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Kliegman: Nelson Textbook of Pediatrics, 18th ed. Copyright © 2007 Saunders, An Imprint of Elsevier

Chapter 92 – Hypoglycemia

Mark A. Sperling

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 87 ). 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

(see Chapter 107 ). Out of concern for possible neurologic, intellectual, or psychologic sequelae in later life,

many 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. Furthermore, there is a correlation between glucose production and estimated brain weight at all

ages.

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 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

of 25Chapter 92 - Hypoglycemia from Kliegman: Nelson Textbook of Pediatrics on MD Consult

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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 fivefold greater than that of

the adult brain. The capacity of the liver to produce ketone bodies, however, 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. Hypoglycemia may

thus lead to permanent impairment of brain growth and function. The potentiating effects of hypoxia may

exacerbate brain damage or indeed be responsible for it when blood glucose values are not in the classic

hypoglycemic range.

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. Infarcts are

absent if hypoxia-ischemia did not contribute to cerebral manifestations; the cerebellum is spared if

hypoglycemia is the sole insult. 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 (SEE Chapter 107 ).

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 three- to fivefold 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 unison, 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 ≈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. 87-1 ).

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 87-1 . 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. 87-1 ). 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 (SEE Chapter 107 )



Clinical features generally fall into two 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 92-1 ). 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 92-1 ). 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 92-1 -- Manifestations of Hypoglycemia in Childhood

FEATURES ASSOCIATED WITH ACTIVATION OF AUTONOMIC NERVOUS SYSTEM AND EPINEPHRINE

RELEASE [*]

Anxiety [†]

Perspiration [†]

Palpitation (tachycardia) [†]

Pallor

Tremulousness

Weakness

Hunger

Nausea

Emesis

Angina (with normal coronary arteries)

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

Somnolence, lethargy



Many neonates have asymptomatic (chemical) hypoglycemia. In contrast to the frequency of chemical

hypoglycemia, the incidence of symptomatic hypoglycemia is highest in small for gestational age infants ( Fig.

92-1 ). 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.

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.



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, 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 92-

2 ).

TABLE 92-2 -- Classification of Hypoglycemia in Infants and Children

Figure 92-1 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 1971;47:831–838.)

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 KATP

channel HI

Focal KATP

channel HI

Dominant KATP

channel HI

Dominant glucokinase HI

Dominant glutamate dehydrogenase HI (hyperinsulinism/hyperammonemia syndrome)

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

GSD, glycogen storage disease; HI, hyperinsulinemia; KATP

, regulated potassium channel.

Secondary carnitine deficiencies

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

OTHER ETIOLOGIES

Substrate-limited

Ketotic hypoglycemia

Poisoning—drugs

Salicylates

Alcohol

Oral hypoglycemic agents

Insulin

Propranolol



Pentamidine

Quinine

Disopyramide

Ackee fruit (unripe)—hypoglycin

Vacor (rate poison)

Trimethoprim-sulfamethoxazole (with renal failure)

Liver disease

Reye syndrome

Hepatitis

Cirrhosis

Hepatoma

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

Renal failure

Diarrhea

Burns

Shock

Postsurgical

Pseudohypoglycemia (leukocytosis, polycythemia)

Excessive insulin therapy of insulin-dependent diabetes mellitus

Factitious

Nissen fundoplication (dumping syndrome)



NEONATAL, TRANSIENT, SMALL FOR GESTATIONAL AGE, AND PREMATURE INFANTS (SEE Chapter 107 ).

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 92-2 and Fig. 92-1 ). 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

92-2 , 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. In most cases, the condition resolves quickly, but it may

persist to 7 mo of life.

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. Some infants with perinatal

asphyxia and some SGA newborns may have transient hyperinsulinemia, which promotes hypoglycemia and

diminishes the supply of FFAs.

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 uU/ml at the time of hypoglycemia should be treated with diazoxide.

INFANTS BORN TO DIABETIC MOTHERS (See Chapter 107 ).

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 acquire neonatal hypoglycemia and other complications

Falciparum malaria



formerly considered typical of such infants (see Chapter 107 ). In supplying glucose to 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 92-2 .

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.

PERSISTENT OR RECURRENT HYPOGLYCEMIA IN INFANTS AND CHILDREN

HYPERINSULINISM.

Most children with hyperinsulinism that causes hypoglycemia present in the neonatal period or later in

infancy; hyperinsulinism is the most common cause of persistent hypoglycemia in early infancy.

Hyperinsulinemic infants may be macrosomic at birth, reflecting the anabolic effects of insulin in utero. There

is no history or biochemical evidence of maternal diabetes. The onset is from birth to 18 mo of age, but

occasionally it is 1st evident in older children. Insulin concentrations are inappropriately elevated at the time

of documented hypoglycemia; with non-hyperinsulinemic hypoglycemia, plasma insulin concentrations should

be <5 µU/mL and no higher than 10 µU/mL. In affected infants, plasma insulin concentrations at the time of

hypoglycemia are commonly >5–10 µU/mL. Some authorities set more stringent criteria, arguing that any

value of insulin >2 µU/mL with hypoglycemia is abnormal. The insulin (µU/mL): glucose (mg/dL) ratio is

commonly >0.4; plasma insulin-like growth factor binding protein-1 (IGFBP-1), ketones, and FFA levels are

low. Macrosomic infants may present with hypoglycemia from the 1st days of life. Infants with lesser degrees

of hyperinsulinemia, however, may manifest hypoglycemia after the 1st few weeks to months, when the

frequency of feedings has been decreased to permit the infant to sleep through the night and hyperinsulinism

prevents the mobilization of endogenous glucose. Increasing appetite and demands for feeding, wilting

spells, jitteriness, and frank seizures are the most common presenting features. Additional clues include the

rapid development of fasting hypoglycemia within 4–8 hr of food deprivation compared with other causes of

hypoglycemia (Tables 92-3 and 92-4 [3] [4]); the need for high rates of exogenous glucose infusion to prevent

hypoglycemia, often at rates >10–15 mg/kg/min; the absence of ketonemia or acidosis; and elevated C-

peptide or proinsulin levels at the time of hypoglycemia. The latter insulin-related products are also absent in

factitious hypoglycemia from exogenous administration of insulin as a form of child abuse (Munchausen by

proxy syndrome). [See Chapter 36.2 .] Provocative tests with tolbutamide or leucine are not necessary in

infants; hypoglycemia is invariably provoked by withholding feedings for several hours, permitting

simultaneous measurement of glucose, insulin, ketones, and FFAs in the same sample at the time of

clinically manifested hypoglycemia. This is termed the “critical sample.” The glycemic response to glucagon

at the time of hypoglycemia reveals a brisk rise in glucose of at least 40 mg/dL, which implies that glucose

mobilization has been restrained by insulin but that glycogenolytic mechanisms are intact (Tables 92-5, 92-6,

and 92-7 [5] [6] [7]).

TABLE 92-3 -- Hypoglycemia in Infants and Children: Clinical and Laboratory Features

GROUP

AGE AT DIAGNOSIS

(MO)

GLUCOSE

(MG/DL)

INSULIN

(U/ML)

FASTING TIME TO HYPOGLYCEMIA

(HR)

HYPERINSULINEMIA (N = 12)

Mean 7.4 23.1 22.4 2.1

SEM 2.0 2.7 3.2 0.6

NONHYPERINSULINEMIA (N = 16)

Mean 41.8 36.1 5.8 18.2

SEM 7.3 2.4 0.9 2.9

of 25Chapter 92 - Hypoglycemia from Kliegman: Nelson Textbook of Pediatrics on MD Co...


Adapted from Antunes JD, Geffner ME, Lippe BM, et al: Childhood hypoglycemia: Differentiating hyperinsulinemic

from nonhyperinsulinemic causes. J Pediatr 1990;116:105–108.

TABLE 92-4 -- Correlation of Clinical Features with Molecular Defects in Persistent Hyperinsulinemic

Hypoglycemia in Infancy

TYPE MACROSOMIA HYPOGLYCEMIA/HYPERINSULINEMIA

FAMILY

HISTORY

MOLECULAR

DEFECTS

ASSOCIATED

CLINICAL,

BIOCHEMICAL,

OR MOLECULAR

FEATURES

Sporadic Present at birth Moderate/severe in 1st days to weeks of

life

Negative ? SUR1/ KIR6.2

Mutations not always

identified in diffuse

hyperplasia

Loss of

heterozygosity in

microadenomatous

tissue

Autosomal

recessive

Present at birth Severe in 1st days to weeks of life Positive SUR/ KIR6.2 Consanguinity

feature in some

populations

Autosomal

dominant

Unusual Moderate onset usually post 6 mo of age Positive Glucokinase

(activating) Some

cases gene unknown

None

Autosomal

dominant

Unusual Moderate onset usually post 6 mo of age Positive Glutamate

Dehydrogenase

(activating)

Modest

hyperammonemia

Beckwith-

Wiedemann

syndrome

Present at birth Moderate, spontaneously resolves post

6 mo of age

Negative Duplicating/imprinting

in chromosome

11p15.1

Macroglossia,

omphalocele,

hemihypertrophy

Congenital

disorders of

Not usual Moderate/onset post 3 mo of age Negative Phosphomannose

isomerase deficiency

Hepatomegaly,

vomiting,



TABLE 92-5 -- Analysis of Critical Blood Sample During Hypoglycemia and 30 Minutes After Glucagon [*]

TABLE 92-6 -- Criteria for Diagnosing Hyperinsulinism Based on “Critical” Samples (Drawn at a Time of

Fasting Hypoglycemia: Plasma Glucose <50 mg/dL)

glycosylation intractable

diarrhea

SUBSTRATES

Glucose

Free fatty acids

Ketones

Lactate

Uric acid

Ammonia

HORMONES

Insulin

Cortisol

Growth hormone

Thyroxine, thyroid-stimulating hormone

IGFBP-1 [†]

IGFBP-1, insulin-like growth factor binding protein–1.

* Glucagon 50 µg/kg with maximum of 1 mg IV or IM.

† Measure once only before or after glucagon administration. Rise in glucose of ≥40 mg/dL after glucagon given at the time of

hypoglycemia strongly suggests a hyperinsulinemic state with adequate hepatic glycogen stores and intact glycogenolytic enzymes.

If ammonia is elevated to 100–200 µM, consider activating mutation of glutamate dehydrogenase.

1. Hyperinsulinemia (plasma insulin >2 µU/mL) [*]

2. Hypofattyacidemia (plasma free fatty acids <1.5 mmol/L)

3. Hypoketonemia (plasma β-hydroxybutyrate: <2.0 mmol/L)

4. Inappropriate glycemic response to glucagon, 1 mg IV (delta glucose >40 mg/dL)

From Stanley CA, Thomson PS, Finegold DN, et al: Hypoglycemia in Infants and Neonates. In Sperling MA

(editor): Pediatric Endocrinology, 2nd ed., Philadelphia, WB Saunders, 2002, pp 135–159.

TABLE 92-7 -- Diagnosis of Acute Hypoglycemia in Infants and Children

* Depends on sensitivity of insulin assay.

ACUTE SYMPTOMS PRESENT

1. Obtain blood sample before and 30 min after glucagon administration.

2.

Obtain urine as soon as possible. Examine for ketones; if not present and hypoglycemia confirmed,

suspect hyperinsulinemia or fatty acid oxidation defect; if present, suspect ketotic, hormone deficiency,



The measurement of serum IGFBP-1 concentration may help diagnose hyperinsulinemia. The secretion of

IGFBP-1 is acutely inhibited by insulin; IGFBP-1 concentrations are low during hyperinsulinism-induced

hypoglycemia. In patients with spontaneous or fasting-induced hypoglycemia with a low insulin level (ketotic

hypoglycemia, normal fasting), IGFBP-1 concentrations are significantly higher.

The differential diagnosis of endogenous hyperinsulinism includes diffuse β-cell hyperplasia or focal β-cell

microadenoma. The distinction between these two major entities is important because the former, if

unresponsive to medical therapy, requires near total pancreatectomy, despite which hypoglycemia may

persist or diabetes mellitus may ensue at some later time. By contrast, focal adenomas diagnosed

preoperatively or intraoperatively permit localized curative resection with subsequent normal glucose

metabolism. About 50% of the autosomal recessive or sporadic forms of neonatal/infantile hyperinsulinism

are due to focal microadenomas, which may be distinguished from the diffuse form by the pattern of insulin

response to selective insulin secretagogues infused into an artery supplying the pancreas with sampling via

the hepatic vein. Positron emission tomography (PET scanning) using 18 fluoro-L-dopa can distinguish the

diffuse form (uniform fluorescence throughout the pancreas) from the focal form (focal uptake of 18 fluoro-L-

dopa and localized fluorescence) [See Fig. 92-3 .].

inborn error of glycogen metabolism, or defective gluconeogenesis.

3. Measure glucose in the original blood sample. If hypoglycemia is confirmed, proceed with

substratehormone measurement as in Table 92-5 .

4. If glycemic increment after glucagon exceeds 40 mg/dL above basal, suspect hyperinsulinemia.

5. If insulin level at time of confirmed hypoglycemia is >5 µU/mL, suspect endogenous hyperinsulinemia;

if >100 µU/mL, suspect factitious hyperinsulinemia (exogenous insulin injection). Admit to hospital for

supervised fast.

6. If cortisol is <10 µg/dL or growth hormone is <5 ng/mL, or both, suspect adrenal insufficiency or

pituitary disease, or both. Admit to hospital for hormonal testing and neuroimaging.

HISTORY SUGGESTIVE: ACUTE SYMPTOMS NOT PRESENT

1. Careful history for relation of symptoms to time and type of food intake, bearing in mind age of patient.

Exclude possibility of alcohol or drug ingestion. Assess possibility of insulin injection, salt craving,

growth velocity, intracranial pathology.

2. Careful examination for hepatomegaly (glycogen storage disease; defect in gluconeogenesis);

pigmentation (adrenal failure); stature and neurologic status (pituitary disease)

3. Admit to hospital for provocative testing:

a. 24 hr fast under careful observation; when symptoms provoked, proceed with steps 1–4 as

when acute symptoms present

b. Pituitary-adrenal function using arginine-insulin stimulation test if indicated

4. Liver biopsy for histologic and enzyme determinations if indicated

5. Oral glucose tolerance test (1.75 g/kg;max 75 g) if reactive hypoglycemia suspected (dumping

syndrome, etc.)



Insulin-secreting macroadenomas are rare in childhood and may be diagnosed preoperatively via CT or MRI.

The plasma levels of insulin alone, however, cannot distinguish the aforementioned entities. The diffuse or

microadenomatous forms of islet cell hyperplasia represent a variety of genetic defects responsible for

abnormalities in the endocrine pancreas characterized by autonomous insulin secretion that is not

appropriately reduced when blood glucose declines spontaneously or in response to provocative maneuvers

such as fasting (see Tables 92-7 and 92-8 [7] [8]). Clinical, biochemical, and molecular genetic approaches

now permit classification of congenital hyperinsulinism, formerly termed nesidioblastosis, into distinct

entities. Persistent hyperinsulinemic hypoglycemia of infancy (PHHI) may be inherited or sporadic, is

severe, and is caused by mutations in the regulation of the potassium channel intimately involved in insulin

secretion by the pancreatic β cell ( Fig. 92-2 ). Normally, glucose entry into the β cell is enabled by the non–

insulin-responsive glucose transporter GLUT-2. On entry, glucose is phosphorylated to glucose-6-phosphate

by the enzyme glucokinase, enabling glucose metabolism to generate ATP. The rise in the molar ratio of ATP

relative to adenosine diphosphate (ADP) closes the ATP-sensitive potassium channel in the cell membrane (KATP channel). This channel is composed of two subunits, the KIR 6.2 channel, part of the family of inward-

rectifier potassium channels, and a regulatory component in intimate association with KIR 6.2 known as the

sulfonylurea receptor (SUR). Together, KIR 6.2 and SUR constitute the potassium-sensitive ATP channel

KATP. Normally, the KATP is open, but with the rise in ATP and closure of the channel, potassium accumulates

intracellularly, causing depolarization of the membrane, opening of voltage-gated calcium channels, influx of calcium into the cytoplasm, and secretion of insulin via exocytosis. The genes for both SUR and KIR 6.2 are

located close together on the short arm of chromosome 11, the site of the insulin gene. Inactivating mutations in the gene for SUR or, less often, KIR 6.2 prevent the potassium channel from opening. It remains essentially

closed with constant depolarization and, therefore, constant inward flux of calcium; hence, insulin secretion is

continuous. A milder autosomal dominant form of these defects is also reported. Likewise, an activating

mutation in glucokinase or glutamate dehydrogenase results in closure of the potassium channel through

overproduction of ATP and hyperinsulinism. Inactivating mutations of the glucokinase gene are responsible

for inadequate insulin secretion and form the basis of maturity-onset diabetes of youth (see Chapter 590 ).

TABLE 92-8 -- Clinical Manifestations and Differential Diagnosis in Childhood Hypoglycemia

Figure 92-3 Congenital hyperinsulinism. I panels (Diffuse): [18F]-DOPA PET of patient with diffuse form of congenital

hyperinsulinism. A, Diffuse uptake of [18F]-DOPA is visualized throughout the pancreas. Transverse views show B, normal

pancreatic tissue on abdominal CT; C, diffuse uptake of [18F]-DOPA in pancreas; and D, confirmation of pancreatic uptake of

[18F]-DOPA with coregistration. H, head of pancreas; T, tail of pancreas. II panels (Focal): [18F]-DOPA PET of patient with focal

form of congenital hyperinsulinism. A, Discrete area of increased [18F]-DOPA uptake is visualized in the head of the pancreas.

The intensity of this area is greater than that observed in the liver and neighboring normal pancreatic tissue. Transverse views

show B, normal pancreatic tissue on abdominal CT; C, focal uptake of [18F]-DOPA in pancreatic head; and D, confirmation of

[18F]-DOPA uptake in the pancreatic head with coregistration. (Courtesy of Dr Olga Hardy, Children's Hospital of Philadelphia).



CONDITION HYPOGLYCEMIA

URINARY

KETONES

OR

REDUCING

SUGARS HEPATOMEGALY SERUM EFFECT OF 24

Normal 0 0 0 LIPIDS URIC

ACID

GLUCOSE INSULIN

Hyperinsulinemia Recurrent severe 0 0 Normal Normal ↓ ↓

Ketotic

hypoglycemia

Severe with

missed meals

Ketonuria

+++

0 Normal

or ↑

Normal ↓↓ ↑↑

Fatty acid

oxidation

disorder

Severe with

missed meals

Absent 0 to + Abnormal

liver function test

results

Normal Normal ↓↓ ↓

Hypopituitarism Moderate with

missed meals

Ketonuria

++

0 Abnormal ↑ Contraindicated

Adrenal

insufficiency

Severe with

missed meals

Ketonuria

++

0 Normal Normal ↓↓ ↓

Enzyme

deficiencies

Severe-constant Ketonuria

+++

+++ Normal Normal ↓↓ ↓

Glucose-6-

phosphatase

debrancher

Moderate with

fasting

Ketonuria

++

++ ↑↑ ↑↑ ↓↓ ↓

Phosphorylase Mild-moderate Ketonuria

++

+ Normal Normal ↓↓ ↓

Fructose-1,6-

diphosphatase

Severe with

fasting

Ketonuria

+++

+++ Normal Normal ↓ ↓

Galactosemia After milk or milk

products

0 Ketones;

(s) +

+++ ↑↑ ↑↑ ↓↓ ↓

Fructose

intolerance

After fructose 0 Ketones;

(s) +

+++ Normal Normal ↓ ↓

Normal Normal ↓ ↓

Details of each condition are discussed in the text. 0, absence; ↑ or ↓ indicates respectively small increase

or decrease; ↑↑ or ↓↓ indicates respectively large increase or decrease.



The familial forms of PHHI are more common in certain populations, notably Arabic and Ashkenazi Jewish

communities, where it may reach an incidence of about 1/2,500, compared with the sporadic rates in the

general population of ≈1/50,000. These autosomal recessive forms of PHHI typically present in the

immediate newborn period as macrosomic newborns with a weight >4.0 kg and severe recurrent or persistent

hypoglycemia manifesting in the initial hours or days of life. Glucose infusions as high as 15–20 mg/kg/min and frequent feedings fail to maintain euglycemia. Diazoxide, which acts by opening KATP channels (see Fig.

92-2 ), fails to control hypoglycemia adequately. Somatostatin, which also opens KATP and inhibits calcium

flux, may be partially effective in ≈50% of patients (see Fig. 92-2 ). Calcium channel blocking agents have

had inconsistent effects. When affected patients are unresponsive to these measures, pancreatectomy is

strongly recommended to avoid the long-term neurologic sequelae of hypoglycemia. If surgery is undertaken,

preoperative CT or MRI rarely reveals an isolated adenoma, which would then permit local resection.

Intraoperative ultrasonography may identify a small impalpable adenoma, permitting local resection.

Adenomas often present in late infancy or early childhood. Distinguishing between focal and diffuse cases of

Figure 92-2 Schematic representation of the pancreatic cell with some important steps in insulin secretion. The membrane-

spanning, adenosine triphosphate (ATP)–sensitive potassium (K + ) channel (KATP

) consists of two subunits: the sulfonylurea

receptor (SUR) and the inward rectifying K channel (KIR 6.2). In the resting state, the ratio of ATP to adenosine diphosphate

(ADP) maintains KATP

in an open state, permitting efflux of intracellular K + . When blood glucose concentration rises, its entry

into the β cell is facilitated by the GLUT-2 glucose transporter, a process not regulated by insulin. Within the β cell, glucose is

converted to glucose-6-phosphate by the enzyme glucokinase and then undergoes metabolism to generate energy. The

resultant increase in ATP relative to ADP closes KATP

, preventing efflux of K + , and the rise of intracellular K + depolarizes the

cell membrane and opens a calcium (Ca 2+ ) channel. The intracellular rise in Ca 2+ triggers insulin secretion via exocytosis.

Sulfonylureas trigger insulin secretion by reacting with their receptor (SUR) to close KATP

; diazoxide inhibits this process,

whereas somatostatin, or its analog octreotide, inhibits insulin secretion by interfering with calcium influx. Genetic mutations in

SUR or KIR 6.2 that prevent K

ATP from being open are responsible for autosomal recessive forms of persistent hyperinsulinemic

hypoglycemia of infancy (PHHI). One form of autosomal dominant PHHI is due to an activating mutation in glucokinase. The

amino acid leucine also triggers insulin secretion by closure of KATP

. Metabolism of leucine is facilitated by the enzyme

glutamate dehydrogenase (GDH), and overactivity of this enzyme in the pancreas leads to hyperinsulinemia with hypoglycemia,

associated with hyperammonemia from overactivity of GDH in the liver. ✓, stimulation; GTP, guanosine triphosphate; X,

inhibition.



persistent hyperinsulinism has been attempted in several ways. Preoperatively, transhepatic portal vein

catheterization and selective pancreatic venous sampling to measure insulin may localize a focal lesion from

the step-up in insulin concentration at a specific site. Selective catheterization of arterial branches supplying

the pancreas, followed by infusion of a secretagogue such as calcium and portal vein sampling for insulin

concentration (arterial stimulation-venous sampling) may localize a lesion. Both approaches are highly

invasive, restricted to specialized centers, and not uniformly successful in distinguishing the focal from the

diffuse forms. 18F-labeled L-dopa combined with PET scanning is a promising means to distinguish the focal

from the diffuse lesions of hyperinsulinism unresponsive to medical management ( Fig. 92-3 ). The “gold

standard” remains intraoperative histologic characterization. Diffuse hyperinsulinism is characterized by large

β cells with abnormally large nuclei, whereas focal adenomatous lesions display small and normal β cell

nuclei. Although SUR1 mutations are present in both types, the focal lesions arise by a random loss of a

maternally imprinted growth-inhibitory gene on maternal chromosome 11p in association with paternal transmission of a mutated SUR1 or KIR 6.2 paternal chromosome 11p. Thus the focal form represents a

double hit-loss of maternal repressor and transmission of a paternal mutation. Local excision of focal

adenomatous islet cell hyperplasia results in a cure with little or no recurrence. For the diffuse form, near-total

resection of 85–90% of the pancreas is recommended. The near-total pancreatectomy required for the diffuse

hyperplastic lesions is, however, often associated with persistent hypoglycemia with the later development of

hyperglycemia or frank, insulin-requiring diabetes mellitus.

Further resection of the remaining pancreas may occasionally be necessary if hypoglycemia recurs and

cannot be controlled by medical measures, such as the use of somatostatin or diazoxide.

Experienced pediatric surgeons in medical centers equipped to provide the necessary preoperative and

postoperative care, diagnostic evaluation, and management should perform surgery. In some patients who

have been managed medically, hyperinsulinemia and hypoglycemia regress over months. This is similar to

what occurs in children with the hyperinsulinemic hypoglycemia seen in Beckwith-Wiedemann syndrome.

If hypoglycemia 1st manifests between 3 and 6 mo of age or later, a therapeutic trial using medical

approaches with diazoxide, somatostatin, and frequent feedings can be attempted for up to 2–4 wk. Failure to

maintain euglycemia without undesirable side effects from the drugs may prompt the need for surgery. Some

success in suppressing insulin release and correcting hypoglycemia in patients with PHHI has been reported

with the use of the long-acting somatostatin analog octreotide. Most cases of neonatal PHHI are sporadic;

familial forms permit genetic counseling on the basis of anticipated autosomal recessive inheritance.

A 2nd form of familial PHHI suggests autosomal dominant inheritance. The clinical features tend to be less

severe, and onset of hypoglycemia is most likely, but not exclusively, to occur beyond the immediate

newborn period and usually beyond the period of weaning at an average age at onset of about 1 yr. At birth,

macrosomia is rarely observed, and response to diazoxide is almost uniform. The initial presentation may be

delayed and rarely occur as late as 30 yr, unless provoked by fasting. The genetic basis for this autosomal dominant form has not been delineated; it is not always linked to KIR 6.2/SUR1. However, the activating

mutation in glucokinase is transmitted in an autosomal dominant manner. If a family history is present,

genetic counseling for a 50% recurrence rate can be given for future offspring.

A 3rd form of persistent PHHI is associated with mild and asymptomatic hyperammonemia, usually as a

sporadic occurrence, although dominant inheritance occurs. Presentation is more like the autosomal

dominant form than the autosomal recessive form. Diet and diazoxide control symptoms, but pancreatectomy

may be necessary in some cases. The association of hyperinsulinism and hyperammonemia is caused by an

inherited or de novo gain-of-function mutation in the enzyme glutamate dehydrogenase. The resulting

increase in glutamate oxidation in the pancreatic β cell raises the ATP concentration and, hence, the ratio of ATP: ADP, which closes K

ATP, leading to membrane depolarization, calcium influx, and insulin secretion (see

Fig. 92-2 ). In the liver, the excessive oxidation of glutamate to β-ketoglutarate may generate ammonia and

divert glutamate from being processed to N-acetylglutamate, an essential cofactor for removal of ammonia

through the urea cycle via activation of the enzyme carbamoyl phosphate synthetase. The hyperammonemia

is mild, with concentrations of 100–200 µM/L, and produces no CNS symptoms or consequences, as seen in

other hyperammonemic states. Leucine, a potent amino acid for stimulating insulin secretion and implicated

in leucine-sensitive hypoglycemia, acts by allosterically stimulating glutamate dehydrogenase. Thus, leucine-

sensitive hypoglycemia may be a form of the hyperinsulinemia-hyperammonemia syndrome or a



potentiation of mild disorders of the KATP

channel.

Hypoglycemia associated with hyperinsulinemia is also seen in ≈50% of patients with the Beckwith-

Wiedemann syndrome. This syndrome is characterized by omphalocele, gigantism, macroglossia,

microcephaly, and visceromegaly. Distinctive lateral earlobe fissures and facial nevus flammeus are present;

hemihypertrophy occurs in many of these infants. Diffuse islet cell hyperplasia occurs in infants with

hypoglycemia. The diagnostic and therapeutic approaches are the same as those discussed previously,

although microcephaly and retarded brain development may occur independently of hypoglycemia. Patients

with the Beckwith-Wiedemann syndrome may acquire tumors, including Wilms tumor, hepatoblastoma,

adrenal carcinoma, gonadoblastoma, and rhabdomyosarcoma. This overgrowth syndrome is caused by mutations in the chromosome 11p15.5 region close to the genes for insulin, SUR, KIR 6.2, and IGF-2.

Duplications in this region and genetic imprinting from a defective or absent copy of the maternally derived

gene are involved in the variable features and patterns of transmission. Hypoglycemia may resolve in weeks

to months of medical therapy. Pancreatic resection may also be needed.

Hyperinsulinemic hypoglycemia in infancy is reported as a manifestation of one form of congenital disorder of

glycosylation. Disorders of protein glycosylation usually present with neurologic symptoms but may also

include liver dysfunction with hepatomegaly, intractable diarrhea, protein-losing enteropathy, and

hypoglycemia (see Chapter 87.6 ). These disorders are often underdiagnosed. One entity associated with

hyperinsulinemic hypoglycemia is caused by phosphomannose isomerase deficiency, and clinical

improvement followed supplemental treatment with oral mannose at a dose of 0.17 g/kg six times per day.

After the 1st 12 mo of life, hyperinsulinemic states are uncommon until islet cell adenomas reappear as a

cause after the patient is several years of age. Hyperinsulinemia due to islet cell adenoma should be

considered in any child 5 yr or older presenting with hypoglycemia. The diagnostic approach is outlined in

Tables 92-7 and 92-8 [7] [8]. Fasting for up to 24–36 hr usually provokes hypoglycemia; coexisting

hyperinsulinemia confirms the diagnosis, provided that factitious administration of insulin by the parents, a

form of Munchausen syndrome by proxy, is excluded. Occasionally, provocative tests may be required.

Exogenously administered insulin can be distinguished from endogenous insulin by simultaneous

measurement of C-peptide concentration. If C-peptide levels are elevated, endogenous insulin secretion is

responsible for the hypoglycemia; if C-peptide levels are low but insulin values are high, exogenous insulin

has been administered, perhaps as a form of child abuse. Islet cell adenomas at this age are treated by

surgical excision; familial multiple endocrine adenomatosis type I (Wermer syndrome) should be considered.

Antibodies to insulin or the insulin receptor (insulin mimetic action) are also rarely associated with

hypoglycemia. Some tumors produce insulin-like growth factors, thereby provoking hypoglycemia by

interacting with the insulin receptor. The astute clinician must also consider the possibility of deliberate or

accidental ingestion of drugs such as a sulfonylurea or related compound that stimulates insulin secretion. In

such cases, insulin and C-peptide concentrations in blood will be elevated. Inadvertent substitution of an

insulin secretagogue by a dispensing error should be considered in those taking medications who suddenly

develop documented hypoglycemia.

A rare form of hyperinsulinemic hypoglycemia has been reported after exercise. Whereas glucose and insulin

remain unchanged in most people after moderate, short-term exercise, rare patients manifest severe

hypoglycemia with hyperinsulinemia 15–50 min after the same standardized exercise. This form of exercise-

induced hyperinsulinism may be caused by an abnormal responsiveness of β-cell insulin release in response

to pyruvate generated during exercise.

Nesidioblastosis has also rarely been reported after bariatric surgery for obesity.

ENDOCRINE DEFICIENCY.

Hypoglycemia associated with endocrine deficiency is usually caused by adrenal insufficiency with or without

associated growth hormone deficiency (see Chapters 558 and 576 ). In panhypopituitarism, isolated

adrenocorticotropic hormone (ACTH) or growth hormone deficiency, or combined ACTH deficiency plus

growth hormone deficiency, the incidence of hypoglycemia is as high as 20%. In the newborn period,

hypoglycemia may be the presenting feature of hypopituitarism; in males, a microphallus may provide a clue

to a coexistent deficiency of gonadotropin. Newborns with hypopituitarism often have a form of “hepatitis” and

the syndrome of septo-optic dysplasia. When adrenal disease is severe, as in congenital adrenal



hyperplasia caused by cortisol synthetic enzyme defects, adrenal hemorrhage, or congenital absence of the

adrenal glands, disturbances in serum electrolytes with hyponatremia and hyperkalemia or ambiguous

genitals may provide diagnostic clues (see Chapter 577 ). In older children, failure of growth should suggest

growth hormone deficiency. Hyperpigmentation may provide the clue to Addison disease with increased

ACTH levels or adrenal unresponsiveness to ACTH owing to a defect in the adrenal receptor for ACTH. The

frequent association of Addison disease in childhood with hypoparathyroidism (hypocalcemia), chronic

mucocutaneous candidiasis, and other endocrinopathies should be considered. Adrenoleukodystrophy

should also be considered in the differential diagnosis of primary Addison disease in older children (see

Chapter 86.2 ).

Hypoglycemia in cortisol–growth hormone deficiency may be caused by decreased gluconeogenic enzymes

with cortisol deficiency, increased glucose utilization due to a lack of the antagonistic effects of growth

hormone on insulin action, or failure to supply endogenous gluconeogenic substrate in the form of alanine

and lactate with compensatory breakdown of fat and generation of ketones. Deficiency of these hormones

results in reduced gluconeogenic substrate, which resembles the syndrome of ketotic hypoglycemia.

Investigation of a child with hypoglycemia, therefore, requires exclusion of ACTH-cortisol or growth hormone

deficiency and, if diagnosed, its appropriate replacement with cortisol or growth hormone.

Epinephrine deficiency could theoretically be responsible for hypoglycemia. Urinary excretion of

epinephrine has been diminished in some patients with spontaneous or insulin-induced hypoglycemia in

whom absence of pallor and tachycardia was also noted, suggesting that failure of catecholamine release,

due to a defect anywhere along the hypothalamic-autonomic-adrenomedullary axis, might be responsible for

the hypoglycemia. This possibility has been challenged, owing to the rarity of hypoglycemia in patients with

bilateral adrenalectomy, provided that they receive adequate glucocorticoid replacement, and because

diminished epinephrine excretion is found in normal patients with repeated insulin-induced hypoglycemia.

Many of the patients described as having hypoglycemia with failure of epinephrine excretion fit the criteria for

ketotic hypoglycemia.

Glucagon deficiency in infants or children may rarely be associated with hypoglycemia.

SUBSTRATE LIMITED

Ketotic Hypoglycemia.

This is the most common form of childhood hypoglycemia. This condition usually presents between the ages

of 18 mo and 5 yr and remits spontaneously by the age of 8–9 yr. Hypoglycemic episodes typically occur

during periods of intercurrent illness when food intake is limited. The classic history is of a child who eats

poorly or completely avoids the evening meal, is difficult to arouse from sleep the following morning, and may

have a seizure or be comatose by midmorning. Another common presentation occurs when parents sleep

late and the affected child is unable to eat breakfast, thus prolonging the overnight fast.

At the time of documented hypoglycemia, there is associated ketonuria and ketonemia; plasma insulin

concentrations are appropriately low, ≤5–10 µU/mL, thus excluding hyperinsulinemia. A ketogenic

provocative diet, formerly used as a diagnostic test, is not essential to establish the diagnosis because fasting

alone provokes a hypoglycemic episode with ketonemia and ketonuria within 12–18 hr in susceptible

individuals. Normal children of similar age can withstand fasting without hypoglycemia developing during the

same period, although even normal children may acquire these features by 36 hr of fasting.

Children with ketotic hypoglycemia have plasma alanine concentrations that are markedly reduced in the

basal state after an overnight fast and decline even further with prolonged fasting. Alanine, produced in

muscle, is a major gluconeogenic precursor. Alanine is the only amino acid that is significantly lower in these

children, and infusions of alanine (250 mg/kg) produce a rapid rise in plasma glucose without causing

significant changes in blood lactate or pyruvate levels, indicating that the entire gluconeogenic pathway from

the level of pyruvate is intact, but that there is a deficiency of substrate. Glycogenolytic pathways are also

intact because glucagon induces a normal glycemic response in affected children in the fed state. The levels

of hormones that counter hypoglycemia are appropriately elevated, and insulin is appropriately low.

The etiology of ketotic hypoglycemia may be a defect in any of the complex steps involved in protein



catabolism, oxidative deamination of amino acids, transamination, alanine synthesis, or alanine efflux from

muscle. Children with ketotic hypoglycemia are frequently smaller than age-matched controls and often have

a history of transient neonatal hypoglycemia. Any decrease in muscle mass may compromise the supply of

gluconeogenic substrate at a time when glucose demands per unit of body weight are already relatively high,

thus predisposing the patient to the rapid development of hypoglycemia, with ketosis representing the attempt

to switch to an alternative fuel supply. Children with ketotic hypoglycemia may represent the low end of the

spectrum of children's capacity to tolerate fasting. Similar relative intolerance to fasting is present in normal

children, who cannot maintain blood glucose after 30–36 hr of fasting, compared with the adult's capacity for

prolonged fasting. Although the defect may be present at birth, it may not be evident until the child is stressed

by more prolonged periods of calorie restriction. Moreover, the spontaneous remission observed in children

at age 8–9 yr might be explained by the increase in muscle bulk with its resultant increase in supply of

endogenous substrate and the relative decrease in glucose requirement per unit of body mass with

increasing age. There is also some evidence to support the contention that impaired epinephrine secretion

from immaturity of autonomic innervation contributes to ketotic hypoglycemia. Rarely, inborn errors of fatty

acid metabolism present as ketotic hypoglycemia, although, typically, fatty acid oxidation defects produce

hypoketotic hypoglycemia.

In anticipation of spontaneous resolution of this syndrome, treatment of ketotic hypoglycemia consists of

frequent feedings of a high-protein, high-carbohydrate diet. During intercurrent illnesses, parents should test

the child's urine for the presence of ketones, the appearance of which precedes hypoglycemia by several

hours. In the presence of ketonuria, liquids of high carbohydrate content should be offered to the child. If

these cannot be tolerated, the child should be admitted to the hospital for intravenous glucose administration.

Branched-Chain Ketonuria (Maple Syrup Urine Disease) [See Chapter 85.6 ].

The hypoglycemic episodes were once attributed to high levels of leucine, but evidence indicates that

interference with the production of alanine and its availability as a gluconeogenic substrate during calorie

deprivation is responsible for hypoglycemia.

GLYCOGEN STORAGE DISEASE.

See Chapter 87.1 .

Glucose-6-Phosphatase Deficiency (Type I Glycogen Storage Disease).

Affected children usually display a remarkable tolerance to their chronic hypoglycemia; blood glucose values

in the range of 20–50 mg/dL are not associated with the classic symptoms of hypoglycemia, possibly

reflecting the adaptation of the CNS to ketone bodies as an alternative fuel.

Affected untreated children manifest growth failure, mental retardation, and a shortened life span unless they

are treated. Continuous intragastric feeding improves the metabolic and clinical findings by reducing the

frequency and severity of hypoglycemia, thereby avoiding the secondary hormonal changes that appear to be

responsible for the metabolic derangements. Continuous intragastric feeding at night, combined with frequent

daytime feedings, produces equally effective amelioration of the biochemical disturbances and avoids the

inconvenience of 24 hr continuous gastric feeding. The daytime feedings are given every 3–4 hr: 60–70% of

the calories as carbohydrate low in fructose and galactose, 12–15% of the calories as protein, and 15–25% of

the calories as fat. At night, a small nasogastric tube is passed by the patient (or a parent for younger

children), and approximately one third of the daily caloric requirements is continuously infused over 8–12 hr

using a small continuous infusion pump. One commercially available formula for nocturnal infusion contains

89% of the calories as glucose and glucose oligosaccharides, 1.8% as safflower oil, and 9.2% as crystalline

amino acids (Vivonex, Novartis Nutrition, St. Louis Park MN 55416). Nocturnal cornstarch therapy is also

beneficial. Transient nocturnal hypoglycemia is not completely prevented, and renal glomerular dysfunction

plus formation of hepatic adenoma remain serious complications. Liver transplantation offers promise of long-

term cure.

Amylo-1,6-Glucosidase Deficiency (Debrancher Enzyme Deficiency; Type III Glycogen Storage Disease).

See Chapter 87 .



Liver Phosphorylase Deficiency (Type VI Glycogen Storage Disease) [See Chapter 87 ].

Low hepatic phosphorylase activity may result from a defect in any of the steps of activation; a variety of

defects have been described. Hepatomegaly, excessive deposition of glycogen in liver, growth retardation,

and occasional symptomatic hypoglycemia occur. A diet high in protein and reduced in carbohydrate usually

prevents hypoglycemia.

Glycogen Synthetase Deficiency (See Chapter 87 ).

The inability to synthesize glycogen is rare. There is hypoglycemia and hyperketonemia after fasting because

glycogen reserves are markedly diminished or absent. After feeding, however, hyperglycemia with glucosuria

may occur because of the inability to assimilate some of the glucose load into glycogen. During fasting

hypoglycemia, levels of the counter-regulatory hormones, including catecholamines, are appropriately

elevated or normal, and insulin levels are appropriately low. The liver is not enlarged. Protein-rich feedings at

frequent intervals result in dramatic clinical improvement, including growth velocity. This condition mimics the

syndrome of ketotic hypoglycemia and should be considered in the differential diagnosis of that syndrome.

DISORDERS OF GLUCONEOGENESIS

Fructose-1,6-Diphosphatase Deficiency (See Chapter 87.3 ).

A deficiency of this enzyme results in a block of gluconeogenesis from all possible precursors below the level

of fructose-1,6-diphosphate. Infusion of these gluconeogenic precursors results in lactic acidosis without a

rise in glucose; acute hypoglycemia may be provoked by inhibition of glycogenolysis. Glycogenolysis remains

intact, and glucagon elicits a normal glycemic response in the fed, but not in the fasted, state. Accordingly,

affected individuals have hypoglycemia only during caloric deprivation, as in fasting, or during intercurrent

illness. As long as glycogen stores remain normal, hypoglycemia does not develop. In affected families, there

may be a history of siblings with known hepatomegaly who died in infancy with unexplained metabolic

acidosis.

Clinical features simulate those of type I glycogen storage disease. Hepatomegaly in individuals with

fructose-1,6-diphosphatase deficiency is due to lipid storage rather than glycogen storage. Lactic acidosis,

ketosis, hyperlipidemia, and hyperuricemia occur; their pathogenesis is related to the severity and duration of

hypoglycemia and the resultant low levels of insulin and high levels of counter-regulatory hormones. Therapy

for these infants, consisting of a diet high in carbohydrates (56%, excluding fructose, which cannot be

utilized), low in protein (12%), and normal in fat composition (32%), has permitted normal growth and

development. Continuous nocturnal provision of calories through the intragastric infusion system described

earlier for type I glycogen storage disease is also applicable to children with fructose-1,6-diphosphatase

deficiency. During intercurrent illnesses with vomiting, intravenous glucose infusion is necessary to prevent

severe hypoglycemia.

Defects in Fatty Acid Oxidation (See Chapter 86 ).

The important role of fatty acid oxidation in maintaining gluconeogenesis is underscored by examples of

congenital or drug-induced defects in fatty acid metabolism that may be associated with fasting

hypoglycemia.

Various congenital enzymatic deficiencies causing defective carnitine or fatty acid metabolism occur. A

severe and relatively common form of fasting hypoglycemia with hepatomegaly, cardiomyopathy, and

hypotonia occurs with long- and medium-chain fatty acid coenzyme-A dehydrogenase deficiency (LCAD and

MCAD). Plasma carnitine levels are low, ketones are not present in urine, but dicarboxylic aciduria is present.

Clinically, patients with acyl CoA dehydrogenase deficiency present with a Reye-like syndrome (see

Chapter 358 ), recurrent episodes of severe fasting hypoglycemic coma, and cardiorespiratory arrest (sudden

infant death syndrome–like events). Severe hypoglycemia and metabolic acidosis without ketosis also occur

in patients with multiple acyl CoA dehydrogenase disorders. Hypotonia, seizures, and acrid odor are other

clinical clues. Survival depends on whether the defects are severe or mild; diagnosis is established from

studies of enzyme activity in liver biopsy tissue or in cultured fibroblasts from affected patients. Tandem mass

spectrometry can be employed for blood samples, even those on filter paper, for screening of congenital



inborn errors. The frequency of this disorder is at least 1/10,000–15,000 births. Avoidance of fasting and

supplementation with carnitine may be lifesaving in these patients who generally present in infancy.

Interference with fatty acid metabolism also underlies the fasting hypoglycemia associated with Jamaican

vomiting sickness, with atractyloside, and with the drug valproate. In Jamaican vomiting sickness, the

unripe ackee fruit contains a water-soluble toxin, hypoglycin, which produces vomiting, CNS depression, and

severe hypoglycemia. The hypoglycemic activity of hypoglycin derives from its inhibition of gluconeogenesis

secondary to its interference with the acyl CoA and carnitine metabolism essential for the oxidation of long-

chain fatty acids. The disease is almost totally confined to Jamaica, where ackee forms a staple of the diet for

the poor. The ripe ackee fruit no longer contains this toxin. Atractyloside is a reagent that inhibits oxidative

phosphorylation in mitochondria by preventing the translocation of adenine nucleotides, such as ATP, across

the mitochondrial membrane. Atractyloside is a perhydrophenanthrenic glycoside derived from Atractylis

gummifera. This plant is found in the Mediterranean basin; ingestion of this “thistle” is associated with

hypoglycemia and a syndrome similar to Jamaican vomiting sickness. The anticonvulsant drug valproate is

associated with side effects, predominantly in young infants, which include a Reye-like syndrome, low serum

carnitine levels, and the potential for fasting hypoglycemia. In all these conditions, hypoglycemia is not

associated with ketonuria.

Acute Alcohol Intoxication.

The liver metabolizes alcohol as a preferred fuel, and generation of reducing equivalents during the oxidation

of ethanol alters the NADH: NAD ratio, which is essential for certain gluconeogenic steps. As a result,

gluconeogenesis is impaired and hypoglycemia may ensue if glycogen stores are depleted by starvation or

by pre-existing abnormalities in glycogen metabolism. In toddlers who have been unfed for some time, even

the consumption of small quantities of alcohol can precipitate these events. The hypoglycemia promptly

responds to intravenous glucose, which should always be considered in a child who presents initially with

coma or seizure, after taking a blood sample to determine glucose concentration. The possibility of the child's

ingesting alcoholic drinks must also be considered if there was a preceding adult evening party. A careful

history allows the diagnosis to be made and may avoid needless and expensive hospitalization and

investigation.

Salicylate Intoxication (See Chapter 58 ).

Both hyperglycemia and hypoglycemia occur in children with salicylate intoxication. Accelerated utilization of

glucose, resulting from augmentation of insulin secretion by salicylates, and possible interference with

gluconeogenesis may contribute to hypoglycemia. Infants are more susceptible than are older children.

Monitoring of blood glucose levels with appropriate glucose infusion in the event of hypoglycemia should form

part of the therapeutic approach to salicylate intoxication in childhood. Ketosis may occur.

Phosphoenol Pyruvate Carboxykinase Deficiency.

Deficiency of this rate-limiting gluconeogenic enzyme is associated with severe fasting hypoglycemia and

variable onset after birth. Hypoglycemia may occur within 24 hr after birth, and defective gluconeogenesis

from alanine can be documented in vivo. Liver, kidney, and myocardium demonstrate fatty infiltration, and

atrophy of the optic nerve and visual cortex may occur. Hypoglycemia may be profound. Lactate and

pyruvate levels in plasma have been normal, but a mild metabolic acidosis may be present. The fatty

infiltration of various organs is caused by increased formation of acetyl CoA, which becomes available for

fatty acid synthesis. Diagnosis of this rare entity can be made with certainty only through appropriate

enzymatic determinations in liver biopsy material. Avoidance of periods of fasting through frequent feedings

rich in carbohydrate should be helpful because glycogen synthesis and breakdown are intact.

Pyruvate Carboxylase Deficiency (See Chapter 87 ).

This is predominantly a disease of the CNS characterized by a subacute necrotizing encephalomyelopathy

and high levels of blood lactate and pyruvate. Hypoglycemia is not a prominent feature of this syndrome,

presumably because gluconeogenesis from precursors other than alanine remains intact, and these

precursors bypass the pyruvate carboxylase step. The utilization of alanine as well as lactate through

pyruvate cannot proceed, however, so these substrates accumulate in blood, and modest hypoglycemia may



result during fasting. Affected patients usually die of progressive CNS disease.

OTHER ENZYME DEFECTS

Galactosemia (Galactose-1-Phosphate Uridyl Transferase Deficiency).

See Chapter 87 .

Fructose Intolerance (Fructose-1-Phosphate Aldolase Deficiency) [See Chapter 87 ].

Acute hypoglycemia is due to the inhibition by fructose-1-phosphate of glycogenolysis via the phosphorylase

system and of gluconeogenesis at the level of fructose-1,6-diphosphate aldolase. Affected individuals usually

learn spontaneously to eliminate fructose from their diet.

DEFECTS IN GLUCOSE TRANSPORTERS

GLUT-1 Deficiency.

Two infants with a seizure disorder were found to have low cerebrospinal fluid (CSF) glucose concentrations

despite normal plasma glucose. Lactate concentrations in CSF were also low, suggesting decreased

glycolysis rather than bacterial infection, which causes low CSF glucose with high lactate. The erythrocyte

glucose transporter was defective, suggesting a similar defect in the brain glucose transporter responsible for

the clinical features. A ketogenic diet reduced the severity of seizures by supplying an alternate source of

brain fuel that bypassed the defect in glucose transport.

GLUT-2 Deficiency.

Children with hepatomegaly, galactose intolerance, and renal tubular dysfunction (Fanconi-Bickel

syndrome) have been shown to have a deficiency of the GLUT-2 glucose transporter of plasma membranes.

In addition to liver and kidney tubules, GLUT-2 is also expressed in pancreatic β cells. Hence, the clinical

manifestations reflect impaired glucose release from liver and defective tubular reabsorption of glucose plus

phosphaturia and aminoaciduria.

SYSTEMIC DISORDERS.

Several systemic disorders are associated with hypoglycemia in infants and children. Neonatal sepsis is often

associated with hypoglycemia, possibly as a result of diminished caloric intake with impaired

gluconeogenesis. Similar mechanisms may apply to the hypoglycemia found in severely malnourished infants

or those with severe malabsorption. Hyperviscosity with a central hematocrit of >65% is associated with

hypoglycemia in at least 10–15% of affected infants. Falciparum malaria has been associated with

hyperinsulinemia and hypoglycemia. Heart and renal failure have also been associated with hypoglycemia,

but the mechanism is obscure. Infants and children with Nissen fundoplication, a relatively common

procedure used to ameliorate gastroesophageal reflux, frequently have an associated “dumping” syndrome

with hypoglycemia. Characteristic features include significant hyperglycemia of up to 500 mg/dL 30 minutes

postprandially and severe hypoglycemia (average 32 mg/dL in one series) 1.5–3.0 hr later. The early

hyperglycemia phase is associated with brisk and excessive insulin release that causes the rebound

hypoglycemia. Glucagon responses have been inappropriately low in some. Although the physiologic

mechanisms are not always clearly apparent, and attempted treatments not always effective, acarbose, an

inhibitor of glucose absorption, has been reported to be successful in one small series.

DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS

Table 92-8 lists the pertinent clinical and biochemical findings in the common childhood disorders associated

with hypoglycemia. A careful and detailed history is essential in every suspected or documented case of

hypoglycemia (see Table 92-7 ). Specific points to be noted include age at onset, temporal relation to meals

or caloric deprivation, and a family history of prior infants known to have had hypoglycemia or of unexplained

infant deaths. In the 1st wk of life, the majority of infants have the transient form of neonatal hypoglycemia

either as a result of prematurity/intrauterine growth retardation or by virtue of being born to diabetic mothers.

The absence of a history of maternal diabetes, but the presence of macrosomia and the characteristic large



plethoric appearance of an “infant of a diabetic mother” should arouse suspicion of hyperinsulinemic hypoglycemia of infancy probably due to a K

ATP channel defect that is familial (autosomal recessive) or

sporadic; plasma insulin concentrations >10 µU/mL in the presence of documented hypoglycemia confirm

this diagnosis. The presence of hepatomegaly should arouse suspicion of an enzyme deficiency; if non–

glucose-reducing sugar is present in the urine, galactosemia is most likely. In males, the presence of a

microphallus suggests the possibility of hypopituitarism, which also may be associated with jaundice in both

sexes.

Past the newborn period, clues to the cause of persistent or recurrent hypoglycemia can be obtained through

a careful history, physical examination, and initial laboratory findings. The temporal relation of the

hypoglycemia to food intake may suggest that the defect is one of gluconeogenesis, if symptoms occur 6 hr

or more after meals. If hypoglycemia occurs shortly after meals, galactosemia or fructose intolerance is most

likely, and the presence of reducing substances in the urine rapidly distinguishes these possibilities. The

autosomal dominant forms of hyperinsulinemic hypoglycemia need to be considered, with measurement of

glucose, insulin, and ammonia, and careful history for other affected family members of any age.

Measurement of IGFBP-1 may be useful; it is low in hyperinsulinemia states and high in other forms of

hypoglycemia. The presence of hepatomegaly suggests one of the enzyme deficiencies in glycogen

breakdown or in gluconeogenesis, as outlined in Table 92-8 . The absence of ketonemia or ketonuria at the

time of initial presentation strongly suggests hyperinsulinemia or a defect in fatty acid oxidation. In most other

causes of hypoglycemia, with the exception of galactosemia and fructose intolerance, ketonemia and

ketonuria are present at the time of fasting hypoglycemia. At the time of the hypoglycemia, serum should be

obtained for determination of hormones and substrates, followed by repeated measurement after an

intramuscular or intravenous injection of glucagon, as outlined in Table 92-7 . Interpretation of the findings is

summarized in Table 92-8 . Hypoglycemia with ketonuria in children between ages 18 mo and 5 yr is most

likely to be ketotic hypoglycemia, especially if hepatomegaly is absent. The ingestion of a toxin, including

alcohol or salicylate, can usually be excluded rapidly by the history. Inadvertent or deliberate drug ingestion

and errors in dispensing medicines should also be considered.

When the history is suggestive, but acute symptoms are not present, a 24–36 hr supervised fast can usually

provoke hypoglycemia and resolve the question of hyperinsulinemia or other conditions (see Table 92-8 ).

Such a fast is contraindicated if a fatty acid oxidation defect is suspected; other approaches such as mass

tandem spectrometry or molecular diagnosis, or both, should be considered. Because adrenal insufficiency

may mimic ketotic hypoglycemia, plasma cortisol levels should be determined at the time of documented

hypoglycemia; increased buccal or skin pigmentation may provide the clue to primary adrenal insufficiency

with elevated ACTH (melanocyte-stimulating hormone) activity. Short stature or a decrease in the growth rate

may provide the clue to pituitary insufficiency involving growth hormone as well as ACTH. Definitive tests of

pituitary-adrenal function such as the arginine-insulin stimulation test for growth hormone IGF-1, IGFBP-1,

and cortisol release may be necessary.

In the presence of hepatomegaly and hypoglycemia, a presumptive diagnosis of the enzyme defect can often

be made through the clinical manifestations, presence of hyperlipidemia, acidosis, hyperuricemia, response

to glucagon in the fed and fasted states, and response to infusion of various appropriate precursors (see

Tables 92-7 and 92-8 [7] [8]). These clinical findings and investigative approaches are summarized in Table

92-8 . Definitive diagnosis of the glycogen storage disease may require an open liver biopsy (see Chapter

87 ). Occasional patients with all the manifestations of glycogen storage disease are found to have normal

enzyme activity. These definitive studies require special expertise available only in certain institutions.

TREATMENT

The prevention of hypoglycemia and its resultant effects on CNS development are important in the newborn

period. For neonates with hyperinsulinemia not associated with maternal diabetes, subtotal or focal

pancreatectomy may be needed, unless hypoglycemia can be readily controlled with long-term diazoxide or

somatostatin analogs.

Treatment of acute symptomatic neonatal or infant hypoglycemia includes intravenous administration of 2 mL/kg of D10 W, followed by a continuous infusion of glucose at 6–8 mg/kg/min, adjusting the rate to maintain

blood glucose levels in the normal range. If hypoglycemic seizures are present, some recommend a 4 mL/kg bolus of D10 W.



The management of persistent neonatal or infantile hypoglycemia includes increasing the rate of intravenous

glucose infusion to 10–15 mg/kg/min or more, if needed. This may require a central venous or umbilical

venous catheter to administer a hypertonic 15–25% glucose solution. If hyperinsulinemia is present, it should

be medically managed initially with diazoxide and then somatostatin analogs or calcium channel blockers. If

hypoglycemia is unresponsive to intravenous glucose plus diazoxide (maximal doses up to 25 mg/kg/day)

and somastostatin analogs, surgery via partial or near-total pancreatectomy should be considered.

Oral diazoxide, 10–25 mg/kg/24 hr given in divided doses every 6 hr, may reverse hyperinsulinemic

hypoglycemia but may also produce hirsutism, edema, nausea, hyperuricemia, electrolyte disturbances,

advanced bone age, IgG deficiency, and, rarely, hypotension with prolonged use. A long-acting somatostatin

analog (octreotide, formerly SMS 201–995) is sometimes effective in controlling hyperinsulinemic hypoglycemia in patients with islet cell disorders not caused by genetic mutations in KATP channel and islet

cell adenoma. Octreotide is administered subcutaneously every 6–12 hr in doses of 20–50 µg in neonates

and young infants. Potential but unusual complications include poor growth due to inhibition of growth

hormone release, pain at the injection site, vomiting, diarrhea, and hepatic dysfunction (hepatitis,

cholelithiasis). Octreotide is usually employed as a temporizing agent for various periods before subtotal pancreatec tomy for K

ATP channel disorders. It may be particularly useful for the treatment of refractory

hypoglycemia despite subtotal pancreatectomy. Total pancreatectomy is not optimal therapy, owing to the

risks of surgery, permanent diabetes mellitus, and exocrine pancreatic insufficiency. Continued prolonged

medical therapy without pancreatic resection if hypoglycemia is controllable is worthwhile because some

children have a spontaneous resolution of the hyperinsulinemic hypoglycemia. This should be balanced

against the risk of hypoglycemia-induced CNS injury and the toxicity of drugs.

PROGNOSIS

The prognosis is good in asymptomatic neonates with hypoglycemia of short duration. Hypoglycemia recurs

in 10–15% of infants after adequate treatment. Recurrence is more common if intravenous fluids are

extravasated or discontinued too rapidly before oral feedings are well tolerated. Children in whom ketotic

hypoglycemia later develops have an increased incidence of neonatal hypoglycemia.

The prognosis for normal intellectual function must be guarded because prolonged, recurrent, and severe

symptomatic hypoglycemia is associated with neurologic sequelae. Symptomatic infants with hypoglycemia,

particularly low-birthweight infants, those with persistent hyperinsulinemic hypoglycemia, and infants of

diabetic mothers, have a poorer prognosis for subsequent normal intellectual development than

asymptomatic infants do.

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