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Hypoglycemia


Glucose has a central role in fuel economy and is a source of energy storage in the form of glycogen, fat, and protein (see Chapter 105 ). As an immediate source of energy, glucose provides 38 mol of adenosine triphosphate (ATP) per mole of glucose oxidized. Glucose is essential for energy metabolism in the brain, where it is usually the preferred substrate and where its utilization accounts for nearly all the brain's oxygen consumption. Cerebral transport of glucose is a GLUT-1, carrier-mediated, facilitated diffusion process that is dependent on blood glucose concentration and not regulated by insulin. Therefore, low concentrations of blood glucose result in cerebral glucopenia. 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 includes the autonomic nervous system and hormones that act in concert to enhance glucose production through enzymatic modulation of glycogenolysis and gluconeogenesis, while simultaneously limiting peripheral glucose utilization, which conserves glucose for cerebral metabolism. 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 sequelae. 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 (see Chapter 127 ). Because of concern for possible neurologic, intellectual, or psychologic sequelae in later life, most authorities recommend that any value of blood glucose <55 mg/dL in neonates be viewed with suspicion, investigated, and vigorously treated if there are symptoms or it persists or recurs after a meal. 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 55-65 mg/dL or higher after 12-24 hr. By day 3 of life in normal full-term newborns, blood glucose averages approximately 65 mg/dL (range 65-100). Therefore, in otherwise normal, full-term infants after day 3 of life and in older infants and children, a whole blood glucose concentration <55 mg/dL (10–15% higher for serum or plasma) represents hypoglycemia, because counter-regulatory mechanisms are activated at these glucose concentrations. In older children an idealized definition of hypoglycemia is based on “Whipple's Triad”; a plasma glucose concentration less than 60 mg/dL, together with concurrent CNS- or catecholamine-based symptoms, and resolution of symptoms when glucose concentration is restored to normal by treatment with glucose.

Significance and Sequelae

Most of the endogenous hepatic glucose production in infants and young children, which occurs several hours after feeding and during fasting, can be accounted for by brain metabolism.

Because the brain grows most rapidly in the 1st yr of life, and 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, can provide structural proteins and myelination 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. However, the capacity of the liver to produce ketone bodies is limited in the immediate newborn period, especially in the presence of hyperinsulinism , 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 particularly the limited availability of alternate fuel sources during hyperinsulinism 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 cognitive impairment, recurrent seizure activity, cerebral palsy, and autonomic dysregulation. Subtle effects on personality are also possible but have not been clearly defined. Permanent neurologic sequelae are present in 25–50% of patients <6 mo old with severe recurrent symptomatic hypoglycemia. These sequelae may be reflected in pathologic changes characterized by reduced myelination in cerebral white matter and atrophy of the cerebral cortex, reflected in enlargement of the sulci and thinning of the gyri of the brain. These sequelae also are more likely when alternative fuel sources are limited, as occurs with hyperinsulinism, 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

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 3-5–fold abrupt increase in glucagon concentration within minutes to hours of birth. The insulin level 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 (GH) secretion by α-adrenergic mechanisms; GH levels are markedly elevated at birth. In addition, cortisol levels are higher in the immediate newborn period in infants born vaginally than by cesarean birth, in part reflecting the stress of labor on fetal cortisol secretion. Acting in concert, these hormonal changes at birth mobilize glucose by 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 approximately 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, followed later 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 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 activity after delivery. Similarly, the activity of the 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. 105.1 ).

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 Fig. 105.1 . 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 per unit of body mass are greater in children. Therefore 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 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, with insulin of central importance. After a meal, plasma insulin concentrations increase to peak levels of 5-10–fold greater than their normal baseline concentration of approximately 5-10 µU/mL, which serves 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 µU/mL, and together with the rise of counter-regulatory hormones, this fall in insulin results in activation of gluconeogenic pathways (see Fig. 105.1 ). 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 ≤55 mg/dL (2.8-3.0 mM), is abnormal, indicating a state of excessive insulin action, termed hyperinsulinism, caused by 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 synergistically and in concert to increase blood glucose concentrations by 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, GH, glucagon); and inhibiting insulin release and promoting GH 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, 4-6 hr in the newborn and 8-12 hr after meals or during fasting in an infant or child. Concurrent deficiency of several hormones ( hypopituitarism-ACTH-cortisol deficiency combined with GH deficiency ) 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 neonates, infants, and children reflect inappropriate adaptation to fasting as a result of (1) excess insulin action, (2) inadequate counter-regulatory hormone response primarily of cortisol and GH, (3) enzymatic defects in the mechanisms for glycogen storage and release, or (4) defects in gluconeogenesis.

Clinical Manifestations

See Chapter 127 .

Clinical features of hypoglycemia generally fall into 2 categories: (1) symptoms associated with the activation of the autonomic nervous system and epinephrine release, usually seen with a rapid decline in blood glucose concentration and (2) symptoms caused by decreased cerebral glucose utilization ( cerebral glucopenia ), usually associated with a slow decline in blood glucose level or prolonged hypoglycemia ( Table 111.1 ). Although these classic symptoms occur in older children, the symptoms of hypoglycemia in newborns and infants may be subtler and include cyanosis, apnea, hypothermia, hypotonia, poor feeding, lethargy, and seizures, all reflecting the deprivation of glucose for normal brain activity. Some of these symptoms may be so mild that they are missed. Occasionally, hypoglycemia may be asymptomatic in the immediate newborn period. Newborns with hyperinsulinism are often large for gestational age (LGA), mimicking the features of the infant born to a mother with poorly controlled diabetes. Older infants with hyperinsulinism 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, headache, hysteria, and developmental delay. A blood glucose determination should always be performed in sick neonates, who should be vigorously treated if concentrations are <55 mg/dL. At any age, hypoglycemia should be considered a cause of an initial episode of convulsions or a sudden deterioration in psychobehavioral functioning or level of consciousness.

Table 111.1
Manifestations of Hypoglycemia in Childhood

Features Associated With Activation of Autonomic Nervous System and Epinephrine Release *

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

  • Anxiety †

    † Common.

  • Perspiration †

  • Palpitation (tachycardia) †

  • Pallor ‡

    ‡ Most common manifestations in the newborn.

  • Tremulousness ‡

  • Weakness

  • Hunger

  • Nausea

  • Emesis

Features Associated With Cerebral Glucopenia

  • Headache †

  • Mental confusion †

  • Visual disturbances (↓ acuity, diplopia) †

  • Organic personality changes †

  • Inability to concentrate †

  • Dysarthria

  • Staring

  • Paresthesias

  • Dizziness

  • Amnesia

  • Ataxia, incoordination

  • Refusal to feed ‡

  • Somnolence, lethargy ‡

  • Seizures ‡

  • Coma

  • Stroke, hemiplegia, aphasia

  • Decerebrate or decorticate posture

Many neonates have asymptomatic (chemical) hypoglycemia. The incidence of symptomatic hypoglycemia is highest in small-for-gestational-age (SGA) infants ( Fig. 111.1 ). 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; CNS anomalies, hemorrhage, or edema; hypocalcemia and hypomagnesemia; asphyxia; drug withdrawal; apnea of prematurity; congenital heart disease; or polycythemia.

Fig. 111.1, Incidence of hypoglycemia by birthweight, gestational age, and intrauterine growth.

The onset of symptoms in neonates varies from a few hours to a week after birth. In approximate order of frequency, symptoms include jitteriness or tremors, apathy, episodes of cyanosis, seizures, intermittent apneic spells or tachypnea, weak or high-pitched cry, limpness or lethargy, difficulty feeding (latching on), and eye rolling. Episodes of sweating, sudden pallor, hypothermia, and cardiac arrest and failure may 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 symptoms disappear with the administration of sufficient glucose to raise the blood glucose 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 111.2 ).

Table 111.2
Classification of Hypoglycemia in Infants and Children

Neonatal Transitional (Adaptive) Hypoglycemia

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

  • Prematurity

  • Small for gestational age

  • Normal newborn

Transient Neonatal Hyperinsulinism

  • Infant of diabetic mother

  • Small for gestational age

  • Discordant twin

  • Birth asphyxia

  • Infant of toxemic mother

Neonatal, Infantile, or Childhood Persistent Hypoglycemia

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

  • Atypical congenital hyperinsulinemia (no mutations in ABCC8 or KCN11 genes)

  • Dominant glucokinase HI

  • Dominant glutamate dehydrogenase HI (hyperinsulinism-hyperammonemia syndrome)

  • Dominant mutations in HNF-4A and HNF-1A (hepatocyte nuclear factors 4α and 1α) HI with monogenic diabetes of youth later in life

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

  • Activating mutations in the calcium channel CACNA1D (permit calcium influx and thus unregulated insulin secretion)

  • Acquired or familial islet adenoma associated with mutations in MEN1 gene

  • Beckwith-Wiedemann syndrome

  • Kabuki 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 (including congenital adrenal hypoplasia, adrenal leukodystrophy, triple A syndrome, ACTH receptor deficiency, and autoimmune disease complex)

  • Epinephrine deficiency

Glycogenolysis and Gluconeogenesis Disorders

  • Glucose-6-phosphatase deficiency (GSD Ia)

  • Glucose-6-phosphate translocase deficiency (GSD Ib)

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

  • Liver phosphorylase deficiency (GSD VI)

  • Phosphorylase kinase deficiency (GSD IX)

  • 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

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