Andrea Kelly and Charles A. Stanley
Hypoglycemic disorders are generally classified as either fasting hypoglycemia or reactive or postprandial hypoglycemia. The risk of hypoglycemia varies depending upon the underlying disorder. With the exception of late dumping syndrome, a form of reactive hypoglycemia associated with Nissen fundoplication or a gastric tube, childhood hypoglycemia is uniformly a disorder of fasting adaptation. Specific endocrine disorders and associated risk factors for hypoglycemia are discussed in this chapter. Defects in the metabolic systems are discussed in Chapter 134.
Normal fasting adaptation involves 5 major systems: 4 metabolic systems (hepatic gluconeogenesis, hepatic glycogenolysis, adipose tissue lipolysis, and oxidation of fatty acids for hepatic ketogenesis), as well as the hormonal system that regulates these metabolic systems. Within 2 to 3 hours of a meal, when intestinal absorption of glucose ceases, hepatic glycogenolysis and gluconeogenesis produce glucose to meet the requirement for brain glucose oxidation and to prevent a decline in blood glucose concentrations. Prolonged fasting of 8 to 12 hours or more depletes glucose and glycogen stores, and adipose tissue lipolysis is activated to provide fatty acids used by muscle and for ketogenesis by the liver. In young children fatty acids become the main fuel source for most of the body after 12 to 24 hours of fasting. Glucose is spared for use by the brain. Ketones become a major fuel for the brain to further spare glucose utilization. The changing serum levels of these fuels obtained during fasting reflect these metabolic processes as shown in Figure 545-1.
The metabolic systems for fasting adaptation are subject to strict hormonal regulation. Insulin negatively regulates all 4 fasting metabolic systems. As blood glucose concentrations decline during the initial phase of fasting, insulin levels fall. This allows increased rates of glucose release from hepatic glycogenolysis and gluconeogenesis. As fasting progresses, the further fall in blood glucose and further suppression of insulin release permit activation of lipolysis and fatty acid oxidation.
FIGURE 545-1. Normal changes in metabolic fuels during fasting. Levels of these fuels obtained during the fast and at the time of hypoglycemia reflect the operation of the metabolic systems. Within 2 to 3 hours of a meal, hepatic gluconeogenesis and glycogenolysis are activated to maintain blood glucose. As hepatic glycogen stores are depleted and gluconeogenesis is activated, blood glucose and lactate levels decline. With more prolonged fasting, adipose tissue lipolysis is activated and plasma free fatty acid concentrations increase, followed by a dramatic increase in β-hydroxybutyrate as the fatty acids are oxidized to ketones in the liver. The high levels of ketones can be used by the brain to spare glucose utilization.
The inhibitory effects of insulin is counterbalanced by actions of glucagon, epinephrine, cortisol, and growth hormone. These hormones activate the metabolic systems required for fasting adaptation. Glucagon release, stimulated by decreasing plasma glucose and insulin, acutely stimulates hepatic glycogenolysis and promotes hepatic gluconeogenesis and ketogenesis. Epinephrine acutely stimulates glycogenolysis and gluconeogenesis but also is a potent stimulator of adipose tissue lipolysis, thereby furnishing free fatty acids for hepatic ketogenesis. Less acute changes result from release of cortisol and growth hormone. Cortisol inhibits peripheral tissue glucose uptake and stimulates hepatic gluconeogenesis. Growth hormone also inhibits glucose utilization and has important effects on stimulating adipose tissue lipolysis.
The rate of progression through the phases of fasting adaptation is largely determined by the ratio of brain versus body weight. Therefore, fasting tolerance is lower in infants and children than in adults, with fasting hyperketonemia occurring in 18 hours in normal neonates, 24 hours in older infants, and 36 hours in children over 1 year.
DIAGNOSIS OF HYPOGLYCEMIA
Symptoms of hypoglycemia are due to decreased metabolic substrate for the brain and elevated catecholamines. They include shakiness, dizziness, sweating, pallor, sudden moodiness, headache, irritability or lethargy (especially in the infant), inattention, and sometimes tingling or even seizures.
A plasma glucose level below 50 mg/dL is commonly used as a diagnostic threshold for diagnosis of hypoglycemia. A treatment goal for a child with a hypoglycemic disorder is to maintain blood glucose concentrations above 70 mg/dL. This therapeutic target of more than 70 mg/dL is particularly important in children with hypoglycemia due to hyperinsulinism, since these infants are unable to produce ketones as an alternative fuel for the brain when glucose is low.
THE CRITICAL SAMPLE AND FASTING TEST
Laboratory specimens obtained at the time of hypoglycemia (blood glucose < 50 mg/dL) are referred to as the critical samples. During hypoglycemia, fasting compensatory mechanisms become manifest. Deviations from the expected pattern of plasma fuels indicate a specific site of defect in one of the systems of fasting adaptation.
The most useful tests to obtain at the time of hypoglycemia are the plasma bicarbonate and urinary ketones because the presence or absence of these form the basis for the initial differential diagnosis as outlined in Figure 545-2. Acidemia may arise from ketosis or lactic acidosis. Ketosis suggests normal fasting adaptation, normal but shortened fasting adaptation (ketotic hypoglycemia), a defect in glycogenolysis, or a defect in counterregulatory hormone production. Lactic acidosis suggests a defect in gluconeogenesis. In contrast, the absence of acidemia suggests either hyperinsulinism or a fatty acid oxidation disorder. Both are associated with inappropriately low or absent urinary ketones but can be differentiated by plasma free fatty acid concentrations. With hyperinsulinism, lipolysis is suppressed and plasma free fatty acid concentrations are low. With a defect in fatty acid oxidation, lipolysis is activated normally and free fatty acid levels are increased. Thus, obtaining a blood sample for free fatty acids, b-hydroxybutyrate, and lactate at the time of hypoglycemia will provide valuable information on the likely site of the defect in fasting adaptation. The neonate with hypoglycemia due to pituitary deficiencies can have biochemical findings that resemble hyperinsulinism.
Measurements of the important hormonal regulators of fasting adaptation in the critical sample are also recommended. In children with hypoglycemia due to hyperinsulinism, insulin levels are often not dramatically elevated at the time of hypoglycemia (eFig. 545.1 ). For this specific reason, the glucagon stimulation test was developed. In the normal child, hepatic glycogen stores are depleted during fasting by the time hypoglycemia occurs. Administration of glucagon does not increase blood glucose. In contrast, in the child with hyperinsulinism, glycogenolysis is suppressed so that glycogen stores are inappropriately not depleted. Glucagon administration leads to a robust glycemic response (Δ blood glucose > 30 mg/dL).
Growth hormone and cortisol levels at the time of hypoglycemia may not provide reliable diagnostic information. However, consideration of hypopituitarism is important in the infant with hypoglycemia. The approach to diagnosis of these disorders is discussed in Chapters 521 and 523. Additional critical sample studies include an acylcarnitine profile, total and free carnitine, and urine organic acids, all of which provide clues to the diagnoses of specific defects in fatty acid oxidation, as discussed in Chapter 150.
Insulin secretion is normally triggered when glucose levels exceed 70 to 90 mg/dL, being controlled by a “thermostat-like” mechanism set by islet glucokinase. Hyperinsulinism refers to the group of hypoglycemic disorders that arise from dysregulated insulin secretion. In infants, hypoglycemia due to dysregulated insulin secretion can be a temporary issue, as occurs in the infant of the diabetic mother (discussed in Chapter 48) and in perinatal stress-induced hyperinsulinism. Alternatively, hyperinsulinism may arise from genetic defects in the pathways of insulin secretion. In the older child, acquired hyperinsulinism as a result of insulinoma, antibody-mediated processes, or medication, are considerations, but congenital defects remain a possibility. The hypoglycemia is frequently severe, and affected infants and children may require far more than the normal glucose infusion rate (6–8 mg/kg/min) to maintain blood glucose in the normal range (> 30–35 mg/kg/min).1-8
PERINATAL STRESS-INDUCED HYPERINSULINISM
Persistent hypoglycemia is common in infants born small for gestational age, to mothers with preeclampsia, or in the setting of other peripartum stress. Hyperinsulinism is now recognized as the cause of this persistent hypoglycemia,11,12 but the mechanism remains poorly understood.13 Perinatal stress-induced hyperinsulinism can last for a few days to several weeks, but may persist for 2 to 6 months.13
Perinatal stress-induced hyperinsulinism is generally amenable to treatment with diazoxide. Fluid retention due to diazoxide can be a limiting factor in its use in infants with significant prematurity and lung disease. In such infants, hydro-chlorothiazide or other diuretics are empirically initiated and signs of fluid retention monitored. If diazoxide is ineffective, octreotide or continuous feeds are an alternative therapy.
Congenital hyperinsulinism is the most common cause of recurrent hypoglycemia in the newborn. Our current understanding of glucose-stimulated insulin secretion is shown in Figure 545-3.
Mutations in the genes encoding sulfonylurea receptor-1 and Kir6.2, which compose the β-cell KATP channel, are responsible for the most common form of congenital hyperinsulinism, KATP hyperinsulinism.21Recessive and dominant22,23 forms of KATP hyperinsulinism result in dysfunction of all of the pancreatic islet cells (eFig. 545.2 ). The incidence of KATP hyperinsulinism is estimated to be 1/20,00 to 1/40,000 live births, with an increased incidence in Saudi Arabia, the Ashkenazi-Jewish population, and a subset of the Finnish population.24-27
Infants with KATP hyperinsulinism are generally born large for gestational age, and hypoglycemia is evident within the first few days of life. The recessive and focal forms of KATP hyperinsulinism are usually resistant to medical therapy with diazoxide, whereas dominant KATP hyperinsulinism is diazoxide responsive. Octreotide is the second-line drug for diazoxide-unresponsive patients, but is often not effective for chronic treatment because of tachyphylaxis. Pancreatectomy is recommended for infants with KATP hyperinsulinism in whom blood glucose cannot safely be maintained above 70 mg/dL.
FIGURE 545-2. Algorithm for evaluation of hypoglycemia based upon blood and urine tests obtained at the time of hypoglycemia. ΔBG, change in blood glucose, FAO, fatty acid oxidation; FDP, fructose-1,6 diphosphatase; FFA, plasma free fatty acids; GH, growth hormone; G-6-Pose, glucose-6-phosphatase; GSD, glycogen storage disease; IGFBP-1, insulin-like growth factor binding protein-1; PE, physical exam; PMH, past medical history.
FIGURE 545-3. Diagram of insulin secretion and sites of defects leading to congenital hyperinsulinism. Glucose enters the β cell through the GLUT-2 transporter and is phosphorylated by glucokinase, the glucosensor of the β cell. Further metabolism leads to an increase in the ATP-to-ADP ratio, closure of the KATP channel, β cell membrane depolarization, opening of voltage-dependent calcium channels, calcium influx, and ultimately insulin secretion. This process is referred to as the KATP channel-dependent pathway. Amino acids also stimulate insulin secretion through a KATP channel pathway via glutamic dehydrogenase (GDH). This process occurs through oxidation of the amino acid glutamate by glutamate dehydrogenase. Additionally, glutamate dehydrogenase is allosterically activated by the amino acid leucine. The mechanisms underlying free fatty acid involvement in insulin secretion are not well-understood. Pyruvate is not normally a fuel-stimulant for insulin secretion. A KATP channel-independent pathway for insulin secretion also exists. Glucokinase, the KATP channel, GDH, SCHAD, and monocarboxylate transporter 1 (MCT1), a pyruvate transporter not normally present on the b cell, are all sites of defects responsible for congenital hyperinsulinism. The sulfonylurea, tolbutamide, enhances insulin secretion by closing the KATP channel while diazoxide, an agent used to treat hyperinsulinism, suppresses insulin secretion by opening the KATP channel. Somatostatin suppresses insulin secretion downstream of calcium entry.
Efforts to identify the focal lesion in the setting of congenital hyperinsulinism are crucial. For infants with diffuse hyperinsulinism, a 98% pancreatectomy is required. In contrast, the child with focal KATPhyperinsulinism can be cured with resection of the lesion. Most recently, [18F]fluorodopa positron emission tomography has successfully been used to distinguish between focal and diffuse hyperinsulinism and to accurately localize a focal lesion (eFig. 545.3 ).28,29
With near-total pancreatectomy, approximately one third of infants with medically unresponsive diffuse hyperinsulinism will continue to have significant hypoglycemia, a third will have hypoglycemia that is much more easily controlled, and a third will have diabetes.30 Late-onset diabetes has also been observed years after pancreatectomy.31 Neurologic outcomes are an additional concern in this population. Learning disabilities, mental retardation, and seizures34-36 have all been described and are likely related to duration and severity of hypoglycemia.
Glutamate Dehydrogenase Hyperinsulinism
Dominantly-inherited and sporadically occurring gain of function mutations in glutamate dehydrogenase (GDH) cause the second most common form of congenital hyperinsulinism, glutamate dehydrogenase hyperinsulinism (GDH-HI).37 These mutations cause loss of normal inhibition of GDH by guanosine tri-phosphate (GTP). As a result, GDH is tonically activated, leading to fasting hypoglycemia (Fig. 545-3). Additionally, amino acid–stimulated insulin secretion is unrestrained, causing affected children to have protein-induced hypoglycemia. This effect is mediated by leucine,38 an allosteric activator of GDH.
Unlike infants with KATP hyperinsulinism, infants with GDH-HI tend to have normal birth weights and may not come to medical attention until later in infancy. While fasting hypoglycemia occurs in GDH-HI, the clinical picture may be dominated by a history of postprandial hypoglycemia.39 Further probing often reveals high-protein food to be the inciting factor. Additionally, GDH-HI is characterized by persistent hyperammonemia (plasma ammonium that is 2 to 5 times normal). Protein intake does not cause a further increase in plasma ammonium as occurs in urea cycle defects.
In general, GDH-HI responds well to diaz-oxide. Affected children are also instructed to avoid “pure” protein meals and, instead, are encouraged to consume carbohydrates in conjunction with any high-protein foods.
Heterozygous activating mutations in glucokinase cause congenital hyperinsulinism by increasing the affinity of glucokinase for glucose. These mutations effectively lower the glucose threshold required for insulin secretion. Clinical information is limited, but available data suggest that the disease spectrum varies from mild, diazoxide-responsive hyperinsulinism that may not come to medical attention until late childhood or even adulthood to severe hyperinsulinism, resistant to treatment and pancreatectomy, presenting largely in the gestational age newborn.41,42,43
Short-Chain Hydroxyacyl CoA Dehydrogenase Hyperinsulinism
Short-chain hydroxyacyl CoA dehydrogenase (SCHAD) catalyzes the penultimate step in fatty acid oxidation. However, unlike defects in other enzymes in the pathway of fatty acid oxidation, defects in SCHAD cause a recessively inherited form of congenital hyperinsulinism.44 The mechanism by which this enzyme defect alters insulin secretion is not understood. Affected infants have been described as having diazoxide-responsive hyper-insulinism. Persistently elevated plasma 3-hydroxybutyrylcarnitine and increased urine 3-hydroxyglutarate are clues to the diagnosis.
Monocarboxylate Transporter 1 Hyperinsulinism
Dominantly inherited mutations in the promoter for the gene encoding monocarboxylate transporter 1 cause exercise-induced hyperinsulinism.45,46 These mutations cause erroneous β-cell expression of monocarboxylate transporter 1, a shuttle for pyruvate. Inappropriate pyruvate-stimulated insulin secretion ensues during a pyruvate load as might occur with strenuous, anaerobic exercise.
Congenital Disorders of Glycosylation
Hyperinsulinism has been described in congenital disorders of glycosylation (CDG) type 1, one of a group of inherited disorders that disrupt oligosaccharide linkage to extracellular protein and cause systemic abnormalities, including developmental delay, cerebellar hypoplasia, coagulopathy, diarrhea, and failure to thrive. The mechanism by which CDG causes hyperinsulinism is not known, but abnormal glycosylation of sulfonylurea receptor 1 leading to dysregulated insulin secretion has been proposed. In affected patients, isoelectric focusing of serum transferrin identifies hypoglycosylation. Reported patients respond to treatment with mannose or diazoxide.47,48
An estimated 30% to 50% of infants with Beck-with-Wiedemann syndrome have hypoglycemia that resembles the hypoglycemia of hyperinsulinism. Spontaneous resolution is reported.49 The underlying mechanism for the hypoglycemia remains unknown. Diazoxide is an effective treatment in the majority of cases.
Insulinomas are the most common functional tumor of the pancreatic islet. They are exceedingly rare in adults (4/1,000,000 person years) and even more rare in children. They can occur sporadically or as part of multiple endocrine neoplasia type 1, a dominant disorder triggering tumor formation in the parathyroid, pituitary, and pancreas.53,54
The diagnosis of insulinoma should be suspected in any child older than 1 year of age who presents with hypoglycemia due to hyperinsulinism. Elevated proinsulin at the time of hypoglycemia is consistent with insulinoma55 but does not exclude congenital hyperinsulinism or sulfonylurea ingestion. Following the diagnosis of insulinoma, localization is required in preparation for definitive treatment. Intraoperative ultrasound is the most sensitive and specific procedure, but preoperative imaging is also recommended.56 Diazoxide has been used with some success in patients in whom surgery is not an option or until such definitive treatment can be performed. The prognosis is excellent. However, multiple endocrine neoplasia type 1 is a risk factor for recurrence.57
Antibodies directed against insulin as well as the insulin receptor have been identified as rare causes of hypoglycemia. Antibody-mediated hyperinsulinism is suspected when evidence of hyperinsulinism is present but C-peptide is suppressed and exogenous insulin administration has been excluded. This phenomenon has most frequently been described in individuals of Japanese descent or in individuals who have other autoimmune diseases such as systemic lupus erythematous.58 Successful treatment with prednisone or intravenous immunoglobulin therapy has been reported.
The possibility of exogenous insulin or sulfonylurea administration must be considered in any child with hypoglycemia. An elevated plasma insulin and suppressed C-peptide at the time of hypoglycemia are consistent with exogenous insulin delivery.59-62 Note that some insulin assays cannot detect certain biosynthetic insulins. In contrast, sulfonylurea ingestion stimulates both insulin and C-peptide secretion and mimics primary β-cell pathology. Specific toxicology screens are available for sulfonylureas if ingestion is suspected. Unusual or inconsistent histories and laboratory evaluations should prompt consideration of factitious hyperinsulinism to avoid unnecessary treatments such as pancreatectomy.64
Growth hormone deficiency and adrenal insufficiency represent the counterregulatory hormonal deficiencies most commonly associated with hypoglycemia. Much less common is catecholamine deficiency; isolated glucagon deficiency has not been identified.
GROWTH HORMONE DEFICIENCY
Hypoglycemia from growth hormone deficiency likely arises from (1) failure to downregulate insulin-mediated glucose uptake and (2) inadequate stimulation of lipolysis to generate glucose-sparing ketones. While only a minority of children with growth hormone deficiency or multiple combined pituitary deficiencies present with hypoglycemia in the newborn period,65-70 hypoglycemia is frequently the first sign of growth hormone deficiency and multiple combined pituitary deficiencies in the neonate.7
Hypoglycemia complicating cortisol deficiency likely arises from not only (1) failure to down-regulate insulin-mediated glucose uptake but also (2) inadequate upregulation of gluconeogenic enzymes. Hypoglycemia from catecholamine deficiency likely arises from impaired stimulation of lipolysis/ketogenesis. Hypoglycemia is described in primary adrenal insufficiency, but it is not a common presenting feature. More frequently, hypoglycemia occurs in the setting of shock with dehydration and electrolyte disturbances. An exception is adrenocortical resistance to adrenocorticotropic hormone (ACTH), which impacts secretion of glucocorticoid but not mineralocorticoid. This rare, recessively inherited disorder arises from mutations at the level of ACTH receptor67 or in the gene encoding the regulatory protein, aladin.68 Defects in aladin give rise to the triple A syndrome, so named for the constellation of ACTH resistance, alacrima, and achalasia.
Congenital disorders of catecholamine biosynthesis are rare causes of hypoglycemia. Defects in dopamine β-hydroxylase cause a recessively inherited form of primary autonomic failure characterized by complete absence of plasma epinephrine and norepinephrine in the setting of an accumulation of plasma dopamine. This pattern arises from the defect in dopamine β-hydroxylase, the key enzyme responsible for converting dopamine to norepinephrine. Neonates with this disorder frequently present with hypotension, hypotonia, hypothermia, and hypoglycemia. Delay in opening of the eyes, ptosis, and vomiting may provide additional clues to the diagnosis. Only limited information is available regarding the hypoglycemia in this disorder; most attention has focused on the significant orthostatic hypotension in this condition.71-78 Hypoglycemia has also been observed in a child with familial dysautonomia. Hypoglycemia has also been observed in infants with aromatic l-amino acid decarboxylase deficiency, a rare disorder of neurotransmitter production that leads to dopamine, epinephrine, norepinephrine, and serotonin deficiency. Affected children have hypotonia and an extrapyramidal movement disorder. Inappropriately low plasma free fatty acids at the time of hypoglycemia have been observed, indicating impaired lipolysis likely from the epinephrine deficiency.
Hypoglycemia has also been described in children treated with beta-blockers. The hypoglycemia typically arises with fasting or prolonged poor caloric intake. Because of the β-adrenergic blockade, tachycardia may not accompany the hypoglycemia-induced catecholamine surge. However, significant hypertension may be present and arises from unopposed α-adrenergic stimulation.
Both the hypoglycemia and hypertension resolve with glucose administration. Given the risk of hypoglycemia, a child treated with β-blockers such as propranolol should avoid prolonged fasting and should receive intravenous dextrose if limited caloric intake is planned or occurs as a result of an intercurrent illness.
FIGURE 545-4. Blood glucose responses to fasting (blue line) and bolus feeding (red line) in a 5-month-old with a Nissen fundoplication/gastric tube and late dumping syndrome.
Dumping syndrome is a gastric motility disorder that complicates any gastric surgery. Dumping refers to the hypoglycemic symptoms that develop 1 to 3 hours after food intake. Rapid transit of food causes an excessive intestinal glucose load. Insulin and glucagon-like peptide 1 are appropriately secreted to accommodate this glucose load. The increase in glucose is short-lived, however, and a mismatch between plasma glucose and insulin occurs, leading to hypoglycemia.
For children, Nissen fundoplication with gastric tube placement is the most common instigator.
Following confirmation that fasting adaptation is normal, blood glucose and insulin are monitored following a feed. Blood glucose is typically increased midfeed and precipitously drops following the feed (Fig. 545-4); the hypoglycemia is accompanied by elevated insulin.
Treatment options for dumping-related hypoglycemia are limited. Decreased administration of simple sugars and increased fat in the diet is often helpful. Manipulation of bolus size or duration, or if side effects are not tolerable, a continuous feeding regimen, may be necessary. Acarbose, an α-glucosidase inhibitor, slows carbohydrate digestion and has been used successfully to treat dumping in children.80,81Side effects include gastrointestinal discomfort and diarrhea.
Published estimates of the incidence of late dumping syndrome among children with Nissen fundoplication are not available. Nonetheless, late dumping syndrome should be considered in any child demonstrating symptoms that could be due to hypoglycemia following any type of gastric surgery.