Sunday, August 10, 2008



Mark A. Sperling in Kliegman: Nelson Textbook of Pediatrics, 18th

Glucose has a central role in fuel economy and is a source of energy storage in the form of glycogen, fat, and protein. 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.


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. Out of concern for possible neurologic, intellectual, or psychologic sequelae in later life, many authorities recommend that any value of blood glucose <50>


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 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.



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 ).


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 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>

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 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 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 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>

TABLE 1 -- Manifestations of Hypoglycemia in Childhood





Palpitation (tachycardia)[†]







Angina (with normal coronary arteries)



Mental confusion[†]

Visual disturbances (↓ acuity, diplopia)[†]

Organic personality changes[†]

Inability to concentrate[†]






Ataxia, incoordination

Somnolence, lethargy



Stroke, hemiplegia, aphasia

Decerebrate or decorticate posture


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


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. 1 ). The exact incidence of symptomatic hypoglycemia has been difficult to establish because many of the symptoms in neonates occur together with other conditions such as infections, especially sepsis and meningitis; central nervous system anomalies, hemorrhage, or edema; hypocalcemia and hypomagnesemia; asphyxia; drug withdrawal; apnea of prematurity; congenital heart disease; or polycythemia.

Figure 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.)

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

TABLE 2 -- Classification of Hypoglycemia in Infants and Children


Associated with inadequate substrate or immature enzyme function in otherwise normal neonates


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


Hormonal disorders


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


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


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



Ketotic hypoglycemia




Oral hypoglycemic agents






Ackee fruit (unripe)—hypoglycin

Vacor (rate poison)

Trimethoprim-sulfamethoxazole (with renal failure)

Liver disease

Reye syndrome




Amino acid and organic acid disorders

Maple syrup urine disease

Propionic acidemia

Methylmalonic acidemia


Glutaric aciduria

3-Hydroxy-3-methylglutaric aciduria

Systemic disorders


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

Heart failure



Anti-insulin receptor antibodies

Anti-insulin antibodies

Neonatal hyperviscosity

Renal failure





Pseudohypoglycemia (leukocytosis, polycythemia)

Excessive insulin therapy of insulin-dependent diabetes mellitus


Nissen fundoplication (dumping syndrome)

Falciparum malari


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 2 and Fig. 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 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.


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 formerly considered typical of such infants. 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 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.



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>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 3 and 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). 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 5, 6, and 7 [5] [6] [7]).

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




























Adapted from Antunes JD, Geffner ME, Lippe BM, et al: Childhood hypoglycemia: Differentiating hyperinsulinemic from nonhyperinsulinemic causes. J Pediatr 1990;116:105–108.

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











Present at birth

Moderate/severe in 1st days to weeks of life


? SUR1/ KIR6.2 Mutations not always identified in diffuse hyperplasia

Loss of heterozygosity in microadenomatous tissue

Generally poor; may respond better to somatostatin than to diazoxide

Partial pancreatectomy if frozen section shows β-cell crowding with small nuclei—microadenoma


Subtotal >95%

Guarded;diabetes mellitus develops in 50% of patients; hypoglycemia persists in 33% pancreatectomy if frozen section shows giant nuclei in β-cells —diffuse hyperplasia

Autosomal recessive

Present at birth

Severe in 1st days to weeks of life



Consanguinity a feature in some populations


Subtotal pancreatectomy


Autosomal dominant


Moderate onset usually post 6 mo of age


Glucokinase (activating) Some cases gene unknown


Very good to excellent

Surgery usually not required


Partial pancreatectomy only if medical management fails

Autosomal dominant


Moderate onset usually post 6 mo of age


Glutamate Dehydrogenase (activating)

Modest hyperammonemia

Very good to excellent

Surgery usually not required


Beckwith-Wiedemann syndrome

Present at birth

Moderate, spontaneously resolves post 6 mo of age


Duplicating/imprinting in chromosome 11p15.1

Macroglossia, omphalocele, hemihypertrophy


Not recommended

Excellent for hypoglycemia; associated with embryonal tumors (Wilms hepatoblastoma)

Congenital disorders of glycosylation

Not usual

Moderate/onset post 3 mo of age


Phosphomannose isomerase deficiency

Hepatomegaly, vomiting, intractable diarrhea

Good with mannose supplement

Not recommended


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



Free fatty acids



Uric acid





Growth hormone

Thyroxine, thyroid-stimulating hormone


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.

TABLE 6 -- Criteria for Diagnosing Hyperinsulinism Based on “Critical” Samples (Drawn at a Time of Fasting Hypoglycemia: Plasma Glucose <50>


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


Hypofattyacidemia (plasma free fatty acids <1.5>


Hypoketonemia (plasma β-hydroxybutyrate: <2.0>


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.


Depends on sensitivity of insulin assay.

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



Obtain blood sample before and 30 min after glucagon administration.


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, inborn error of glycogen metabolism, or defective gluconeogenesis.


Measure glucose in the original blood sample. If hypoglycemia is confirmed, proceed with substratehormone measurement as in Table 5 .


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


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.


If cortisol is <10>



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.


Careful examination for hepatomegaly (glycogen storage disease; defect in gluconeogenesis); pigmentation (adrenal failure); stature and neurologic status (pituitary disease)


Admit to hospital for provocative testing:


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


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


Liver biopsy for histologic and enzyme determinations if indicated


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

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. 3 .].

Figure 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).

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 7 and 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. 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.

Table 8. Clinical Manifestation and Differential Diagnosis in Childhood Hypoglycemia

Figure 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 (Ca2+) channel. The intracellular rise in Ca2+ 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 KATP 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.

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. 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. 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 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. 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 KATP, leading to membrane depolarization, calcium influx, and insulin secretion (see Fig. 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. 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 7 and 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.


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

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.


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.


Table 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 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 KATP 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 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 7 . Interpretation of the findings is summarized in Table 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 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 7 and 8 [7] [8]). These clinical findings and investigative approaches are summarized in Table 8 . Definitive diagnosis of the glycogen storage disease may require an open liver biopsy. 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.


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 KATP 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.


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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