of glucose homeostasis in infants and children (Table 86-2).

Table 86-2 CLASSIFICATION OF HYPOGLYCEMIA IN INFANTS AND CHILDREN

NEONATAL TRANSIENT HYPOGLYCEMIA

Associated with Inadequate Substrate or Immature Enzyme Function in Otherwise Normal Neonates

Prematurity

Small for gestational age

Normal newborn

Transient Neonatal Hyperinsulinism Also Present in:

Infant of diabetic mother

Small for gestational age

Discordant twin

Birth asphyxia

Infant of toxemic mother

NEONATAL, INFANTILE, OR CHILDHOOD PERSISTENT HYPOGLYCEMIAS

Hormonal Disorders

Hyperinsulinism

Recessive K_ATP channel HI

Recessive HADH (hydroxyl acyl CoA dehydrogenase) mutation HI

Recessive UCP2 (mitochondrial uncoupling protein 2) mutation HI

Focal K_ATP channel HI

Dominant K_ATP channel HI

Dominant glucokinase HI

Dominant glutamate dehydrogenase HI (hyperinsulinism/hyperammonemia syndrome)

Dominant mutation in HNF4A (hepatic nuclear factor 4 alpha) HI with MODY later in life

Dominant mutation in SLC16A1(the pyruvate transporter)-exercise-induced hypoglycemia

Acquired islet adenoma

Beckwith-Wiedemann syndrome

Insulin administration (Munchausen syndrome by proxy)

Oral sulfonylurea drugs

Congenital disorders of glycosylation

Counter-Regulatory Hormone Deficiency

Panhypopituitarism

Isolated growth hormone deficiency

Adrenocorticotropic hormone deficiency

Addison disease

Epinephrine deficiency

Glycogenolysis and Gluconeogenesis Disorders

Glucose-6-phosphatase deficiency (GSD 1a)

Glucose-6-phosphate translocase deficiency (GSD 1b)

Amylo-1,6-glucosidase (debranching enzyme) deficiency (GSD 3)

Liver phosphorylase deficiency (GSD 6)

Phosphorylase kinase deficiency (GSD 9)

Glycogen synthetase deficiency (GSD 0)

Fructose-1,6-diphosphatase deficiency

Pyruvate carboxylase deficiency

Galactosemia

Hereditary fructose intolerance

Lipolysis Disorders

Fatty Acid Oxidation Disorders

Carnitine transporter deficiency (primary carnitine deficiency)

Carnitine palmitoyltransferase-1 deficiency

Carnitine translocase deficiency

Carnitine palmitoyltransferase-2 deficiency

Secondary carnitine deficiencies

Very long, long-, medium-, short-chain acyl CoA dehydrogenase deficiency

OTHER ETIOLOGIES

Substrate-Limited

Oral hypoglycemic agents

Ackee fruit (unripe)—hypoglycin

Vacor (rate poison)

Trimethoprim-sulfamethoxazole (with renal failure)

Liver Disease

Amino Acid and Organic Acid Disorders

Maple syrup urine disease

Propionic acidemia

Methylmalonic acidemia

Tyrosinosis

Glutaric aciduria

3-Hydroxy-3-methylglutaric aciduria

Systemic Disorders

Sepsis

Carcinoma/sarcoma (secreting—insulin-like growth factor II)

Heart failure

Malnutrition

Malabsorption

Anti-insulin receptor antibodies

Anti-insulin antibodies

Neonatal hyperviscosity

Pseudohypoglycemia (leukocytosis, polycythemia)

Excessive insulin therapy of insulin-dependent diabetes mellitus

Factitious

Nissen fundoplication (dumping syndrome)

Falciparum malaria

GSD, glycogen storage disease; HI, hyperinsulinemia; K_ATP, regulated potassium channel.

Neonatal, Transient, Small for Gestational Age, and Premature Infants (Chapter 101)

The estimated incidence of symptomatic hypoglycemia in newborns is 1-3/1,000 live births. This incidence is increased severalfold in certain high-risk neonatal groups (see Table 86-2 and Fig. 86-1). The premature and small for gestational age (SGA) infants are vulnerable to the development of hypoglycemia. The factors responsible for the high frequency of hypoglycemia in this group, as well as in other groups outlined in Table 86-2, are related to the inadequate stores of liver glycogen, muscle protein, and body fat needed to sustain the substrates required to meet energy needs. These infants are small by virtue of prematurity or impaired placental transfer of nutrients. Their enzyme systems for gluconeogenesis may not be fully developed. Transient hyperinsulinism responsive to diazoxide has also been reported as contributing to hypoglycemia in asphyxiated, SGA, and premature newborn infants. This form of hyperinsulinism associated with perinatal asphyxia, intrauterine growth restriction (IUGR), maternal toxemia and other perinatal stressors, is probably the most common cause of hyperinsulinemic hypoglycemia in neonates and may be quite severe. In most cases, the condition resolves quickly, but it may persist to 7 mo of life or more. A genetic cause of this form of dysregulated insulin secretion has not been established.

In contrast to deficiency of substrates or enzymes, the hormonal system appears to be functioning normally at birth in most low-risk neonates. Despite hypoglycemia, plasma concentrations of alanine, lactate, and pyruvate are higher, implying their diminished rate of utilization as substrates for gluconeogenesis. Infusion of alanine elicits further glucagon secretion but causes no significant rise in glucose. During the initial 24 hr of life, plasma concentrations of acetoacetate and β-hydroxybutyrate are lower in SGA infants than in full-term infants, implying diminished lipid stores, diminished fatty acid mobilization, impaired ketogenesis, or a combination of these conditions. Diminished lipid stores are most likely because fat (triglyceride) feeding of newborns results in a rise in the plasma levels of glucose, FFAs, and ketones. For infants with perinatal asphyxia and some SGA newborns who have transient hyperinsulinemia, hypoglycemia and diminished concentrations of FFAs are the hallmark of hyperinsulinemia.

The role of FFAs and their oxidation in stimulating neonatal gluconeogenesis is essential. The provision of FFAs as triglyceride feedings from formula or human milk together with gluconeogenic precursors may prevent the hypoglycemia that usually ensues after neonatal fasting. For these and other reasons, milk feedings are introduced early (at birth or within 2-4 hr) after delivery. In the hospital setting, when feeding is precluded by virtue of respiratory distress or when feedings alone cannot maintain blood glucose concentrations at levels >50 mg/dL, intravenous glucose at a rate that supplies 4-8 mg/kg/min should be started. Infants with transient neonatal hypoglycemia can usually maintain the blood glucose level spontaneously after 2-3 days of life, but some require longer periods of support. In these latter infants, insulin values >5 µU/ml at the time of hypoglycemia should be treated with diazoxide.

Infants Born to Diabetic Mothers (Chapter 101)

Of the transient hyperinsulinemic states, infants born to diabetic mothers are the most common. Gestational diabetes affects some 2% of pregnant women, and ≈1/1,000 pregnant women have insulin-dependent diabetes. At birth, infants born to these mothers may be large and plethoric, and their body stores of glycogen, protein, and fat are replete.

Hypoglycemia in infants of diabetic mothers is mostly related to hyperinsulinemia and partly related to diminished glucagon secretion. Hypertrophy and hyperplasia of the islets is present, as is a brisk, biphasic, and typically mature insulin response to glucose; this insulin response is absent in normal infants. Infants born to diabetic mothers also have a subnormal surge in plasma glucagon immediately after birth, subnormal glucagon secretion in response to stimuli, and, initially, excessive sympathetic activity that may lead to adrenomedullary exhaustion as reflected by decreased urinary excretion of epinephrine. The normal plasma hormonal pattern of low insulin, high glucagon, and high catecholamines is reversed to a pattern of high insulin, low glucagon, and low epinephrine. As a consequence of this abnormal hormonal profile, the endogenous glucose production is significantly inhibited compared with that in normal infants, thus predisposing them to hypoglycemia.

Mothers whose diabetes has been well controlled during pregnancy, labor, and delivery generally have infants near normal size who are less likely to develop neonatal hypoglycemia and other complications formerly considered typical of such infants (Chapter 101). In supplying exogenous glucose to these hypoglycemic infants, it is important to avoid hyperglycemia that evokes a prompt exuberant insulin release, which may result in rebound hypoglycemia. When needed, glucose should be provided at continuous infusion rates of 4-8 mg/kg/min, but the appropriate dose for each patient should be individually adjusted. During labor and delivery, maternal hyperglycemia should be avoided because it results in fetal hyperglycemia, which predisposes to hypoglycemia when the glucose supply is interrupted at birth. Hypoglycemia persisting or occurring after 1 wk of life requires an evaluation for the causes listed in Table 86-2.

Infants born with erythroblastosis fetalis may also have hyperinsulinemia and share many physical features, such as large body size, with infants born to diabetic mothers. The cause of the hyperinsulinemia in infants with erythroblastosis is not clear.