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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
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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
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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 )
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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
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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.
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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
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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
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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)
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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
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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
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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,
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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,
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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.)
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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).
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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.
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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.
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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
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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
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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
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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 .
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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
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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
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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
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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.
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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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