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Hypoglycemia results from one or more of the following:
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Excessive glucose utilization owing to excess insulin or insulin-like action
Deficient energy production owing to defective glycogenolysis, gluconeogenesis, ketogenesis, or ketone utilization
Energy needs which exceed carbohydrate reserves (eg, illness with prolonged vomiting and anorexia, SGA infant)
Exogenous medications or toxic ingestions
5 Reactive hypoglycemia
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A detailed list of etiologies of childhood hypoglycemia is presented in Table 12-1.
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Excess Insulin or Insulin-Like Action
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Transient congenital hyperinsulinism occurs most commonly secondary to maternal factors. Hyperglycemia as a result of uncontrolled gestational diabetes induces fetal β-cell hyperplasia and hyperinsulinism, often leading to macrosomia, risk for shoulder dystocia, and hypoglycemia within a few hours of birth. This usually resolves within days to 2 weeks of birth. Hyperinsulinism may also occur as a result of intravenous glucose administered during labor and delivery; secondary to tocolytic and other medications administered to the pregnant woman (terbutaline, propranolol, oral sulfonylureas, and other hypoglycemic agents used to treat gestational or type 2 diabetes); and from perinatal stress (birth asphyxia, low birth weight, preeclampsia, maternal toxemia, premature labor, or premature birth).
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Congenital hyperinsulinism (CHI) is the most common etiology of hypoglycemia persisting beyond the immediate neonatal period (first hours of life). Several inborn errors of pancreatic β-cell function disrupt the normal coupling of insulin release to the ambient glucose concentration. At least eight gene mutations have been associated with CHI. These include diffuse or focal mutations of the SUR1 or Kir6.2 genes; mutations of the gene encoding glutamate dehydrogenase (autosomal dominant gain-of-function GLUD1); glucokinase deficiency (autosomal dominant GK gene mutation); select fatty acid oxidation gene defects (eg, SCHAD); defective glycoprotein synthesis (congenital disorder of glycosylation); mutations in transcription factor genes (hepatic nuclear factor 4α, or HNF4α); and loss-of-function mutations in mitochondrial uncoupling protein 2 (UCP2). Genetic tests currently available can identify diagnostic mutations in 40% to 50% of patients affected by these disorders.
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Autosomal recessive defects caused by either homozygous mutations in the SUR1 gene (ABCC8) or in the Kir6.2 gene (KCNJ11) which render critical components of the KATP channel inactive (ie, constitutively closed) result in diffuse β-cell dysfunction and intractable severe hypoglycemia soon after birth. Other sporadic variants may create focal adenomatous hyperplasia (40%-60% of all cases of KATP-CHI hypoglycemia) caused by loss of the maternal allele imprinted at 11p15 in a patient harboring an SUR1 mutation on the paternal allele. It is postulated that the loss of heterozygosity either unmasks a recessively inherited SUR1 or Kir6.2 mutation located on the paternal allele or leads to loss of suppressor genes which normally would inhibit islet cell growth-promoting actions of IGF-II. The significance of identifying diffuse versus focal disease lies in the potential of curative, focused partial versus 95% pancreatectomy. Over the past decade, PET scans with 18-fluoro-l-3,4-dihydroxyphenylalanine (18F-DOPA) have been shown to accurately discriminate focal CHI from diffuse CHI.2
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Four autosomal dominant forms of hyperinsulinism tend to have milder clinical presentations and sequelae than autosomal recessive forms. Infants are frequently not large for gestational age and may not present symptomatically until later in infancy or even childhood. Of these four forms, the most common activating mutation in GLUD1, the gene for mitochondrial glutamate dehydrogenase, causes relatively mild hyperinsulinemia accompanied by persistent mild hyperammonemia (blood ammonia levels ~100-200 μmol/L, or three-five times normal). These mutations in GLUD1 cause impaired sensitivity to inhibition by GTP, resulting in gain-of-function and excessive sensitivity to activation by leucine (ie, “leucine sensitivity”). Increased conversion of glutamate to α-ketoglutarate ultimately increases the intracellular ATP to ADP ratio, stimulates insulin release, and yields excessive ammonia (which does not depend on concurrent protein intake).
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The second autosomal dominant form of CHI results from defective glucokinase (GCK), causing increased affinity of the enzyme for glucose and an abnormally low “set point” for glucose-stimulated insulin release. Importantly, a defect in GCK can be missed if the critical sample is obtained at a blood sugar below the threshold for insulin secretion.
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The third autosomal dominant form of CHI is caused by mutated HNF4α, a transcription factor involved in development and function of the pancreas, liver, and kidney. In the pancreatic β-cell, HNF4α regulates the genes involved in glucose-stimulated insulin secretion. These mutations have previously been linked to early-onset, monogenic, autosomal dominant, non-insulin- dependent diabetes (MODY1). These mutations can lead to presentation with macrosomia and hyperinsulinism during the first week of life (followed bydiabetes later in adolescence or adulthood).
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The fourth autosomal dominant form of CHI derives from a loss-of-function mutation in the gene encoding uncoupling protein 2 (UCP2).11 UCP2 is a mitochondrial carrier protein involved in oxidative phosphorylation of ATP synthesis, which ultimately acts as a downregulator of insulin secretion in β-cells. Mutation of UCP2 leads to insulin hypersecretion.11, 13 Patients described to date have shown resolution of symptoms by approximately 6 years of age (and some as early as 7 months).
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GLUD1, GCK, HNF4α, or UCP2 mutations causing CHI are typically distinguished by a favorable therapeutic response to diazoxide. A description of these various causes of CHI with their genetic and clinical features appears in Table 12-2.
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Hypoglycemia also occurs in 50% of infants with Beckwith-Wiedemann syndrome. This most likely results from disordered imprinting at chromosome 11p15 encompassing the IGF2, SUR1, and Kir6.2 genes which gives rise to islet cell hyperplasia (nonimprinted IGF2 produces excessive growth in utero) and dysregulated insulin release from abnormal SUR1 function.
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Counter-regulatory hormone deficiencies clinically (although not biochemically) can resemble CHI during the first month of life, since glycogen reserves may be inappropriately conserved during hypoglycemia in both the infants with CHI and those with either GH deficiency or hypopituitarism, and ketone production in response to hypoglycemia is limited in neonates, complicating the distinction between “ketotic” and “nonketotic” disorders at this age.
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Postsurgical dumping syndrome14 typically occurs after Nissen fundoplication or Roux-en-Y gastric bypass. In normal circumstances, when nutrient absorption is complete, plasma glucose levels frequently decrease to below the premeal value. Overly rapid gastric emptying of elemental formulas leads to rapid transluminal absorption of glucose and rapid glucose-stimulated insulin release; the circulating insulin level climbs so high that it does not fall quickly enough to coincide with the empty gut’s lack of ongoing glucose absorption, leading to postprandial hyperinsulinemic hypoglycemia. Classical symptoms of dumping syndrome are loss of consciousness or mild neuroglycopenic signs within 3 hours after each meal, which are rapidly relieved by carbohydrate. Nonclassical symptoms include borborygmi (loud, small bowel sounds) and adrenergic signs as the hypoglycemia resolves in response to secretion of catecholamines.
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Iatrogenic hyperinsulinemic hypoglycemia may occur as a result of abruptly discontinued hypertonic dextrose infusions, including total parenteral nutrition. Excessive glucose utilization leading to hypoglycemia may also result from surreptitious insulin or sulfonylurea administration, either unintentionally from insulin overdose or, rarely, as part of homicidal, suicidal, or Munchausen-by-proxy behaviors.
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Whether in isolation or as part of multiple endocrine neoplasia type 1 (MEN1), islet cell adenomas (insulinomas) are rare in children, and rarer still in infants. Hypoglycemia may result from tumors that overutilize fuel substrates or that produce IGFs. Such nonislet cell tumor hypoglycemia (NICTH) results from excessive free IGF concentrations acting via insulin and hybrid insulin-IGF receptors at the cell surface. These tumors release immature IGF molecules which nevertheless retain binding properties of the mature forms. The immature forms are often fully glycosylated, raising molecular weight and thus labeled as “big” IGFs. These variant IGF molecules may not be detected on routine commercial assays, requiring consultation with an academic center or a reference laboratory for special testing.
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Deficient Energy Production Caused by Defective Glycogenolysis, Gluconeogenesis, Ketogenesis, or Ketone Utilization
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Insufficient production of glucose during the postabsorptive state results from either: (1) intrinsic enzymatic abnormalities in glycogenolysis or gluconeogenesis; (2) deficient mobilization of glucose precursors for otherwise normal gluconeogenesis; or (3) inability to effectively produce and/or utilize fatty acids for energy.
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Disorders of glycogenolysis are more accurately described as glycogen release diseases (GRD, listed in Table 12-1), rather than the traditional designation as glycogen storage diseases. These GRD patients share the clinical feature of usually minimally ketotic hypoglycemia and markedly impaired fasting tolerance (usually < 6 hours to onset of symptoms related to tissue ATP deficiency). Patients with GRD type 1 present most often after 6 months of age with growth retardation, cherubic facies, and hepatomegaly. Laboratory tests reveal fasting hypoglycemia, lactic acidemia, and hyperlipidemia (reflecting intact counter-regulatory hormone responses), hyperuricemia (from increased nucleic acid catabolism and decreased renal tubular secretion), and a markedly blunted glucose response to glucagon challenge. Prolonged fasting (typically over 8-12 hours) or a vigorous catecholaminergic response to hypoglycemia is usually required in patients with GRD or defective gluconeogenesis to elicit ketonuria. Neurological symptoms are usually absent in patients with GRD type 1 because the brain (and other tissues) utilize high lactate levels as an alternate fuel for ATP (an important distinction from lack of alternate substrate with hyperinsulinemic hypoglycemia). Other forms of GRD (see Table 12-1) show similar, but milder, manifestations (GRD types 3 and 6).
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Disorders of gluconeogenesis include autosomal recessive hereditary fructose intolerance (HFI; fructose-1-phosphate aldolase deficiency) and fructose-1,6-diphosphatase deficiency. HFI presents with vomiting, hypoglycemia, and seizures after initiation of fructose ingestion. Continued fructose exposure can lead to failure to thrive, jaundice, hepatosplenomegaly, proteinuria, aminoaciduria, and death. Fructose 1,6-diphosphatase deficiency results in fasting hypoglycemia, lactic acidosis, hepatomegaly, and ketonemia. Patients with galactosemia, an inherited autosomal recessive deficiency of galactose-1-phosphate uridyl transferase (included routinely in newborn screening programs), after exposure to lactose (hydrolyzed to glucose and galactose), develop vomiting, failure to thrive, cataracts, susceptibility to infection, and hepatic and renal dysfunction.
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Deficient mobilization of substrate required for gluconeogenesis can also lead to fasting hypoglycemia. Beyond the immediate neonatal period, the second most common cause of infantile hypoglycemia arises from deficiencies of the counter-regulatory (ie, energy substrate mobilizing) actions of GH and/or cortisol. This spectrum includes disorders associated with isolated GH deficiency or panhypopituitarism including congenital malformations of the hypothalamus and pituitary; disorders of the adrenal cortex; and inborn errors of cortisol synthesis. Isolated GH deficiency may have an idiopathic basis or, rarely, be due to either autoimmune hypophysitis or a GH gene mutation. Congenital hypopituitarism results from malformations, such as holoprosencephaly or lissencephaly; mutations in any of the pituitary gland transcription factors (PROP1, POU1F1, LHX3, LHX4, PITX1, PITX2, SOX2, or SOX3) that can cause failure of either somatotroph (GH) and/or corticotroph (ACTH) development; and optic nerve hypoplasia/septo-optic dysplasia (associated, in a small number of cases, with a HESX1 mutation). Acquired GH deficiency can occur secondary to tumor, radiation, infection, and trauma. Several defects inadrenal development or steroid synthesis can cause cortisol deficiency, including both congenital adrenal hyperplasia (most commonly caused by 21-hydroxylase deficiency, but also seen with many other rarer varieties) or hypoplasia (caused by DAX1 mutation).
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The most common cause of (noniatrogenic) hypoglycemia in the preschool-aged child is described simply as “ketotic hypoglycemia.” This entity usually presents with early morning symptoms of hypoglycemia (from lethargy to seizures to coma) in a child exposed to an exaggerated fasting stress of 12 to 24 hours (eg, decreased intake due to intercurrent illness or a missed evening meal after a strenuous day). Typically, but not always, the child is light in weight for age and the clinical presentation of hypoglycemia during fasting stress occurs beyond the age of infancy, but prior to age 6 years. This diagnosis of exclusion is made after careful consideration of other inborn errors of metabolism or hormonal deficiencies associated with fasting hypoglycemia with ketonemia (eg, glycogen release disease types 0 and IX, and short-chain fatty acid oxidation defects).
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The precise pathophysiology of ketotic hypoglycemia, also referred to as “fasting functional hypoglycemia,”“accelerated starvation,” or “transient intolerance of fasting,” remains unclear. As noted earlier, muscle tissue plays an important role in maintaining normal glucose concentrations through its release of substrates for gluconeogenesis, especially alanine and pyruvate (which can be reduced to lactate and transaminated to form alanine). Low alanine levels in ketotic hypoglycemia have been hypothesized to reflect decreased muscle mass, decreased protein catabolism, and decreased muscle glucose uptake (leading to inhibition of alanine release by increased FFA and ketone production). Infusion of alanine into affected children has been shown to increase glucose levels appropriately, confirming normal underlying capacity for gluconeogenesis. Others have demonstrated reduced catecholamine response in somecases, but this observation is complicated by the adaptive elevation in the threshold for epinephrine release that is seen in normal subjects who have had prior episodes of hypoglycemia. Since approximately 25% of children will develop hypoglycemia after a fast of 24 to 36 hours, ketotic hypoglycemia is perhaps best described as a developmental disorder of homeostasis representing one extreme end of the spectrum of alanine or lactate recycling required to sustain gluconeogenesis in the small child.
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Disorders of fatty acid oxidation/ketone production or utilization predispose the patient to fasting hypoglycemia owing to ongoing glucose utilization in the absence of an ability to use ketones as an energy source. Metabolic errors throughout the pathway of fatty acid uptake, activation, and β-oxidation have been described (caused by mutations in the genes encoding MCAD, LCAD, VLCAD, and SCHAD; see Table 12-1); these tend to share clinical features and to occur during prolonged fasting when normal reliance on fatty acid metabolism is maximal. Defective ketogenesis (eg, carnitine deficiency) fails to yield circulating and urinary ketones during hypoglycemia, and abnormal dicarboxylic acids are present in the urine. In addition to skeletal and cardiac muscle and liver dysfunction, a distinctive and threatening feature of some fatty acid oxidation disorders (eg, MCAD) is early profound neurological depression and subsequent damage that is out of proportion to the degree of hypoglycemia. This is thought to reflect direct central nervous system (CNS) toxicity of very high levels of abnormal fatty acid metabolites. Fortunately, newborn screening using mass spectrometry is increasingly allowing early detection of most of these disorders. The two known ketone utilization defects (β-ketothiolase deficiency and succinyl-CoA transferase deficiency) typically present with persistent, marked ketoacidosis in the first months of life. Defective gluconeogenesis arises from a defect in one of several enzymatic actions (in mitochondria and in the cytosol) which create glucose from noncarbohydrate carbon substrates (including lactic acid, glycerol, and amino acids [other than lysine or leucine]).
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Energy Needs Which Exceed Carbohydrate Reserves—Other Causes
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Hypoglycemia may occur when glucose needs exceed the patients’ ability to meet them for reasons not discussed above. Occasionally, energy requirements associated with intercurrent illness can exceed carbohydrate reserves (eg, prolonged vomiting or anorexia). Hypoglycemia owing to a complex and multifactorial etiology is also a complication of intrauterine growth restriction (IUGR). During the first several days of extrauterine life, without the placental source of nutrients, maintenance of normal glucose levels requires adequate glycogen stores; intact glycogenolytic, gluconeogenic, and lipogenic mechanisms; and appropriate counter-regulatory hormone responses. Hypoglycemia in infants born IUGR is typically attributable to decreased glycogen reserves, with a possible contribution from diminished liver gluconeogenesis derived from alanine and lactate substrates. Growth-restricted infants also have limited fat stores, appear to not oxidize FFA and triglycerides effectively, and may show decreased counter-regulatory hormone responses to falling blood glucose levels. In addition, hyperinsulinism or excessive sensitivity to insulin appears to exacerbate hypoglycemia and, in some cases, leads to the prolonged need for high glucose infusion rates. Short-term treatment with diazoxide to reduce insulin secretion can be helpful in weaning these particular infants from dependency on intravenousglucose or continuous nasogastric feedings.15
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Exogenous Medicationsor Toxic Ingestions
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Most hypoglycemic agents impair hepatic gluconeogenesis, stimulate insulin release, or block ATP metabolism. Table 12-1 (subheading 7) lists the agents most commonly associated with hypoglycemia, highlighted by insulin, salicylates, antimalarials, oral hypoglycemics (sulfonylureas and acarbose), and the rodenticide Vacor.
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In diabetic patients, hypoglycemia most commonly results from exogenous insulin overdose, delayed feeding, increased physical exertion without decreasing insulin dose, or rarely malabsorption (eg, acute diarrhea, sprue, etc). Despite the overwhelming advantage of improved glycemic control, intensive insulin therapy carries higher risk of hypoglycemia. Recurrent hypoglycemia blunts the threshold for counter-regulatory responses, resulting in hypoglycemic unawareness. With critical illness, hypoglycemia associated with autonomic failure may impair cognition. This sets in motion a vicious cycle of more frequent and severe hypoglycemia, which over time leads to neurological injury ranging from memory loss to motor and cognitive impairments.
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Reactive Hypoglycemia
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Reactive hypoglycemia is a widely used term for a poorly defined and controversial condition of postprandial adrenergic symptoms in the absence of surgery or apparent pathology. Hypoglycemia cannot always be documented. Empirical therapy includes frequent small meals with limited intake of carbohydrates with high glycemic index. Acarbose may help those who fail dietary interventions.